Clinical trial NCT03501277
Conditions: Healthy Volunteers
Keywords: Drug therapy
Sponsor: Takeda
Start date: 2018-05-26; Completion date: 2018-07-11
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to assess the relative bioavailability and bioequivalence of 2 strengths of the FDC tablet product SYR-322-4833 BL compared to the individual alogliptin and pioglitazone tablets in healthy Russian participants.

Detailed description:
The drug being tested in this study are called Incresync (SYR-322-4833 BL), alogliptin, and pioglitazone. This study will assess the bioequivalence, pharmacokinetics (PK), and safety of alogliptin and pioglitazone administered as individual tablets and as the FDC tablet product in healthy volunteers.

The study will enroll approximately 72 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the 4 treatment sequences to receive one of the following treatments:

* Regimen A: SYR-322-4833 BL (25 mg + 15 mg)
* Regimen B: Alogliptin 25 mg + pioglitazone 15 mg
* Regimen C: SYR-322-4833 BL (25 mg + 30 mg)
* Regimen D: Alogliptin 25 mg + pioglitazone 30 mg

All participants will be asked to take single dose of study medication on Day 1 of each intervention period.

This single center trial will be conducted in Russia. The overall time to participate in this study is 66 days. Participants will make multiple visits to the clinic, and will be contacted by telephone 14 days after their last dose of drug for a follow-up assessment.

Arms: arm 1: SYR-322-4833 BL (alogliptin 25 \[milligram\] mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 1 (Regimen A), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 2 (Regimen B), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 3 (Regimen C), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 4 (Regimen D). arm 2: Alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 1 (Regimen B), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 2 (Regimen C), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 3 (Regimen D), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 4 (Regimen A). arm 3: SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 1 (Regimen C), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 2 (Regimen D), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 3 (Regimen A), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 4 (Regimen B). arm 4: Alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 1 (Regimen D), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 2 (Regimen A), followed by a 7-day washout period, followed by alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 3 (Regimen B), followed by a 7-day washout period, followed by SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 4 (Regimen C).
Interventions: intervention 1: Alogliptin intervention 2: Pioglitazone intervention 3: SYR-322-4833 BL
Intervention descriptions: intervention 1: Alogliptin tablets. intervention 2: Pioglitazone tablets. intervention 3: SYR-322-4833 BL FDC tablets.

Protocol documents:
Prot_000.pdf: 


•
Title: A  Randomized, Open-Label, Single-Dose, 4-Period Crossover Study to Determine the 
Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 and 30 mg) When Administered as 
Individual Tablets and as Fixed-Dose Combination Tablets to Healthy Russian Subjects
NCT Number: NCT03501277
Protocol Approve Date: 23 January 2018 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TITLE PAGE
TAKEDA PHARMACEUTICALS
PROTOCOL
A Randomized, Open-Label, Single-Dose, 4-Period Crossover Study to Determine the 
Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 and 30 mg) When Administered 
as Individual Tablets and as Fixed-Dose Combination Tablets to Healthy Russian Subjects
Bioequivalence Study of Medicinal Product – SYR-322-4833 BL
Sponsor:
Takeda Pharmaceuticals LLC 
2 bld 1, Usatchyova Str.
Moscow 119048
Russian Federation
Study Number:
Alogliptin-1002
IND Number:
Not Applicable 
EudraCT Number:
Not Applicable 
Compound:
SYR-322-4833 BL
Date:
23 January 2018
Amendment 
Number:
02
Amendment History:
Date
Amendment Number
Amendment Type 
Region
25 July 2017
Initial version
Not applicable
Global
19 October 2017
01
Substantial
Global
23 January 2018
02
Substantial
Global
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.


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CONFIDENTIAL
1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 
A separate contact information list will be provided.
Contact Type / Role
Contact
Serious adverse event and pregnancy reporting
Medical Monitor
(medical advice on protocol and study drug)
Responsible Medical Officer (carries overall 
responsibility for the conduct of the study)
PPD


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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
PPD


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CONFIDENTIAL
INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator (Appendix B).
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)


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CONFIDENTIAL
1.3
Protocol Amendment 02 Summary of Changes 
Rationale for Amendment 02
This document describes the changes in reference to the protocol incorporating 
Amendment No. 02. 
The primary reason for this amendment is to align with local requirements for clinical supplies. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix F.
Changes in Amendment 02
1. Revised descriptions of study drugs to align with local requirements.
2. Corrected inconsistency in length of pregnancy monitoring time after the end of the study.
3. Updated information for shipping label and contact information for the bioanalytical 
laboratory.


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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 02 Summary of Changes ..........................................................5
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Principal Investigator...............................................................................................14
3.3
List of Abbreviations ...............................................................................................15
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.1.1
Alogliptin....................................................................................................17
4.1.2
Pioglitazone ................................................................................................17
4.1.3
SYR-322-4833 BL......................................................................................18
4.2
Summary of Relevant Clinical Studies.....................................................................18
4.2.1
Summary of Clinical Studies With Alogliptin .............................................18
4.2.2
Summary of Clinical Studies With Pioglitazone ..........................................19
4.2.3
Summary of Clinical Studies With Alogliptin in Combination With 
Pioglitazone ................................................................................................19
4.3
Benefit/Risk Profile .................................................................................................20
4.4
Rationale for the Proposed Study.............................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................22
5.1
Objectives................................................................................................................22
5.1.1
Primary Objective .......................................................................................22
5.1.2
Additional Objective ...................................................................................22
5.2
Endpoints.................................................................................................................22
5.2.1
Primary Endpoints.......................................................................................22
5.2.2
Additional Endpoints ..................................................................................22
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................23
6.1
Study Design ...........................................................................................................23
6.2
Justification for Study Design, Dose, and Endpoints ................................................24
6.3
Premature Termination or Suspension of Study or Study Site...................................25
6.3.1
Criteria for Premature Termination or Suspension of the Study...................25
6.3.2
Criteria for Premature Termination or Suspension of Study Sites ................25


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6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site...........................................................................25
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............26
7.1
Inclusion Criteria .....................................................................................................26
7.2
Exclusion Criteria ....................................................................................................26
7.3
Excluded Medications, Supplements, Dietary Products............................................28
7.4
Diet, Fluid, Activity Control ....................................................................................29
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................30
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................30
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................32
8.1
Study Drug ..............................................................................................................32
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling..............................32
8.1.2
Storage........................................................................................................33
8.1.3
Dose and Regimen ......................................................................................33
8.1.4
Overdose.....................................................................................................34
8.2
Study Drug Assignment and Dispensing Procedures................................................34
8.3
Randomization Code Creation and Storage..............................................................35
8.4
Accountability and Destruction of Sponsor-Supplied Drugs.....................................35
9.0
STUDY PLAN ..............................................................................................................37
9.1
Study Procedures.....................................................................................................37
9.1.1
Informed Consent Procedure.......................................................................37
9.1.2
Demographics, Medical History, and Medication History Procedure...........37
9.1.3
Physical Examination Procedure .................................................................37
9.1.4
Weight, Height and BMI.............................................................................38
9.1.5
Vital Sign Procedure ...................................................................................38
9.1.6
Documentation of Concomitant Medications...............................................38
9.1.7
Documentation of Concurrent Medical Conditions......................................38
9.1.8
Procedures for Clinical Laboratory Samples................................................38
9.1.9
Contraception and Pregnancy Avoidance Procedure....................................40
9.1.10
Pregnancy ...................................................................................................41
9.1.11
ECG Procedure ...........................................................................................42
9.1.12
PK Sample Collection.................................................................................42
9.1.13
PK Parameters.............................................................................................43
9.1.14
Documentation of Screen Failure ................................................................43
9.1.15
Documentation of Randomization ...............................................................44
9.2
Monitoring Subject Dosing Compliance...................................................................44


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9.3
Schedule of Observations and Procedures................................................................44
9.3.1
Screening ....................................................................................................44
9.3.2
Study Randomization..................................................................................44
9.3.3
Drug Intake/Washout Period .......................................................................44
9.3.4
Final Visit/ Early Termination.....................................................................45
9.3.5
Follow-Up Visit/Telephone Call .................................................................45
9.4
Blood Volume .........................................................................................................45
10.0
PREDOSE EVENTS AND ADVERSE EVENTS .........................................................47
10.1
Definitions...............................................................................................................47
10.1.1
Predose AEs................................................................................................47
10.1.2
AEs.............................................................................................................47
10.1.3
Additional Points to Consider for AEs.........................................................47
10.1.4
SAEs...........................................................................................................48
10.1.5
AEs of Special Interest................................................................................49
10.1.6
Intensity of AEs ..........................................................................................49
10.1.7
Relationship of AEs to Study Drug(s) .........................................................50
10.1.8
Relationship to Study Procedures................................................................50
10.1.9
Start Date....................................................................................................50
10.1.10
Stop Date ....................................................................................................50
10.1.11
Frequency ...................................................................................................50
10.1.12
Action Concerning Study Drug ...................................................................50
10.1.13
Outcome .....................................................................................................50
10.2
Procedures...............................................................................................................51
10.2.1
Collection and Reporting of AEs.................................................................51
10.2.2
Collection and Reporting of SAEs...............................................................52
10.2.3
Reporting of Abnormal Liver Function Tests ..............................................53
10.3
Follow-up of SAEs ..................................................................................................53
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ..................................................................................................53
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................54
12.0
DATA HANDLING AND RECORDKEEPING............................................................55
12.1
CRFs (Electronic)....................................................................................................55
12.2
Record Retention .....................................................................................................55
13.0
STATISTICAL METHODS..........................................................................................57
13.1
Statistical and Analytical Plans ................................................................................57
13.1.1
Analysis Sets...............................................................................................57


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13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................57
13.1.3
PK Analysis ................................................................................................57
13.1.4
Subject Condition Assessments...................................................................58
13.2
Interim Analysis and Criteria for Early Termination ................................................59
13.3
Determination of Sample Size..................................................................................59
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................60
14.1
Study-Site Monitoring Visits ...................................................................................60
14.2
Protocol Deviations..................................................................................................60
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................61
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................62
15.1
IRB and/or IEC Approval ........................................................................................62
15.2
Subject Information, Informed Consent, and Subject Authorization .........................63
15.3
Subject Confidentiality ............................................................................................64
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................65
15.4.1
Publication and Disclosure..........................................................................65
15.4.2
Clinical Trial Registration...........................................................................65
15.4.3
Clinical Trial Results Disclosure .................................................................65
15.5
Insurance and Compensation for Injury....................................................................66
16.0
REFERENCES..............................................................................................................67
LIST OF IN-TEXT TABLES
Table 7.a
Prohibited Medications ......................................................................................29
Table 8.a
Dose and Regimen .............................................................................................34
Table 9.a
Clinical Laboratory Tests...................................................................................39
Table 9.b
Collection of Blood Samples for PK Analysis ....................................................42
Table 9.c
Approximate Blood Volume ..............................................................................46
Table 10.a
Takeda Medically Significant AE List................................................................49
Table 14.a
Windows for PK Blood Sample Collection ........................................................61
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................24


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LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................69
Appendix B
Responsibilities of the Investigator.....................................................................71
Appendix C
Elements of the Subject Informed Consent.........................................................73
Appendix D
Investigator Consent to Use of Personal Information..........................................76
Appendix E
Collection, Storage, and Shipment of PK Samples .............................................77
Appendix F
Detailed Description of Amendments to Text.....................................................80


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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Pharmaceuticals LLC
Compound:
SYR-322-4833
Title of Protocol: A Randomized, Open-Label, 
Single-Dose, 4-Period Crossover Study to Determine the 
Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 
and 30 mg) When Administered as Individual Tablets and 
as Fixed-Dose Combination Tablets to Healthy Russian 
Subjects
IND No.: 
Not applicable
EudraCT No.:
Not applicable
Study Number: Alogliptin-1002
Phase: Bioequivalence
Study Design:
This is a single-center randomized, open-label, 4-sequence, 4-period, single-dose, crossover study to assess the 
bioequivalence, pharmacokinetics (PK), and safety of alogliptin and pioglitazone administered as individual tablets 
and as the fixed-dose combination (FDC) tablet product. 
Subjects will be randomized in the order in which they are enrolled into the study. The 72 eligible subjects will be 
randomized to 1 of 4 drug intake sequences in a 1:1:1:1 ratio. Due to the large sample size, volunteers may be divided 
into 2 or 3 cohorts according to space limitations at the site. All cohorts will be dosed sequentially.
The study consists of a Screening Period (Days -28 to Day-2) and 4 Drug Intake Periods. A washout interval of 7 days 
(beginning immediately after dosing on Day 1) will separate the doses of each study period. Subjects will be admitted 
into the clinic on Day -1 (Day 7 of the preceding period for Periods 2, 3, and 4) and will be dosed on Day 1 of each 
period. Starting on Day 1 of each period, blood samples for determination of alogliptin and pioglitazone plasma 
concentrations will be collected predose through 72 hours postdose. The subjects will be discharged from the clinic 
after the 24-hour blood sample collection on Day 2 of each period and will return to the clinic for the 36-hour blood 
sample collection on Day 2 and on Days 3 and 4 of each period to complete study procedures. Final Visit procedures 
will be performed on Day 4 of Period 4 and a Follow-up call will be made 14 days ±2 days following the last dose of 
study drug.
Primary Objective:
To assess the relative bioavailability and bioequivalence of 2 strengths of the fixed-dose combination tablet product 
SYR-322-4833 BL compared to the individual alogliptin and pioglitazone tablets in healthy Russian subjects.
Additional Objectives:
To perform a comparative analysis of adverse event (AE) data after the administration of SYR-322-4833 BL and after 
coadministration of alogliptin and pioglitazone to healthy volunteers within the scope of the trial.
Subject Population: Healthy subjects aged 18 to 55 years, inclusive.
Number of Subjects:
Approximately 144 subjects will be screened. 
72 subjects (18 per sequence) will be enrolled.
Number of Sites:
1 site in Russia
Dose Level(s):
A= SYR-322-4833 BL (25 mg + 15 mg) (test regimen)
B= alogliptin 25 mg + pioglitazone 15 mg (reference regimen)
C= SYR-322-4833 BL (25 mg + 30 mg) (test regimen)
D= alogliptin 25 mg + pioglitazone 30 mg (reference regimen)
Route of Administration:
Oral
Duration of Treatment:
4 single doses, 1 dose in each of 4 periods
Period of Evaluation:
Total study duration: approximately 66 days 
(including Screening Period, Drug Intake Period, 
and Follow-up telephone call).


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Main Criteria for Inclusion:
!
The subject is a healthy male or female 18 to 55 years of age, inclusive.
!
The subject has an estimated glomerular filtration rate (eGFR) ≥ 90 mL/min.
!
The subject has a body mass index (BMI) of within 18.5 to 30 kg/m2.
Main Criteria for Exclusion:
!
Female subjects of childbearing potential who have had unprotected sex with nonsterilized men within 30 days 
before the investigational medicinal product administration.
!
The subject has a history of clinically significant allergic reactions or has a known hypersensitivity to any 
component of the formulation of alogliptin, pioglitazone or related compounds.
!
The subject has a positive alcohol breath test at Screening or Check-in (Day -1).
!
The subject has a fasting blood glucose level lower than 3.88 mmol/L.
!
The subject experienced acute infectious diseases within 4 weeks prior to Screening.
!
The subject has a non-standard diet (eg, vegetarian or vegan) or lifestyle (including nighttime work, extreme 
physical activity such as weights lifting), which may interfere with the trial.
!
The subject has participated in a clinical study within 3 months prior to Day -1 of Period 1.
!
The subject has taken medicines with pronounced effects on blood circulation, liver function (barbiturates, 
omeprazole, cimetidine, etc.) within 2 months prior to Day -1 of Period 1.
!
The subject has abnormalities in routine clinical examination, laboratory and/or ECG findings.
!
The subject has current or a history of cardiovascular, respiratory, neurological, endocrine, hematopoietic, 
immune, urinary, genital, gastrointestinal, hepatic, or psychiatric diseases or a history of epilepsy or convulsive 
seizures.
Main Criteria for Evaluation and Analyses:
Primary: The following plasma PK parameters of alogliptin and pioglitazone will be derived on Day 1 of each period:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from the time 0 to time 72 hours (AUC72).
Exploratory/Additional: 
Criteria of Subject Condition Assessment: The following variables will be used to characterize the safety and 
tolerability of SYR-322-4833 BL, alogliptin, and pioglitazone.
!
Percentage of subjects who experience at least 1 postdose AE.
!
Percentage of subjects who have clinically significant changes in laboratory tests at least once postdose.
!
Percentage of subjects who have clinically significant changes in vital sign measurements at least once postdose. 
!
Percentage of subjects who have clinically significant changes in electrocardiogram (ECG) parameters at least 
once postdose.
!
Percentage of subjects who experience at least 1 postdose event of hypoglycemia.
PPD


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Statistical Considerations:
Descriptive statistics (N, mean, SD, SE, percent coefficient of variation [%CV], median, minimum, and maximum) 
will be used to summarize the PK parameters of alogliptin and pioglitazone for each regimen. Geometric means will 
be computed for AUCs and Cmax.
Statistical inference to determine if the test regimens are bioequivalent to the reference regimens will be performed 
using an analysis of variance (ANOVA) model with effects for regimen, period, sequence, and subjects nested within 
sequence. The effect due to subject nested within sequence will be considered a random effect in the ANOVA model 
while all other effects will be treated as fixed. The ANOVA model will be applied to the natural logarithms of AUC72
and Cmax of alogliptin or pioglitazone as dependent variables to compare the test and reference regimens. Within the 
framework of the ANOVA model for natural logarithms of AUC72 and Cmax, the ratios and the 90% confidence 
intervals (CIs) for the ratios of central values of each test regimen relative to the corresponding reference regimen of 
alogliptin or pioglitazone will be provided. The ratios will be obtained as the antilog of the difference of the least 
squares (LS) means on a natural logarithm scale, and the 90% CIs will be obtained by taking the antilog of the 90% CI 
for the difference between the LS means on the natural logarithmic scale.
Alternative statistical analyses will be used if deemed appropriate.
All subject condition assessments, including AEs, physical examinations, clinical laboratory evaluations, 12-lead 
ECGs, and vital signs will be presented in the data listings and summarized with descriptive statistics, if appropriate.
Sample Size Justification: A sample size of 72 subjects (18 per sequence) will be enrolled in this 4-period, 
4-sequence crossover study. The sample size is appropriate to assess the bioavailability of alogliptin and pioglitazone 
from the FDC relative to the individual tablets and also provide greater than 80% power for Cmax of pioglitazone 
establishing bioequivalence between regimens for both strengths (SYR-322-4833 BL 25 mg+15 mg and 
SYR-322-4833 BL 25 mg+30 mg). This is based on acceptance ranges of 80% to 125%, the intra-subject variability 
(%CV) of 33% for Cmax of pioglitazone; the expected ratios of the central values for Cmax are between 0.95 and 1.05, 
and drop-out rate of 14%. Since the intra-subject variability for pioglitazone area under the concentration-time curve 
from time 0 to time t (AUCt), and alogliptin Cmax and AUCt is less than 33%, the power for assessing bioequivalence 
for pioglitazone AUCt and alogliptin Cmax and AUCt are each greater than 80% for both strengths. 


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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor. 
3.2
Principal Investigator
The Principal Investigator will be confirmed once the study site is selected. The Principal 
Investigator will be required to complete the investigator agreement on page 4 of the protocol.
PPD


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3.3
List of Abbreviations
λz
terminal disposition phase rate constant
%CV
percent coefficient of variation
AE
adverse event
AESI
adverse event special interest
ALT
alanine aminotransferase
ANOVA
analysis of variables
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
AUC72
area under the concentration-time curve time from time 0 to 72 hours
AUCt
area under the concentration-time curve from time 0 to time t
BMI
body mass index
bpm
beats per minute
CI
confidence interval
CL/F
apparent clearance after extravascular administration
Cmax
maximum observed concentration
CS
clinically significant
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FDC
fixed-dose combination
FPG
fasting plasma glucose
GCP
Good Clinical Practice
HbA1c
glycosylated hemoglobin
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
ICH
International Conference on Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
IRB
institutional review board
K2EDTA
potassium ethylenediamine tetra-acetic acid
LDL
low-density lipoprotein
CCI


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LFT
liver function test
LS
least square
MedDRA
Medical Dictionary for Regulatory Activities
NCS
not clinically significant
PK
pharmacokinetic(s)
PPAR-γ
peroxisome proliferator-activated receptor-gamma
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
SU
sulfonylurea
SUSAR
suspected unexpected serious adverse reaction
t1/2z
terminal disposition phase half-life
T2DM
type 2 diabetes mellitus
tmax
time of first occurrence of Cmax
TZD
thiazolidinedione
ULN
upper limit of normal
WHO
World Health Organization


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4.0
INTRODUCTION
4.1
Background
4.1.1
Alogliptin
Alogliptin is an orally available, selective and highly potent inhibitor of dipeptidyl peptidase-4 
(DPP-4), the primary enzyme involved in the in vivo degradation of at least 2 incretin hormones 
released in response to nutrient ingestion: glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP). The incretin hormones exert important effects on pancreatic islet 
-cells to stimulate glucose-dependent insulin secretion and regulate -cell proliferation and 
cytoprotection. By preventing the rapid degradation of these hormones, alogliptin enhances the 
body’s ability to control elevated blood glucose by triggering pancreatic insulin secretion and 
suppressing pancreatic glucagon secretion, resulting in reductions in glycemia. 
Alogliptin has been approved as an adjunct to diet and exercise to improve glycemic control in 
patients with type 2 diabetes mellitus (T2DM). Alogliptin has been commercially available since 
2010 and is approved in several major markets including Japan, the United States (US), the 
European Union (EU), and Russia.
4.1.2
Pioglitazone
Pioglitazone is an insulin sensitivity enhancer, which decreases insulin resistance by binding to 
peroxisome proliferator-activated receptor-gamma (PPAR-γ). Pioglitazone depends on the 
presence of insulin for its mechanism of action. It decreases insulin resistance in the periphery and 
in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic 
glucose output. Pioglitazone is a potent and highly selective agonist for PPAR-γ. Activation of 
PPAR-γ leads to increased insulin-mediated glucose uptake in skeletal muscle [1], decreased 
hepatic glucose production, reduced lipolysis, enhanced adipose differentiation [2], improved 
fibrinolysis, decreased microalbuminuria [3], and improved inflammatory markers, such as 
C-reactive protein [4].
Pioglitazone has been commercially available since 1999 and is approved in several major markets 
including the United States, Japan, and the European Union as an adjunct to diet and exercise to 
improve glycemic control in adults with T2DM in multiple clinical settings. 
Pioglitazone is a thiazolidinedione (TZD) that depends on the presence of insulin for its 
mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver 
resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 
Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for PPARγ. PPAR receptors 
are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. 
Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin 
responsive genes involved in the control of glucose and lipid metabolism.
Treatment with pioglitazone as monotherapy or in combination with metformin, a sulfonylurea, or 
insulin results in improvements in glycosylated hemoglobin (HbA1c) and fasting plasma glucose 
(FPG). Pioglitazone also appears to preserve β-cell function, which may explain its 


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antihyperglycemic durability [5]. Pioglitazone has favorable effects on lipids, including increasing 
high-density lipoprotein (HDL) cholesterol, decreasing triglycerides, and shifting low-density 
lipoprotein (LDL) particle size and concentration to a less atherogenic profile [6]. Pioglitazone 
treatment has also been associated with improvements in several other cardiovascular risk factors, 
such as markers of vascular effects (eg, reduced blood pressure, reduced smooth muscle 
proliferation, improved endothelial function, reduced microalbuminuria, and increased nitric 
oxide levels), anti-inflammatory effects (eg, decreased C-reactive protein levels, decreased 
interleukin-6 levels), and antithrombotic effects (eg, decreased plasminogen activator inhibitor-1 
levels) [7,8]. 
4.1.3
SYR-322-4833 BL
SYR-322-4833 BL is an oral, immediate-release, alogliptin fixed-dose combination (FDC) 
product with pioglitazone developed by Takeda as an adjunct to diet and exercise to improve 
glycemic control in patients with T2DM. Alogliptin FDC with pioglitazone has also been 
approved in several major markets including United States and European Union. 
4.2
Summary of Relevant Clinical Studies
4.2.1
Summary of Clinical Studies With Alogliptin
Alogliptin has been evaluated in 59 completed clinical studies (31 phase 1, 1 phase 2, and 27 phase 
3 studies) in both healthy subjects and subjects with T2DM, as part of the alogliptin clinical 
program. Alogliptin doses ranged from 6.25 to 800 mg in the clinical pharmacology studies, and 
from 6.25 to 100 mg in the phase 2 efficacy and safety study. Alogliptin doses of 12.5 and 25 mg 
were used in the pivotal phase 3 studies.
Results from 5 main, pivotal phase 3 double-blinded placebo-controlled studies (monotherapy and 
add-on to a sulfonylurea, metformin, TZD, and insulin) indicated that subjects with T2DM who 
were treated with alogliptin 12.5 or 25 mg once daily (QD) for 26 weeks achieved significantly 
greater least squares (LS) mean reductions in HbA1c levels versus those who received placebo.
Both doses of alogliptin evaluated in the phase 3 clinical program (12.5 and 25 mg QD) had an 
acceptable safety profile whether administered as monotherapy or in combination to other 
established antidiabetic therapies. Alogliptin was generally hypoglycemia and weight neutral. The 
following adverse drug reactions were associated with alogliptin in the clinical program: 
headache, upper respiratory tract infection, nasopharyngitis, abdominal pain, gastroesophageal 
reflux disease, pruritus, and rash. In addition, the following post-marketing adverse drug reactions 
have been spontaneously reported: acute pancreatitis, hepatic dysfunction including hepatic 
failure, hypersensitivity, and exfoliative skin conditions including Stevens-Johnson syndrome, 
erythema multiforme, angioedema, and urticaria.
See the investigator brochure for detailed information about alogliptin clinical studies.


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4.2.2
Summary of Clinical Studies With Pioglitazone
The clinical trial database for pioglitazone consists of 47 studies (36 controlled, 11 uncontrolled) 
in a total of >27,000 treated subjects. These studies include 12 long-term controlled trials, ≥1 year 
in duration. Across these studies, the efficacy of pioglitazone has been evaluated in terms of 
glycemic control, lipid metabolism, and cardiovascular effects. 
Pioglitazone 7.5 to 45 mg daily has been compared with placebo in several randomized, double 
blind, parallel-group studies in patients with T2DM. Pioglitazone 15, 30, and 45 mg produced 
significant improvements in HbA1c (–0.3% to –1.8% and up to –2.6%, respectively) and FPG. 
Pioglitazone also produced significant decreases in triglycerides and significant increases in high 
density lipoprotein [9].
In combination trials with metformin, patients poorly controlled with a sulfonylurea (SU) were 
randomly assigned to metformin or pioglitazone, with comparable improvements seen in both 
compounds with respect to HbA1c and FPG [9]. In a combination trial, metformin plus 
pioglitazone 30 mg was compared with metformin plus placebo in patients with poorly controlled 
T2DM. Treatment with pioglitazone 30 mg plus metformin resulted in significant improvements 
in HbA1c, FPG, and lipid profiles compared with placebo plus metformin. [9,10]. In 2 
active-comparator trials, treatment with metformin and pioglitazone resulted in equal, significant 
reduction in HbA1c while insulin sensitivity measured by homeostasis model assessment showed 
significant improvement in the pioglitazone, but not the metformin group at 32 weeks [9].
In comparative/combination trials with SUs, pioglitazone produced comparable reduction in 
HbA1c and FPG as SU. Pioglitazone produced a slower but more sustained reduction in HbA1c 
compared with an earlier effect in the SU treated group, and improvements in insulin sensitivity 
were not seen in the SU treatment group [9]. Similar to results observed in combination trials with 
metformin, pioglitazone-treated subjects demonstrated significant improvements in glycemic 
control and lipid profiles compared with treatment with SU [9]. 
4.2.3
Summary of Clinical Studies With Alogliptin in Combination With Pioglitazone
The coadministration of alogliptin and pioglitazone has been studied in subjects with T2DM 
inadequately controlled on either diet and exercise alone, pioglitazone alone, or pioglitazone in 
combination with metformin. 
There have been no completed clinical efficacy studies conducted with alogliptin/ pioglitazone 
FDC; however, bioequivalence of alogliptin/ pioglitazone FDC with coadministered alogliptin and 
pioglitazone tablets was demonstrated, and efficacy of the combination of alogliptin and 
pioglitazone has been demonstrated in 4 phase 3 efficacy studies. 
Results from 4 phase 3 double-blinded placebo or active-controlled clinical safety and efficacy 
studies ranging from 16 to 52 weeks indicated that subjects with T2DM who were treated with 
alogliptin (12.5 mg or 25 mg) and pioglitazone (15, 30, or 45 mg) combination therapy achieved 
significantly greater LS mean reductions in HbA1c compared to placebo and each individual 
monotherapy. 


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All dose combinations studied in the alogliptin/pioglitazone FDC program were well tolerated. 
The majority of subjects completed the studies, and the overall discontinuation rate due to adverse 
events (AEs) was low. The safety profile of combination treatment was consistent with the known 
safety profiles of pioglitazone and alogliptin.
The following adverse drug reactions were associated with alogliptin and pioglitazone 
combination therapy in the clinical program: upper respiratory tract infection, sinusitis, headache, 
nausea, dyspepsia, abdominal pain, pruritus, myalgia, edema peripheral, and weight increased. 
See the investigator brochure for detailed information about alogliptin/pioglitazone combination 
clinical studies.
4.3
Benefit/Risk Profile 
Data from the clinical studies have demonstrated that the coadministration of alogliptin and 
pioglitazone results in improved glycemic control. In these studies, combination therapy with 
alogliptin with pioglitazone resulted in greater clinically meaningful reductions in HbA1c than 
with either agent given alone. This greater reduction in HbA1c resulted in a higher percentage of 
subjects who achieved the HbA1c goal of ≤7%. An additional glycemic benefit of combination 
therapy was a reduction in FPG levels without a corresponding increase in risk of hypoglycemia, 
an AE that often restricts use with other antidiabetic agents. 
Another goal of T2DM treatment is to reduce cardiovascular risk factors such as dyslipidemia and 
elevated inflammatory markers, which are common in patients with T2DM. Combination therapy 
of pioglitazone and alogliptin enhanced the pioglitazone effects of reduced triglycerides, increased 
HDL, decreased LDL, improved LDL particle size, and decreased C-reactive protein levels. 
Some risks that have been identified with the use of pioglitazone or other TZDs are congestive 
heart failure, edema, bladder cancer, hepatic effects, hematological effects, hypoglycemia (when 
used with other antihyperglycemic medicinal products), bone fractures, and macular edema. Risks 
that have been identified with the use of alogliptin or other DPP-4 inhibitors are hypoglycemia 
(when used with other antihyperglycemic medicinal products), cardiac failure, hypersensitivity 
reactions, acute pancreatitis, and hepatic effects.
The alogliptin/ pioglitazone FDC will provide flexibility in reaching efficacy goals without 
compromising safety, thereby allowing prescribers to individualize therapy. In addition, it is 
generally accepted that the convenience of an FDC product provides significant improvement with 
respect to compliance and alleviation of pill burden in patients with chronic illnesses such as 
T2DM [11-13]. Based on the efficacy and safety data, the benefit:risk ratio is favorable for the use 
of alogliptin/ pioglitazone FDC to improve glycemic control in adults with T2DM. 
4.4
Rationale for the Proposed Study
Takeda has developed an FDC product with alogliptin and pioglitazone (SYR-322-4833 BL). 
Alogliptin and pioglitazone potentially have complimentary mechanisms of action and could 
potentially be prescribed in combination. An FDC product may provide improve convenience for 
the patient, and therefore, may improve compliance.


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The bioequivalence of alogliptin/pioglitazone FDC with co-administration of alogliptin and 
pioglitazone tablets has been established in the US and EU population. However, this 
bioequivalence has not been demonstrated specifically in the Russian population. In order to better 
bridge the alogliptin and pioglitazone combination therapy clinical data to the Russian population 
and meet local regulatory requirements for further alogliptin/pioglitazone FDC registration in 
Russia, this study is designed to determine whether peak and total exposures to alogliptin and to 
pioglitazone are bioequivalent when the 2 agents are administered as an FDC product and as 
individual tablets in Russian subjects.


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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
To assess the relative bioavailability and bioequivalence of 2 strengths of the fixed-dose 
combination tablet product SYR-322-4833 BL compared to the individual alogliptin and 
pioglitazone tablets in healthy Russian subjects.
5.1.2
Additional Objective 
To perform a comparative analysis of AE data after the administration of SYR-322-4833 BL and 
after coadministration of alogliptin and pioglitazone to healthy volunteers within the scope of the 
trial.
5.2
Endpoints
5.2.1
Primary Endpoints
The following plasma pharmacokinetic (PK) parameters of alogliptin and pioglitazone will be 
derived on Day 1 of each period:
!
Maximum observed concentration (Cmax).
!
Area under the concentration-time curve from the time 0 to time 72 hours (AUC72).
5.2.2
Additional Endpoints
5.2.2.1
Exploratory 
5.2.2.2
Criteria of Subject Condition Assessment
!
Percentage of subjects who experience at least 1 postdose AE.
!
Percentage of subjects who have clinically significant changes in laboratory tests at least once 
postdose.
!
Percentage of subjects who have clinically significant changes in vital sign measurements at 
least once postdose. 
!
Percentage of subjects who have clinically significant changes in electrocardiogram (ECG) 
parameters at least once postdose.
!
Percentage of subjects who experience at least 1 postdose event of hypoglycemia.
CCI


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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a single-center, open-label, randomized, 4-sequence, 4-period, single dose crossover study 
involving 72 healthy adult, male and female subjects between the ages of 18 and 55 years, 
inclusive. 
Subjects will be randomized in the order in which they are enrolled into the study. The 72 eligible 
subjects will be randomized to 1 of 4 drug intake sequences in a 1:1:1:1 ratio. Due to the large 
sample size, volunteers may be divided into 2 or 3 cohorts according to space limitations at the 
site. All cohorts will be dosed sequentially.
The study consists of a Screening Period (Days -28 to Day-2) and 4 Drug Intake Periods. A 
washout interval of 7 days (beginning immediately after dosing on Day 1) will separate the doses 
of each study period. Subjects will be admitted into the clinic on Day -1 (Day 7 of the preceding 
period for Periods 2, 3, and 4) and will be dosed on Day 1 of each period. Starting on Day 1 of each 
period, blood samples for determination of alogliptin and pioglitazone plasma concentrations will 
be collected predose through 72 hours postdose. The subjects will be discharged from the clinic 
after the 24-hour blood sample collection on Day 2 of each period and will return to the clinic for 
the 36-hour blood sample collection on Day 2 and on Days 3 and 4 of each period to complete 
study procedures. Final Visit procedures will be performed on Day 4 of Period 4 and a Follow-up 
call will be made 14 days ±2 days following the last dose of study drug.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in 
Appendix A.


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Figure 6.a
Schematic of Study Design
Predose Period 
Drug Intake Period (c)
Screening (a) Check-in (b)
Period 1
Period 2
Period 3
Period 4
Days -28 to -2
Day -1
Day 1
Dosing
Days
2 to at 
least 7
Day 1
Dosing
Days
2 to at 
least 7
Day 1
Dosing
Days
2 to at 
least 7
Day 1 
(d)
Dosing
Days
2 to 3
Day 4
Final
Visit/ET
Sequence I
(n=18)
A
WO
B
WO
C
WO
D
WO
Sequence II
(n=18)
B
C
D
A
Sequence III
(n=18)
C
D
A
B
Sequence IV
(n=18)
D
A
B
C
A=SYR-322-4833 BL (25 mg + 15 mg) (test regimen), B=alogliptin 25 mg + pioglitazone 15 mg (reference regimen), 
C=SYR-322-4833 BL (25 mg + 30 mg) (test regimen), D=alogliptin 25 mg + pioglitazone 30 mg (reference regimen), ET=Early 
Termination, WO=Washout of 7 days between dosing.
(a) Screening may consist of 1 or more visits. Subjects will sign an informed consent form at the first visit and return to the clinic in 
a fasted state for safety laboratory testing at the second visit.
(b) Subjects are admitted into the clinic on Day -1 of each period (~Day 7 of the preceding period for Periods 2, 3, and 4).
(c) Randomization occurs on Day 1 of Period 1. Subjects check out of the unit on Day 2 following the 24-hour blood sample 
collection but return to the clinic for the 36-hour blood sample collection on Day 2 and on Days 3 and 4 of each period to complete 
study procedures.
(d) Follow-up call will be made 14 days ±2 days following the last dose of study drug.
6.2
Justification for Study Design, Dose, and Endpoints
The dose of alogliptin selected for this study (25 mg) is the approved daily dose, which was 
efficacious and well-tolerated in the monotherapy program. The doses of pioglitazone (15 and 
30 mg) chosen for this study are approved therapeutic doses.
A randomization schedule for dose administration assignment will be used to reduce the potential 
for bias. A crossover design will be used to allow for intrasubject comparisons. To minimize the 
potential for carryover effect, a 7-day washout interval, which is >5 half-lives of either alogliptin 
or pioglitazone, will separate the dose administrations.
Single doses will be administered because single doses generally allow for a more sensitive 
assessment of the release of the drug substance from the drug product into the systemic circulation. 
Only parent drug released from the dosage form, rather than metabolites, will be measured, 
because the concentration-time profile of the parent drug is more sensitive to changes in 
formulation performance than a metabolite. 
The safety endpoints in this study, including AEs, vital signs, 12-lead ECGs, clinical laboratory 
tests and physical examination data, are standard methods for assessing safety and tolerability in 
clinical pharmacology studies.
This study is being conducted for the purpose of registration of SYR-322-4833 BL by the Russian 
Ministry of Health.


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6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 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 compound, such that the 
risk/benefit is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is 
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable study sites during the course of termination 
or study suspension.


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed prior to randomization or first dose.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria prior to entry into the study:
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements.
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures including requesting that a subject 
fast for any laboratory evaluations. 
3. The subject is a healthy male or female.
4. The subject is aged 18 to 55 years, inclusive, at the time of informed consent and first study 
drug dose.
5. The subject has an eGFR ≥90 mL/min.
6. The subject weighs at least 50 kg and has a body mass index (BMI) from 18.5 to 30.0 kg/m2, 
inclusive at Screening.
7. A male subject who is nonsterilized* and sexually active with a female partner of childbearing 
potential* agrees to use barrier method of contraception (eg, condom with or without 
spermicide)* from signing of informed consent throughout the duration of the study and for 35 
days after last dose. A female subject of childbearing potential* who is sexually active with a 
nonsterilized* male partner agrees to use an effective method of contraception* from signing of 
informed consent and throughout the duration of the study and for 35 days after last dose.
* Definitions and effective methods of contraception are defined in Section 9.1.9
and reporting responsibilities are defined in Section 9.1.10.
7.2
Exclusion Criteria
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. The subject has received any investigational compound or has participated in a clinical study 
within 3 months prior to Check-in (Day-1).
2. The subject has received alogliptin or pioglitazone in a previous clinical study or as a 
therapeutic agent within 90 days prior to Check-in (Day-1).
3. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in the conduct of this study (eg, 
spouse, parent, child, sibling) or may consent under duress.


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4. The subject has current or a history of cardiovascular, respiratory, neurological, endocrine, 
hematopoietic, immune, urinary, genital, gastrointestinal, hepatic, or psychiatric diseases, or a 
history of epilepsy or convulsive seizures. 
5. The subject has a fasting blood glucose level lower than 3.88 mmol/L.
6. The subject experienced acute infectious diseases within 4 weeks prior to Screening.
7. The subject has a history of clinically significant allergic reactions or has a known 
hypersensitivity to any component of the formulation of alogliptin, pioglitazone or related 
compounds.
8. The subject has a positive urine drug result for super potent substances and drugs of abuse 
(defined as any illicit drug use) or positive alcohol breath test at Screening or Check-in 
(Day -1). 
9. The subject consumes over 10 drinks weekly (1 drink is equivalent to 0.5 liters of beer, 200 mL 
of dry wine or 50 mL of ardent spirits) or has a history of alcoholism, drug and/or substance 
abuse. 
10. The subject has taken any excluded medication, supplements, or food products during the time 
periods listed in the Excluded Medications and Dietary Products table listed in Section 7.3, 
including intake of medicines with pronounced effects on blood circulation, liver function 
(barbiturates, omeprazole, cimetidine, etc.) within 2 months prior to Day -1 of Period 1.
11. If female, the subject is pregnant (confirmed by a positive pregnancy test) or lactating or 
intending to become pregnant before, during, or within 35 days after participating in this study; 
or intending to donate ova during such time period. 
12. Female subjects of childbearing potential who have had unprotected sex with nonsterilized 
men within 30 days before the investigational medicinal product administration.
13. The subject has current or recent (within 6 months) gastrointestinal disease that would be 
expected to influence the absorption of drugs (ie, a history of malabsorption, esophageal 
reflux, peptic ulcer disease, erosive esophagitis, frequent [more than once per week] 
occurrence of heartburn, or any surgical intervention).
14. The subject has a non-standard diet (eg, vegetarian or vegan) or lifestyle (including nighttime 
work, extreme physical activity such as weights lifting), which may interfere with the trial.
15. The subject has a history of cancer, except basal cell carcinoma which has been in remission 
for at least 5 years prior to Day 1 of Period 1. 
16. The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus 
(HCV) antibody, human immunodeficiency virus (HIV) antibody or syphilis at Screening.
17. The subject has used nicotine-containing products (including but not limited to cigarettes, 
pipes, cigars, chewing tobacco, nicotine patch or nicotine gum) within 28 days prior to 
Check-in Day -1. Cotinine test is positive at Screening or Check-in (Day -1).
18. The subject has poor peripheral venous access.


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19. The subject has donated or lost 450 mL or more of his or her blood volume (including 
plasmapheresis), or had a transfusion of any blood product within 30 days prior to Day 1 of 
Period 1.
20. The subject has abnormalities in routine physician examination, laboratory and/or ECG 
findings.
21. The subject has a systolic blood pressure >130 mm Hg or <100 mm Hg, diastolic blood 
pressure >90 mm Hg or <70 mm Hg; heart rate <60 beats per minute (bpm) or >80 bpm at 
Screening (Day -28 to Day -2) or Check-in to Period 1 (Day -1).
22. The subject has consumed caffeine or xanthine-containing food or drinks within 72 hours prior 
to Check-in (Day -1).
23. The subject has dehydration due to vomiting, diarrhea, or any other reason within 24 hours 
prior to study start.
24. The subject has drug intolerance.
7.3
Excluded Medications, Supplements, Dietary Products
Use of the agents in Table 7.a (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities.


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Table 7.a
Prohibited Medications
90 days prior to 
Check-in (Day -1)
60 days prior to 
Check-in (Day -1)
28 days prior to 
Check-in (Day -1)
7 days prior to 
Check-in (Day -1)
72 hours prior to 
Check-in (Day -1)

Alogliptin 

Pioglitazone 
Medicines with 
pronounced effects 
on blood 
circulation, liver 
function 
(barbiturates, 
omeprazole, 
cimetidine, etc.)
Female subjects:
hormonal 
contraceptives 
should have been 
discontinued 60 
days prior to Day-1
Prescription 
medications
Neutraceuticals (eg, 
St. John’s wort, 
ginseng, kava kava, 
ginkgo biloba, 
Chinese herbs, and 
melatonin)
Immunization / 
Vaccines 
Nicotine-containing 
products
OTC medications
Vitamin 
supplements
Foods or beverages 
containing 
grapefruit or 
Seville-type (sour)
oranges and 
marmalade, apple, 
orange, or 
pineapple juices, 
vegetables from the 
mustard green 
family (eg, kale, 
broccoli, 
watercress, collard 
greens, kohlrabi, 
Brussels sprouts, 
mustard), and 
charbroiled meats
Alcohol containing 
products
Products 
containing 
caffeine or 
xanthine
poppy seeds
OTC=over-the-counter. 
Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator.
7.4
Diet, Fluid, Activity Control 
Subjects will be confined to the clinic from Check-in (Day -1) of Dosing Period 1 until the 24-hour 
blood sample has been collected on Day 2 of Dosing Period 1 and from Day 7 of Dosing Periods 1, 
2, and 3 until the 24-hour blood sample has been collected on Day 2 of Dosing Periods 2, 3, and 4, 
respectively. During confinement, subjects will be given a menu that includes 3 meals and an 
evening snack, except dosing days when breakfast will not be served. Study drug will be 
administered with 240 mL of water. Subjects may consume water ad libitum with the exception of 
1 hour before and 1 hour after drug administration. On Day 1 of each period, all subjects will 
remain fasted until a standard lunch is served approximately 4 hours postdose (after the 4-hour 
blood collection). Each meal will contain approximately 30% fat (relative to the total calories). 
The meals served in each period should be identical. Each meal provided in the study clinic should 
be completed within 30 minutes. The meal start and stop times and whether or not a meal was 
consumed will be recorded on the source documentation and the electronic case report form 
(eCRF) for the Day-1 snack and all meals on Day 1 of each period. The study menu should be 


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documented and submitted to the study file with a copy provided to the sponsor prior to the start of
the study.
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence 
followed by the study procedure and then the meal. Subjects will remain upright (seated, standing, 
or ambulatory) for at least 2 hours following administration of study medication, except as 
necessitated by the occurrence of an adverse event. Subjects will refrain from strenuous exercise 
throughout the entire course of the study.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the eCRF using the following categories. For screen failure subjects, refer to 
Section 9.1.14.
1. AE. The subject has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the subject’s health or the subject is unwilling to 
continue because of the AE.
2. Significant protocol deviation. The discovery post-randomization that the subject failed to 
meet protocol entry criteria or did not adhere to protocol requirements, and continued 
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source 
documentation.
4. Voluntary withdrawal. The subject wishes to withdraw from the study. The reason for 
withdrawal, if provided, should be recorded in the eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an
AE should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, IEC, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10.
7. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by 


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the investigator. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit.


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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
8.1
Study Drug 
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study medication refers to: 

Alogliptin 25 mg film-coated tablets No. 28 (commercially available on the Russian market) 
manufactured by Takeda (product released by Takeda Ireland)

Pioglitazone 15 and 30 mg tablets No. 30 manufactured by Pliva Hrvatska d.o.o., Croatia and 
sourced as commercial packs from the commercial market of Croatia. 

Alogliptin/Pioglitazone FDC 25/15 mg film-coated tablets No. 28 manufactured by Takeda 
(product released by Takeda Ireland) and sourced as commercial packs from the commercial 
market under the name NesinaAct. For this clinical study, NesinaAct will be supplied to the 
site as commercial packs and labeled as SYR-322-4833 BL 25/15.

Alogliptin/Pioglitazone FDC 25/30 mg film-coated tablets No. 28 manufactured by Takeda 
(product released by Takeda Ireland) and sourced as commercial packs from the commercial 
market under the name Incresync. For this clinical study, Incresync will be supplied to the site 
as commercial packs and labeled as SYR-322-4833 BL 25/30.
All medication sourced by the Sponsor as follows: 

Commercial alogliptin 25 mg tablets, sourced locally from the Russian market.

Commercial pioglitazone 15 and 30 mg tablets sourced locally from the Croatian market.

Commercial alogliptin/pioglitazone FDC 25/15 mg tablets and 25/30 mg tablets in commercial 
packs sourced from Takeda and labeled as SYR-322-4833 BL 25/15 and SYR-322-4833 BL 
25/30, respectively. 
Each commercial pack supplied will be labeled with a single panel open computer- generated label 
containing the required information including information “For clinical trial only”
8.1.1.1
Study Drug
Alogliptin/Pioglitazone FDC 25/15 mg and 25/30 mg tablets are manufactured by Takeda Ireland. 
Pioglitazone tablets are manufactured and packed by Pliva Hrvatska d.o.o., Croatia. 
Alogliptin tablets are manufactured and packaged by Takeda Pharmaceuticals. These will be 
supplied to the site as commercial packs sourced from the Russian market and labelled with “for 
clinical trials use only.”


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These will be supplied to the site as commercial packs with a Takeda clinical label that will 
contain, but will not be limited to, the following: sponsor’s name and address, protocol number, 
packaging job/lot number, name and strength of the product, medication identification number, 
caution statement, directions for use, and storage conditions.
8.1.1.2
Sponsor-Supplied Drug 
Sponsor-supplied drugs referenced in other sections of the protocol include the following: 

Alogliptin, 25 mg.

Pioglitazone, 15 and 30 mg. 

SYR-322-4833 BL 25/15 mg and SYR-322-4833 BL 25/30 mg (Alogliptin/Pioglitazone FDC, 
25/15 mg and 25/30 mg.)
8.1.2
Storage
Investigational drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Investigational drug, must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day.
Drug supplies must be stored, as defined on the commercial packs provided, in a secure location 
until dispensed to study subjects or returned to Takeda. Temperature excursions must be reported 
to the sponsor. In order to protect drug supply from moisture, the container should be kept tightly 
closed (bottle) or stored in the original package (blister). Do not take a tablet out of the blister foil 
until the subject is ready to take it.
8.1.3
Dose and Regimen
On Day 1 of each period, study medication will be administered at 08:00 (±1) hour with 240 mL of 
water following a minimum 8-hour fast. On Day 1 of each period, all subjects will remain fasted 
until a standard lunch is served approximately 4 hours postdose (after the 4-hour blood collection). 
The sequence of drug intake administration for each subject as described in Table 8.a will follow 
the randomization schedule. The investigator or investigator’s designee will instruct the subject on 
dosing procedures.
Following administration of study drug, hand-and-mouth checks will be performed to ensure that 
the dose was swallowed and will be recorded on the source document. Although timing of events 
requires that each subject receive the appropriate dose at specific times, the exact dose time of 
consecutive subjects may be staggered to obviate the need to have all subjects on precisely the 
same study schedule. The actual date and time of administration of the dose of study medication 
will be recorded on the source documents and the appropriate eCRF.


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Table 8.a
Dose and Regimen
Group
Dose
Drug Description
Alogliptin/
Pioglitazone 
FDC
25/15 mg 
Tablet
Alogliptin/
Pioglitazone 
FDC
25/30 mg 
Tablet
Alogliptin
25 mg Tablet
Pioglitazone 
15 mg Tablet
Pioglitazone 
30 mg Tablet
A
SYR-322-4833 BL 
(25 mg + 15 mg)
1 Tablet
N/A
N/A
N/A
N/A
B
Alogliptin 25 mg + 
pioglitazone 15 mg
N/A
N/A
1 Tablet
1 Tablet
N/A
C
SYR-322-4833 BL 
(25 mg + 30 mg)
N/A
1 Tablet
N/A
N/A
N/A
D
Alogliptin 25 mg + 
pioglitazone 30 mg
N/A
N/A
1 Tablet
N/A
1 Tablet
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE CRF(s) according to Section 10.0.
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 10.2.2.
In the event of drug overdose, the subject should be treated symptomatically.
8.2
Study Drug Assignment and Dispensing Procedures
Subjects will be assigned to receive a 4-digit medication identification number. The number will 
be assigned by the clinic site personnel in sequential order beginning with 1001 and ending with 
1072. This 4-digit number will be used by the clinical site to facilitate the prelabeling of PK 
samples, and will be the only subject identifier used on all PK sample collections. It should also be 
contained on the PK transport vials shipped to the bioanalytical laboratory, and will be used by the 
laboratory to report the subject data results. This 4-digit number should only be used for the 
purposes described in this section. It does not replace the 3-digit subject number which is assigned 
at the time the informed consent is obtained and which is used for all other procedures to identify 
the subjects throughout the study.


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8.3
Randomization Code Creation and Storage
The randomization schedule will be generated prior to the start of the study, and will be provided 
to the site pharmacist prior to the start of this study. All randomization information will be stored 
in a secured area, accessible only by authorized personnel.
8.4
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug is used in accordance with 
the protocol and is dispensed only to subjects enrolled in the study. To document appropriate use 
of sponsor-supplied drug, the investigator or designee must maintain records of all 
sponsor-supplied drug delivery to the site, site inventory, dispensation and use by each subject, and 
return to the sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, and the 
medication is in good condition. If quantity and conditions are acceptable, investigator or designee 
should acknowledge the receipt of the shipment by signing bottom half of the packing list and 
faxing per instructions provided on the form. If there are any discrepancies between the packing 
list versus the actual product received, Takeda must be contacted to resolve the issue. The packing 
list should be filed in the investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to:

Continuously monitoring expiration dates if expiration date is provided to the investigator or 
designee. 

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the drug lot used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a 
sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, description 
of sponsor-supplied drugs, expiry/retest date, date and amount dispensed, including initials, seal, 
or signature of the person dispensing the drug, and the date and amount returned to the site by the 
subject, including the initials, seal, or signature of the person receiving the sponsor-supplied drug. 
The log should include all required information as a separate entry for each subject to whom 
sponsor-supplied drug is dispensed.


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Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will 
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or 
destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the site 
must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction.


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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed, including requesting that a subject fast for laboratory 
evaluations.
A unique subject identification number (subject number) will be assigned to each subject at the 
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, race as described by the 
subject, height, weight, caffeine consumption, xanthine consumption, alcohol use, reproductive 
status (including last menstrual period) and smoking status of the subject at Screening. 
Medical history to be obtained will include determining whether the subject has any significant 
conditions that resolved at or prior to signing of informed consent. Ongoing conditions are 
considered concurrent medical conditions (see Section 9.1.7).
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days prior to signing of informed consent.
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; (7) extremities; (8) 
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
Any abnormal finding on a predose physical examination assessment must be assessed as not 
clinically significant (NCS) or clinically significant (CS) by the investigator and recorded in the 
source document and eCRF. All CS findings/changes will be recorded as a predose event or 
concurrent medical condition in the source document and on the appropriate eCRF described in 
Section 10.0 or Section 9.1.7. Any abnormal findings at Screening or prior to first dose, will 
exclude the subject from participating.
On subsequent examinations, any abnormal change or new diagnosis as a result of the abnormal 
change, compared to physical examination prior to first dose, as determined by the investigator, 
will be recorded as an AE in source documentation and on the AE eCRF described in Section 10.0. 


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9.1.4
Weight, Height and BMI
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off. The BMI is calculated using metric units with the formula provided below. Height is recorded 
in centimeters without decimal places. Weight is collected in kilograms (kg) with 1 decimal place. 
BMI should be derived as:
Metric:
BMI = weight (kg)/height (m)2
Note that although height is reported in centimeters, the formula uses meters for height; meters can
be determined from centimeters by dividing by 100. Thus, for example, if height=176 cm 
(1.76 meters) and weight=79.2 kg, then BMI=79.2/1.762=25.56818 kg/m2.
The values should be reported to 1 decimal place by rounding. Thus, in the above example BMI 
would be reported as 25.6 kg/m2. If the BMI is used as an entry criterion based on the 18.5 to 
30.0 kg/m2 cut-off point, then this determination must be made after rounding.
9.1.5
Vital Sign Procedure
Vital signs will include body temperature oral measurement, respiratory rate, sitting blood 
pressure (resting at least 5 minutes), and pulse (bpm).
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
9.1.6
Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by Takeda. At each study visit, subjects will be asked whether they have taken any 
medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Administration of any 
concomitant medications will result in exclusion of the subject from the trial. Documentation will 
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use. 
9.1.7
Documentation of Concurrent Medical Conditions
Any abnormal medical conditions, abnormalities in laboratory, ECG or physical examination 
findings found at Screening will exclude the subject from participating in this clinical trial. 
9.1.8
Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. Laboratory 
samples will be taken following a minimum 8-hour overnight fast on the days stipulated in the 
Schedule of Study Procedures (Appendix A).
Table 9.a lists the tests that will be obtained for each laboratory specimen.


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Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis 
RBC
WBC with differential 
(Neutrophils, Eosinophils, 
basophils, Lymphocytes, 
Monocytes)
Hemoglobin
Hematocrit
Platelets
ESR 
ALT
Albumin
Alkaline phosphatase
AST
Total bilirubin
Direct bilirubin (a)
Total protein
Creatinine
Blood urea nitrogen
Creatine kinase
-Glutamyl transferase
Potassium
Sodium
Glucose
pH
Specific gravity
Protein
Glucose
Blood 
Ketones
Urine color 
Presence of bile pigments
Microscopic Analysis:
RBC/high power field
WBC/high power field
Epithelial cells, casts, etc
Diagnostic Screening:
Serum
Urine (b)
HIV test, syphilis test
Hepatitis panel, including HBsAg and anti-HCV
Drug screen including amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, opiates and 
cotinine.
Female Subjects only:
Female Subjects only:
FSH (c)
hCG (for pregnancy) for female subjects of child bearing 
potential
ALT=alanine aminotransferase, AST= aspartate aminotransferase, ESR=erythrocyte sedimentation rate, 
FSH=follicle-stimulating hormone, hCG=human chorionic gonadotropin, RBC=red blood cell, WBC=white blood 
cell.
(a) Direct bilirubin will be measured only if total bilirubin is elevated.
(b) Urine screen for the presence of drugs of abuse will also be conducted on Day-1 and Days 3 and 4 of each study 
period (alcohol will be measured by administering an alcohol breath test at these time-points). 
(c) At Screening, if menopause is suspected (defined as at least 12 months since last regular menses) and subject is not 
surgically sterile. FSH must be >40 IU/L to confirm menopausal status.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible for 
reviewing and filing these results.
If subjects experience ALT or AST >3 ×upper limit of normal (ULN), follow-up laboratory tests 
(at a minimum, serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and international 
normalized ratio [INR]) should be performed within a maximum of 7 days and preferably within 
48 to 72 hours after the abnormality was noted. (Refer to Section 10.2.3 for the appropriate 
guidance on reporting abnormal liver function tests.)
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study drug, discussion of the relevant subject details and possible 


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alternative etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3
for reporting requirements).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for 
the laboratory used.
Laboratory reports must be signed and dated by the investigator indicating that the report has been 
reviewed and any abnormalities have been assessed for clinical significance. 
All laboratory abnormalities must be recorded as an AE in the subject’s source documents and on 
the appropriate eCRF. A clinically significant laboratory abnormality that has been verified by 
retesting will be followed until the abnormality returns to an acceptable level or a satisfactory 
explanation has been obtained.
9.1.9
Contraception and Pregnancy Avoidance Procedure
From signing of informed consent, throughout the duration of the study, and for 35 days after last 
dose of study medication, female subjects of childbearing potential* who are sexually active with a 
nonsterilized male partner** must use an effective or highly effective method of contraception 
from the list below. 
In addition, they must be advised not to donate ova during this period.
The following definitions apply for contraception and pregnancy avoidance procedures.
* A woman is considered a woman of childbearing potential, ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, and bilateral oophorectomy. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to confirm a 
postmenopausal state in younger women (eg, those <45 years old) or women who are not using 
hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.
** Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that they 
have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy.
Highly effective methods of contraception are defined as those, alone or in combination, that result 
in a low failure rate (ie, less than a 1% failure rate per year when used consistently and correctly). 
In this study, where medications and devices containing hormones are excluded, highly effective 
methods of contraception are: 
Non-Hormonal Methods

Copper T PLUS condom or spermicide.

Bilateral Tubal Occlusion.


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
Vasectomized partner (provided that partner is the sole sexual partner of the trial participant 
and that the vasectomized partner has received medical assessment of the surgical success.
Genotoxicity/teratogenicity/embryotoxicity is unlikely to be caused by the investigational drugs. 
Therefore, an effective method of contraception where there may be a higher than 1% failure rate 
can be used. An effective method of contraception is: 
Barrier methods:

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal 
jellies or creams PLUS male condom).
Female subjects must discontinue any use of hormonal contraceptives (if applicable), at least 
2 months before the start (Day-1) of the trial.
Subjects will be provided with information on effective and highly effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a consent 
form stating that they understand the requirements for avoidance of pregnancy and donation of ova 
during the course of the study.
During the course of the study, regular urine human chorionic gonadotropin (hCG) pregnancy tests 
will be performed only for women of childbearing potential and subjects will receive continued 
guidance with respect to the avoidance of pregnancy as part of the study procedures (Appendix A). 
In addition to a negative urine hCG pregnancy test at Screening, subjects also must have a negative 
urine hCG pregnancy test at Check-in (Day-1 of each Period) prior to receiving any dose of study 
medication.
9.1.10 Pregnancy
If any subject 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 
partner of a male subject during the study or for 35 days after the last dose should also be recorded 
following authorization from the subject’s partner. 
If the pregnancy occurs during administration of active study medication, or within 35 days of the 
last dose of active study medication, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.0.
If the subject and/or female partner of a male subject agree to the primary care physician being 
informed, the investigator should notify the primary care physician that the subject or female 
partner of the subject was participating in a clinical study at the time she became pregnant and 
provide details of the dose that the subject received.
All reported pregnancies will be followed up to final outcome, using the pregnancy form. 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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9.1.11 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study 
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal but 
not clinically significant, or abnormal and clinically significant. The time that the ECG was 
performed will be recorded. 
9.1.12 PK Sample Collection
9.1.12.1
Collection of Blood for PK Sampling
Blood samples (one 6-mL sample per scheduled time) for the determination of alogliptin, 
pioglitazone, and potential pioglitazone M-IV metabolite plasma concentrations will be collected 
into chilled vacutainers containing anticoagulant potassium ethylenediamine tetra-acetic acid 
(K2EDTA) according to the schedule in Appendix A. Instructions for sample processing and 
shipment are provided in Appendix E.
Serial blood samples for determination of alogliptin and pioglitazone will be collected according 
to Table 9.b.
Table 9.b
Collection of Blood Samples for PK Analysis
Analyte
Matrix
Dosing Day
Scheduled Time (hours)
Alogliptin
Plasma
1
Predose (within 15 minutes prior to dose) and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 
72 hours postdose
Pioglitazone and 
(potential) pioglitazone 
M-IV metabolite
Plasma
1
Predose (within 15 minutes prior to dose) and 
0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 
72 hours postdose
The actual time of sample collection will be recorded on the source document and eCRF.
Note that bioanalytical data for pioglitazone M-IV metabolite will be collected and stored for 
possible future use but that plasma concentrations will not be calculated or reported at this time.
9.1.12.2
Bioanalytical Methods
Plasma concentrations of alogliptin will be measured using a validated high-performance liquid 
chromatography with tandem mass spectrometry method. Plasma concentrations of pioglitazone 
will be measured using a validated high-performance liquid chromatography with tandem mass 
spectrometry method.


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9.1.13 PK Parameters
The PK parameters of alogliptin and pioglitazone will be determined from the concentration-time 
profiles for all evaluable subjects. Actual sampling times, rather than scheduled sampling times, 
will be used in all computations involving sampling times. The following PK parameters will be 
calculated for plasma concentration values of alogliptin and pioglitazone: 
Symbol/Term
Definition
Plasma
AUC72
Area under the concentration-time curve from the time 0 to time 72 hours. 
AUCt
Area under the concentration-time curve from time 0 to time t.
Cmax
Maximum observed concentration.
CL/F
Apparent clearance after extravascular administration, calculated using the observed value of 
the last quantifiable concentration.
λz
Terminal disposition phase rate constant.
t1/2z
Terminal disposition phase half-life.
tmax
Time of first occurrence of Cmax.
9.1.14 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If a subject is withdrawn at 
the screening visit, the investigator should complete the eCRF screen failure form.
The primary reason for screen failure is recorded in the eCRF using the following categories:
!
Predose event/AE.
!
Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.
!
Significant protocol deviation.
!
Lost to follow-up.
!
Voluntary withdrawal <specify reason>.
!
Study termination.
!
Other <specify reason>.
Subject identification numbers assigned to subjects who fail screening should not be reused. 
CCI


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9.1.15 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the dosing phase.
If the subject is found to be not eligible for randomization, the investigator should record the 
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Dosing Compliance
Study medication will be administered while subjects are under observation in the clinical research 
unit. Following administration of the study drug, appropriate mouth and/or hand checks will be 
performed to ensure that the dose is swallowed and noted in the source document. The date and 
time of each dose will be recorded in the source documents and on the eCRFs. An inventory of the 
study drug supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the subject’s source document records 
or equivalent. The exact dose time of consecutive subjects may be staggered to facilitate logistics 
at the site.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening 
Subjects will be screened within 28 days prior to randomization. Screening may consist of 1 or 
more visits. Subjects will sign an informed consent form at the first visit and return to the clinic in 
a fasted state for safety laboratory testing at the second visit. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. A screen 
failure rate of approximately 50% is anticipated. Therefore, an estimated 144 subjects will be 
screened in order to enroll 72 subjects. See Section 9.1.14 for procedures for documenting 
screening failures.
9.3.2
Study Randomization 
Study randomization will take place on Day 1 of Period 1.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. Subjects will be 
administered the first dose of test or reference drug in the unit under the supervision of the 
investigator or designee, as described in Section 8.2. The procedure for documenting Screening 
failures is provided in Section 9.1.14.
9.3.3
Drug Intake/Washout Period 
Subjects will be confined to the clinic from Check-in (Day -1) of Dosing Period 1 until the 24-hour 
blood sample has been collected on Day 2 of Dosing Period 1 and from Day 7 of Dosing Periods 1, 


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2, and 3 until the 24-hour blood sample has been collected on Day 2 of Dosing Periods 2, 3, and 4, 
respectively. Subjects will be discharged or released from the unit unless deemed inappropriate by 
the investigator because of safety concerns. Subjects will return to the clinic for the 36-hour blood 
sample collection on Day 2 and on Days 3 and 4 of each period to complete study procedures.
There is a 7-day washout interval between the dose in each period.
The study consists of a Screening Period (Days -28 to Day-2) and 4 Drug Intake Periods. A 
washout interval of 7 days (beginning immediately after dosing on Day 1 of Period 1) will separate 
the doses of each study period. Subjects will be admitted into the clinic on Day -1 (at least 10 hours 
prior to study drug administration), will be dosed on Day 1 and discharged from the clinic after the 
24-hour blood sample has been collected on Day 2 of each period. Blood samples for 
determination of alogliptin and pioglitazone plasma concentrations will be collected prior to 
dosing on Day 1 through 72 hours postdose. 
9.3.4
Final Visit/ Early Termination
If a subject discontinues, the reason for discontinuation must be documented in the source 
document and eCRF. The PK sample collection should be collected at the Early Termination Visit, 
if possible and relatively close to a protocol-specified time point. The site may seek guidance. For 
example, collect samples if early withdrawal is due to an AE, and/or if several hours elapsed since 
last blood draw.
Final Visit procedures will be performed on Day 4 of Period 4.
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.5
Follow-Up Visit/Telephone Call 
At 14 days ±2 days following the last dose of study drug a Follow-up telephone call will be made 
by the site to inquire for any ongoing AEs or SAEs, new AEs or SAEs, and concomitant 
medications taken since final dose of study medication. Subject who withdrew consent should still 
be contacted for a safety Follow-up telephone call, but the contact should only be recorded in the 
medical records and not in the eCRF, according to data protection regulations.
9.4
Blood Volume
Total blood sampling volume for an individual subject is shown in Table 9.c


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Table 9.c
Approximate Blood Volume
Sample Type
Sample 
Volume 
(mL)
Number of Samples
Total 
Volume 
(mL)
Screening 
Period 1
Period 2
Period 3
Period 4
Clinical laboratory test 
samples
10 (a)
1
1
0
0
1
33
PK samples alogliptin and 
pioglitazone
6
-
16
16
16
16
384 (b)
Total Approximate Blood Sampling Volume
417
(a) The sample volume at Screening will be 13 mL.
(b) Additionally, up to 52 mL of blood will be discarded at time points when blood is drawn using a catheter.
The approximate total volume of blood collected from one subject for the study is 469 mL.
Blood samples for PK analysis will be collected via venous catheter through the 24-hour postdose 
PK sample in each period. With use of a peripheral venous catheter, the catheter will be irrigated 
with 0.5 mL heparinized saline solution (500 ME per 100 mL of 0.9% NaCl) after each blood 
sampling or after the catheter is inserted, in order to avoid catheter thrombosis. In addition, prior to 
taking each PK blood sample from the catheter, 1 mL blood will be drawn and discarded, in order 
to take into account the holdup volume (approximately 0.1 mL) within the catheter. Blood samples 
will be collected via venipuncture in cases of catheter thrombosis and for outpatient blood 
sampling at 36, 48, and 72 hours postdose. 


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10.0
PREDOSE EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 Predose AEs
A predose AE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to administration of any study 
medication. Any AE, including abnormalities in laboratory, ECG, vital signs, or physical 
examination, will exclude the subject from participating in this clinical study. 
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this dosing.
An AE can therefore be any unfavorable and unintended sign (eg, abnormal laboratory value), 
symptom, or disease temporally associated with the use of a drug whether or not it is considered 
related to the drug.
10.1.3 Additional Points to Consider for AEs
An untoward finding generally may:

Indicate a new diagnosis.

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason. 
AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as an AE.
Diagnoses vs 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 findings are considered to be AEs. Repeated or 
additional noninvasive testing for verification, evaluation or monitoring of an abnormality is 
allowed.

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.


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Pre-existing conditions:

Subjects with pre-existing medical conditions will not be enrolled to this study.
Worsening of AEs:

If the subject experiences a worsening or complication of an AE, 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 intensity of AEs:

If the subject experiences changes in intensity of an AE, the event should be captured once 
with the maximum intensity recorded.
Elective surgeries or procedures:

Elective surgeries or procedures are not permitted during the trial; should they be required, the 
subject will be withdrawn. 
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Is a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 10.a).


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Table 10.a
Takeda Medically Significant AE List 
Term
Acute respiratory failure/acute respiratory distress 
syndrome
Hepatic necrosis
Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis 
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome Confirmed or suspected transmission of infectious agent by a 
medicinal product
Neuroleptic malignant syndrome / malignant hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as 
“Important Medical Events” satisfying SAE reporting requirements.
Predose events that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 AEs of Special Interest
An AE of special interest (AESI), serious or non-serious, is one of scientific and medical concern 
specific to the compound or program, for which ongoing monitoring and rapid communication by 
the investigator to Takeda may be appropriate. Such events may require further investigation in 
order to characterize and understand them and would be described in protocols and instructions 
provided for investigators as to how and when they should be reported to Takeda. Pancreatitis, 
hypersensitivity, and hepatic events are considered AESIs and full details of the event should be 
recorded using the relevant AESI forms.
10.1.6 Intensity of AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
Severe:
The event causes considerable interference with the subject’s usual activities.


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10.1.7 Relationship of AEs to Study Drug(s)
The relationship (causality) of each AE to study drug(s) will be assessed using the following 
categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including the 
course after withdrawal of the drug), or for which possible involvement of the drug cannot be 
ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug and/or 
that can reasonably be explained by other factors, such as underlying diseases, complications, 
concomitant medications and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.
10.1.9 Start Date
The start date of the AE is the date that the first signs/symptoms were noted by the subject and/or 
investigator.
10.1.10 Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died.
10.1.11 Frequency 
Episodic AEs (eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous.
10.1.12 Action Concerning Study Drug 

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not Applicable – a study drug was stopped for a reason other than the particular AE eg, the 
study has been terminated, the subject died, dosing with study drug was already stopped before 
the onset of the AE.
10.1.13 Outcome

Recovered/Resolved – Subject returned to first assessment status with respect to the AE.


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
Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 
returned to the normal range or to Baseline; the subject died from a cause other than the 
particular AE with the condition remaining “recovering/resolving”.

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE state remaining “Not recovered/not 
resolved”.

Resolved with sequelae – the subject recovered from an acute AE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis.

Fatal – the AEs which are considered as the cause of death.

Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1
AE Collection Period
Collection of AEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until 14±2 days after Study Exit Visit or the last dose of study 
medication.
10.2.1.2
AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to Baseline or until there is a satisfactory explanation for the 
changes observed. All AEs will be documented in the AE page of the eCRF, whether or not the 
investigator concludes that the event is related to the study drug. The following information will be 
documented for each event:
1. Event term.
2. Start and stop date.
3. Frequency.


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4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study 
drug(s) (related or not related).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of 
the suspected procedure.
7. Action concerning study drug.
8. Outcome of event.
9. Seriousness.
10.2.1.3
AEs of Special Interest 
If an AESI, including but not limited to hypersensitivity, pancreatitis, hepatic disorders, occurs 
during the drug intake period or the follow-up period, is considered to be clinically significant 
based on the criteria below, it should be recorded in a targeted form or an SAE Form. The form 
should be completed and reported to the SAE email address within 24 hours.
AESI criteria include:

Laboratory value threshold if applicable.

Premature termination for the AESI, if applicable.

Any other specific criteria.
The AESIs have to be recorded as AEs in the eCRF. An evaluation form along with all other 
required documentation must be submitted to the sponsor.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum:

A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s).

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0. 


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Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation.
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE. In addition, a liver function test (LFT) Increases eCRF 
must be completed providing additional information on relevant recent history, risk factors, 
clinical signs and symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the 
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or 
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory 
tests as described in Section 9.1.8 must also be performed. In addition, an LFT Increases eCRF 
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
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.
10.3.1 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, including the European 
Medicines Agency (EMA), 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 to the regulatory authorities as expedited report 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 the study drug/sponsor supplied drug 
or that would be sufficient to consider changes in the study drug/sponsor supplied drug 
administration or in the overall conduct of the trial. The study site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with local regulations.


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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.


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12.0
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 medical conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary.
12.1
CRFs (Electronic)
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
eCRFs must be completed in English.
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 to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included. 
The principal investigator must review the eCRFs for completeness and accuracy and must e-sign 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the sponsor or its designee. The sponsor or its designee will be permitted to review the subject’s 
medical and hospital records pertinent to the study to ensure accuracy of the eCRFs. The 
completed eCRFs are the sole property of the sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, 
International Conference on Harmonisation (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 


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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 study site agreement between the investigator and sponsor.
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.


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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1 Analysis Sets
The safety set will include all randomized subjects who receive at least 1 dose of study medication, 
including subjects who do not complete the study. Subjects in this set will be used for demographic 
and baseline characteristics as well as safety summaries.
The PK set will consist of all subjects in the safety set who have sufficient plasma concentration 
data to facilitate the derivation of at least 1 PK parameter. Details regarding how to handle missing 
data will be predefined in the statistical analysis plan.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized for the Safety Set by sequence and 
overall. Summary statistics [number of non-missing values (N), mean, standard deviation (SD), 
median, minimum, and maximum] will be presented for continuous variables (eg, age and weight) 
and the number and percentage of subjects within each category will be presented for categorical 
variables (eg, gender, ethnicity, race). Individual subject demographic and baseline characteristics 
data will be listed.
13.1.3 PK Analysis
Descriptive statistics (eg, N, mean, SD, median, minimum, and maximum) will be used to 
summarize the plasma concentrations of alogliptin and pioglitazone by regimen and scheduled 
sampling time point. Individual plasma concentration data for alogliptin and pioglitazone will be 
presented in the data listings.
Descriptive statistics (N, mean, SD, SE, percent coefficient of variation [%CV], median, 
minimum, and maximum) will be used to summarize the PK parameters of alogliptin and 
pioglitazone for each regimen. Geometric means will be computed for AUCs and Cmax.
Statistical inference to determine if the FDC tablet is bioequivalent to alogliptin and pioglitazone 
administered as individual tablets will be performed using an analysis of variance (ANOVA) 
model with effects for regimen, period, sequence, and subjects nested within sequence. The effect 
due to subject nested within sequence will be considered a random effect in the ANOVA model 
while all other effects will be treated as fixed. The ANOVA model will be applied to the natural 
logarithms of AUC72 and Cmax of alogliptin or pioglitazone as dependent variables to compare the 
test and reference regimens.
Within the framework of ANOVA model for natural logarithms of AUC72 and Cmax, the ratios and 
the 90% confidence intervals (CIs) for the ratios of central values of the test regimen relative to the 


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reference regimen will be provided. The ratios will be obtained as the antilog of the difference of 
the LS means on a natural logarithm scale, and the 90% CIs will be obtained by taking the antilog 
of the 90% CI for the difference between the LS means on the natural logarithmic scale. 
Bioequivalence between administration of alogliptin and pioglitazone as an FDC tablet and as 
individual tablets will be concluded if the 90% CIs are within the range of (0.80, 1.25) for Cmax and 
AUC72.
Alternative statistical analyses will be used if deemed appropriate.
13.1.4 Subject Condition Assessments
Subject condition assessments will be performed using the Safety Set. All subject condition 
assessments, including AEs, clinical laboratory evaluations, 12-lead ECG results, and vital signs 
will be summarized with descriptive statistics, where appropriate, and presented in the data 
listings.
All AEs will be coded using MedDRA and presented in the data listings.
A postdose AE is defined as an AE that occurs after the subject receives the first dose of study 
medication and within 30 days after the last dose of study medication is received. Summary of AEs 
will include numbers and percentages of subjects experiencing AEs by system organ class and 
preferred term. AEs will also be summarized based on their intensity and relationship to study 
medication by system organ class and preferred term. If a subject has more than 1 AE that codes to 
the same preferred term, the subject will be counted only once for that preferred term within 
regimen. Similarly, if a subject has more than 1 AE within a system organ class category, the 
subject will be counted only once in the system organ class category within the regimen. In the 
intensity summary, a subject will be counted only in the highest intensity category for each 
preferred term and each organ class. In the relationship to study medication summary, a subject 
will be counted only in the highest relationship category for each preferred term and each system 
organ class. Each summary table will include incidences of adverse events for each regimen and 
overall.
All AE summary tables will be listed in the SAP.
AEs will be summarized using preferred term and primary system organ class. 
Individual results for clinical hematology and serum chemistry laboratory tests that are outside of 
normal range and results that meet Takeda predefined criteria for markedly abnormal values will 
be considered as clinically significant and identified in summary tables, if applicable. Observed 
values and change from Baseline will be summarized by regimen. All laboratory values will be 
presented in the data listings.
Individual vital sign values that meet the Takeda predefined markedly abnormal criteria will be 
considered as clinically significant and identified in a summary table. The vital sign measurements 
at predefined time points and change from Baseline will be summarized by regimen. All vital signs 
data will be presented in the data listing. 


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Individual ECG measurements that meet the Takeda predefined markedly abnormal criteria will 
be considered as clinically significant and flagged and summarized in a table. Observed values will 
be summarized by regimens. All ECG data will be listed in the data listings.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
A sample size of 72 subjects (18 per sequence) will be enrolled in this 4-period, 4-sequence 
crossover study. The sample size is appropriate to assess the bioavailability of alogliptin and 
pioglitazone from the FDC relative to the individual tablets and also provide greater than 80% 
power for Cmax of pioglitazone establishing bioequivalence between regimens for both strengths 
(SYR-322-4833 BL 25 mg+15 mg and SYR-322-4833 BL 25 mg+30 mg). This is based on 
acceptance ranges of 80% to 125%, the intra-subject variability (%CV) of 33% for Cmax of 
pioglitazone; the expected ratios of the central values for Cmax are between 0.95 and 1.05, and 
drop-out rate of 14%. Since the intra-subject variability for pioglitazone AUCt, and alogliptin Cmax
and AUCt is less than 33%, the power for assessing bioequivalence for pioglitazone AUCt and 
alogliptin Cmax and AUCt are each greater than 80% for both strengths. 


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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and study site guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB 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, subject 
medical records, informed consent documentation, documentation of subject authorization to use 
personal health information (if separate from the informed consent forms), and review of eCRFs 
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.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
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.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. Significant protocol violations are 
entered on the eCRF.
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 14.a
defines the windows allowed for sample collections. 
However, blood samples not collected within the interval specified for the scheduled sample time 
should be reported to Takeda using the Protocol Deviation Form.
Protocol Deviation Forms are to be completed for PK samples collected outside of the following 
intervals:


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Table 14.a
Windows for PK Blood Sample Collection
Minutes
Nominal Sampling Time
no more than 30 minutes predose
0 hour
±5
immediately postdose to ≤6 hours
±10
>6 hours to 12 hours postdose
±15
>12 hours to 24 hours
±30
>24 hours
14.3
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. If the 
study site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and study site guarantee access for quality assurance auditors to all 
study documents as described in Section 14.1.


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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the 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 B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
This study will also be conducted in accordance to the following local regulations: 

The Constitution of the Russian Federation.

Federal Law of the Russian Federation dated 21 November 2011 N 323-FZ“Basic Principles 
of health protection in the RussianFederation.”

Federal Law of the Russian Federation of 12 April 2010 No. 61-FZ “On Circulation of 
Medicines” (in up-to-date edition of the Federal Law).

Government Decree of the Russian Federation of 13 September 2010 No. 714 “Regulations on 
compulsory life and health insurance of the patient participating in the clinical studies of the 
drug” (with changes from 18 May 2011).

National Standard GOST R 52379-2005 RF “Good Clinical Practice.”

Guidelines on Expertise of Drugs edited by A.N. Mironov, Federal StateBudgetary Institution 
Scientific Center of Expertise of Medicinal Drugs, volume I.2013, Chapter 7.

Rules for conduction of bioequivalence studies of medicines of the Eurasian Economic Union, 
version 2.0 dated 20 February 2015.

Eurasian Economic Union Council, Decision. No. 85, 03 November 2016, on Approval of the 
Rules for Conducting Bioequivalence Studies of Medicinal Products within the Eurasian 
Economic Union. 

Order of the Ministry of Health of the Russian Federation No. 200n from 01 April 2016 “On 
approval of the rules of Good Clinical Practice.”
15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of 
the informed consent form, and, if applicable, subject recruitment materials and/or advertisements 


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and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and 
subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will 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 notification no 
protocol activities, including screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals specified 
by the respective IRB or IEC, and submission of the investigator’s final status report to IRB or 
IEC. All IRB and IEC approvals and relevant documentation for these items must be provided to
the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject. 
It is the responsibility of the investigator to explain the detailed elements of the informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) to the 
subject. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. 


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The subject must be given ample opportunity to: (1) inquire about details of the study and (2) 
decide whether or not to participate in the study. If the subject determines he or she will participate 
in the study, then the informed consent form and subject authorization form (if applicable) must be 
signed and dated by the subject at the time of consent and prior to the subject entering into the 
study. The subjects should be instructed to sign using their legal names, not nicknames, using blue 
or black ballpoint ink. The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent and prior to subject entering into the 
study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects in the same 
manner as the original informed consent. The date the revised consent was obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent form.
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any 
regulatory authority (eg, Ministry of Health of Russian Federation, Food and Drug Administration, 
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical Devices 
Agency), the sponsor’s designated auditors, and the appropriate IRBs and IECs to review the 
subject’s original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports. Access to a 
subject’s original medical records requires the specific authorization of the subject as part of the 
informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).


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15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 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 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 study site agreement. In the event of any discrepancy between the protocol and 
the study site agreement, the study site agreement will prevail.
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for America), country, and recruiting 
status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to the sponsor providing this information to callers must provide the 
sponsor with a written notice requesting that their information not be listed on the registry site. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.


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15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to 
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor 
or sponsor’s designee. 
Subjects will be provided with their individual insurance policy. Takeda has insured subjects with 
the following insurance company:
«INGOSSTRAKH» Insurance Company (Pyatnitskaya Street 12, bld.2, Moscow, 117997, Russia)


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16.0
REFERENCES
1. Kawamori R, Matsuhisa M, Kinoshita J, Mochizuki K, Niwa M, Arisaka T, et al. Pioglitazone 
enhances splanchnic glucose uptake as well as peripheral glucose uptake in 
non-insulin-dependent diabetes mellitus. AD-4833 Clamp-OGL Study Group. Diabetes Res 
Clin Pract 1998;41(1):35-43.
2. Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl 2001(121):13-8.
3. Nakamura T, Ushiyama C, Shimada N, Hayashi K, Ebihara I, Koide H. Comparative effects of 
pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in 
diabetes patients. J Diabetes Complications 2000;14(5):250-4.
4. Pfutzner A, Marx N, Lubben G, Langenfeld M, Walcher D, Konrad T, et al. Improvement of 
cardiovascular risk markers by pioglitazone is independent from glycemic control: results 
from the pioneer study. J Am Coll Cardiol 2005;45(12):1925-31.
5. Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, et al. Effect of pioglitazone 
on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational 
diabetes. Diabetes 2006;55(2):517-22.
6. Pioglitazone versus rosiglitazone in subjects with type 2 diabetes mellitus and dyslipidemia. 
Takeda Pharmaceuticals North America, Inc. and Eli Lilly and Company, Report No. 
H6E-US-GLAI, 22 November 2004.
7. A double-blind, randomized, comparator-controlled study in subjects with type 2 diabetes 
mellitus comparing the effects of pioglitazone HCl vs glimepiride on the rate of progression of 
atherosclerotic disease as measured by carotid intima-media thickness (CHICAGO). Takeda 
Pharmaceuticals America, Inc, Report No. 01-02-TL-OPI-518, 04 October 2006.
8. A double-blind, randomized, comparator-controlled study in subjects with type 2 diabetes 
mellitus comparing the effects of pioglitazone HCl versus glimepiride on the rate of 
progression of coronary atherosclerotic disease as measured by intravascular ultrasound 
(PERISCOPE). Takeda Global Research & Development Center, Inc., Report No. 
01-01-TL-OPI-516, 28 February 2008.
9. Dorkhan M, Frid A. A review of pioglitazone HCL and glimepiride in the treatment of type 2 
diabetes. Vasc Health Risk Manag 2007;3(5):721-31.
10. Einhorn D, Rendell M, Rosenzweig J, Egan JW, Mathisen AL, Schneider RL. Pioglitazone 
hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a 
randomized, placebo-controlled study. The Pioglitazone 027 Study Group. Clin Ther 
2000;22(12):1395-409.
11. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve 
medication compliance: a meta-analysis. Am J Med 2007;120(8):713-9.
12. Sleight P, Pouleur H, Zannad F. Benefits, challenges, and registerability of the polypill. Eur 
Heart J 2006;27(14):1651-6.


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13. Dailey GE, 3rd. Improving oral pharmacologic treatment and management of type 2 diabetes. 
Manag Care 2004;13(2):41-7.


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Appendix A
Schedule of Study Procedures
Drug Intake Periods 1 through 4 (a)
Study Exit (Day 4 of 
Period 4)/ Early 
Termination Visit
Follow-up 
Phone Call (d)
Study Day:
Days
-28 to -2 (b)
Day -1 
(Check-in) Day 1 (c)
Day 2
Day 3
Day 4
(Periods 1, 2, and 3)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
Vital signs (e)
X
X
X
X
X
Height, weight and BMI
X
Concomitant medications
X
X
X
X
X
X
X
X
12-lead ECG (f)
X
X
X
Clinical laboratory evaluations (g)
X
X (h)
X
Urine drug, cotinine, and alcohol 
breath screen
X
X
X
X
X
Urine pregnancy test (hCG) (i) 
X
X
X
HBsAg, Anti-HCV, HIV, and 
syphilis (i)
X
Confinement
X
X (j)
X (j)
Study drug dosing (k)
X
PK blood collection (l)
X
X
X
X
X
Predose/AE assessment (m)
X
X
X
X
X
X
X
X 
Footnotes are on the following page.


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(a) There will be at least 7 days between the dose in 1 period and the dose in a subsequent period.
(b) Screening may consist of 1 or more visits. Subjects will sign an informed consent form at the first visit and return to the clinic in a fasted state for safety laboratory testing at the 
second visit. Screening procedures must be performed within 28 days prior to administration of investigational product. 
(c) Day 1 of each drug intake period.
(d) Follow-up phone call will be made 14 ± 2 days after study exit to inquire about any AE or SAEs, and concomitant medications taken since final dose. Any AE/SAE spontaneously 
reported within 30 days postdose will be included within the database as AEs.
(e) Vital signs: oral body temperature, sitting blood pressure (after resting 5 minutes), respiratory rate, and pulse (beats per minute). Vital signs will be measured just prior to dosing 
on Day 1 of periods 1 through 4. When vital signs are scheduled at the same time as blood draws, the blood draw will take priority and vital signs will be obtained within 0.5 hour 
before or after the scheduled blood draw.
(f) ECG performed at Screening, Check-in (Day -1 of Period 1), and Study Exit Day 4 of Period 4, or if a subject terminates early from the study.
(g) Hematology, serum chemistries, and urinalysis tests will be done at a local laboratory.
(h) Predose hematology, serum chemistries, and urinalysis tests will be done for Period 1 only.
(i) A urine pregnancy test and HBsAg, Anti-HCV, HIV, and syphilis tests will be done locally.
(j) Following the 24-hour blood sample collection on Day 2 of each period, subjects will be discharged from the clinic and will return to the clinic for the 36-hour blood sample 
collection on Day 2 and on Days 3 and 4 of each period to complete study procedures. 
(k) Study drug will be administered on Day 1 of each period at 08:00 (±1) hours, following an 8- hour fast. Dosing may be staggered to help facilitate logistics at the site.
(l) Blood samples for PK obtained predose (within 15 minutes prior to dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. The PK sample should not be 
collected at the Early Termination Visit if a PK collection is not scheduled.
(m) Predose AEs will be captured immediately following the signing of the informed consent at Screening until dosing on Day 1 of Period 1. The routine collection of AEs will 
continue through to the follow-up phone call.


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Appendix B
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 investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who 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 (non-routine/non-standard 
panel) screening assessments, are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
ICH and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are 
met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.


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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 C
Elements of the Subject Informed Consent 
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each 
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research. When there is no intended clinical benefit to the subject, the subject should be 
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB/IEC, 
and the monitor may inspect the records. By signing a written informed consent form, the 
subject is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a 
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 


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participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject.
21. A statement that the subject will be informed in a timely manner if information becomes 
available that may be relevant to the subject’s willingness to continue participation in the 
study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and 
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs;
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country; 
however, Takeda will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to 
Takeda’s research databases for purposes of developing a better understanding of the 
safety and effectiveness of the study drug(s), studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and
e) that the subject’s identity will remain confidential in the event that study results are 
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective contraception (as defined in the informed 
consent) from Screening and throughout the duration of the study, and for 35 days after the last 
dose of study drug. Regular pregnancy tests will be performed throughout the study for all 


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female subjects of childbearing potential. If a subject is found to be pregnant during study,
study drug will be discontinued and the investigator will offer the subject the choice to receive 
unblinded treatment information. 
25. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 


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Appendix D
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.


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Appendix E
Collection, Storage, and Shipment of PK Samples
Instructions for Processing of Plasma Samples for PK Analysis of Alogliptin and 
Pioglitazone
1. Collect 6 mL of venous blood into a chilled Becton-Dickinson Vacutainer. All alogliptin and 
pioglitazone blood samples should be collected into vacutainers containing K2EDTA.
2. Gently invert the vacutainer several times to mix the additive with the collected blood prior to 
centrifugation and place immediately on ice.
3. Centrifuge the vacutainers for 10 minutes at approximately 1100 to 1300 relative centrifugal 
force (RCF) at room temperature. Note: if using a collection device other than 
Becton-Dickinson, refer to manufacturer’s instruction for proper centrifugation force and time.
4. Immediately following centrifugation, gently remove plasma from the packed cells. To ensure 
a more homogeneous sample, all plasma should first be transferred into 1 aliquot. From there, 
split the plasma evenly between the 4 aliquots. A minimum of 0.5 mL needs to be obtained for 
each sample. Labeling may include protocol number (Alogliptin-1002), sample matrix (ie, 
plasma), analyte (alogliptin or pioglitazone), randomization sequence number, period, nominal 
day and time, and either “SET 1” (for original sample) or “SET 2” (for duplicate sample). 
Note: the “SET 1” samples should be transferred first and then the “SET 2” tubes transferred.
5. Cap the labeled storage tubes and freeze the plasma samples immediately at 
approximately -20°C or lower until shipment. No more than 45-60 minutes will elapse 
between blood collection and freezing the plasma sample.
Shipping of Plasma Samples Alogliptin and Pioglitazone
The following instructions are recommended unless they differ from the site’s standard operating 
procedures for labeling, packaging, or shipping of PK samples.
1. Biological samples (plasma) should be shipped on dry ice to prevent thawing during transit. 
Samples should be shipped only on Monday, Tuesday, or Wednesday, and at least 2 days prior 
to a national holiday, in order to minimize the possibility of samples in transit over a weekend 
or holiday. If duplicate samples are to be shipped, send SET 1 samples and await confirmation 
of arrival before shipping the duplicate SET 2 samples.
2. Before shipping, make sure the sample tubes are tightly sealed. Separate each subject’s 
samples as follows:
3. Separate the duplicate SET 2 samples from the SET 1 samples.
4. Place SET 1 samples for each subject into self-sealing bag (eg, Ziploc) containing additional 
absorbent material.
5. Using a permanent marker, write the 4-digit randomization sequence number, sample matrix 
(ie, plasma), number of samples, and “SET 1” on each self-sealing bag.
6. Place the bags of individual subject’s samples into a larger plastic bag so that samples are 
double bagged. Duplicate SET 2 samples should be returned to the freezer for storage. Repeat 


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steps 3 through 6 above when preparing duplicate samples for shipment, except self-sealing 
bags should be marked “SET 2.”
7. An inventory of individual samples should accompany each shipment and should include the 
Sponsor’s name (Takeda), study medication (alogliptin, pioglitazone), protocol number 
(Alogliptin-1002), investigator’s name, sample type (ie, plasma) analyte (alogliptin, 
pioglitazone), subject randomization sequence number, period, nominal collection day and 
time, and intended sample storage conditions. When duplicate SET 2 samples are being 
shipped, make a copy of the original SET 1 sample inventory and mark as “SET 2.” Place the 
inventory paperwork into a large self-sealing bag. SET 1 samples will be shipped first on dry 
ice, followed by shipment of duplicate SET 2 samples after SET 1 samples have been received 
by the analytical laboratory.
8. For sample packing, utilize dry ice generously (eg, 20-25 pounds per day of transit) to 
safeguard against longer than expected shipping times and delays. Use newspaper or other 
material to insulate the double-bagged samples from direct contact with the dry ice. Place the 
sample bundles into a Styrofoam container (or other suitable container) and fill the excess 
space with dry ice slabs or ice pellets (preferably the latter). Make a note of the estimated 
weight of the dry ice used per shipping container.
9. Place the inventory paperwork (in a large self-sealing bag) on top of the dry ice in the 
Styrofoam container. Place the lid on the Styrofoam container and seal completely with 
strapping tape. Place the Styrofoam container in a cardboard shipping carton and seal securely 
with strapping tape.
10. Mark the outside of shipping carton(s) with a tally number (eg, 1 of 5, 2 of 5).
11. Affix an address label to each shipping carton. Complete the address label with the following 
information:
Plasma samples for alogliptin and pioglitazone
Affix a carbon dioxide label on each carton, specifically:
Carbon Dioxide Solid UN-1845
Class 9 PKG GR III
Quantity _____________________
(fill in weight to nearest lb/kg and specify unit of measure used)
12. Affix 2 dry ice symbol labels on opposite sides of the carton. Mark KEEP FROZEN on each 
carton. Specify a return address and contact person on the carton.
PPD


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13. Obtain the airway bill number and a receipt of shipment from the carrier.
14. After shipping of the samples, please contact the bioanalytical laboratory.
For alogliptin and pioglitazone plasma samples, please contact:
15. When calling, provide the following information:
Name of courier or transport company
Time and date the shipment left the clinical site
Airway bill number
PPD


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Appendix F
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 02 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Revised descriptions of study drugs to align with local requirements.
The primary change occurs in Section 8.1.1 Dosage Form, Manufacturing, Packaging, and 
Labeling.
Initial 
wording:
In this protocol, the term study medication refers to: 

Alogliptin 25 mg tablets (commercially available on the Russian market).

Pioglitazone 15 and 30 mg tablets manufactured by Takeda, Japan and sourced as 
commercial packs from the commercial market.

Alogliptin/Pioglitazone FDC 25/15 mg and 25/30 mg tablets manufactured by 
Takeda, Japan and sourced as commercial packs from the commercial market. 
All medication sourced by the Sponsor as defined below. 

Commercial alogliptin 25 mg tablets, locally available on the Russian market.

Commercial pioglitazone 15 and 30 mg tablets (in commercial packs).

Commercial alogliptin/pioglitazone FDC 25/15 mg tablets and 25/30 mg tablets 
(in commercial packs).
Each commercial pack supplied will be labeled with a single panel open computer-
generated label containing the required information.
Amended 
or new 
wording:
In this protocol, the term study medication refers to: 

Alogliptin 25 mg film-coated tablets No. 28 (commercially available on the 
Russian market) manufactured by Takeda (product released by Takeda 
Ireland).

Pioglitazone 15 and 30 mg tablets No. 30 manufactured by Pliva Hrvatska d.o.o., 
Croatia Takeda, Japan and sourced as commercial packs from the commercial 
market of Croatia.

Alogliptin/Pioglitazone FDC 25/15 mg film-coated and 25/30 mg tablets No. 28 
manufactured by Takeda, Japan (product released by Takeda Ireland), Japan
and sourced as commercial packs from the commercial market under the name 
NesinaAct. For this clinical study, NesinaAct will be supplied to the site as 
commercial packs and labeled as SYR-322-4833 BL 25/15.

Alogliptin/Pioglitazone FDC 25/30 mg film-coated tablets No. 28 
manufactured by Takeda (product released by Takeda Ireland) and sourced 
as commercial packs from the commercial market under the name 


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Incresync. For this clinical study, Incresync will be supplied to the site as 
commercial packs and labeled as SYR-322-4833 BL 25/30.
All medication sourced by the Sponsor as follows: defined below. 

Commercial alogliptin 25 mg tablets, sourced locally available on from the 
Russian market.

Commercial pioglitazone 15 and 30 mg tablets sourced locally from the 
Croatian market (in commercial packs).

Commercial alogliptin/pioglitazone FDC 25/15 mg tablets and 25/30 mg tablets 
(in commercial packs) sourced from Takeda and labeled as SYR-322-4833 BL 
25/15 and SYR-322-4833 BL 25/30, respectively.
Each commercial pack supplied will be labeled with a single panel open 
computer-generated label containing the required information including information 
“For clinical trial only”.
The following sections also contain this change:

Section 8.1.1.1 Study Drug.

Section 8.1.1.2 Sponsor-Supplied Drug.
Change 2: Corrected inconsistency in length of pregnancy monitoring time after the end of the 
study.
The primary change occurs in Section 7.2 Exclusion Criteria.
Initial 
wording:
11.
If female, the subject is pregnant (confirmed by a positive pregnancy test) or 
lactating or intending to become pregnant before, during, or within 30 days after 
participating in this study; or intending to donate ova during such time period.
Amended 
or new 
wording:
11.
If female, the subject is pregnant (confirmed by a positive pregnancy test) or 
lactating or intending to become pregnant before, during, or within 30 35 days after 
participating in this study; or intending to donate ova during such time period.
Rationale for Change:
Corrected inconsistency in length of pregnancy monitoring time after the end of the study.
The following section also contain this change:

Appendix C Elements of the Subject Informed Consent (item 24).
Change 3: Updated information for shipping label and contact information for the bioanalytical 
laboratory.
The primary change occurs in  Appendix E Collection, Storage, and Shipment of PK Samples.
Initial 
11. Affix an address label to each shipping carton. Complete the address label with the 


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wording:
following information:
Plasma samples for alogliptin
Plasma samples for pioglitazone
14. After shipping of the samples, please contact the bioanalytical laboratory.
For alogliptin plasma samples, please contact:
For pioglitazone plasma samples, please contact;
Amended 
or new 
wording:
11. Affix an address label to each shipping carton. Complete the address label with the 
following information:
Plasma samples for alogliptin
Plasma samples for alogliptin and pioglitazone
PPD
PPD
PPD
PPD
PPD
PPD


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14. After shipping of the samples, please contact the bioanalytical laboratory.
For alogliptin plasma samples, please contact:
For alogliptin and pioglitazone plasma samples, please contact:
Rationale for Change:
Updated shipping address label and contact information for the bioanalytical laboratory.
PPD
PPD
PPD


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PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, Open-Label, Single-Dose, 4-Period Crossover Study to Determine the 
Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 and 30 mg) When Administered as 
Individual Tablets and as Fixed-Dose Combination Tablets to Healthy Russian Subjects
NCT Number: NCT03501277
SAP Approve Date: 20 June 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Alogliptin-1002
A Randomized, Open-Label, Single-Dose, 4-Period Crossover Study to Determine the
Bioequivalence of Alogliptin (25 mg) and Pioglitazone (15 and 30 mg) When Administered
as Individual Tablets and as Fixed-Dose Combination Tablets to Healthy Russian Subjects
Bioequivalence Study of Medicinal Product – SYR-322-4833 BL
PHASE 1
Version: 1.0
Date: 20 June 2018
Prepared by:
Based on:
Protocol Version: 2
Protocol Date: 23 January 2018
CONFIDENTIAL PROPERTY OF TAKEDA
PPD


Alogliptin-1002
Page 2 of 22
Statistical Analysis Plan Final
20 June 2018
CONFIDENTIAL
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.


Alogliptin-1002
Page 3 of 22
Statistical Analysis Plan Final
20 June 2018
CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


Alogliptin-1002
Page 4 of 22
Statistical Analysis Plan Final
20 June 2018
CONFIDENTIAL
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................3
2.0
TABLE OF CONTENTS.................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Additional Objectives ................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................9
5.1
Primary Endpoints .....................................................................................................9
5.2
Additional Endpoints .................................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................10
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................11
7.1
General Principles....................................................................................................11
7.1.1
Study Definitions ...............................................................................................11
7.1.2
Definition of Study Days....................................................................................11
7.1.3
Definition of Study Visit Windows ....................................................................11
7.1.4
Conventions for Missing Adverse Event Dates...................................................12
7.1.5
Conventions for Missing Concomitant Medication Dates...................................12
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................12
7.4
Demographic and Other Baseline Characteristics.....................................................13
7.5
Medical History and Concurrent Medical Conditions...............................................13
7.6
Medication History and Concomitant Medications...................................................13
7.7
Study Drug Exposure and Compliance.....................................................................13
7.8
Efficacy Analysis.....................................................................................................13
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................13
7.9.1
Pharmacokinetic Analysis ..................................................................................14
7.9.2
Pharmacodynamic Analysis ...............................................................................15
7.10
Other Outcomes.......................................................................................................15
7.11
Safety Analysis........................................................................................................15
7.11.1 Adverse Events ..................................................................................................15
7.11.2 Clinical Laboratory Evaluations .........................................................................16


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7.11.3 Vital Signs .........................................................................................................17
7.11.4 12-Lead ECGs ...................................................................................................17
7.11.5 Other Observations Related to Safety.................................................................17
7.12
Interim Analysis ......................................................................................................17
7.13
Changes in the Statistical Analysis Plan...................................................................17
8.0
REFERENCES..............................................................................................................18
LIST OF IN-TEXT TABLES
Table 1 Collection of blood samples for PK analysis.................................................................14
Table 2 Pharmacokinetic Parameters.........................................................................................14
LIST OF IN-TEXT FIGURES
Figure 1 Schematic of Study Design............................................................................................8
APPENDICIES
Appendix A Study Procedures...................................................................................................19
Appendix B Criteria for Identification of Markedly Abnormal Laboratory Values.....................19
Appendix C Criteria for Abnormal Changes from Baseline of Vital Signs.................................22


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
BMI
body mass index
Cmax
maximum concentration
CPK
creatine phosphokinase
CV
coefficient of variation
ECG
electrocardiogram
eCRF
electronic case report form
GGT
-glutamyl transferase
ICF
informed consent form
HIV
human immunodeficiency virus
LLN
lower limit of normal
MAV
markedly abnormal value
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
SAE
serious adverse event
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary


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4.0
OBJECTIVES
4.1
Primary Objectives
To assess the relative bioavailability and bioequivalence of 2 strengths of the fixed-dose 
combination tablet product SYR-322-4833 BL compared to the individual alogliptin and
pioglitazone tablets in healthy Russian subjects
4.2
Secondary Objectives
None
4.3
Additional Objectives
To perform a comparative analysis of AE data after the administration of SYR-322-4833 BL and 
after coadministration of alogliptin and pioglitazone to healthy volunteers within the scope of the 
trial.
4.4
Study Design
This is a single-center, open-label, randomized, 4-sequence, 4-period, single dose crossover 
study involving 72 healthy adult, male and female subjects between the ages of 18 and 55 years,
inclusive.
Subjects will be randomized in the order in which they are enrolled into the study. The 72 
eligible subjects will be randomized to 1 of 4 drug intake sequences in a 1:1:1:1 ratio. Due to the 
large sample size, volunteers may be divided into 2 or 3 cohorts according to space limitations at 
the site. All cohorts will be dosed sequentially.
The study consists of a Screening Period (Days -28 to Day-2) and 4 Drug Intake Periods. A
washout interval of 7 days (beginning immediately after dosing on Day 1) will separate the doses
of each study period. Subjects will be admitted into the clinic on Day -1 (Day 7 of the preceding
period for Periods 2, 3, and 4) and will be dosed on Day 1 of each period. Starting on Day 1 of 
each period, blood samples for determination of alogliptin and pioglitazone plasma 
concentrations will be collected predose through 72 hours postdose. The subjects will be 
discharged from the clinic after the 24-hour blood sample collection on Day 2 of each period and 
will return to the clinic for the 36-hour blood sample collection on Day 2 and on Days 3 and 4 of 
each period to complete study procedures. Final Visit procedures will be performed on Day 4 of 
Period 4 and a Follow-up call will be made 14 days ±2 days following the last dose of study 
drug.
A schematic of the study design is included as Figure 1. A schedule of assessments is listed in
Appendix A.


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Figure 1 Schematic of Study Design


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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
The following plasma pharmacokinetic (PK) parameters of alogliptin and pioglitazone will be
derived on Day 1 of each period:
∀
Maximum observed concentration (Cmax).
∀
Area under the concentration-time curve from the time 0 to time 72 hours (AUC72).
5.2
Additional Endpoints
∀
∀
Percentage of subjects who experience at least 1 postdose AE.
∀
Percentage of subjects who have clinically significant changes in laboratory tests at least 
once postdose.
∀
Percentage of subjects who have clinically significant changes in vital sign measurements 
at least once postdose.
∀
Percentage of subjects who have clinically significant changes in electrocardiogram 
(ECG) parameters at least once postdose.
∀
Percentage of subjects who experience at least 1 postdose event of hypoglycemia.
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6.0
DETERMINATION OF SAMPLE SIZE
A sample size of 72 subjects (18 per sequence) will be enrolled in this 4-period, 4-sequence
crossover study. The sample size is appropriate to assess the bioavailability of alogliptin and
pioglitazone from the fixed dose combination relative to the individual tablets and also provide 
greater than 80% power for Cmax of pioglitazone establishing bioequivalence between regimens 
for both strengths (SYR-322-4833 BL 25 mg+15 mg and SYR-322-4833 BL 25 mg+30 mg). 
This is based on acceptance ranges of 80% to 125%, the intra-subject variability (%CV) of 33% 
for Cmax of pioglitazone; the expected ratios of the central values for Cmax are between 0.95 and 
1.05, and drop-out rate of 14%. Since the intra-subject variability for pioglitazone AUCt, and 
alogliptin Cmax and AUCt is less than 33%, the power for assessing bioequivalence for 
pioglitazone AUCt and alogliptin Cmax and AUCt are each greater than 80% for both strengths.


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
Continuous data will be summarized using descriptive statistics, including the number of 
subjects, mean, standard deviation (SD), median, minimum, and maximum. The coefficient of 
variation (%CV) and geometric mean will be included in the summary of continuous data where 
indicated. Categorical data will be tabulated as the number and percentage of subjects in each 
category; unless otherwise specified the denominator for percentage is total number of subjects 
with non-missing data.
Arithmetic means, geometric means, and medians will be presented to 1 more decimal place than 
the recorded data, and SDs will be presented to 2 more decimal places than the recorded data, 
where appropriate. Where applicable, confidence intervals about a parameter estimate will be 
presented using the same number of decimal places as the parameter estimate and p-values will 
be rounded to 3 decimal places prior to assessment of statistical significance.
All study-related raw data for enrolled subjects, including derived data, will be presented in data 
listings. In addition, the actual day relative to the first dose will be presented, where applicable.
All statistical analyses will be performed using the SAS System® Version 9.4.
7.1.1
Study Definitions
Generally, Baseline is defined as the value or observation prior to first dose of study drug, i.e. 
Day 1 Period 1. Were applicable, pre-dose values will be obtained for each dosing Period.
7.1.2
Definition of Study Days
Study Day 1 is defined as the date of the first dose of study drug, as recorded on the electronic 
case report form (eCRF) dosing page. Other study days are defined relative to Study Day 1, with 
Day 1 being Study Day 1 and Day -1 being the day prior to Study Day 1. Study days prior to the 
first dose of study drug will be calculated as: {date of assessment/event – date of first dose of 
study drug}. Study days on or after the first dose of study drug will be calculated as: {date of 
assessment/event – date of first dose of study drug + 1}. The calculation of day within a period 
will be similar to study day but relative to the date of administration of the first dose of study 
drug within the period.
7.1.3
Definition of Study Visit Windows
All blood samples should be identifiable by date and time.  If actual time is missing then the 
nominal time may be used in the analyses. Safety laboratory collections (i.e. clinical laboratory 
evaluations) are obtained Pre-dose on Day 1 (baseline) and Day 4 of Period 4 (post-baseline). If 
a subject has more than one laboratory value (eg. a repeat laboratory draw) then the latter will be 
used for data analyses.


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7.1.4
Conventions for Missing Adverse Event Dates
Missing AE dates will not be imputed. In the event an AE is missing onset date information a 
consistent and reasonable effort will be made to associate the event to one of the 4 regimens in 
the study. A few illustrative examples follow:

Onset date is missing and event stop date predates Day 1 then the event will be evaluated 
as pre-treatment.

Onset date is missing and event stop date is within Period X, then AE will be associated 
with the regimen for Period X.

Onset date is partial, day missing month available. Then the event will be associated to 
the Regimen given in earliest Period compatible for the month of onset. 
7.1.5
Conventions for Missing Concomitant Medication Dates
Missing dates for concomitant medication will not be imputed. However, if necessary, similar 
strategies as described in section 7.1.4 will be used to associate the concomitant medication to 
the trial periods/regimens. 
7.2
Analysis Sets
The safety set will include all randomized subjects who receive at least 1 dose of study 
medication, including subjects who do not complete the study. Subjects in this set will be used 
for demographic and baseline characteristics as well as safety summaries.
The PK set will consist of all subjects in the safety set who have sufficient plasma concentration 
data to facilitate the derivation of at least 1 PK parameter. Details regarding how to handle 
missing data will be predefined in the Clinical Pharmacology Analysis Plan.
7.3
Disposition of Subjects
Study Information, including date of first subject signing Informed Consent Form (ICF), date of 
first/last study drug, date of last subject’s last visit/contact, date of last subject’s last procedure 
for collection of data for primary endpoint, Medical Dictionary for Drug Regulatory Activities 
(MedDRA) Version, World Health Organization Drug Dictionary (WHODrug) Version, and 
SAS Version used for creating the datasets, will be summarized.
The eligibility of subjects will be summarized, along with the primary reasons of screen failure 
as recorded in eCRF.
Number of subjects randomized will be tabulated by treatment sequence and overall. 
Disposition of all enrolled subjects will be tabulated. Categories will include:

Subjects who were randomized but not treated

Subjects who completed the study


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
Subjects who prematurely discontinued study
Primary reasons for discontinuing study, as entered on the eCRF will be tabulated. 
7.4
Demographic and Other Baseline Characteristics
Demographic and study baseline characteristics, including age at first dose administration, sex, 
ethnicity, race, height (cm), weight (kg), and body mass index (kg/m2),  will be summarized by 
sequence and overall. Demographic and baseline characteristics variables will not be analyzed
inferentially. Demographic variables for subjects screen but not randomized, i.e. screen failure, 
will be summarize similarly.
7.5
Medical History and Concurrent Medical Conditions
Medical history, defined as significant conditions or diseases that resolved at or prior to the time 
of informed consent, and concurrent medical conditions, defined as significant conditions or 
diseases that are present at signing of informed consent, will be coded using the MedDRA 
coding system. Medical history and concurrent medical conditions will be listed by subject 
number. There will be no summary or inferential analysis of medical history and concurrent 
medical conditions.
7.6
Medication History and Concomitant Medications
Medication history information includes any medication relevant to eligibility criteria stopped at 
or within 28 days prior to signing of informed consent. Concomitant medication is any drug 
given in addition to the study drug, taken at any time from signing of informed consent through 
the end of study. Medication history and concomitant medications will be coded using the
WHODrug. Listings for medication history and concomitant medications will be produced by 
subject number.  There will be no summary or inferential analysis of medication history and 
concomitant medications.
7.7
Study Drug Exposure and Compliance
All doses of study medication will be administered during confinement. Dosing data, including 
dosing time will be provided by subject and visit in the listings. Data on eCRFs for meals 
received will also be provide in the data listings.
7.8
Efficacy Analysis
Not applicable.
7.9
Pharmacokinetic/Pharmacodynamic Analysis


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7.9.1
Pharmacokinetic Analysis
The schedule for blood samples for PK analysis of alogliptin and pioglitazone is listed in Table 
1.
The concentration of both alogliptin and pioglitazone in plasma will be summarized by regimen 
over each scheduled sampling time point using descriptive statistics (arithmetic mean, SD, CV%,
median, minimum and maximum). Individual plasma concentration data versus time will be 
listed. In addition, the figures for mean plasma concentrations of alogliptin (pioglitazone) versus 
time (linear and semi-log scale) will be generated. 
PK parameters for alogliptin and pioglitazone will be estimated using non-compartmental 
methods. Additional details concerning the calculation and reporting of PK parameters can be 
found in the Clinical Pharmacology Analysis Plan (CPAP) .
Descriptive statistics (N, mean, SD, CV%, median, minimum and maximum) will be used to 
summarize the PK parameters for alogliptin and pioglitazone by regimen. In addition, geometric 
means will be computed for AUCs and Cmax. The PK parameters of interest are listed in Table 2.
Box plots for both alogliptin and pioglitazone Cmax and AUC72 will be generated by regimen and 
will be presented Regimen A versus Regimen B and Regimen C versus Regimen D. 
Table 1 Collection of blood samples for PK analysis
Analyte
Matrix
Dosing 
Day
Scheduled Time (hours)
Alogliptin
Plasma
1
Predose (within 15 minutes prior to dose) 
and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 
36, 48, and 72 hours postdose
Pioglitazone 
Plasma
1
Predose (within 15 minutes prior to dose) 
and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 
36, 48, and 72 hours postdose
Table 2 Pharmacokinetic Parameters
Symbol/Term
Definition
AUC72
Area under the concentration-time curve from the time 0 to time 72 hours.
AUCt
Area under the concentration-time curve from time 0 to time t.
Cmax
Maximum observed concentration
CCI


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CL/F 
Apparent clearance after extravascular administration, calculated using the 
observed value of the last quantifiable concentration.
λz
Terminal disposition phase rate constant
t1/2z
Terminal disposition phase half-life
tmax
Time of first occurrence of Cmax
For each analyte, an analysis of variance (ANOVA) will be performed on natural logarithm 
transformed Cmax and AUC72 with factors for sequence, the subject nested within sequence, 
period and regimen. The random effect subject nested within sequence will be the error term for 
testing the sequence effect. Other factors will be tested with the residual as the error term. For 
the relative bioavailability (BA) determination, pairwise comparisons will be performed to assess 
the relative BA of alogliptin and pioglitazone via point estimates and 90% confidence interval 
(CI) for the ratio of Cmax and AUC72 central values for Regimen A (test) versus Regimen B 
(reference) as wells as Regimen C (test) versus Regimen D (reference). 
 
A conclusion of bioequivalence in the PK of each analyte between test regimen will be reached if 
the 90% CIs for Cmax and AUC72 are within the (0.80-1.25) interval.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
7.11
Safety Analysis
All summaries and analyses of safety data are based on subjects in the Safety Analysis Set.
Unless otherwise specified, the safety data will be summarized by study arm. 
7.11.1 Adverse Events
A treatment-emergent adverse event (TEAE) is defined as an adverse event (AE) or serious 
adverse event (SAE) that started or worsened after first study drug administration and within 14
days (30 days if SAE) of last dose of study drug (onset date – date of last dose + 1 ≤14), see 
Protocol Section 10.2.1.1. A TEAE will be attributed to a regimen if the TEAE occurs after 
administration of the study drug in a period and up to just prior to study drug administration in 
the next period. A TEAE that occurs after administration of the study drug in the last period and 
up to 14 days after the last study drug dose is attributed to the regimen received in the last period.
All AE verbatim terms will be coded by system organ class (SOC) and preferred term using (PT) 
the MedDRA coding system. Any subject that doesn’t not complete all 4 regimens/periods will 
be included in the AE summaries, and will be included in each of the regimens for which they 
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were treated and any AEs happening after their last regimen exposure (inclusive of 30 days) will 
be included in the tally of that regimen.
TEAEs will be summarized by regimen and overall. The tables will include the number and 
percentage (N [%]) of subjects reporting any event for that term. The denominator, within a 
regimen summary, will be the total number of subjects that received the regimen. 
The following TEAE tables will be summarized by part. 
–
Overview of TEAEs.
–
TEAEs by SOC and PT.
–
Most Frequent TEAEs by PT term
–
Most Frequent Non-Serious TEAEs by PT 
–
Relationship of TEAEs to Study Drug by SOC and PT.
–
Study Drug-Related TEAEs by SOC and PT.
–
Severity of TEAEs by SOC and PT.
–
Severity of Drug-Related TEAEs by SOC and PT.
In addition, pretreatment events (PTEs) will be summarized overall by SOC and PT.
For each regimen and overall, subjects reporting more than one occurrence for a term (SOC or 
PT) being summarized will be counted only once using the most extreme incident (most severe 
for the severity tables and related for the relationship to study drug tables).
Most frequent TEAEs are those events occurred in at least ≥5% (before any rounding) of 
subjects in a regimen. 
Data listings will be provided for all TEAEs, PTEs, TEAEs that led to study discontinuation, 
TEAEs that led to abnormal liver functions, SAEs, AEs that resulted in death, and AEs occurring 
more than 30 days after the last dose of study medication.
7.11.2 Clinical Laboratory Evaluations
Laboratory samples will be obtained following a minimum 8-hour overnight fast on Day 1 of 
Period 1 (pre-dose), and Day 4 of Period 4 (or Study Exit in case of early termination), see 
Appendix A. Baseline will be defined as the Day 1 value.
Laboratory values for hematology, serum chemistry, and urinalysis, see protocol section 9.1.8, 
will be summarized by regimen and by all subjects Overall. Individual subject values together 
with treatment sequence assignment will be presented in data listing; values that meet the Takeda 
predefined markedly abnormal value (MAV) criteria, Appendix B, and/or outside normal range 
will be flagged in the data listing. For each laboratory parameter, where possible, the following 
will be performed: 

Descriptive statistics for change from baseline, 


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
Number and percentage of subjects with a value outside normal range,

Number and percentage of subjects with a value meeting MAV criteria.
Individual results for hematology and chemistry laboratory tests that meet the Takeda predefined 
laboratory markedly abnormal value (MAV) criteria in Appendix B will be presented in a data 
listing. If a subject has an MAV for a laboratory test, all visits for that subject for that parameter 
will be listed. 
All clinical laboratory data will be presented in both SI and conventional units in the data 
listings. Laboratory data outside of the normal reference range will be listed. Out of normal 
range values and MAVs will be flagged in data listings.
7.11.3 Vital Signs
Refer to Appendix A for scheduled vital signs measurement visits. Individual results for vital 
sign measurements that meet the Takeda predefined vital signs MAV criteria in Appendix C will 
be presented in a data listing. All vital sign data will be presented in the listings. Vital sign 
MAVs will be flagged in the listings.
7.11.4 12-Lead ECGs
The scheduled 12-lead ECG data will be collected according to Appendix A, including baseline 
and the final visit. The ECG evaluations will be categorized as Normal; Abnormal, not clinically 
significant; and Abnormal, clinically significant. ECG results will be presented as a shift from 
baseline table and all ECG data will be presented in data listings.
7.11.5 Other Observations Related to Safety
Physical examination findings will be presented in data listings. No summary tables will be 
provided.
All cases of overdose will be listed. 
Follow-up phone call information will be listed.
7.12
Interim Analysis
Not applicable.
7.13
Changes in the Statistical Analysis Plan 
Not applicable.


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8.0
REFERENCES
Not applicable


Appendix A Study Procedures
Study Day:
Days
-28 to -2 
(b)
Drug Intake Periods 1 through 4 (a)
Study Exit 
(Day 4 of
Period 4)/ 
Early
Termination 
Visit
Follow-up 
Phone Call 
(d)
Day -1
(Check-
in)
Day 1 
(c)
Day 2
Day 3
Day 4
(Period
s 1, 2, 
and 3)
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics and medical history
X
Medication history
X
Physical examination
X
X
X
Vital signs (e)
X
X
X
X
X
Height, weight and BMI
X
Concomitant medications
X
X
X
X
X
X
X
X
12-lead ECG (f)
X
X
X
Clinical laboratory evaluations (g)
X
X (h)
X
Urine drug, cotinine, and alcohol breath screen
X
X
X
X
X
Urine pregnancy test (hCG) (i)
X
X
X
HBsAg, Anti-HCV, HIV, and syphilis (i)
X
Confinement
X
X (j)
X (j)
Study drug dosing (k)
X
PK blood collection (l)
X
X
X
X
X
Predose/AE assessment (m)
X
X
X
X
X
X
X
X
(a) There will be at least 7 days between the dose in 1 period and the dose in a subsequent period.


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(b) Screening may consist of 1 or more visits. Subjects will sign an informed consent form at the first visit and return to the clinic in a fasted state for 
safety laboratory testing at the second visit. Screening procedures must be performed within 28 days prior to administration of investigational product.
(c) Day 1 of each drug intake period.
(d) Follow-up phone call will be made 14 ± 2 days after study exit to inquire about any AE or SAEs, and concomitant medications taken since final 
dose. Any AE/SAE spontaneously reported within 30 days postdose will be included within the database as AEs.
(e) Vital signs: oral body temperature, sitting blood pressure (after resting 5 minutes), respiratory rate, and pulse (beats per minute). Vital signs will be 
measured just prior to dosing on Day 1 of periods 1 through 4. When vital signs are scheduled at the same time as blood draws, the blood draw will take 
priority and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw.
(f) ECG performed at Screening, Check-in (Day -1 of Period 1), and Study Exit Day 4 of Period 4, or if a subject terminates early from the study.
(g) Hematology, serum chemistries, and urinalysis tests will be done at a local laboratory.
(h) Predose hematology, serum chemistries, and urinalysis tests will be done for Period 1 only.
(i) A urine pregnancy test and HBsAg, Anti-HCV, HIV, and syphilis tests will be done locally.
(j) Following the 24-hour blood sample collection on Day 2 of each period, subjects will be discharged from the clinic and will return to the clinic for 
the 36-hour blood sample collection on Day 2 and on Days 3 and 4 of each period to complete study procedures.
(k) Study drug will be administered on Day 1 of each period at 08:00 (±1) hours, following an 8- hour fast. Dosing may be staggered to help facilitate 
logistics at the site.
(l) Blood samples for PK obtained predose (within 15 minutes prior to dose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. 
The PK sample should not be collected at the Early Termination Visit if a PK collection is not scheduled.
(m) Predose AEs will be captured immediately following the signing of the informed consent at Screening until dosing on Day 1 of Period 1. The 
routine collection of AEs will continue through to the follow-up phone call.


Appendix B Criteria for Identification of Markedly Abnormal Laboratory Values
Hematology—Criteria for Markedly Abnormal Values
Parameter
Unit
Low Abnormal
High Abnormal
Hemoglobin
Both 
< 0.8 × LLN
> 1.2 × ULN
Hematocrit
Both
< 0.8 × LLN
> 1.2 × ULN
RBC count 
Both
< 0.8 × LLN 
> 1.2 × ULN
WBC count 
Both 
<0.5 x LLN
>1.5 x ULN
Platelet count
Conventional
<75 x 103/L
>600 x 103/L
SI
<75 x 109/L
>600 x 109/L
LLN= lower limit of normal, RBC= red blood cell, ULN= upper limit of normal, WBC= white blood cell. 
Serum Chemistry—Criteria for Markedly Abnormal Values
Parameter
Unit 
Low Abnormal
High Abnormal
ALT
Both
--
>3x ULN
AST
Both
--
>3x ULN
Alkaline phosphatase
Both
--
>3x ULN
Total bilirubin
Conventional
--
>2.0 mg/dL
SI
--
>34.2 mol/L
GGT
Albumin
Both
Conventional 
--
<2.5 g/dL
>3x ULN
--
SI 
<25 g/L
--
Total protein
Both
<0.8x LLN
>1.2x ULN
Creatinine
Conventional 
--
>2.0 mg/dL
SI
--
>177 mol/L
Blood urea nitrogen
Conventional 
--
>30 mg/dL
SI
--
>10.7 mmol/L
Sodium
Conventional
<130 mEq/L
>150 mEq/L
SI
<130 mmol/L
>150 mmol/L
Potassium
Conventional
<3.0 mEq/L
>6.0 mEq/L
CPK
SI
Both
<3.0 mmol/L
--
>6.0 mmol/L
>5x ULN
ALT= alanine aminotransferase, AST= aspartate aminotransferase, GGT= -glutamyl transferase, CPK= creatine 
phosphokinase, LLN= lower limit of normal, ULN= upper limit of normal.


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


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GF
䣃䣮䣱䣩䣮䣫䣲䣶䣫䣰䢯䢳䢲䢲䢴䢢䣕䣶䣣䣶䣫䣵䣶䣫䣥䣣䣮䢢䣃䣰䣣䣮䣻䣵䣫䣵䢢䣒䣮䣣䣰䢢䢾䣻䣻䣻䣻䢯䣯䣯䢯䣦䣦䣀
6WDWLVWLFDO$SSURYDO
-XQ87&
3KDUPDFRYLJLODQFH$SSURYDO
-XQ87&
%LRVWDWLVWLFV$SSURYDO
-XQ87&
&OLQLFDO3KDUPDFRORJ\$SSURYDO
-XQ87&
&OLQLFDO6FLHQFH$SSURYDO
-XO87&
PPD