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

Study Overview
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Brief Summary
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To demonstrate bioequivalence of a 2.5 mg saxagliptin/500 mg metformin (glucophage) immediate release (IR) fixed dose combination (FDC) tablet to the 2.5 mg saxagliptin tablet and 500 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 500 mg Metformin Immediate Release (IR) Tablet Relative to 2.5 mg Saxagliptin Tablet and 500 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: Co-administration of Saxagliptin and Metformin IR, Fasted
* Drug: Saxagliptin/Metformin, Fasting
* Drug: Co-administration of Saxagliptin and Metformin IR, Fed
* Drug: Saxagliptin/Metformin, Fed


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 |
| --- | --- |
| Experimental: S+ M, (fasted)> S/M (fed)> S/M (fasted)>S+M (fed)<br>Participants were randomized to receive oral co-administration of a 2.5 mg tablet of saxagliptin plus a 500 mg tablet of metformin immediate release (IR) under fasted conditions (S + M [fasted]) followed by a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions (S/M [fed]) followed by S/M under fasting conditions (S/M [fasted]) followed by S + M under fed conditions (S + M [fed]) | Drug: Co-administration of Saxagliptin and Metformin IR, Fasted<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin, Fasting<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions<br>* Other names: Glucophage;Drug: Co-administration of Saxagliptin and Metformin IR, Fed<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions<br>Drug: Saxagliptin/Metformin, Fed<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions<br>|
| Experimental: S/M (fasted)> S+M (fasted)> S+M (fed)> S/M (fed)<br>Participants were randomized to receive S/M (fasted) followed by S + M (fasted) followed by S + M (fed) followed by S/M (fed) | Drug: Co-administration of Saxagliptin and Metformin IR, Fasted<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin, Fasting<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions<br>* Other names: Glucophage;Drug: Co-administration of Saxagliptin and Metformin IR, Fed<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions<br>Drug: Saxagliptin/Metformin, Fed<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions<br>|
| Experimental: S+M (fed)> S/M (fasted) >S/M (fed)> S+M (fasted)<br>Participants were randomized to receive S + M (fed) followed by S/M (fasted) followed by S/M (fed) followed by S+M (fasted) | Drug: Co-administration of Saxagliptin and Metformin IR, Fasted<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin, Fasting<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions<br>* Other names: Glucophage;Drug: Co-administration of Saxagliptin and Metformin IR, Fed<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions<br>Drug: Saxagliptin/Metformin, Fed<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions<br>|
| Experimental: S/M (fed)> S+M (fed)> S+M (fasted)> S/M (fasted)<br>Participants were randomized to receive S/M (fed) followed by S+M (fed) followed by S+M (fasted) followed by S/M (fasted) | Drug: Co-administration of Saxagliptin and Metformin IR, Fasted<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fasted conditions<br>* Other names: Onglyza;Drug: Saxagliptin/Metformin, Fasting<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fasting conditions<br>* Other names: Glucophage;Drug: Co-administration of Saxagliptin and Metformin IR, Fed<br>* Participants received oral co-administration of a 2.5 mg tablet of saxagliptin and a 500 mg tablet of metformin immediate release (IR) under fed conditions<br>Drug: Saxagliptin/Metformin, Fed<br>* Participants received a single oral dose of a fixed dose combination (FDC) tablet of 2.5 mg saxagliptin/500 mg metformin IR under fed conditions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saxagliptin Mean Maximum Observed Plasma Concentration (Cmax) | Cmax of single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Saxagliptin Mean Area Under the Plasma Concentration Time Curve From Time Zero To Time of Last Quantifiable Concentration (AUC [0-T]} | AUC (0-T) for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Saxagliptin Mean Area Under the Plasma Concentration Time Curve From Time Zero To Infinity (AUC [0-INF]) | AUC (0-T) for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg), or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Saxagliptin Mean Plasma Half-life (T-half) and Mean Time of Maximum Observed Plasma Concentration (T-max) | T-half and T-max for single-dose saxagliptin (2.5 mg), either coadministered with metformin IR (500 mg) or administered as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Metformin Mean Cmax | Cmax of single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Metformin Mean AUC (0-T) | AUC (0-T for single-dose metformin (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Metformin Mean AUC(0-INF) | AUC (0-INF) for single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg) or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Metformin T-half and T-max | T-half and T-max for single-dose metformin IR (500 mg), either coadministered with saxagliptin (2.5 mg), or administerd as FDC 2.5 mg saxagliptin/500 mg metformin IR, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMS-510849 Mean Cmax | Cmax of the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administered as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| BMS-510849 Mean AUC (0-T) | AUC (0-T) for the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administration as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| BMS-510849 Mean AUC (0-INF) | AUC (0-T)= for the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administered as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| BMS-510849 Mean T-half and T-max | T-half and Tmax of the saxagliptin metabolite BMS-510849, following single-dose saxagliptin (2.5 mg) coadministered with metformin IR (500 mg) or administerd as an FDC 2.5 mg saxagliptin/500 mg metformin IR tablet, under fasted and fed conditions. | Day 1: 0 hr, 0.25 hr, 0.5 hr, 0.75 hr, 1 hr, 1.5 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 18 hr, Day 2: 0 hr, 12 hr, Day 3: 0 hr | 
| Number of Participants With at Least 1 Adverse Event (AE), Death, Serious AE (SAE), or AEs Leading to Discontinuation | AE=any new untoward medical occurrence or worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment. SAE=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, results in development of drug dependency or drug abuse, is an important medical event. | From Day 1 through Day 45, including up to 56 days after last dose of study medication | 
| Number of Participants With Laboratory Marked Abnormalities | High=greater than Upper Normal Limit (ULN), Low=lower than Lower Normal Limit (LLN). LLN/ULN= Leukocytes: <0.9 x LLN/ >1.2 x ULN; blood urea nitrogen (BUN): >1.1 x ULN; creatinine: >1.33 x BL; phosphorous (P): <0.75 x LLN/ >1.2 5 x ULN; creatinine kinase (CK): >1.5 x ULN; urine blood=use ≥2 x BL if value ≥2+ or BL1+ | From Day 1 through Day 45, including up to 56 days after last dose of study medication | 
| Number of Participants With Clinically Relevant Electrocardiogram (ECG) Abnormalities | PR interval, QRS complex, width of QRS, QT interval, and QT corrected for heart rate adjusting for heart rate using either Bazett formula or Fridericia formula were measured. ECG abnormalities were judged to be of medical importance by the Investigator. | Period 1 Day 1, Period 2 Day 1, Period 3 Day 1, Period 4 Day 1, Period 4 Day 3 | 
| Number of Participants With Clinically Relevant Vital Sign Abnormalities | Mean systolic and diastolic blood pressure, heart rate, respiration, and temperature were assessed.Vital sign abnormalities abnormalities were judged to be of medical importance by the Investigator. | Period 1 Day 1, Period 2 Day 1, Period 3 Day 1, Period 4 Day 1, Period 4 Day 3 | 
| Number of Participant With Clinically Relevant Physical Examination Abnormalities | A physical examination was conducted which included height and weight measurements, from which the Body Mass Index was determined. Physical examination abnormalities were judged to be of medical importance by the Investigator. | Screen, Period 1 Day -1, prior to discharge |