Bioequivalence Study of Fixed-dose Combinations and Coadm... | NCT01365091

Bioequivalence Study of Fixed-dose Combinations and Coadm... | NCT01365091 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm 1: Treatments A,B/B,A	Experimental	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A).	Drug: Saxagliptin/metformin fixed-dose combination (FDC) Drug: Saxagliptin Drug: Metformin extended-release (XR)
Arm 2: Treatments C,D/D,C	Experimental	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metforminXR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fed state (Treatment C).	Drug: Saxagliptin/metformin fixed-dose combination (FDC) Drug: Saxagliptin Drug: Metformin extended-release (XR)
Arm 3: Treatments E, F/F,E	Experimental	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fasted state (Treatment E), followed by a washout period of at least 7 days. Participants received single oral doses of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fasted state (Treatment F). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5- mg and metformin XR, 1000-mg tablets together in the fasted state (Treatment F), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fasted state (Treatment E).

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Saxagliptin/metformin fixed-dose combination (FDC)	Drug	Tablet, oral, 5 mg/500 mg FDC, once on Day 1 only, 1 day	Arm 1: Treatments A,B/B,A Arm 2: Treatments C,D/D,C

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Maximum Observed Concentrations (Cmax) of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets		Days 1, 2, and 3 of Periods 1 and 2
AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets	AUC=Area under the concentration-time curve	Days 1, 2, and 3 of Periods 1 and 2
AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) for Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets	AUC=Area Under the Concentration-time Curve	Days 1, 2, and 3 of Periods 1 and 2

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Death as Outcome and Serious Adverse Events (SAEs)	SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.	Continuously, from screening through Day 1 to within 30 days of drug discontinuation on Day 1

Contacts/Locations Module

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

Facility	Status	City	State	ZIP	Country	Contacts
Local Institution		Campinas	São Paulo	13073	Brazil

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Arm 1: Treatments A/B, B/A	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A).

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Adverse Event		FG0001 subjects FG0010 subjects FG0022 subjects FG0033 subjects
Positive test result for drugs of abuse		FG0001 subjects FG0010 subjects FG0020 subjects FG0030 subjects
No longer met study criteria		FG0000 subjects FG0011 subjects FG0020 subjects FG0030 subjects
Withdrawal by Subject		FG0000 subjects FG0011 subjects FG0020 subjects FG0030 subjects
Personal reasons		FG0000 subjects FG0010 subjects FG0021 subjects FG0030 subjects

Period 2

Type	Comment	Milestone Data
STARTED		FG00026 subjects FG00126 subjects FG00225 subjects FG00325 subjects
COMPLETED		FG00025 subjects FG00126 subjects FG00224 subjects FG00325 subjects
NOT COMPLETED		FG0001 subjects FG0010 subjects FG0021 subjects FG0030 subjects

Type	Comment	Reasons
Withdrawal by Subject		FG0001 subjects FG0010 subjects FG0020 subjects FG003

Arm/Group Information

ID	Title	Description
BG000	Arm 1: Treatments A/B, B/A	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A).
BG001	Arm 2: Treatments C/D, D/C	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metforminXR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fed state (Treatment C).
BG002	Arm 3:Treatments E/ F, F/E	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fasted state (Treatment E), followed by a washout period of at least 7 days. Participants received single oral doses of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fasted state (Treatment F). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5- mg and metformin XR, 1000-mg tablets together in the fasted state (Treatment F), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fasted state (Treatment E).
BG003	Arm 4: Treatments G/ H, H/G	Period 1: Participants received a single oral dose of saxagliptin , 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fed state (Treatment G), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fed state (Treatment H). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fed state (Treatment H), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fed state (Treatment G).
BG004	Total	Total of all reporting groups

Units	Counts
Participants	BG00028 BG00128 BG00228 BG00328 BG004112

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Customized

Number

Participants

Title

Denominators

Categories

<=18 years

Title	Measurements
	BG0000 BG0010 BG0020 BG003

Sex/Gender, Customized

The clinical study report (CSR) stated only that participants of both genders were enrolled. The CSR did not report the number of each gender enrolled.

Number

Participants

Title

Denominators

Categories

Both genders

Title	Measurements
	BG00028 BG00128

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

Maximum Observed Concentrations (Cmax) of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets

Participants who received study medication and were evaluable

Posted

Mean

Standard Deviation

μg/mL

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

ID	Title	Description
OG000	Sax, 5 mg/Met 500 mg XR FDC vs Individual Tablets, Fasted	Arm 1: Treatments A, B/B, A. Period 1: Participants received a single oral dose of saxagliptin (sax), 5-mg/metformin (met), 500-mg extended-release (XR) fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500-mg FDC, in the fasted state (Treatment A).
OG001	Sax, 5 mg/Met 500 mg vs FDC to Individual Tablets, Fed	Arm 2: Treatment C, D/D, C. Period 1: Participants received a single oral dose of saxagliptin (sax) 5-mg/metformin (met) 500-mg, extended-release (XR) fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg/metformin, 500-mg XR FDC, in the fed state (Treatment C).
OG002	Sax, 5 mg/Met 1000 mg XR FDC to Individual Tablets, Fasted	Arm 3: Treatment E, F/F, G. Period 1: Participants received a single oral dose of saxagliptin (sax), 5-mg/metformin (met), 1000-mg extended-release (XR) fixed-dose combination (FDC), in the fasted state (Treatment E), followed by a washout period of at least 7 days. Participants received single oral doses of saxagliptin, 5-mg, and metformin XR, 1000-mg tablets, together in the fasted state (Treatment F). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fasted state (Treatment F), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg/metformin, 1000-mg FDC, in the fasted state (Treatment E).
OG003	Sax, 5 mg/Met 1000 mg XR FDC to Individual Tablets, Fed	Arm 4: Treatments G,H/H,G. Period 1: Participants received a single oral dose of saxagliptin (sax), 5-mg/metformin (met), 1000-mg extended-release (XR) fixed-dose combination (FDC), in the fed state (Treatment G), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fed state (Treatment H). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fed state (Treatment H), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg/metformin, 1000-mg FDC, in the fed state (Treatment G).

Units	Counts
Participants	OG00025 OG00126 OG00224 OG003

Title

Denominators

Categories

Metformin Cmax (individual tablet)

Title	Measurements
	OG000713± 176(87.618 to 103.446) OG001654± 118(82.368 to 94.419) OG0021177± 399

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		ANCOVA				Geometric mean ratio	95.204			2-Sided	90	87.618	103.446			Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 1: The corresponding power and coefficient of variation between test and reference drugs are 98% and 17.24%, respectively

Primary

AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets

AUC=Area under the concentration-time curve

Participants who received study medication and were evaluable

Posted

Mean

Standard Deviation

pg*h/mL

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

ID	Title	Description
OG000	Sax, 5 mg/Met, 500 mg: Sax, 5 mg/Met, 500 mg FDC Fasting	Arm 1: Treatments A, B/B, A. Period 1: Participants received a single oral dose of saxagliptin (sax), 5-mg/metformin (met), 500-mg extended-release (XR) fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500-mg FDC, in the fasted state (Treatment A).
OG001	Sax, 5 mg/Met, 500 mg: Sax, 5 mg/Met 500 mg FDC Fed	Arm 2: Treatment C, D/D, C. Period 1: Participants received a single oral dose of saxagliptin (sax) 5-mg/metformin (met) 500-mg, extended-release (XR) fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg/metformin, 500-mg XR FDC, in the fed state (Treatment C).

Secondary

Number of Participants With Death as Outcome and Serious Adverse Events (SAEs)

SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

All enrolled participants who receive study medication

Posted

Number

Participants

Continuously, from screening through Day 1 to within 30 days of drug discontinuation on Day 1

ID	Title	Description
OG000	Arm 1: Treatments A,B/B,A	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A).
OG001	Arm 2: Treatments C,D/D,C	Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metforminXR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fed state (Treatment C).

Primary

AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) for Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets

AUC=Area Under the Concentration-time Curve

Participants who received study medication and were evaluable

Posted

Mean

Standard Deviation

ng*h/mL

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

ID	Title	Description
OG000	Sax, 5 mg/Met 500 mg XR FDC to Individual Tablets, Fasted	Arm 1: Treatments A, B/B, A. Period 1: Participants received a single oral dose of saxagliptin (sax), 5-mg/metformin (met), 500-mg extended-release (XR) fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500-mg FDC, in the fasted state (Treatment A).
OG001	Sax, 5 mg/Met 500 mg XR FDC to Individual Tablets, Fed	Arm 2: Treatment C, D/D, C. Period 1: Participants received a single oral dose of saxagliptin (sax) 5-mg/metformin (met) 500-mg, extended-release (XR) fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin XR, 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg/metformin, 500-mg XR FDC, in the fed state (Treatment C).

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Saxagliptin, 5 mg/Metformin XR, 1000 mg Fasting	XR=extended release	28	7	28
EG001	Saxagliptin, 5 mg/Metformin XR, 1000 mg Fed	XR=extended release	28	13	26
EG002	Saxagliptin, 5 mg/Metformin XR, 500 mg Fasting	XR=extended release	28	10	27
EG003	Saxagliptin, 5 mg/Metformin XR, 500 mg Fed	XR=extended release	28	6	26
EG004	Saxagliptin, 5 mg/Metformin, 1000 mg FDC Fasting	FDC=fixed-dose combination	28	8	25
EG005	Saxagliptin, 5 mg/Metformin, 1000 mg FDC Fed	FDC=fixed-dose combination	28	4	27
EG006	Saxagliptin, 5 mg/Metformin, 500 mg FDC Fasting	FDC=fixed-dose combination	28	8	28
EG007	Saxagliptin, 5 mg/Metformin, 500 mg FDC Fed	FDC=fixed-dose combination	28	14	28

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain upper	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected28 at risk EG0010 affected26 at risk EG0020 affected27 at risk EG0030 affected26 at risk EG0041 affected25 at risk EG0051 affected27 at risk EG0060 affected28 at risk EG0070 affected28 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0011 affected26 at risk EG0021 affected27 at risk EG003
White blood cell disorder	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected28 at risk EG0012 affected26 at risk EG0020 affected27 at risk EG003
Dysgeusia	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected28 at risk EG0010 affected26 at risk EG0022 affected27 at risk EG003
Alanine aminotransferase abnormal	Investigations	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0012 affected26 at risk EG0020 affected27 at risk EG003
Headache	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected28 at risk EG0013 affected26 at risk EG00210 affected27 at risk EG003
Aptyalism	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0010 affected26 at risk EG0021 affected27 at risk EG003
Hypertension	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0001 affected28 at risk EG0013 affected26 at risk EG0020 affected27 at risk EG003
Blood creatinine abnormal	Investigations	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0010 affected26 at risk EG0020 affected27 at risk EG003
Dysmenorrhoea	Reproductive system and breast disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0010 affected26 at risk EG0020 affected27 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0002 affected28 at risk EG0010 affected26 at risk EG0022 affected27 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 affected28 at risk EG0010 affected26 at risk EG0020 affected27 at risk EG003
Red blood cell abnormality	Blood and lymphatic system disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0013 affected26 at risk EG0020 affected27 at risk EG003
Flatulence	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 affected28 at risk EG0011 affected26 at risk EG0020 affected27 at risk EG003

Title	Organization	Phone	Extension	Email
Boaz Hirschberg	AstraZeneca Pharmaceuticals			ClinicalTrialTransparency@astrazeneca.com

ID	Term
D003924	Diabetes Mellitus, Type 2

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

ID	Term
C502994	saxagliptin
D008687	Metformin

ID	Term
D001645	Biguanides
D006146	Guanidines
D000578	Amidines
D009930	Organic Chemicals

5-OH Saxagliptin Cmax (individual tablets)

Title	Measurements
	OG00054709± 16816(96.504 to 112.883) OG00152628± 12850(91.470 to 98.714) OG00256444± 14731(96.589 to 108.52) OG00355177± 13751(95.572 to 103.144)

Title

Denominators

Categories

Metformin AUC(0-T) (individual tablets)

Title	Measurements
	OG0005816± 1859(82.596 to 101.380) OG0015071± 821(85.560 to 98.035) OG0028174± 2394(96.956 to 109.407) OG0039628± 3270(85.502 to 101.053)

Metformin AUC(0-T) (FDC)

Title	Measurements
	OG0005386± 1896 OG0014701± 1028 OG0028500± 2713 OG003

Saxagliptin AUC(0-T) (individual tablets)

Title	Measurements
	OG000106070± 26733 OG001110285± 22139 OG002102913± 22067 OG003

Saxagliptin AUC(0-T) (FDC)

Title	Measurements
	OG000103865± 31088 OG001109345± 23947 OG00299215± 20146 OG003

5-OH Saxagliptin AUC(0-T) (individual tablets)

Title	Measurements
	OG000320743± 68176 OG001305354± 53254 OG002324163± 59358 OG003

5-OH Saxagliptin AUC(0-T) (FDC)

Title	Measurements
	OG000331332± 67491 OG001292515± 45404 OG002323039± 56031(96.512 to 103.648) OG003

Group IDs	Statistical Method	Parameter Type	Parameter Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment
OG000	ANCOVA	Geometric mean ratio	91.508	2-Sided	90	82.596	101.380	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 1: The corresponding power and coefficient of variation are 98% and 17.24%, respectively.
OG000	ANCOVA	Geometric mean ratio	97.437	2-Sided	90	93.889	101.119	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 1: The corresponding power and the coefficient of variation are 99% and 07.66%, respectively.
OG000	ANCOVA	Geometric mean ratio	96.770	2-Sided	90	93.350	100.316	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 1: The corresponding power and the coefficient of variation are 99% and 07.43%, respectively.
OG001	ANCOVA	Geometric mean ratio	91.585	2-Sided	90	85.56	98.035	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 2: The corresponding power and the variation coefficient are 96% and 14.37%, respectively.
OG001	ANCOVA	Geometric mean ratio	98.529	2-Sided	90	96.028	101.095	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 2: The corresponding power and the variation coefficient are 96.028% and 101.095%, respectively.
OG001	ANCOVA	Geometric mean ratio	96.239	2-Sided	90	93.286	99.286	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 2: The corresponding power and the variation coefficient are 99% and 6.55%, respectively
OG002	ANCOVA	Geometric mean ratio	102.994	2-Sided	90	96.956	109.407	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 3: The corresponding power and the variation coefficient are 99% and 12.19%, respectively.
OG002	ANCOVA	Geometric mean ratio	97.135	2-Sided	95	93.778	100.613	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 3: The corresponding power and the variation coefficient are 99% and 7.07%, respectively.
OG002	ANCOVA	Geometric mean ratio	100.01	2-Sided	90	96.512	103.648	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 3: The corresponding power and the variation coefficient are 99% and 7.18%, respectively.
OG003	ANCOVA	Geometric mean ratio	92.953	2-Sided	90	85.502	101.053	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 1:The corresponding power and the variation coefficient are 93% and 17.35%, respectively.
OG003	ANCOVA	Geometric mean ratio	101.281	2-Sided	95	98.494	104.147	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 4: The corresponding power and the variation coefficient are 99% and 5.75%, respectively.
OG003	ANCOVA	Geometric mean ratio	100.111	2-Sided	90	97.367	102.932	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 4: The corresponding power and the variation coefficient are 99% and 5.73%, respectively.

Title

Denominators

Categories

Metformin AUC (0-inf) (individual tablets)

Title	Measurements
	OG0005877± 1858 OG0015127± 816 OG0028338± 2414 OG0039731± 3277

Metformin AUC (0-inf) (FDC)

Title	Measurements
	OG0005443± 1905(82.697 to 101.226) OG0014754± 1037(85.573 to 97.939) OG0028618± 2726(96.589 to 108.525) OG003

Saxagliptin AUC (0-inf) (individual tablets)

Title	Measurements
	OG000107425± 26828(93.955 to 101.132) OG001111677± 22315(96.044 to 101.090) OG002104293± 22149(93.832 to 100.662) OG003

Saxagliptin AUC (0-inf) (FDC)

Title	Measurements
	OG000105248± 31314 OG001110705± 24091 OG002100620± 20264 OG003

5-OH Saxagliptin AUC (0-inf) (individual tablets)

Title	Measurements
	OG000337345± 67941(93.393 to 100.247) OG001310983± 53447(93.319 to 99.290) OG002330247± 59863(96.560 to 103.594) OG003

5-OH Saxagliptin AUC (0-inf) (FDC)

Title	Measurements
	OG000326501± 68475 OG001298037± 45636 OG002329085± 56298 OG003

Group IDs	Statistical Method	Parameter Type	Parameter Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment
OG000	ANCOVA	Geometric mean ratio	91.494	2-Sided	90	82.697	101.226	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value).	Yes	Non-Inferiority or Equivalence	For AUC(0-inf) metformin, Arm 1, the corresponding power and coefficient of variation are 80% and 21.06%, respectively.
OG000	ANCOVA	Geometric mean ratio	97.477	2-Sided	90	93.955	101.132	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 1: The corresponding power and the coefficient of variation are 99% and 07.60%, respectively.
OG000	ANCOVA	Geometric mean ratio	96.760	2-Sided	90	93.393	100.247	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value).	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 1. The corresponding power and the coefficient of variation are 99% and 07.31%, respectively.
OG001	ANCOVA	Geometric mean ratio	91.548	2-Sided	90	85.573	97.939	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 2: The corresponding power and the variation coefficient are 96% and 14.25%, respectively.
OG001	ANCOVA	Geometric mean ratio	98.535	2-Sided	95	96.044	101.090	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 2: The corresponding power and the variation coefficient are 99% and 5.38%,respectively.
OG001	ANCOVA	Geometric mean ratio	96.258	2-Sided	95	93.319	99.290	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 2: The corresponding power and the variation coefficient are 99% and 6.52%, respectively.
OG002	ANCOVA	Geometric mean ratio	102.383	2-Sided	95	96.589	108.525	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Metformin, Arm 3: The corresponding power and the variation coefficient are 99% and 11.75%, respectively.
OG002	ANCOVA	Geometric mean ratio	97.187	2-Sided	90	93.832	100.662	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 5: The corresponding power and the variation coefficient are 99% and 7.07%, respectively.
OG002	ANCOVA	Geometric mean ratio	100.015	2-Sided	95	96.560	103.594	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Sarexagliptin, Arm 3: The corresponding power and the variation coefficient are 99% and 7.08%, respectively.
OG002 OG003	ANCOVA	Geometric mean ratio	93.219	2-Sided	90	85.835	101.238		Yes	Non-Inferiority or Equivalence	Metformin, Arm 4: The corresponding power and the variation coefficient are 94% and 17.13%, respectively.
OG003	ANCOVA	Geometric mean ratio	101.346	2-Sided	90	98.574	104.196	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	Saxagliptin, Arm 4: The corresponding power and the variation coefficient are 99% and 5.72%, respectively.
OG003	ANCOVA	Geometric mean ratio	100.056	2-Sided	90	97.324	102.864	Geometric mean ratio is calculated as B/A, where A=individual tablets (reference value) and B=FDC (test value)	Yes	Non-Inferiority or Equivalence	5-OH Saxagliptin, Arm 4: The corresponding power and the variation coefficient are 99% and 5.71%, respectively.