To Compare the Similarity of a Combination Dapagliflozin/Metformin Tablet With the Two Drugs Administered Separately

Study Overview
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Brief Summary
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This is an open-label, randomised study to compare the similarity of a combination Dapagliflozin/Metformin tablet with the two drugs administered separately under fasting and fed conditions in healthy volunteers.

Detailed Description
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A Bioequivalence Study of the Fixed Dose Combination Dapagliflozin/Metformin Tablet (5.0 mg/850 mg) Relative to a 5.0 mg Dapagliflozin Tablet and an 850 mg Metformin (Glucophage® Marketed in Canada by Sanofi-Aventis) Tablet Co-Administered to Healthy Subjects in the Fasted and Fed States

Official Title
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A Bioequivalence Study of the Fixed Dose Combination Dapagliflozin/Metformin Tablet (5 mg/850 mg) Relative to a 5 mg Dapagliflozin Tablet and an 850 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: Dapagliflozin + Glucophage tablet fasted
* Drug: Dapagliflozin/metformin IR FDC tablet fasted
* Drug: Dapagliflozin + Glucophage tablet fed
* Drug: Dapagliflozin/metformin IR FDC tablet fed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers aged 18 to 55 years inclusive with suitable veins for cannulation or repeated vein puncture Male subjects should be willing to use barrier contraception ie, condoms and spermicide, from the day of dosing until at least 3 months after dosing with the investigational product Non-pregnant, non-lactating female subjects who if pre-menopausal are using adequate birth control eg, oral, injectable, transdermal or implanted hormonal contraceptives, vaginal contraceptive ring, intrauterine device (IUD)/intrauterine systems Have a body mass index (BMI) between 18.5 and 30.0 kg/m2 inclusive (ie, within 15% of normal range) and weigh at least 50 kg and no more than 100 kg. Exclusion Criteria: History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG that may interfere with individual safety evaluation Current smokers who smoke more than 5 cigarettes per day (or equivalent use of tobacco products) or cannot give up smoking during the study Excessive intake of caffeine containing drinks eg, coffee, tea, caffeine containing energy drinks and cola (more than 5 cups of coffee or equivalent per day) Plasma donation within one month of screening or any blood donation/blood loss >500 mL during the 3 months prior to screening

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

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>5 mg dapagliflozin and 850 mg Glucophage in fasted state | Drug: Dapagliflozin + Glucophage tablet fasted<br>* Single oral doses of 5 mg dapagliflozin and 850 mg Glucophage® tablets administered together in the fasted state<br>|
| Experimental: 2<br>dapagliflozin/metformin (5 mg/850 mg) immediate release (IR) FDC in fasted | Drug: Dapagliflozin/metformin IR FDC tablet fasted<br>* single oral dose of dapagliflozin/metformin (5 mg/850 mg) IR FDC tablet in the fasted state<br>|
| Experimental: 3<br>5 mg dapagliflozin and 850 mg Glucophage in fed state | Drug: Dapagliflozin + Glucophage tablet fed<br>* Single oral doses of 5 mg dapagliflozin and 850 mg Glucophage® tablets administered together in the fed state<br>|
| Experimental: 4<br>dapagliflozin/metformin (5 mg/850 mg) IR FDC in fed state | Drug: Dapagliflozin/metformin IR FDC tablet fed<br>* single oral dose of dapagliflozin/metformin (5 mg/850 mg) IR FDC tablet in the fed state<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve over the time (AUC) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| AUC from time zero to the time of last quantifiable analyte concentration (AUC(0-t)) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Maximum concentration (Cmax) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach maximum analyte concentration (tmax) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Terminal rate constant (λz) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Time of last quantifiable analyte concentration (tlast) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Terminal half-life (t1/2) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Observed maximum analyte concentration (Cmax) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration (AUC(0 t)) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Elimination terminal half-life (t1/2) | No statistical analysis will be performed | pre-dose, 0.25 min, 0.5 min, 1h, 1.5h, 2 h, 3h , 4 h, 5 h , 6 h, 8 h, 10 h, 12 h, 16 h, 24 h, 30 h, 36 h, 42 h, 48 h, 54 h, 60 h and 72 h post-dose | 
| Safety profile description in term of Adverse Events | No statistical analysis will be performed | from first dose in treatment period 1 up to 10 days after final dose | 
| Safety profile description in term of Blood Pressure | No statistical analysis will be performed | at screening, once daily during the residential period (5 days each) and up to 10 days after final dose | 
| Safety profile description in term of Physical Examination | No statistical analysis will be performed | at screening, Day -1 and Day 4 at Visits 2 to 5 and up to 10 days after final dose | 
| Safety profile description in term of Electrocardiogram ECG | No statistical analysis will be performed | at screening and up to 10 days after final dose | 
| Safety profile description in term of Heart Rate | No statistical analysis will be performed | at screening, once daily during the residential period (5 days each) and up to 10 days after final dose | 
| Safety profile description in term of Safety Labs | No statistical analysis will be performed | at screening, on Day -1 and Day 4 (72 hours post-dose) at Visits 2 to 5 and up to 10 days after final dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, healthy volunteers, cross-over study, Bioavailability, Bioequivalence, Cmax, tmax, AUC, AUC(0-t), λz, tlast