A Study to Determine the Bioequivalence of Alogliptin and Pioglitazone When Administered as Individual Tablets and as Fixed-Dose Combination (FDC)-SYR-322-4833 BL Tablets to Healthy Russian Participants

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03501277
• Collaborator: (none)
• Enrollment: 72
• Location: 1
• Arms: 4
• Actual Duration (Months): 1.5
• Patients Per Site Per Month: 47.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Alogliptin; Drug: Pioglitazone; Drug: SYR-322-4833 BL	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official 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
• Actual Study Start Date: May 26, 2018
• Actual Primary Completion Date: Jul 11, 2018
• Actual Study Completion Date: Jul 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence I: ABCD 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).	Drug: Alogliptin; Alogliptin tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Drug: SYR-322-4833 BL; SYR-322-4833 BL FDC tablets.; Other Names: Incresync
Experimental: Sequence II: BCDA 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).	Drug: Alogliptin; Alogliptin tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Drug: SYR-322-4833 BL; SYR-322-4833 BL FDC tablets.; Other Names: Incresync
Experimental: Sequence III: CDAB 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).	Drug: Alogliptin; Alogliptin tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Drug: SYR-322-4833 BL; SYR-322-4833 BL FDC tablets.; Other Names: Incresync
Experimental: Sequence IV: DABC 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).	Drug: Alogliptin; Alogliptin tablets.; Drug: Pioglitazone; Pioglitazone tablets.; Drug: SYR-322-4833 BL; SYR-322-4833 BL FDC tablets.; Other Names: Incresync

Outcome Measures

Primary Outcome Measures

1. Cmax: Maximum Observed Plasma Concentration for Alogliptin and Pioglitazone [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose]

2. AUC(0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Alogliptin and Pioglitazone [Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Is a healthy male or female.

2. Has an estimated glomerular filtration rate (eGFR) greater than or equal to (>=) 90 milliliter per minute (mL/min).

3. Weighs at least 50 kilogram (kg) and has a body mass index (BMI) from 18.5 to 30.0 kilogram per square meter (kg/m^2), inclusive at Screening.

Exclusion Criteria:

1. Has participated in a clinical study within 3 months prior to Check-in (Day-1).

2. Has a fasting blood glucose level lower than 3.88 millimole per liter (mmol/L).

3. Has received alogliptin or pioglitazone in a previous clinical study or as a therapeutic agent within 90 days prior to Check-in (Day-1).

4. Experienced acute infectious diseases within 4 weeks prior to Screening.

5. 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).

6. Consumes over 10 drinks weekly (1 drink is equivalent to 0.5 liters of beer, 200 milliliter (mL) of dry wine or 50 mL of ardent spirits) or has a history of alcoholism, drug and/or substance abuse.

7. Has a non-standard diet (example, vegetarian or vegan) or lifestyle (including night time work, extreme physical activity such as weights lifting), which may interfere with the trial.

8. 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).

9. Has poor peripheral venous access.

10. 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.

11. Has consumed caffeine or xanthine-containing food or drinks within 72 hours prior to Check-in (Day -1).

12. Has dehydration due to vomiting, diarrhea, or any other reason within 24 hours prior to study start.

13. Has drug intolerance.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Non-governmental healthcare Institution Road Clinical Hospital at the station Yaroslavl JSC Russian Railways	Yaroslavl		Russian Federation	150047

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

• Study Protocol - Jan 23, 2018
• Statistical Analysis Plan - Jun 20, 2018

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03501277
• Other Study ID Numbers: Alogliptin-1002; U1111-1196-9223
• First Posted: Apr 18, 2018
• Last Update Posted: Aug 8, 2019
• Last Verified: Jun 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Pioglitazone; Alogliptin

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in Russia from 26 May 2018 to 11 July 2018.
Pre-assignment Detail	Healthy participants were enrolled in 1 of the 4 treatment sequences to receive: SYR-322-4833 BL (25 milligram [mg] + 15 mg) (Regimen A), alogliptin 25 mg + pioglitazone 15 mg (Regimen B), SYR-322-4833 (25 mg + 30 mg) (Regimen C), and alogliptin 25 mg + pioglitazone 30 mg (Regimen D).

Arm/Group Title	Sequence I: ABCD	Sequence II: BCDA	Sequence III: CDAB	Sequence IV: DABC
Arm/Group Description	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) fixed dose combination (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).	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).	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).	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).
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	18	18
Safety Analysis Set	18	18	17	17
COMPLETED	18	18	17	17
NOT COMPLETED	0	0	1	1
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	17
COMPLETED	18	18	17	17
NOT COMPLETED	0	0	0	0
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	17
COMPLETED	18	18	17	16
NOT COMPLETED	0	0	0	1
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	16
COMPLETED	18	18	17	16
NOT COMPLETED	0	0	0	0
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	16
COMPLETED	18	18	17	15
NOT COMPLETED	0	0	0	1
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	15
COMPLETED	18	18	17	15
NOT COMPLETED	0	0	0	0
Period Title: Intervention Period 1 (4 Days)
STARTED	18	18	17	15
COMPLETED	18	18	17	15
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Sequence I: ABCD	Sequence II: BCDA	Sequence III: CDAB	Sequence IV: DABC	Total
Arm/Group Description	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) fixed dose combination (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).	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).	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).	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).	Total of all reporting groups
Overall Participants	18	18	17	17	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.9 (7.95)	23.9 (4.60)	29.4 (8.46)	27.5 (6.36)	27.4 (7.18)
Sex: Female, Male (Count of Participants)
Female	9 50%	7 38.9%	8 47.1%	9 52.9%	33 47.1%
Male	9 50%	11 61.1%	9 52.9%	8 47.1%	37 52.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	18 100%	18 100%	17 100%	17 100%	70 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%
White	18 100%	18 100%	17 100%	17 100%	70 100%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Russia	18 100%	18 100%	17 100%	17 100%	70 100%
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	68.77 (12.527)	69.86 (12.409)	75.06 (14.643)	71.22 (15.894)	71.17 (13.806)
Body mass index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	24.21 (3.411)	24.06 (2.959)	24.78 (3.575)	24.89 (3.628)	24.48 (3.342)
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	168.3 (8.56)	169.9 (8.02)	173.6 (10.22)	168.4 (9.44)	170.0 (9.14)

Outcome Measures

1. Primary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Alogliptin and Pioglitazone
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) analysis set included all participants in the safety set who had sufficient plasma concentration data to facilitate the derivation of at least 1 PK parameter.

Arm/Group Title	Regimen A	Regimen B	Regimen C	Regimen D
Arm/Group Description	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	Alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	Alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.
Measure Participants	70	69	68	70
Alogliptin	165.3 (42.87)	154.9 (44.71)	162.3 (51.19)	157.4 (44.24)
Pioglitazone	678.3 (267.58)	706.5 (254.12)	1052.1 (478.13)	1141.5 (509.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A, Regimen B
	Comments
	Type of Statistical Test	Equivalence
	Comments	Alogliptin: For each analyte, an analysis of variance (ANOVA) was performed on natural logarithm transformed Cmax with factors for sequence, the participant nested within sequence, period, and regimen. For the relative bioavailability (BA) determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90 percent (%) confidence interval (CI) for the ratio of Cmax for Regimen A (test) versus Regimen B (reference).
Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square Mean (LSM) difference
	Estimated Value	1.0706
	Confidence Interval	(2-Sided) 90%; 1.0230 to 1.1204
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen C, Regimen D
	Comments
	Type of Statistical Test	Equivalence
	Comments	Alogliptin: For each analyte, ANOVA was performed on natural logarithm transformed Cmax with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of Cmax for Regimen C (test) versus Regimen D (reference).
Statistical Test of Hypothesis	p-Value	0.326
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.0276
	Confidence Interval	(2-Sided) 90%; 0.9817 to 1.0757
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen A, Regimen B
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pioglitazone: For each analyte, ANOVA was performed on natural logarithm transformed Cmax with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of Cmax for Regimen A (test) versus Regimen B (reference).
Statistical Test of Hypothesis	p-Value	0.405
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM diiference
	Estimated Value	0.9594
	Confidence Interval	(2-Sided) 90%; 0.8837 to 1.0415
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Regimen C, Regimen D
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pioglitazone: For each analyte, ANOVA was performed on natural logarithm transformed Cmax with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of Cmax for Regimen C (test) versus Regimen D (reference).
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.9257
	Confidence Interval	(2-Sided) 90%; 0.8523 to 1.0053
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	AUC(0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Postdose for Alogliptin and Pioglitazone
Time Frame	Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants in the safety set who had sufficient plasma concentration data to facilitate the derivation of at least 1 PK parameter.

Arm/Group Title	Regimen A	Regimen B	Regimen C	Regimen D
Arm/Group Description	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	Alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.	Alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.
Measure Participants	70	69	68	70
Alogliptin	2197.3 (340.92)	2163.4 (362.83)	2194.7 (379.27)	2195.0 (379.80)
Pioglitazone	5726.0 (1826.18)	5471.9 (1766.76)	10141.6 (3611.38)	9907.6 (3495.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A, Regimen B
	Comments
	Type of Statistical Test	Equivalence
	Comments	Alogliptin: For each analyte, ANOVA was performed on natural logarithm transformed AUC(0-72) with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of Cmax for Regimen A (test) versus Regimen B (reference).
Statistical Test of Hypothesis	p-Value	0.081
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.0157
	Confidence Interval	(2-Sided) 90%; 1.0009 to 1.0308
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen C, Regimen D
	Comments
	Type of Statistical Test	Equivalence
	Comments	Alogliptin: For each analyte, ANOVA was performed on natural logarithm transformed AUC(0-72) with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of AUC(0-72) for Regimen C (test) versus Regimen D (reference).
Statistical Test of Hypothesis	p-Value	0.922
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.0009
	Confidence Interval	(2-Sided) 90%; 0.9862 to 1.0158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen A, Regimen B
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pioglitazone: For each analyte, ANOVA was performed on natural logarithm transformed AUC(0-72) with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of AUC(0-72) for Regimen A (test) versus Regimen B (reference).
Statistical Test of Hypothesis	p-Value	0.066
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.0486
	Confidence Interval	(2-Sided) 90%; 1.0051 to 1.0939
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Regimen C, Regimen D
	Comments
	Type of Statistical Test	Equivalence
	Comments	Pioglitazone: For each analyte, ANOVA was performed on natural logarithm transformed AUC(0-72) with factors for sequence, the participant nested within sequence, period, and regimen. For the relative BA determination, pairwise comparisons were performed to assess the relative BA of alogliptin and pioglitazone via point estimates and 90% CI for the ratio of AUC(0-72) for Regimen C (test) versus Regimen D (reference).
Statistical Test of Hypothesis	p-Value	0.308
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	1.0267
	Confidence Interval	(2-Sided) 90%; 0.9839 to 1.0714
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent adverse events (TEAEs) are adverse events that started after the first dose of study drug and no more than 14 days (approximately Day 35) or 30 days (approximately Day 51) for a serious adverse event after the last dose of study drug
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Regimen A		Regimen B		Regimen C		Regimen D
Arm/Group Description	SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 15 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.		Alogliptin 25 mg tablet and pioglitazone 15 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.		SYR-322-4833 BL (alogliptin 25 mg and pioglitazone 30 mg) FDC tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.		Alogliptin 25 mg tablet and pioglitazone 30 mg tablet, orally, once, on Day 1 of Period 1, 2, 3 or 4.
All Cause Mortality
	Regimen A		Regimen B		Regimen C		Regimen D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/69 (0%)		0/68 (0%)		0/70 (0%)
Serious Adverse Events
	Regimen A		Regimen B		Regimen C		Regimen D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/70 (0%)		0/69 (0%)		0/68 (0%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Regimen A		Regimen B		Regimen C		Regimen D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/70 (2.9%)		1/69 (1.4%)		1/68 (1.5%)		2/70 (2.9%)
Immune system disorders
Allergic oedema	0/70 (0%)		1/69 (1.4%)		0/68 (0%)		0/70 (0%)
Injury, poisoning and procedural complications
Contusion	1/70 (1.4%)		0/69 (0%)		0/68 (0%)		0/70 (0%)
Hand fracture	1/70 (1.4%)		0/69 (0%)		0/68 (0%)		0/70 (0%)
Investigations
Blood creatinine increased	0/70 (0%)		0/69 (0%)		0/68 (0%)		1/70 (1.4%)
Nervous system disorders
Dizziness	1/70 (1.4%)		0/69 (0%)		0/68 (0%)		1/70 (1.4%)
Headache	0/70 (0%)		0/69 (0%)		1/68 (1.5%)		0/70 (0%)
Syncope	1/70 (1.4%)		0/69 (0%)		0/68 (0%)		0/70 (0%)
Vascular disorders
Hypotension	1/70 (1.4%)		0/69 (0%)		0/68 (0%)		0/70 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.