Clinical trial NCT03811834
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2019-01-22; Completion date: 2019-03-11
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine:

Period 1 (ABA): ABA of mobocertinib following single microdose intravenous administration of 50 microgram (mcg) (approximately 2 microcurie \[mcCi\]) \[14 C\]-\]-mobocertinib and single oral administration of 160 milligram (mg) mobocertinib.

Period 2 (absorption, distribution, metabolism, and elimination \[ADME\]): the mass balance and metabolic profile of mobocertinib in plasma, urine, and feces, to characterize the PK of mobocertinib and its metabolites (AP32960 and AP32914) in plasma, whole blood, and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral administration of 160 mg (approximately 100 mcCi) \[14C\]-mobocertinib solution.

Detailed description:
The drug being tested in this study is called mobocertinib. The study will determine ABA of mobocertinib following single microdose of 50 mcg \[14C\]-mobocertinib and single oral administration of 160 mg mobocertinib and will assess the mass balance and metabolic profile of mobocertinib in plasma, urine, and feces following a single oral administration of 160 mg \[14C\]-mobocertinib solution, and will characterize the PK of mobocertinib and its metabolites in plasma, whole blood, and urine, and total radioactivity concentration equivalents in plasma and whole blood following a single dose of 160 mg \[14C\]-mobocertinib.

The study will enroll approximately 6 participants. The study is designed to consist of 2 periods: Period 1 (ABA study period) and Period 2 (ADME study period). In Period 1, all participants will receive single unlabeled oral 160 mg dose of mobocertinib as capsules. At 3.75 hours post oral dosing, participants will receive 15-minute intravenous infusion of a microdose of 50 mcg (approximately 2mcCi) \[14C\]-mobocertinib. In Period 2, participants will receive single dose of 160 mg (approximately 100 mcCi) \[14C\]-mobocertinib as an oral solution.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 65 days including screening period. Participants will be contacted approximately 30 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: Mobocertinib 160 mg, capsule, orally, once under fasted state, followed by \[14C\]-mobocertinib 50 mcg (approximately 2 microcurie \[mcCi\]), infusion, intravenously, once on Day 1 of Period 1, further followed by a washout period of 9 days, followed by \[14C\]-mobocertinib 160 mg (approximately 100 mcCi), solution, orally, once under fasted state on Day 1 of Period 2.
Interventions: intervention 1: Mobocertinib
Intervention descriptions: intervention 1: Mobocertinib capsule, \[14C\]-Mobocertinib intravenous infusion, \[14C\]-Mobocertinib oral solution.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-788 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]-TAK-788 
in Male Healthy Subjects
NCT Number: NCT03811834
Protocol Approve Date: 27 February 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS 
PROTOCOL
A Phase 1 Study to Assess Absolute Bioavailability of TAK-788 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]-TAK-788 
in Male Healthy Subjects
Study Identifier:
TAK-788-1002
Compound:
TAK-788
Date:
27 February 2019
Version/Amendment 
Number:
Amendment 1
Amendment History: 
Date
Amendment Number
Amendment Type
Region
18 December 2018
Initial Version
United States
27 February 2019
01
Not Applicable
United States
Prop
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................7
2.0
STUDY SCHEMATIC..................................................................................................12
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................13
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.2
Rationale for the Proposed Study.............................................................................20
4.3
Benefit/Risk Profile .................................................................................................21
5.0
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................22
5.1
Hypothesis...............................................................................................................22
5.2
Trial Objectives .......................................................................................................22
5.2.1
Trial Primary Objectives .............................................................................22
5.2.2
Trial Secondary Objectives .........................................................................22
5.2.3
Trial Exploratory Objective.........................................................................22
5.3
Endpoints.................................................................................................................22
5.3.1
Primary Endpoints.......................................................................................23
5.3.2
Secondary Endpoints...................................................................................23
5.3.3
Exploratory Endpoints.................................................................................24
6.0
TRIAL DESIGN AND DESCRIPTION ........................................................................25
6.1
Trial Design.............................................................................................................25
6.2
Dose Escalation .......................................................................................................26
6.3
Rationale for Trial Design, Dose, and Endpoints......................................................26
6.3.1
Rationale of Trial Design ............................................................................26
6.3.2
Rationale for Dose ......................................................................................26
6.3.3
Rationale for Endpoints...............................................................................27
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures .........27
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................27
6.5
Trial Beginning and End/Completion.......................................................................28
6.5.1
Definition of Beginning of the Trial ............................................................28
6.5.2
Definition of End of the Trial......................................................................28
6.5.3
Definition of Trial Completion....................................................................28
6.5.4
Definition of Trial Discontinuation..............................................................28
6.5.5
Criteria for Premature Termination or Suspension of the Trial.....................28
6.5.6
Criteria for Premature Termination or Suspension of a Site.........................28
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............29
7.1
Excluded Medications, Supplements, Dietary Products............................................29
7.2
Diet, Fluid, Activity.................................................................................................30
7.2.1
Diet and Fluid .............................................................................................30
7.2.2
Activity.......................................................................................................30
7.3
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.4
Procedures for Discontinuation or Withdrawal of a Subject......................................30
7.5
Subject Replacement................................................................................................31
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................32
8.1
Clinical Study Drug .................................................................................................32
8.1.1
TAK-788 Capsule .......................................................................................32
8.1.2
[14C]-TAK-788 IV Sterile Solution..............................................................32
8.1.3
[14C]-TAK-788 Oral Solution......................................................................32
8.1.4
Clinical Study Drug Labeling......................................................................32
8.1.5
Clinical Study Drug Inventory and Storage .................................................32
8.1.6
Clinical Study Drug Blinding ......................................................................33
8.1.7
Randomization Code Creation and Storage .................................................33
8.1.8
Clinical Trial Blind Maintenance/Unblinding Procedure .............................33
8.1.9
Accountability and Destruction of Sponsor-Supplied Drugs ........................33
9.0
STUDY PROCEDURES...............................................................................................34
9.1
Administrative Procedures.......................................................................................34
9.1.1
Informed Consent Procedure.......................................................................34
9.1.2
Inclusion and Exclusion ..............................................................................34
9.1.3
Medical History/Demography .....................................................................36
9.1.4
Concomitant Medications............................................................................36
9.2
Clinical Procedures and Assessments.......................................................................36
9.2.1
Full Physical Exam .....................................................................................37
9.2.2
Height and Weight ......................................................................................37
9.2.3
BMI ............................................................................................................37
9.2.4
Vital Signs ..................................................................................................37
9.2.5
12-Lead ECG..............................................................................................37
9.2.6
Pulmonary Function Test ............................................................................38
9.2.7
Study Drug Administration .........................................................................38
9.2.8
AE Monitoring............................................................................................38
9.2.9
Laboratory Procedures and Assessments .....................................................38
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9.3
PK Samples .............................................................................................................40
9.3.1
PK Measurements .......................................................................................41
9.3.2
Biomarker Measurements............................................................................44
9.3.3
PGx Measurements .....................................................................................44
9.3.4
Confinement ...............................................................................................44
10.0
ADVERSE EVENTS ....................................................................................................46
10.1
Definitions and Elements of AEs .............................................................................46
10.1.1
SAEs...........................................................................................................48
10.1.2
Special Interest AEs....................................................................................48
10.2
AE Procedures.........................................................................................................48
10.2.1
Assigning Severity of AEs ..........................................................................48
10.2.2
Assigning Causality of AEs.........................................................................49
10.2.3
Start Date....................................................................................................49
10.2.4
End Date.....................................................................................................49
10.2.5
Action Taken With Study Treatment ...........................................................49
10.2.6
Outcome .....................................................................................................50
10.2.7
Collection and Reporting of AEs, SAEs, Special Interest AEs, and 
Abnormal LFTs...........................................................................................50
10.2.8
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................52
10.2.9
Procedures for Reporting Product Complaints or Medication Errors 
(Including Overdose) ..................................................................................52
11.0
STATISTICAL METHODS..........................................................................................54
11.1
Statistical and Analytical Plans ................................................................................54
11.1.1
Analysis Sets...............................................................................................54
11.1.2
Analysis of Demography and Other Baseline Characteristics.......................54
11.1.3
PK Analysis ................................................................................................54
11.1.4
Analysis of Mass Balance ...........................................................................55
11.1.5
Whole Blood to Plasma Partitioning Ratio ..................................................55
11.1.6
Metabolite Profiling ....................................................................................55
11.1.7
PD Analysis ................................................................................................55
11.1.8
Safety Analysis ...........................................................................................55
11.2
Interim Analysis and Criteria for Early Termination ................................................56
11.3
Determination of Sample Size..................................................................................56
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................57
12.1
Study-Site Monitoring Visits ...................................................................................57
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12.2
Protocol Deviations..................................................................................................57
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................57
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................58
13.1
IRB and/or IEC Approval ........................................................................................58
13.2
Subject Information, Informed Consent, and Subject Authorization .........................59
13.3
Subject Confidentiality ............................................................................................60
13.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................60
13.4.1
Publication and Disclosure..........................................................................60
13.4.2
Clinical Trial Registration...........................................................................61
13.4.3
Clinical Trial Results Disclosure .................................................................61
13.5
Insurance and Compensation for Injury....................................................................61
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................62
14.1
Administrative Information......................................................................................62
14.1.1
Study Contact Information ..........................................................................62
14.1.2
Investigator Agreement ...............................................................................63
14.1.3
Study-Related Responsibilities....................................................................64
14.1.4
Protocol Amendment 01 Summary of Changes ...........................................64
14.1.5
List of Abbreviations...................................................................................64
15.0
DATA HANDLING AND RECORD KEEPING...........................................................67
15.1
CRFs .......................................................................................................................67
15.2
Record Retention .....................................................................................................67
16.0
REFERENCES..............................................................................................................69
17.0
APPENDICES...............................................................................................................70
LIST OF IN-TEXT TABLES
Table 3.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-788 
(Period 1 - ABA Study Period)...........................................................................15
Table 3.b
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period)..................16
Table 3.c
Blood Collection Schedule (Period 2 - ADME Study Period).............................17
Table 3.d
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period) ...............18
Table 6.a
Planned TAK-788 and [14C]-TAK-788 Doses ....................................................26
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................29
Table 9.a
Primary Specimen Collections ...........................................................................41
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LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................70
Appendix B
Elements of the Subject Informed Consent.........................................................72
Appendix C
Investigator Consent to the Use of Personal Information ....................................75
Appendix D
Pregnancy and Contraception.............................................................................76
Appendix E
Detailed Description of Amendments to Text.....................................................80
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1.0
STUDY SUMMARY
Name of Sponsor:
Millennium Pharmaceuticals, Inc. a wholly owned subsidiary of 
Takeda Pharmaceutical Company, Ltd
40 Landsdowne Street
Cambridge, Massachusetts USA 02139
Telephone: +1 (617) 679-7000
Compound:
TAK-788
Study Identifier: TAK-788-1002 (CA25518)
Phase: 1
Protocol Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-788 and to Characterize Mass Balance, 
Pharmacokinetics, Metabolism, and Excretion of [14C]-TAK-788 in Male Healthy Subjects
Trial Design:
An open-label, 2-period, single-dose study in 6 male healthy subjects. 
On Day 1 of Period 1 (absolute bioavailability [ABA] Study Period), after at least a 10-hour fast, 6 subjects will 
receive a single unlabeled oral 160 mg dose of TAK-788 as capsules. At 3.75 hours post oral dosing (ie, 15 minutes 
prior to the median tmax for the oral unlabeled dose [approximately (~) 4 hours]), subjects will receive a 15-minute 
intravenous (IV) infusion of a microdose of 50 µg (approximately equivalent to 2 microcurie ~[2 µCi]) 
[14C]-TAK-788. Serial blood sampling will be performed to determine the pharmacokinetics (PK) of TAK-788 and its 
metabolites (AP32960 and AP32914) in the plasma for the oral dose and [14C]-total radioactivity and PK of 
[14C]-TAK-788 and its metabolites (AP32960 and AP32914) in the plasma for the IV dose. Urine and fecal output will 
also be collected up to the morning of Day 5 postdose to determine [14C]-TAK-788 and until a discharge criterion is 
met (ie, 80% or greater of the total dose of radioactivity administered is recovered in urine and fecal samples or the 
excretion of radioactivity in the urine and feces combined has declined to ≤1% of the total administered radioactivity 
per day for at least 2 consecutive intervals where both a urine and fecal sample are collected) but no less than Day 5 for 
[14C]-total radioactivity excretion in urine and feces. 
In Period 1, subjects will be confined in the clinical research unit (CRU) for at least 5 days (until after the last PK 
sample and morning urine and fecal sample [when passed] are collected) and until a discharge criterion is met or up to 
Day 8. Subjects will return to the clinic on Day 9 (Period 2, Day -1) for Period 2.
There will be a washout period of approximately 9 days between doses in Period 1 and the dose in Period 2.
On Day 1 of Period 2 (absorption, distribution, metabolism, and elimination [ADME] Study Period), after at least a 
10-hour fast, subjects will receive a single dose of 160 mg (~100 μCi) [14C]-TAK-788 as an oral solution. Serial blood 
sampling will be performed and urine and feces will be collected to determine the PK of TAK-788 and its metabolites 
(AP32960 and AP32914) in plasma, whole blood, and urine, and total radioactivity in plasma, whole blood, urine, and 
feces, and to characterize the metabolite profiles of TAK-788 in plasma, urine, and feces. Complete urinary and fecal 
output will be collected during confinement period until discharge criteria are met (anticipated to be 10 days or less).
In Period 2 subjects will be confined in the clinic until a discharge criterion is met (ie, 80% or greater of the total dose 
of radioactivity administered is recovered in urine and fecal samples or the excretion of radioactivity in the urine and 
feces combined has declined to ≤1% of the total administered radioactivity per day for at least 2 consecutive intervals 
where both a urine and fecal sample are collected) or up to 10 days postdose. Release of subjects who do not meet a 
discharge criterion by Day 11 will be reviewed on a case-by-case basis. Since up to an approximate 24-hour time lag is 
anticipated for radioactivity counting of samples, actual subject release from the CRU may occur 1 day after discharge 
criteria are met.
In both Periods 1 and 2, any subject who experiences emesis within 8 hours post the dose will be excluded in the final 
data analysis and will be replaced with a new subject. If a subject experiences emesis after dosing in Period 2, vomitus 
will need to be collected as much as possible and assayed for total radioactivity.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after the last study 
drug administration to determine if any adverse events have occurred since the last study visit.
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Trial Primary Objectives:
Period 1 (ABA)
!
To determine absolute bioavailability of TAK-788 following single microdose IV administration of 
50 μg (~2 μCi) [14C]-TAK-788 and single oral administration of 160 mg TAK-788.
Period 2 (ADME)
!
To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and feces) and metabolic 
profile of TAK-788 in plasma, urine, and feces following a single oral administration of 160 mg (~100 μCi) 
[14C]-TAK-788 solution.
!
To characterize the PK of TAK-788 and its metabolites (AP32960 and AP32914) in plasma, whole blood, and 
urine, and total radioactivity concentration equivalents in plasma and whole blood following a single oral solution 
dose of 160 mg (~100 μCi) [14C]-TAK-788.
Secondary Objectives:
Period 1 (ABA)
!
To determine the PK of [14C]-TAK-788 and its metabolites (AP32960 and AP32914) following a single IV 
administration of 50 μg [14C]-TAK-788 and the PK of TAK-788 and its metabolites (AP32960 and AP32914) 
following a single oral administration of 160 mg TAK-788.
Periods 1 (ABA) and 2 (ADME)
!
To assess the safety of TAK-788 during the ABA and ADME study periods.
Exploratory Objective:
Trial Subject Population: Healthy adult male subjects 
Planned Number of Subjects:
6
Planned Number of Sites:
1
Dose Levels:
Period 1:
160 mg of TAK-788
50 μg (∀2 μCi) [14C]-TAK-788
Period 2:
160 mg (~100 μCi) [14C]-TAK-788
Route of Administration:
Period 1:
Oral (capsules)
IV infusion
Period 2:
Oral (solution)
Duration of Treatment:
Period 1:
On Day 1, subject will receive a single oral dose 
followed by a 15 minute IV dose at 3.75 hours post oral 
dose.
Period 2:
On Day 1, subject will receive a single oral dose.
Planned Trial Duration:
Approximately 65 days including Screening Period
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Criteria for Inclusion:
Subjects must fulfill the following inclusion criteria to be eligible for participation in the study: 
1.
Healthy, adult, male, 19 - 55 years of age, inclusive, at screening.
2.
Continuous non-smoker who has not used nicotine-containing products for at least 20 years prior to the first 
dosing and throughout the study, based on subject self-reporting.
3.
Body mass index (BMI) ≥18 and ˂30.0 kg/m2 at screening. 
4.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs, or electrocardiograms (ECGs), as deemed by the investigator or designee.
5.
Normal baseline pulmonary function tests (PFTs) (≥80% of predicted normal for spirometry and lung volumes) 
within 7 days prior to the first dosing.
6.
Subjects who are sexually active with a female partner of childbearing potential must use barrier contraception as 
indicated in Appendix D or abstain from sexual intercourse during the study until 94 days after the last dosing. 
Total abstinence (no sexual intercourse) may be considered an acceptable method of birth control if it agrees with 
your preferred and usual lifestyle.
7.
Must agree not to donate sperm from the first dosing until 94 days after the last dosing.
8.
Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the 
protocol.
Criteria for Exclusion:
The subject must be excluded from participating in the study if the subject: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
investigator or designee.
3.
History of any illness that, in the opinion of the investigator or designee, might confound the results of the study 
or poses an additional risk to the subject by their participation in the study.
4.
History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
5.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
6.
History or presence of any lung disease and current lung infection.
7.
Positive urine drug or alcohol results at screening or first check-in.
8.
Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or 
hepatitis C virus (HCV).
9.
Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
11. QTcF interval is >460 msec or ECG findings are deemed abnormal with clinical significance by the investigator 
or designee at screening.
12. Estimated creatinine clearance <80 mL/min at screening.
13. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may interfere with infusion 
site examination, in the opinion of the investigator.
14. Subject has infrequent bowel movements (less than approximately once per day) within 30 days prior to first 
dosing.
15. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, within 2 weeks of 
first dosing.
16. Has received radiolabeled substances or has been exposed to radiation sources within 12 months of first dosing or 
is likely to receive radiation exposure or radioisotopes within 12 months of first dosing such that participation in 
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this study would increase their total exposure beyond the recommended levels considered safe (ie, weighted 
annual limit recommended by the International Commission on Radiological Protection [ICRP] of 3000 millirem 
[mrem]).
17. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or vitamin supplements 
within 14 days prior to the first dosing and throughout the study. Thyroid hormone replacement medication 
may be permitted if the subject has been on the same stable dose for the immediate 3 months prior to first 
study drug administration. Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, 
only after first dosing, if necessary to treat adverse events (AEs). Milk of Magnesia (ie, magnesium 
hydroxide) (≤60 mL per day) may be administered approximately on Day 4 (Period 1) or Day 8 (Period 2) to 
ensure defecation, with agreement between the study investigator and Takeda physician. Additional 
administration of milk of Magnesia may be needed on other days at discretion of the study investigator and 
Takeda Physician.

Any drugs known to be significant inducers of cytochrome P450 (CYP) 3A enzymes and/or P-glycoprotein 
(P-gp), including St. John’s Wort, within 28 days prior to the first dosing and throughout the study. 
Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamics 
interaction with study drug.
18. Has been on a diet incompatible with the on-study diet, in the opinion of the investigator or designee, within the 
30 days prior to the first dosing and throughout the study.
19. Donation of blood or significant blood loss within 56 days prior to the first dosing.
20. Plasma donation within 7 days prior to the first dosing.
21. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be derived 
from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of Period 1 
of the current study.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is:
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-788.
Period 2 (ADME):

Percent of total radioactivity recovered in urine (Cum%Dose[UR]) and feces (Cum%Dose[UR]) relative to the 
administered radioactive dose (Combined Cum%Dose).

Total radioactive recovery in urine (Ae[UR]) and feces (Ae[FE]) and the percent of the radioactive dose excreted 
in the urine (%Dose[UR]) and feces (%Dose[FE]).

TAK-788 metabolic profiling in plasma, urine, and feces containing sufficient amounts of radioactivity. 

PK parameters Cmax, tmax, t½, AUC∞, AUClast, and AUCt for TAK-788 and its metabolites (AP32960 and 
AP32914) in plasma and whole blood. 

PK parameters Cmax, tmax, t½, AUC∞, AUClast, and AUCt for total radioactivity concentration equivalents in plasma
and whole blood.

PK parameters for amount excreted in each collection interval (Aet1-t2) and renal clearance (CLR) for TAK-788
and its metabolites (AP32960 and AP32914) in urine.

The change over time in percentage of [14C]-radioactivity in whole blood relative to plasma (ie, whole 
blood:plasma partitioning ratio).
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The secondary endpoints will be assessed through evaluation of the following parameters:
Period 1 (ABA):
!
PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, AUCt, and t½ for TAK-788, and 
[14C]-TAK-788 and the metabolites (AP32960 and AP32914) in plasma; 
Periods 1 (ABA) and 2 (ADME):
!
Tabulated TEAEs and summary statistics for clinically relevant 12-lead ECGs, vital signs, and clinical laboratory 
tests results.
The exploratory endpoints will be assessed through evaluation of the following parameters: 
Statistical Considerations:
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, 
, and if applicable, 
emesis), plasma TAK-788 and metabolites concentrations and PK parameters, [14C]-TAK-788 plasma and 
 
radioactivity concentration equivalent, using appropriate summary statistics to be fully specified in the statistical 
analysis plan (SAP).
Absolute bioavailability of TAK-788 will be estimated using a ninety percent (90%) confidence interval (CI) 
constructed for the difference in least-squares (LS) mean on the log scale for dose normalized AUC∞ between a single 
oral dose and the IV microdose. Exponentiating the log-scale 90% CI will provide a 90% CI for the dose normalized 
AUC∞geometric mean ratio (GMR; TAK-788 administered as oral dose / [14C]-TAK-788 administered as IV 
microdose). The AUClast, AUCt, and Cmax, will be analyzed in a similar fashion. 
Mass balance will be calculated as a sum of the percent of the 
 relative 
to the administered radioactivity dose minus any radioactivity lost due to emesis (if any occurred).
Sample Size Justification: 
The sample size of 6 male healthy subjects was selected without statistical considerations and is deemed adequate to 
meet the study objectives. In addition, this sample size is limited based on clinical considerations for this type of study 
and in order to limit exposure to radioactivity.
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2.0
STUDY SCHEMATIC
Screening
Treatment Period 1 a
Within 28 days first 
dosing on Period 1 
Day -1
Day 1
Days 2 - 8
Check-in
Oral Dosing 
at Hour 0
IV Dosing at 
Hour 3.75 
Plasma, 
sampling for ABA and safety monitoring for at least 
96 hours post oral dose b
< - - - - - - - - - - - -  confinement b - - - - - - - - - - - - >
a Dosing in each period will be separated by approximately 9 days.
b Subjects will be confined in the clinic for at least 5 days
 
 
 or up to Day 8.
Treatment Period 2
Follow-up
Day -1
Day 1
Days 2 - 11
30 ± 2 days after last 
dosing
Check-in
Oral Dosing at Hour 0
Plasma, 
sampling for PK c, total radioactivity, and metabolic 
profiling, and safety monitoring up to approximately 240 hours postdose
< - - - - - - - - - - - -  confinement d - - - - - - - - - - - - >
c Predose plasma samples from in Period 2 will also be used as Day 10 samples for Period 1, as appropriate.
d Subjects will be confined in the clinic until a discharge criterion is met (ie, 80% or greater of the total dose of 
radioactivity administered is recovered in 
 samples 
 
Release of subjects who do not meet a 
discharge criterion by Day 11 will be reviewed on a case-by-case basis. Since up to an approximate 24-hour time lag is 
anticipated for radioactivity counting of samples, actual subject release from the CRU may occur 1 day after discharge 
criteria are met.
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3.0
SCHEDULE OF STUDY PROCEDURES 
Study Procedures a
Days →
S b
Study Days in Period 1 c
-1 (C-Id)
1
2
3
4
5
6-8 e
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Medical History
X
Safety Evaluations 
Full Physical Examination f
X
X g
Height
X
Weight
X
X g
12-Lead Safety ECGs
X
X h
X i
X
Vital Signs (heart rate and blood pressure)
X
X h
X j
X
Vital Signs (respiratory rate and temperature)
X
Pulmonary Function Test
X k
Hematology, Serum Chemistryl, and UA
X
X
X
Urine Drug and Alcohol Screen
X
X
HIV/Hepatitis Screen
X
AE Monitoring
X
Concomitant Medication Monitoring
X
X
Study Drug Administration / Pharmacokinetics
TK-788 Administration (oral)
X m
[14C]- TAK-788 Administration (IV)
X n
Blood for TAK-788 Plasma PK o
X
X
X
X
X
X
Blood for [14C]-TAK-788 Plasma PK o
X
X
X
X
X
X
Other Procedures
Confinement in the CRU (e, q)
X
X
Visit
X
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Study Procedures a
Study Days in Period 2 c
FU r
-1 
(C-I d)
1
2
3
4
5
6
7
8
9
10
11
Safety Evaluations 
Full Physical Examination f
X
X s
12-Lead Safety ECG
X h
X t
X
X s
Vital Signs (heart rate and blood pressure)
X h
X u
X
X s
Hematology, Serum Chemistry l, and UA
X
X
X s
Urine Drug and Alcohol Screen
X
AE Monitoring
X
Concomitant Medication Monitoring
X
Study Drug Administration / 
Pharmacokinetics
[14C]- TAK-788 Administration (oral) m
X
Blood for Total Radioactivity v
X
X
X
X
X
X
X
X
X
X
X
Blood for TAK-788 Whole Blood PK v
X
X
X
X
X
X
X
X
X
X
X
Blood for TAK-788 Plasma PK v
X
X
X
X
X
X
X
X
X
X
X
Blood for TAK-788 Metabolic Profiling v
X
X
X
X
X
X
X
Other Procedures
Confinement in the CRU x
X
Phone call
X
a For details on Procedures, refer to Section 9.2.
b Within 28 days prior to the first study drug administration.
c There will be a washout period of approximately 9 days between doses in Period 1 and the dose in Period 2.
d Subjects will be admitted to the CRU on Day -1, at the time indicated by the CRU. If the CRU decides to confine the subjects 
throughout the washout period, some safety events at check-in (eg, clinical laboratory tests, urine drug and alcohol screen, serum
pregnancy test, vital signs, and ECGs) may not be performed, following a decision by investigator’s.
e Subjects who do not meet a discharge criterion (ie, 80% or greater of the total dose of radioactivity administered is recovered in 
urine and fecal samples or the excretion of radioactivity in the urine and feces combined has declined to ≤1% of the total 
administered radioactivity per day for at least 2 consecutive intervals where both a urine and fecal sample are collected) by Day 5, 
will remain confined and undergo study procedures until a discharge criterion is met or up to Day 8.
f Full physical examinations will be conducted at scheduled time points. Symptom-driven physical examination may be performed 
at additional times, at the investigator’s or designee’s discretion.
g If the screening assessment was conducted within 4-7 days prior to dosing (Day 1), assessment will be conducted at check-in only 
if, in the opinion of the investigator, there is reason to believe they have substantially changed.
h To be performed within 24 hours prior to oral dosing.
i To be performed between 4.5 – 5 hours post oral drug administration.
j To be performed between 4.5 – 5 hours and at 12 hours post oral drug administration.
k To be conducted within 7 days prior to first dosing.
l Samples for serum chemistry will be obtained following a fast of at least 8 hours, however, in case of dropouts or rechecks, 
subjects may not have fasted for 8 hours prior to the serum chemistry sample being taken.
m Oral drug administration will be performed at Hour 0 of Day 1.
n A 15 minute IV drug administration will begin at 3.75 hours post oral dose on Day 1 of Period 1.
o For a detailed blood sampling schedule refer to Table 3.a. Predose plasma samples from Period 2 will also be used as Day 10
samples for Period 1.
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q As per site preference, subjects may be confined throughout the washout period.
r The clinic will contact all subjects (including subjects who terminate the study early) 30 ±2 days after the last study drug 
administration to determine if any adverse events have occurred since the last study visit.
s To be performed at the end of Period 2 (prior to discharge) or prior to early termination from the study.
t To be performed at 4 hours post oral drug administration.
u To be performed at 4 and 12 hours post oral administration. 
v For a detailed blood sampling schedule refer to Table 3.c.
w Fo
 schedule refer to Table 3.d.
x Subjects will remain confined to the CRU until discharge criteria are met or up to a maximum stay of 10 days postdose (Day 11).
Abbreviations: AE = Adverse event, C-I = Check-in, CRU = Clinical research unit, ECG = Electrocardiogram, FU = Follow-up, 
HIV = Human immunodeficiency virus, IV = Intravenous, PK = Pharmacokinetics, S = Screening, UA = Urinalysis.
Table 3.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-788 
(Period 1 - ABA Study Period)
Time 
(relative to oral dosing)
Time 
(relative to IV infusion)
Blood Sample 
Collection
(oral dose)
Blood Sample 
Collection
(IV dose)
Matrix
Plasma 
Sample 1 a
Plasma 
Sample 2 b
0 (predose)
X c
X c
0.5 hour postdose (± 2 min)
X c
1 hour postdose (± 2 min)
X c
2 hours postdose (± 2 min)
X c
3 hours postdose (± 2 min)
X c
3 hours 45 min post dose
0 (predose) 
X c
4 hours postdose (± 2 min)
End of infusion
X
X
10 min after the end of infusion (± 2 min)
X
20 min after the end of infusion (± 2 min)
X
30 min after the end of infusion (± 2 min)
X
5 hours postdose (± 2 min)
1 hours after the end of infusion (± 2 min)
X
X
6 hours postdose (± 2 min)
2 hours after the end of infusion (± 2 min)
X
X
8 hours postdose (± 2 min)
4 hours after the end of infusion (± 2 min)
X
X
12 hours postdose (± 5 min)
8 hours after the end of infusion (± 2 min)
X
X
24 hours postdose (± 5 min)
20 hours after the end of infusion (± 5 min)
X
X
36 hours postdose (± 10 min)
32 hours after the end of infusion (± 10 min)
X
X
48 hours postdose (± 10 min)
44 hours after the end of infusion (± 10 min)
X
X
72 hours postdose (± 10 min)
68 hours after the end of infusion (± 10 min)
X
X
96 hours postdose (± 15 min)
92 hours after the end of infusion (± 15 min)
X
X
120 hours postdose (± 15 min)
116 hours postdose (± 15 min)
X d
X d
144 hours postdose (± 15 min)
140 hours postdose (± 15 min)
X d
X d
Day 10 (Predose Day 1 of Period 2)
X e
X e
a For determination of TAK-788 and metabolites in plasma following oral capsule dose.
b For determination of [14C]-total radioactivity, and [14C]-TAK-788 and metabolites in plasma following IV infusion.
c Pre-IV dose samples should be stored separately away from the postdose samples to avoid cross contamination.
d For subjects who do not meet the discharge criteria by Day 5, blood samples will continue to be collected in 24-hour intervals until 
radioactivity in urine and feces combined is ≤1% of the total administered radioactivity per day for at least 2 consecutive intervals 
where both a urine and fecal sample are collected, the excretion of radioactivity is ≥80% of the administered radioactive dose, or up 
to Day 7.
e Predose plasma samples from in Period 2 will also be used as Day 10 samples for Period 1, as appropriate.
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Table 3.c
Blood Collection Schedule (Period 2 - ADME Study Period)
Matrix 
Sample collected for analysis 
in Whole Blood
Sample collected for analysis in Plasma 
Time 
(Relative to Oral Solution 
Dosing)
Blood 
Sample 1 a
Blood 
Sample 2 b
Plasma 
Sample 1 c
Plasma 
Sample 2 d
Plasma 
Sample 3e
0 (predose)
X f
X f
X f
X f
X f
0.5 hour postdose (± 2 min)
X
X
X
X
1 hour postdose (± 2 min)
X
X
X
X
X
2 hours postdose (± 2 min)
X
X
X
X
X
3 hours postdose (± 2 min)
X
X
X
X
4 hours postdose (± 2 min)
X
X
X
X
X
5 hours postdose (± 2 min)
X
X
X
X
6 hours postdose (± 2 min)
X
X
X
X
X
8 hours postdose (± 2 min)
X
X
X
X
12 hours postdose (± 5 min)
X
X
X
X
X
24 hours postdose (± 5 min)
X
X
X
X
X
36 hours postdose (± 10 min)
X
X
X
X
48 hours postdose (± 10 min)
X
X
X
X
X
72 hours postdose (± 10 min)
X
X
X
X
X
96 hours postdose (± 15 min)
X
X
X
X
X
120 hours postdose (± 15 min)
X
X
X
X
X
144 hours postdose (± 15 min)
X
X
X
X
168 hours postdose (± 15 min)
X
X
X
X
X
192 hours postdose (±1 hour)
X
X
X
X
216 hours postdose (±1 hour)
X
X
X
X
240 hours postdose (±1 hour)
X
X
X
X
a Blood Sample 1 - Blood sample for total [14C] determination (total radioactivity) in whole blood.
b Blood Sample 2 – Blood sample for PK analysis of TAK-788 and metabolites in whole blood. 
c Plasma sample 1 – Blood sample collected for total [14C] determination in plasma.
d Plasma sample 2 – Blood sample collected for TAK-788 and metabolites PK in plasma.
e Plasma sample 3 – Blood sample collected for metabolite profiling.
f Predose blood and plasma samples should be stored separately away from the postdose samples to avoid cross contamination. 
Predose plasma samples from Period 2 will also be used as Day 10 samples for Period 1, as appropriate.
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4.0
INTRODUCTION
4.1
Background
Aberrant activation of epidermal growth factor receptor (EGFR) and human epidermal growth 
factor 2 (HER2) plays a causal role in a subset of non–small cell lung cancer (NSCLC) and other 
cancers. As inhibition of wild-type (WT) EGFR is associated with dose-limiting toxicities, a 
tyrosine kinase inhibitor (TKI) that inhibits oncogenic EGFR and HER2 variants more potently 
than WT EGFR is more likely to be able to be dosed to efficacious levels. Multiple classes of 
activating mutations have been identified in EGFR and HER2 that vary widely in their sensitivity 
to available TKIs. TAK-788, formerly known as AP32788, was designed to be a potent, selective 
inhibitor of all activated forms of EGFR and HER2, including exon 20 insertions (not targeted by 
any approved TKI), more potently than it inhibits WT EGFR.
Pharmacokinetics
Clinical experience
TAK-788 is currently being investigated in the first-in-human phase 1/2 trial (AP32788-15-101) to 
determine safety and maximum tolerated dose, PK and recommended phase 2 dose, and its 
preliminary efficacy profile.
In mid-January 2018, 160 mg QD was identified as the maximum tolerated dose (MTD). In 
combination with the efficacy, safety, and pharmacokinetic (PK) results observed in the dose 
escalation phase of this study, 160 mg QD was also recommended as the recommended Phase 2 
dose (RP2D) for phase expansion phase of the study.
As of August 2018, 95 patients have been exposed to treatment at doses of 5 to 180 mg once daily 
(QD) and 40 to 60 mg twice daily as part of a phase 1/2 Study of the Safety, PK, and Anti-Tumor 
Activity of the oral EGFR/HER2 inhibitor AP32788 in patients with NSCLC.
The early proof-of-concept assessment on the basis of Parts 1 and 2 of the study (the dose 
escalation and expansion phases) confirmed that 160 mg QD was the RP2D for the Part 3 
extension cohort of AP32788-15-101. The unconfirmed ORR and DCR at the 160 mg QD dose 
were 47.6% (10 of 21) and 85.7% (18 of 21), respectively. With respect to the safety profile, the 
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most common all-grade treatment-emergent adverse events (AEs) (greater than 20% incidence in 
all patients treated at doses ranging from 80 to 160 mg total daily dose) had the following 
incidences at 160 mg QD: diarrhea (71.9%), nausea (40.6%), vomiting (31.3%), and decreased 
appetite (28.1%). The most common Grade ≥3 treatment-emergent AE was diarrhea; the incidence 
was 15.6% at 160 mg QD. The dose reduction rate for patients who received 160 mg total daily 
dose was 27.5%. 
In summary, the early proof-of-concept results suggest a clinically meaningful benefit of 
TAK-788 in a patient population with locally advanced or metastatic NSCLC whose tumors have 
EGFR exon 20 insertion mutations regardless of prior treatment history with safety profile 
consistent with other EGFR TKIs. 
A randomized, double-blind, placebo-controlled single rising dose (SRD) study (Part 1 of Study 
TAK-788-1001) followed by crossover evaluation of the effects of a low-fat meal on the 
pharmacokinetics of TAK-788 (Part 2) in healthy subjects has been initiated in April 2018. The 
starting dose was 20 mg and then with each subsequent 8-subject (2 in placebo and 6 in TAK-788) 
cohort the dose escalated to a single dose of 40, 80, 120, up to 160 mg administered under fasting 
conditions (no food for at least 10 hours before and 4 hours after the TAK-788 dose). Following 
the completion of Part 1 where safe and tolerable doses in healthy subjects were identified, Part 2 
(low-fat meal effect phase) was conducted at 120 mg and 160 mg doses where the effects of a 
low-fat meal on TAK-788 were evaluated in a cross-over study design with 7-day washout 
between 2 doses. A total of 30 subjects were administered a single dose of TAK-788 at 160 mg in 
Part 1 of the study and 16 subjects took 2 single doses of TAK-788 at 160 mg in Part 2 of the study. 
TAK-788 was generally well tolerated after 1 single dose or 2 single doses up to 160 mg TAK-788. 
There were no SAEs. The common AEs were Grade 1 nausea and diarrhea. 
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-788 
(IB 2018).
4.2
Rationale for the Proposed Study
The PK of TAK-788, metabolic pathways, and routes of elimination have been evaluated in vitro
and in vivo in preclinical species, being summarized in the IB (IB 2018). The pharmacokinetic 
profile in humans is being evaluated in an ongoing dose escalation study in patients with NSCLC, 
as summarized in the IB (IB 2018) and in an ongoing SRD study in healthy subjects
The primary purposes of the present study are to characterize the ABA (Period 1) and the 
absorption, metabolism, excretion, and mass balance of TAK-788 after single oral administration 
(Period 2) in healthy adult male subjects, by collecting plasma, urine, and feces samples for drug 
concentration analysis, and plasma, whole blood, 
 
 The study will provide data required to evaluate the mass balance 
and the metabolic profile of TAK-788 in humans. Based on preliminary data in healthy subjects, 
the geometric mean plasma terminal t½ of TAK-788 is approximately 21 hours (13-28 hours); thus, 
more than 90% of the radioactivity should be eliminated within 96 hours postdose.
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4.3
Benefit/Risk Profile
Based on the clinical safety data available as of 10 August 2018 from the ongoing first-in-human 
study in NSCLC patients (Study AP32788-15-101) and the SRD/low-fat meal effect study in 
healthy subjects, TAK-788 exhibits a similar safety profile to other epidermal growth factor 
receptor tyrosine kinase inhibitors. The MTD was determined to be 160 mg QD in NSCLC 
patients. A single dose of 160 mg TAK-788 selected for this study has been demonstrated to be 
safe and well tolerated in healthy subjects.
The estimated radiation dose from a single IV administration of [14C]-TAK-788 (~2 µCi) and a 
single oral dose of [14C]-TAK-788 (~100 μCi) is below the radiation dose limits set forth in 
21 CFR 361 for the whole body, active blood forming organs, lens of the eye, gonads, and other 
organs (see Section 6.3.2). Thus, the health risk resulting from exposure to radiation in the study 
drug is very low.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed by this 
protocol (ie, 12-lead ECG, vital signs, clinical laboratory tests, AE questioning, PFTs, and 
physical examination) are adequate to protect the subjects’ safety and should detect all TEAEs.
There will be no direct health benefit for study participants from receipt of study drug. An indirect 
health benefit to the healthy subjects enrolled in this study is the free medical tests received at 
screening and during the study.
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5.0
TRIAL OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
NA
5.2
Trial Objectives
5.2.1
Trial Primary Objectives
Period 1 (ABA)
!
To determine absolute bioavailability of TAK-788 following single microdose IV 
administration of 50 μg (~2 μCi) [14C]-TAK-788 and single oral administration of 160 mg 
TAK-788.
Period 2 (ADME)
!
To assess the mass balance (ie, cumulative excretion of total radioactivity in urine and feces) 
and metabolic profile of TAK-788 in plasma, urine, and feces following a single oral 
administration of 160 mg (~100 μCi) [14C]-TAK-788 solution.
!
To characterize the PK of TAK-788 and its metabolites (AP32960 and AP32914) in plasma, 
whole blood, and urine, and total radioactivity concentration equivalents in plasma and whole 
blood following a single oral solution dose of 160 mg (~100 μCi) [14C]-TAK-788.
5.2.2
Trial Secondary Objectives
Period 1 (ABA)
!
To determine the PK of [14C]-TAK-788 and its metabolites (AP32960 and AP32914) 
following a single IV administration of 50 μg [14C]-TAK-788 and the PK of TAK-788 and its 
metabolites (AP32960 and AP32914) following a single oral administration of 160 mg 
TAK-788.
Periods 1 (ABA) and 2 (ADME)
!
To assess the safety of TAK-788 during the ABA and ADME study periods.
5.2.3
Trial Exploratory Objective
5.3
Endpoints
For full description of the PK parameters indicated below see Section 9.3.1.
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5.3.1
Primary Endpoints
The primary endpoint of the study is:
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-788.
Period 2 (ADME):

Percent of total radioactivity recovered in urine (Cum%Dose[UR]) and feces 
(Cum%Dose[FE]) relative to the administered radioactive dose (Combined Cum%Dose).

Total radioactive recovery in urine (Ae[UR]) and feces (Ae[FE]) and the percent of the 
radioactive dose excreted in the urine (%Dose[UR]) and feces (%Dose[FE]).

TAK-788 metabolic profiling in plasma, urine, and feces containing sufficient amounts of 
radioactivity. 

PK parameters Cmax, tmax, t½, AUC∞, AUClast, and AUCt for TAK-788 and its metabolites 
(AP32960 and AP32914) in plasma and whole blood.

PK parameters Cmax, tmax, t½, AUC∞, AUClast, and AUCt for total radioactivity concentration 
equivalents in plasma and whole blood.

PK parameters for amount excreted in each collection interval (Aet1-t2) and renal clearance 
(CLR) TAK-788 and its metabolites (AP32960 and AP32914) in urine.

The change over time in percentage of [14C]-radioactivity in whole blood relative to plasma (ie, 
whole blood:plasma partitioning ratio).
5.3.2
Secondary Endpoints
The secondary endpoints will be assessed through evaluation of the following parameters:
Period 1 (ABA):

PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, AUCt, and t½ for 
TAK-788, and [14C]-TAK-788 and the metabolites (AP32960 and AP32914) in plasma; 
Periods 1 (ABA) and 2 (ADME):

Tabulated TEAEs and summary statistics for clinically relevant 12-lead ECGs, vital signs, and 
clinical laboratory tests results.
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5.3.3
Exploratory Endpoints
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6.0
TRIAL DESIGN AND DESCRIPTION
6.1
Trial Design 
An open-label, 2-period, single-dose study in 6 male healthy subjects. 
On Day 1 of Period 1 (ABA Study Period), after at least a 10-hour fast, 6 subjects will receive a 
single unlabeled oral 160 mg dose of TAK-788 as capsules. At 3.75 hours post oral dosing (ie, 
15 minutes prior to the median tmax for the oral unlabeled dose (~4 hours), subjects will receive a 
15-minute IV infusion of a microdose of 50 μg (~2 μCi) [14C]-TAK-788. Serial blood sampling 
will be performed to determine the PK of TAK-788 and its metabolites (AP32960 and AP32914) 
in the plasma for the oral dose and [14C]-total radioactivity and PK of [14C]-TAK-788 and its 
metabolites (AP32960 and AP32914) in the plasma for the IV dose. 
 
 
 
 
In Period 1, subjects will be confined in the clinical research unit (CRU) for at least 5 days (until 
after the last PK sample and morning urine and fecal sample [when passed] are collected) and until 
a discharge criterion is met or up to Day 8. Subjects will return to the clinic on Day 9 (Period 2, 
Day -1) for Period 2.
There will be a washout period of approximately 9 days between doses in Period 1 and the dose in 
Period 2.
On Day 1 of Period 2 (ADME Study Period), after at least a 10-hour fast, subjects will receive a 
single dose of 160 mg (~100 μCi) [14C]-TAK-788 as an oral solution. Serial blood sampling will 
be performed and urine and feces will be collected to determine the PK of TAK-788 and its 
metabolites (AP32960 and AP32914) in plasma, whole blood, and urine, and total radioactivity in 
plasma, whole blood, 
, and to characterize the metabolite profiles of TAK-788 in 
plasma, 
 will be collected during confinement 
period until discharge criteria are met (anticipated to be 10 days or less).
In Period 2 subjects will be confined in the clinic until a discharge criterion is met (ie, 80% or 
greater of the 
 
 
 
 
In both Periods 1 and 2, any subject who experiences emesis within 8 hours post the dose will be 
excluded in the final data analysis and will be replaced with a new subject. If a subject experiences
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emesis after dosing in Period 2, vomitus will need to be collected as much as possible and assayed 
for total radioactivity.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days 
after the last study drug administration to determine if any AEs have occurred since the last study 
visit.
The planned dose levels of TAK-788 to be evaluated are outlined in Table 6.a.
Table 6.a
Planned TAK-788 and [14C]-TAK-788 Doses
Dose
Route of 
Administration
Period 1 (Treatment A)
TAK-788
160 mg
Oral capsule
[14C]-TAK-788
50 μg (~2 μCi)
IV
Period 2 (Treatment B)
[14C]-TAK-788
160 mg (~100 μCi)
Oral solution
6.2
Dose Escalation
NA
6.3
Rationale for Trial Design, Dose, and Endpoints
6.3.1
Rationale of Trial Design
In Period 1 of the study, the ABA of TAK-788 will be estimated using a labeled IV microdose 
administered 3.75 hours after an unlabeled oral dose in order to characterize the disposition 
properties of TAK-788. In order to determine absolute bioavailability accurately and reliably, a 
healthy adult population is chosen.
Characterization of the disposition of a drug following IV administration facilitates the 
understanding of fundamental aspects of TAK-788’s PK that cannot be determined from oral 
dosing alone, including bioavailability, intrinsic clearance, and volume of distribution. The results 
of this trial will contribute to a robust understanding of the PK characteristics of TAK-788.
In Period 2 of the study, characterization of the absorption, metabolism, excretion, and mass 
balance of TAK-788 after oral administration of a single 160 mg (~100 μCi) [14C]-TAK-788 will 
be achieved by collecting plasma samples for drug concentration analysis, and plasma, 
 
and metabolic profiling. The study will provide data 
required to evaluate the mass balance and the metabolic profile of TAK-788 in humans. 
6.3.2
Rationale for Dose 
The likely therapeutic dose of TAK-788 is expected to be 160 mg for oral administration. The 
160 mg dose is likely to provide exposures commensurate with a clinically efficacious dose, and 
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was selected in order to have sufficient mass of drug, and sufficient specific radioactivity, for 
detection and analysis of parent drug and/or metabolites in plasma, urine, and fecal samples. 
A radioactive IV dose of ~2 µCi was selected for Period 1 (ABA) followed by an oral dose of 
~100 µCi in Period 2 (ADME) were selected based on organ exposure data derived from a rat 
quantitative whole-body autoradiography/autoradioluminography study (see below) and the need 
to have sufficient specific radioactivity, for detection and analysis of parent drug and/or 
metabolites in plasma, urine, and fecal samples.
The estimated radiation absorbed doses to human tissues of the concomitant dosing in both periods 
of the study was estimated based on data from pigmented and non-pigmented Long-Evans rats 
following a single oral 10 mg/kg (~100 μCi/kg) dose of [14C]-TAK-788. The overall whole body 
effective dose, defined as the equivalent total detriment to the health of the affected individual 
from non-uniform doses to tissues, based on assigned tissue weighting factors, was calculated. 
Based on the rat ADME study, the bioavailability of the oral drug in rat is 25%. For safety 
purposes, a conservative approach was taken for the purpose of exposure calculations (accounting 
for potential differences between the animal model and human estimate) and the bioavailability 
was assumed to be 10%. The overall whole-body radiation dose in male subjects following 
administration of a single IV dose of 2 µCi of [14C]-TAK-788 (using a conversion ratio of x10 to 
account for a 10% bioavailability) followed by a single oral dose of 100 μCi (3.7 megabecquerels 
[MBq]) of [14C]-TAK-788 was calculated to be 6.3996 mrem (0.06399 milliSieverts [mSv]), 
approximately 0.21% of the allowable 3000 mrem-exposure limit established by the Food and 
Drug Administration (FDA) and approximately 6.40% of the allowable 1 mSv ICRP limit. The 
highest estimated absorbed dose was in the adrenal gland modulla, which had a value of 
555.04 mrem (5.550 mSv), and represented 11.10% of the allowable 5000 mrem exposure limit 
for a single tissue specified by the FDA.
6.3.3
Rationale for Endpoints
NA
6.3.4
Critical Procedures Based on Trial Objectives: Timing of Procedures 
For this study, the blood, urine, and feces collection for radioactivity, plasma concentrations, and 
metabolite profiling for TAK-788 is the critical procedure and are required to be collected, as 
appropriate, as close to the scheduled times defined in this protocol as possible.
6.4
Trial Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drug to any subject may not be modified. If necessary a 
subject must be discontinued for the reasons described in Section 6.5.5.
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6.5
Trial Beginning and End/Completion
6.5.1
Definition of Beginning of the Trial
The beginning of the trial will be defined as the beginning of the screening (ie, signing of the ICF) 
of the first subject.
6.5.2
Definition of End of the Trial
The end of study is defined as the date of the last scheduled study procedure as outlined in the 
Schedule of Study Procedures (Section 3.0).
6.5.3
Definition of Trial Completion
The end of the study is scheduled after completion of the evaluations in the follow-up phone call 
for the last subject in the study.
This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
6.5.4
Definition of Trial Discontinuation
Celerion reserves the right to terminate the study in the interest of subject welfare.
The Sponsor reserves the right to suspend or terminate the study at any time.
6.5.5
Criteria for Premature Termination or Suspension of the Trial
Celerion reserves the right to terminate the study in the interest of subject welfare.
Sponsor reserves the right to suspend or terminate the study at any time.
6.5.6
Criteria for Premature Termination or Suspension of a Site
6.5.6.1
Criteria for Premature Termination or Suspension of a Site
NA
6.5.6.2
Procedures for Premature Termination or Suspension of a Site
NA
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 9.1.2.2.
After the first dose, acetaminophen (up to 2 g per 24 hour period) may be administered at the 
discretion of the investigator or designee. Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior to first 
study drug administration.
Milk of Magnesia (ie, magnesium hydroxide) (≤60 mL per day) may be administered 
approximately on Day 4 (Period 1) or Day 8 (Period 2) to ensure defecation, with agreement 
between the study investigator and Takeda physician. Additional administration of milk of 
Magnesia may be needed on other days at discretion of the study investigator and Takeda 
Physician.
If deviations occur, the investigator or designee in consultation with the Sponsor if needed will 
decide on a case-by-case basis whether the subject may continue participation in the study.
All medications taken by subjects during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and Randomization 
(Days -28 to predose [Day 1])
Post-Randomization (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from 48 hours prior to 
first dosing in each period and 
throughout the period of PK
sample collection in each 
Treatment period.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing a
Prohibited from 24 hours prior to 
first dosing in each period and 
throughout the period of PK 
sample collection in each 
Treatment period a.
Medications
See Sections 7.1 and 9.1.2.2
See Sections 7.1 and 9.1.2.2
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited until end of PK 
collection in Treatment Period 2.
a small amounts of caffeine derived from normal foodstuffs eg, 250 mL/8 oz./1 cup decaffeinated coffee or other 
decaffeinated beverage, per day, with the exception of espresso; 45 g/1.5 oz. chocolate bar, per day, would not be 
considered a deviation to this restriction.
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7.2
Diet, Fluid, Activity 
7.2.1
Diet and Fluid
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 1 hour 
after each oral study drug administration, but will be allowed ad libitum at all other times, when 
dosing occurs at the CRU. Other fluids may be given as part of meals and snacks but will be 
restricted at all other times throughout the confinement period.
Subjects will fast overnight for at least 10 hours prior to each oral study drug administration and 
will continue to fast for at least 4 hours postdose.
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, subjects will be required to fast from all food 
and drink except water between meals and snacks.
7.2.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose, except when they 
are supine or semi-reclined for study procedures (eg, IV dosing on Day 1 of Period 1).
7.3
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the investigator or designee for the 
following reasons:

AEs.

Positive urine drug or alcohol results.

Difficulties in blood collection.
Any subject who experiences emesis within 8 hours post the oral dose will be discontinued, 
excluded from the final data analysis, and may be replaced with a new subject. In Period 2, if a 
subject experiences emesis after dosing, vomitus will need to be collected as much as possible and 
assayed for total radioactivity.
A subject may be withdrawn by the investigator (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.
7.4
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.3. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
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7.5
Subject Replacement
Discontinued subjects may be replaced at the discretion of the Sponsor and the investigator.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
8.1.1
TAK-788 Capsule 
A single unlabeled 160 mg dose of TAK-788 capsules will be administered in Period 1 of the 
study. 
Oral dose of TAK-788 drug product is a nonsterile, oral, capsule dosage form, supplied in a hard 
gelatin capsule of TAK-788 succinate salt. TAK-788 succinate salt is the active pharmaceutical 
ingredient. The drug product is supplied as a hard gelatin capsule shell. No other ingredients are 
included in the drug product.
8.1.2
[14C]-TAK-788 IV Sterile Solution
An IV dose of approximately 50 μg [14C]-TAK-788 (~2 µCi) will be administered 3.75 hours after 
the TAK-788 oral dose (Section 6.1) in Treatment Period 1 of the study. 
The drug product is prepared in the CRU pharmacy as an IV solution. The solution will be 
prepared and labeled by licensed pharmacy staff according to the procedures outlined in the 
pharmacy manual. 
8.1.3
[14C]-TAK-788 Oral Solution
A dose of 160 mg [14C]-TAK-788 (~100 µCi) as oral solution will be administered in Treatment 
Period 2 of the study.
The drug product is prepared in the CRU pharmacy as an oral solution. The solution will be 
prepared and labeled by licensed pharmacy staff according to the procedures outlined in the 
pharmacy manual.
8.1.4
Clinical Study Drug Labeling
TAK-788 capsule containers will be affixed with a clinical label in accordance with local 
regulatory requirements.
8.1.5
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-788 products to allow completion of this 
study. 
Celerion will provide sufficient quantities of preparation and/or dilution solutions to allow 
completion of the study. The same lot number will be used throughout the study.
The lot numbers and expiration dates (where available) of the study drugs supplied will be 
recorded in the final report.
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Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied. All TAK-788 products will be prepared and labeled by licensed pharmacy staff 
according to the procedures outlined in the pharmacy manual.
8.1.6
Clinical Study Drug Blinding
This is an open-label study.
8.1.7
Randomization Code Creation and Storage 
NA
8.1.8
Clinical Trial Blind Maintenance/Unblinding Procedure
NA
8.1.9
Accountability and Destruction of Sponsor-Supplied Drugs
At the conclusion of the study, any unused TAK-788 study drug will be retained by Celerion, 
returned to the Sponsor or designee, or destroyed, as per Sponsor instructions. If no supplies 
remain, this fact will be documented in the pharmacy product accountability records.
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9.0
STUDY PROCEDURES
9.1
Administrative Procedures
9.1.1
Informed Consent Procedure
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date an 
ICF summarizing the discussion prior to screening, and will be assured that they may withdraw 
from the study at any time without jeopardizing their medical care.
Subjects will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each subject will be assigned a unique identification number upon screening. Subjects who 
complete the study screening assessments and meet all the eligibility criteria will be assigned a 
unique identification number at the time of the first dosing, different from the screening number.
9.1.1.2
Study Drug Assignment
This is a fixed-sequence study. All subjects will receive the same treatments as detailed in 
Section 6.1.
9.1.2
Inclusion and Exclusion 
9.1.2.1
Inclusion Criteria
Subjects must fulfill the following inclusion criteria to be eligible for participation in the study:
1. Healthy, adult, male, 19 - 55 years of age, inclusive, at screening.
2. Continuous non-smoker who has not used nicotine-containing products for at least 20 years 
prior to the first dosing and throughout the study, based on subject self-reporting.
3. BMI ≥18 and ˂30.0 kg/m2 at screening. 
4. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs, or ECGs, as deemed by the investigator or designee.
5. Normal baseline PFTs (≥80% of predicted normal for spirometry and lung volumes) within 
7 days prior to the first dosing.
6. Subjects who are sexually active with a female partner of childbearing potential must use 
barrier contraception as indicated in Appendix D or abstain from sexual intercourse during the 
study until 94 days after the last dosing. Total abstinence (no sexual intercourse) may be 
considered an acceptable method of birth control if it agrees with your preferred and usual 
lifestyle.
7. Must agree not to donate sperm from the first dosing until 94 days after the last dosing.
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8. Understands the study procedures in the ICF, and be willing and able to comply with the 
protocol.
9.1.2.2
Exclusion Criteria
The subject must be excluded from participating in the study if the subject:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the investigator or designee.
3. History of any illness that, in the opinion of the investigator or designee, might confound the 
results of the study or poses an additional risk to the subject by their participation in the study.
4. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dosing.
5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related 
compounds.
6. History or presence of lung disease and current lung infection.
7. Positive urine drug or alcohol results at screening or first check-in.
8. Positive results at screening for HIV, HBsAg, or HCV.
9. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
11. QTcF interval is >460 msec or ECG findings are deemed abnormal with clinical significance 
by the investigator or designee at screening.
12. Estimated creatinine clearance <80 mL/min at screening.
13. Has tattoo(s) or scarring at or near the site of IV infusion or any other condition which may 
interfere with infusion site examination, in the opinion of the investigator.
14. Subject has infrequent bowel movements (less than approximately once per day) within 
30 days prior to first dosing.
15. Recent history of abnormal bowel movements, such as diarrhea, loose stools, or constipation, 
within 2 weeks of first dosing.
16. Has received radiolabeled substances or has been exposed to radiation sources within 
12 months of first dosing or is likely to receive radiation exposure or radioisotopes within 
12 months of first dosing such that participation in this study would increase their total 
exposure beyond the recommended levels considered safe (ie, weighted annual limit 
recommended by the ICRP of 3000 mrem).
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17. Unable to refrain from or anticipates the use of:

Any drug, including prescription and non-prescription medications, herbal remedies, or 
vitamin supplements within 14 days prior to the first dosing and throughout the study. 
Thyroid hormone replacement medication may be permitted if the subject has been on the 
same stable dose for the immediate 3 months prior to first study drug administration. 
Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, only 
after first dosing, if necessary to treat AEs. Milk of Magnesia (ie, magnesium hydroxide) 
(≤60 mL per day) may be administered approximately on Day 4 (Period 1) or Day 8 
(Period 2) to ensure defecation, with agreement between the study investigator and Takeda 
physician. Additional administration of milk of Magnesia may be needed on other days at 
discretion of the study investigator and Takeda Physician.

Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, including 
St. John’s Wort, within 28 days prior to the first dosing and throughout the study. 
Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of 
PK/pharmacodynamics interaction with study drug.
18. Has been on a diet incompatible with the on-study diet, in the opinion of the investigator or 
designee, within the 30 days prior to the first dosing and throughout the study.
19. Donation of blood or significant blood loss within 56 days prior to the first dosing.
20. Plasma donation within 7 days prior to the first dosing.
21. Participation in another clinical study within 30 days prior to the first dosing. The 30-day 
window will be derived from the date of the last blood collection or dosing, whichever is later, 
in the previous study to Day 1 of Period 1 of the current study.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.1 and in Section 9.1.2.2. All 
medications taken by subjects during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the investigator or designee and/or the Sponsor 
for reasons related to subject safety.
For this study, the collection for blood, urine, and feces for total radioactivity, plasma 
concentrations, and metabolite profiling for TAK-788 are the critical parameter and need to be 
collected as close to the exact time point as possible. All other procedures should be completed as 
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close to the prescribed/scheduled time as possible, but can be performed prior or after the 
prescribed/scheduled time.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence 
over all routine scheduled procedures.
9.2.1
Full Physical Exam
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Symptom-driven physical examinations may be performed at other times, if deemed 
necessary by the investigator or designee.
9.2.2
Height and Weight
Body height (cm) and weight (kg) will be reported as outlined in the Schedule of Study Procedures 
(Section 3.0).
9.2.3
BMI
BMI will be calculated based on the height and weight measured at screening.
9.2.4
Vital Signs
Single measurements of body temperature, respiratory rate, blood pressure, and heart rate, will be 
measured as outlined in the Schedule of Study Procedures (Section 3.0). Additional vital signs 
may be taken at any other times, if deemed necessary.
Blood pressure and heart rate measurements will be performed with subjects in a seated position, 
except when they are supine or semi-reclined because of study procedures and/or AEs (eg, nausea, 
dizziness) or if deemed necessary by the investigator or designee.
Blood pressure and heart rate will be measured within 24 hours prior to Day 1 dosing of each 
period for the predose time point. When scheduled postdose, vital signs will be performed within 
approximately 15 minutes of the scheduled time point. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the 
investigator or designee.
ECGs will be performed with subjects in a supine position. All ECG tracings will be reviewed by 
the investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of each period for the predose time 
point. When scheduled postdose, ECGs will be performed within approximately 20 minutes of the 
scheduled time point.
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9.2.6
Pulmonary Function Test
9.2.6.1
Spirometry
Spirometry measures will be taken at screening (within 7 days prior to first dosing) using a 
standard calibrated spirometer to determine the parameters detailed below. 

FEV1 (forced expiratory volume);

FVC (forced vital capacity);

FEV1/FVC.
9.2.7
Study Drug Administration
TAK-788 oral capsule and [14C]-TAK-788 oral and IV solution will be provided as described in 
Section 8.1.
Subjects will be instructed not to crush, split, or chew the TAK-788 capsules.
Treatments A and B are described as: 
Treatment A: 160 mg TAK-788 in capsules administered at Hour 0 on Day 1 followed by 50 µg 
(~2 μCi) [14C]-TAK-788 IV solution administered at Hour 3.75 for 15 minutes.
Treatment B: 160 mg (~100 μCi) [14C]-TAK-788 oral solution administered at Hour 0 on Day 1.
The oral doses of TAK-788 and [14C]-TAK-788 will be administered following an overnight fast 
with approximately 240 mL of water. The exact clock time of oral dosing will be recorded. 
The IV dose will be administered over approximately 15 minutes. The start and end time of the IV 
infusion will be recorded.
The pharmacy at the CRU will provide the IV dose ready for the 15 minute infusion, and the oral 
capsules dose in individual unit dose containers and the oral solution dose in a glass bottle for each 
subject.
9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study formulations 
and/or procedures as described in Section 10.0.
9.2.9
Laboratory Procedures and Assessments
All tests listed below will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the investigator or designee.
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9.2.9.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total and differential leukocyte count
Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of dropouts 
or rechecks, subjects may not have fasted for 8 hours prior to the serum chemistry sample is taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Amylase
Albumin
Lipase
Sodium
Blood Urea Nitrogen
Potassium
Bilirubin (total and direct)
Chloride
Alkaline phosphatase
Glucose 
Aspartate aminotransferase
Creatinine *
Alanine aminotransferase (ALT)
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
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Other 
HIV test
Urine drug screen
–
Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)
–
Amphetamines
–
Barbiturates
–
Benzodiazepines
–
Cocaine
–
Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
Urine alcohol screen
9.3
PK Samples
Primary specimen collection parameters are provided in Table 9.a. Instructions for plasma, urine, 
fecal samples processing and handling will be provided in a separate document(s). Predose plasma 
samples from in Period 2 will also be used as Day 10 samples for Period 1.
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Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary 
Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Period 1
Plasma for TAK-788 PK and 
metabolites
Plasma
PK analysis
Mandatory
Plasma for total radioactivity, 
[14C]-TAK-788 PK and 
metabolites
Plasma
Total radioactivity and PK 
analysis
Mandatory
Blood for total radioactivity 
Blood
Total radioactivity
Mandatory
Blood for TAK-788 and 
metabolites PK
Blood
PK analysis
Mandatory
Plasma for total radioactivity 
Plasma
Total radioactivity
Mandatory
Plasma for TAK-788 and 
metabolites PK
Plasma
PK analysis
Mandatory
Plasma for TAK-788 Metabolic 
Profiling
Plasma
Metabolic profiling
Mandatory
Urine for TAK-788 PK
Urine
PK analysis
Mandatory
Urine for TAK-788 Metabolic 
Profiling
Urine
Metabolic profiling
Mandatory
Feces for total radioactivity
Feces
Total radioactivity
Mandatory
Feces for TAK-788 Metabolic 
Profiling
Feces
Metabolic profiling
Mandatory
9.3.1
PK Measurements 
9.3.1.1
Plasma and Whole Blood PK Measurements
PK parameters for whole blood and plasma radioactivity concentration equivalents (Period 2) and 
for plasma TAK-788 concentrations and metabolites (Periods 1 and 2) will be calculated as 
follows, as appropriate, following oral administration:
AUClast:
The area under the concentration versus time curve, from time 0 to the last 
observed non-zero concentration, as calculated by the linear trapezoidal 
method.
AUCt:
Area under the concentration versus time curve, from 0 to the time of the last 
common time point “t” at which plasma total radioactivity and plasma 
TAK-788 are quantifiable for all subjects (plasma only).
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AUC∞:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUC∞is calculated as AUCt plus the ratio of the last 
measurable blood concentration to the elimination rate constant.
AUC%extrap:
Percent of AUC∞ extrapolated, represented as (1 - AUCt/AUC∞)*100.
Cmax:
Maximum observed concentration.
tmax:
Time to reach Cmax. If the maximum value occurs at more than one time 
point, tmax is defined as the first time point with this value.
t½:
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel.
Where Kel is the apparent first-order terminal elimination rate constant 
calculated from a semi-log plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares regression 
analysis using the maximum number of points in the terminal log-linear 
phase (eg, three or more non-zero plasma concentrations).
PK parameters for plasma concentrations of [14C]-TAK-788 and metabolites following IV 
infusion (Period 1) will be calculated as follows, as appropriate:
AUClast:
The area under the concentration versus time curve, from time 0 to the 
last observed non-zero concentration, as calculated by the linear 
trapezoidal method.
AUCt:
Area under the concentration versus time curve, from 0 to the time of the 
last common time point “t” at which plasma total radioactivity and 
plasma TAK-788 are quantifiable for all subjects (plasma only).
AUC∞:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUC∞is calculated as AUCt plus the ratio of the 
last measurable blood concentration to the elimination rate constant.
AUC%extrap:
Percent of AUC∞ extrapolated, represented as (1 - AUCt/AUC∞)*100.
Ceoi:
Concentration at the end of infusion.
t½:
Apparent first-order terminal elimination half-life will be calculated as 
0.693/Kel.
Where Kel is the apparent first-order terminal elimination rate constant 
calculated from a semi-log plot of the plasma concentration versus time 
curve. The parameter will be calculated by linear least-squares 
regression analysis using the maximum number of points in the terminal 
log-linear phase (eg, three or more non-zero plasma concentrations).
No value for Kel, AUC∞, AUC%extrap, or t½ will be reported for cases that do not exhibit a terminal 
log-linear phase in the concentration versus time profile. 
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No PK parameters will be calculated for subjects with detectable concentrations or radioactivity 
concentration equivalents at 2 or fewer consecutive time points. 
Individual and mean plasma concentration- or radioactivity concentration equivalent-time curves 
(both linear and log-linear) will be included in the final report.
The absolute bioavailability parameters for TAK-788 (Period 1) will be calculated as follows:
F:
Absolute bioavailability, calculated for plasma TAK-788.
%F:
Percent absolute bioavailability, calculated for plasma TAK-788 as 
[Dose (IV) x AUC∞(oral)] / [Dose (oral) x AUC∞(IV)] x 100.
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9.3.1.4
Additional PK Measurements
9.3.2
Biomarker Measurements 
NA
9.3.3
PGx Measurements 
NA
9.3.4
Confinement
In Period 1, subjects will be housed on Day -1, at the time indicated by the CRU until at least after 
the 96-hour blood draw and/or study procedures and until a discharge criterion is met or up to 
Day 8. As per site preference, subjects may be confined throughout the washout period.
In Period 2, subjects will be housed on Day -1, at the time indicated by the CRU, until discharge 
criteria are met, or a maximum of 10 days (ie, Day 11). 
All urine and fecal collections will be analyzed for radioactivity levels to determine if the 
discharge criteria are met. Subjects will be eligible for discharge if they meet either of the 
following discharge criteria from Day 5 (Period 1) and prior to Day 11 (Period 2):
!
≥80% of the total dose of radioactivity administered has been recovered in the urine and feces; 
or 
!
There is ≤1% of the total administered radioactivity in each of two consecutive 24-hour 
intervals where both a urine and fecal sample is provided.
It is expected that the majority (≥90%) of the administered radioactivity will be recovered within 
96 hours post TAK-788 dose.
Release of subjects who do not meet criteria discharge criterion by Day 7 (Period 1) and/or Day 11 
(Period 2) will be reviewed on a case-by-case basis. 
Since up to an approximate 24-hour time lag is anticipated for radioactivity counting of samples, 
actual subject release from the CRU may occur 1 day after discharge criteria are met.
At all times, a subject may be required to remain at the CRU for longer at the discretion of the 
investigator or designee. 
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The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days 
after the last study drug administration to determine if any adverse events have occurred since the 
last study visit.
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10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with the treatment.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or 
not it is considered related to the drug.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as 
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded 
appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless 
related to a study procedure. However, if the subject experiences a worsening or complication 
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of such a concurrent medical history condition, the worsening or complication should be 
recorded appropriately as an AE (worsening or complication occurs after informed consent is 
signed). Investigators should ensure that the event term recorded captures the change in the 
condition (eg, “worsening of…”).

If a subject has a pre-existing episodic condition (eg, asthma, epilepsy), any occurrence of an 
episode should only be captured as an AE if the episodes become more frequent, serious, or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change from Baseline in the condition (eg, “worsening of…”).

If a subject has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent to 
that which would be expected. Again, investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Worsening of AEs:

If the subject experiences a worsening or complication of an AE after the first administration of 
study medication or after any change in study medication, the worsening or complication 
should be recorded as a new AE. Investigators should ensure that the AE term recorded 
captures the change in the condition (eg, “worsening of…”).
Changes in severity of AEs:

If the subject experiences a change in the severity of an AE that is not associated with a change 
in study medication, the event should be captured once with the maximum severity recorded.
Preplanned surgeries or procedures:

Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is performed 
early (eg, as an emergency) due to a worsening of the pre-existing condition, the worsening of 
the condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.
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
All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the CRF, in order to capture this important safety information consistently in the 
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 10.2.7.

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.
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1.1 and 10.2.7.3).
10.1.2 Special Interest AEs
There are no AEs of Special Interest for TAK-788.
10.2
AE Procedures
10.2.1 Assigning Severity of AEs
In this study, intensity for each AE, including any laboratory abnormality, will be determined 
using the National Cancer Institute, Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 5.0, dated 27 November 2017 [CTCAE 2017]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4) because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
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medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on subject/event outcome or action criteria described above and is usually associated with 
events that pose a threat to a subject’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to <2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations.
10.2.2 Assigning Causality of AEs
The relationship of each AE to study medication(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which a causal 
relationship is at least a reasonable possibility, ie, the relationship cannot be 
ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be 
responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant medications and concurrent 
treatments.
10.2.3 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.2.4 End Date 
The end date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.2.5 Action Taken With Study Treatment

Drug withdrawn – a study medication is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study medication.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the subject died, dosing with study medication had not yet 
started or dosing with study medication was already stopped before the onset of the AE.

Dose reduced – the dose was reduced due to the particular AE.

Dose increased – the dose was increased due to the particular AE.
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
Drug interrupted – the dose was interrupted due to the particular AE.
10.2.6 Outcome 

Recovered/resolved – subject returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the subject died from a cause other 
than the particular AE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/symptoms or laboratory value on the last day of the observed 
study period has become worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved.”

Recovered/ Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis).

Fatal – an AE that is considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2.7 Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal LFTs
10.2.7.1 Collection Period
Collection of AEs (ie, AEs, SAEs, Special Interest AEs, and Abnormal liver function tests [LFTs]) 
will commence at the time the subject signs the informed consent. Routine collection of AEs will 
continue until the follow-up phone call on Day 31 (±2 days), approximately 30 days after the last 
dose of investigational product. For subjects who discontinue prior to the administration of study 
medication, AEs will be followed until the subject discontinues study participation. 
10.2.7.2 Reporting AEs
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing an 
SAE prior to the first exposure to investigational product must be monitored until the symptoms 
subside and any clinically relevant changes in laboratory values have returned to Baseline or there
is a satisfactory explanation for the change. Nonserious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
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All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Action taken with trial drug.

Outcome of event.

Seriousness.
10.2.7.3 Reporting SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
procedure outlined below:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study medication(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 14.1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the Sponsor if considered related to study participation.
Reporting of SAEs that begin before first administration of investigational product will follow the 
same procedure for SAEs occurring on treatment.
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SAE Follow-Up
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report.
10.2.7.4 Reporting Special Interest AEs 
NA
10.2.7.5 Reporting of Abnormal Liver Test Results
If a subject has elevated ALT ≥3x upper limit of normal (ULN) with concurrent elevated total 
bilirubin >2× ULN or elevated international normalized ratio (INR) >1.5, contact the sponsor’s 
medical monitor within 24 hours. 
For any subject with ALT ≥3x ULN and total bilirubin >2x ULN or INR >1.5x ULN for which an 
alternative etiology has not been found, report the event as an SAE (Section 10.2.7.3) and contact 
the sponsor immediately. 
10.2.8 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and Institutional 
Review Boards (IRBs) or Independent Ethics Committees (IECs), as applicable, in accordance 
with national regulations in the countries where the study is conducted. Relative to the first 
awareness of the event by/or further provision to the Sponsor or Sponsor’s designee, SUSARs will 
be submitted within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The Sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal products administration or in the overall conduct of the trial. The 
investigational site also will forward a copy of all expedited reports to his or her IRB or IEC in 
accordance with national regulations.
10.2.9 Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses provided below.
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A medication error is a preventable event that involves an identifiable patient and leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Product
Call Center
Phone Number
Email
Fax
TAK-788
Dohmen Life Science 
Services, or DLSS 
(formerly known as 
MedComm)
1-844-662-8532 
Non-toll-free number: 
1-510-740-1273 
GlobalOncologyMedinfo@
takeda.com 
1-800-881-6092
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a SAP. The SAP will be prepared by Celerion and agreed upon with the 
Sponsor. This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoints definition and/or its analysis will also be reflected in a 
protocol amendment. Additional statistical analyses other than those described in this section may 
be performed if deemed appropriate.
11.1.1 Analysis Sets
11.1.1.1 Safety Set
All subjects who received at least one dose of the study drug will be included in the safety 
evaluations.
11.1.1.2 PK Set
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) will 
be included in the statistical analyses.
11.1.1.3 PD Set
NA
11.1.2 Analysis of Demography and Other Baseline Characteristics
Continuous demographic data (ie, age, weight, height, and BMI) will be listed and summarized 
using appropriate summary statistics. Categorical demographic data (ie, gender, race, and 
ethnicity) will also be listed and tabulated.
11.1.3 PK Analysis
Descriptive statistics will be provided for the total radioactivity (whole blood, plasma, 
 
and if applicable, emesis), TAK-788 and metabolites concentrations and PK parameters (blood, 
plasma and urine), [14C]-TAK-788 plasma radioactivity concentrations equivalent, and the 
metabolic profile of TAK-788, using appropriate summary statistics to be fully specified in the 
SAP.
PK parameters for whole blood and plasma concentrations and total radioactivity will be 
calculated as described in Section 9.3.1.1 and for 
, as described in Sections 9.3.1.2
and 9.3.1.3, respectively. 
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Absolute bioavailability of TAK-788 (Period 1) will be estimated using a ninety percent (90%) CI 
constructed for the difference in LS mean on the log scale for dose normalized AUC∞between a 
single oral dose and the IV microdose. Exponentiating the log-scale 90% CI will provide a 90% CI 
for the dose normalized AUC∞geometric mean ratio (TAK-788 administered as oral dose / 
[14C]-TAK-788 administered as IV microdose). The AUClast, AUCt, and Cmax, will be analyzed in 
a similar fashion.
11.1.4 Analysis of Mass Balance
In Period 2, mass balance will be calculated as a sum of the percent of the total radioactivity 
recovered in urine and feces relative to the administered radioactivity dose minus any radioactivity 
lost due to emesis (if any occurred).
11.1.5 Whole Blood to Plasma Partitioning Ratio 
In Period 2, the change over time in percentage of [14C]-radioactivity, TAK-788, and metabolites
in whole blood relative to plasma will be estimated (eg, whole blood:plasma partitioning ratio). 
11.1.6 Metabolite Profiling
In Period 2, TAK-788 metabolite profiling will be performed in plasma, urine, and feces 
containing sufficient amounts of radioactivity. The percent of dose represented by each of the 
metabolites, if any, will be calculated using the radioactivity concentration equivalent data 
combined with the metabolite profiling data. The percentage of each identified metabolite, if any, 
to total radioactivity in the plasma will be estimated based on plasma metabolite profiling data.
11.1.7 PD Analysis 
NA
11.1.8 Safety Analysis
All safety data will be populated in the individual CRFs. 
Dosing dates and times will be listed by subject.
Quantitative safety data as well as the difference to baseline, when appropriate, will be 
summarized using the appropriate descriptive statistics.
11.1.8.1 AEs
AEs will be coded using the most current version of Medical Dictionary for Regulatory Activities 
(MedDRA®) available at Celerion and summarized by treatment for the number of subjects 
reporting the TEAE and the number of TEAEs reported. A by-subject AE data listing including 
verbatim term, coded term, treatment, severity, and relationship to treatment will be provided.
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11.1.8.2 Clinical Laboratory Evaluation
Clinical laboratory results will be summarized by treatment and point of time of collection and a 
shift table describing out of normal range shifts will be provided.
11.1.8.3 Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
11.1.8.4 Other Safety Parameters
Physical examination findings will be presented in the data listings.
ECGs will be summarized by treatment and point of time of collection.
Medical history, and concurrent conditions will be coded using the MedDRA® and concomitant 
medications will be coded using the World Health Organization drug and will be listed by subject.
11.2
Interim Analysis and Criteria for Early Termination
NA
11.3
Determination of Sample Size
The sample size of 6 male healthy subjects was selected without statistical considerations and is 
deemed adequate to meet the study objectives. In addition, this sample size is limited based on 
clinical considerations for this type of study and in order to limit exposure to radioactivity.
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12.0
QUALITY CONTROL AND QUALITY ASSURANCE
12.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the Sponsor or its 
designee (Clinical Research Organization) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the Sponsor or the 
Sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, trial drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to trial subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. 
12.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency, the Pharmaceuticals and Medical Devices Agency of Japan). If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The investigator guarantees access for quality assurance auditors to all study 
documents as described in Section 12.1.
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13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline 
for Good Clinical Practice (GCP). Each investigator will conduct the study according to applicable 
local or regional regulatory requirements and align his or her conduct in accordance with the 
“Responsibilities of the Investigator” that are listed in Appendix A. The principles of Helsinki are 
addressed through the protocol and through appendices containing requirements for informed 
consent and investigator responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those American sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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13.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and, if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the Sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study, and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of 
consent and prior to the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and prior to subject entering 
into the study; however, the Sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
13.3
Subject Confidentiality
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 13.2).
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF).
13.4
Publication, Disclosure, and Clinical Trial Registration Policy
13.4.1 Publication and Disclosure
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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13.4.2 Clinical Trial Registration 
In order to ensure that information on clinical 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 investigator’s city, state (for American investigators), country, and 
recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
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14.0
ADMINISTRATIVE AND REFERENCE INFORMATION
14.1
Administrative Information
14.1.1 Study Contact Information 
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
SAE Reporting Contact Information
Cognizant
US and Canada
Toll-free fax #: 1-800-963-6290
E-mail: takedaoncocases@cognizant.com
Please refer to Safety Management Plan.
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14.1.2 Investigator Agreement
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the Sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation, E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.8 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3 Study-Related Responsibilities
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4 Protocol Amendment 01 Summary of Changes
Rationale for Amendment No. 01
The purpose of this amendment is to to extend the period of feces collection in Period 1. Based on 
the extent of excreted radioactivity up to Day 5 of Period 1, excretion in urine is below level of 
quantification but excretion in feces is still ongoing for the majority of subjects. The sampling 
period for drug excretion in feces for subjects who do not meet the release criteria is therefore 
extended from up to Day 7 to up to Day 8. For specific descriptions of text changes and where the 
changes are located, see Appendix E.
14.1.5 List of Abbreviations
μCi
Microcurie
µg
Microgram
%Dose(FE)
Percent of administered radioactive dose excreted in feces within a given collection 
interval
%Dose(UR)
Percent of administered radioactive dose excreted in urine within a given collection 
interval
%F
Percent absolute oral bioavailability
ABA
Absolute bioavailability
ADME
Absorption, distribution, metabolism, and elimination
AE
Adverse event
Aet1-t2
Amount of unchanged drug excreted in the urine collection interval from t1 to t2.
Ae(FE)
Amount of total radioactivity excreted in feces within a given collection interval
Ae(UR)
Amount of total radioactivity excreted in urine within a given collection interval
ALT
Alanine aminotransferase
AUC
Area under the concentration-time curve
AUC%extrap
Percent of AUC0-inf extrapolated 
AUClast
Area under the concentration-time curve, from time 0 to the last observed non-zero 
concentration
AUCt
Area under the concentration versus time curve, from 0 to the time of the last common 
time point “t” at which plasma total radioactivity and plasma TAK-788 are quantifiable 
for all subjects
AUC∞
Area under the concentration-time curve, from time 0 extrapolated to infinity
BMI
Body mass index
bpm
Beats per minute
[14C]
Carbon-14; radiocarbon
Ceoi
Concentration at end of infusion
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CFR
Code of Federal Regulations
CI
Confidence interval
CLR
Renal clearance
cm
Centimeter
Cmax
Maximum observed concentration 
CO
Carbon monoxide
CRF
Case report form
CRU
Clinical Research Unit
CYP
Cytochrome P450
ECG
Electrocardiogram
EGFR
Epidermal growth factor receptor
F
Bioavailability
FVC
Forced vital capacity
FEV
Forced expiratory volume
g
Gram
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
He
Helium
HER2
Human epidermal growth factor 2
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICRP
Commission on Radiological Protection
IEC
Independent Ethics Committee
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
Kel
Apparent first-order terminal elimination rate constant
kg
Kilogram
LFT
Liver function tests
LS
Least-squares
m2
Meters squared
MBq
Megabecquerel
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
mrem
Millirem
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msec
Millisecond
mSv
Millisievert
MTD
Maximum tolerated dose
NA
Not applicable
nCi
Nanocurie
NSCLC
Non–small cell lung cancer
oz
Ounce
P-gp
P-glycoprotein
PFT
Pulmonary function tests
PK
Pharmacokinetic(s)
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SRD
Single rising dose
SUSARs
Suspected unexpected serious adverse reactions
t½
Apparent first-order terminal elimination half-life
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitors
tmax
Time to reach maximum observed concentration [Cmax]
TRA
Total radioactivity
ULN
Upper limit of normal
US
United States
USA
United States of America
WT
Wild type
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15.0
DATA HANDLING AND RECORD KEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
15.1
CRFs
The Sponsor or its designee will supply investigative sites with access to CRFs. The Sponsor or its 
designee will train appropriate site staff in the use of the CRF. These forms are used to transmit the 
information collected in the performance of this study to the Sponsor and regulatory authorities. 
CRFs must be completed in English. 
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the reason 
for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the data 
on the CRFs should be made by the investigator with use of change and modification records of the 
CRFs. The principal investigator must review the data change for completeness and accuracy, and 
must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The investigator agrees to keep the records stipulated in Section 15.0 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
copy of CRFs, including the audit trail, and detailed records of drug disposition to enable 
evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
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(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
TAK-788. Millennium Pharmaceuticals, Inc. Global Investigator Brochure. Edition 2.0, 
January 2018.
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department of 
Health and Human Services National Cancer Institute. 27 Nov 2017.
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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigator s by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
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10. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the Sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject, as 
applicable:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
legally acceptable representative may discontinue participation at any time without penalty or 
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.
22. A statement that results of PGx analysis will not be disclosed to an individual, unless 
prevailing laws require the Sponsor to do so.
23. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
24. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study medication(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
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25. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 94 after the last 
dose of study drug. 
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 medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
Pr


TAK-788
Study ID TAK-788-1002
Page 76 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
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 94 days after last 
dose of study drug, male subjects who are sexually active with a female partner of childbearing 
potential* must use barrier contraception (eg, condom with spermicidal cream or jelly). In 
addition, they must be advised not to donate sperm throughout the duration of the study, and for 
94 days after last dose of study drug. 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. Total abstinence (no sexual intercourse) may be 
considered an acceptable method of birth control if it agrees with your preferred and usual 
lifestyle.
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.
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 excluded, the 
only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomised partner has received medical assessment of the 
surgical success.
–
True sexual abstinence, only if this is in line with the preferred and usual lifestyle of the 
subject. True abstinence is defined as refraining from heterosexual intercourse during 
the entire period of the study, from 1 month prior to the first dose until 94 days after last 
dose.
Pr


TAK-788
Study ID TAK-788-1002
Page 77 of 82
Protocol Incorporating Amendment No.1 
27 February 2019

Hormonal Methods: 
–
Combined (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;

Oral.

Intravaginal (eg, ring).

transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
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 shorter till she has been 
on contraceptive for 3 months;

oral.

Injectable.

Implantable.
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.
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.
4. During the course of the study, regular {serum/urine} human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for women of childbearing potential and all subjects 
(male and female) will receive continued guidance with respect to the avoidance of pregnancy 
and sperm donation as part of the study procedures. Such guidance should include a reminder 
of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
Pr


TAK-788
Study ID TAK-788-1002
Page 78 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
c) assessment of subject compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
5. In addition to a negative {serum/urine} hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses), a negative {serum/urine} hCG pregnancy test prior to receiving any dose of 
study medication. In addition, subjects must also have a negative {serum/urine} hCG 
pregnancy test prior to receiving first dose of investigational drug as close as possible and prior 
to first dose of investigational drug, preferably on the same day.
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? 
–
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Women will not be included in this study.
If a female partner of a male subject becomes pregnant during the male subject’s participation in 
this study, the sponsor must be contacted immediately by faxing a completed pregnancy form to 
the Takeda Global Pharmacovigilance department or designee (see Section 14.1.1). 
Any pregnancies in the partner of a male subject during the study or for 94 days after the last dose, 
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).
Pr


TAK-788
Study ID TAK-788-1002
Page 79 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
All pregnancies of female partners of male subjects on active study drug (including comparator, if 
applicable) 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.
Pr


TAK-788
Study ID TAK-788-1002
Page 80 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
Appendix E
Detailed Description of Amendments to Text
Change 1. Update of last day of confinement and feces sample collection in Period 1 for subjects 
who do not meet release criteria by Day 5, from Day 7 to Day 8. 
The change occurs in Section 1.0 – Study Summary, under Study Design (first sentence in the third 
paragraph), and in Section 6.1 – Study Design (first sentence in the third paragraph).
Initial 
wording:
In Period 1, subjects will be confined in the clinical research unit (CRU) for at least 
5 days (until after the last PK sample and morning urine and fecal sample [when 
passed] are collected) and until a discharge criterion is met or up to Day 7. 
Amended 
or new 
wording:
In Period 1, subjects will be confined in the clinical research unit (CRU) for at least 
5 days (until after the last PK sample and morning urine and fecal sample [when 
passed] are collected) and until a discharge criterion is met or up to Day 8. 
Section 2.0 – Study Schematics, under Treatment Period 1 (column header for Study Days and 
footnote ‘b’),
Initial 
wording:
Screening
Treatment Period 1
Day -1
Day 1
Days 2 - 7
b Subjects will be confined in the clinic for at least 5 days (until after the last PK 
sample and morning urine and fecal sample [when passed] are collected) and until a 
discharge criterion is met (i.e., 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity 
in the urine and feces combined has declined to ≤1% of the total administered 
radioactivity per day for at least 2 consecutive intervals where both a urine and fecal 
sample is collected) or up to Day 7.
Amended 
or new 
wording:
Screening
Treatment Period 1
Day -1
Day 1
Days 2 - 8
b Subjects will be confined in the clinic for at least 5 days (until after the last PK 
sample and morning urine and fecal sample [when passed] are collected) and until a 
discharge criterion is met (ie, 80% or greater of the total dose of radioactivity 
administered is recovered in urine and fecal samples or the excretion of radioactivity 
in the urine and feces combined has declined to ≤1% of the total administered 
radioactivity per day for at least 2 consecutive intervals where both a urine and fecal 
sample is collected) or up to Day 8.
Pr


TAK-788
Study ID TAK-788-1002
Page 81 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
Section 3.0 – Schedule of Study Procedures (column header for Study Days 6-7 and footnote ’e’) 
Initial 
wording:
Study Procedures a
Days →
S b
Study Days in Period 1 c
-1 (C-Id)
1
2
3
4
5
6-7 e
e Subjects who do not meet a discharge criterion (i.e., 80% or greater of the total 
dose of radioactivity administered is recovered in urine and fecal samples or the 
excretion of radioactivity in the urine and feces combined has declined to ≤1% of 
the total administered radioactivity per day for at least 2 consecutive intervals where 
both a urine and fecal sample are collected) by Day 5, will remain confined and 
undergo study procedures until a discharge criterion is met or up to Day 7.
Amended 
or new 
wording:
Study Procedures a
Days →
S b
Study Days in Period 1 c
-1 (C-Id)
1
2
3
4
5
6-8 e
e Subjects who do not meet a discharge criterion (ie, 80% or greater of the total dose 
of radioactivity administered is recovered in urine and fecal samples or the excretion 
of radioactivity in the urine and feces combined has declined to ≤1% of the total 
administered radioactivity per day for at least 2 consecutive intervals where both a 
urine and fecal sample are collected) by Day 5, will remain confined and undergo 
study procedures until a discharge criterion is met or up to Day 8.
Section 3.0 – Schedule of Study Procedures, under Table 3.b - Urine and Fecal Sampling Schedule 
(Period 1 – ABA Study Period), a row was added for feces collection on study Days 7 to 8.
Amended 
or new 
wording:
Added row:
Study Day
Time Interval (hours)
(Relative to Oral Dosing)
Urine Sample 
Collection
Feces Sample 
Collection
Matrix
Urine a
Feces b
(…)
Day 7 to 8
144-168 hours 
X g
Section 3.0 – Schedule of Study Procedures, under Table 3.b - Urine and Fecal Sampling Schedule 
(Period 1 – ABA Study Period) (footnote ‘g’)
Initial 
wording:
For subjects who do not meet a discharge criterion by Day 5, samples will continue 
to be collected in 24-hour intervals until radioactivity in urine and feces combined is 
≤1% of the total administered radioactivity per day for at least 2 consecutive 
intervals where both a urine and fecal sample are collected, the excretion of 
radioactivity is ≥80% of the administered radioactive dose, or up to Day 7.
Pr


TAK-788
Study ID TAK-788-1002
Page 82 of 82
Protocol Incorporating Amendment No.1 
27 February 2019
Amended 
or new 
wording:
For subjects who do not meet a discharge criterion by Day 5, samples will continue 
to be collected in 24-hour intervals until radioactivity in urine and feces combined is 
≤1% of the total administered radioactivity per day for at least 2 consecutive 
intervals where both a urine and fecal sample are collected, the excretion of 
radioactivity is ≥80% of the administered radioactive dose, or up to Day 8.
Section 9.0 – Confinement (first paragraph)
Initial 
wording:
In Period 1, subjects will be housed on Day -1, at the time indicated by the CRU
until at least after the 96-hour blood draw and/or study procedures and until a 
discharge criterion is met or up to Day 7. As per site preference, subjects may be 
confined throughout the washout period.
Amended 
or new 
wording:
In Period 1, subjects will be housed on Day -1, at the time indicated by the CRU
until at least after the 96-hour blood draw and/or study procedures and until a 
discharge criterion is met or up to Day 8. As per site preference, subjects may be 
confined throughout the washout period.
Rationale for Change:
Based on the extent of excreted radioactivity up to Day 5, excretion in urine is below level of 
quantification but excretion in feces is still ongoing for the majority of subjects. The sampling 
period for drug excretion in feces for subjects who do not meet the release criteria is therefore 
extended from up to Day 7 to up to Day 8.
Change 2. Clarification of the duration of blood sample collection for TRA and PK in Period 1. 
The change occurs in Section 3.0 - Schedule of Study Procedures, under Table 3.a - Blood 
Collection Schedule after the Oral and Intravenous Doses of TAK-788 (Period 1 - ABA Study 
Period), footnote d.
Initial 
wording:
For subjects who do not meet the discharge criteria by Day 5, samples will continue 
to be collected in 24-hour intervals until radioactivity in urine and feces combined is 
≤1% of the total administered radioactivity per day for at least 2 consecutive 
intervals where both a urine and fecal sample are collected, the excretion of 
radioactivity is ≥80% of the administered radioactive dose, or up to Day 7.
Amended 
or new 
wording:
For subjects who do not meet the discharge criteria by Day 5, blood samples will 
continue to be collected in 24-hour intervals until radioactivity in urine and feces 
combined is ≤1% of the total administered radioactivity per day for at least 
2 consecutive intervals where both a urine and fecal sample are collected, the 
excretion of radioactivity is ≥80% of the administered radioactive dose, or up to 
Day 7.
Rationale for Change:
Clarification was added to make sure blood samples are not collected on Day 8 following the 
extension of fecal sample collection from Day 7 to Day 8.
Pr


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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1 Study to Assess Absolute Bioavailability of TAK-788 and to Characterize Mass 
Balance, Pharmacokinetics, Metabolism, and Excretion of [14C]-TAK-788 
in Male Healthy Subjects 
NCT Number: NCT03811834
SAP Approve Date: 08 August 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


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PPD


TAK-788-1002
Celerion Study Number CA25518
Page 3 of 25
Statistical Analysis Plan Final
08 August 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................4
4.0
OBJECTIVES .................................................................................................................7
4.1
Hypothesis.................................................................................................................7
4.2
Primary Objectives ....................................................................................................7
4.3
Secondary Objective..................................................................................................7
4.4
Exploratory Objectives ..............................................................................................7
4.5
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Study Definitions ...............................................................................................14
7.1.2
Definition of Study Days....................................................................................14
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................16
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................16
7.9.1
Pharmacokinetic Analysis ..................................................................................16
7.9.2
Pharmacodynamic Analysis ...............................................................................20
7.10
Other Outcomes.......................................................................................................20
7.11
Safety Analysis........................................................................................................20
7.11.1 Adverse Events ..................................................................................................21
7.11.2 Clinical Laboratory Evaluations .........................................................................21
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TAK-788-1002
Celerion Study Number CA25518
Page 4 of 25
Statistical Analysis Plan Final
08 August 2019
7.11.3 Vital Signs .........................................................................................................22
7.11.4 12-Lead ECGs ...................................................................................................23
7.11.5 Physical Exams..................................................................................................23
7.11.6 Overdose............................................................................................................23
7.12
Interim Analysis ......................................................................................................23
7.13
Preliminary Analysis................................................................................................23
7.14
Changes in the Statistical Analysis Plan...................................................................24
8.0
REFERENCES..............................................................................................................25
LIST OF IN-TEXT TABLES
Table 4.a
Study Schematic ..................................................................................................9
Table 4.b
Planned TAK-788 and [14C]-TAK-788 Doses ......................................................9
Table 7.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-788 
(Period 1 - ABA Study Period)...........................................................................16
Table 7.b
Urine and Fecal Sampling Schedule (Period 1 – ABA Study Period)..................17
Table 7.c
Blood Collection Schedule (Period 2 - ADME Study Period).............................18
Table 7.d
Urine and Fecal Sampling Schedule (Period 2 - ADME Study Period) ...............19
Table 7.e
Collection of Vital Signs....................................................................................22
Table 7.f
Collection of Electrocardiograms .......................................................................23
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TAK-788-1002
Celerion Study Number CA25518
Page 5 of 25
Statistical Analysis Plan Final
08 August 2019
3.0
LIST OF ABBREVIATIONS
ABA
absolute bioavailability; F (often expressed as a percent, ie, %F)
ADME
absorption, distribution, metabolism, and elimination
Ae
amount of drug eliminated
AE
adverse event
AUC
area under the curve
AUC∞
area under the concentration-time curve from time 0 extrapolated to 
infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
AUCt
area under the concentration-time curve from time 0 to time at which the 
both the analyte of interest and total radioactivity are quantifiable, ie, 
time-matched AUC.
BLQ
below the limit of quantitation
BMI
body mass index
Ceoi
concentration at the end of infusion
CLR
renal clearance
Cmax
maximum observed concentration
CPAP
Clinical Pharmacology Analysis Plan
CRF
case report form
CRU
clinical research unit
CS
clinically significant
CSR
clinical study report
CV
coefficient of variation
DMP
Data Management Plan
ECG
electrocardiogram
eCRF
electronic case report form
Geom CV
geometric coefficient of variation
Geom Mean
geometric mean
ICF
informed consent form
ICH
International Conference on Harmonisation
IV
intravenous
ln
natural log
LSM
least-square means
Mean
arithmetic mea
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TAK-788-1002
Celerion Study Number CA25518
Page 6 of 25
Statistical Analysis Plan Final
08 August 2019
MedDRA
Medical Dictionary for Regulatory Activities
PD
pharmacodynamics
PI
Principal Investigator
PK
pharmacokinetics
SAE
serious adverse event
SD
standard deviation
SEM
standard error of the mean
SOC
system organ class
t1/2z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
tmax
time of maximum observed concentration
WHO
World Health Organisation
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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TAK-788-1002
Celerion Study Number CA25518
Page 10 of 25
Statistical Analysis Plan Final
08 August 2019
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoints of the study are the following PK parameters:
Period 1 (ABA):

Absolute bioavailability (F) as percent F (%F) for TAK-788.
Period 2 (ADME):

Percent of total radioactivity recovered in urine and feces relative to the administered 
radioactive dose.

Total radioactive recovery in urine and feces and the percent of the radioactive dose excreted 
in the urine and feces.

TAK-788 metabolic profiling in plasma, urine, and feces containing sufficient amounts of 
radioactivity. 

PK parameters Cmax, tmax, t1/2z, AUC∞, AUClast, and AUCt for TAK-788 and its metabolites 
(AP32960 and AP32914) in plasma and whole blood.

PK parameters Cmax, tmax, t1/2z, AUC∞, AUClast, and AUCt for total radioactivity concentration 
equivalents in plasma and whole blood.

PK parameters for amount excreted in each collection interval (Aet1-t2) and renal clearance 
(CLR) TAK-788 and its metabolites (AP32960 and AP32914) in urine.

The change over time in [14C]-radioactivity in whole blood relative to plasma (ie, whole 
blood:plasma partitioning ratio).
5.2
Secondary Endpoints
The secondary endpoints are the following PK and safety parameters:
Period 1 (ABA):

PK parameters Ceoi (IV infusion), Cmax (oral), tmax (oral), AUC∞, AUClast, AUCt, and t1/2z for 
TAK-788, and [14C]-TAK-788 and the metabolites (AP32960 and AP32914) in plasma; 
Periods 1 (ABA) and 2 (ADME):

Treatment-emergent adverse events (TEAEs) assessments.

12-Lead electrocardiogram (ECG).

Vital Signs.

Clinical laboratory testing (serum chemistry, hematology, and urinalysis).
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use



")".*'-#$%&$2(".
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CCI


TAK-788-1002
Celerion Study Number CA25518
Page 12 of 25
Statistical Analysis Plan Final
08 August 2019
6.0
DETERMINATION OF SAMPLE SIZE
The sample size of 6 male healthy subjects was selected without statistical considerations and is 
deemed adequate to meet the study objectives. In addition, this sample size is limited based on 
clinical considerations for this type of study and in order to limit exposure to radioactivity.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-788-1002
Celerion Study Number CA25518
Page 13 of 25
Statistical Analysis Plan Final
08 August 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 7.0, or higher. All 
statistical analyses will be conducted using SAS® Version 9.3, or higher. All data recorded on the 
CRF will be listed by subject. All tables, figures and listings (TFLs) shells and numbering list 
specified in the Clinical Pharmacology Analysis Plan (CPAP) will be included.
Arithmetic mean (mean), median, and geometric mean (Geom Mean) values will be presented to 
1 more level of precision than the individual values. Standard deviation (SD) and standard error 
of the mean (SEM) will be presented to 2 more levels of precision than the individual values. 
Minimum and maximum values will be presented to the same precision as the individual values. 
Arithmetic percent coefficient of variation (CV%) and geometric percent coefficient of variation 
(Geom CV%) will be presented to 1 decimal place. 
Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
recorded data. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) around the 
ratio will be reported using 2 decimal places. 
Concentration values below the limit of quantitation (BLQ) will be presented as ‘BLQ’ in the 
concentration table listings and footnoted accordingly. BLQ values will be treated as zero for the 
calculation of summary statistics, the generation of concentration plots, and the calculation of PK 
parameters, unless they are obvious outliers (eg, BLQ value between 2 measurable values), in 
which case they will be treated as missing.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics if one or more of the following criteria are met: 

A predose (0 hr) concentration is greater than 5% of that subject’s maximum concentration
value in that period

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist).

A subject deviates substantially from the protocol defined study procedures including but not 
limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist).
The details on PK parameter calculations will be outlined in the CPAP including specifics on the 
following:

Insufficient data to determine a reliable t1/2z value and other terminal disposition phase rate 
constant dependent parameters.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


TAK-788-1002
Celerion Study Number CA25518
Page 14 of 25
Statistical Analysis Plan Final
08 August 2019

PK parameters presented by treatment, including the units, precision, and summary statistics 
that will be presented in in-text and end-of-text tables.

Concentration data presented by treatment, including the units, precision, and summary 
statistics that will be presented in end-of-text tables.

Concentration data file used for PK analysis.

PK parameter WinNonlin® output file used to generate the TFLs.

Data presented in in-text and end-of-text figures.

Figures for individual subjects presented in Appendix 16.2.6.
For demographic data where appropriate, variables will be summarized descriptively over all 
subjects. For the categorical variables, the count and proportions of each possible value will be 
tabulated over all subjects, where applicable. The denominator for the proportion will be based 
on the number of subjects who provided non missing responses to the categorical variable. For 
continuous variables, the number of subjects with non-missing values, mean, SD, minimum, 
median, and maximum values will be tabulated.
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Day 1 for each period is defined as the date on which a subject is administered their first dose of 
the study drug(s) in each period. Other study days are defined relative to Day 1 with Day -1 
being the day prior to Day 1 of each period. Study day prior to the first dose of each treatment 
will be calculated as: date of assessment/event - date of treatment (Day 1); study day on or after 
the date of first dose will be calculated as: date of assessment/event - date of treatment 
(Day 1) + 1.
7.2
Analysis Sets
Safety Set:
All subjects who received at least one dose of the study drug(s) will be included in the safety set. 
Subjects in this analysis set will be used for demographic, baseline characteristics and safety 
summaries.
PK Set:
Samples from all subjects will be assayed even if the subjects do not complete the study. All 
subjects who comply sufficiently with the protocol and display an evaluable PK profile (eg, 
exposure to treatment, availability of measurements and absence of major protocol violations) 
will be included in the statistical analyses. In terms of criteria for evaluable subjects, please see 
CPAP.
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TAK-788-1002
Celerion Study Number CA25518
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Statistical Analysis Plan Final
08 August 2019
7.3
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized overall. Study completion status, 
including reason for discontinuation, will also be listed by subject. 
7.4
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized over all subjects. Summary 
statistics (number of subjects [n], mean, SD, minimum, median, and maximum) will be 
generated for continuous variables (age [calculated from the date of signed Informed Consent 
Form [ICF], weight, height and body mass index [BMI]) and the number and percentage of 
subjects within each category will be presented for categorical variables (sex, race, and 
ethnicity). Height, weight, and BMI collected at screening will be used in the baseline 
summaries. Demographics data will also be listed as recorded on the CRF, including the date of 
informed consent. Spirometry (pulmonary function test) measures will be taken within 7 days 
prior to first dosing and results will be listed by subject. 
7.5
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include any significant conditions or diseases relevant to the 
disease under study that resolved at or before signing the ICF. Concurrent medical conditions are 
those significant ongoing conditions or diseases that are present at signing the ICF. Each 
subject’s medical history and concurrent medical conditions will be listed. Any medical 
condition started after taking the study drug will be classified as an adverse event. All medical 
and surgical history recorded during the study will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA®), Version 21.1, and listed. The medical history listing will 
include whether the event was medical or surgical, the body system or organ class involved, the 
MedDRA system organ class (SOC) and preferred term (PT), the start date (if known) and end 
date or whether the condition was ongoing, and a description of the condition or event. There 
will be no statistical analysis of medical history.
7.6
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and 
efficacy/safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant 
medication includes any medication other than study drug taken at any time between time of 
signing the ICF through the end of the study (including follow-up visit). All medication history 
and concomitant medications recorded during the study will be coded with the World Health 
Organization (WHO) Dictionary, Version 01-Sep-2018, and listed. The listing will include the 
medication name, coded term, dosage, route of administration, start date and time (if known), 
end date and time, or whether it continued after study completion, and indication for use. 
7.7
Study Drug Exposure and Compliance
Not applicable.
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Celerion Study Number CA25518
Page 16 of 25
Statistical Analysis Plan Final
08 August 2019
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Blood, urine, and feces were collected as specified in Table 7.a to Table 7.d.
Table 7.a
Blood Collection Schedule after the Oral and Intravenous Doses of TAK-788 
(Period 1 - ABA Study Period)
Time 
(relative to oral dosing)
Time 
(relative to IV infusion)
Blood Sample 
Collection
(oral dose)
Blood Sample 
Collection
(IV dose)
Matrix
Plasma 
Sample 1 a
Plasma 
Sample 2 b
0 (predose)
X
X
0.5 hour postdose (± 2 min)
X
1 hour postdose (± 2 min)
X
2 hours postdose (± 2 min)
X
3 hours postdose (± 2 min)
X
3 hours 45 min post dose
0 (predose) 
X
4 hours postdose (± 2 min)
End of infusion
X
X
4 hours 10 min postdose (± 2 min)
10 min after the end of infusion (± 2 min)
X
4 hours 20 min postdose (± 2 min)
20 min after the end of infusion (± 2 min)
X
4 hours 30 min postdose (± 2 min)
30 min after the end of infusion (± 2 min)
X
5 hours postdose (± 2 min)
1 hours after the end of infusion (± 2 min)
X
X
6 hours postdose (± 2 min)
2 hours after the end of infusion (± 2 min)
X
X
8 hours postdose (± 2 min)
4 hours after the end of infusion (± 2 min)
X
X
12 hours postdose (± 5 min)
8 hours after the end of infusion (± 2 min)
X
X
24 hours postdose (± 5 min)
20 hours after the end of infusion (± 5 min)
X
X
36 hours postdose (± 10 min)
32 hours after the end of infusion (± 10 min)
X
X
48 hours postdose (± 10 min)
44 hours after the end of infusion (± 10 min)
X
X
72 hours postdose (± 10 min)
68 hours after the end of infusion (± 10 min)
X
X
96 hours postdose (± 15 min)
92 hours after the end of infusion (± 15 min)
X
X
120 hours postdose (± 15 min)
116 hours postdose (± 15 min)
X c
X c
144 hours postdose (± 15 min)
140 hours postdose (± 15 min)
X c
X c
Day 10 (Predose Day 1 of Period 2)
X d
X d
a For determination of TAK-788 and metabolites in plasma following oral capsule dose.
b For determination of [14C]-total radioactivity, and [14C]-TAK-788 and metabolites in plasma following IV infusion.
c For subjects who did not meet the discharge criteria by Day 5, blood samples continued to be collected in 24-hour intervals until 
radioactivity in urine and feces combined was ≤1% of the total administered radioactivity per day for at least 2 consecutive 
intervals where both a urine and fecal sample were collected, the excretion of radioactivity was ≥80% of the administered 
radioactive dose, or up to Day 7.
d Predose plasma samples from in Period 2 will also be used as Day 10 samples for Period 1, as appropriate.
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TAK-788-1002
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Page 18 of 25
Statistical Analysis Plan Final
08 August 2019
Table 7.c
Blood Collection Schedule (Period 2 - ADME Study Period)
Matrix 
Sample collected for 
analysis in Whole Blood
Sample collected for analysis in Plasma 
Time 
(Relative to Oral Solution 
Dosing)
Blood 
Sample 1 a
Blood 
Sample 2 b
Plasma 
Sample 1 c
Plasma 
Sample 2 d
Plasma 
Sample 3e
0 (predose)
X f
X f
X f
X f
X f
0.5 hour postdose (± 2 min)
X
X
X
X
1 hour postdose (± 2 min)
X
X
X
X
X
2 hours postdose (± 2 min)
X
X
X
X
X
3 hours postdose (± 2 min)
X
X
X
X
4 hours postdose (± 2 min)
X
X
X
X
X
5 hours postdose (± 2 min)
X
X
X
X
6 hours postdose (± 2 min)
X
X
X
X
X
8 hours postdose (± 2 min)
X
X
X
X
12 hours postdose (± 5 min)
X
X
X
X
X
24 hours postdose (± 5 min)
X
X
X
X
X
36 hours postdose (± 10 min)
X
X
X
X
48 hours postdose (± 10 min)
X
X
X
X
X
72 hours postdose (± 10 min)
X
X
X
X
X
96 hours postdose (± 15 min)
X
X
X
X
X
120 hours postdose (± 15 min)
X
X
X
X
X
144 hours postdose (± 15 min)
X
X
X
X
168 hours postdose (± 15 min)
X
X
X
X
X
192 hours postdose (±1 hour)
X
X
X
X
216 hours postdose (±1 hour)
X
X
X
X
240 hours postdose (±1 hour)
X
X
X
X
a Blood Sample 1 - Blood sample for total [14C] determination (total radioactivity) in whole blood.
b Blood Sample 2 – Blood sample for PK analysis of TAK-788 and metabolites in whole blood. 
c Plasma sample 1 – Blood sample collected for total [14C] determination in plasma.
d Plasma sample 2 – Blood sample collected for TAK-788 and metabolites PK in plasma.
e Plasma sample 3 – Blood sample collected for metabolite profiling.
f Predose plasma samples from Period 2 will be used as Day 10 samples for Period 1, as appropriate.
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CCI


TAK-788-1002
Celerion Study Number CA25518
Page 20 of 25
Statistical Analysis Plan Final
08 August 2019
PK parameters will be summarized descriptively using the summary statistics listed in the CPAP.
Excluded parameters will be presented and footnoted as such in the PK parameter table listings, 
and those values will be excluded from the descriptive summary statistics. 
A comparison of ln-transformed dose normalized PK parameter AUC∞will be made to evaluate 
the absolute bioavailability (Period 1) of TAK-788 administered as oral dose versus 
[14C]-TAK-788 administered as IV microdose. The comparison will be done by performing an 
ANOVA model using PROC MIXED of SAS®. The ANOVA model will include route of 
administration (oral and intravenous) as fixed effect and subject as a random effect. The 
inferential results (least-squares [LS] means, difference between LS means, and 90% CIs of the 
difference) will be exponentiated to the original scale. Geometric LS means, geometric mean 
ratios (GMR) and 90% CIs will be presented. The GMRs and CIs will be expressed as a 
percentage relative to the reference route of administration (ie, [14C]-TAK-788 administered as 
IV microdose).
The ANOVA analysis will be performed using the following SAS® code:
PROC MIXED;
CLASS ROUTE;
MODEL LN(PK_PARAMETER) = ROUTE/ DDFM = KR;
RANDOM SUBJECT;
ESTIMATE “Oral vs Intravenous” ROUTE 1 -1 / cl alpha=0.1 e;
RUN;
Programmer Note: The coefficient estimates will be adjusted according to the route of 
administration decodes. 
7.9.2
Pharmacodynamic Analysis
Not applicable. 
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and type of TEAEs, changes from 
baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s using the safety set. 
All clinical safety data will be listed by subject and assessment time points, including rechecks, 
unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
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Statistical Analysis Plan Final
08 August 2019
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.11.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = 
Life-threatening, Grade 5 = Death), relationship to study drug (related or not related), action 
relative to the study drug, outcome, and procedures. All AEs occurring during this study will be 
coded using MedDRA®, Version 21.1. However, only TEAEs occurring after administration of 
the first dose of study drug and through the follow-up (30 +/- 2 days after the last study drug 
administration) will be summarized. A TEAE is defined as an AE that is starting or worsening at 
the time of or after study drug administration. TEAEs occurring at or after Period 1 Day 1 oral 
dosing and prior to Period 2 Day 1 dosing will be considered treatment-emergent to Treatment A
(ie, Single oral dose of 160 mg TAK-788 followed by a single intravenous dose of 50 µg [14C]-
TAK-788 [Period 1]) and those occurring at or after Period 2 Day 1 dosing will be considered 
treatment-emergent to Treatment B (ie, single oral dose of 160 mg [14C]-TAK-788 [Period 2]).
For each treatment, TEAEs will be coded using MedDRA® and tabulated by System Organ Class 
(SOC) and Preferred Term. Summary tables will include number of subjects reporting the AE 
and as percent of safety set by treatment. The most commonly reported TEAEs (ie, those events 
reported by >5% of all subjects in each treatment, excluding SAEs) will also be summarized. For 
the list of all AE summary tables see CPAP. In addition, TEAEs will be summarized as number 
of AEs and percentage of AEs for each treatment for the overview of TEAEs. Additional TEAE 
summary tables will be presented by severity and relationship to study drug. If a subject has 
multiple AEs with different severity levels within the same term, the subject will be counted in 
the most severe category only. If a subject has both related and unrelated AEs with the same 
term, the subject will be counted as having related TEAEs only. 
Should any SAEs (including all-cause mortalities) occur, they will be listed and summarized the 
same way as TEAE. All AEs will be displayed in the data listings and TEAEs will be discussed 
in the text of the study report. 
7.11.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1)
of Period 1, Day 3 in each period, and prior to discharge or early termination. In addition, 
laboratory safety tests may be performed at various unscheduled time points, if deemed 
necessary by the Principal Investigator (PI).
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points. Change from baseline will be summarized in a similar way. Baseline is defined as the last 
assessment including rechecks taken prior to oral dosing on Day 1 of Period 1 (Day -1 Check-in 
of Period 1). 
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For each laboratory test, a shift table will be developed comparing the frequency of the results at 
treatment baseline (above normal (H), normal (N), or below normal (L)) with those postdose 
time points for each treatment. For urinalysis tests, the categories are normal (N) and abnormal 
(A). Out-of-range values and corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
range, it will be noted as “N” for not clinical significant. If the value fails the CS range, it will be 
flagged with a “Y” which prompts the PI to determine how the out-of-range value should be 
followed using 4 Investigator flags: “N”, not clinically significant, “R”, requesting a recheck, 
“^”, checking at the next scheduled visit, or “Y”, clinically significant. All clinically significant 
laboratory tests, as indicated by the PI (either in the PI flag or in PI comments), and the 
corresponding values will be listed by subject. All clinical laboratory data will be presented in 
by-subject data listings.
7.11.3 Vital Signs
Single measurements of vital signs will be collected as outlined in Table 7.e. 
Table 7.e
Collection of Vital Signs 
Measurement Type
Period
Day
Time Point
Vital Signs (Heart Rate and Blood 
Pressure)
Screen
1
-1
1, 2 
1
5 (Period 1) / 4 (Period 2) and 12 hours 
post oral dose
2
Hour 24 
2
Discharge or 
ET*
Vital Signs (Respiratory Rate and 
Temperature)
Screen
* ET = Early termination.
Additional unscheduled vital signs measurements may be taken at other times, if deemed 
necessary by the PI.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results by treatment and time point of collection. Change from baseline will be summarized 
in a similar way. Baseline is defined as the last assessment including rechecks taken prior to 
Day 1 oral dosing in Period 1 (Day -1 Check-in of Period 1). Vital signs will also be displayed in 
a data listing by subject.
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Statistical Analysis Plan Final
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7.11.4 12-Lead ECGs
Standard 12-lead ECGs will be recorded as outlined in Table 7.f. 
Table 7.f
Collection of Electrocardiograms
Measurement Type
Period
Day
Time Point
12-Lead ECG
Screen
1
-1
1, 2 
1
5 (Period 1) / 4 (Period 2) hours post 
oral dose
2
Hour 24
2
Discharge or 
ET*
* ET = Early termination.
Additional unscheduled ECGs may be recorded at other times if deemed necessary by the PI. 
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for ECG 
results and change from baseline by treatment and time point of collection. Baseline is defined as 
the last assessment including rechecks taken prior to Day 1 oral dosing in Period 1 (Day -1 
Check-in of Period 1). ECG data will also be displayed in a data listing by subject with 
QTcF >450 ms and QTcF change from baseline >30 ms flagged.
7.11.5 Physical Exams
A full physical exam will be performed at screening and may be performed at Check-in in each 
period and prior to discharge or early termination. Symptom driven physical exams may be 
performed at other times at the discretion of the PI. Physical exam findings, as recorded on the 
CRF, will be presented in a data listing by subject. 
7.11.6 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs. 
7.12
Interim Analysis
No interim analysis will be performed. 
7.13
Preliminary Analysis
If requested, QCed whole blood and plasma concentration data will be plotted using nominal 
times to aid in the determination of samples for repeat bioanalysis. If requested, a preliminary 
PK analysis will be completed as described in the CPAP and Section 7.9.1 of the SAP, with the 
following changes: 1) QCed data will be used (not QAed); 2) nominal times (not actual sampling 
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Statistical Analysis Plan Final
08 August 2019
times) will be used for the calculation of PK parameters in whole blood and plasma; 3) tables 
and figures will be created using Phoenix® WinNonlin® Version 7.0 or higher for whole blood 
and plasma data, and using SAS® Version 9.3, or higher for urine and feces data.
7.14
Changes in the Statistical Analysis Plan 
There are no changes in the statistical analysis plan from the protocol analysis.
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Statistical Analysis Plan Final
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8.0
REFERENCES
Not applicable.
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