Clinical trial NCT04441255
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2020-07-01; Completion date: 2020-08-10
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to characterize the effect of a high-fat meal on the PK of TAK-788 administered in healthy participants.

Detailed description:
The drug being tested in this study is called TAK-788. The study will characterize the effect of a high-fat meal on the PK of TAK-788 administered in healthy participants.

The study will enroll approximately 14 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment sequence

* TAK-788 160 mg Fasted (Reference) in Period 1 + TAK-788 160 mg Fed (Test) in Period 2
* TAK-788 160 mg Fed (Test) in Period 1 + TAK-788 160 mg Fasted (Reference) in Period 2

All participants will be asked to take capsules of assigned TAK-788 on Day 1 of each period.

This single-center trial will be conducted in the United States. The overall time to participate in this study is 61 days. Participants will be contacted by telephone for 30 days after the last dose of study drug for a follow-up assessment.

Arms: arm 1: TAK-788 160 milligram (mg), capsule, orally, once on Day 1 of Period 1 under fasted conditions (Treatment A), followed by 10 days washout period, followed by TAK-788 160 mg, capsule, orally, once on Day 1 of Period 2 under fed conditions (Treatment B). arm 2: TAK-788 160 mg, capsule, orally, once on Day 1 of Period 1 under fed conditions (Treatment B), followed by 10 days washout period, followed by TAK-788 160 mg, capsule, orally, once on Day 1 of Period 2 under fasted conditions (Treatment A).
Interventions: intervention 1: TAK-788
Intervention descriptions: intervention 1: TAK-788 Capsule.

Protocol documents:
Prot_000.pdf: 



Title: A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate the Effect of 
High-Fat Meal on TAK-788 Pharmacokinetics in Healthy Adult Subjects
NCT Number: NCT04441255
Protocol Approve Date: 09 June 2020
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.
A protocol clarification letter for the final protocol, dated 09-June-2020, explaining the discrepancies within the 
protocol is appended to the back of the protocol.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate the Effect of 
High-Fat Meal on TAK-788 Pharmacokinetics in Healthy Adult Subjects
Study Identifier:
TAK-788-1005
Compound:
TAK-788
Date:
09 June 2020
Version/Amendment 
Number:
Final


TAK-788
Study ID TAK-788-1005
Page 2 of 61
Final Protocol
09 June 2020
TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................10
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................11
4.0
INTRODUCTION.........................................................................................................15
4.1
Background .............................................................................................................15
4.2
Rationale for the Proposed Study.............................................................................16
4.3
Benefit/Risk Profile .................................................................................................16
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................17
5.1
Hypothesis...............................................................................................................17
5.2
Study Objectives......................................................................................................17
5.2.1
Study Primary Objective..................................................................................17
5.2.2
Study Secondary Objective..............................................................................17
5.2.3
Study Exploratory Safety Objective .................................................................17
5.3
Endpoints.................................................................................................................17
5.3.1
Primary Endpoints ...........................................................................................17
5.3.2
Secondary Endpoints .......................................................................................18
5.3.3
Exploratory Safety Endpoints ..........................................................................18
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................18
6.1
Study Design ...........................................................................................................18
6.2
Rationale for Study Design, Dose, and Endpoints ....................................................19
6.2.1
Rationale of Study Design and Dose................................................................19
6.2.2
Rationale for Endpoints ...................................................................................19
6.2.3
Future Biomedical Research ............................................................................20
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures ............20
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................20
6.4
Study Beginning and End/Completion .....................................................................20
6.4.1
Definition of Beginning of the Study ...............................................................20
6.4.2
Definition of End of the Study.........................................................................20
6.4.3
Definition of Study Completion.......................................................................20
6.4.4
Definition of Study Discontinuation.................................................................21
6.4.5
Criteria for Premature Termination or Suspension of the Study........................21
6.4.6
Criteria for Premature Termination or Suspension of a Site..............................21
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............21


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Study ID TAK-788-1005
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09 June 2020
7.1
Inclusion Criteria .....................................................................................................21
7.2
Exclusion Criteria ....................................................................................................22
7.3
Excluded Medications, Supplements, Dietary Products............................................23
7.4
Diet, Fluid, Activity.................................................................................................24
7.4.1
Diet and Fluid..................................................................................................24
7.4.2
Activity ...........................................................................................................25
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................25
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................25
7.7
Subject Replacement................................................................................................25
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................26
8.1
Clinical Study Drugs................................................................................................26
8.1.1
Clinical Study Drug Labeling ..........................................................................26
8.1.2
Clinical Study Drug Inventory and Storage......................................................26
8.1.3
Clinical Study Drug Blinding...........................................................................26
8.1.4
Randomization Code Creation and Storage......................................................26
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................26
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................27
9.0
STUDY PROCEDURES...............................................................................................27
9.1
Administrative Procedures.......................................................................................27
9.1.1
Informed Consent Procedure............................................................................27
9.1.2
Inclusion and Exclusion...................................................................................27
9.1.3
Medical History/Demography..........................................................................27
9.1.4
Concomitant Medications ................................................................................27
9.2
Clinical Procedures and Assessments.......................................................................28
9.2.1
Full Physical Exam..........................................................................................28
9.2.2
Height and Weight...........................................................................................28
9.2.3
BMI.................................................................................................................28
9.2.4
Vital Signs.......................................................................................................28
9.2.5
12-Lead ECG...................................................................................................29
9.2.6
Pulmonary Function Test.................................................................................29
9.2.7
Study Drug Administration..............................................................................29
9.2.8
AE Monitoring ................................................................................................30
9.2.9
Laboratory Procedures and Assessments..........................................................30
9.3
Pharmacokinetic Samples ........................................................................................31
9.3.1
PK Measurements............................................................................................32


TAK-788
Study ID TAK-788-1005
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Final Protocol
09 June 2020
9.3.2
Biomarker Measurements ................................................................................32
9.3.3
PGx Measurements..........................................................................................32
9.3.4
Confinement....................................................................................................33
10.0
ADVERSE EVENTS ....................................................................................................33
10.1
Definitions and Elements of AEs .............................................................................33
10.1.1
SAEs ...............................................................................................................35
10.1.2
Special Interest AEs.........................................................................................36
10.2
AE Procedures.........................................................................................................36
10.2.1
Assigning Severity/Intensity of AEs ................................................................36
10.2.2
Assigning Causality of AEs .............................................................................37
10.2.3
Start Date.........................................................................................................37
10.2.4
End Date..........................................................................................................37
10.2.5
Action Taken With Study Treatment................................................................37
10.2.6
Outcome..........................................................................................................37
10.2.7
Collection and Reporting of AEs, SAEs, Special Interest AEs, and Abnormal 
LFTs................................................................................................................38
10.2.8
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...40
10.2.9
Procedures for Reporting Product Complaints or Medication Errors 
(Including Overdose).......................................................................................40
11.0
STATISTICAL METHODS..........................................................................................41
11.1
Statistical and Analytical Plans ................................................................................41
11.1.1
Analysis Sets ...................................................................................................41
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................41
11.1.3
PK Analysis.....................................................................................................42
11.1.4
Pharmacodynamic Analysis.............................................................................42
11.1.5
Safety Analysis................................................................................................42
11.2
Determination of Sample Size..................................................................................43
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................43
12.1
Study-Site Monitoring Visits ...................................................................................43
12.2
Protocol Deviations..................................................................................................43
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................44
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................44
13.1
IRB and/or IEC Approval ........................................................................................44
13.2
Subject Information, Informed Consent, and Subject Authorization .........................45
13.3
Subject Confidentiality ............................................................................................46
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................47


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09 June 2020
13.4.1
Publication and Disclosure...............................................................................47
13.4.2
Clinical Study Registration ..............................................................................47
13.4.3
Clinical Study Results Disclosure ....................................................................47
13.5
Insurance and Compensation for Injury....................................................................47
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................48
14.1
Administrative Information......................................................................................48
14.1.1
Study Contact Information...............................................................................48
14.1.2
INVESTIGATOR AGREEMENT ...................................................................49
14.1.3
Study-Related Responsibilities.........................................................................50
14.1.4
List of Abbreviations .......................................................................................50
15.0
DATA HANDLING AND RECORDKEEPING............................................................52
15.1
CRFs .......................................................................................................................52
15.2
Record Retention .....................................................................................................52
16.0
REFERENCES..............................................................................................................53
17.0
APPENDICES...............................................................................................................54
LIST OF IN-TEXT TABLES
Table 3.a
Pharmacokinetic Plasma Concentration Sampling Schedule...............................14
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................24
Table 9.a
Primary Specimen Collections ...........................................................................31
Table 10.a
Takeda Medically Significant AE List................................................................36
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................54
Appendix B
Elements of the Subject Informed Consent.........................................................56
Appendix C
Investigator Consent to the Use of Personal Information ....................................59
Appendix D
Pregnancy and Contraception.............................................................................60


TAK-788
Study ID TAK-788-1005
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Final Protocol
09 June 2020
1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDC Americas)
95 Hayden Avenue
Lexington, Massachusetts USA 02421
Telephone: +1 (617) 349-0200
Compound:
TAK-788
Study Identifier: TAK-788-1005 (CA24171)
Phase: 1
Protocol Title: A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate the Effect of High-Fat 
Meal on TAK-788 Pharmacokinetics in Healthy Adult Subjects
Study Design:
This is an open-label, randomized, 2-period, and 2-sequence crossover high-fat meal effect study in healthy adult 
subjects.
Subjects will undergo screening evaluations to determine eligibility within 21 days prior to dosing. 
In this study, subjects will be admitted to the clinical facility the day prior to dosing in each period (Day -1). Subjects 
will randomized on Day 1 of Period 1 to a crossover sequence in a 1:1 ratio and administered a single oral dose of 160 
mg TAK-788 on Day 1 with or without a high-fat meal of each period (ie, Period 1 and Period 2). Each dose will be 
separated by a washout period of 10 days. Blood samples for TAK-788 PK will be collected predose and up to 240 
hours following each TAK-788 dose.
Subjects will receive the following treatments on one occasion in a crossover fashion to evaluate the effect of a 
high-fat meal:

Treatment A (reference): 4 40 mg TAK-788 capsules, fasted conditions

Treatment B (test): 4 40 mg TAK-788 capsules with a high-fat meal*
* 800-1000 total calories, 500-600 calories, 55-65 g, or 50% from fat (FDA FE 2019)
Subjects will remain at the clinical site until the 240-hour study assessments in Period 2 are completed.
All doses of TAK-788 will be administered at the clinic during this study. 
Spirometry as the pulmonary function test (PFT) may be performed in the event of a pulmonary adverse event (AE) 
and deemed clinically necessary, as determined by the Investigator or designee.
A final safety follow-up phone call will occur 30 ± 2 days after the last TAK-788 dose to determine if any AEs have 
occurred since the last study visit. Replacement of discontinued or withdrawn subjects due to any reason will be 
assessed on a case by case basis by the Sponsor and PI to ensure a minimum of 12 PK-evaluable subjects complete the
study.
Study Primary Objective:

To characterize the effect of a high-fat meal on the PK of TAK-788 administered as a proposed commercial 
product.
Study Secondary Objective:

To assess the PK of active metabolites AP32960 and AP32914 of TAK-788.
Study Exploratory Safety Objective:

To collect the safety data of TAK-788 following a single oral dose in healthy adult subjects.
Study Subject Population: Healthy male and female subjects aged 19 to 55 years inclusive, at screening. Body Mass 
Index (BMI) 18.5-30.0 kg/m2, inclusive, at screening.


TAK-788
Study ID TAK-788-1005
Page 7 of 61
Final Protocol
09 June 2020
Planned Number of Subjects:
Fourteen healthy adult subjects will be enrolled, 
randomized, and dosed in the high-fat meal effect 
study.
Planned Number of Sites:
1
Dose Levels:
Treatment A (reference): 4 x 40 mg TAK-788 capsules, 
fasted conditions
Treatment B (test): 4 x 40 mg TAK-788 capsules with a 
high-fat meal
All doses of TAK-788 will be orally administered at 
the clinic with 8 fluid oz (240 mL) of water.
Route of Administration:
Oral
Duration of Treatment:
Single oral dose of TAK-788 (4 x 40 mg) on Day 1 of 
each period.
There will be a washout period of 10 days between the 
dose of TAK-788 in Period 1 and Period 2.
Planned Study Duration:
Approximately 61 days ± 2 days including screening period 
and follow-up.
Criteria for Inclusion:
Subjects must fulfill the following inclusion criteria to be eligible for participation in the study: 
1.
Healthy, adult, male or female, 19 - 55 years of age, inclusive, at screening. 
2.
Continuous non-smoker who has not used nicotine-containing products for at least 20 years prior to the first 
dosing and throughout the study, based on subject self-reporting.
3.
Body mass index (BMI) ≥18.5 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. Has liver function tests (LFTs) 
including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and 
total bilirubin less than or equal to the upper limit of normal at screening and at first check-in.
5.
For a female of nonchildbearing potential, must have undergone one of the following sterilization procedures at 
least 6 months prior to the first dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;

bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and follicle stimulating hormone 
(FSH) serum levels consistent with postmenopausal status.
6.
Female subjects of childbearing potential will be advised to remain sexually inactive or to keep the same birth 
control method for at least 30 days following the last TAK-788 dosing as indicated in Appendix D.
7.
Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days following the last 
TAK-788 dosing as indicated in Appendix D.
8.
A non-vasectomized male subject must agree to use a condom with spermicide or abstain from sexual intercourse 
during the study until 30 days after the last dosing. (No restrictions are required for a vasectomized male provided 
his vasectomy has been performed 4 months or more prior to the first dosing of study drug. A male who has been 
vasectomized less than 4 months prior to study first dosing must follow the same restrictions as a 
non-vasectomized male).
9.
Male subjects must agree not to donate sperm from the first dosing until 30 days after the last TAK-788 dosing.


TAK-788
Study ID TAK-788-1005
Page 8 of 61
Final Protocol
09 June 2020
10. 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 (including hyperlipidemia and diabetes since high fat meal is required) that, in the opinion of 
the Investigator or designee, might confound the results of the study or poses an additional risk to the subjects 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 drugs or related compounds.
6.
History or presence of any previous lung disease and/or current lung infection.
7.
Female subjects with a positive pregnancy test or who are lactating.
8.
Positive urine drug or alcohol results at screening or first check-in.
9.
Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
10. Positive test result for active COVID-19.
11. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
12. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
13. QTcF interval is >460 msec (males) or >470 msec (females) or ECG findings are deemed abnormal with clinical 
significance by the Investigator or designee at screening.
14. Creatinine clearance <90 mL/min at screening (calculated using the Cockcroft-Gault formula).
15. 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. Medication listed as part of acceptable birth 
control methods will be allowed (refer to Appendix D). Thyroid hormone replacement medication may be 
permitted if the subject has been on the same stable dose for the immediate 3 months prior to the first dosing. 
Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, only after initial dosing, if 
necessary, to treat AEs.

Any drugs known to be inhibitors or 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 Table™) will be consulted to confirm lack of PK/pharmacodynamics 
interaction with study drugs.
16. 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.
17. Donation of blood or significant blood loss within 56 days prior to the first dosing.
18. Plasma donation within 7 days prior to the first dosing.
19. Participation in another clinical study within 30 days for a small molecular drug or 90 days for a biologic drug 
prior to the first dosing. The 30-day or 90-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.


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Study ID TAK-788-1005
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Final Protocol
09 June 2020
Main Criteria for Evaluation and Analyses:
Primary Endpoints
The following PK parameters will be analyzed for TAK-788.

Time of first occurrence of Cmax (Tmax).

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the last 
quantifiable concentration (AUC).

Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast). 
Secondary Endpoints
The following PK parameters will be analyzed for active metabolites (AP32960 and AP32914) of TAK-788.

Time of first occurrence of Cmax (Tmax).

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed value of the last 
quantifiable concentration (AUC).

Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast).
Exploratory Safety Endpoints
Safety will be assessed by summarizing the incidence of treatment emergent AEs (TEAEs), clinical laboratory values, 
physical examinations, 12-lead ECGs, and vital signs
Statistical Considerations:
Pharmacokinetics:
The PK parameters of TAK-788 and its active metabolites (AP32960 and AP32914) will be calculated based on 
plasma concentration - time profiles of TAK-788 and its active metabolites (AP32960 and AP32914) as described in 
Section 11.0, and outlined in the SAP.
A linear mixed-effects model will be used for the analysis on the natural log (ln)-transformed Cmax, AUC, and AUClast
for TAK-788and its active metabolites (AP32960 and AP32914). The model will include sequence, treatment, and 
period as a fixed-effect and subject nested within sequence as a random-effect. Each model will include calculation of 
least squares means (LSMs) as well as the difference between treatment LSMs.
Geometric mean ratios (GMR) and 90% confidence intervals (CI), consistent with the two one sided test [Schuirmann 
1987], will be calculated using the exponentiation of the difference between treatment LSMs from the analyses on the 
ln-transformed Cmax, AUC, and AUClast (if it is needed) for TAK-788 and the combined molar Cmax, AUC, and 
AUClast (if it is needed) for TAK-788 and its active metabolites. These ratios will be expressed as a ratio of test 
treatment relative to the appropriate reference treatment. 
Safety:
Quantitative safety data as well as the difference to baseline, when appropriate, will be summarized using the 
appropriate descriptive statistics.
Sample Size Justification: 
The sample size calculation was based on the expected 2-sided 90% CI for the difference in the paired, 
log-transformed AUC∞means of TAK-788 in the presence and absence of a high-fat meal. The within-patient 
coefficient of variation for TAK-788 Cmax was estimated to be 17.2% on the basis of data from a clinical study 
conducted in healthy subjects (TAK-788-1001). If the observed GMR for the TAK-788 AUCin the presence and 
absence of high-fat is 1, with a sample size of 12, the 90% CI for the AUCGMR is expected to be 0.881 to 1.13 on the 
basis of the variance assumptions. Fourteen (14) healthy adult subjects will be enrolled into this high-fat meal effect 
study to get at least 12 PK-evaluable subjects in each treatment arm according to the FDA guidance Assessing the 
Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations Guidance for Industry 
(FDA FE 2019).


TAK-788
Study No. TAK-788-1005
Page 10 of 61
Final Protocol
09 June 2020
CONFIDENTIAL
2.0
STUDY SCHEMATIC
Screening
Study Days in Periods 1 and 2 (a)
Follow-up
Check-in and 
Predose 
Assessments (b)
TAK-788 Dosing, 
PK sampling, and 
Study 
Assessments
PK sampling and Study Assessments
PK sampling and Study 
Assessments (c)
Within 
21 days 
prior to first 
dosing
Day -1
Day 1
Days 2, 3, 4 
Days 6 & 8 
Day 11 
30 days ± 2 
following last 
TAK-788 dose 
Outpatient 
Visit
Confinement (d)
Outpatient Visit
(a) There is a washout of 10 days between TAK-788 dose in Period 1 and Period 2.
(b) Subjects will be confined to the CRU at the time indicated by the staff from Day -1 of Period 1.
(c) Period 1 Day 11 PK sample will serve as the pre-dose PK sample for Period 2 Day 1.
(d) Subjects will start the confinement on Day -1 and will be released from confinement after the 240-hour study assessments in Period 2 are complete.


TAK-788
Study No. TAK-788-1005
Page 11 of 61
Final Protocol
08 June 2020
CONFIDENTIAL
3.0
SCHEDULE OF STUDY PROCEDURES 
Study Procedures a
S b
Study Days in Periods 1 and 2 c
Days in Period →
-1
1
2
3
4
6
8
11 e
EOS or 
ET p
FU q
Hours →
C-I d
0
0.5
1
2
4
6
8
12
24
48
72
120
168
240
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
X f
Medical History
X
Safety Evaluations 
Full Physical Examination g
X
Height
X
Weight
X
X h
12-Lead Safety ECG
X
X k
X
X
Vital Signs (HR and BP)
X
X k
X
X
X
X
Vital Signs (RR and T)
X
X
Pulmonary function test i
X
Hem, Serum Chem j, and UA 
X
X l
X
X
Serum Pregnancy Test (♀only)
X
X
Serum FSH (PMP ♀ only)
X
Urine Drug and Alcohol Screen
X
X
HIV/Hepatitis Screen
X
AE Monitoring
X
X
ConMeds Monitoring
X


TAK-788
Study No. TAK-788-1005
Page 12 of 61
Final Protocol
08 June 2020
CONFIDENTIAL
Study Procedures a
S b
Study Days in Periods 1 and 2 c
Days in Period →
-1
1
2
3
4
6
8
11 e
EOS or 
ET p
FU q
Hours →
C-I d
0
0.5
1
2
4
6
8
12
24
48
72
120
168
240
Study Drug Administration / 
PK
TAK-788 Administration
X
Blood for TAK-788 and 
metabolites (AP32960 and 
AP32914) PK
X m
X
X
X
X
X
X
X
X
X
X
X
X
X n
Other Procedures
Confinement in the CRU o
X
Visit and Return Visits
X
a.
For details on Procedures, refer to Section 9.0.
b.
Within 21 days prior to the first study drug administration.
c.
There will be a washout period of 10 days between the dose in Period 1 and the dose in Period 2.
d.
Subjects will be admitted to the CRU on Day -1 of Period 1, at the time indicated by the CRU.
e.
Day 11 of Period 1 will be the same as Day 1 of Period 2. Study procedures will only be performed once.
f.
To be conducted in Period 1 only.
g.
Symptom-driven physical examinations may be performed at other times, at the PI’s or designee’s discretion.
h.
If the screening assessment was conducted within 4-7 days prior to the first dosing (Day 1 of Period 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.
i.
Pulmonary function tests may be performed in the event of a pulmonary AE and deemed clinically necessary, as determined by the Investigator or designee.
j.
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.
k.
To be performed within 24 hours prior to dosing.
l.
To be repeated prior to dosing in Period 2.
m. Prior to dosing.
n.
The Period 1 Day 11 PK sample will serve as the pre-dose PK sample for Period 2.
o.
Subjects will start confinement on Day -1 of Period 1 and will be released from confinement after the 240-hour study assessments in Period 2 are completed. At 
all times, subjects may be required to remain at the CRU for longer at the discretion of the Investigator or designee.
p.
To be performed at the end of Period 2 or prior to early termination from the study.


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CONFIDENTIAL
Study Procedures a
S b
Study Days in Periods 1 and 2 c
Days in Period →
-1
1
2
3
4
6
8
11 e
EOS or 
ET p
FU q
Hours →
C-I d
0
0.5
1
2
4
6
8
12
24
48
72
120
168
240
q.
The clinic will contact all subjects (including subjects who terminate the study early) 30 ± 2 days after the last TAK-788 dose to determine if any AEs have 
occurred since the last study visit.
Abbreviations: ♀= Females, AE = Adverse events, BP = Blood pressure, C-I = Check-in, Chem = Chemistry, ConMeds = Concomitant medication, 
CRU = Clinical research unit, ECG = Electrocardiogram, EOS/ET = End-of-Study or early termination, FSH = Follicle-stimulating hormone, FU = Follow-up, 
Hem = Hematology, HIV = Human immunodeficiency virus, HR = Heart rate, PI = Principal Investigator, PK = Pharmacokinetics, PMP = Postmenopausal, 
Preg = Pregnancy, RR = Respiratory rate, S = Screening, T = Temperature, UA = Urinalysis


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Table 3.a
Pharmacokinetic Plasma Concentration Sampling Schedule
Study Day
Sample Collection 
Time
Time 
(Relative to Dosing)
h:min
Plasma Concentrations of 
TAK-788, AP32960, and 
AP32914
1
(Period 1)
0 h
(predose)
00:00 a
(predose)

0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)

4 h
04:00 (±10 min)

6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

2
0 h
24:00 (±30 min)

3
0 h
48:00 (±30 min)

4
0 h
72:00 (±60 min)

6
0 h
120:00 (±60 min)

8
0 h
168:00 (±60 min)

11
(Predose Day 1 
Period 2)
0 h
240:00 (±60 min) a, b
(predose)

0.5 h
00:30 (±5 min)

1 h
01:00 (±10 min)

2 h
02:00 (±10 min)

4 h
04:00 (±10 min)

6 h
06:00 (±20 min)

8 h
08:00 (±20 min)

12 h
12:00 (±20 min)

2
0 h
24:00 (±30 min)

3
0 h
48:00 (±30 min)

4
0 h
72:00 (±60 min)

6
0 h
120:00 (±60 min)

8
0 h
168:00 (±60 min) 

11
0 h
240:00 (±60 min)

Number of samples per profile: 
27
a The Day 1 dose must be administered shortly after the PK sample is taken.
b The Period 1 Day 11 PK sample will serve as the pre-dose PK sample for Period 2. The predose PK sample in Period 2 must be 
collected before the scheduled Period 2 Day 1 dose even though the collection window implies it can be taken after.


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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 dosed at the more 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.
Clinical Pharmacokinetics
The clinical development program for TAK-788 includes an ongoing phase 1/2 clinical efficacy 
and safety study in patients with NSCLC (AP32788-15-101), 2 completed clinical pharmacology 
studies: 1) Single rising dose study (Part 1), low-fat meal effect study (Part 2), and relative 
bioavailability study (Part 3) in healthy subjects (TAK-788-1001) and 2) a drug-drug interaction 
study to characterize TAK-788 drug-drug interaction with either a strong cytochrome P-450 
(CYP)3A inhibitor, itraconazole (Part 1) or with a strong CYP3A inducer, rifampin (Part 2) in 
healthy subjects (TAK-788-1006); and 4 ongoing clinical pharmacology studies: TAK-788-1002, 
-1004, -1007, and -1008. The objectives and study design of these studies are presented in 
TAK-788 IB Edition 4 (IB 2020). Only preliminary PK results from AP32788-15-101, and final 
PK results from TAK-788-1001 and TAK-788-1006 are presented in this document.
In the AP32788-15-101 study, following daily oral (PO) administration of TAK-788 once daily 
(QD), TAK-788 was readily absorbed with a median time to reach Cmax concentration (Tmax) of 
4 hours postdose. The single-dose Cmax and AUC24 of TAK-788 increased in a dose proportional 
manner in the dose range of 5 to 180 mg TAK-788. However, its steady state Cmax and AUC24
following multiple doses increased in a less than dose proportional manner across the dose range 
of 5 to 180 mg. Minimal to modest TAK-788 accumulation ratios were observed at steady state 
(geometric mean range 1.23 to 1.52) in the dose range of 20 to 120 mg QD. At 160 mg QD, the 
geometric mean accumulation ratio following repeated doses was 1.06, suggesting autoinduction 
of the apparent oral clearance of TAK-788 likely via induction of CYP3A.
The emerging finding of autoinduction by TAK-788 at the 160 mg QD dose is consistent with the 
results of in vitro induction studies that have shown concentration-dependent CYP3A induction by 
TAK-788 and its active metabolites, suggesting a possible risk for drug-drug interactions due to 
induction of CYP3A and other co-regulated enzymes/transporters by TAK-788 as a potential 
perpetrator. The PK of the 2 active metabolites (AP32960 and AP32914) of TAK-788 were also 
evaluated in clinical studies. Systemic exposures to metabolites AP32960 and AP32914 in terms 
of molar AUC24 were approximately 62% (%CV: 25%) and 8% (%CV: 13%) of parent AUC24
respectively. 


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In the healthy subject study TAK-788-1001, a low-fat meal (ie, ≤350 calories and ≤15% calories 
from fat) did not affect the PK of TAK-788 in healthy subjects. At 160 mg TAK-788, 90% CIs of 
the GMR with a low-fat meal versus fasted conditions for Cmax (GMR 0.964) and AUC(GMR 
0.951) fell completely within 80 -125% range.
In the TAK-788-1006 study, a DDI between the CYP3A4 inhibitor, itraconazole, and TAK-788 
was observed. Following coadministration of multiple oral doses of 200 mg itraconazole with a 
single oral dose of 20 mg TAK-788, overall (AUC∞) and peak (Cmax) exposures were increased by 
approximately 743% and 282% from the corresponding values obtained following TAK-788 alone. 
Similar results were observed for combined molar AUC∞and combined molar Cmax data when 
comparing itraconazole + TAK-788 to TAK-788 alone. A significant reduction in TAK-788 
AUC∞and Cmax was observed when TAK-788 was concomitantly administered with the strong 
CYP3A4 inducer, rifampin. Following coadministration of multiple oral doses of 600 mg rifampin 
with a single oral dose of 160 mg TAK-788, overall (AUC∞) and peak (Cmax) exposures were 
reduced by approximately 96% and 95% compared to the corresponding values obtained 
following TAK-788 alone. Similar results were observed for combined molar AUC∞and 
combined molar Cmax data when comparing rifampin + TAK-788 to TAK-788 alone.
Refer to the Investigator’s Brochure (IB) for detailed background information and safety data on 
TAK-788 IB Edition 4, 01-Apr-2020 (IB 2020).
4.2
Rationale for the Proposed Study
TAK-788, formerly known as AP32788, was designed to be a selective inhibitor of all mutant 
forms of EGFR and HER2, including exon 20 insertions, more potently than it inhibits WT EGFR. 
Although TAK-788 is intended for the treatment of NSCLC, it is neither a mutagenic nor 
genotoxic agent and was generally well tolerated in the previous clinical pharmacology studies 
(TAK-788-1001, TAK-788-1002, and TAK-788-1006, a total of 88 subjects) in healthy subjects in 
the single dose range of 20 – 160 mg.
It has been demonstrated that a low-fat meal does not impact the PK of TAK-788. (Study 
TAK-788-1001) so cancer patients in TAK-788 clinical development program can currently 
administer TAK-788 orally with or without a low-fat meal. In this study, the effect of high-fat meal 
on the PK of the proposed commercial product will be characterized to support the product 
labeling of TAK-788. 
4.3
Benefit/Risk Profile
The clinical safety data from study AP32788-15-101 available as of 27 January 2020 indicated no 
particular safety findings that are unique to TAK-788 compared with other approved EGFR TKIs 
for NSCLC patients. The most common TEAEs occurring in ≥20% of NSCLC patients by 
preferred term (PT) overall were diarrhea 84.7%, nausea 45.3%, decreased appetite 31.0%, 
vomiting 31.0%, fatigue 30.0%, and anemia (23.2%). There is some variety in the characterization 
of TEAEs of the skin resulting in different PTs to describe it. The most common skin-related PTs 
were rash (30.5%), dry skin (23.6%), maculo-papular rash (17.2%), paronychia (14.8%), 
dermatitis acneiform (12.3%), and pruritus (10.8%) (IB 2020).


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There will be no direct health benefit for study participants from receipt of the study drugs. An 
indirect health benefit to the healthy subjects enrolled in this study is the free medical tests 
received at screening and during the study.
In Study TAK-788-1001 in healthy subjects (n=69), the most common AEs by PT (≥2 subjects 
overall) were nausea (12.5%), diarrhea (10.0%), headache (7.5%), and abdominal pain upper 
(5.0%) in Part 1 of study; and headache (31.3%), nausea (31.3%), abdominal pain upper (18.8%), 
feces soft (12.5%), and flatulence (12.5%) in Part 2 of study. No AEs occurred in more than 1 
subject in Part 3 of study. All TEAEs recovered or resolved. One Grade ≥3 AE occurred, which 
was lipase increased and was assessed as not related to TAK-788 (120 mg dose, no treatment 
given). One subject permanently discontinued TAK-788 due to an AE of Grade 1 vomiting. The 
majority of TEAEs were gastrointestinal and were Grade ≤2 in severity. There were no clinically 
meaningful pulmonary, renal, hepatic, or cardiac abnormalities during this study. Overall, 
TAK-788 was well tolerated at single oral doses from 20 mg to 160 mg.
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, and physical 
examination are adequate to protect the subject’s safety and should detect all TEAEs.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Hypothesis
Not applicable
5.2
Study Objectives
5.2.1
Study Primary Objective

To characterize the effect of a high-fat meal on the PK of TAK-788 administered as a proposed 
commercial product.
5.2.2
Study Secondary Objective

To assess the PK of active metabolites AP32960 and AP32914 of TAK-788.
5.2.3
Study Exploratory Safety Objective

To collect the safety data of TAK-788 following a single oral dose in healthy adult subjects.
5.3
Endpoints
5.3.1
Primary Endpoints
The following PK parameters will be analyzed for TAK-788.

Time of first occurrence of Cmax (Tmax).

Maximum observed concentration (Cmax).


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
Area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration (AUC).

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast). 
5.3.2
Secondary Endpoints
The following PK parameters will be analyzed for active metabolites (AP32960 and AP32914) of 
TAK-788.

Time of first occurrence of Cmax (Tmax).

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration (AUC).

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast). 
5.3.3
Exploratory Safety Endpoints
The exploratory endpoint will be assessed through evaluation of the following safety parameters:

TEAEs assessments.

Clinical laboratory testing (hematology, serum chemistry and urinalysis).

Physical examinations.

12-lead ECG.

Vital signs.
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is an open-label, randomized, 2-period, and 2-sequence crossover high-fat meal effect study 
in healthy adult subjects. 
Subjects will undergo screening evaluations to determine eligibility within 21 days prior to dosing. 
Subjects will be admitted to the clinical facility the day prior to dosing in each period (Day -1).
Subjects will be randomized on Day 1 of Period 1 to a crossover sequence in a 1:1 ratio and 
administered a single oral dose of 160 mg of TAK-788 with or without a high-fat meal on Day 1 of 
each period (ie, Period 1 and Period 2). Each dose will be separated by a washout period of 10 days. 
Blood samples for TAK-788 PK will be collected predose and up to 240 hours following each 
TAK-788 dose.


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Subjects will receive the following treatments on one occasion in a crossover fashion to evaluate 
the effect of a high-fat meal:

Treatment A (reference): 4 40 mg TAK-788 capsules, fasted conditions

Treatment B (test): 4 40 mg TAK-788 capsules with a high-fat meal
* 800-1000 total calories, 500-600 calories, 55-65 g, or 50% from fat (FDA FE 2019)
Subjects will remain at the clinical site until the 240-hour study assessments in Period 2 are 
completed. 
All doses of TAK-788 will be administered at the clinic during this study. 
A final safety follow-up phone call will occur 30 ± 2 days after the last TAK-788 dose to determine 
if any AEs have occurred since the last study visit.
Replacement of discontinued or withdrawn subjects due to any reason will be assessed on a case 
by case basis by the Sponsor and PI to ensure a minimum of 12 PK-evaluable subjects complete
the study.
Any subject who experiences emesis within 8 hours post dose will be excluded in the final PK data 
analysis and will be replaced with a new subject.
Dose administration, PK collection, and study assessments scheme for the treatment periods are 
outlined in Section 2.0.
6.2
Rationale for Study Design, Dose, and Endpoints
6.2.1
Rationale of Study Design and Dose
In this study, the effect of a high-fat meal on the PK of the proposed commercial product will be 
characterized to support the product labeling of TAK-788. A randomized, 2-treatment (ie, fed 
versus fasted), 2-period, 2-way crossover design will be utilized in accordance with FDA guidance 
Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology 
Considerations Guidance for Industry (FDA FE 2019). The washout period between doses is 
considered sufficient to prevent carryover effects of the treatments. 
6.2.2
Rationale for Endpoints
6.2.2.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this study type.
6.2.2.2
Safety Endpoints 
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring of 
AEs, vital signs, ECGs, laboratory assessments, and physical examinations.


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6.2.3
Future Biomedical Research
Any residual plasma samples will be stored by the Sponsor or Bioanalytical facility for the 
maximal 5 years determined by the Sponsor following the last dosing and may be used in the 
future to perform metabolite profiling. Tubes or containers will be identified with a barcode using 
an appropriate label.
No diseases/conditions, deoxyribonucleic acid, or ribonucleic acid (RNA) will be the focus of 
these analyses. The analyses will focus on metabolite profiling for TAK-788 compound. Samples 
will not be submitted to a public database. The Sponsor and contract research organizations 
involved in the clinical conduct, bioanalytical analyses and PK and statistical analysis of the data 
will have access to the samples and/or the data that resulted from the analysis, if performed. 
By signing the ICF, subjects agree to the possible future analysis of these samples. At any time, the 
subjects can contact the CRU staff to request destruction of the residual samples once PK 
assessments required to meet the primary objective of the study are completed. Any additional 
research on these samples unspecified by this protocol will require approval from the subjects.
6.2.4
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
TAK-788 its active metabolites (AP32960 and AP32914) and samples are required to be collected, 
as appropriate, as close to the scheduled times defined in this protocol as possible.
6.3
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of the study drugs to any subject may not be modified. If necessary, a 
subject may be discontinued for the reasons described in in Section 7.5 and Section 7.6. Any 
subject who experiences emesis within 8 hours post dose will be excluded in the final PK data 
analysis and may be replaced with a new subject.
6.4
Study Beginning and End/Completion
6.4.1
Definition of Beginning of the Study
The beginning of the study will be defined as the beginning of the screening (ie, signing of the ICF) 
of the first subject.
6.4.2
Definition of End of the Study
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)
6.4.3
Definition of Study 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.


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This time period may change in the event that the study is terminated early or the last subject is lost 
to follow-up.
6.4.4
Definition of Study 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.
6.4.5
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study:

New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.4.6
Criteria for Premature Termination or Suspension of a Site
Not applicable.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
7.1
Inclusion Criteria
Subjects must fulfill the following inclusion criteria to be eligible for participation in the study: 
1. Healthy, adult, male or female, 19 - 55 years of age, inclusive, at screening. 
2. Continuous non-smoker who has not used nicotine-containing products for at least 20 years 
prior to the first dosing and throughout the study, based on subject self-reporting.
3. BMI ≥18.5 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. Has LFTs 
including ALT, AST, ALP, and total bilirubin less than or equal to the upper limit of normal at 
screening and at first check-in.
5. For a female of nonchildbearing potential, must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dosing:

hysteroscopic sterilization;

bilateral tubal ligation or bilateral salpingectomy;

hysterectomy;


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
bilateral oophorectomy;
or be postmenopausal with amenorrhea for at least 1 year prior to the first dosing and FSH 
serum levels consistent with postmenopausal status.
6. Female subjects of childbearing potential will be advised to remain sexually inactive or to keep 
the same birth control method for at least 30 days following the last TAK-788 dosing as 
indicated in Appendix D.
7. Female subjects must agree not to donate ova/oocytes during the study and for at least 30 days 
following the last TAK 788 dosing as indicated in Appendix D.
8. A non vasectomized male subject must agree to use a condom with spermicide or abstain from 
sexual intercourse during the study until 30 days after the last dosing. (No restrictions are 
required for a vasectomized male provided his vasectomy has been performed 4 months or 
more prior to the first dosing of study drug. A male who has been vasectomized less than 
4 months prior to study first dosing must follow the same restrictions as a non vasectomized 
male).
9. Male subjects must agree not to donate sperm from the first dosing until 30 days after the last 
TAK-788 dosing.
10. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
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 (including hyperlipidemia and diabetes since high fat meal is required)
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 drugs or related 
compounds.
6. History or presence of any previous lung disease and/or current lung infection.
7. Female subjects with a positive pregnancy test or who are lactating.
8. Positive urine drug or alcohol results at screening or first check-in.
9. Positive results at screening for HIV, HBsAg, or HCV.
10. Positive test result for active COVID-19.


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11. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
12. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
13. QTcF interval is >460 msec (males) or >470 msec (females) or ECG findings are deemed 
abnormal with clinical significance by the Investigator or designee at screening.
14. Creatinine clearance <90 mL/min at screening (calculated using the Cockcroft-Gault formula).
15. 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. 
Medication listed as part of acceptable birth control methods will be allowed (refer to 
Appendix D). Thyroid hormone replacement medication may be permitted if the subject 
has been on the same stable dose for the immediate 3 months prior to the first dosing. 
Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study, only 
after initial dosing, if necessary, to treat AEs.

Any drugs known to be inhibitors or 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 Table™) will be consulted to confirm lack of 
PK/pharmacodynamics interaction with study drugs.
16. 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.
17. Donation of blood or significant blood loss within 56 days prior to the first dosing.
18. Plasma donation within 7 days prior to the first dosing.
19. Participation in another clinical study within 30 days for small molecular drug or 90 days for a 
biologic drug prior to the first dosing. The 30-day or 90-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.
7.3
Excluded Medications, Supplements, Dietary Products
Concomitant medications will be prohibited as listed in the exclusion criteria in Section 7.2. 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 the first dosing.
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.


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Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing 
(Days -28 to predose [Day 1 of Period 1])
After First Dosing (Day 1 of 
Period 1) to Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited until end of PK 
collection in Period 2.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing a
Prohibited until end of PK 
collection in Period 2 a.
Medications 
See Sections 7.2 and 7.3.
See Sections 7.2 and 7.3.
Food substance
Grapefruit/Seville orange
Prohibited from 28 days prior to first dosing
Prohibited until end of PK 
collection in Period 2.
Other Fruit Juice
Prohibited from 72 hours prior to first dosing
Prohibited until end of PK 
collection in Period 2.
Vegetables from the 
mustard green family 
(eg, kale, broccoli, 
watercress, collard greens, 
kohlrabi, Brussels sprouts, 
mustard), and charbroiled 
meats
Prohibited from 7 days prior to first dosing
Prohibited until end of PK 
collection in Period 2.
a: small amounts of caffeine derived from normal foodstuffs 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.
7.4
Diet, Fluid, Activity 
7.4.1
Diet and Fluid
Water (except water provided with each oral dosing) will be restricted 1 hour prior to and 1 hour 
after each study drug administration, but will be allowed ad libitum at all other times. Other fluids 
may be given as part of meals and snacks but will be restricted at all other times throughout the 
confinement period.
Treatment A: On Day 1 of Period 1 or Period 2 (per randomization), subjects will fast overnight for 
at least 10 hours prior to oral study drug administration and will continue to fast for at least 4 hours 
postdose.
Treatment B: On Day 1 of Period 1 or Period 2 (per randomization), subjects will be required to 
fast overnight for at least 10 hours until 30 minutes prior to their scheduled morning dose, when 
they will be given a high-fat/high-calorie breakfast which will be entirely consumed within 
30 minutes. An example of high-fat/high-calorie breakfast would be 2 slices of buttered toast, 
2 eggs fried in butter, 2 strips of bacon, 4 oz of hash brown potatoes, and 8 fluid oz (240 mL) of 
whole milk (providing approximately 150, 250, and 500-600 calories from protein, carbohydrate, 
and fat, respectively) (FDA FE 2019). Following dosing, subjects will fast for at least 4 hours 
postdose.


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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.
7.4.2
Activity
Subjects will remain ambulatory or seated upright for the first 4 hours postdose on Day 1 of each 
period, except when they are supine or semi-reclined for study procedures or AEs. 
Subjects will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from screening until completion of the study. 
7.5
Criteria for Discontinuation or Withdrawal of a Subject
Subjects are free to withdraw from the study at any time for any reason. 
In addition, subjects may be withdrawn from the study by the Investigator or designee for the 
following reasons:

AEs.

A positive pregnancy test for females.

Positive urine drug or alcohol results.

Difficulties in blood collection.

Taking prohibited concomitant medications.

Emesis within 8 hours post dose.
A subject may be withdrawn by the Investigator (or designee) or the Sponsor if enrollment into the 
study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The Investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by 
the Investigator. In addition, efforts should be made to perform all procedures scheduled for the 
end-of-study or early termination as described in Section 3.0.
7.7
Subject Replacement
Replacement of discontinued or withdrawn subject(s) due to any reason will be assessed on a case 
by case basis by the Sponsor and PI to ensure a minimum of 12 PK-evaluable subjects complete 
the study.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drugs 
TAK-788 capsule used in this clinical study is a drug-in-capsule (DiC) product without any 
excipient. The TAK-788 capsule product contained a nominal 40 mg (expressed as free base 
equivalent) of the active ingredient, provided as succinate salt and manufactured from Process C. 
The drug substance (DS-C) is filled into a size 2 capsule as the intended DiC commercial product 
(DiC-C).
All TAK-788 products will be prepared by licensed pharmacy staff at the CRU according to the 
procedures outlined in the pharmacy manual.
Details of the dosage form description and strengths can be found in the pharmacy manual.
8.1.1
Clinical Study Drug Labeling
TAK-788 drug product will be supplied in white high-density polyethylene bottles with 
child-resistant caps with liner. TAK-788 will bear the appropriate label text as required by 
governing regulatory agencies. At a minimum, such text will include product name, product 
strength, and lot number.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
subject and for each study period.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-788 products to allow completion of this 
study. 
The recommended storage condition for TAK-788 is controlled room temperature. Additional 
details regarding the storage and handling of TAK-788 are provided in the pharmacy manual.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
8.1.3
Clinical Study Drug Blinding
This is an open-label study.
8.1.4
Randomization Code Creation and Storage 
A randomization schedule will be generated by Celerion for each study part.
Subjects will be randomized to a crossover sequence in a 1:1 ratio and administered a single dose 
of 160 mg TAK-788 on Day 1 of each period per the randomization sequences, AB and BA.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable


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8.1.6
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.
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 Allocation 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.
If replacement subjects are used, the replacement subject number will be 100 more than the 
original (eg, Subject No. 101 will replace Subject No. 1).
9.1.1.2
Study Drug Assignment
This is an open-label, randomized, 2-period, and 2-sequence crossover high-fat meal effect study. 
Subjects will receive each of the two treatments detailed in Section 9.2.7 according to the 
randomization scheme detailed in Section 8.1.4.
9.1.2
Inclusion and Exclusion 
Each subject will be assessed through randomization, according to the eligibility criteria provided 
in Section 7.0.
9.1.3
Medical History/Demography
Medical history and demographic data, including name, sex, age, race, ethnicity, and history of 
tobacco use will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.2 and Section 7.3. All 
medications taken by subjects during the course of the study will be recorded.


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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 of blood for TAK-788 and its metabolites PK is the critical parameter 
and needs to be collected as close to the exact time point as possible. All other procedures should 
be completed as close to the prescribed/scheduled time as possible, but can be performed prior to 
or after the prescribed/scheduled time (refer to Section 3.0 and Table 3.a).
COVID-19 testing and related risk assessments will be detailed in a separate document following 
up-to-date local regulations.
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 Period 1 and Period 2 
Day 1 dosing for the predose time point. When scheduled postdose, vital signs will be performed 
within approximately 15 minutes of the scheduled time point.


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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 Period 1 and Period 2 Day 1 dosing for the 
predose time point. When scheduled postdose, ECGs will be performed within approximately 
20 minutes of the scheduled time point.
9.2.6
Pulmonary Function Test
9.2.6.1
Spirometry
Spirometry as the PFT may be performed in the event of a pulmonary AE and deemed clinically 
necessary, as determined by the Investigator or designee.
9.2.7
Study Drug Administration
TAK-788 oral capsules will be provided as described in Section 8.0.
Subjects will be instructed not to crush, split, or chew the TAK-788 capsules.
Treatments are described as: 
Treatment A
(reference)
4 40 mg TAK-788 capsules administered at Hour 0 on Day 1 of Period 1 
or 2 per randomization following an overnight fast.
Treatment B
(test)
4 40 mg TAK-788 capsules administered at Hour 0 on Day 1 of Period 1 
or 2 per randomization with a high-fat meal.
TAK-788 will be administered following an overnight fast (Treatment A) or with a high-fat meal 
(Treatment B). 
For Treatment B, subjects will be required to fast overnight for at least 10 hours until 30 minutes 
prior to their scheduled morning dose, when they will be given a high-fat/high-calorie breakfast
which will be entirely consumed within 30 minutes (FDA FE 2019). 
Following dosing, subjects will fast for at least 4 hours postdose (both treatments).
All study drugs will be administered with approximately 8 fluid oz (240 mL) of water. The exact 
clock time of oral dosing will be recorded. 
The pharmacy at the CRU will provide each dose of study drug(s) in individual unit dose 
containers for each subject as appropriate.


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9.2.8
AE Monitoring
Subjects will be monitored throughout the study for adverse reactions to the study drugs and/or 
procedures as described in Section 10.0.
9.2.9
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.
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 when 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
ALP
Glucose 
AST
Creatinine *
ALT
Magnesium
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.


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Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
Other 
HIV test
Urine drug screen
–
Opiates (includes morphine, heroin 
(diacetylmorphine), codeine, 6-acetylmorphine, 
dihydrocodeine, hydrocodone, thebaine, and, 
hydromorphone)
–
Amphetamines
–
Barbiturates
–
Benzodiazepines
–
Cocaine
–
Cannabinoids
HBsAg
HCV (if antibody positive, confirm RNA negative)
COVID-19 test
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
9.3
Pharmacokinetic Samples
Instructions for plasma samples processing and handling will be provided in a separate document. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Description of Intended Use
Sample 
Collection
Plasma sample for TAK-788 and 
metabolites PK
Plasma
Plasma sample for TAK-788 and 
metabolites PK analysis
Mandatory


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9.3.1
PK Measurements 
9.3.1.1
Plasma PK Measurements
PK parameters from plasma concentrations of TAK-788 and its metabolites, AP32960 and 
AP32914, 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.
AUC:
The area under the concentration versus time curve, from time 0 
extrapolated to infinity. AUCis calculated as AUClast plus the ratio of the 
last measurable blood concentration to the elimination rate constant.
AUC%extrap:
Percent of AUCextrapolated, represented as (1 – AUClast/AUC)*100.
CL/F:
Apparent total plasma clearance after oral (extravascular) administration,
calculated as Dose/AUC(TAK-788 only).
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.
t½z:
Apparent first-order terminal disposition phase half-life will be calculated as 
0.693/λz.
λz:
Apparent first order terminal disposition phase rate constant calculated from 
a semilog plot of the plasma concentration versus time curve.
Vz/F:
Apparent volume of distribution during the terminal disposition phase after 
oral (extravascular) administration, calculated as Dose/(AUCx λz) 
(TAK-788 only).
No value for λz, AUC, AUC%extrap, CL/F, Vz/F, or t½z will be reported for cases that do not exhibit 
a linear terminal log-linear phase in the concentration versus time profile. 
No PK parameters will be calculated for subjects with detectable concentrations at 2 or fewer 
consecutive time points. 
Individual and mean plasma concentration-curves (both linear and log-linear) will be included in 
the final report.
9.3.2
Biomarker Measurements 
Not applicable
9.3.3
PGx Measurements 
Not applicable 


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9.3.4
Confinement
In each period, subjects will be housed on Day -1, at the time indicated by the CRU, until after the 
240-hour PK sample is collected and scheduled safety assessments in Period 2 are completed.
Subjects will return for study assessments/PK blood sampling as indicated in the Section 3.0. At 
all times, a subject may be required to remain at the CRU for longer at the discretion of the 
Investigator or designee.
The CRU will contact all subjects (including subjects who terminate the study early) 30 ± 2 days 
after the last TAK-788 administration to determine if any AEs have occurred since the last study 
visit.
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 


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addition, repeated or additional noninvasive testing for verification, evaluation or monitoring 
of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing of informed consent) is considered a 
concurrent medical history condition and should NOT be recorded as an AE. A baseline 
evaluation (eg, laboratory test, ECG, X-ray) should NOT be recorded as an AE unless related 
to a study procedure. However, if the subject experiences a worsening or complication of such 
a concurrent medical history condition, the worsening or complication should be recorded 
appropriately as an AE (worsening or complication occurs after informed consent is signed). 
Investigators 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.


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Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as AEs but should be documented in the subject’s source documents. 
Complications resulting from an elective surgery should be reported as AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of investigational 
drug, to or by a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. It is up to the Investigator or the reporting physician to decide 
whether a dose is to be considered an overdose, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an Overdose 
page of the CRF, in order to capture this important safety information consistently in the 
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).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent by 
a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
AEs that fulfill 1 or more of the serious criteria above are to be considered SAEs and should be 
reported and followed up in the same manner (see Sections 10.1 and 10.1.1).
10.1.2
Special Interest AEs
There are no AEs of Special Interest for this study.
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity 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 
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.


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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.

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.


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
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 LFTs) will commence at 
the time the subject signs the informed consent. Routine collection of AEs will continue until the 
follow-up phone call 30 ± 2 days after the last dose of TAK-788. For subjects who discontinue 
prior to the administration of TAK-788, 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. Non-serious AEs that begin prior to the first exposure 
to investigational product, related or unrelated to the study procedure, need not be followed-up for 
the purposes of the protocol.
All subjects experiencing AEs, whether considered associated with the use of the study medication 
or not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the CRF, whether or not the 
Investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event:


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
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 Study 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.
10.2.7.3.1
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.


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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 
Not applicable
10.2.7.5
Reporting of Abnormal LFTs
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 IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the Sponsor or 
Sponsor’s designee, SUSARs will be submitted within 7 days for fatal and life-threatening events 
and 15 days for other serious events, unless otherwise required by national regulations. The 
Sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal products administration or in the 
overall conduct of the Study. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
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.
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.


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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.
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 statistical analysis plan (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
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. Any subject who experiences emesis within 8 hours post 
dosing with TAK-788 will be excluded in the final data analysis.
11.1.1.2
Safety Set
All subjects who received at least one dose of a study drug will be included in the safety 
evaluations.
11.1.1.3
Pharmacodynamic Set 
Not applicable.
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.


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11.1.3
PK Analysis
The plasma TAK-788 and its active metabolites (AP32960 and AP32914) concentrations will be 
listed and plotted against sample collection times. PK parameters derived from the plasma 
concentrations of TAK-788 and its active metabolites (AP32960 and AP32914) and sample 
collection times will be calculated as described in Section 9.3.1.1 using appropriate summary 
statistics to be fully outlined in the SAP.
11.1.3.1
Analysis of Variance
A linear mixed-effects model will be used for the analysis on the ln-transformed Cmax, AUC, and 
AUClast for TAK-788 and its active metabolites (AP32960 and AP32914). The model will include 
sequence, treatment, and period as a fixed-effect and subject nested within sequence as a 
random-effect. Each model will include calculation of LSMs as well as the difference between 
treatment LSMs.
11.1.3.2
Ratios and Confidence Intervals
GMR and 90% CI, consistent with the two one sided test [Schuirmann 1987], will be calculated 
using the exponentiation of the difference between treatment LSMs from the analyses on the 
ln-transformed Cmax, AUC, and AUClast (if it is needed) for TAK-788 and the combined molar 
Cmax, AUC, and AUClast (if it is needed) for TAK-788 and its active metabolites. These ratios will 
be expressed as a ratio of test treatment relative to the appropriate reference treatment. 
11.1.4
Pharmacodynamic Analysis 
Not applicable.
11.1.5
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.
11.1.5.1
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.
11.1.5.2
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.


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11.1.5.3
Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
11.1.5.4
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
Determination of Sample Size
The sample size calculation was based on the expected 2-sided 90% CI for the difference in the 
paired, log-transformed AUC∞means of TAK-788 in the presence and absence of a high-fat meal. 
The within-patient coefficient of variation for TAK-788 Cmax was estimated to be 17.2% on the 
basis of data from a clinical study conducted in healthy subjects (TAK-788-1001). If the observed 
GMR for the TAK-788 AUCin the presence and absence of high-fat is 1, with a sample size of 12, 
the 90% CI for the AUCGMR is expected to be 0.881 to 1.13 on the basis of the variance 
assumptions. Fourteen (14) adult subjects will be enrolled into this high-fat meal effect study to get 
at least 12 PK-evaluable subjects in each treatment arm according to the FDA guidance Assessing 
the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations 
Guidance for Industry (FDA FE 2019).
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, Study drug, subject medical records, informed consent documentation, and 
review of CRFs and associated source documents. It is important that the Investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to Study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the Investigator should consult with the sponsor or 


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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.
13.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the International Council on Harmonisation (ICH) Harmonised Tripartite Guideline for GCP. 
Each Investigator will conduct the study according to applicable local or regional regulatory 
requirements and align his or her conduct in accordance with the “Responsibilities of the 
Investigator” that are listed in Appendix A. The principles of Helsinki are addressed through the 
protocol and through appendices containing requirements for informed consent and Investigator 
responsibilities.
13.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable state and federal/local requirements 
of each participating region. The Sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. Those Americas sites unwilling to provide names and titles of all 
members due to privacy and conflict of interest concerns should instead provide a Federal Wide 
Assurance Number or comparable number assigned by the Department of Health and Human 
Services.
The Sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 


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subject informed consent must be obtained and submitted to the Sponsor or designee before 
commencement of the study (ie, before shipment of the Sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The Sponsor will ship drug/notify site once the Sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the Sponsor has 
received permission from competent authority to begin the Study. Until the site receives 
drug/notification no protocol activities, including screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the Investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
Sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and Sponsor.
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.


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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.
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 (eg, subject name, address, and other identifier fields 
not collected on the subject’s CRF).


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13.4
Publication, Disclosure, and Clinical Study Registration Policy
13.4.1
Publication and Disclosure
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor.
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
13.4.2
Clinical Study Registration 
In order to ensure that information on clinical studies reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical studies it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for 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 Study 
information. Once subjects receive Investigator contact information, they may call the site 
requesting enrollment into the Study. The investigative sites are encouraged to handle the Study 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of Study enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide the 
Sponsor with a written notice requesting that their information not be listed on the registry site.
13.4.3
Clinical Study Results Disclosure 
Takeda will post the results of clinical studies on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
13.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the Sponsor or Sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the Sponsor’s policy on subject compensation and treatment for 


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injury. If the Investigator has questions regarding this policy, he or she should contact the Sponsor 
or Sponsor’s designee.
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 on Harmonisation, E6 [R2] Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2.8 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix A).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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14.1.3
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4
List of Abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUClast
Area under the concentration-time curve, from time 0 to the last observed non-zero 
concentration
AUC
Area under the concentration-time curve, from time 0 extrapolated to infinity
BMI
Body mass index
bpm
Beats per minute
Cav
Average concentration
CFR
Code of Federal Regulations
CI
Confidence interval
CL/F
Apparent clearance after extravascular administration
cm
Centimeter
Cmax
Maximum observed concentration 
CRA
Clinical Research Associate
CRF
Case report form
CRU
Clinical Research Unit
CV
Coefficient of variation
CYP
Cytochrome P450
DDI
Drug-drug interaction
DiC
Drug-in-Capsule
ECG
Electrocardiogram
EGFR
Epidermal growth factor receptor 
EMEA
European Medicines Agency
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HDPE
High-density polyethylene
HER2
Human epidermal growth factor 2


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HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
kg
Kilogram
LFT
Liver function test
LSM
Least square mean
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
min
Minute
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
NSCLC
Non–small cell lung cancer
oz
Ounce
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PFT
Pulmonary function test
PT
Preferred term
QD
Once daily
QTcF
QT interval corrected for heart rate using Fridericia’s formula
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SUSAR
Suspected unexpected serious adverse reaction
t½z
Apparent first-order terminal disposition phase half-life
TBD
To be determined
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
tmax
Time to reach Cmax
ULN
Upper limit of normal
US
United States
USA
United States of America
Vz/F
Apparent volume of distribution after extravascular administration
WHO
World Health Organization
WT
Wild-type
λz
Apparent first order terminal disposition phase rate constant


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15.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan.
15.1
CRFs
Celerion standard CRFs will be supplied. CRFs are produced, stored electronically, and are 
available to the designated study team members. Each CRF is reviewed and signed by the PI. The 
final signed CRFs are provided to the Sponsor in the format as decided upon between Celerion and 
the Sponsor (eg, CD, flashdrive, SFTP). This will be documented in the Data Management Plan (if 
applicable).
After completion of the entry process, edit checks are then performed for appropriate databases as 
a validation routine using SAS® or comparable statistical program to check for missing data, data 
inconsistencies, data ranges, etc. Corrections are made prior to database lock. 
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. 
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/designee with use of change and modification 
records of the CRFs. The Principal Investigator must review the data change for completeness and 
accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the Sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the Sponsor.
15.2
Record Retention
The Investigator agrees to keep the records stipulated in Section 15.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of CRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the Sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 [R2] Section 4.9.5 requires the Investigator to retain essential documents specified in ICH E6 
[R2] (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, 


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09 June 2020
ICH E6 [R2] 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.
16.0
REFERENCES
European Medicines Agency Committee for Medicinal Products for Human Use: Guideline on the 
Investigation of Bioequivalence. January 2010. 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequival
ence-rev1_en.pdf
National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE), Revised: 
Nov-2017 (v5.0). Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for 
assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987;15: 
657-680.
TAK-788. Millennium Pharmaceuticals, Inc. Global Investigator Brochure. Edition 4.0,
01-April-2020.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) Draft Guidance Bioavailability Studies Submitted in NDAs or 
INDs — General Considerations Guidance for Industry. February 2019. 
https://www.fda.gov/media/121311/download
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug 
Evaluation and Research (CDER) Draft Guidance Assessing the Effects of Food and Drugs in 
INDs and NDAs — Clinical Pharmacology Considerations Guidance for Industry. February 2019. 
https://www.fda.gov/media/121313/download


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17.0
APPENDICES
Appendix A
Responsibilities of the Investigator
Clinical research studies sponsored by the Sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on Investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the Investigator may participate in this study.
The Investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. If the Investigator/institution retains the services of any individual or party to perform 
Study-related duties and functions, the Investigator/institution should ensure that this 
individual or party is qualified to perform those Study-related duties and functions and should 
implement procedures to ensure the integrity of the Study-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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09 June 2020
Appendix B
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s).
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. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from signing the informed consent and throughout the duration of the study, and for 
30 days after the last dose of study drug. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing and non-childbearing potential. If a subject is 
found to be pregnant during study, study drug will be discontinued and the Investigator will 
offer the subject the choice to receive unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) 
from signing the informed consent throughout the duration of the study and for 30 days after 
the last dose of study drug. If the partner or wife of the subject is found to be pregnant during 
the study, the Investigator will offer the subject the choice to receive unblinded treatment 
information. 
27. A statement that clinical Study information from this Study 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 Study registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix D
Pregnancy and Contraception 
Contraception and Pregnancy Avoidance Procedure
TAK-788 may pose a risk to developing fetuses or to babies who are being breastfed. Because 
TAK-788 may affect an unborn baby, female participants should not become pregnant while in 
this study, and male participants should not conceive with their female partner(s) while in this 
study. Women who are pregnant or breastfeeding will not be allowed to take part in this study.
Women of childbearing potential and male patients must use medically acceptable birth control. 
Avoiding sexual activity is the only certain way to prevent pregnancy. 
Males Subjects and Their Female Partners:
It is not known whether the study medication will affect sperm or an unborn baby. Based on animal 
studies, taking TAK-788 may lead to testicular changes that could impact reproduction. For this 
reason, to be in the study males must agree not to father a child or donate sperm during the study 
and for 30 days after the last dose of TAK-788. 
If a male has not had a vasectomy and is sexually active with any person who is pregnant, or could 
get pregnant, he must use a condom with spermicide each time he has sex during the study and for 
30 days after last dose of TAK-788. No restrictions are required for a vasectomized male provided 
his vasectomy has been performed 4 months or more prior to the first dosing of study drug. A male 
who has been vasectomized less than 4 months prior to study first dosing must follow the same 
restrictions as a non vasectomized male and must agree to use an appropriate method of barrier 
contraception (latex condom with a spermicidal agent) during the entire study, and for 30 days 
after his last dose of TAK-788. Or, he should completely avoid having heterosexual intercourse.
If a female partner does become pregnant while a male subject is taking part in the study, the 
subject must tell the study doctor immediately.
In this situation, the female partner should be under medical supervision during her pregnancy, and 
the baby should be under supervision after it is born. The female partner may be asked to give her 
consent to the collection of information related to both herself as well as the baby.
Acceptable birth control for males with female partners includes any of the following:

total abstinence (no sexual intercourse) if it agrees with his preferred and usual lifestyle

a barrier method (latex condom with a spermicidal agent)
Males must use acceptable birth control during the study treatment period and for at least 30 days 
after their last dose of TAK-788 and should tell their female partner(s) that they are in research 
study.
Females:
Females must agree not to become pregnant, breastfeed a baby or donate an egg or eggs (ova) 
during the study and for 30 days after the last dose of TAK-788. Women of childbearing potential 
must use acceptable birth control from the time of signing the informed consent form until at least 
30 days after their last dose of TAK-788.


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If a female has been surgically sterilized or is postmenopausal, she does not need to meet any 
contraception requirements to take part in this study. If a female is of childbearing potential and is 
sexually active with a male partner, she must be willing to use an acceptable method of 
contraception during the study and for 30 days after the last dose of TAK-788.
TAK-788 may decrease effectiveness of hormonal contraceptives, therefore, women of 
childbearing potential must use effective non-hormonal methods of contraception. Acceptable 
birth control for women of childbearing potential with male partners must include one form of 
highly effective non-hormonal contraception and one additional effective (barrier) method, as 
described below:
Highly effective non-hormonal methods
Additional effective (barrier) methods 
Non-hormonal intrauterine device 
Male or female condom with or without spermicide 
(female and male condoms should not be used together)
Vasectomised sole sexual partner (removal of the tube 
that carries sperm from the testicle to the penis)
Sexual abstinence (no sexual intercourse, additional 
effective barrier method therefore not applicable)
Cap, diaphragm or sponge with spermicide
Total abstinence (no sexual intercourse) may be considered an acceptable method of birth control 
if it agrees with her preferred and usual lifestyle. 
In order to enter the study, all females must have a pregnancy test to confirm that she is not 
pregnant. This test will be repeated just before she starts taking the first study medication and then 
regularly throughout the study, at each check-in. If a pregnancy test during the study shows that 
she may be pregnant, she will be withdrawn from the study and the treatment will end. She will be 
asked for the results of any tests and procedures carried out during pregnancy and up to the birth. 
She may also be asked for the results from any evaluation of the baby after the birth.


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate the Effect of 
High-Fat Meal on TAK-788 Pharmacokinetics in Healthy Adult Subjects
NCT Number: NCT04441255
SAP Approve Date: 10 August 2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: TAK-788-1005
CELERION STUDY NUMBER: CA24171
A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate the Effect of
High-Fat Meal on TAK-788 Pharmacokinetics in Healthy Adult Subjects
PHASE 1
Version: Final
Date: 10 August 2020
Prepared by:
Based on:
Final Protocol Date: 09 June 2020
PPD


TAK-788-1005
Celerion Study Number CA24171
Page 2 of 20
Statistical Analysis Plan Final
10 August 2020
1.1
Approval Signatures
Study Title:
A Phase 1, Randomized, 2-Period, 2-Sequence, Crossover Study to Evaluate 
the Effect of High-Fat Meal on TAK-788 Pharmacokinetics in Healthy 
Adult Subjects
PPD


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Celerion Study Number CA24171
Page 3 of 20
Statistical Analysis Plan Final
10 August 2020
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objective......................................................................................................7
4.2
Secondary Objective..................................................................................................7
4.3
Exploratory Safety Objective .....................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoints .....................................................................................................8
5.2
Secondary Endpoints .................................................................................................8
5.3
Exploratory Safety Endpoints ....................................................................................8
5.4
Additional Endpoints .................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................12
7.2
Analysis Sets ...........................................................................................................13
7.3
Study Information....................................................................................................13
7.4
Disposition of Subjects ............................................................................................13
7.5
Demographic and Other Baseline Characteristics.....................................................13
7.6
Medical History and Concurrent Medical Conditions...............................................13
7.7
Medication History and Concomitant Medications...................................................14
7.8
Study Drug Exposure and Compliance.....................................................................14
7.9
Efficacy Analysis.....................................................................................................14
7.10
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................14
7.10.1 Pharmacokinetic Analysis ..................................................................................14
7.10.2 Pharmacodynamic Analysis ...............................................................................16
7.11
Other Outcomes.......................................................................................................16
7.12
Safety Analysis........................................................................................................16
7.12.1 Adverse Events ..................................................................................................16
7.12.2 Clinical Laboratory Evaluations .........................................................................17
7.12.3 Vital Signs .........................................................................................................18


TAK-788-1005
Celerion Study Number CA24171
Page 4 of 20
Statistical Analysis Plan Final
10 August 2020
7.12.4 12-Lead ECGs ...................................................................................................18
7.12.5 Pulmonary Function Test ...................................................................................18
7.12.6 Physical Exams..................................................................................................18
7.12.7 Overdose............................................................................................................18
7.13
Interim Analysis ......................................................................................................19
7.14
Preliminary Analysis................................................................................................19
7.15
Changes in the Statistical Analysis Plan...................................................................19
8.0
REFERENCES..............................................................................................................20


TAK-788-1005
Celerion Study Number CA24171
Page 5 of 20
Statistical Analysis Plan Final
10 August 2020
3.0
LIST OF ABBREVIATIONS
AE
adverse event
ANOVA
analysis of variance
AUC
area under the curve 
AUCextrap%
percent of AUC∞extrapolated
AUC∞
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of the last 
quantifiable concentration
BLQ
below the limit of quantitation 
BMI
body mass index
CI
confidence interval
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CPAP
clinical pharmacology analysis plan
CRF
case report form
CS
clinically significant 
DMP
Data Management Plan
ECG
electrocardiogram
FDA
Food and Drug Administration
FE
food effect
GMR
geometric mean ratio
ICF
informed consent form
IND
Investigational New Drug
λz
terminal disposition phase rate constant
LSM
least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
MPR
metabolite to parent ratio
NDA
New Drug Application
PFT
pulmonary function test
PI
Principal Investigator 
PK
pharmacokinetics
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
System Organ Class
t½z
terminal disposition phase half-life
TEAE
treatment-emergent adverse event
TFL
tables, figures, and listings 
tmax
time of first occurrence of Cmax
Vz/F
apparent volume of distribution during the terminal disposition phase after 


TAK-788-1005
Celerion Study Number CA24171
Page 6 of 20
Statistical Analysis Plan Final
10 August 2020
extravascular administration
WHO
World Health Organization


TAK-788-1005
Celerion Study Number CA24171
Page 7 of 20
Statistical Analysis Plan Final
10 August 2020
4.0
OBJECTIVES
4.1
Primary Objective
To characterize the effect of a high-fat meal on the pharmacokinetics (PK) of mobocertinib 
(referred to as TAK-788 in the protocol) administered as a proposed commercial product.
4.2
Secondary Objective
To assess the PK of active metabolites AP32960 and AP32914 of mobocertinib.
4.3
Exploratory Safety Objective 
To collect the safety data of mobocertinib following a single oral dose in healthy adult subjects.
4.4
Study Design
This is an open-label, randomized, 2-period, and 2-sequence crossover high-fat meal effect study 
in healthy adult subjects.
Subjects will undergo screening evaluations to determine eligibility within 21 days prior to 
dosing. Subjects will be admitted to the clinical facility the day prior to dosing in each period 
(Day -1). Subjects will be randomized on Day 1 of Period 1 to a crossover sequence in a 1:1 ratio 
and administered a single oral dose of 160 mg of mobocertinib with or without a high-fat meal 
on Day 1 of each period (i.e., Period 1 and Period 2). Each dose will be separated by a washout 
period of 10 days. Blood samples for mobocertinib PK will be collected predose and up to 
240 hours following each mobocertinib dose.
Subjects will receive the following treatments on one occasion in a crossover fashion to evaluate 
the effect of a high-fat meal:

Treatment A: Administration of a single oral dose of 160 mg mobocertinib (4 x 40 mg 
capsules) following an overnight fast. 

Treatment B: Administration of a single oral dose of 160 mg mobocertinib (4 x 40 mg 
capsules) with a high-fat meal.
* 800-1000 total calories, 500-600 calories, 55-65 g, or 50% from fat
Subjects will remain at the clinical site until the 240-hour study assessments in Period 2 are 
completed. All doses of mobocertinib will be administered at the clinic during this study. A final 
safety follow-up phone call will occur 30 ± 2 days after the last mobocertinib dose to determine 
if any adverse events (AEs) have occurred since the last study visit. Replacement of discontinued 
or withdrawn subjects due to any reason will be assessed on a case by case basis by the Sponsor 
and the Principal Investigator (PI) to ensure a minimum of 12 PK-evaluable subjects complete 
the study.
Any subject who experiences emesis within 8 hours postdose will be excluded in the final PK 
data analysis and may be replaced with a new subject.


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints 
The following PK parameters will be analyzed for mobocertinib: 

Time of first occurrence of Cmax (tmax).

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞).

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).
5.2
Secondary Endpoints 
The following PK parameters will be analyzed for active metabolites (AP32960 and AP32914) 
of mobocertinib: 

Time of first occurrence of Cmax (tmax).

Maximum observed concentration (Cmax).

Area under the concentration-time curve from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞).

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast).
5.3
Exploratory Safety Endpoints 
The exploratory endpoint will be assessed through evaluation of the following safety parameters: 

Treatment-emergent adverse events (TEAEs) assessments.

Clinical laboratory (hematology, serum chemistry, and urinalysis). 

Physical examinations.

12-lead electrocardiograms (ECGs).

Vital signs.


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5.4
Additional Endpoints 
In addition, the following plasma PK parameters for mobocertinib and its active metabolites 
(AP32960 and AP32914) will be calculated: 

Terminal disposition phase half-life (t½z).

Terminal disposition phase rate constant (λz).

Percent of AUC∞extrapolated

Apparent clearance after extravascular administration (CL/F) for mobocertinib only.

Apparent volume of distribution during the terminal disposition phase after extravascular 
administration (Vz/F) for mobocertinib only.

The metabolite to parent ratio for molar AUC∞(MPR AUC∞) for AP32960 and 
AP32914.


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6.0
DETERMINATION OF SAMPLE SIZE
The sample size calculation was based on the expected 2-sided 90% confidence interval (CI) for 
the difference in the paired, log-transformed AUC∞means of mobocertinib in the presence and 
absence of a high-fat meal. The within-patient coefficient of variation for mobocertinib Cmax was 
estimated to be 17.2% on the basis of data from a clinical study conducted in healthy subjects 
(TAK-788-1001). If the observed geometric mean ratio (GMR) for the mobocertinib AUC∞in 
the presence and absence of high-fat is 1, with a sample size of 12, the 90% CI for the AUC∞
GMR is expected to be 0.881 to 1.13 on the basis of the variance assumptions. Fourteen (14) 
adult subjects will be enrolled into this high-fat meal effect study to get at least 12 PK-evaluable 
subjects in each treatment according to the Food and Drug Administration (FDA) guidance 
Assessing the Effects of Food on Drugs in Investigational New Drugs (INDs) and New Drug 
Applications (NDAs) – Clinical Pharmacology Considerations Guidance for Industry (FDA food 
effect [FE] 2019).


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 8.1, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4, or higher. All data recorded on the 
case report form (CRF) will be listed by subject. All tables, figures, and listings (TFLs) shells 
and numbering list will be included.
The concentration data will be used as reported by the respective bioanalytical groups without 
rounding for all analyses. 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 (e.g. BLQ value 
between 2 measurable values [except in cases where more than 2 samples are BLQ between 
measurable concentrations, BLQ values will be set to 0 instead of missing]), in which case they 
will be treated as missing. In log-linear plots, these values would not be presented. Missing 
concentration values will be flagged in the concentration tables and footnoted as missing or not 
reportable (i.e., for subjects withdrawn or dropped from the study, subjects missing blood 
draws). Plasma concentration data from subjects excluded from PK parameter analysis will be 
included in the concentration tables and individual figures, but will be excluded from summary 
statistics and in the presentation of mean figures.
All concentration and PK parameter values will be presented to 3 significant figures. For 
concentration and PK parameter tables, all summary statistics will be presented to 3 significant 
figures. Geometric least-squares means (LSMs) will be presented with 3 significant figures. 
GMRs and 90% CIs around the ratio will be reported using 2 decimal places.
For the calculation of PK parameters, if actual times are missing, nominal times will be used 
instead.
A subject’s PK parameter data will be included in the listings but excluded from the descriptive 
statistics and statistical evaluation if one or more of the following criteria are met:

A predose (0 hr) concentration is greater than 5% of that subject’s Cmax value in that 
period

A subject did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist)

A subject deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing/consumption, etc. (as 
determined by the Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic 
Scientist)


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See CPAP for details on the PK parameter calculations and data presentation including specifics 
on the following:

Insufficient data to determine a reliable t½z value and other terminal elimination rate 
constant dependent parameters

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

Analysis of variance (ANOVA) results presented in in-text and end of text tables

Arithmetic mean concentration-time figures presented as in-text and end-of-text figures

Individual concentration-time figures presented in Appendix 16.2.6

Any subject, PK concentration, and PK parameter that are excluded in the PK data 
analyses or summary statistical analyses will be provided in end of text tables.
For demographic data where appropriate, variables will be summarized descriptively. For the 
categorical variables, the count and proportions of each possible value will be tabulated, where 
applicable. The denominator for the proportion will be based on the number of subjects who 
provided non-missing responses to the categorical variable. For appropriate continuous variables, 
the number of subjects with non-missing values, mean, standard deviation (SD), minimum, 
median, and maximum values will be tabulated.
7.1.1
Study Definitions
7.1.1.1
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 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-date of first dose in each period; study day on or after the date 
of first dose will be calculated as: date of assessment-date of first dose in each period +1.
For all clinical laboratory evaluations, vital signs, and 12-lead ECGs, baseline is defined as the 
last assessment including rechecks taken prior to mobocertinib dosing at each period.


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7.2
Analysis Sets
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. Any subject who experiences emesis within 8 hours 
post dosing with mobocertinib will be excluded in the final data analysis.
Safety Set: 
All subjects who received at least one dose of a study drug will be included in the safety 
evaluations.
7.3
Study Information
A study information table will be generated including the following items: date of first subject’s 
signed informed consent form (ICF), date of first dose, date of last dose, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint, the 
version of Medical Dictionary for Regulatory Activities (MedDRA®), the version of World 
Health Organization (WHO) Dictionary, and SAS version used for creating the datasets.
7.4
Disposition of Subjects
Disposition of subjects (number of subjects dosed, completed the study, discontinued from the 
study, and reason(s) for discontinuation) will be summarized by randomized treatment sequence 
and overall. Study completion status, including reason for discontinuation, will also be listed by 
subject.
7.5
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized descriptively by randomized 
treatment sequence and overall. Summary statistics (number of subjects [n], mean, SD, 
minimum, median, and maximum) will be generated for continuous variables (age [recorded in 
the CRF], weight, height and body mass index [BMI]) and the number and percentage of 
subjects within each category will be presented for categorical variables (sex, race, and 
ethnicity). Height, weight, and BMI recorded at screening will be used in the baseline 
summaries. Demographics data will also be listed as recorded on the CRF, including the date of 
informed consent.
7.6
Medical History and Concurrent Medical Conditions
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or before signing the 
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 


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be listed. Any medical condition started after taking the study drug will be classified as an 
adverse event. All medical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®), as described in the Data Management Plan (DMP). The medical history 
listing will include whether the event was medical or surgical, the body system or organ class 
involved, coded term, start date (if known) and end date or whether the condition was ongoing, 
and a description of the condition or event. There will be no statistical analysis of medical 
history.
7.7
Medication History and Concomitant Medications
Medication history to be obtained includes any medication relevant to eligibility criteria and 
safety evaluation stopped at or within 28 days prior to signing the ICF. Concomitant medication 
includes any medication other than study drug taken at any time between time of signing the ICF 
through the end of the study (including follow-up visit). All medication history and concomitant 
medications recorded during the study will be coded with the MedDRA® Version 23.0, as 
described in the DMP, and listed. If appropriate, the listing will include the medication name, 
coded term, dosage, route of administration, start date and time (if known), end date and time, or 
whether it continued after study completion, and indication for use.
7.8
Study Drug Exposure and Compliance
The date, time, and dosage of each mobocertinib dose along with meal data will be listed by 
subject.
7.9
Efficacy Analysis
Not applicable. 
7.10
Pharmacokinetic/Pharmacodynamic Analysis
7.10.1 Pharmacokinetic Analysis
Blood samples for PK analysis of mobocertinib, AP32960, and AP32914 will be collected as 
specified in Table 7:1 following administration of mobocertinib under fasted conditions 
(Treatment A) or with a high-fat meal (Treatment B).
Table 7:1
Collection of Blood Samples for Pharmacokinetic Analysis
Analyte
Matrix
Sampling Day
Period
Scheduled Time (hours)
mobocertinib, 
AP32960, and 
AP32914
Plasma
1
1 and 2
Predose and 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 120, 168, and 240 
hours postdose (a) (b)
(a) If a subject experiences a serious adverse event (SAE), a blood sample for PK analysis should also be obtained 
at the unscheduled visit. PK samples will be collected at Early Termination at the discretion of the PI.
(b) The Period 1 Day 11 PK sample will serve as the pre-dose PK sample for Period 2.


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The actual date and time of sample collection will be recorded on the source document in the 
CRF.
Concentrations will be listed and summarized descriptively by PK sampling time in mass units 
for plasma mobocertinib, AP32960, and AP32914. Summary will be done by treatment using the 
summary statistics listed in the CPAP. Excluded concentrations will be presented and footnoted 
as such in the concentration table listings, and those values will be excluded from the descriptive 
summary statistics. Individual subject and arithmetic mean profiles of the concentration-time 
data will be plotted by treatment on linear (with and without SD) and semi-log scales in mass 
units for each analyte. For summary statistics and arithmetic mean plots by sampling time, the 
nominal PK sampling time will be used, for individual subject plots by time, the actual PK 
sampling time will be used.
The PK parameters of mobocertinib, AP32960, and AP32914 listed in the CPAP for this study 
will be determined from the concentration-time profiles for subjects in the PK set using a 
noncompartmental analysis method in mass units. The molar AUClast, AUC∞, and Cmax PK
parameters will also be calculated for plasma mobocertinib, AP32960, and AP32914 using the 
molecular weights of each analyte as outlined in the CPAP. Combined molar AUClast, AUC∞,
and Cmax for plasma mobocertinib, AP32960, and AP32914 will also be presented. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations involving 
sampling times. If actual sample times are missing, nominal times may be used.
PK parameters will be summarized descriptively by treatment using the summary statistics listed 
in the CPAP in mass units and molar units. 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.
Food Effect
For evaluation of potential effect of a high-fat meal on mobocertinib PK, a linear mixed-effects 
model will be used for the analysis on the ln-transformed Cmax, AUC∞, and AUClast (only if 
AUC∞is not available for at least 12 subjects) for mobocertinib (mass units) and combined molar 
Cmax, AUC∞, and AUClast (only if AUC∞is not available for at least 12 subjects) for 
mobocertinib, AP3260, and AP32914. The mixed effects models will include sequence, 
treatment, and period as fixed effects, and subject nested within sequence as a random effect. 
Each model will include calculation of LSMs as well as the difference between LSMs.
GMR and 90% CIs, consistent with the two one-sided tests, will be calculated using the 
exponentiation of the difference between treatment LSMs from the analyses on the 
ln-transformed Cmax, AUC∞, and AUClast (only if AUC∞is not available for at least 12 subjects) 
for mobocertinib, as well as the ln-transformed molar combined Cmax, AUC∞, and AUClast (only 
if AUC∞is not available for at least 12 subjects) for mobocertinib, AP32960, and AP32914. The 
comparison of interest is as follows: 
Treatment B (High-Fat Meal) relative to Treatment A (Fasted)
The following SAS code will be used: 


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PROC MIXED DATA=XXXX;
CLASS Treatment Subject Period Sequence;
MODEL <PK_Parameter> = Treatment Period Sequence / DDFM=KR;
RANDOM Subject(Sequence);
ESTIMATE ‘Treatment B vs A’ Treatment -1 1 / CL ALPHA = 0.10 E;
LSMEANS Treatment;
Run;
Nonparametric Analysis of tmax
A nonparametric analysis for tmax will be performed to compare treatment differences using the 
Wilcoxon Signed Rank test. Median difference (Test-Reference), the Hodges-Lehmann 
estimator, and estimated confidence interval will be used to examine the location shift in tmax. 
The tmax parameter will not be ln-transformed. The median difference, associated 95% CI, and 
p-value will be presented.
7.10.2 Pharmacodynamic Analysis
Not applicable.
7.11
Other Outcomes
Not applicable. 
7.12
Safety Analysis
Safety will be evaluated by the incidence of TEAEs, severity and type of TEAEs, changes from 
baseline in the subjects’ clinical laboratory results, vital signs, and ECG’s using the safety set. 
All clinical safety data will be listed by subject and assessment time points, including rechecks, 
unscheduled assessments, and early termination, chronologically. 
Continuous variables will be summarized using n, mean, SD, minimum, median, and maximum. 
Frequency counts and percentages will be reported for categorical data when appropriate. Where 
individual data points are missing because of dropouts or other reasons, the data will be 
summarized based on reduced denominators.
7.12.1 Adverse Events 
All AEs captured in the database will be listed in by-subject data listings including verbatim 
term, coded term, severity (1=Grade 1: Mild, 2=Grade 2: Moderate, 3=Grade 3: Severe or 
medically significant but not immediately life-threatening, 4=Grade 4: Life-threatening , 
5=Grade 5: Death), relationship to study drug (related or not related) and action relative to the 
study drug mobocertinib. Study procedure taken due to AE will also be listed. All AEs occurring 
during this study will be coded using the MedDRA® Version 23.0. However, only TEAEs 
occurring after administration of the first dose of study drug and through the end of the study 
will be summarized. 


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A TEAE is defined as an AE that is starting or worsening at the time of or after study drug 
administration. 
For each treatment, TEAEs will be tabulated by System Organ Class (SOC) and Preferred Term. 
Summary tables will include number of subjects reporting the AE and as percent of safety set by 
treatment. The most commonly reported non-serious TEAEs (i.e., those events reported by >5% 
of all subjects in each treatment, excluding SAEs) will also be summarized. For the list of all AE 
summary tables, see TFL Shell document.
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.
Should any SAEs occur or AEs leading to study drug discontinuation they will be summarized 
the same way as TEAE. All AEs will be displayed in the data listings and TEAEs will be 
discussed in the text of the Clinical Study Report (CSR).
7.12.2 Clinical Laboratory Evaluations
Hematology, serum chemistry, and urinalysis will be performed at screening, check-in (Day -1) 
of each period, Day 4 of each period or prior to early termination from the study, and at the end 
of Period 2. In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the PI.
For all laboratory values that are numeric, summary statistics (n, mean, SD, minimum, median, 
and maximum) will be presented for each laboratory test by treatment and assessment time 
points. Change from baseline will be summarized. Baseline is defined as the last assessment 
including rechecks taken prior to the first dosing in each period (Day -1). 
For each laboratory test, a shift table will be developed comparing the frequency and percentage
of the results at baseline (above normal (H), normal (N), or below normal (L)) with the postdose 
time points. For urinalysis tests, the categories are normal (N) and abnormal (A). Out-of-range 
values and corresponding recheck results will be listed. 
Out-of-normal range flags will be recorded as follows: high (H) and low (L) for numerical 
results and did-not-match (*) for categorical results. If a value fails the reference range, it will 
automatically be compared to a clinically significant (CS) range. If the value falls within the CS 
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. Additionally, the PI will 


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provide a 4th flag when the 3rd flag indicates “R” or “^”.  This 4th flag is intended to capture 
final CS (+)/NCS (-) when the 3rd flag does not document significance. All clinically significant 
laboratory tests, as indicated by the PI, and the corresponding values will be listed by subject. All 
clinical laboratory data will be presented in by-subject data listings. CS results will also be 
presented in a table.
7.12.3 Vital Signs
Single measurements of heart rate and blood pressure will be obtained at screening, predose
(Day -1), 4 and 12 hours of Day 1, and Day 2 postdose (times relative to mobocertinib dose) in 
each period or upon early termination, and at the end of Period 2. Respiration rate and 
temperature will only be collected at screening. Additional unscheduled vital signs 
measurements may be taken at other times, if deemed necessary by the PI.
Summary statistics (n, mean, SD, minimum, median, and maximum) will be reported for vital 
sign results and change from baseline by treatment and time point of collection. Baseline is 
defined as the last assessment including rechecks taken prior to dosing in each period (Day -1). 
Change from baseline will not be calculated for respiratory rate and temperature. Vital signs will 
also be displayed in a data listing by subject.
7.12.4 12-Lead ECGs
12-lead ECGs will be recorded at screening, predose (Day -1), 4 hours of Day 1 postdose (time
relative to mobocertinib dose) or upon early termination, and at the end of Period 2. 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 dosing in each period (Day -1). ECG data 
will also be displayed in a data listing by subject.
7.12.5 Pulmonary Function Test
Pulmonary function tests (PFTs) may be performed in the event of a pulmonary AE and deemed 
clinically necessary, as determined by the PI. PFT results if present will be presented in a data 
listing by subject.
7.12.6 Physical Exams
A full physical exam will be performed at screening. Symptom-driven physical exams may be 
performed at other times at the discretion of the PI. Physical exam findings will be presented in a 
data listing by subject. Reproductive system findings will also be listed by subject.  
7.12.7 Overdose 
All cases of overdose will be presented in a data listing by subject. Any AEs associated with 
overdose will be documented as AEs.


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7.13
Interim Analysis
Not applicable. 
7.14
Preliminary Analysis
Analysis will be completed as described in the CPAP and Section 7.10.1 of the SAP, with the 
following changes: 1) QCed data will be used (not QAed); 2) nominal times will be used for the 
calculation of PK parameters (not actual sampling times); 3) tables and figures will be created 
using Phoenix® WinNonlin® Version 8.1 or higher.
7.15
Changes in the Statistical Analysis Plan 
Section 11.1.3.1 of the protocol stated that AUClast will be included in the ANOVA for 
TAK-788. However, Section 11.1.3.2 of the protocol stated that AUClast will be included in the 
calculation of GMR and 90% CI only if it is needed. The SAP clarified that AUClast will be 
included in the ANOVA only if AUC∞is not available for at least 12 subjects. 


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8.0
REFERENCES
Not applicable. 


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