Bioequivalence Study of Fixed-dose Combinations and Coadministered Individual Tablets of Saxagliptin/Metformin-Brazil

Study Overview
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Brief Summary
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To demonstrate the bioequivalence of saxagliptin and metformin in a saxagliptin, 5-mg/metformin extended-release (XR), 500-mg, fixed-dose combination (FDC) tablet with saxagliptin, 5-mg and metformin, 500-mg XR tablets administered together in both the fasted and fed states. In addition, to demonstrate the bioequivalence of saxagliptin and metformin in a saxagliptin, 5-mg/metformin XR, 1000-mg, FDC tablet with saxagliptin, 5-mg and metformin, 1000-mg XR tablets administered together in both the fasted and fed states.

Official Title
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Bioequivalence Study of Fixed Dose Combinations of Saxagliptin/Metformin Extended Release (XR) Relative to Co-administration of the Individual Components in 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/metformin fixed-dose combination (FDC)
* Drug: Saxagliptin
* Drug: Metformin extended-release (XR)
* Drug: Saxagliptin/Metformin FDC
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Healthy men and women women of childbearing potential who are using acceptable method of contraception Women who are not pregnant or nursing Body Mass Index (BMI) of 18 to 29.9 kg/m^2, inclusive. BMI=weight(kg)/height(m)^2. Key Exclusion Criteria: Any significant acute or chronic medical illness. History of gastrointestinal (GI) disease Major surgery within 4 weeks of study drug administration Any GI surgery that could impact study drug absorption Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within the 6 months of study drug administration. Blood transfusion within 3 months of study drug administration for women and within 2 months for men Inability to be venipunctured and/or tolerate venous access Current smoker or recent (within 1 month) history of regular tobacco use Recent (within 6 months of study drug administration) drug or alcohol abuse Participation in a bioequivalence study within the last 6 months of study drug administration Estimated creatinine clearance of <80 mL/min using Cockcroft-Gault formula History of allergy to drug class or related compounds History of allergy to metformin or other similar acting agents History of any significant drug allergy

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 |
| --- | --- |
| Experimental: Arm 1: Treatments A,B/B,A<br>Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC) in the fasted state (Treatment A), followed by a washout period of at least 7 days. Then, participants received single oral doses of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg, tablets together in the fasted state (Treatment B). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5-mg and metformin XR, 500-mg tablets together in the fasted state (Treatment B), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fasted state (Treatment A). | Drug: Saxagliptin/metformin fixed-dose combination (FDC)<br>* Tablet, oral, 5 mg/500 mg FDC, once on Day 1 only, 1 day<br>* Other names: Onglyza/Glucophage extended release (XR);Drug: Saxagliptin<br>* Tablet, oral, 5 mg, once on Day 1 only, 1 day<br>* Other names: Onglyza;Drug: Metformin extended-release (XR)<br>* Tablet, oral, 500 mg, once on Day 1 only, 1 day<br>* Other names: Glifage XR;|
| Experimental: Arm 2: Treatments C,D/D,C<br>Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg fixed-dose combination (FDC), in the fed state (Treatment C), followed by a washout period of at least 7 days. Then, participants received a single oral dose of saxagliptin, 5-mg, and metformin extended-release (XR), 500-mg tablets together in the fed state (Treatment D). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metforminXR, 500-mg tablets together in the fed state (Treatment D), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 500 mg FDC, in the fed state (Treatment C). | Drug: Saxagliptin/metformin fixed-dose combination (FDC)<br>* Tablet, oral, 5 mg/500 mg FDC, once on Day 1 only, 1 day<br>* Other names: Onglyza/Glucophage extended release (XR);Drug: Saxagliptin<br>* Tablet, oral, 5 mg, once on Day 1 only, 1 day<br>* Other names: Onglyza;Drug: Metformin extended-release (XR)<br>* Tablet, oral, 500 mg, once on Day 1 only, 1 day<br>* Other names: Glifage XR;|
| Experimental: Arm 3: Treatments E, F/F,E<br>Period 1: Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fasted state (Treatment E), followed by a washout period of at least 7 days. Participants received single oral doses of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fasted state (Treatment F). Followed by a washout period of at least 4 days. Period 2: Participants received single oral doses of saxagliptin, 5- mg and metformin XR, 1000-mg tablets together in the fasted state (Treatment F), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fasted state (Treatment E). | Drug: Saxagliptin<br>* Tablet, oral, 5 mg, once on Day 1 only, 1 day<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin FDC<br>* Tablet, Oral, 5 mg/1000 mg FDC, once on Day 1 only, 1 day<br>* Other names: Onglyza/Glucophage XR;Drug: Metformin<br>* Tablet, oral, 1000 mg, once on Day 1 only, 1 day<br>* Other names: Glifage XR;|
| Experimental: Arm 4: Treatments G,H/H,G<br>Period 1: Participants received a single oral dose of saxagliptin , 5 mg/metformin, 1000 mg fixed-dose combination (FDC), in the fed state (Treatment G), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5-mg and metformin extended-release (XR), 1000-mg tablets together in the fed state (Treatment H). Followed by a washout period of at least 4 days. Period 2: Participants received a single oral dose of saxagliptin, 5-mg and metformin XR, 1000-mg tablets together in the fed state (Treatment H), followed by a washout period of at least 7 days. Participants received a single oral dose of saxagliptin, 5 mg/metformin, 1000 mg FDC, in the fed state (Treatment G). | Drug: Saxagliptin<br>* Tablet, oral, 5 mg, once on Day 1 only, 1 day<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin FDC<br>* Tablet, Oral, 5 mg/1000 mg FDC, once on Day 1 only, 1 day<br>* Other names: Onglyza/Glucophage XR;Drug: Metformin<br>* Tablet, oral, 1000 mg, once on Day 1 only, 1 day<br>* Other names: Glifage XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentrations (Cmax) of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets |  | Days 1, 2, and 3 of Periods 1 and 2 | 
| AUC From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-T])of Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets | AUC=Area under the concentration-time curve | Days 1, 2, and 3 of Periods 1 and 2 | 
| AUC From Time 0 Extrapolated to Infinite Time (AUC[0-inf]) for Metformin, Saxagliptin, and 5-Hydroxy (5-OH) Saxagliptin as a Fixed-dose Combination (FDC) and as Individual Tablets | AUC=Area Under the Concentration-time Curve | Days 1, 2, and 3 of Periods 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Death as Outcome and Serious Adverse Events (SAEs) | SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | Continuously, from screening through Day 1 to within 30 days of drug discontinuation on Day 1 |