Clinical trial NCT05818956
Conditions: Healthy Volunteers
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2023-05-25; Completion date: 2023-06-26
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main aim of this study is to test the effects of food consumption with sponsor compound TAK-227 in healthy participants. The study will also measure side effects, and to check how much TAK-227 stays in the blood over time to work out the best dose.

Detailed description:
The drug being tested in this study is called TAK-227. This study will assess the effect of food on single-dose of TAK-227 in healthy participants.

The study will enroll approximately 24 participants. A single dose of 50 milligram (mg) TAK-227 will be administered orally under one of 3 different feeding conditions.

* Fasting (Treatment A),
* Fed following a high-fat or high-calorie meal prior to dosing (Treatment B), and
* Fed following a high-fat or high-calorie meal after dosing (Treatment C)

Participants will be randomly assigned to 1 of the 6 treatments sequences based on the 3 feeding conditions.

* Sequence 1: (Treatment A + Treatment B + Treatment C)
* Sequence 2: (Treatment B + Treatment C + Treatment A)
* Sequence 3: (Treatment C + Treatment A + Treatment B)
* Sequence 4: (Treatment A + Treatment C + Treatment B)
* Sequence 5: (Treatment B + Treatment A + Treatment C)
* Sequence 6: (Treatment C + Treatment B + Treatment A)

All participants will receive all 6 treatment regimens. This is a single-center trial. Participants will be followed up for up to 7 days after the last dose of study drug for a follow-up assessment. The overall time to participate in this study is approximately 40 days including screening period and follow-up period.

Arms: arm 1: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 under fasting condition as Treatment A, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C. There will be a washout period of at least 4 days between each dosing. arm 2: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 under fasting condition as Treatment A . There will be a washout period of at least 4 days between each dosing. arm 3: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 under fasting condition as Treatment A, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B. There will be a washout period of at least 4 days between each dosing. arm 4: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 under fasting condition as Treatment A, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B. There will be a washout period of at least 4 days between each dosing. arm 5: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 under fasting condition as Treatment A, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C. There will be a washout period of at least 4 days between each dosing. arm 6: TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 1 administered with a high fat/high calorie meal 30 minutes after dosing as Treatment C, followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 2 administered with a high fat or high calorie meal 30 minutes prior to dosing as Treatment B, and further followed by TAK-227 50 mg, capsule, single oral dose on Day 1 of Treatment Period 3 under fasting condition as Treatment A. There will be a washout period of at least 4 days between each dosing.
Interventions: intervention 1: TAK-227
Intervention descriptions: intervention 1: TAK-227 capsules.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


 
CONFIDENTIAL INFORMATION
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Open-Label, Single-Dose, Three-Way Crossover Evaluation of the Effect of 
Food on the Pharmacokinetics, Safety, and Tolerability of TAK-227 in Healthy Adult 
Participants
Study Identifier:
TAK-227-1001
Compound:
TAK-227
Date:
15 February 2023 
Version/Amendment 
Number:
Amendment History
Amendment 1 Protocol 
Date
Amendment Number
Amendment Type
Region
14 November 2022
Initial Version
United States
15 February 2023 
01
Not Applicable
United States
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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TABLE OF CONTENTS
1.0
STUDY SUMMARY ......................................................................................................6
2.0
STUDY SCHEMATIC..................................................................................................11
3.0
SCHEDULE OF STUDY PROCEDURES ....................................................................12
4.0
INTRODUCTION.........................................................................................................14
4.1
Background .............................................................................................................14
4.2
Rationale for the Proposed Study.............................................................................15
4.3
Benefit/Risk Profile .................................................................................................15
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................16
5.1
Hypothesis...............................................................................................................16
5.2
Study Objectives......................................................................................................16
5.2.1
Study Primary Objective..................................................................................16
5.2.2
Study Secondary Objective..............................................................................16
5.2.3
Study Exploratory Objectives ..........................................................................16
5.3
Endpoints.................................................................................................................17
5.3.1
Primary Endpoint.............................................................................................17
5.3.2
Secondary Endpoints .......................................................................................17
5.3.3
Exploratory Endpoint.......................................................................................17
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................18
6.1
Study Design ...........................................................................................................18
6.2
Dose Escalation .......................................................................................................19
6.3
Stopping Rules.........................................................................................................19
6.4
Rationale for Study Design, Dose, and Endpoints ....................................................19
6.4.1
Rationale of Study Design ...............................................................................19
6.4.2
Rationale for Dose...........................................................................................19
6.4.3
Rationale for Endpoints ...................................................................................19
6.4.4
Future Biomedical Research ............................................................................19
6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures ............20
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters...............................................................................................................20
6.6
Study Beginning and End/Completion .....................................................................20
6.6.1
Definition of Beginning of the Study ...............................................................20
6.6.2
Definition of End of the Study.........................................................................20
6.6.3
Definition of Study Discontinuation.................................................................20
6.6.4
Criteria for Premature Termination or Suspension of the Study........................20
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6.6.5
Criteria for Premature Termination or Suspension of a Site..............................21
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS .....21
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 Participant......................................25
7.6
Procedures for Discontinuation or Withdrawal of a Participant ................................27
7.7
Participant Replacement ..........................................................................................27
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................27
8.1
Clinical Study Drug .................................................................................................27
8.1.1
Clinical Study Drug Labeling ..........................................................................27
8.1.2
Clinical Study Drug Inventory and Storage......................................................27
8.1.3
Clinical Study Drug Blinding...........................................................................28
8.1.4
Randomization Code Creation and Storage......................................................28
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure.................................28
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs.............................28
9.0
STUDY PROCEDURES...............................................................................................28
9.1
Administrative Procedures.......................................................................................28
9.1.1
Informed Consent Procedure............................................................................28
9.1.2
Inclusion and Exclusion...................................................................................29
9.1.3
Medical History/Demography..........................................................................29
9.1.4
Concomitant Medications ................................................................................29
9.2
Clinical Procedures and Assessments.......................................................................29
9.2.1
Full Physical Exam..........................................................................................30
9.2.2
Height and Weight...........................................................................................30
9.2.3
BMI.................................................................................................................30
9.2.4
Vital Signs.......................................................................................................30
9.2.5
12-Lead ECG...................................................................................................30
9.2.6
Study Drug Administration..............................................................................30
9.2.7
AE Monitoring ................................................................................................31
9.2.8
Laboratory Procedures and Assessments..........................................................31
9.3
PK Samples .............................................................................................................33
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9.3.1
PK Measurements............................................................................................33
9.3.2
Biomarker Measurements ................................................................................34
9.3.3
PGx Measurements..........................................................................................34
9.3.4
Confinement....................................................................................................34
10.0
ADVERSE EVENTS ....................................................................................................34
10.1
Definitions and Elements of AEs .............................................................................34
10.1.1
SAEs ...............................................................................................................37
10.2
AE Procedures.........................................................................................................38
10.2.1
Assigning Severity/Intensity of AEs ................................................................38
10.2.2
Assigning Causality of AEs .............................................................................38
10.2.3
Start Date.........................................................................................................39
10.2.4
End Date..........................................................................................................39
10.2.5
Pattern of Adverse Event (Frequency)..............................................................39
10.2.6
Action Taken With Study Treatment................................................................39
10.2.7
Outcome..........................................................................................................40
10.2.8
Collection and Reporting of AEs, SAEs, and Abnormal LFTs .........................40
10.2.9
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...42
11.0
STATISTICAL METHODS..........................................................................................43
11.1
Statistical and Analytical Plans ................................................................................43
11.1.1
Analysis Sets ...................................................................................................43
11.1.2
Analysis of Demography and Other Baseline Characteristics ...........................43
11.1.3
PK Analysis.....................................................................................................43
11.1.4
PD Analysis.....................................................................................................44
11.1.5
Safety Analysis................................................................................................44
11.2
Interim Analysis and Criteria for Early Termination ................................................45
11.3
Determination of Sample Size..................................................................................45
12.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................45
12.1
Study-Site Monitoring Visits ...................................................................................45
12.2
Protocol Deviations..................................................................................................46
12.3
Quality Assurance Audits and Regulatory Agency Inspections ................................46
13.0
ETHICAL ASPECTS OF THE STUDY........................................................................46
13.1
IRB and/or IEC Approval ........................................................................................46
13.2
Participant Information, Informed Consent, and Participant Authorization...............47
13.3
Participant Confidentiality .......................................................................................48
13.4
Publication, Disclosure, and Clinical Study Registration Policy ...............................49
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13.4.1
Publication and Disclosure...............................................................................49
13.4.2
Clinical Study Registration ..............................................................................49
13.4.3
Clinical Study Results Disclosure ....................................................................50
13.5
Insurance and Compensation for Injury....................................................................50
14.0
ADMINISTRATIVE AND REFERENCE INFORMATION.........................................50
14.1
Administrative Information......................................................................................50
14.1.1
Study Contact Information...............................................................................50
14.1.2
INVESTIGATOR AGREEMENT ...................................................................51
14.1.3
Study-Related Responsibilities.........................................................................52
14.1.4
List of Abbreviations .......................................................................................52
15.0
DATA HANDLING AND RECORDKEEPING............................................................54
15.1
CRFs (Electronic and Paper)....................................................................................54
15.2
Record Retention .....................................................................................................54
16.0
REFERENCES..............................................................................................................55
17.0
APPENDICES...............................................................................................................56
LIST OF IN-TEXT TABLES
Table 2.a
Study Schematic ................................................................................................11
Table 2.b
Study Treatments for Study Drug.......................................................................11
Table 7.a
Excluded Medications, Supplements, and Dietary Products................................24
Table 8.a
Randomization Sequence ...................................................................................28
Table 9.a
Primary Specimen Collections ...........................................................................33
Table 10.a
Takeda Medically Significant AE List................................................................38
LIST OF APPENDICES
Appendix A
Responsibilities of the Investigator.....................................................................56
Appendix B
Elements of the Participant Informed Consent....................................................58
Appendix C
Investigator Consent to the Use of Personal Information ....................................61
Appendix D
Pregnancy and Contraception.............................................................................62
Appendix E
Summary of Changes from Previous Version.....................................................66
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1.0
STUDY SUMMARY
Name of Sponsor:
Takeda Development Center Americas, Inc. (TDCA)
95 Hayden Avenue
Lexington, Massachusetts 02421
Telephone: +1 (617) 679-7000
Compound:
TAK-227
Study Identifier: TAK-227-1001
Phase: 1
Protocol Title: A Randomized, Open-Label, Single-Dose, Three-Way Crossover Evaluation of the Effect of Food 
on the Pharmacokinetics, Safety, and Tolerability of TAK-227 in Healthy Adult Participants
Study Design:
This is a single-center, open-label, single-dose, randomized, 3-period, 6-sequence, crossover study in healthy adults.
Study schematic and dose regimens are shown in Table 2.a and Table 2.b. The schedule of assessments is shown in 
Schedule of Study Procedures (Section 3.0).
On Day 1 of Treatment Period 1 participants will be randomly assigned to one of 6 possible treatment sequences 
(Table 8.a). On Day 1 of each treatment period, a single dose of TAK-227 will be administered orally under one of 
3 different feeding conditions as per the randomization schedule:

Fasting (Treatment A),

Fed pre-dose, high-fat/high-calorie meal administered 30 minutes prior to dosing (Treatment B), and

Fed post-dose, high-fat/high-calorie meal administered ~30 minutes after dosing (Treatment C).
For details on food and water consumption in the different treatments refer to Section 7.4.1 and Section 9.2.6.
There will be a washout period of not less than 4 days between TAK-227 dosing in each period.
Pharmacokinetic (PK) sample collections will be conducted pre-dose and up to 36 hours post-dose in each treatment 
period.
Safety and tolerability will be assessed throughout the study by treatment-emergent adverse events (TEAEs), vital 
signs, electrocardiograms (ECGs), clinical laboratory evaluations, and physical examinations.
The clinical research unit (CRU) will contact all participants (including participants who terminate the study early) 
7 (± 3) days after the last TAK-227 administration by telephone or other methods per CRU standards to determine if 
any adverse event (AE) has occurred or concomitant medications have been taken since the last study visit. If 
clinically significant findings are observed upon discharge, participants may return to the CRU for re-evaluation per 
Investigator’s discretion.
Study Primary Objective:

To assess the PK of a single oral dose of 50 mg TAK-227 administered 30 minutes following the start of a 
high-fat/high-calorie meal or ~30 minutes before the start of a high-fat/high-calorie meal in healthy adult 
participants relative to administration under fasting conditions in healthy adult participants.
Study Secondary Objectives:

To evaluate the safety and tolerability of a single oral dose of 50 mg TAK-227 when administered under fasting 
conditions, 30 minutes following the start of a high-fat/high-calorie meal, and ~30 minutes before the start of a 
high-fat/high-calorie meal in healthy adult participants.
Study Exploratory Objective:

To evaluate other TAK-227 PK parameters for a single oral dose of 50 mg TAK-227 when administered under 
fasting conditions, 30 minutes following the start of a high-fat/high-calorie meal, and ~30 minutes before the 
start of a high-fat/high-calorie meal in healthy adult participants.

To evaluate TAK-227 metabolites PK parameters for a single oral dose of 50 mg TAK-227 when administered 
under fasting conditions, 30 minutes following the start of a high-fat/high-calorie meal, and ~30 minutes before 
the start of a high-fat/high-calorie meal in healthy adult participants.
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Study Participant Population: Healthy male and female participants aged 18 to 55 years inclusive, at screening. 
Body Mass Index (BMI) 18.0-32.0 kg/m2, inclusive, at screening.
Planned Number of Participants:
Twenty-four (24) participants may be enrolled
Planned Number of Sites:
1
Dose Levels:
50 mg TAK-227 capsule
Route of Administration:
Oral
Duration of Treatment:
Single-dose
Planned Study Duration:
Approximately 40 days including screening period of up to 
28 days and follow-up.
Criteria for Inclusion:
Participants must fulfill the following inclusion criteria to be eligible for participation in the study: 
1.
Healthy, adult, male or female, 18-55 years of age, inclusive, at screening.
* Females of childbearing potential are defined as all females physiologically capable of becoming pregnant. 
Females of non-childbearing potential are defined as follows:

Females who 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

Females who are postmenopausal with amenorrhea for at least 12 month prior to the first dosing and
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status at screening.
2.
BMI ≥18 and ≤32.0 kg/m2 at screening visit. 
3.
Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital 
signs or ECGs, as deemed by the Investigator or designee, including the following:

Seated blood pressure ≥ 90/40 mmHg and ≤ 140/90 mmHg at screening visit.

Seated heart rate ≥ 40 bpm and ≤ 99 bpm at screening visit.

QTcF interval ≤ 460 msec (males) or ≤ 470 msec (females) and has ECG findings considered normal 
or not clinical significance by the Investigator or designee at screening visit.

Estimated creatinine clearance ≥ 90 mL/min at screening visit.

Total bilirubin <1.25 × ULN at screening visit unless the participant has known Gilbert’s syndrome 
that can explain the elevation of bilirubin.

Serum alanine aminotransferase (ALT) <1.25 × ULN at screening visit.

Creatinine ≤1.1 × ULN at screening visit.
4.
A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use a 
highly effective/effective method of contraception from signing of the informed consent form (ICF) throughout 
the duration of the study and for 30 days after the last dose of study drug as described in Appendix D.
5.
A male participant who is nonsterilized and sexually active with a female partner of childbearing potential 
agrees to use highly effective method of contraception from signing of the ICF throughout the duration of the 
study and for 100 days after last dose of study drug as described in Appendix D.
6.
If male, must agree not to donate sperm from the first dosing until 100 days after the last dosing. 
7.
Continuous non-smoker who has not used nicotine and tobacco containing products for at least 3 months prior 
to the first dosing based on participant self-reporting. 
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8.
Understands the study procedures in the ICF, and be willing and able to comply with the protocol.
Criteria for Exclusion:
Participants must not be enrolled in the study if they meet any of the following criteria: 
1.
Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or 
expected during the conduct of the study.
2.
History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the 
Investigator or designee.
3.
History of any illness that, in the opinion of the Investigator or designee, might confound the results of the study 
or poses an additional risk to the participant by their participation in the study.
4.
Drink alcohol in excess of 21 units per week for males or 14 units per week for females, with one unit = 150 mL 
of wine or 360 mL of beer or 45 mL of 45% alcohol.
5.
History of alcoholism or drug abuse within the past 2 years prior to the first dosing.
6.
Positive urine drug or alcohol results at screening or first check-in.
7.
History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or related compounds.
8.
History or presence of Celiac disease (CeD) or other gastrointestinal inflammatory disorder such as 
inflammatory bowel disease or eosinophilic disorder. 
9.
History of lactose intolerance.
10. Female participants with a positive pregnancy test at screening visit or first check-in or who are lactating.
11. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or 
hepatitis C virus (HCV).
12. 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 participant has been on the same stable dose for the immediate 
3 months prior to first study drug administration. Hormone replacement therapy will also be allowed.

Any drugs known to be significant inducers or inhibitors of Cytochrome P450 (CYP)3A4 enzymes and/or 
P-gp, including St. John’s Wort, within 28 days prior to the first dosing and throughout the study. 
Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack of PK/pharmacodynamics 
interaction with study drug.

Chronic use of non-steroidal anti-inflammatory (define as more that 7 days of use) within 2 weeks prior to 
screening and throughout the study.
13. 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.
14. Donation of blood or significant blood loss within 56 days prior to the first dosing.
15. Plasma donation within 7 days prior to the first dosing.
16. Participation in another clinical study within 30 days prior to the first dosing. The 30-day window will be 
derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of 
Period 1 of the current study. 
17. The participant is an immediate family member, study site employee, or is in a dependent relationship with a 
study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent 
under duress.
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Main Criteria for Evaluation and Analyses:
Primary Endpoint:
The primary endpoints will be assessed through evaluation of the following PK parameters for TAK-227 in plasma:

Maximum observed concentration (Cmax)

Area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast)

Area under the concentration-time curve (AUC) from time 0 to infinity, calculated using the observed value of 
the last quantifiable concentration (AUC∞)
Secondary endpoints:
The secondary endpoints will be assessed through evaluation of the following safety parameters: 

Treatment emergent adverse events (TEAEs) and their frequency, severity, seriousness, and causality 
assessments 

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and urinalysis) from 
baseline to post-baseline time points, and findings from physical examinations.
Exploratory Endpoints:
The exploratory endpoint will be assessed through evaluation of the following PK parameters for TAK-227 and its 
metabolites in plasma (if applicable, but are not limited to): 

Time to first occurrence of Cmax (tmax)

Lag time to first quantifiable concentration in plasma (tlag)

Terminal disposition phase rate constant (λz)

Terminal disposition phase half-life (t½z)

Apparent volume of distribution during the terminal disposition phase after oral administration, calculated using 
the observed value of the last quantifiable concentration (Vz/F; parent only)

Apparent clearance after oral administration, calculated using the observed value of the last quantifiable 
concentration (CL/F; parent only)

Area under the concentration-time curve (AUC) from the last quantifiable concentration to infinity, calculated 
using the observed value of the last quantifiable concentration, expressed as a percentage of AUC∞ (AUCextrap%)
The following PK parameters will also be evaluated for TAK-227 metabolites:

Maximum observed concentration (Cmax)

Area under the concentration-time curve (AUC) from time 0 to the time of the last quantifiable concentration 
(AUClast)

Area under the concentration-time curve (AUC) from time 0 to infinity, calculated using the observed value of 
the last quantifiable concentration (AUC∞)
Statistical Considerations:
Pharmacokinetic analysis:
Individual TAK-227 and its metabolites plasma concentrations and PK parameters will be listed by participant and 
treatment, and summarized by treatment (TAK-227 plasma concentrations and PK parameters) and nominal time 
(TAK-227 plasma concentrations).
PK parameters (Cmax, AUClast, AUC∞, AUCextrap%, tmax, λz, t½z, CL/F, Vz/F, and tlag) will be computed using standard 
non-compartmental analysis (NCA). Actual time of sampling will be used to calculate the PK parameters.
All individual concentration data and PK parameters will be listed with summary statistics such as geometric mean, 
median, arithmetic mean, standard deviation (SD), coefficient of variation (CV), minimum and maximum. 
Individual plasma concentration/time curves will be presented in linear/linear and log/linear scale. At least 3 PK 
time points within the terminal log-linear phase will be used to estimate the terminal rate constant for each 
participant in each treatment period. The appropriate PK analysis will be fully specified in the Clinical 
Pharmacology Analysis Plan (CPAP). 
TAK-227 metabolites PK may be reported separately from the clinical study report as a standalone document.
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A linear mixed-effect model will be applied to log-transformed Cmax, AUClast, and AUC∞for TAK-227 with 
treatment, period, and sequence as fixed effects, and participant within sequence as a random effect. Point estimates 
and their associated 90% confidence intervals (CIs) will be constructed for the differences between Treatment B (fed 
pre-dose) versus Treatment A (fasting), and Treatment C (fed post-dose) versus Treatment A (fasting). The point 
estimates and their associated 90% CIs will be then back transformed to provide point estimates and 90% CIs for the 
ratios of Treatment B (fed pre-dose) versus Treatment A (fasting) and Treatment C (fed post-dose) versus Treatment 
A (fasting). 
Analysis of tmax and tlag will be performed by nonparametric Wilcoxon Signed Rank test.
Safety analysis:
The safety data will be summarized descriptively for TEAEs, and potentially clinically significant values for clinical 
laboratory tests, vital signs, 12-lead ECG, and use of concomitant medications by treatment.
Sample Size Justification: 
The study is designed to have approximately 18 evaluable participants complete all treatment periods of the study. 
Sample size calculations were performed using R package PowerTOST based on the following:

The intra-participant CV was assumed at ~0.4 for Cmax and AUC, which were estimated based on data in 
Study CEC-2

Reference data set is Cmax or AUC under fasting condition; test data set is Cmax or AUC under fed 
conditions

If the observed geometric mean ratio (GMR) is at 0.90 or 1.10, the estimated 90% CI of the GMR, with N = 
18, is within (0.70, 1.43) for both Cmax and AUC
Accounting for possible dropouts, a total of 24 participants may be enrolled.
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2.0
STUDY SCHEMATIC
Table 2.a
Study Schematic
Pretreatment
Treatment Periods 1-2-3 
Study Exit
Follow-up 
(a)
Screening
Check-in
Dosing and Safety 
and PK Assessments
Safety and PK 
Assessments
Washout 
(b)
Day 2 of 
Treatment 
Period 3
7 (±3) days 
after last 
dose
Day -28 to 
first dosing 
Day -1 of 
Treatment 
Period 1
Day 1
Day 2
Not less 
than 4 
days
Confinement (c) 
(a) The CRU will contact all participants (including participants who terminate the study early) 7 (± 3) days after the 
last TAK-227 administration by telephone or other methods per CRU standards to determine if any AE has occurred 
or concomitant medications have been taken since the last study visit. If clinically significant findings are observed 
upon discharge, participants may return to the CRU for re-evaluation per Investigator’s discretion.
(b) There will be a washout period of not less than 4 days between TAK-227 dosing in each period.
(c) Participants will start the confinement on Day -1 of Treatment Period 1 and will remain confined until Day 2 of 
Treatment Period 3.
Table 2.b
Study Treatments for Study Drug
Treatment (a)
Study Drug
Dose
Dose Regimen
Days on Study Drug
Treatment A
TAK-227 
capsule
50 mg
Fasted, single dose, oral 
Day 1
Treatment B
TAK-227 
capsule
50 mg
Fed pre-dose: after a 
high-fat/high-calorie meal (b), 
single dose, oral 
Day 1
Treatment C
TAK-227 
capsule
50 mg
Fed post-dose: before a 
high-fat/high-calorie meal (c), 
single dose, oral, 
Day 1
(a) There will be a washout period of not less than 4 days between TAK-227 dosing in each treatment.
(b) TAK-227 will be administered 30 minutes following the start of a high-fat/high-calorie meal.
(c) A high-fat/high-calorie meal will be administered ~30 minutes following administration of TAK-227.
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4.0
INTRODUCTION
4.1
Background
Celiac disease (CeD) is a common intestinal inflammatory disease characterized by an altered 
immune response to dietary wheat gluten and related proteins from rye and barley. CeD is 
triggered and maintained in genetically predisposed patients carrying human lymphocyte antigen 
(HLA) type DQ2 or DQ8, and it is dominated by an acquired T cell mediated immune response 
to gluten. Currently the only therapeutic option is a strictly followed gluten-free diet (GFD), and 
many patients do not achieve symptomatic and histologic remission with dietary modification 
alone. Thus, there is a great unmet medical need for a pharmacological treatment of CeD.
Extracellular transglutaminase 2 (TG2) in the small intestinal mucosa plays a key role in the 
pathogenesis of CeD. TG2 can either cross-link or deamidate glutamine-residues in gliadin 
peptides derived from gluten. The deamidated or cross-linked peptides bind strongly to the HLA 
types DQ2 or DQ8 which results in T helper 1 T-cell activation, inflammation and mucosal 
destruction. Given its pivotal role in the pathophysiology of this disease, TG2 is a rational target 
for therapeutic approaches in CeD. Inhibition of the enzymatic activity of TG2 would prevent 
deamidation of gliadin and could therefore block an initial and crucial step in CeD pathogenesis.
The compound TAK-227 (also known as ZED1227) is a newly developed peptidomimetic 
showing an efficient and highly selective inhibition of TG2. In preclinical and early clinical 
studies, TAK-227 demonstrated a favorable safety profile, justifying its further clinical 
development. 
Through to 8-Sep-2022, a total of 270 healthy volunteers and participants with CeD were 
exposed to TAK-227 in 5 completed clinical studies: Phase 1 single ascending dose study in 
healthy participants (CEC-1), Phase 1 multiple ascending dose study in healthy participants 
(CEC-2), Phase 2a efficacy and tolerability, proof-of-concept, study in participants with 
well-controlled CeD undergoing gluten challenge (CEC-3), Phase 1 PK study in healthy 
participants (CEC-5), and Phase 1 mass balance study in healthy participants (CEC-6). A total 
of 26 additional participants have received either TAK-227 or placebo in the double blinded 
ongoing Phase 2b dose-finding study of efficacy and tolerability in adults with CeD experiencing 
symptoms and with intestinal injury despite gluten-free diet (CEC-4).
Following single administration of 5 to 500 mg doses and multiple dose administration of 10 to 
100 mg doses, TAK-227 was rapidly absorbed, reaching peak plasma concentrations in 
approximately 1 to 2 hours. Multiple dose administration had no relevant effect on exposure at 
the dose levels 10, 20, and 100 mg, and elimination half-life ranged between 4 to 9 hours post-
dose.
Following single dose administration in rats and minipigs, TAK-227 displayed low absolute 
bioavailability (1.5% to 4% in rat and 3.2% to 6.0% in minipigs). Due to the large differences in 
abundance of the biotransformation products detected in vivo to the in vitro profile of TAK-227 
in hepatocytes, it is currently assumed that the biotransformation of TAK-227 occurs mainly 
extra-hepatically. The metabolism of TAK-227 in human liver microsomes was significantly 
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reduced in the presence of the CYP3A4 inhibitor ketoconazole, with the conclusion of a possible 
drug-drug interaction risk due to inhibition of CYP3A4 in the liver and the intestines.
In the course of the two Phase 1 studies (CEC-1; CEC-2) no serious adverse events (SAEs) have 
been documented. In the recently completed phase 2a study CEC-3, a total of 4 SAEs were 
reported. Two (2) out of 4 were reported as suspected unexpected serious adverse reactions 
(SUSARs). The remaining 2 were reported after completion of study and they were considered 
unrelated to TAK-227.
The majority of adverse drug reactions were observed in the system organ classes 
Gastrointestinal Disorders and Nervous System Disorders. They were mostly mild in nature, with 
the most frequent events being diarrhea and headaches. Overall, the Phase 1 studies in healthy 
volunteers and the Phase 2 study in CeD patients demonstrated a favorable safety profile, which 
was comparable to placebo.
Refer to the Investigator’s Brochure (IB) for detailed background information on TAK-227.
4.2
Rationale for the Proposed Study
The purpose of this single-center, open-label, single-dose, randomized, 3-way crossover study in 
healthy adult participants is to determine if the systemic exposure to TAK-227 will be altered 
when dosed with a high-fat/high-calorie meal or under fasting conditions. TAK-227 is currently 
administered 30 minutes prior to a meal to allow for local drug exposure prior to any dietary 
gluten intake. This study will evaluate a potential food effect scenario if the dosing is conducted 
prior to a meal (current dosing conditions are followed; Treatment C) and following a meal 
(current dosing conditions are not followed; Treatment B). Enrolled participants will each 
receive a single oral dose of TAK-227 in each of the 3 treatment periods. The dosing in each 
treatment period will be separated by a washout period of not less than 4 days (single-dose 
plasma TAK-227 half-life of 5 to 8 hours). Participants will be dosed at approximately the same 
time each morning on Day 1 of each treatment period, with the dosing of each participant timed 
for sequential PK sampling. Thus, TAK-227 PK will be evaluated under 3 different feeding 
conditions:

Fasting (Treatment A)

Fed pre-dose, high-fat/high-calorie meal administered 30 minutes prior to dosing (Treatment 
B)

Fed post-dose, high-fat/high-calorie meal administered ~30 minutes after dosing (Treatment 
C)
The high-fat/high-calorie meal should contain in total 800-1000 kCal with 500-600 kCal from 
fat, 250 kCal from carbohydrates, and 150 kCal from proteins [FDA, 2022].
4.3
Benefit/Risk Profile
The 50 mg dose of TAK-227 will be administered according to the adult dosing regimen used in 
the previous studies, as detailed in the IB.
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There will be no direct health benefit for study participants from receipt of TAK-227. An indirect 
health benefit to the healthy participants enrolled in this study is the free medical tests received at 
screening and during the study.
The inclusion and exclusion criteria, screening, and safety monitoring practices employed in this 
protocol (ie, 12-lead ECG, vital signs, clinical laboratory tests, AE monitoring, and physical 
examination) are considered adequate to protect the participant’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 assess the PK of a single oral dose of 50 mg TAK-227 administered 30 minutes following 
the start of a high-fat/high-calorie meal or ~30 minutes before the start of a 
high-fat/high-calorie meal in healthy adult participants relative to administration under 
fasting conditions in healthy adult participants.
5.2.2
Study Secondary Objective

To evaluate the safety and tolerability of a single oral dose of 50 mg TAK-227 when 
administered under fasting conditions, 30 minutes following the start of a 
high-fat/high-calorie meal, and ~30 minutes before the start of a high-fat/high-calorie meal in 
healthy adult participants.
5.2.3
Study Exploratory Objectives

To evaluate other pharmacokinetic parameters for a single oral dose of 50 mg TAK-227
when administered under fasting conditions, 30 minutes following the start of a 
high-fat/high-calorie meal, and ~30 minutes before the start of a high-fat/high-calorie meal in 
healthy adult participants.

To evaluate TAK-227 metabolites PK parameters for a single oral dose of 50 mg TAK-227 
when administered under fasting conditions, 30 minutes following the start of a 
high-fat/high-calorie meal, and ~30 minutes before the start of a high-fat/high-calorie meal in 
healthy adult participants.
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5.3
Endpoints
5.3.1
Primary Endpoint
The primary endpoints will be assessed through evaluation of the following PK parameters for 
TAK-227 in plasma:

Maximum observed concentration (Cmax)

Area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration (AUClast)

Area under the concentration-time curve (AUC) from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞)
5.3.2
Secondary Endpoints 
The secondary endpoints will be assessed through evaluation of the following safety parameters:

TEAEs and their frequency, severity, seriousness, and causality assessments

Changes in vital signs, ECGs, and clinical laboratory results (hematology, chemistry, and 
urinalysis) from baseline to post-baseline time points, and findings from physical 
examinations.
5.3.3
Exploratory Endpoint
The exploratory endpoint will be assessed through evaluation of the following PK parameters for 
TAK-227 and its metabolites in plasma (as applicable, but are not limited to):

Time to first occurrence of Cmax (tmax)

Lag time to first quantifiable concentration in plasma (tlag)

Terminal disposition phase rate constant (λz)

Terminal disposition phase half-life (t½z)

Apparent volume of distribution during the terminal disposition phase after oral 
administration, calculated using the observed value of the last quantifiable concentration 
(Vz/F)

Apparent clearance after oral administration, calculated using the observed value of the last 
quantifiable concentration (CL/F)

Area under the concentration-time curve (AUC) from the last quantifiable concentration to 
infinity, calculated using the observed value of the last quantifiable concentration, expressed 
as a percentage of AUC∞ (AUCextrap%)
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The following PK parameters will also be evaluated for TAK-227 metabolites:

Maximum observed concentration (Cmax)

Area under the concentration-time curve (AUC) from time 0 to the time of the last 
quantifiable concentration (AUClast)

Area under the concentration-time curve (AUC) from time 0 to infinity, calculated using the 
observed value of the last quantifiable concentration (AUC∞)
6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design 
This is a single-center, open-label, single-dose, randomized, 3-period, 6-sequence, crossover 
study in healthy adults.
Study schematic and dose regimens are shown in Table 2.a and Table 2.b. The schedule of 
assessments is shown in Schedule of Study Procedures (Section 3.0).
On Day 1 of Treatment Period 1 participants will be randomly assigned to one of 6 possible 
treatment sequences (Table 8.a). On Day 1 of each treatment period, a single dose of TAK-227 
will be administered orally under one of 3 different feeding conditions as per the randomization 
schedule:

Fasting (Treatment A),

Fed pre-dose, high-fat/high-calorie meal administered 30 minutes prior to dosing 
(Treatment B), and

Fed post-dose, high-fat/high-calorie meal administered ~30 minutes after dosing 
(Treatment C).
For details on food and water consumption in the different treatments refer to Section 7.4.1 and 
Section 9.2.6.
There will be a washout period of not less than 4 days between TAK-227 dosing in each period.
PK sample collections will be conducted pre-dose and up to 36 hours post-dose in each treatment 
period.
Safety and tolerability will be assessed throughout the study by TEAEs, vital signs, ECGs, 
clinical laboratory evaluations, and physical examinations.
The CRU will contact all participants (including participants who terminate the study early) 
7 (± 3) days after the last TAK-227 administration by telephone or other methods per CRU 
standards to determine if any AE has occurred or concomitant medications have been taken since 
the last study visit. If clinically significant findings are observed upon discharge, participants 
may return to the CRU for re-evaluation per Investigator’s discretion.
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6.2
Dose Escalation
Not applicable.
6.3
Stopping Rules
Not applicable.
6.4
Rationale for Study Design, Dose, and Endpoints
6.4.1
Rationale of Study Design 
TAK-227 is currently administered 30 minutes prior to a meal to allow for local drug exposure 
prior to any dietary gluten intake. This study is being conducted to assess the effect of food on 
the PK profile of TAK-227 in 2 clinical scenarios: either dosing instructions are followed and 
TAK-227 is administered prior to food (fed post-dose; Treatment C) or dosing instructions are 
not followed and TAK-227 is administered after the meal (fed pre-dose; Treatment B). 
Participants will be randomized to treatment sequences to minimize assignment bias. A 
crossover design is being used to reduce the residual variability as every participant acts as their 
own control.
The washout period of not less than 4 days between doses is considered sufficient to prevent 
carryover effects of the preceding treatment.
6.4.2
Rationale for Dose 
The 50 mg TAK-227 dose was selected because it is the highest single dose currently being 
evaluated in clinical studies. Single doses of up to 500 mg were evaluated in healthy participants 
and were found well tolerated. As such, this dose is expected to provide a robust PK profile 
under the different food condition in this study while providing sufficient safety margin in case 
of increased exposure either one or more of the treatment conditions.
6.4.3
Rationale for Endpoints
6.4.3.1
Pharmacokinetic Endpoints
The PK endpoints are standard for this type of study.
6.4.3.2
Safety Endpoints
The key safety endpoints are typical for Phase 1 studies and will be assessed through monitoring 
of TEAEs, vital signs, ECGs, laboratory assessments, and physical examinations.
6.4.4
Future Biomedical Research
No additional analysis is planned to be performed on the PK plasma samples for possible future 
research. Any additional research on these samples unspecified by this protocol will require 
approval from the participants.
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6.4.5
Critical Procedures Based on Study Objectives: Timing of Procedures 
For this study, the critical component is the blood collection for plasma concentrations of 
TAK-227, and is to be collected as close to the scheduled times defined in this protocol as 
possible.
6.5
Study Design/Dosing/Procedures Modifications Permitted Within Protocol 
Parameters
The dose and administration of TAK-227 to any participant may not be modified. If necessary, a 
participant may be discontinued for the reasons described in Section 7.5 and Section 7.6
6.6
Study Beginning and End/Completion
6.6.1
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 participant.
6.6.2
Definition of End of the Study
The end of study is defined as the date of the last scheduled procedure ie, the follow-up contact, 
as outlined in the Schedule of Study Procedures (Section 3.0).
A participant is considered to have completed the study if the participant completed the last 
scheduled procedure ie, the follow-up contact shown in the Schedule of Study Procedures 
(Section 3.0).
6.6.3
Definition of Study Discontinuation
In consultation with the Sponsor, Celerion reserves the right to terminate the study in the 
interests of participants’ welfare. 
The Sponsor reserves the right to suspend or terminate the study at any time and not allow
additional enrollment, but to continue the study safety.
6.6.4
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 drug that 
indicates a change in the known risk/benefit profile for the product, such that the risk is no 
longer acceptable for participants participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises participants’ safety.
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6.6.5
Criteria for Premature Termination or Suspension of a Site
Not applicable.
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PARTICIPANTS
7.1
Inclusion Criteria 
Participants must fulfill the following inclusion criteria to be eligible for participation in the 
study:
1. Healthy, adult, male or female, 18-55 years of age, inclusive, at screening.
* Females of childbearing potential are defined as all females physiologically capable of 
becoming pregnant. 
Females of non-childbearing potential are defined as follows:

Females who 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

Females who are postmenopausal with amenorrhea for at least 12 month prior to the 
first dosing and follicle-stimulating hormone (FSH) serum levels consistent with 
postmenopausal status at screening.
2. BMI ≥18 and ≤32.0 kg/m2 at screening visit. 
3. Medically healthy with no clinically significant medical history, physical examination, 
laboratory profiles, vital signs or ECGs, as deemed by the Investigator or designee, including 
the following:

Seated blood pressure ≥ 90/40 mmHg and ≤ 140/90 mmHg at screening visit.

Seated heart rate ≥ 40 bpm and ≤ 99 bpm at screening visit.

QTcF interval ≤ 460 msec (males) or ≤ 470 msec (females) and has ECG findings 
considered normal or not clinical significance by the Investigator or designee at 
screening visit.

Estimated creatinine clearance ≥ 90 mL/min at screening visit.

Total bilirubin <1.25 × ULN at screening visit unless the participant has known 
Gilbert’s syndrome that can explain the elevation of bilirubin
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
Serum ALT <1.25 × ULN at screening visit.

Creatinine ≤1.1 × ULN at screening visit.
4. A female of childbearing potential who is sexually active with a nonsterilized male partner 
agrees to use a highly effective/effective method of contraception from signing of the ICF 
throughout the duration of the study and for 30 days after the last dose of study drug as 
described in Appendix D. 
5. A male participant who is nonsterilized and sexually active with a female partner of 
childbearing potential agrees to use highly effective method of contraception from signing of 
the ICF throughout the duration of the study and for 100 days after last dose of study drug as 
described in Appendix D.
6. If male, must agree not to donate sperm from the first dosing until 100 days after the last 
dosing.
7. Continuous non-smoker who has not used nicotine and tobacco containing products for at 
least 3 months prior to the first dosing based on participant self-reporting. 
8. Understands the study procedures in the ICF and be willing and able to comply with the 
protocol.
7.2
Exclusion Criteria
Participants must not be enrolled in the study if they meet any of the following criteria:
1. Is mentally or legally incapacitated or has significant emotional problems at the time of the 
screening visit or expected during the conduct of the study.
2. History or presence of clinically significant medical or psychiatric condition or disease in the 
opinion of the Investigator or designee.
3. History of any illness that, in the opinion of the Investigator or designee, might confound the 
results of the study or poses an additional risk to the participant by their participation in the 
study.
4. Drink alcohol in excess of 21 units per week for males or 14 units per week for females, with 
one unit = 150 mL of wine or 360 mL of beer or 45 mL of 45% alcohol.
5. History of alcoholism or drug abuse within the past 2 years prior to the first dosing.
6. Positive urine drug or alcohol results at screening or first check-in.
7. History or presence of hypersensitivity or idiosyncratic reaction to the study drug(s) or 
related compounds.
8. History or presence of CeD or other gastrointestinal inflammatory disorder such as 
inflammatory bowel disease or eosinophilic disorder.
9. History of lactose intolerance.
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10. Female participants with a positive pregnancy test at screening visit or first check-in or who 
are lactating.
11. Positive results at screening for HIV, HBsAg, or HCV.
12. 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 
participant has been on the same stable dose for the immediate 3 months prior to first 
study drug administration. Hormone replacement therapy will also be allowed.

Any drugs known to be significant inducers or inhibitors of CYP3A4 enzymes and/or 
P-gp, including St. John’s Wort, within 28 days prior to the first dosing and throughout 
the study. Appropriate sources (eg, Flockhart TableTM) will be consulted to confirm lack 
of PK/pharmacodynamics interaction with study drug.

Chronic use of non-steroidal anti-inflammatory (define as more that 7 days of use) within 
2 weeks prior to screening and throughout the study.
13. 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.
14. Donation of blood or significant blood loss within 56 days prior to the first dosing.
15. Plasma donation within 7 days prior to the first dosing.
16. Participation in another clinical study within 30 days prior to the first dosing. The 30-day 
window will be derived from the date of the last blood collection or dosing, whichever is 
later, in the previous study to Day 1 of Treatment Period 1 of the current study.
17. The participant is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress.
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 participant has been on the same stable dose for the immediate 3 months prior to 
the first dosing. Hormonal contraceptives (refer to Appendix D) and hormonal replacement 
medication may be permitted if the female participant has been on the same stable dose for at 
least 3 months prior to the first dose of the study drug.
If deviations occur, the Investigator or designee in consultation with the Sponsor if needed will 
decide on a case by case basis whether the participant may continue participation in the study.
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All medications taken by participants during the course of the study will be recorded.
Use of excluded agents (prescription or non-prescription) or dietary products is outlined in 
Table 7.a.
Table 7.a
Excluded Medications, Supplements, and Dietary Products
Category
Between Screening and First Dosing (Days -
28 to pre-dose [Day 1])
After First Dosing (Day 1) to 
Follow-Up 
Alcohol
Prohibited from 48 hours prior to first dosing
Prohibited from first dosing until 
the last PK sample on Day 2 of 
Treatment Period 3.
Xanthine and/or caffeine
Prohibited from 24 hours prior to first dosing a
Prohibited from first dosing until 
the last PK sample on Day 2 of 
Treatment Period 3.a
Medications 
See Sections 7.1 and 7.2
See Sections 7.1 and 7.2
Nicotine- and tobacco-
containing and/or cannabis 
products
Prohibited from 3 month prior to first dosing
Prohibited from first dosing until 
the follow-up visit.
Food substance
Grapefruit/Seville orange
Prohibited from 14 days prior to first dosing
Prohibited from first dosing until 
the follow-up visit.
(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
Drinking water (except water provided with each dosing) will be restricted 1 hour prior to and 
1 hour after each dosing 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:
Participants will be required to fast overnight for at least 10 hours prior to dosing and will 
continue the fast for at least 4 hours post-dose.
Treatment B:
Participants 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. Participants will fast for at least 4 hours post-dose.
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Treatment C:
Participants will be required to fast overnight for at least 10 hours prior to dosing and will 
continue the fast for ~30 minutes post-dose, at which time they will be given a 
high-fat/high-calorie breakfast* which will be entirely consumed within 30 minutes. Participants 
will fast for at least 3 hours following the meal.
* A high-fat/high-calorie breakfast will contain 800-1000 calories and approximately 50% fat. 
An example of high fat would be 2 slices of buttered toast, 2 eggs fried in butter, 2 strips of 
bacon, 4 oz of hash brown potatoes, and 8 ounces (approximately 240 mL) of whole milk 
[FDA, 2022].
All Treatments:
Each meal and/or snacks served at the CRU will be standardized and will be similar in caloric 
content and composition (except for the meals served as part of Treatments B and C) and will be 
taken at approximately the same time in each treatment period. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from all 
food and drink except water between meals and snacks.
7.4.2
Activity
Participants will remain ambulatory or seated upright for the first 4 hours post-dose, except when 
they are supine or semi reclined for study procedures. 
Should TEAEs occur at any time, participants may be placed in an appropriate position or will be 
permitted to lie down on their right side. 
Participants 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 Participant
The primary reason for discontinuation or withdrawal of the participant from the study or 
TAK-227 administration should be recorded in the case report form (CRF) using the following 
categories:
1. PTE and TEAE: The participant has experienced a PTE or a TEAE that requires early 
termination because continued participation imposes an unacceptable risk to the participant’s 
health or the participant is unwilling to continue because of the PTE or TEAE. 
Liver Function Test (LFT) Abnormalities: 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a participant’s laboratory profile has returned to 
normal/baseline status, see Section 9.2.7), if the following circumstances occur at any time 
during study drug treatment: 
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
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper limit of 
normal (ULN), or 

ALT or AST >5 × ULN and persists for more than 2 weeks, or 

ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN, or 

ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 

QTcF interval: 
TAK-227 should be discontinued immediately with appropriate clinical follow-up if a 
QTcF interval >500 msec or if there is an increase of QTcF >60 msec above baseline 
detected by ECG and confirmed with a repeat ECG. Appropriate clinical follow-up 
includes a repeat ECG.
2. Significant protocol deviation: The discovery post-enrollment that the participant failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the participant’s health. 
3. Lost to follow-up: Attempts to contact the participants were unsuccessful. Attempts to 
contact the participant must be documented in the participant’s source documents. 
4. Voluntary withdrawal: The participant (or participant’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to 
an AE should not be recorded in the “voluntary withdrawal” category). If a participant 
chooses to withdraw from study participation due to personal concerns related to the 
coronavirus disease 2019 (COVID-19) pandemic (other than a COVID-19-related AE), this 
should be specified as the reason for participant withdrawal in the CRF. 
5. Study termination: The Sponsor, Institutional Review Board (IRB)/ Independent Ethics 
Committee (IEC), or regulatory agency terminates the study. 
6. Pregnancy: as described in Appendix D. 
7. Participants may be withdrawn from the study by the Investigator or designee for the 
following reasons: 

Difficulties in blood collection. 

Positive urine drug or alcohol test. 
8. Other. The specific reasons for discontinuation should be entered into the CRF including 
unavoidable circumstances such as the COVID-19 pandemic. Participants may be withdrawn 
from the study at any time at the discretion of the Investigator or Sponsor for safety reasons 
which should be entered into the CRFs.
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7.6
Procedures for Discontinuation or Withdrawal of a Participant
The Investigator may discontinue a participant’s study participation at any time during the study 
when the participant meets the study termination criteria described in Section 7.5. In addition, a 
participant may discontinue his or her participation without giving a reason at any time during 
the study. Should a participant’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
Participant Replacement
Replacement of discontinued or withdrawn participants due to any reason will be assessed on a 
case by case basis by the Sponsor and Investigator to ensure a minimum of 18 PK-evaluable 
participants complete the study.
8.0
CLINICAL STUDY MATERIAL MANAGEMENT
8.1
Clinical Study Drug 
Drug Name (add this bold when multiple drugs):
Product Name:
TAK-227
Strength:
50 mg
Dose:
50 mg
Dosage Form/Formulation:
Capsule
Dosing regimen:
Single dose
Route of Administration:
Oral
8.1.1
Clinical Study Drug Labeling
TAK-227 blister strips will be labeled for the study and placed in cartons. Each carton will be 
labeled with a study label in accordance with local regulatory requirements and tamper sealed.
8.1.2
Clinical Study Drug Inventory and Storage
The Sponsor will supply sufficient quantities of TAK-227 to allow completion of this study.
The same lot number will be used throughout the study. The lot numbers and expiration dates 
(where available) of the study drugs supplied will be recorded in the final report. Study drugs 
will be stored according to the product labels provided with the product.
Records will be made of the receipt, preparation, dispensing, and final disposition of the study 
drugs supplied.
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8.1.3
Clinical Study Drug Blinding
This is an open-label study. 
8.1.4
Randomization Code Creation and Storage 
A computerized randomization scheme will be created by a Celerion statistician. 
Participants will be randomized to 1 of 6 sequences as indicated in Table 8.a.
Table 8.a
Randomization Sequence
Sequence
Number of 
participants 
(N)
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
1
4
A
B
C
2
4
B
C
A
3
4
C
A
B
4
4
A
C
B
5
4
B
A
C
6
4
C
B
A
Treatment A: Fasting 
Treatment B: Fed pre-dose, high-fat/high-calorie meal administered 30 minutes prior 
to dosing.
Treatment C: Fed post-dose, high-fat/ high-calorie meal administered ~30 minutes 
after dosing.
8.1.5
Clinical Study Blind Maintenance/Unblinding Procedure
Not applicable
8.1.6
Accountability and Destruction of Sponsor-Supplied Drugs
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused TAK-227 will be retained by Celerion, returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. Any remaining supplies that were 
purchased by Celerion will be destroyed, if appropriate. 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 participants in non-technical terms. Participants will be required to read, sign, 
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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.
Participants will be given a copy of their signed ICF.
9.1.1.1
Assignment of Screening and Randomization Numbers 
Each participant will be assigned a unique identification number upon screening. Participants 
who complete the study screening assessments and meet all the eligibility criteria will be 
assigned a unique randomization number at the time of first dosing, different from the screening 
number.
If replacement participants are used, the replacement participant number will be 100 more than 
the original (eg, Participant No. 101 will replace Participant No. 1).
9.1.1.2
Study Drug Assignment
All participants will receive the treatments as detailed in Section 9.2.6. 
9.1.2
Inclusion and Exclusion 
Please refer to Section 7.1 and Section 7.2.
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. 
All medication taken by the participants within 6 month prior to first dosing will be recorded.
9.1.4
Concomitant Medications
Concomitant medications will be prohibited as listed in Section 7.3. All medications taken by 
participants during the course of the study will be recorded.
9.2
Clinical Procedures and Assessments
The Schedule of Study Procedures (Section 3.0) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the Sponsor 
for reasons related to participant’s safety.
For this study, collection of blood for TAK-227 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. 
Any nonscheduled procedures required for urgent evaluation of safety concerns will take 
precedence over all routine scheduled procedures.
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9.2.1
Full Physical Exam
A full physical examination will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional 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 temperature, respiratory rate, BP, and pulse 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 by the Investigator or designee.
BP and pulse rate measurements will be performed with participants in a seated position, except 
when they are supine or semi-reclined because of study procedures and/or AEs (e.g. nausea, 
dizziness) or if deemed necessary by the Investigator or designee.
Vital signs will be measured within 24 hours prior to Day 1 dosing of each treatment period for 
the pre-dose time point. When scheduled post-dose, vital signs will be performed within 
approximately 15 minutes of the scheduled time point. 
9.2.5
12-Lead ECG
Single 12-lead ECGs will be performed as outlined in the Schedule of Study Procedures 
(Section 3.0). Additional ECGs may be taken at any other times, if deemed necessary by the
Investigator or designee.
ECGs will be performed with participants in a supine position. All ECG tracings will be 
reviewed by the Investigator or designee.
ECGs will be measured within 24 hours prior to Day 1 dosing of each treatment period for the 
pre-dose time point. When scheduled post-dose, ECGs will be performed within approximately 
20 minutes of the scheduled time point.
9.2.6
Study Drug Administration
TAK-227 will be provided as described in Section 8.1.
Treatments are described in Table 2.b.
The pharmacy at the CRU will provide each dose in individual unit dose containers for each 
participant, as appropriate. 
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TAK-227 will be administered under fasting or fed conditions as detailed in Section 7.4.1. 
TAK-227 will be administered with approximately 240 mL of water. Water consumption will be 
restricted as detailed in Section 7.4.1. 
Participants will be instructed not to crush, split, or chew the capsules.
The exact clock time of dosing will be recorded.
A qualified designee will be responsible for monitoring the administration of the timed oral 
doses. A mouth check will be performed by the qualified designee to ensure that the participants 
have swallowed the study drug. Once a participant has finished the dosing water, the qualified 
designee will use a flashlight and a tongue depressor to check the participant’s mouth. 
Participants’ hands will also be verified to ensure that the study drug was ingested.
9.2.7
AE Monitoring
Participants will be monitored throughout the study for adverse reactions to the study drug and/or 
procedures as described in Section 10.0.
9.2.8
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. 
9.2.8.1
Clinical Laboratory Tests
Hematology
Hematology will consist of the following tests:
Hemoglobin
Red blood cell count
Hematocrit 
Platelet count
Total white blood cell count and differentials 
(neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, and leukocytes)
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Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, participants may not have fasted for 8 hours prior to when the serum 
chemistry sample being taken.
Chemistry evaluations will consist of the following standard chemistry panel:
Blood Urea Nitrogen
Sodium
Bilirubin (total and direct)
Potassium
Alkaline phosphatase (ALP)
Chloride
Aspartate aminotransferase (AST)
Glucose 
Alanine aminotransferase (ALT)
Creatinine *
Albumin
* At screening, creatinine clearance will be calculated using the Cockcroft-Gault formula.
Urinalysis
Urinalysis will consist of the following tests:
pH
Bilirubin
Specific gravity
Blood *
Protein *
Nitrite *
Glucose
Urobilinogen
Ketones
Leukocyte esterase *
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed.
9.2.8.1.1
Other 
HIV test
Urine drug screen
Opiates (includes morphine, heroin [diacetylmorphine], 
codeine, 6-acetylmorphine, dihydrocodeine, hydrocodone, 
thebaine, and, hydromorphone)
Opioids
Amphetamines
Barbiturates
Benzodiazepines
Cocaine
Cannabinoids
Methadone
Phencyclidine
HBsAg
HCV
Urine alcohol screen
Serum pregnancy test (for females only)
FSH (for postmenopausal females only)
COVID-19 (Severe acute respiratory 
syndrome-Coronavirus-1 [SARS-CoV-2] 
polymerase chain reaction test or equivalent)
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9.3
PK Samples
Samples for TAK-227 and its metabolites PK assessment will be collected as outlined in the 
Schedule of Study Procedures (Section 3.0).
Instructions for sample collection, processing, and shipping will be provided in separate 
documents. 
Primary specimen collection parameters are provided in Table 9.a.
Table 9.a
Primary Specimen Collections
Specimen Name
Primary 
Specimen
Primary Specimen 
Derivative
Description of Intended Use
Sample 
Collection
Plasma sample for PK
Blood
Plasma
Plasma sample for PK analysis
Mandatory
9.3.1
PK Measurements 
Samples from all participants will be assayed even if the participants do not complete the study. 
Samples for determination of plasma TAK-227 and its metabolites, will be analyzed using 
validated bioanalytical methods.
PK parameters of TAK-227 and its metabolites will be calculated from the individual 
concentration-time profiles from all evaluable participants using NCA methods. Actual sampling 
times, rather than scheduled sampling times, will be used in all computations involving sampling 
times. 
9.3.1.1
Plasma PK Measurements
The following PK parameters will be calculated from plasma concentrations of TAK-227 and its 
metabolites, unless otherwise specified:
AUClast:
Area under the concentration-time curve, from time 0 to the last 
quantifiable concentration.
AUC:
Area under the concentration-time curve, from time 0 extrapolated to 
infinity, calculated using the observed value of the last quantifiable 
concentration.
AUCextrap%:
Area under the curve from the last quantifiable concentration to infinity 
calculated using the observed value of the last quantifiable concentration, 
expressed as a percentage of AUC.
CL/F:
Apparent clearance after extravascular administration (parent only).
Cmax:
Maximum observed concentration.
tmax:
Time of first occurrence of Cmax
tlag:
Lag time to first quantifiable concentration
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t½z:
Terminal disposition phase half-life
λz
Terminal disposition phase rate constant
Vz/F:
Apparent volume of distribution during the terminal disposition phase after 
extravascular administration (parent only).
No value for λz, AUC, AUCextrap%, CL/F, Vz/F, or t½z will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile.
No PK parameters will be calculated for participants 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.
Additional PK parameters may be estimated as appropriate.
9.3.2
Biomarker Measurements 
Not applicable.
9.3.3
PGx Measurements 
Not applicable.
9.3.4
Confinement
Participants will be housed on Day -1 of each treatment period, at the time indicated by the CRU, 
until after the 36-hour blood draw and/or study procedures of Treatment Period 3.
At all times, a participant may be required to remain at the CRU for longer at the discretion of 
the Investigator or designee.
10.0
ADVERSE EVENTS
10.1
Definitions and Elements of AEs
An AE is defined as any untoward medical occurrence in a clinical investigation participant who 
has signed the ICF 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.
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A pretreatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation participant who has signed the ICF to participate in a study but before 
administration of any study drug; it does not necessarily have to have a causal relationship with 
study participation.
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a preexisting condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study medication or a concomitant 
medication.

Be considered unfavorable by the Investigator for any reason.
Diagnoses versus signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG parameters maybe considered AEs if they are judged to 
be clinically significant (ie, if some action or intervention is required or if the Investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
re-test and/or continued monitoring of an abnormal value are not considered an intervention. 
In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is 
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE.
Pre-existing conditions:

A pre-existing condition (present at the time of signing the ICF) is considered a concurrent 
medical history condition and should NOT be recorded as an AE. A baseline evaluation (eg, 
laboratory test, ECG, X-ray, etc) should NOT be recorded as an AE unless related to a study 
procedure. However, if the participant 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 the ICF is signed). 
Investigators should ensure that the event term recorded captures the change in the condition 
(eg, “worsening of…”).
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
If a participant 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 participant 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 participant 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 participant 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 the 
ICF are not considered AEs. However, if a preplanned procedure is performed early (eg, as 
an emergency) due to a worsening of the pre-existing condition, the worsening of the 
condition should be captured appropriately as an AE. Complications resulting from any 
planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the participant’s medical 
condition should not be recorded as AEs but should be documented in the participant’s 
source documents. Complications resulting from an elective surgery should be reported as 
AEs.
Overdose:

An overdose is defined as a known deliberate or accidental administration of study drug, to 
or by a study participant, at a dose above the maximum scheduled dose being used in this 
study irrespective of the participant’s assigned 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 or considered as a medication dosing error, in consultation with the Sponsor.

All cases of overdose (with or without associated AEs) will be documented on an overdose 
page of the (e)CRF, in order to capture this important safety information consistently in the 
database. Cases of overdose in itself without manifested signs or symptoms are considered as 
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AEs and should be captured with the appropriate Preferred Term of Overdose in the AE 
eCRF. AEs associated with an overdose will be documented on AE CRF(s) according to 
Section 10.2.8.

Serious adverse events of overdose should be reported according to the procedure outlined in 
Section 10.2.8.

In the event of drug overdose, the participant should be treated according to the standard 
practices of the Investigator and the site.
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 participant 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 participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory 
distress syndrome
Hepatic necrosis
Acute liver failure
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia
Anaphylactic shock
Acute renal failure
Malignant hypertension
Pulmonary hypertension
Convulsive seizures
Pulmonary fibrosis
Agranulocytosis
Confirmed or suspected endotoxin shock
Aplastic anemia
Confirmed or suspected transmission of infectious agent 
by a medicinal product
Toxic epidermal necrolysis/
Stevens-Johnson syndrome
Neuroleptic malignant syndrome / malignant hyperthermia
COVID-19-related disease
COVID-19 pneumonia
Spontaneous abortion / stillbirth and fetal death
Abbreviations: COVID-19 = Coronavirus disease-2019
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).
10.2
AE Procedures
10.2.1
Assigning Severity/Intensity of AEs
The different categories of severity/intensity are:
Mild:
An adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
Moderate:
An adverse event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
Severe:
An adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
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 
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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.
In addition, relationship (causality) to COVID-19 should be determined for all PTEs and TEAEs. 
The relationship should be assessed as related if the Investigator considers that there is 
reasonable possibility that an event is due to COVID-19. Otherwise, the relationship should be 
assessed as not related.
Similarly, relationship (causality) to COVID-19 vaccines should be determined for all PTEs and 
TEAEs. The relationship should be assessed as related if the Investigator considers that there is 
reasonable possibility that an event is due to COVID-19 vaccines. Otherwise, the relationship 
should be assessed as not related. If the AE has relationship to vaccination, specific verbatim 
term should be used, eg, post-vaccination fever, vaccination site burning.
In addition, if the causality assessment done by the Investigator determines that the event or 
events are related or possible related to COVID-19 or the COVID-19 vaccine, the events should 
be assessed as not related to the study drug. If the AE is related to COVID-19 vaccination, 
specific verbatim term(s) should be used, eg, post-vaccination fever, vaccination site burning.
10.2.3
Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or Investigator.
10.2.4
End Date 
The end date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae or the participant died.
10.2.5
Pattern of Adverse Event (Frequency) 
Episodic AEs (eg, headache) or those which occur repeatedly over a period of consecutive days 
are intermittent. All other events are continuous.
10.2.6
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 a dose change, including stopping a 
study medication.

Unknown – only to be used if it has not been possible to determine what action has been 
taken.
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
Not applicable – a study medication was stopped for a reason other than the particular AE 
eg, the study has been terminated, the participant died, dosing with study medication had not 
yet started or dosing with study medication was already stopped before the onset of the AE.
10.2.7
Outcome 

Recovered/resolved – participant returned to first assessment status with respect to the AE.

Recovering/resolving – the intensity is lowered by one or more stages: the diagnosis has or 
signs/symptoms have almost disappeared; the abnormal laboratory value improved, but has 
not returned to the normal range or to the baseline value; the participant 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 participant died from another cause with the particular AE state remaining “Not 
recovered/not resolved.”

Recovered/ Resolved with sequelae – the participant 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 participant’s participation in the study.
10.2.8
Collection and Reporting of AEs, SAEs, and Abnormal LFTs
10.2.8.1
Collection Period
Collection of AEs (ie, PTEs, AEs, SAEs, Overdose, and Abnormal LFTs) will commence at the 
time the participant signs the ICF. Routine collection of AEs will continue until the follow-up 
phone call on Day 7 (± 3 days), approximately 7 days after the last dose of study drug. For 
participants who discontinue prior to the administration of study medication, AEs will be 
followed until the participant discontinues study participation. 
10.2.8.2
Reporting AEs
At each study visit, the Investigator or designee 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. Participants may report AEs occurring at any other time during the study. Participants 
experiencing an SAE prior to the first exposure to study drug 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.
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All participants experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 
for the changes observed. All AEs will be documented in the AE page of the CRF, whether or 
not the Investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event:

Event term.

Start and end date and time.

Pattern of AE (frequency).

Severity/Intensity.

Causality (Investigator’s opinion of the causal relationship between the event and 
administration of study drug[s]).

Relationship to COVID-19.

Relationship to COVID-19 vaccine.

Action taken with study drug.

Outcome of event.

Seriousness.
10.2.8.3
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.

Participant 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 
Appendix 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.
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Reporting of SAEs that begin before first administration of study drug will follow the same 
procedure for SAEs occurring on treatment.
10.2.8.3.1
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.
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.
10.2.8.4
Reporting Special Interest AEs 
Not Applicable. There are no AEs of Special Interest for TAK-227.
10.2.8.5
Reporting of Abnormal LFTs
If a participant is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, an LFT Increases CRF must be completed 
providing additional information on relevant recent history, risk factors, clinical signs and 
symptoms and results of any additional diagnostic tests performed.
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.8.3. The Investigator must contact the Medical Monitor for discussion of the 
relevant participant details and possible alternative etiologies, such as acute viral hepatitis A or B 
or other acute liver disease. Follow-up laboratory tests as described in Section 9.2.8 must also be 
performed. In addition, an LFT Increases CRF must be completed and transmitted with the 
Takeda SAE form (as per Section 10.2.9). 
10.2.9
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.
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11.0
STATISTICAL METHODS
11.1
Statistical and Analytical Plans
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a 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
Safety Set
All participants who received at least one dose of the study drug(s) will be included in the safety 
evaluations.
11.1.1.2
PK Set
All participants 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 PK analyses.
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, sex, race, and ethnicity) 
will also be listed and tabulated.
11.1.3
PK Analysis
Statistical analysis of PK data will be based on the PK set. 
Individual TAK-227 and its metabolites plasma concentrations and PK parameters will be listed 
by participant and treatment, and summarized by treatment (TAK-227 and metabolites plasma 
concentrations and PK parameters) and nominal time (TAK-227 and metabolites plasma 
concentrations).
PK parameters (Cmax, AUClast, AUC∞, AUCextrap%, tmax, λz, t½z, CL/F, Vz/F, and tlag) will be 
computed using standard NCA. Actual time of sampling will be used to calculate the PK 
parameters. 
All individual concentration data and PK parameters will be listed with summary statistics such 
as geometric mean, median, arithmetic mean, SD, CV, minimum and maximum. Individual 
plasma concentration/time curves will be presented in linear/linear and log/linear scale. At least 3 
PK time points within the terminal log-linear phase will be used to estimate the terminal rate 
constant for each participant in each treatment period.
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The appropriate PK analysis will be fully specified in the CPAP.
TAK-227 metabolites PK may be reported separately from the clinical study report as a 
standalone document.
11.1.3.1
Food-effect estimation
A linear mixed-effect model will be applied to log-transformed Cmax, AUClast, and AUC∞for 
TAK-227 with treatment, period, and sequence as fixed effects, and participant within sequence 
as a random effect. Point estimates and their associated 90% CIs will be constructed for the 
differences between Treatment B (fed pre-dose) versus Treatment A (fasting), and Treatment C 
(fed post-dose) versus Treatment A (fasting). The point estimates and their associated 90% CIs 
will be then back transformed to provide point estimates and 90% CIs for the ratios of Treatment 
B (fed pre-dose) versus Treatment A (fasting) and Treatment C (fed post-dose) versus Treatment 
A (fasting).
11.1.3.2
Non-Parametric Analysis
Analysis of tmax and tlag will be performed by nonparametric Wilcoxon Signed-Rank test.
11.1.4
PD Analysis 
Not applicable.
11.1.5
Safety Analysis
Dosing dates and times will be listed by participant.
TEAEs will be tabulated. The remaining 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 
participants reporting the TEAE and the number of TEAEs reported. A by-participant AE data 
listing including verbatim term, coded term, treatment, severity, and relationship to the study 
drug 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.
11.1.5.3
Vital Signs
Vital signs assessments will be summarized by treatment and point of time of collection.
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11.1.5.4
Other Safety Parameters
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 (WHO) drug dictionary and will 
be listed by participant.
11.2
Interim Analysis and Criteria for Early Termination
Not applicable.
11.3
Determination of Sample Size
The study is designed to have approximately 18 evaluable participants complete all treatment 
periods of the study. 
Sample size calculations was performed using R package PowerTOST based on the following:

The intra-participant CV was assumed at ~0.4 for Cmax and AUC, which were estimated 
based on data in Study CEC-2

Reference data set is Cmax or AUC under fasting condition; test data set is Cmax or AUC under 
fed conditions

If the observed GMR is at 0.90 or 1.10, the estimated 90% CI of the GMR, with N = 18, is 
within (0.70, 1.43) for both Cmax and AUC
Accounting for possible dropouts, a total of 24 participants may be enrolled.
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. Due to COVID-19, monitoring visits may also be conducted 
remotely. 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 (contract 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, including but not limited to the Investigator’s Binder, study drug, participant 
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.
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12.2
Protocol Deviations
The Investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the Investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria.
For COVID-19-related protocol deviations, the specific protocol deviation, the reason for the 
deviation, and the relationship to COVID-19 should be documented using CRU standard 
processes.
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the participant, 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 participants (ie, 
participants) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the International Conference on Harminsation (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 
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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 ICF, and, if applicable, participant 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 
participant 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, ICF) 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 ICF, recruitment 
materials intended for viewing by participants, 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.
Participant incentives should not exert undue influence for participation. Payments to 
participants must be approved by the IRB or IEC and Sponsor.
13.2
Participant Information, Informed Consent, and Participant 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 ICF, participant authorization form (if applicable), and 
participant information sheet (if applicable) describe the planned and permitted uses, transfers, 
and disclosures of the participant’s personal and personal health information for purposes of 
conducting the study. The ICF and the participant 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 ICF 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 ICF 
and, if applicable, the participant authorization form. The ICF, participant authorization form (if 
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applicable), and participant information sheet (if applicable) must be approved by both the IRB 
or IEC and the Sponsor prior to use.
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It 
is the responsibility of the Investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. 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 participant is not capable of 
rendering adequate written informed consent, then the participant’s legally acceptable 
representative may provide such consent for the participant in accordance with applicable laws 
and regulations.
The participant, or the participant’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 participant, or the participant’s legally acceptable representative, determines 
he or she will participate in the study, then the ICF and participant authorization form (if 
applicable) must be signed and dated by the participant, or the participant’s legally acceptable 
representative, at the time of consent and prior to the participant entering into the study. The 
participant or the participant’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 ICF and participant authorization (if applicable) at the time of consent and 
prior to participant 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 ICF, participant authorization form (if applicable), and participant 
information sheet (if applicable) will be stored in the Investigator’s site file. The Investigator 
must document the date the participant signs the ICF in the participant’s medical record. Copies 
of the signed ICF, the signed participant authorization form (if applicable), and participant 
information sheet (if applicable) shall be given to the participant.
All revised ICFs must be reviewed and signed by relevant participants or the relevant 
participant’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 participant’s 
medical record, and the participant should receive a copy of the revised ICF.
13.3
Participant Confidentiality
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’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 participant attributes, such as sex, age, 
or date of birth, and participant initials may be used to verify the participant and accuracy of the 
participant’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 
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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 participant’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 participant’s study 
participation, and autopsy reports. Access to a participant’s original medical records requires the 
specific authorization of the participant as part of the informed consent process (see 
Section 13.2).
Copies of any participant source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (ie, participant name, address, and other identifier 
fields not collected on the participant’s CRF).
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 trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all
interventional clinical trials it Sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with Investigator’s city, state (for Americas Investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the Investigator name, address, and phone number to the callers requesting trial 
information. Once participants receive Investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
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inquiries according to their established participant screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the Sponsor.
Any Investigator who objects to the Sponsor providing this information to callers must provide 
the Sponsor with a written notice requesting that their information not be listed on the registry 
site.
13.4.3
Clinical 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 participant in the study must be insured in accordance with the regulations applicable to the 
site where the participant 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 
participants. Refer to the study site agreement regarding the Sponsor’s policy on participant 
compensation and treatment for 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
Pharmacovigilance
Takeda Development Center Americas, Inc.
Fax: 224-554-1052
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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 participants in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference 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 10.2.9 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 D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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14.1.3
Study-Related Responsibilities 
The Sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities template. The vendors identified for specific study-related 
activities will perform these activities in full or in partnership with the Sponsor.
14.1.4
List of Abbreviations
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC
The area under the concentration-time curve, from time 0 to infinity
AUC%extrap
Percent of AUCextrapolated
AUClast
The area under the concentration-time curve, from time 0 to the last quantifiable 
concentration, as calculated by the linear-log trapezoidal method.
BMI
Body mass index
bpm
Beats per minute
CeD
Celiac disease
CFR
Code of Federal Regulations
CI
Confidence interval
CL/F
Apparent clearance after extravascular administration
cm
Centimeter
Cmax
Maximum observed concentration 
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRU
Clinical Research Unit
CV
Coefficient of variance
CYP
Cytochrome P450
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GMR
Geometric mean ratio
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
HLA
Human lymphocyte antigen
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
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INR
International normalized ratio
IRB
Institutional Review Board
kg
Kilogram
LFT
Liver function test
m2
Meters squared
MedDRA®
Medical Dictionary for Regulatory Activities®
mg
Milligram
mL
Milliliter
mmHg
Millimeter of mercury
msec
Millisecond
NCA
Non-compartmental analysis
PK
Pharmacokinetic(s)
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
Terminal disposition phase half-life
tlag
Lag time to first quantifiable concentration in plasma
tmax
Time to first occurrence of maximum observed concentration
TDCA
Takeda Development Center Americas
TEAE
Treatment-emergent adverse event
TG2
Transglutaminase 2
ULN
Upper limit of normal
US
United States
USA
United States of America
Vz/F
Apparent volume of distribution during the terminal disposition phase after 
extravascular administration
λz
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. AEs, medical history, and concurrent conditions will be coded using the MedDRA®. Drugs 
will be coded using the World Health Organization Drug Dictionary.
15.1
CRFs (Electronic and Paper)
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 
Investigator. The final signed CRFs are provided to the Sponsor in the format as decided upon 
between Celerion and the Sponsor (eg, compact disc, flashdrive, secure file transfer protocol). 
This will be documented in the Data Management Plan (if applicable).
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Corrections are recorded in an audit trail that captures the old information, the new information, 
identification of the person making the correction, the date the correction was made, and the 
reason for change. Reasons for significant corrections should additionally be included. 
The Principal Investigator must review the CRFs for completeness and accuracy and must sign 
and date the appropriate CRFs as indicated. Furthermore, the Investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs.
After the lock of the clinical study database, any change of, modification of, or addition to the 
data on the CRFs should be made by the Investigator with use of change and modification 
records of the CRFs. The Principal Investigator must review the data change for completeness 
and accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’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 participants, medical records, temporary media such as thermal sensitive paper, 
source worksheets, all original signed and dated ICFs, participant authorization forms regarding 
the use of personal health information (if separate from the ICFs), 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 
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degradable thermal sensitive paper should be photocopied by the site and filed with the original 
in the participant’s chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 
requires the Investigator to retain essential documents specified in ICH E6 (Section 8) until at 
least 2 years after the last approval of a marketing application for a specified drug indication 
being investigated or, if an application is not approved, until at least 2 years after the 
investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 Section 
4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the Investigator and Sponsor.
Refer to the Clinical Study Site Agreement for the Sponsor’s requirements on record retention. 
The Investigator and the head of the institution should contact and receive written approval from 
the Sponsor before disposing of any such documents.
16.0
REFERENCES
1. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance 
for Industry: Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical 
Pharmacology Considerations. June 2022. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/assessing-effects-food-drugs-inds-and-ndas-
clinical-pharmacology-considerations. 
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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 
trial-related duties and functions, the Investigator/institution should ensure that this 
individual or party is qualified to perform those trial-related duties and functions and should 
implement procedures to ensure the integrity of the trial-related duties and functions 
performed and any data generated.
4. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential participants, 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 participants. 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 participant who participates in the study, and 
document the date of consent in the participant’s medical chart. Valid informed consent is the 
most current version approved by the IRB/IEC. Each ICF should contain a participant 
authorization section that describes the uses and disclosures of a participant’s personal 
information (including personal health information) that will take place in connection with 
the study. If an ICF does not include such a participant authorization, then the Investigator 
must obtain a separate participant authorization form from each participant or the 
participant’s legally acceptable representative.
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 
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2 years following notification by the Sponsor that all investigations have been discontinued
or that the regulatory authority has approved the marketing application. The Investigator 
should contact and receive written approval from the Sponsor before disposing of any such 
documents.
11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of Sponsor-supplied 
drugs, and return all unused Sponsor-supplied drugs to the Sponsor. 
13. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the Sponsor 
within 24 hours.
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Appendix B
Elements of the Participant Informed Consent
In seeking informed consent, the following information shall be provided to each participant:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the participant’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 participants involved in the study.
7. A description of the participant’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the participant may receive.
11. A description of any reasonably foreseeable risks or discomforts to the participant and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the participant or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the participant, the participant 
should be made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might 
be advantageous to the participant and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the 
participant 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 ICF, the 
participant or the participant’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 participant for participating in the study.
17. The anticipated expenses, if any, to the participant for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(Investigator), participant’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the participant.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty 
or loss of benefits to which the participant otherwise is entitled, and that the participant or the 
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participant’s legally acceptable representative may discontinue participation at any time 
without penalty or loss of benefits to which the participant is otherwise entitled.
20. The consequences of a participant’s decision to withdraw from the research and procedures 
for orderly termination of participation by the participant.
21. A statement that the participant or the participant’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to the 
participant’s willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the participant’s participation in the 
study may be terminated.
23. A written participant authorization (either contained within the ICF or provided as a separate 
document) describing to the participant the contemplated and permissible uses and 
disclosures of the participant’s personal information (including personal health information) 
for purposes of conducting the study. The participant authorization must contain the 
following statements regarding the uses and disclosures of the participant’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 
participants 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 participants 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 participant’s identity will remain confidential in the event that study results are 
published.
24. Female participants of childbearing potential (eg, nonsterilized, premenopausal female 
participants) who are sexually active must use highly effective contraception (as defined in 
the ICF) from signing the ICF and throughout the duration of the study, and for 30 days after 
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the last dose of study drug. Regular pregnancy tests will be performed throughout the study 
for all female participants of childbearing potential. If a participant is found to be pregnant 
during study, study drug will be discontinued, and the Investigator will offer the participant 
the choice to receive treatment information. 
25. Male participants must use highly effective contraception (as defined in the ICF) from 
signing the informed consent throughout the duration of the study and for 100 days after the 
last dose of study drug. If the partner of the participant is found to be pregnant during the 
study, the Investigator will offer the participant the choice to receive treatment information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a 
publicly accessible website, such as ClinicalTrials.gov.
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Appendix C
Investigator Consent to the Use of Personal Information 
Takeda will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of Investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance activities relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting Investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in Investigator’s 
own country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Pregnancy and Contraception
Contraception and Pregnancy Avoidance Procedure
Male Participants
From signing of the ICF, throughout the duration of the study, and for 100 days after last dose of 
study drug, nonsterilized** male participants who are sexually active with a female partner of 
childbearing potential* must use barrier contraception (eg, condom with or without spermicidal 
cream or jelly). In combination with this measures, females of childbearing potential who are 
partners of male subjects are also advised to use additional contraception as shown in the list 
containing highly effective/effective contraception below. In addition, male subjects must be 
advised not to donate sperm during this period. 
Female Participants and Their Male Partners
From signing of the ICF, throughout the duration of the study, and for 30 days after last dose of 
study drug, female participants of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use a highly effective method (from the list below). 
In addition they must be advised not to donate ova during this period.
Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
* A female is considered a female of childbearing potential, i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral tubal ligation, bilateral salpingectomy, hysteroscopic sterilization,
and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range (FSH >40 IU/L) may be used to confirm a post-menopausal state in 
younger females (eg, those <45 year old) or females who are not using hormonal contraception 
or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly). In this study, where medications and devices containing hormones are 
included, the only acceptable methods of contraception are: 

Non-Hormonal Methods: 
–
Intrauterine device (IUD).
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–
Bilateral tubal occlusion.
–
Vasectomised partner (provided that partner is the sole sexual partner of the study 
participant and that the vasectomised partner has received medical assessment of the 
surgical success.

Hormonal Methods: Hormonal contraception may be susceptible to interaction with the 
investigative compound, comparator, concomitant medications, which may reduce the 
efficacy of the contraception method.
–
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if 
for shorter duration until she has been on contraceptive for 3 months;

Oral.

Intravaginal (eg, ring).

transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter until she has 
been on contraceptive for 3 months;

oral.

Injectable.

Implantable.
2. In addition, effective methods of contraception (there may be a higher than 1% failure rate) 
are: 

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with 
spermicidal jellies or creams PLUS male condom).
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.

No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.
4. Participants will be provided with information on highly effective/effective methods of 
contraception as part of the participant informed consent process and will be asked to sign a 
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consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the course of the study, regular serum human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for females of childbearing potential and all 
participants (male and female) will receive continued guidance with respect to the avoidance 
of pregnancy and sperm donation as part of the study procedures. Such guidance should 
include a reminder of the following:
a) contraceptive requirements of the study
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners
c) assessment of participant compliance through questions such as
i. Have you used the contraception consistently and correctly since the last visit?
ii. Have you forgotten to use contraception since the last visit?
iii. Are your menses late (even in females with irregular or infrequent menstrual cycles 
a pregnancy test must be performed if the answer is “yes”)
iv. Is there a chance you could be pregnant?
6.
In addition to a negative serum hCG pregnancy test at Screening, female participants of 
childbearing potential must also have confirmed menses in the month before first dosing (no 
delayed menses; with the exception of female participants using a protocol acceptable 
contraception method that has a known side effect of delayed or irregular menses). In 
addition, participants must also have a negative serum hCG pregnancy test at first check-in, 
within approximately 24 hours prior to receiving first dose of stud drug as close as possible 
and prior to first dose of study drug, preferably on the same day.
General Guidance With Respect to the Avoidance of Pregnancy
Such guidance should include a reminder of the following:
7. contraceptive requirements of the study.
8. reasons for use of barrier methods (ie, condom) in males with pregnant partners.
9. assessment of participant compliance through questions such as:
–
Have you used the contraception consistently and correctly since the last visit?
–
Have you forgotten to use contraception since the last visit? 
–
Are your menses late (even in females with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
–
Is there a chance you could be pregnant?
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Pregnancy
If any participant is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
female partner of a male participant during the study or for 165 days after the last dose, should 
also be recorded following authorization from the participant’s partner. 
If a female subject’s pregnancy occurs within 105 days of administration of TAK-227, the 
pregnancy should be reported immediately, using a pregnancy notification form, to the contact 
listed in the medical monitoring plan
If the female participant and/or female partner of a male participant agrees to the primary care 
physician being informed, the Investigator should notify the primary care physician of her or her 
male partner (ie, male participant) participation in a clinical study at the time she became 
pregnant and provide details of the study drug the female participant or her male partner (ie, 
male participant) received.
All pregnancies, including female participants and female partners of male participants on active 
study drug (including comparator, if applicable) will be followed up to final outcome, using the 
pregnancy form. Pregnancies will remain blinded to the study team. The outcome, including any 
premature termination, must be reported to the sponsor. An evaluation after the birth of the child 
will also be conducted.
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Appendix E
Summary of Changes from Previous Version 
A summary of changes incorporated into Amendment 1 is provided in the table below.
Summary of Changes(s) Since Last Version of Approved Protocol
Description of Change
Section(s) Affected by Change
Change creatine clearance in inclusion 
criteria from 80 mL/min to 90 mL/min
Section 1.0 (Study Summary)
Section 7.1 (Inclusion Criteria)
Change washout period in table from 
“Days 3-4” to “Not less than 4 days”. 
Also, change “at least 96 hours” to “not 
less than 4 days”.
Section 1.0 (Study Summary)
Table 2.a (Study Schematic)
Table 2.b (Study Treatments for Study Drug)
Section 3.0 (Schedule of Study Procedures)
Section 4.2 (Rationale for the Proposed Study) 
Section 6.1 (Study Design) 
Section 6.4.1 (Rationale of Study Design) 
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For non-commercial use only

SAP_001.pdf: 
For non-commercial use only


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-227-1001 
A Randomized, Open-Label, Single-Dose, Three-Way Crossover Evaluation of the Effect of 
Food on the Pharmacokinetics, Safety, and Tolerability of TAK-227 in Healthy Adult 
Participants 
Phase: 1 
Version: Final 
Date: 02 March 2023 
Prepared by:  
, MS 
 
Data Management and Biometrics 
Celerion 
, MSc 
, Clinical Pharmacology & Pharmacometrics 
Data Management and Biometrics 
Celerion 
Based on: 
Protocol Version: Amendment 1 
Protocol Date: 15 February 2023 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Takeda. 
For non-commercial use only


TAK-227-1001 
Celerion Study Number CA39134 
Page 2 of 22
Statistical Analysis Plan Final 
02 March 2023
 
CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
02-Mar-2023 
Not Applicable 
 
 
 
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Statistical Analysis Plan Final 
02 March 2023
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8 
1.1 
Objectives ......................................................................................................................8 
1.1.1 
Primary Objective ..................................................................................................8 
1.1.2 
Secondary Objective ..............................................................................................8 
1.1.3 
Exploratory Objectives ..........................................................................................8 
1.2 
Endpoints .......................................................................................................................8 
1.2.1 
Primary Endpoints .................................................................................................8 
1.2.2 
Secondary Endpoints .............................................................................................9 
1.2.3 
Exploratory Endpoints ...........................................................................................9 
1.2.4 
Additional Exploratory Endpoints .........................................................................9 
1.3 
Estimands .....................................................................................................................10 
2.0 
STUDY DESIGN...............................................................................................................10 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................12 
3.1 
Statistical Hypotheses ..................................................................................................12 
3.2 
Statistical Decision Rules ............................................................................................12 
3.3 
Multiplicity Adjustment ...............................................................................................12 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................13 
5.0 
ANALYSIS SETS .............................................................................................................13 
5.1 
Safety Set .....................................................................................................................13 
5.2 
PK Set ..........................................................................................................................13 
6.0 
STATISTICAL ANALYSIS .............................................................................................13 
6.1 
General Considerations ................................................................................................13 
6.1.1 
Handling of Treatment Misallocations ................................................................15 
6.2 
Study Information ........................................................................................................15 
6.3 
Disposition of Participants ...........................................................................................15 
6.4 
Demographic and Other Baseline Characteristics .......................................................15 
6.4.1 
Demographics ......................................................................................................15 
6.4.2 
Medical History and Concurrent Medical Conditions .........................................16 
6.5 
Medication History and Concomitant Medications .....................................................16 
6.6 
Efficacy Analysis .........................................................................................................16 
6.7 
Safety Analysis ............................................................................................................16 
6.7.1 
Adverse Events ....................................................................................................17 
6.7.2 
Adverse Events of Special Interest ......................................................................17 
6.7.3 
Clinical Laboratory Evaluation ...........................................................................18 
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6.7.4 
Vital Signs ...........................................................................................................19 
6.7.5 
12-Lead ECG .......................................................................................................19 
6.7.6 
Physical Examinations .........................................................................................20 
6.7.7 
Overdose ..............................................................................................................20 
6.7.8 
Extent of Exposure and Compliance ...................................................................20 
6.8 
Pharmacokinetic Analysis ............................................................................................20 
6.9 
Patient Reported Outcomes and Health Care Utilization Endpoints Analysis ............21 
6.10 
Interim Analysis ...........................................................................................................21 
6.11 
Preliminary Analysis ....................................................................................................21 
6.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................22 
7.0 
REFERENCES ..................................................................................................................22 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................22 
9.0 
APPENDIX ........................................................................................................................22 
9.1 
Changes From the Previous Version of the SAP .........................................................22 
9.2 
Data Handling Conventions .........................................................................................22 
9.3 
Analysis Software ........................................................................................................22 
 
LIST OF IN-TEXT TABLES 
Table 2.a 
Study Schematic.....................................................................................................10 
Table 2.b 
Randomization Sequence .......................................................................................11 
Table 2.c 
Study Treatments for Study Drug ..........................................................................12 
Table 6.a 
Collection of Laboratory Samples .........................................................................18 
Table 6.b 
Collection of Vital Signs ........................................................................................19 
Table 6.c 
Collection of ECGs ................................................................................................19 
Table 6.d 
Collection of Blood Samples for Pharmacokinetic Analysis .................................20 
 
 
 
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ABBREVIATIONS 
λz 
terminal disposition phase rate constant 
AE 
adverse event 
AUC∞ 
area under the concentration-time curve from time 0 to infinity, calculated using the observed 
value of the last quantifiable concentration 
AUC∞_pred 
area under the concentration-time curve from time 0 to infinity, calculated using the predicted 
value of the last quantifiable concentration 
AUCextrap% 
area under the curve from the last quantifiable concentration to infinity, calculated using the 
observed value of the last quantifiable concentration, expressed as a percentage of AUC∞ 
AUCextrap%_pred 
area under the curve from the last quantifiable concentration to infinity, calculated using the 
predicted value of the last quantifiable concentration, expressed as a percentage of AUC∞_pred 
AUClast 
area under the concentration-time curve from time 0 to the time of the last quantifiable 
concentration 
BLQ 
below the lower limit of quantitation 
CI 
confidence interval 
CL/F 
apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration 
CL/F_pred 
apparent clearance after extravascular administration, calculated using the predicted value of 
the last quantifiable concentration 
Cmax 
maximum observed concentration 
COVID-19 
coronavirus disease 2019  
CPAP 
clinical pharmacology analysis plan 
CRF 
case report form 
CRU 
clinical research unit 
CSR 
clinical study report 
CV 
coefficient of variance 
DMP 
data management plan 
ECG 
electrocardiogram 
Geom CV 
geometric coefficient of variance 
Geom Mean 
geometric mean 
GMR 
geometric least-squares mean ratio 
ICF 
informed consent form 
LSM 
least-squares mean 
Mean 
arithmetic mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPR AUC∞ 
metabolite-to parent AUC∞ ratio 
MPR AUC∞_pred 
metabolite-to parent AUC∞_pred ratio 
MPR Cmax 
metabolite-to parent Cmax ratio 
n 
number of observations 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
System Organ Class 
t1/2z 
terminal disposition phase half-life 
TEAE  
treatment-emergent adverse event 
TFL 
table, figure, and listing 
tlag 
lag time to first quantifiable concentration (calculated as lag time to observation prior to the 
first observation with a measurable (non-zero) concentration) 
tmax 
time to first occurrence of Cmax 
Vz/F 
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the observed value of the last quantifiable concentration 
Vz/F_pred 
apparent volume of distribution during the terminal disposition phase after extravascular 
administration, calculated using the predicted value of the last quantifiable concentration 
WHO 
World Health Organization 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To assess the pharmacokinetics (PK) of a single oral dose of 50 mg TAK-227 administered 
30 minutes following the start of a high-fat/high-calorie meal or ~30 minutes before the start of a 
high-fat/high-calorie meal in healthy adult participants relative to administration under fasting 
conditions in healthy adult participants. 
1.1.2 
Secondary Objective 
To evaluate the safety and tolerability of a single oral dose of 50 mg TAK-227 when 
administered under fasting conditions, 30 minutes following the start of a high-fat/high-calorie 
meal, and ~30 minutes before the start of a high-fat/high-calorie meal in healthy adult 
participants. 
1.1.3 
Exploratory Objectives 
• To evaluate other PK parameters for a single oral dose of 50 mg TAK-227 when 
administered under fasting conditions, 30 minutes following the start of a high-fat/ 
high-calorie meal, and ~30 minutes before the start of a high-fat/high-calorie meal in healthy 
adult participants. 
• To evaluate TAK-227 metabolites PK parameters for a single oral dose of 50 mg TAK-227 
when administered under fasting conditions, 30 minutes following the start of a 
high-fat/high-calorie meal, and ~30 minutes before the start of a high-fat/high-calorie meal 
in healthy adult participants. 
1.2 
Endpoints 
1.2.1 
Primary Endpoints 
The primary endpoints will be assessed through evaluation of the following PK parameters for 
TAK-227 in plasma: 
• Maximum observed concentration (Cmax) 
• Area under the concentration-time curve (AUC) from time 0 to the time of the last 
quantifiable concentration (AUClast) 
• AUC from time 0 to infinity, calculated using the observed value of the last quantifiable 
concentration (AUC∞) 
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1.2.2 
Secondary Endpoints  
The secondary endpoints will be assessed through evaluation of the following safety parameters: 
• Treatment-emergent adverse events (TEAEs) and their frequency, severity, seriousness, and 
causality assessments 
• Changes in vital signs, electrocardiograms (ECGs), and clinical laboratory results 
(hematology, chemistry, and urinalysis) from baseline to post-baseline time points, and 
findings from physical examinations. 
1.2.3 
Exploratory Endpoints  
The exploratory endpoints will be assessed through evaluation of the following PK parameters 
for TAK-227 and its metabolites in plasma (if applicable, but are not limited to): 
• Time to first occurrence of Cmax (tmax) 
• Lag time to first quantifiable concentration in plasma (tlag) 
• Terminal disposition phase rate constant (λz) 
• Terminal disposition phase half-life (t½z) 
• Apparent volume of distribution during the terminal disposition phase after oral 
administration, calculated using the observed value of the last quantifiable concentration 
(Vz/F; parent only) 
• Apparent clearance after oral administration, calculated using the observed value of the last 
quantifiable concentration (CL/F; parent only) 
• AUC from the last quantifiable concentration to infinity, calculated using the observed value 
of the last quantifiable concentration, expressed as a percentage of AUC∞ (AUCextrap%) 
The following PK parameters will also be evaluated for TAK-227 metabolites: 
• Cmax 
• AUClast 
• AUC∞ 
1.2.4 
Additional Exploratory Endpoints  
The following additional endpoints will be calculated for TAK-227 and any metabolites (if 
applicable): 
• AUC from time 0 to infinity, calculated using the predicted value of the last quantifiable 
concentration (AUC∞_pred) 
• Apparent volume of distribution during the terminal disposition phase after oral 
administration, calculated using the predicted value of the last quantifiable concentration 
(Vz/F_pred; parent only) 
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• Apparent clearance after oral administration, calculated using the predicted value of the last 
quantifiable concentration (CL/F_pred; parent only) 
• AUC from the last quantifiable concentration to infinity, calculated using the predicted value 
of the last quantifiable concentration, expressed as a percentage of AUC∞_pred 
(AUCextrap%_pred) 
• Metabolite-to-parent AUC∞ ratio (MPR AUC∞) 
• Metabolite-to-parent AUC∞_pred ratio (MPR AUC∞_pred) 
• Metabolite-to-parent Cmax ratio (MPR Cmax) 
1.3 
Estimands 
Not applicable. 
2.0 
STUDY DESIGN 
This is a single-center, open-label, single-dose, randomized, 3-period, 6-sequence, crossover 
study in healthy adults. A study schematic is shown in Table 2.a.  
Table 2.a 
Study Schematic 
Pretreatment 
Treatment Periods 1-2-3  
Study Exit 
Follow-up 
(a) 
Screening 
Check-in 
Dosing and Safety 
and PK 
Assessments 
Safety and PK 
Assessments 
Washout 
(b) 
Day 2 of 
Treatment 
Period 3 
7 (±3) days 
after last 
dose 
Day -28 to 
first dosing  
Day -1 of 
Treatment 
Period 1 
Day 1 
Day 2 
Not less 
than 4 
days 
 
Confinement (c)  
 
(a) The clinical research unit (CRU) will contact all participants (including participants who terminate the study 
early) 7 (± 3) days after the last TAK-227 administration by telephone or other methods per CRU standards to 
determine if any adverse event (AE) has occurred or concomitant medications have been taken since the last 
study visit. If clinically significant findings are observed upon discharge, participants may return to the CRU for 
re-evaluation per Investigator’s discretion. 
(b) There will be a washout period of not less than 4 days between TAK-227 dosing in each period. 
(c) Participants will start the confinement on Day -1 of Treatment Period 1 and will remain confined until Day 2 of 
Treatment Period 3. 
On Day 1 of Treatment Period 1, participants will be randomly assigned to one of 6 possible 
treatment sequences (Table 2.b).  
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Table 2.b 
Randomization Sequence 
Sequence 
Number of participants (N) 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
1 
4 
A 
B 
C 
2 
4 
B 
C 
A 
3 
4 
C 
A 
B 
4 
4 
A 
C 
B 
5 
4 
B 
A 
C 
6 
4 
C 
B 
A 
Treatment A: Fasting  
Treatment B: Fed predose, high-fat/high-calorie meal administered 30 minutes prior to dosing. 
Treatment C: Fed postdose, high-fat/ high-calorie meal administered ~30 minutes after dosing. 
 
On Day 1 of each treatment period, a single dose of 50 mg TAK-227 will be administered orally 
under one of 3 different feeding conditions as per the randomization schedule: 
• 
Fasting (Treatment A), 
• 
Fed predose, high-fat/high-calorie meal administered 30 minutes prior to dosing 
(Treatment B), and 
• 
Fed postdose, high-fat/high-calorie meal administered ~30 minutes after dosing 
(Treatment C). 
Drinking water (except water provided with each dosing) will be restricted 1 hour prior to and 
1 hour after each dosing 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. 
For Treatment A, participants will be required to fast overnight for at least 10 hours prior to 
dosing and will continue the fast for at least 4 hours postdose. 
For Treatment B, participants 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. Participants will fast for at least 
4 hours postdose. 
For Treatment C, participants will be required to fast overnight for at least 10 hours prior to 
dosing and will continue the fast for ~30 minutes postdose, at which time they will be given a 
high fat/high calorie breakfast* which will be entirely consumed within 30 minutes. Participants 
will fast for at least 3 hours following the meal. 
The dose regimens are shown in Table 2.c. 
                                                 
* A high fat/high-calorie breakfast will contain 800-1000 calories and approximately 50% fat.  An example of high 
fat would be 2 slices of buttered toast, 2 eggs fried in butter, 2 strips of bacon, 4 oz of hash brown potatoes, and 
8 ounces (approximately 240 mL) of whole milk [FDA, 2022]. 
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Table 2.c 
Study Treatments for Study Drug 
Treatment (a) 
Study Drug 
Dose 
Dose Regimen 
Days on Study Drug 
Treatment A 
TAK-227 
capsule 
50 mg 
Fasted, single dose, oral  
Day 1 
Treatment B 
TAK-227 
capsule 
50 mg 
Fed predose: after a 
high-fat/high-calorie meal (b),  
single dose, oral  
Day 1 
Treatment C 
TAK-227 
capsule 
50 mg 
Fed postdose: before a 
high-fat/high-calorie meal (c),  
single dose, oral,  
Day 1 
(a) There will be a washout period of not less than 4 days between TAK-227 dosing in each treatment. 
(b) TAK-227 will be administered 30 minutes following the start of a high-fat/high-calorie meal. 
(c) A high-fat/high-calorie meal will be administered ~30 minutes following administration of TAK-227. 
 
Following all treatments, each meal and/or snacks served at the CRU will be standardized and 
will be similar in caloric content and composition (except for the meals served as part of 
Treatments B and C) and will be taken at approximately the same time in each treatment period. 
When confined, standard meals and snacks will be provided at appropriate times, except when 
they are required to fast. When confined in the CRU, participants will be required to fast from 
all food and drink except water between meals and snacks. 
There will be a washout period of not less than 4 days between TAK-227 dosing in each period. 
PK sample collections will be conducted predose and up to 36 hours postdose in each treatment 
period. 
Safety and tolerability will be assessed throughout the study by TEAEs, vital signs, ECGs, 
clinical laboratory evaluations, and physical examinations. The CRU will contact all 
participants (including participants who terminate the study early) 7 (± 3) days after the last 
TAK-227 administration by telephone or other methods per CRU standards to determine if any 
AE has occurred or concomitant medications have been taken since the last study visit. If 
clinically significant findings are observed upon discharge, participants may return to the CRU 
for re-evaluation per the Investigator’s discretion. 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES  
3.1 
Statistical Hypotheses 
Not applicable. 
3.2 
Statistical Decision Rules 
Not applicable. 
3.3 
Multiplicity Adjustment 
Not applicable. 
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4.0 
SAMPLE-SIZE DETERMINATION 
The study is designed to have approximately 18 evaluable participants complete all treatment 
periods of the study.  
Sample size calculations was performed using R package PowerTOST based on the following: 
• 
The intra-participant CV was assumed at ~0.4 for Cmax and AUC, which were estimated 
based on data in Study CEC-2 (a completed Phase 1 Multiple Ascending Dose study) 
• 
Reference data set is Cmax or AUC under fasting condition; test data set is Cmax or AUC 
under fed conditions 
• 
If the observed geometric least-squares mean ratio (GMR) is at 0.90 or 1.10, the estimated 
90% confidence interval (CI) of the GMR, with N = 18, is within (0.70, 1.43) for both Cmax 
and AUC 
Accounting for possible dropouts, a total of 24 participants may be enrolled. 
5.0 
ANALYSIS SETS 
5.1 
Safety Set 
All participants who received at least one dose of the study drug(s) will be included in the safety 
evaluations. 
5.2 
PK Set  
All participants 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 PK analyses. 
6.0 
STATISTICAL ANALYSIS  
6.1 
General Considerations 
All PK analyses will be conducted using Phoenix® WinNonlin® Version 8.3.4, or higher. All 
statistical analyses will be conducted using SAS® Version 9.4. All relevant safety data will be 
listed by participant and treatment. All table, figure, and listing (TFL) shells and numbering list 
will be included and specified in the TFL Shells document.  
The number of observations (n) will be presented as an integer (no decimal places), arithmetic 
mean (mean), median, and geometric mean (geom mean) values will be presented to 1 more 
level of precision than the individual values. Standard deviation (SD) and standard error of the 
mean (SEM) will be presented to 2 more levels of precision than the individual values. Minimum 
and maximum values will be presented to the same precision as the individual values. Arithmetic 
percent coefficient of variation (CV%) and geometric percent coefficient of variation (geom 
CV%) will be presented to 1 decimal place. 
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Geometric least-squares means (LSMs) will be reported with 1 more level of precision than the 
individual data. Geometric LSM ratios (GMRs) and 90% confidence intervals (CIs) for the 
GMRs will be reported to 2 decimal places. Intra-participant CVs will be reported to 1 decimal 
place. 
Noncompartmental analyses will be used in this study. Concentration values below the lower 
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 deemed questionable (eg, BLQ value between measurable values), in which case they will be 
treated as missing and excluded from the concentration summary statistics and the PK analysis. 
Values of 0 are not included in the calculation of geom mean and geom CV%.  
A participant’s PK parameter data will be included in the listings but may be excluded from the 
descriptive and inferential statistics if one or more of the following criteria are met: 
• A predose (0 hour) concentration is greater than 5% of that participant’s Cmax value for the 
same treatment 
• A participant did not meet inclusion/exclusion criteria that may have an effect on the PK (as 
determined by the Takeda Pharmacology Lead and Celerion Pharmacokinetic Scientist) 
• A participant deviates substantially from the protocol defined study procedures including but 
not limited to dosing, dose timing, sample collection, meal timing, etc. (as determined by the 
Takeda Clinical Pharmacology Lead and Celerion Pharmacokinetic Scientist)  
• A participant may be excluded due to vomiting within twice the median tmax of TAK-227 
(2 × 2 hours = 4 hours) 
The details on PK parameter calculations and TFLs will be outlined in the clinical pharmacology 
and analysis plan (CPAP) and TFL Shells document including specifics on the following: 
• Insufficient data to determine a reliable t1/2z value and other λz-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 Phoenix® WinNonlin® output file used to generate the TFLs 
• Linear mixed-effect model and non-parametric statistical analysis results presented in in-text 
and end-of-text tables 
• Arithmetic mean concentration-time figures presented as in-text and end-of-text figures 
• Listings of concentration data for individual participants in Appendix 16.2.5. 
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• Individual concentration-time figures presented in Appendix 16.2.6. 
Continuous demographic and safety data will be summarized descriptively. For categorical 
variables, the count and percentages of each possible value will be tabulated, where applicable. 
The denominator for the percent calculation will be the number of participants in the safety set 
for overall summaries, and the number of participants dosed with each treatment in by-treatment 
summaries. For continuous variables, n, mean, SD, minimum, median, and maximum values will 
be tabulated. The level of precision will be presented as follows: minimum/maximum in the 
same precision as in the database, mean/median in one more precision level than 
minimum/maximum, SD in one more precision level than mean/median, and n will be presented 
as an integer. Counts and percentages will be presented as integers. Baseline is defined as the last 
observation prior to dosing in each period, unless specified otherwise. 
6.1.1 
Handling of Treatment Misallocations 
Participants with any treatment misallocations will be analyzed based on the treatment the 
participants actually received. 
6.2 
Study Information 
A study information table will be generated including the following items: date of first 
participant’s signed informed consent form (ICF), date of dosing, date of last participant’s last 
visit/contact, date of last participant’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) Drug Dictionary, and SAS version used for creating the datasets. 
6.3 
Disposition of Participants 
Disposition of participants (number of participants dosed, completed the study, discontinued 
from the study and/or study drug, and reason(s) for discontinuation(s)) will be summarized by 
randomized treatment sequence and overall. Study completion status, including reason for 
discontinuation of study and/or study drug, will be listed by participant.  
6.4 
Demographic and Other Baseline Characteristics 
6.4.1 
Demographics 
Demographic and baseline characteristics will be summarized by randomized treatment sequence 
and overall based on the safety set. Summary statistics (n, mean, SD, minimum, median, and 
maximum) will be generated for continuous variables (age, weight, height, and body mass index 
[BMI]) and the number and percentages of participants within each category will be presented 
for categorical variables (sex, race, and ethnicity). Height, weight, and BMI measured at 
screening will be used in the summaries. Other demographic data will also be listed as recorded 
on the CRF, including date of informed consent and protocol version. 
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6.4.2 
Medical History and Concurrent Medical Conditions 
Medical history will include determining whether the participant has any significant conditions 
or diseases that resolved at or before signing the ICF. All medical history reported by the 
participant will be recorded regardless of when it may have occurred. Concurrent medical 
conditions are those significant ongoing conditions or diseases that are present at signing the 
ICF. Each participant’s medical history and concurrent medical conditions will be listed. 
Any medical condition starting or worsening after taking the first dose of study drug will be 
classified as a TEAE. All medical history will be coded using MedDRA® version specified in the 
data management plan (DMP). If available, the medical history and concurrent medical condition 
listings will include the coded term (preferred term and system organ class [SOC]), start date (if 
known) and end date (if known) or whether the condition was ongoing, and a description of the 
condition or event. No summaries or statistical analysis will be performed for these data. 
6.5 
Medication History and Concomitant Medications  
Medication history includes any relevant medication stopped at or within 28 days before signing 
the ICF. Concomitant medication includes any medication other than the study drug taken at any 
time between screening and the end of the study (including follow-up contact). All medication 
history and concomitant medications recorded during the study will be coded with the WHO 
Drug Dictionary version specified in the DMP and listed. If available, the listings will include 
the medication name, coded term, dosage, route of administration, start date and time (if known), 
end date and time (if known), or whether it continued after study completion, and indication for 
use. No summaries or statistical analysis will be performed for these data.  
6.6 
Efficacy Analysis 
Not applicable. 
6.7 
Safety Analysis 
Safety will be evaluated by the incidence of TEAEs, severity and relationship(s) of TEAEs, and 
changes from baseline in the participants’ clinical laboratory results, vital signs, and 12-lead 
ECGs using the safety set. Clinically significant laboratory values and vital signs will be reported 
as AEs, as applicable. All safety data will be listed by participant, treatment, and assessment time 
points, including rechecks, unscheduled assessments, and early termination (ET), 
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. Postdose recheck, unscheduled, or ET results will 
not be used in summaries. 
Tables summarizing safety data by assessment time point will only include summaries for 
baseline and post-baseline time points. 
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6.7.1 
Adverse Events 
All AEs captured in the database will be listed in by-participant data listings including verbatim 
term, coded term, severity (mild, moderate, severe), relationship to study drug (related or not 
related), relationship to COVID-19 and COVID-19 vaccine, frequency, and action relative to the 
study drug as recorded in the CRF. Study procedure taken due to AE will also be listed. All AEs 
occurring during this study will be coded using the MedDRA® version specified in the DMP. 
Only TEAEs will be summarized. 
A TEAE is defined as an AE that is starting or worsening at the time of or after the first dose of 
study drug. Each TEAE will be attributed to the treatment prior to and the closest to the AE 
based on the AE onset date and time. 
If the onset time of an AE is missing and the onset date is the same as a treatment dosing date, 
then the AE will be counted under the treatment given on the same day. If onset time of an AE is 
missing and the onset date does not fall on a dosing date, then the AE will be considered 
treatment emergent for the most recent treatment administered. If the onset date of an AE is 
missing, then the AE will be considered treatment emergent and attributed to the first treatment 
received. If severity is missing, the AE will be counted as severe, and if relationship is missing, 
the AE will be counted as related.  
TEAEs will be tabulated by treatment (including overall), SOC, and preferred term. Summary 
tables will include number of participants reporting the TEAE as percent of safety set by 
treatment and overall. The most commonly reported non-serious TEAEs (i.e., those events 
reported by >5% of participants in any treatment, excluding serious adverse events (SAEs) will 
also be summarized. The denominators for percent calculations will be the number of 
participants dosed for each treatment. In addition, TEAEs will be summarized as number of 
TEAEs and percentage of TEAEs for each treatment and overall.  
Additional TEAE summary tables will be presented by severity and relationship to study drug. If 
a participant has multiple TEAEs with different severity levels within the same preferred term, 
the participant will be counted in the most severe category only. For relationship to study drug, if 
a participant has both related and unrelated TEAEs with the same preferred term, the participant 
will be counted as having related TEAEs. 
An overview summary of TEAEs table, including number of participants with TEAEs, 
treatment-emergent SAEs, treatment-related TEAEs, treatment-related SAEs, TEAEs by 
severity, and AEs leading to discontinuation will be provided. 
Should any SAEs (including all-cause mortalities) occur, they will be summarized the same way 
as TEAEs. All AEs will be displayed in the data listings and TEAEs will be discussed in the text 
of the clinical study report (CSR). 
6.7.2 
Adverse Events of Special Interest  
Not applicable. 
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6.7.6 
Physical Examinations 
Full physical examinations will be performed at screening, prior to dosing in each period, and 24 
hours postdose in Period 3, or early termination. Additional physical examinations may be 
performed at other times at the discretion of the Investigator. Physical examination findings will 
be presented in the data listings by participant. 
6.7.7 
Overdose 
All cases of overdose will be presented in a data listing by participant. Any AEs associated with 
overdose will be documented on the AE page of the CRF.  
6.7.8 
Extent of Exposure and Compliance 
The dates, times, and doses of TAK-227 will be listed by participant and study period. Dates and 
times of critical meals for the fed treatments will also be listed. 
6.8 
Pharmacokinetic Analysis 
Blood samples for assessment of plasma concentrations of TAK-227 and its metabolites will be 
collected as outlined in Table 6.d below:  
Table 6.d 
Collection of Blood Samples for Pharmacokinetic Analysis 
Analytes 
Matrix 
Scheduled Time (Hours)* 
TAK-227 and 
metabolites 
Plasma 
Predose and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, and 36 hours 
postdose.  
*The actual date and time of sample collection will be recorded on the source document in the case report form.  
Plasma concentrations of TAK-227 and its metabolites will be listed and summarized 
descriptively by PK sampling time and treatment using the following descriptive statistics: n, 
mean, SD, CV%, SEM, minimum, median, and maximum. Excluded concentrations will be 
presented and footnoted as such in the concentration table listings, and those values will be 
excluded from the descriptive statistics.  
Individual participant concentration-time curves will be plotted by treatment on linear and 
semi-log scales. The arithmetic mean profiles of the concentration-time data will be plotted by 
treatment on linear (with and without SD) and semi-log scales. For summary statistics and 
arithmetic mean plots by sampling time, the nominal PK sampling time will be used. For 
individual participant plots by time, the actual PK sampling time will be used. 
PK parameters will be calculated from plasma concentration-time profiles using 
non-compartmental analysis methods where all calculations will be based on actual sampling 
times after dosing. The PK parameters will be summarized by treatment using the following 
descriptive statistics: n, mean, SD, CV%, SEM, minimum, median, maximum, geom mean, and 
geom CV%. Excluded parameters will be presented and footnoted as such in the PK parameter 
table listings, and those values will be excluded from descriptive statistics. 
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CONFIDENTIAL 
Food-Effect Estimation 
A linear mixed-effects model will be applied to natural log-transformed Cmax, AUClast, AUC∞, 
and AUC∞_pred for TAK-227 with treatment, period, and sequence as fixed effects, and 
participant within sequence as a random effect. Point estimates and their associated 90% CIs will 
be constructed for the differences between Treatment B (fed predose) versus Treatment A 
(fasting), and Treatment C (fed postdose) versus Treatment A (fasting). The point estimates and 
their associated 90% CIs will be then back transformed to provide point estimates and 90% CIs 
for the ratios of Treatment B (fed predose) versus Treatment A (fasting) and Treatment C (fed 
postdose) versus Treatment A (fasting). 
The food-effect estimation will be performed using the following SAS code: 
PROC MIXED; 
CLASS TREAT PERIOD SEQUENCE PARTICIPANT; 
MODEL LN(PARAM) = TREAT PERIOD SEQUENCE / DDFM = KR; 
RANDOM PARTICIPANT(SEQUENCE); 
ESTIMATE “Treatment B vs Treatment A” TREAT -1 1 0 / CL ALPHA=0.1 E; 
ESTIMATE “Treatment C vs Treatment A” TREAT -1 0 1 / CL ALPHA=0.1 E; 
LSMEANS TREAT; 
RUN; 
 
Non-Parametric Analysis 
Analysis of tmax and tlag will be performed by nonparametric Wilcoxon Signed-Rank test. The 
Hodges-Lehmann method and Walsh averages will be used to estimate the median difference 
between treatments. The tmax and tlag parameters will not be ln-transformed. The comparisons of 
interest are the same as in the linear mixed-effects model. 
6.9 
Patient Reported Outcomes and Health Care Utilization Endpoints Analysis 
Not applicable. 
6.10 
Interim Analysis 
Not applicable. 
6.11 
Preliminary Analysis 
A preliminary PK analysis will be completed as described in the CPAP and Section 6.8 of the 
statistical analysis plan (SAP), with the following changes: 1) Quality-controlled data (not 
quality-assured data) will be used; 2) nominal times (not actual sampling times) will be used to 
calculate PK parameters; 3) tables and figures will be created using Phoenix® WinNonlin® 
Version 8.3.4 or higher. 
For non-commercial use only


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6.12 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not applicable. 
7.0 
REFERENCES 
Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for 
Industry: Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology 
Considerations. June 2022. Available at: https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/assessing-effects-food-drugs-inds-and-ndas-clinical-pharmacology-
considerations.  
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Additional PK parameters will be calculated as listed in Section 1.2.4. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
Not applicable. 
9.2 
Data Handling Conventions  
Not applicable. 
9.3 
Analysis Software  
SAS® Version 9.4 or higher will be used for all statistical analysis provided in the CSR. 
For non-commercial use only