Bioequivalence Study of 2.5-mg Saxagliptin and 500-mg Glu... | NCT01068717

Bioequivalence Study of 2.5-mg Saxagliptin and 500-mg Glu... | NCT01068717 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state)	Other	Single oral doses of saxagliptin, 2.5 mg, and metformin, 500 mg, administered together as tablets in the fasted state	Drug: Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state)
Saxagliptin, 2.5 mg/Metformin, 500 mg FDC (fasted state)	Other	Single oral dose of a 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) tablet administered in the fasted state	Drug: Saxagliptin, 2.5 mg /Metformin, 500 mg FDC (fasted state)
Saxagliptin, 2.5 mg + Metformin, 500 mg (fed state)	Other	Single oral doses of saxagliptin, 2.5 mg, and metformin, 500 mg, administered together as tablets in the fed state	Drug: Saxagliptin, 2.5 mg + Metformin, 500 mg (fed state)
Saxagliptin, 2.5 mg/Metformin, 500 mg FDC (fed state)	Other	Single oral dose of saxagliptin, 2.5 mg/metformin, 500 mg, FDC tablet administered in the fed state	Drug: Saxagliptin, 2.5 mg /Metformin, 500 mg FDC (fed state)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state)	Drug	Tablets, oral, 2.5-mg saxagliptin and 500-mg metformin, once daily, 1 week	Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
Observed Cmax of Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
Terminal Half-life (t1/2) of Saxagliptin and Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC[0-t]) for Saxagliptin, Tablets and FDC, Given in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
AUC[0-t] for Metformin, Tablets and FDC, Given in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
AUC From Time 0 Extrapolated to Infinity (AUC[0-inf]) for Saxagliptin, Tablets and FDC, Given in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
AUC[0-inf] for Metformin, Tablets and FDC, Administered in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4
Time to Achieve the Observed Maximum Plasma Concentration (Tmax) for Saxagliptin and Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States		Days 1, 2, and 3 of Periods 1, 2, 3, and 4

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Death as Outcome, Serious Adverse Events, and Adverse Events (AEs) Leading to Discontinuation	An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

Contacts/Locations Module

Name	Affiliation	Role
Bristol-Myers Squibb	Bristol-Myers Squibb	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Ppd Development, Lp		Austin	Texas	78744	United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Treatment Schedule ADBC	(Treatment A) A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period. Then, (Treatment D) a single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) in the fasted state, followed by a 7-day (minimum) washout period. Then, (Treatment B) a single oral dose of 2.5-mg saxagliptin/500-mg metformin FDC in the fasted state, followed by a 7-day (minimum) washout period. Then, (Treatment C) a single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fed state.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Period 2: Treatment Schedule Phase 2

Type	Comment	Milestone Data
STARTED		FG0006 subjects FG0016 subjects FG0027 subjects FG0037 subjects
COMPLETED		FG0006 subjects FG0016 subjects FG0027 subjects FG0037 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects

Period 3: Treatment Schedule Phase 3

Type	Comment	Milestone Data
STARTED		FG0007 subjectsPatient who withdrew during Treatment Period 1 returned for Treatment Periods 3 and 4. FG0016 subjects FG0027 subjects FG0037 subjects
COMPLETED		FG0007 subjects FG0016 subjects FG0027 subjects FG0037 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects

Period 4: Treatment Schedule Phase 4

Type	Comment	Milestone Data
STARTED		FG0007 subjectsPatient who withdrew during Treatment Period 1 returned for Treatment Periods 3 and 4. FG0016 subjects FG0027 subjects FG0037 subjects
COMPLETED		FG0007 subjects FG0016 subjects FG0027 subjects FG0037 subjects
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0030 subjects

ID	Title	Description
BG000	All Treated	All participants who received study medication.

Units	Counts
Participants	BG00027

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Customized

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00033.6± 7.42

Age, Customized

Median

Full Range

Years

Title

Denominators

Categories

Title	Measurements
	BG00032(23 to 49)

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00013
Male	BG00014

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0008
Not Hispanic or Latino	BG00019

Race/Ethnicity, Customized

Number

Participants

Title

Denominators

Categories

Black or African American

Title	Measurements
	BG0005

White

Title	Measurements
	BG000

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States

All participants who received at least 1 of the 4 treatments and had sufficient plasma concentration data to facilitate the calculation of at least 1 primary pharmacokinetic parameter for at least 1 of the treatments.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin and Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin and Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin and Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.
OG003	Treatment D: Saxagliptin and Metformin FDC, Fed	A single oral dose of 2.5-mg saxagliptin/500-mg metformin FDC administered in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Units	Counts
Participants	OG00027 OG00126 OG00226 OG003

Title

Denominators

Categories

Title	Measurements
	OG00010.54± 26 OG00111.53± 26 OG00212.71± 36 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric least squares (LS) mean	109.53			2-Sided	90	102.67	116.85				Yes	Non-Inferiority or Equivalence

Primary

Observed Cmax of Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin and Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin and Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin and Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

Terminal Half-life (t1/2) of Saxagliptin and Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States

Posted

Mean

Standard Deviation

Hours

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC[0-t]) for Saxagliptin, Tablets and FDC, Given in the Fasted and Fed States

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin and Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin and Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin and Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Secondary

Number of Participants With Death as Outcome, Serious Adverse Events, and Adverse Events (AEs) Leading to Discontinuation

An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have a causal relationship with treatment. An SAE is any unfavorable medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency or abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

All enrolled participants who received study medication.

Posted

Number

Participants

Continuously over Days 1 to 3 of treatment Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed

Secondary

Number of Participants With Clinically Significant Abnormalities in Hematology, Serum Chemistry, and Urinalysis Laboratory Test Results

Clinically significant was determined by the investigator. Hematology tests included hemoglobin, hematocrit, red blood cell count, total leukocyte count (including differential), and platelet count. Serum chemistry tests included aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, lactate dehydrogenase, creatinine, blood urea nitrogen, uric acid, fasting glucose, total protein, albumin, sodium, potassium, chloride, calcium, phosphorus, and creatine kinase. Urinalysis included protein, glucose, blood, leukocyte esterase, specific gravity, and pH.

All enrolled participants who received study medication.

Posted

Number

Participants

At screening visit, at Day -1 of Periods 1 through 4, and at discharge

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002

Secondary

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Results

Clinically significant was determined by the investigator. ECGs were recorded after participants had been supine for at least 5 minutes.

All enrolled participants who received study medication.

Posted

Number

Participants

At screening visit, Day -1 of Period 1, and at study discharge

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Secondary

Number of Participants With Clinically Significant Abnormalities in Body Temperature, Blood Pressure, or Heart Rate

Clinically significant was determined by the investigator. Blood pressure and heart rate were measured after the participant had been seated quietly for at least 5 minutes.

All enrolled participants who received study medication.

Posted

Number

Participants

At screening visit, prior to dosing on Day 1 of Periods 1 through 4, and at study discharge.

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

AUC[0-t] for Metformin, Tablets and FDC, Given in the Fasted and Fed States

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin and Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin and Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin and Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

AUC From Time 0 Extrapolated to Infinity (AUC[0-inf]) for Saxagliptin, Tablets and FDC, Given in the Fasted and Fed States

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

AUC[0-inf] for Metformin, Tablets and FDC, Administered in the Fasted and Fed States

Posted

Geometric Mean

Geometric Coefficient of Variation

ng*h/mL

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Primary

Time to Achieve the Observed Maximum Plasma Concentration (Tmax) for Saxagliptin and Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States

Posted

Median

Full Range

Hours

Days 1, 2, and 3 of Periods 1, 2, 3, and 4

ID	Title	Description
OG000	Treatment A: Saxagliptin + Metformin Tablets, Fasted	A single oral dose of saxagliptin, 2.5-mg and metformin 500-mg tablets administered together in the fasted state, followed by a 7-day (minimum) washout period.
OG001	Treatment B: Saxagliptin/Metformin FDC, Fasted	A single oral dose of 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) administered in the fasted state, followed by a 7-day (minimum) washout period.
OG002	Treatment C: Saxagliptin + Metformin Tablets, Fed	A single oral dose of saxagliptin 2.5-mg and metformin 500-mg tablets administered together in the morning within 5 minutes of completing a standard high-fat, high-calorie breakfast (fed state), followed by a 7-day (minimum) washout period.

Arm/Groups

ID	Title	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Fasted: 2.5mg Onglyza + 500mg Glucophage	27	2	27
EG001	Fasted: 2.5mg Saxa/500mg Metformin FDC	26	1	26
EG002	Fed: 2.5mg Onglyza + 500mg Glucophage	26	7	26
EG003	Fed: 2.5mg Saxa/500mg Metformin FDC	26	4	26

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Asthenopia	Eye disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG0030 affected26 at risk
Abnormal dreams	Psychiatric disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Headache	Nervous system disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0022 affected26 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0001 affected27 at risk EG0010 affected26 at risk EG0022 affected26 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0001 affected27 at risk EG0010 affected26 at risk EG0020 affected26 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0023 affected26 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Eructation	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0020 affected26 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Bowel movement irregularity	Gastrointestinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0011 affected26 at risk EG0020 affected26 at risk EG003
Hidradenitis	Skin and subcutaneous tissue disorders	MedDRA 12.1	Systematic Assessment	EG0001 affected27 at risk EG0010 affected26 at risk EG0020 affected26 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0020 affected26 at risk EG003
Vessel puncture site pain	General disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003
Venipuncture site inflammation	General disorders	MedDRA 12.1	Systematic Assessment	EG0000 affected27 at risk EG0010 affected26 at risk EG0021 affected26 at risk EG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states					Ratio geometric LS mean	99.02			2-Sided	90	91.29	107.41				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.
OG002 OG003	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	100.21			2-Sided	90	96.86	103.67				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.

Title

Denominators

Categories

t1/2 saxagliptin

Title	Measurements
	OG0006.16± 1.06 OG0016.69± 0.90 OG0025.99± 0.91 OG0036.15± 0.79

t1/2 metformin

Title	Measurements
	OG00011.05± 3.94 OG00113.02± 5.37 OG00210.72± 2.61 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	102.34			2-Sided	90	97.96	106.91				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.
OG002 OG003	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	99.78			2-Sided	90	96.61	103.05				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.

Title

Denominators

Categories

Death

Title	Measurements
	OG0000 OG0010 OG0020 OG0030

Serious Adverse Events

Title	Measurements
	OG0000 OG0010 OG0020 OG003

AEs Leading to Discontinuation

Title	Measurements
	OG0000 OG0010 OG0020 OG003

Title

Denominators

Categories

Hematology test results

Title	Measurements
	OG0000 OG0010 OG0020 OG0030

Serum chemistry test results

Title	Measurements
	OG0000 OG0010 OG0020 OG003

Urinalysis results

Title	Measurements
	OG0000 OG0010 OG0020 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	102.34			2-Sided	90	97.96	106.91				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.
OG002 OG003	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	101.82			2-Sided	90	96.10	107.88				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio (%) of geometric LS mean	102.64			2-Sided	90	98.31	107.16				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.
OG002 OG003	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio (%) of geometric LS mean	99.22				90	96.48	102.04				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	99.04			2-Sided	95	92.90	105.59				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.
OG002 OG003	To demonstrate the bioequivalence of FDC tablet versus coadministration of saxagliptin and metformin tablets in the fasted and fed states, linear mixed model analyses were performed on log(Cmax), log[AUC(INF)], and log[AUC(0-T)] of saxagliptin and metformin, respectively. The factors in the model were sequence, period, and treatment as fixed effects and measurements within each subject as repeated measurements allowing for different covariance structures for the fasted and fed states.					Ratio geometric LS mean	102.77			2-Sided	95	96.82	109.09				Yes	Non-Inferiority or Equivalence	Point estimates and 90% confidence intervals (CIs) were calculated for Treatment B to Treatment A and Treatment D to Treatment C ratios of geometric means for Cmax, AUC(INF), and AUC(0-T) of saxagliptin and metformin, respectively. Potency-corrected results were also provided. Bioequivalence will be concluded if the 90% CIs for the test-to-reference ratios of geometric means are entirely contained within 80% to 125% for both Cmax and AUC(INF). No adjustments were made for multiplicity.

Title

Denominators

Categories

Tmax saxagliptin

Title	Measurements
	OG0001.00(0.25 to 3.00) OG0010.75(0.30 to 4.00) OG0021.50(0.50 to 8.00) OG0031.00(0.50 to 3.00)

Tmax metformin

Title	Measurements
	OG0003.00(0.50 to 4.00) OG0013.00(1.00 to 6.00) OG0024.00(2.00 to 6.00) OG003

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
D001645	Biguanides
D006146	Guanidines
D000578	Amidines
D009930	Organic Chemicals