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)

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate bioequivalence (BE) of a 5 mg saxagliptin/500 mg metformin extended release (XR) fixed-dose combination (FDC) tablet (manufactured in Mt Vernon, Indiana [IN]) to coadministered 5 mg saxagliptin and 500 mg metformin XR tablet (manufactured in Evansville, IN) in fed healthy subjects.

Detailed Description
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This study is designed to evaluate if the FDC tablet of 5 mg saxagliptin/500 mg metformin extended release (manufactured in Mt Vernon, Indiana) is bioequivalent to the coadministered 5 mg saxagliptin and 500 mg metformin XR tablet (manufactured in Evansville, Indiana)

Official Title
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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) Coadministered to Healthy Subjects in a Fed Condition

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: saxagliptin
* Drug: metformin XR
* Drug: saxagliptin + metformin XR (FDC tablet)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and female subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiogram (ECG), and clinical laboratory determinations Body Mass Index (BMI) of 18 to 32 kg/m2, inclusive Ages 18 to 45, inclusive Exclusion Criteria: Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations beyond what is consistent with the target population Major surgical procedure within 4 weeks prior to randomization Positive serology test for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) Clinically significant history or presence of any of the following conditions: heart, liver, or kidney disease, neurologic or psychiatric disease History of gastrointestinal disease within the past 3 months Any clinically significant medical condition that could potentially affect your participation in the study and/or personal well-being, as judged by the investigator Donated blood or blood products to a blood bank, blood transfusion or participated in a clinical study (except a screening visit) requiring withdrawal of blood within 4 weeks prior to randomization Unable to tolerate oral and/or intravenous (IV) medications Unable to tolerate the puncturing of veins for drawing of blood Known allergy or hypersensitivity to any component of the study medication History of any significant drug allergies (such as anaphylaxis or hepatotoxicity) Used any prescription drugs or over the counter products to control acid (for example, Prevacid, Mylanta or Rolaids) within 4 weeks prior to randomization Used any other drugs including over the counter medications and herbal preparations within 1 week prior to randomization Taken any investigational drug or placebo (inactive drug) within 4 weeks prior to randomization

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 mg saxagliptin + a single 500 mg metformin XR tablet<br> | Drug: saxagliptin<br>* Tablets, Oral, 5 mg, once daily, Single dose<br>* Other names: Onglyza;Drug: metformin XR<br>* Tablets, Oral, 500 mg. once daily, Single dose<br>* Other names: Glucophage XR;|
| Experimental: FDC tablet (5 mg saxagliptin + 500 mg metformin XR) (Fed)<br>under fed state | Drug: saxagliptin + metformin XR (FDC tablet)<br>* Tablet, Oral, (saxagliptin 5 mg)(metformin XR 500 mg), once daily, Single dose<br>|
| Experimental: FDC tablet (5 mg saxagliptin + 500 mg metformin XR) (Fasting)<br>under fasted state | Drug: saxagliptin + metformin XR (FDC tablet)<br>* Tablet, Oral, (saxagliptin 5 mg)(metformin XR 500 mg), once daily, Single dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant | 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) | 
| Saxagliptin Observed Maximum Plasma Concentration (Cmax) |  | 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) | 
| Metformin AUC(0-inf) | Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant | 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) | 
| Metformin Cmax |  | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saxagliptin Terminal Half-life (T1/2) | terminal half life; calculated as ln(2)/Kel | 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) | 
| Saxagliptin Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) | Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule. | 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) | 
| Time to Achieve the Observed Maximum Saxagliptin Plasma Concentration (Tmax) |  | 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) | 
| Saxagliptin Fraction of AUC(0-inf) Contributed by AUC(0-t) (AUC[0-t]/AUC[0-inf]) |  | 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) | 
| Active Metabolite BMS-510849 AUC(0-inf) | Area under the plasma concentration versus time curve from time 0 extrapolated to infinity; calculated as AUC0-t [calculated using the linear trapezoidal rule] + Ct/Kel, where Ct was the last measurable concentration and Kel was the terminal rate constant | 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) | 
| Active Metabolite BMS-510849 AUC(0-t) | Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule. | 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) | 
| Active Metabolite BMS-510849 Cmax |  | 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) | 
| Active Metabolite BMS-510849 T1/2 | terminal half life; calculated as ln(2)/Kel | 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) | 
| Active Metabolite BMS-510849 Tmax |  | 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) | 
| Active Metabolite BMS-510849 AUC(0-t)/AUC(0-inf) |  | 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) | 
| Metformin AUC(0-t) | Area under the plasma concentration versus time curve from time 0 to the time of the last quantifiable concentration (Ct), calculated using the linear trapezoidal rule. | 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) | 
| Metformin T1/2 | terminal half life; calculated as ln(2)/Kel | 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) | 
| Metformin Tmax |  | 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) | 
| Metformin Fraction of AUC(0-inf) Contributed by AUC(0-t)(AUC[0-t]/AUC[0-inf]) |  | 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) | 
| Safety: Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | 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. | 
| Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and Electrocardiogram (ECG) Abnormalities | Abnormalities considered by the investigator to be clinically significant and/or reported as an AE. | From Day 1 of Period 1 through Day 3 of Period 3 (study discharge) |