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

Study Overview
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Brief Summary
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To demonstrate the bioequivalence of a 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC) tablet to that of 2.5-mg saxagliptin (Onglyza) and 500-mg metformin (Glucophage, marketed in Canada by Sanofi-Aventis) tablets coadministered to healthy participants in the fasted and fed states.

Official Title
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Bioequivalence Study of the Fixed Dose Combination of 2.5 mg Saxagliptin and 500 mg Metformin Tablet Relative to a 2.5 mg Saxagliptin (Onglyza) Tablet and a 500 mg Metformin (Glucophage Marketed in Canada by Sanofi-Aventis) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed States

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, aged 18 to 55 years, inclusive Healthy participants as determined by a lack of clinically significant deviation from normal in medical history, physical examination, electrocardiograms, and clinical laboratory determinations Body Mass Index of 18 to 32 kg/m^2, inclusive Exclusion Criteria: Any significant acute or chronic medical illness Current or recent (within 3 months) gastrointestinal disease Any major surgery within 4 weeks of study drug administration History of allergy to DPP-4 inhibitors or related compounds History of allergy or intolerance to metformin or other similar acting agents Previous exposure to saxagliptin Exposure to metformin within 3 months pervious to study drug administration Estimated creatinine clearance of <80 mL/min using the Cockcroft Gault formula

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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 |
| --- | --- |
| Other: Saxagliptin, 2.5 mg + Metformin, 500 mg (fasted state)<br>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)<br>* Tablets, oral, 2.5-mg saxagliptin and 500-mg metformin, once daily, 1 week<br>* Other names: Glucophage™;|
| Other: Saxagliptin, 2.5 mg/Metformin, 500 mg FDC (fasted state)<br>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)<br>* Tablets, oral, 2.5-mg saxagliptin/500-mg metformin fixed-dose combination (FDC), once daily, 1 week<br>|
| Other: Saxagliptin, 2.5 mg + Metformin, 500 mg (fed state)<br>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)<br>* Tablets, oral, 2.5-mg saxagliptin and 500-mg metformin, once daily, 1 week<br>* Other names: Glucophage™;|
| Other: Saxagliptin, 2.5 mg/Metformin, 500 mg FDC (fed state)<br>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)<br>* Tablets, oral, 2.5-mg saxagliptin and 500-mg metformin FDC, once daily, 1 week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 Outcome Measures

| Outcome Measure | 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. | Continuously over Days 1 to 3 of treatment Periods 1, 2, 3, and 4 | 
| 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. | At screening visit, at Day -1 of Periods 1 through 4, and at discharge | 
| 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. | At screening visit, Day -1 of Period 1, and at study discharge | 
| 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. | At screening visit, prior to dosing on Day 1 of Periods 1 through 4, and at study discharge. |