Bioequivalence Study of Fixed Dose Combination of 2.5 mg Saxagliptin/850 mg Metformin Tablet relative to 2.5 mg Onglyza and 850 mg Glucophage Tablets Co-Administered

Study identifier:CV181-121

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

Bioequivalence Study of the Fixed Dose Combination of 2.5 mg Saxagliptin and 850 mg Metformin Tablet Relative to a 2.5 mg Saxagliptin (Onglyza) Tablet and a 850 mg Metformin (Glucophage Marketed by Merck Serono) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed Conditions

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 1

Healthy volunteers

Yes

Study drug

saxagliptin, metformin, saxagliptin + metformin (FDC tablet)

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 55 Years

Date

Study Start Date: 01 Feb 2010

Primary Completion Date: 01 Mar 2010

Study Completion Date: 01 Mar 2010

Study design

Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Other

Verification:

Verified 01 Mar 2015 by AstraZeneca Pharmaceuticals

Collaborators

Astra-Zeneca

Inclusion and exclusion criteria

Location

PPD Development, LP

Austin, TX, United States, 78744

Arms	Assigned Interventions
Other: Arm A (saxagliptin 2.5 mg + metformin 850 mg; Fasting) A single oral dose of 2.5-mg Onglyza tablet and 850-mg Glucophage (marketed by Merck Serono) tablet administered together in the fasted condition.	Drug: saxagliptin Tablets, Oral, 2.5 mg, once daily, single dose Other Name: Onglyza Drug: metformin Tablets, Oral, 850 mg, once daily, single dose Other Name: Glucophage
Other: Arm B (saxagliptin 2.5 mg + metformin 850 mg FDC; Fasting) A single oral dose of 2.5-mg saxagliptin/850-mg metformin fixed dose combination (FDC) administered in the fasted condition.	Drug: saxagliptin + metformin (FDC tablet) Tablet, oral, (saxagliptin 2.5 mg) (metformin 850 mg), once daily, single dose
Other: Arm C (saxagliptin 2.5 mg + metformin 850 mg; Fed) A single oral dose of 2.5-mg Onglyza tablet and 850-mg Glucophage (marketed by Merck Serono) tablet administered together in the fed condition.	Drug: saxagliptin Tablets, Oral, 2.5 mg, once daily, single dose Other Name: Onglyza Drug: metformin Tablets, Oral, 850 mg, once daily, single dose Other Name: Glucophage
Other: Arm D (saxagliptin 2.5 mg + metformin 850 mg FDC; Fed) A single oral dose of 2.5-mg saxagliptin/850-mg metformin FDC administered in the fed condition.	Drug: saxagliptin + metformin (FDC tablet) Tablet, oral, (saxagliptin 2.5 mg) (metformin 850 mg), once daily, single dose

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants (N = 24) who met all of the inclusion and none of the exclusion criteria were recruited from a single site in the United States.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants were screened for eligibility within 21 days before Day 1 of period 1. On Day −1 of each period, the participants were admitted to the clinical facility and confined for 4 days. All the 24 participants were randomly assigned to 1 of 4 treatment sequences (ADBC, BACD, CBDA, or DCAB). The washout between each dose was at least 7 days.

Reporting Groups

	Description
Treatment Sequence ADBC	Treatment A (period 1): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition; Treatment D (period 2): Fixed dose combination (FDC) tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition; Treatment B (period 3): FDC tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition; Treatment C (period 4): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fed condition.
Treatment Sequence BACD	Treatment B (period 1): FDC tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition; Treatment A (period 2): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition; Treatment C (period 3): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fed condition; Treatment D (period 4): Fixed dose combination (FDC) tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition.
Treatment Sequence CBDA	Treatment C (period 1): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fed condition; Treatment B (period 2): FDC tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition; Treatment D (period 3): Fixed dose combination (FDC) tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition; Treatment A (period 4): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition.
Treatment Sequence DCAB	Treatment D (period 1): Fixed dose combination (FDC) tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition; Treatment C (period 2): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fed condition; Treatment A (period 3): 2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition; Treatment B (period 4): FDC tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition.

Participant Flow for 4 periods

Period 1: Period 1

	Treatment Sequence ADBC	Treatment Sequence BACD	Treatment Sequence CBDA	Treatment Sequence DCAB
STARTED	6	6	6	6
COMPLETED	6	6	6	6
NOT COMPLETED	0	0	0	0

Period 2: Period 2

	Treatment Sequence ADBC	Treatment Sequence BACD	Treatment Sequence CBDA	Treatment Sequence DCAB
STARTED	6	6	6	6
COMPLETED	6	6	6	6
NOT COMPLETED	0	0	0	0

Period 3: Period 3

	Treatment Sequence ADBC	Treatment Sequence BACD	Treatment Sequence CBDA	Treatment Sequence DCAB
STARTED	6	6	6	6
COMPLETED	6	5	6	6
NOT COMPLETED	0	1	0	0
Adverse Event	0	1	0	0

Period 4: Period 4

	Treatment Sequence ADBC	Treatment Sequence BACD	Treatment Sequence CBDA	Treatment Sequence DCAB
STARTED	6	5	6	6
COMPLETED	6	5	6	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

Reporting Groups

	Description
All Enrolled and Treated Participants

Baseline Measures

	All Enrolled and Treated Participants
Number of Participants [units: Participants]	24
Age Continuous [units: years] Mean ± Standard Deviation	35.5 ± 10.61
Gender, Male/Female [units: participants]
Female	8
Male	16
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	11
Not Hispanic or Latino	13
Unknown or Not Reported	0
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0
Asian	0
Native Hawaiian or Other Pacific Islander	0
Black or African American	3
White	21
More than one race	0
Unknown or Not Reported	0
Region of Enrollment [units: participants] United States	24
Height [units: cm] Mean ± Standard Deviation	170.2 ± 12.0
Weight [units: kg] Mean ± Standard Deviation	79.7 ± 13.7
Body Mass Index (BMI) [units: kg/m^2] Mean ± Standard Deviation	27.4 ± 3.05

Outcome Measures

1. Primary Outcome Measure: Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Primary
Measure Name	Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	22
Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	49.23 (18.52%)	49.94 (19.72%)	52.50 (17.95%)	53.15 (17.81%)

Statistical Analysis 1 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	101.45
90% Confidence Interval	( 98.17 to 104.84 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 98% and 99% power to conclude bioequivalence (BE) with respect to Cmax and AUC0-inf, respectively. If there was a 5% difference, then 20 participants would have provided 93% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% confidence intervals (CIs) for the test-to-reference ratios (B/A) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of saxagliptin.
[5]	Other relevant estimation information:
	Ratio=Treatment B/Treatment A. Geometric least squares means values are presented in other statistical analysis entries. LS=Least Squares.

Statistical Analysis 2 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	102.43
90% Confidence Interval	( 99.53 to 105.42 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 98% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively. If there was a 5% difference, then 20 participants would have provided 93% and 99% power to conclude BE with respect to Cmax and AUC0-inf,respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (D/C) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of saxagliptin.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values are presented in other statistical analysis entries.

Statistical Analysis 3 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	49.23

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment A.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	49.94

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment B.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	52.71

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment C.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	53.99

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment D.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

2. Primary Outcome Measure: Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Primary
Measure Name	Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	22
Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax) [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	9.73 (20.44%)	9.97 (29.07%)	10.25 (26.87%)	10.88 (23.72%)

Statistical Analysis 1 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	102.46
90% Confidence Interval	( 94.68 to 110.88 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 98% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively. If there was a 5% difference, then 20 participants would have provided 93% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (B/A) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of saxagliptin.
[5]	Other relevant estimation information:
	Ratio=Treatment B/Treatment A. Geometric least squares means values are presented in other statistical analysis entries.

Statistical Analysis 2 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	106.24
90% Confidence Interval	( 98.43 to 114.66 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of saxagliptin from the FDC tablet versus saxagliptin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 98% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively. If there was a 5% difference, then 20 participants would have provided 93% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (D/C) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of saxagliptin.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 3 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	9.73

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment A.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	9.97

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment B.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	10.33

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment C.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax)

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	10.97

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment D.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

3. Primary Outcome Measure: Metformin PK Parameter AUC(0-inf) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Primary
Measure Name	Metformin PK Parameter AUC(0-inf)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	23	23	22
Metformin PK Parameter AUC(0-inf) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	11998.00 (23.68%)	12271.61 (20.42%)	11988.30 (16.94%)	11838.11 (18.18%)

Statistical Analysis 1 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	102.10
90% Confidence Interval	( 97.26 to 107.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 99% power to conclude BE with respect to each of Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would provide 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (B/A) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of metformin.
[5]	Other relevant estimation information:
	Ratio = Treatment B/Treatment A. Geometric least squares means values are presented in other statistical analysis entries.

Statistical Analysis 2 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	99.17
90% Confidence Interval	( 96.23 to 102.21 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 99% power to conclude BE with respect to each of Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would provide 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (B/A) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of metformin.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values are presented in other statistical analysis entries.

Statistical Analysis 3 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11998

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares mean for Treatment A.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	12250

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment B.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	12036

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment C.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Metformin PK Parameter AUC(0-inf)

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11937

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment D.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

4. Primary Outcome Measure: Metformin PK Parameter Cmax [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Primary
Measure Name	Metformin PK Parameter Cmax
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition.
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition.
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition.

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
Metformin PK Parameter Cmax [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	1724.38 (25.49%)	1715.79 (23.59%)	1571.21 (15.64%)	1541.76 (17.45%)

Statistical Analysis 1 for Metformin PK Parameter Cmax

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	99.50
90% Confidence Interval	( 90.41 to 109.5 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 99% power to conclude BE with respect to each of Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would provide 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (B/A) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of metformin.
[5]	Other relevant estimation information:
	Ratio=Treatment B/Treatment A. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 2 for Metformin PK Parameter Cmax

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	Yes
Other^[5]	98.22
90% Confidence Interval	( 94.28 to 102.32 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	If there was no difference between the bioavailabilities of metformin from the FDC tablet versus metformin from coadministration of saxagliptin and metformin tablets under both fasted and fed conditions, then 20 participants would have provided 99% power to conclude BE with respect to each of Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would provide 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.
[2]	Additional details about a non-inferiority or equivalence analysis:
	BE was concluded if the 90% CIs for the test-to-reference ratios (D/C) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf of metformin.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 3 for Metformin PK Parameter Cmax

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	1724.4

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment A.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 4 for Metformin PK Parameter Cmax

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	1715.8

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment B.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 5 for Metformin PK Parameter Cmax

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	1581.4

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment C.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 6 for Metformin PK Parameter Cmax

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	1553.2

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Geometric least squares means for Treatment D.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: 5-hydroxy Saxagliptin PK Parameter AUC(0-inf) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Secondary
Measure Name	5-hydroxy Saxagliptin PK Parameter AUC(0-inf)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
5-hydroxy Saxagliptin PK Parameter AUC(0-inf) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	118.58 (24.08%)	119.54 (21.16%)	121.99 (25.42%)	125.54 (24.82%)

No statistical analysis provided for 5-hydroxy Saxagliptin PK Parameter AUC(0-inf)

6. Secondary Outcome Measure: 5-hydroxy saxagliptin PK parameter Cmax [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Secondary
Measure Name	5-hydroxy saxagliptin PK parameter Cmax
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
5-hydroxy saxagliptin PK parameter Cmax [units: ng/mL] Geometric Mean (Geometric Coefficient of Variation)	16.83 (32.95%)	16.72 (32.92%)	17.35 (32.95%)	18.59 (30.78%)

No statistical analysis provided for 5-hydroxy saxagliptin PK parameter Cmax

7. Secondary Outcome Measure: 5-hydroxy Saxagliptin PK parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Secondary
Measure Name	5-hydroxy Saxagliptin PK parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t])
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC[0-t] is the area under the plasma concentration-time curve from time zero to time of last measurable concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
5-hydroxy Saxagliptin PK parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	109.60 (25.81%)	110.61 (22.77%)	113.15 (26.53%)	117.04 (25.74%)

No statistical analysis provided for 5-hydroxy Saxagliptin PK parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t])

8. Secondary Outcome Measure: 5-hydroxy Saxagliptin PK Parameter Terminal Half-life (T 1/2) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Secondary
Measure Name	5-hydroxy Saxagliptin PK Parameter Terminal Half-life (T 1/2)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
5-hydroxy Saxagliptin PK Parameter Terminal Half-life (T 1/2) [units: hr] Mean (Standard Deviation)	7.58 (1.32)	7.58 (1.35)	7.48 (1.10)	7.22 (1.01)

No statistical analysis provided for 5-hydroxy Saxagliptin PK Parameter Terminal Half-life (T 1/2)

9. Secondary Outcome Measure: 5-hydroxy Saxagliptin PK parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Secondary
Measure Name	5-hydroxy Saxagliptin PK parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
5-hydroxy Saxagliptin PK parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax) [units: hr] Mean (Standard Deviation)	2.21 (0.75)	1.86 (0.71)	2.65 (0.83)	2.46 (0.72)

No statistical analysis provided for 5-hydroxy Saxagliptin PK parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax)

10. Secondary Outcome Measure: Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs). [ Time Frame: AEs: from study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening). ]

Measure Type	Secondary
Measure Name	Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs).
Measure Description	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.
Time Frame	AEs: from study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening).
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received at least one dose of study medication.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs). [units: participants]
Number of Participants With at Least 1 AE	4	5	3	4
Discontinuation Due to AE	1	0	0	0
Deaths	0	0	0	0
SAEs	0	0	0	0

No statistical analysis provided for Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs).

11. Secondary Outcome Measure: Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities [ Time Frame: From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). ]

Measure Type	Secondary
Measure Name	Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities
Measure Description	Abnormalities that were considered clinically significant and/or reported as an AE by the investigator.
Time Frame	From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening).
Safety Issue?	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who received at least one dose of study medication.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities [units: participants]
Clinical Laboratory Abnormalities	0	0	1	0
Vital Sign Abnormalities	0	0	0	0
Physical Examination Abnormalities	0	0	0	0
12-Lead ECG Abnormalities	0	0	0	0

No statistical analysis provided for Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities

12. Other Pre-specified Outcome Measure: Saxagliptin PK parameter AUC(0-t) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Saxagliptin PK parameter AUC(0-t)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(0-t) is the area under the plasma concentration-time curve from time zero to time of last measurable concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	22
Saxagliptin PK parameter AUC(0-t) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	47.15 (17.98%)	47.83 (19.77%)	50.69 (17.74%)	51.37 (17.63%)

Statistical Analysis 1 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	101.43
90% Confidence Interval	( 98.07 to 104.90 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Ratio=Treatment B/Treatment A. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 2 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	102.52
90% Confidence Interval	( 99.56 to 105.57 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 3 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	47.15

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment A.

Statistical Analysis 4 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	47.83

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment B.

Statistical Analysis 5 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	50.89

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment C.

Statistical Analysis 6 for Saxagliptin PK parameter AUC(0-t)

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	52.17

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment D.

13. Other Pre-specified Outcome Measure: Saxagliptin PK parameter T1/2 [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Saxagliptin PK parameter T1/2
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	22
Saxagliptin PK parameter T1/2 [units: hr] Mean (Standard Deviation)	6.45 (1.00)	6.21 (1.25)	5.86 (0.92)	6.09 (0.94)

No statistical analysis provided for Saxagliptin PK parameter T1/2

14. Other Pre-specified Outcome Measure: Saxagliptin PK parameter Tmax [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Saxagliptin PK parameter Tmax
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	22
Saxagliptin PK parameter Tmax [units: hr] Mean (Standard Deviation)	1.38 (0.79)	0.96 (0.61)	1.94 (0.95)	1.48 (0.58)

No statistical analysis provided for Saxagliptin PK parameter Tmax

15. Other Pre-specified Outcome Measure: Metformin PK parameter AUC(0-t) [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Metformin PK parameter AUC(0-t)
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC(0-t) is the area under the plasma concentration-time curve from time zero to time of last measurable concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
Metformin PK parameter AUC(0-t) [units: ng*hr/mL] Geometric Mean (Geometric Coefficient of Variation)	11826.52 (23.86%)	11875.08 (21.47%)	11796.60 (17.03%)	11681.05 (17.59%)

Statistical Analysis 1 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment A, Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	100.41
90% Confidence Interval	( 95.40 to 105.68 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Ratio=Treatment B/Treatment A. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 2 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment C, Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	99.06
90% Confidence Interval	( 96.19 to 102.02 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Ratio=Treatment D/Treatment C. Geometric least squares means values presented in other statistical analysis entries.

Statistical Analysis 3 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment A
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11827

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment A.

Statistical Analysis 4 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment B
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11875

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment B.

Statistical Analysis 5 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment C
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11845

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment C.

Statistical Analysis 6 for Metformin PK parameter AUC(0-t)

Groups^[1]	Treatment D
Non-Inferiority/Equivalence Test^[2]	No
Other^[5]	11734

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[5]	Other relevant estimation information:
	Geometric least squares means for Treatment D.

16. Other Pre-specified Outcome Measure: Metformin PK parameter T1/2 [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Metformin PK parameter T1/2
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study. One participant in period 3 (treatment D) was excluded from the pharmacokinetic analysis due to a predose concentration greater than 5% of Cmax.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	23	23	22
Metformin PK parameter T1/2 [units: hr] Mean (Standard Deviation)	10.94 (4.13)	13.15 (6.67)	10.82 (3.18)	11.13 (3.08)

No statistical analysis provided for Metformin PK parameter T1/2

17. Other Pre-specified Outcome Measure: Metformin PK parameter Tmax [ Time Frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing ]

Measure Type	Other Pre-specified
Measure Name	Metformin PK parameter Tmax
Measure Description	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.
Time Frame	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All treated participants not discontinuing prior to the end of the study.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Measured Values

	Treatment A	Treatment B	Treatment C	Treatment D
Number of Participants Analyzed [units:participants]	24	24	23	23
Metformin PK parameter Tmax [units: hr] Mean (Standard Deviation)	2.41 (0.78)	2.54 (0.92)	3.74 (0.54)	3.74 (0.45)

No statistical analysis provided for Metformin PK parameter Tmax

Serious Adverse Events

Time Frame	AEs: from study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening).
Additional Description	No text entered.

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Serious Adverse Events

	Treatment A	Treatment B	Treatment C	Treatment D
Total, serious adverse events
# participants affected / at risk	0/24 (0.00%)	0/24 (0.00%)	0/23 (0.00%)	0/23 (0.00%)

Other Adverse Events

Time Frame	AEs: from study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening).
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	0%

Reporting Groups

	Description
Treatment A	2.5 mg saxagliptin tablet + metformin 850 mg tablet single dose under fasted condition
Treatment B	Fixed dose combination (FDC) tablet (saxagliptin 2.5 mg + metformin 850 mg) single dose under fasted condition
Treatment C	2.5 mg saxagliptin tablet and metformin 850 mg tablet single dose under fed condition
Treatment D	FDC tablet (2.5 mg saxagliptin + metformin 850 mg) single dose under fed condition

Other Adverse Events

Treatment A

Treatment B

Treatment C

Treatment D

Total, other (not including serious) adverse events

# participants affected / at risk

4/24 (16.67%)

5/24 (20.83%)

3/23 (13.04%)

4/23 (17.39%)

Eye disorders

Vision blurred¹,^†

# participants affected / at risk

0/24 (0.00%)

1/24 (4.17%)

0/23 (0.00%)

Nervous system disorders

Headache¹,^†

# participants affected / at risk

1/24 (4.17%)

0/24 (0.00%)

0/23 (0.00%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/24 (4.17%)

0/23 (0.00%)

1/23 (4.35%)

Nervous system disorders

Presyncope¹,^†

# participants affected / at risk

0/24 (0.00%)

1/24 (4.17%)

0/23 (0.00%)

Gastrointestinal disorders

Nausea¹,^†

# participants affected / at risk

1/24 (4.17%)

0/24 (0.00%)

0/23 (0.00%)

Gastrointestinal disorders

Diarrhoea¹,^†

# participants affected / at risk

1/24 (4.17%)

2/24 (8.33%)

1/23 (4.35%)

3/23 (13.04%)

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

2/24 (8.33%)

1/24 (4.17%)

0/23 (0.00%)

1/23 (4.35%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

0/24 (0.00%)

1/23 (4.35%)

0/23 (0.00%)

Injury, poisoning and procedural complications

Muscle strain¹,^†

# participants affected / at risk

1/24 (4.17%)

0/24 (0.00%)

0/23 (0.00%)

Musculoskeletal and connective tissue disorders

Arthralgia¹,^†

# participants affected / at risk

1/24 (4.17%)

0/24 (0.00%)

0/23 (0.00%)

Musculoskeletal and connective tissue disorders

Synovial cyst¹,^†

# participants affected / at risk

0/24 (0.00%)

1/24 (4.17%)

0/23 (0.00%)

General disorders and administration site conditions

Fatigue¹,^†

# participants affected / at risk

0/24 (0.00%)

1/23 (4.35%)

General disorders and administration site conditions

Vessel puncture site pain¹,^†

# participants affected / at risk

0/24 (0.00%)

1/24 (4.17%)

0/23 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 12.1
2	Term from vocabulary,

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days . The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period of <= 60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trail's primary publication.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact

Name/Title:	Boaz Hirschberg
Organization:	AstraZeneca Pharmaceuticals
E-mail:	[email protected]

Documents available

BMS Clinical Trials Disclosure
Download
Investigator Inquiry form
Download
For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Bristol-Myers Squibb

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

PPD Development, LP

BMS Clinical Trials Disclosure

Investigator Inquiry form

For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm

Trial Results Summaries