Bioequivalence Study of the Fixed Dose Combination of 5 mg Saxagliptin and 500 mg Metformin XR Tablet (Manufactured in Mt Vernon, IN) Relative to 5 mg Saxagliptin Tablet and 500 mg Metformin XR Tablet (Manufactured in Evansville, IN)

This study has been completed.

Sponsor:

Information provided by:

Bristol-Myers Squibb

ClinicalTrials.gov Identifier:

NCT01192139

First received: August 30, 2010

Last updated: April 19, 2011

Last verified: April 2011

History of Changes

Results First Received: March 11, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Bio-equivalence Study; Intervention Model: Crossover Assignment; Masking: Open Label
Condition:	Diabetes Mellitus
Interventions:	Drug: saxagliptin Drug: metformin XR Drug: saxagliptin + metformin XR (FDC tablet)

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants underwent screening evaluations to determine eligibility within 21 days before dosing, and were admitted to the clinical facility the evening before dosing (Day –1). On Day 1 of Period 1, a total of 30 participants who met all of the inclusion and none of the exclusion criteria were randomly assigned to 1 of 6 treatment sequences.

Reporting Groups

	Description
Treatment Sequence ABC	Treatment A (period 1): 5 mg saxagliptin + a single 500 mg metformin XR tablet; Treatment B (period 2): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions; Treatment C (period 3): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions. Participants underwent at least a 3-day washout period between each treatment.
Treatment Sequence ACB	Treatment A (period 1): 5 mg saxagliptin + a single 500 mg metformin XR tablet; Treatment C (period 2): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions; Treatment B (period 3): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions. Participants underwent at least a 3-day washout period between each treatment.
Treatment Sequence BAC	Treatment B (period 1): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions; Treatment A (period 2): 5 mg saxagliptin + a single 500 mg metformin XR tablet; Treatment C (period 3): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions. Participants underwent at least a 3-day washout period between each treatment.
Treatment Sequence BCA	Treatment B (period 1): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions; Treatment C (period 2): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions; Treatment A (period 3): 5 mg saxagliptin + a single 500 mg metformin XR tablet. Participants underwent at least a 3-day washout period between each treatment.
Treatment Sequence CAB	Treatment C (period 1): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions; Treatment A (period 2): 5 mg saxagliptin + a single 500 mg metformin XR tablet; Treatment B (period 3): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions. Participants underwent at least a 3-day washout period between each treatment.
Treatment Sequence CBA	Treatment C (period 1): FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions; Treatment B (period 2): fixed-dose combination (FDC) Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions; Treatment A (period 3): 5 mg saxagliptin + a single 500 mg metformin XR tablet. Participants underwent at least a 3-day washout period between each treatment.

Participant Flow for 3 periods

Period 1: Period 1

	Treatment Sequence ABC	Treatment Sequence ACB	Treatment Sequence BAC	Treatment Sequence BCA	Treatment Sequence CAB	Treatment Sequence CBA
STARTED	5	5	5	5	5	5
COMPLETED	5	5	5	5	5	5
NOT COMPLETED	0	0	0	0	0	0

Period 2: Period 2

	Treatment Sequence ABC	Treatment Sequence ACB	Treatment Sequence BAC	Treatment Sequence BCA	Treatment Sequence CAB	Treatment Sequence CBA
STARTED	5	5	5	5	5	5
COMPLETED	5	5	5	5	5	5
NOT COMPLETED	0	0	0	0	0	0

Period 3: Period 3

	Treatment Sequence ABC	Treatment Sequence ACB	Treatment Sequence BAC	Treatment Sequence BCA	Treatment Sequence CAB	Treatment Sequence CBA
STARTED	5	5	5	5	5	5
COMPLETED	5	5	5	5	5	5
NOT COMPLETED	0	0	0	0	0	0

Baseline Characteristics

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Reporting Groups

	Description
All Enrolled and Treated Participants	No text entered.

Baseline Measures

	All Enrolled and Treated Participants
Number of Participants [units: participants]	30
Age [units: years] Mean ± Standard Deviation	29.1 ± 8.0
Gender [units: participants]
Female	14
Male	16
Race/Ethnicity, Customized [units: participants]
White	17
Black or African American	12
Asian	1
Race/Ethnicity, Customized [units: participants]
Hispanic or Latino	9
Not Hispanic or Latino	21
Height [units: cm] Mean ± Standard Deviation	170.0 ± 9.22
Weight [units: kg] Mean ± Standard Deviation	78.31 ± 13.74
Body Mass Index [units: kg/m^2] Mean ± Standard Deviation	26.97 ± 3.07

Outcome Measures

Show All Outcome Measures

1. Primary:

Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 1

2. Primary:

Saxagliptin Observed Maximum Plasma Concentration (Cmax) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 2

3. Primary:

Metformin AUC(0-inf) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 3

4. Primary:

Metformin Cmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 4

5. Secondary:

Saxagliptin Terminal Half-life (T1/2) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 5

6. Secondary:

Saxagliptin 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, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 6

7. Secondary:

Time to Achieve the Observed Maximum Saxagliptin Plasma Concentration (Tmax) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 7

8. Secondary:

Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 8

9. Secondary:

Active Metabolite BMS-510849 AUC(0-inf) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 9

10. Secondary:

Active Metabolite BMS-510849 AUC(0-t) [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 10

11. Secondary:

Active Metabolite BMS-510849 Cmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 11

12. Secondary:

Active Metabolite BMS-510849 T1/2 [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 12

13. Secondary:

Active Metabolite BMS-510849 Tmax [ Time Frame: Periods 1, 2, and 3 (samples taken before dosing, and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 13

14. Secondary:

Active Metabolite BMS-510849 AUC(0-t)/AUC(0-inf) [ Time Frame: Period 1 (samples taken before dosing, and at 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]

Show Outcome Measure 14

15. Secondary:

Metformin AUC(0-t) [ Time Frame: Period 1 (samples taken before dosing, and at 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]

Show Outcome Measure 15

16. Secondary:

Metformin T1/2 [ Time Frame: Period 1 (before dosing, 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]

Show Outcome Measure 16

17. Secondary:

Metformin Tmax [ Time Frame: Periods 1, 2, and 3 (before dosing, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, 24, 36 and 48 hours after dosing) ]

Show Outcome Measure 17

18. Secondary:

Metformin Fraction of AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) [ Time Frame: Period 1 (before dosing, 0.167,0.25,0.5,0.75,1,1.5,2,3,4,5,6,7,8,10,12,18,24,36 and 48 hours after dosing) ]

Show Outcome Measure 18

19. Secondary:

Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) [ Time Frame: AEs: from initiation of study drug administration on Day 1/Period 1 through study discharge Day 3/Period 3. SAEs: from date of written consent until 30 days after discontinuation of dosing or participation in study if last scheduled visit occurred later. ]

Show Outcome Measure 19

20. Secondary:

Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and Electrocardiogram (ECG) Abnormalities [ Time Frame: From Day 1 of Period 1 through Day 3 of Period 3 (study discharge) ]

Show Outcome Measure 20

Serious Adverse Events

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Other Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	3%

Reporting Groups

	Description
Treatment A	5 mg saxagliptin tablet + a single 500 mg metformin XR tablet under fed conditions
Treatment C	FDC Tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fasting conditions
Treatment B	Fixed-dose combination (FDC) tablet (5 mg Saxagliptin + 500 mg Metformin XR) under fed conditions

Other Adverse Events

	Treatment A	Treatment C	Treatment B
Total, other (not including serious) adverse events
# participants affected / at risk	3/30	4/30	2/30
Gastrointestinal disorders
NAUSEA ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	0/30 (0.00%)
DIARRHOEA ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	1/30 (3.33%)
DRY MOUTH ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	0/30 (0.00%)
FLATULENCE ^{† 1}
# participants affected / at risk	0/30 (0.00%)	0/30 (0.00%)	1/30 (3.33%)
CHAPPED LIPS ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	0/30 (0.00%)
CONSTIPATION ^{† 1}
# participants affected / at risk	0/30 (0.00%)	0/30 (0.00%)	1/30 (3.33%)
LIP SWELLING ^{† 1}
# participants affected / at risk	1/30 (3.33%)	0/30 (0.00%)	0/30 (0.00%)
ABDOMINAL DISTENSION ^{† 1}
# participants affected / at risk	0/30 (0.00%)	0/30 (0.00%)	1/30 (3.33%)
Musculoskeletal and connective tissue disorders
BACK PAIN ^{† 1}
# participants affected / at risk	1/30 (3.33%)	1/30 (3.33%)	0/30 (0.00%)
Nervous system disorders
HEADACHE ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	1/30 (3.33%)
PRESYNCOPE ^{† 1}
# participants affected / at risk	0/30 (0.00%)	1/30 (3.33%)	0/30 (0.00%)
Renal and urinary disorders
DYSURIA ^{† 1}
# participants affected / at risk	1/30 (3.33%)	0/30 (0.00%)	0/30 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 12.0

More Information

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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 ≤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 trial'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: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com

No publications provided by Bristol-Myers Squibb

Publications automatically indexed to this study:

Boulton DW, Smith CH, Li L, Huang J, Tang A, LaCreta FP. Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31(9):619-30.

Responsible Party:	Study Director, Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT01192139 History of Changes
Other Study ID Numbers:	CV181-111
Study First Received:	August 30, 2010
Results First Received:	March 11, 2011
Last Updated:	April 19, 2011
Health Authority:	United States: Food and Drug Administration

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