Bioequivalence Study of 2.5-mg Saxagliptin and 500-mg Glucophage in Tablets and a Fixed-dose Combination Tablet in Healthy Participants

This study has been completed.

Sponsor:

Collaborator:

AstraZeneca

Information provided by (Responsible Party):

Bristol-Myers Squibb

ClinicalTrials.gov Identifier:

NCT01068717

First received: February 12, 2010

Last updated: November 1, 2011

Last verified: November 2011

History of Changes

Results First Received: August 10, 2011

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Bio-equivalence Study; Intervention Model: Crossover Assignment; Masking: Open Label
Condition:	Type 2 Diabetes Mellitus
Interventions:	Drug: Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state) Drug: Saxagliptin, 2.5 mg /Metformin, 500 mg FDC (fasted state) Drug: Saxagliptin, 2.5 mg + Metformin, 500 mg (fed state) Drug: Saxagliptin, 2.5 mg /Metformin, 500 mg FDC (fed state)

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
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
A total of 27 participants were enrolled and randomly assigned to 1 of 4 treatment sequences: ADBC, BACD, CBDA, or DCAB. One participant withdrew from the study on Day –1 of Period 2 due to a family emergency and returned for early termination assessments on Day 4 of Period 2. She did not receive study drug in Period 2.

Reporting Groups

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

Participant Flow for 4 periods

Period 1: Period 1: Treatment Schedule Phase 1

	Treatment Schedule ADBC	Treatment Schedule BACD	Treatment Schedule CBDA	Treatment Schedule DCAB
STARTED	7	6	7	7
COMPLETED	6 ^[1]	6	7	7
NOT COMPLETED	1	0	0	0
Patient withdrew; returned for period 3	1	0	0	0

[1]	Patient who withdrew returned for Treatment Periods 3 and 4.

Period 2: Period 2: Treatment Schedule Phase 2

	Treatment Schedule ADBC	Treatment Schedule BACD	Treatment Schedule CBDA	Treatment Schedule DCAB
STARTED	6	6	7	7
COMPLETED	6	6	7	7
NOT COMPLETED	0	0	0	0

Period 3: Period 3: Treatment Schedule Phase 3

	Treatment Schedule ADBC	Treatment Schedule BACD	Treatment Schedule CBDA	Treatment Schedule DCAB
STARTED	7 ^[1]	6	7	7
COMPLETED	7	6	7	7
NOT COMPLETED	0	0	0	0

[1]	Patient who withdrew during Treatment Period 1 returned for Treatment Periods 3 and 4.

Period 4: Period 4: Treatment Schedule Phase 4

	Treatment Schedule ADBC	Treatment Schedule BACD	Treatment Schedule CBDA	Treatment Schedule DCAB
STARTED	7 ^[1]	6	7	7
COMPLETED	7	6	7	7
NOT COMPLETED	0	0	0	0

[1]	Patient who withdrew during Treatment Period 1 returned for Treatment Periods 3 and 4.

Baseline Characteristics

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Reporting Groups

	Description
All Treated	All participants who received study medication.

Baseline Measures

	All Treated
Number of Participants [units: participants]	27
Age, Customized [units: years] Mean ± Standard Deviation	33.6 ± 7.42
Age, Customized [units: Years] Median ( Full Range )	32 ( 23 to 49 )
Gender [units: participants]
Female	13
Male	14
Ethnicity (NIH/OMB) [units: participants]
Hispanic or Latino	8
Not Hispanic or Latino	19
Unknown or Not Reported	0
Race/Ethnicity, Customized [units: Participants]
Black or African American	5
White	22

Outcome Measures

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1. Primary:

Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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Measure Type	Primary
Measure Title	Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States
Measure Description	No text entered.
Time Frame	Days 1, 2, and 3 of Periods 1, 2, 3, and 4
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 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.

Reporting Groups

	Description
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.
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.
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.
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.

Measured Values

	Treatment A: Saxagliptin and Metformin Tablets, Fasted	Treatment B: Saxagliptin and Metformin FDC, Fasted	Treatment C: Saxagliptin and Metformin Tablets, Fed	Treatment D: Saxagliptin and Metformin FDC, Fed
Number of Participants Analyzed [units: participants]	27	26	26	26
Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States [units: ng/mL] Geometric Mean ( Geometric Coefficient of Variation )	10.54 ( 26% )	11.53 ( 26% )	12.71 ( 36% )	12.79 ( 37% )

Statistical Analysis 1 for Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States

Groups ^[1]	Treatment A: Saxagliptin and Metformin Tablets, Fasted vs. Treatment B: Saxagliptin and Metformin FDC, Fasted
Non-Inferiority/Equivalence Test ^[2]	Yes
Ratio geometric least squares (LS) mean ^[3]	109.53
90% Confidence Interval	( 102.67 to 116.85 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	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.
[3]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Observed Maximum Plasma Concentration (Cmax) of Saxagliptin, Tablets and Fixed-dose Combination (FDC), Administered to Participants in the Fasted and Fed States

Groups ^[1]	Treatment C: Saxagliptin and Metformin Tablets, Fed vs. Treatment D: Saxagliptin and Metformin FDC, Fed
Non-Inferiority/Equivalence Test ^[2]	Yes
Ratio geometric LS mean ^[3]	100.37
90% Confidence Interval	( 85.70 to 117.56 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	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.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	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.
[3]	Other relevant estimation information:
	No text entered.

2. Primary:

Observed Cmax of Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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3. Primary:

Terminal Half-life (t1/2) of Saxagliptin and Metformin, Tablets and FDC, Administered to Participants in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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4. 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 [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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5. Primary:

AUC[0-t] for Metformin, Tablets and FDC, Given in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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6. Primary:

AUC From Time 0 Extrapolated to Infinity (AUC[0-inf]) for Saxagliptin, Tablets and FDC, Given in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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7. Primary:

AUC[0-inf] for Metformin, Tablets and FDC, Administered in the Fasted and Fed States [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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8. 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 [ Time Frame: Days 1, 2, and 3 of Periods 1, 2, 3, and 4 ]

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9. Secondary:

Number of Participants With Death as Outcome, Serious Adverse Events, and Adverse Events (AEs) Leading to Discontinuation [ Time Frame: Continuously over Days 1 to 3 of treatment Periods 1, 2, 3, and 4 ]

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10. Secondary:

Number of Participants With Clinically Significant Abnormalities in Hematology, Serum Chemistry, and Urinalysis Laboratory Test Results [ Time Frame: At screening visit, at Day -1 of Periods 1 through 4, and at discharge ]

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11. Secondary:

Number of Participants With Clinically Significant Abnormalities in Electrocardiogram (ECG) Results [ Time Frame: At screening visit, Day -1 of Period 1, and at study discharge ]

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12. Secondary:

Number of Participants With Clinically Significant Abnormalities in Body Temperature, Blood Pressure, or Heart Rate [ Time Frame: At screening visit, prior to dosing on Day 1 of Periods 1 through 4, and at study discharge. ]

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Serious Adverse Events

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Other Adverse Events

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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

Responsible Party:	Bristol-Myers Squibb
ClinicalTrials.gov Identifier:	NCT01068717 History of Changes
Other Study ID Numbers:	CV181-118
Study First Received:	February 12, 2010
Results First Received:	August 10, 2011
Last Updated:	November 1, 2011
Health Authority:	United States: Food and Drug Administration

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