Bioequivalence Study of Fixed Dose Combination of 2.5 mg Saxagliptin/850 mg Metformin Tablet Relative to 2.5 mg Onglyza and 850 mg Glucophage Tablets Co-Administered

Study Overview
=================
Brief Summary
-----------------
To demonstrate bioequivalence of a 2.5 mg saxagliptin/850 mg metformin fixed dose combination (FDC) tablet relative to the 2.5 mg saxagliptin tablet and 850 mg metformin (Glucophage Marketed by Merck-Serono) tablet co-administered to healthy subjects in the fasted and fed condition.

Official Title
-----------------
Bioequivalence Study of the Fixed Dose Combination of 2.5 mg Saxagliptin and 850 mg Metformin Tablet Relative to a 2.5 mg Saxagliptin (Onglyza) Tablet and a 850 mg Metformin (Glucophage Marketed by Merck Serono) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed Conditions

Conditions
-----------------
Type 2 Diabetes Mellitus

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women ages 18 to 55 inclusive Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations Body Mass Index (BMI) of 18 to 32 kg/m^2, inclusive. BMI = weight (kg)/ [height (m)]^2 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 a dipeptidyl peptidase-IV (DPP4) inhibitor or related compound History of allergy or intolerance to metformin or other similar acting agents Prior exposure to saxagliptin Prior exposure to metformin within 3 months of study drug administration Estimated creatinine clearance (Clcr) of < 80 mL/min using the Cockcroft Gault formula

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm A (saxagliptin 2.5 mg + metformin 850 mg; Fasting)<br>A single oral dose of 2.5-mg Onglyza tablet and 850-mg Glucophage (marketed by Merck Serono) tablet administered together in the fasted condition. | Drug: saxagliptin<br>* Tablets, Oral, 2.5 mg, once daily, single dose<br>* Other names: Onglyza;Drug: metformin<br>* Tablets, Oral, 850 mg, once daily, single dose<br>* Other names: Glucophage;|
| Other: Arm B (saxagliptin 2.5 mg + metformin 850 mg FDC; Fasting)<br>A single oral dose of 2.5-mg saxagliptin/850-mg metformin fixed dose combination (FDC) administered in the fasted condition. | Drug: saxagliptin + metformin (FDC tablet)<br>* Tablet, oral, (saxagliptin 2.5 mg) (metformin 850 mg), once daily, single dose<br>|
| Other: Arm C (saxagliptin 2.5 mg + metformin 850 mg; Fed)<br>A single oral dose of 2.5-mg Onglyza tablet and 850-mg Glucophage (marketed by Merck Serono) tablet administered together in the fed condition. | Drug: saxagliptin<br>* Tablets, Oral, 2.5 mg, once daily, single dose<br>* Other names: Onglyza;Drug: metformin<br>* Tablets, Oral, 850 mg, once daily, single dose<br>* Other names: Glucophage;|
| Other: Arm D (saxagliptin 2.5 mg + metformin 850 mg FDC; Fed)<br>A single oral dose of 2.5-mg saxagliptin/850-mg metformin FDC administered in the fed condition. | Drug: saxagliptin + metformin (FDC tablet)<br>* Tablet, oral, (saxagliptin 2.5 mg) (metformin 850 mg), once daily, single dose<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf]) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| Saxagliptin PK Parameter Observed Maximum Plasma Concentration (Cmax) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| Metformin PK Parameter AUC(0-inf) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| Metformin PK Parameter Cmax | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-hydroxy Saxagliptin PK Parameter AUC(0-inf) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| 5-hydroxy Saxagliptin PK Parameter Cmax | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| 5-hydroxy Saxagliptin PK Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t]) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC[0-t] is the area under the plasma concentration-time curve from time zero to time of last measurable concentration. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| 5-hydroxy Saxagliptin PK Parameter Terminal Half-life (T 1/2) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing | 
| 5-hydroxy Saxagliptin PK Parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration. | Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-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 study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening). | 
| Safety: Clinically Significant Laboratory, Vital Sign, Physical Examination, and/or 12-Lead Electrocardiogram (ECG) Abnormalities | Abnormalities that were considered clinically significant and/or reported as an AE by the investigator. | From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). |