Bioequivalence Study of Saxagliptin and Glucophage Combination Formulations in Healthy Subjects (B)

Study Overview
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Brief Summary
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To demonstrate bioequivalence of a 2.5 mg saxagliptin/1000 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 1000 mg metformin IR tablet co-administered to healthy subjects in a fasted and in a fed state.

Official Title
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Bioequivalence Study of the Fixed Dose Combination of 2.5 mg Saxagliptin and 1000 mg Metformin Immediate Release (IR) Tablet Relative to 2.5 mg Saxagliptin Tablet and 1000 mg Metformin IR Tablet Co-administered to Healthy Subjects in a Fasted and in a Fed State

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Saxagliptin
* Drug: Metformin IR (glucophage)
* Drug: Saxagliptin + Metformin IR (FDC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ages 19 to 45 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/m2, inclusive. BMI = weight (kg)/ [height (m)]2 Exclusion Criteria: Women of child-bearing potential (WOCBP) who are unwilling or unable to use acceptable barrier methods (condoms and spermicides) to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of investigational product 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 Dipeptidyl peptidase 4 (DPP4) inhibitor or related compounds 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 < 80ml/min using the Cockcroft Gault formula

Ages Eligible for Study
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Minimum Age: 19 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 |
| --- | --- |
| Other: Arm A<br>Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fasted conditions | Drug: Saxagliptin<br>* Tablet, Oral, 2.5 mg, Once Daily, 1 week<br>* Other names: Onglyza;Drug: Metformin IR (glucophage)<br>* Tablets, Oral, 1000 mg, Once Daily, 1 week<br>* Other names: Glucophage;|
| Other: Arm B<br>Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fasted conditions | Drug: Saxagliptin + Metformin IR (FDC)<br>* Tablet, Oral, Saxagliptin 2.5 mg + metformin IR 1000 mg, Once Daily, 1 Week<br>* Other names: Glucophage;|
| Other: Arm C<br>Co-administration of single oral doses of a 2.5 mg tablet of saxagliptin and a 1000 mg tablet of metformin IR under fed conditions with a standard meal | Drug: Saxagliptin<br>* Tablet, Oral, 2.5 mg, Once Daily, 1 week<br>* Other names: Onglyza;Drug: Metformin IR (glucophage)<br>* Tablets, Oral, 1000 mg, Once Daily, 1 week<br>* Other names: Glucophage;|
| Other: Arm D<br>Single oral dose of a FDC tablet consisting of 2.5 mg saxagliptin/ 1000 mg metformin IR under fed conditions with a standard meal | Drug: Saxagliptin + Metformin IR (FDC)<br>* Tablet, Oral, Saxagliptin 2.5 mg + metformin IR 1000 mg, Once Daily, 1 Week<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saxagliptin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinite Time (AUC[INF]) | Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Saxagliptin PK Parameter Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Plasma Concentration (AUC[0-T]) | Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Saxagliptin PK Parameter Maximum Observed Plasma Concentration (Cmax) | Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Saxagliptin PK Parameter Plasma Terminal Half-life (T-HALF) | Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Saxagliptin PK Parameter Time of Maximum Observed Plasma Concentration (Tmax) | Single-dose PK parameters of saxagliptin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Metformin PK Parameter AUC(INF) | Single-dose PK parameters of metformin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Metformin PK Parameter AUC(0-T) | Single-dose PK parameters of metformin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Metformin PK Parameter Cmax | Single-dose PK parameters of metformin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Metformin PK Parameter T-HALF | Single-dose PK parameters of metformin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Metformin PK Parameter Tmax | Single-dose PK parameters of metformin were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMS-510849 PK Parameter AUC(INF) | Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| BMS-510849 PK Parameter AUC(0-T) | Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| BMS-510849 PK Parameter Cmax | Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| BMS-510849 PK Parameter T-Half | Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from their respective plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| BMS-510849 PK Parameter T-Max | Single-dose PK parameters of the active metabolite of saxagliptin, BMS-510849, were derived from plasma concentration versus time data. | pre-dose, post-dose at 15, 30, 45, 90 minutes, hours 1, 2, 3, 4, 6, 8, 12, 18, 24, 36 and 48 of each period | 
| Deaths, Serious Adverse Events (SAEs), Adverse Events (AEs), and Discontinuations Due to AEs | An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). SAEs collected from date of written consent until 30 days post discontinuation of dosing or subject's participation in the study. | 
| AEs of Special Interest | See Outcome Measure 16 for a definition of AEs. AEs of clinical interest for saxagliptin were defined as those relating to the following:skin disorders, infection-related AEs (system organ class [SOC]: Infections and Infestations), thrombocytopenia, lymphopenia, hypoglycemia, cardiovascular AEs indicative of acute cardiovascular events, localized edema, fractures, pancreatitis, and AEs of hypersensitivity. | AEs collected from Day 1/Period 1 through study discharge (study duration: approximately 45 days). | 
| Number of Participants With Marked Laboratory Abnormalities (MA) | Laboratory abnormalities=any result that is clinically significant, met the definition of an SAE, required discontinuation or interruption of study drug, or required specific corrective therapy. Upper normal (UN)/lower normal (LN) values: leukocytes UN, 11.40x10^3 c/uL; absolute neutrophils/bands LN, 1.500x10^3 c/uL; aspartate aminotransferase UN, 48 U/L; alanine aminotransferase UN, 67 U/L; blood urea nitrogen UN, 20.0 mg/dL; creatine kinase UN, 350 U/L; lactate dehydrogenase UN, 249 U/L. | Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. | 
| Number of Participants With Marked Urinalysis Abnormalities | Protein, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Glucose, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). Blood, Urine Abnormality: if value >= 2+ (or if pretreatment value >= 1+, then >= 2 * pretreatment). White Blood Cell (WBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). Red Blood Cell (RBC), Urine Abnormality: if value >= 2+ (or if pretreatment value >= 2+, then >= 4+). (The '+' is a normal lab result and refers to the magnitude of the finding.) | Within 21 days of study Day 1, Days 1-3 of Periods 1, 2, 3, and 4. | 
| Electrocardiogram (ECG), Vital Sign, and Physical Finding Abnormalities | 12-lead Electrocardiogram (ECG), Vital Sign (body temperature, respiratory rate, seated blood pressure and heart rate), and Physical Finding Abnormalities reported by investigator as AEs. | At Screening (within 21 days of Study Day 1), Day -1 of Period 1 (ECG and Physical only), Day 1 of Periods 1-4 (Vitals only), at Study Discharge (Day 3 of Period 4) or Discontinuation |