The Purpose of the Study is to Compare Two Fixed Dose Combination Tablets of Dapagliflozin/Metformin XR in Healthy Subjects Under Fasting and Fed Conditions

Study Overview
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Brief Summary
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This is a bioequivalence study of two doses of the dapagliflozin/metformin XR tablet manufactured at two different plants.

Detailed Description
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This is a two part, open-label, randomized, 4-period, 4-treatment (per study part) crossover study in healthy subjects (males and females of non-childbearing potential), performed at a single study center, conducted to establish the bioequivalence of 2 strengths of dapagliflozin/metformin XR tablets manufactured at two different plants.

Official Title
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A Two Part Bioequivalence Study to Compare Two Fixed Dose Combination (FDC) Tablets of Dapagliflozin/Metformin XR 5/500 mg (Part 1) and 10/1000 mg (Part 2) Manufactured at Two Different Plants (Humacao, Puerto Rico and Mount Vernon, US) in Healthy Subjects Under Fasting and Fed Conditions

Conditions
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Healthy Subjects in Fasted and Fed State

Intervention / Treatment
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* Drug: Dapagliflozin/metformin XR 5/500mg
* Drug: Dapagliflozin/metformin XR 5/500 mg
* Drug: Dapagliflozin/metformin XR 5/500mg
* Drug: Dapagliflozin/metformin XR 5/500mg
* Drug: Dapagliflozin/metformin XR 10/1000mg
* Drug: Dapagliflozin/metformin XR 10/1000mg
* Drug: Dapagliflozin/metformin XR 10/1000mg
* Drug: Dapagliflozin/metformin XR 10/1000mg


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Provision of signed and dated, written informed consent prior to any study-specific procedures Healthy male and female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture Females must have a negative serum pregnancy test at screening and negative urine pregnancy test on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: Post-menopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the post menopausal range Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation Have a body mass index (BMI) between 18.50 and 24.90 kg/m2 inclusive [15% variance on the upper limit is permitted (i.e., up to 28.63 kg/m2)] and weigh between 50 and 100 kg inclusive at screening Exclusion Criteria History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study 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 significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator Any clinically significant abnormal findings in vital signs, as judged by the investigator Any clinically significant abnormalities on 12-lead electrocardiogram (ECG) as judged by the investigator Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV) antibody Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN Total bilirubin >2.0 mg/dL (34.2 µmol/L) Known or suspected history of drug abuse, as judged by the investigator Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose. Note: Subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the investigator or history of hypersensitivity to drugs with a similar chemical structure or class to dapagliflozin/metformin XR. Current smokers or those who have smoked or used nicotine products within the 3 months prior to screening. Positive screen for drugs of abuse or alcohol at screening or on each admission to the study center Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, vitamins and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life Note: Hormonal replacement therapy is allowed for females. Known or suspected history of alcohol abuse or excessive intake of alcohol, as judged by the investigator Inclusion of any AstraZeneca or study site employee or their close relatives Judgment by the investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Dapagliflozin/metformin XR 5/500 Mount Vernon Test Product Fed | Drug: Dapagliflozin/metformin XR 5/500mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Mt Vernon plant;|
| Active Comparator: Treatment B<br>Dapagliflozin/metformin XR 5/500 Humacao Reference Product Fed | Drug: Dapagliflozin/metformin XR 5/500 mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Humacao plant;|
| Experimental: Treatment C<br>Dapagliflozin/metformin XR 5/500 Mount Vernon Test Product Fasted | Drug: Dapagliflozin/metformin XR 5/500mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Dapagliflozin/metformin XR 5/500mg Mount Vernon plant;|
| Active Comparator: Treatment D<br>Dapagliflozin/metformin XR 5/500 Humacao Reference Product Fasted | Drug: Dapagliflozin/metformin XR 5/500mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Humacao plant;|
| Experimental: Treatment E<br>Dapagliflozin/metformin XR 10/1000 Mount Vernon Test Product Fed | Drug: Dapagliflozin/metformin XR 10/1000mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Mount Vernon plant;|
| Active Comparator: Treatment F<br>Dapagliflozin/metformin XR 10/1000 Humacao Reference Product Fed | Drug: Dapagliflozin/metformin XR 10/1000mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Humacao plant;|
| Experimental: Treatment G<br>Dapagliflozin/metformin XR 10/1000 Mount Vernon Test Product Fasted | Drug: Dapagliflozin/metformin XR 10/1000mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Dapagliflozin/metformin XR 10/1000mg Mount Vernon plant;|
| Active Comparator: Treatment H<br>Dapagliflozin/metformin XR 10/1000 Humacao Reference Product Fasted | Drug: Dapagliflozin/metformin XR 10/1000mg<br>* Tablets for oral administration, once daily, once per treatment period<br>* Other names: Dapagliflozin/metformin XR 10/1000mg Humacao plant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 - Area under the plasma concentration versus time curve (AUC) for each analyte and each state | To demonstrate the bioequivalence of dapagliflozin/metformin XR 5/500 mg manufactured at Mount Vernon plant and dapagliflozin/metformin XR 5/500 mg manufactured at Humacao plant in metformin and in dapagliflozin plasma concentrations for the fed state and, separately, the fasted state. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Part 2 - Area under the plasma concentration versus time curve (AUC) for each analyte and each state | To demonstrate the bioequivalence of dapagliflozin/metformin XR 10/1000 mg manufactured at Mount Vernon plant and dapagliflozin/metformin XR 10/1000 mg manufactured at Humacao plant in metformin and dapagliflozin plasma concentrations for the fed state and, separately, the fasted state. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Part 1 - Peak Plasma Concentration (Cmax) for each analyte and each state | To demonstrate the bioequivalence of dapagliflozin/metformin XR 5/500 mg manufactured at Mount Vernon plant and dapagliflozin/metformin XR 5/500 mg manufactured at Humacao plant in metformin and in dapagliflozin plasma concentrations for the fed state and, separately, the fasted state. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Part 2 - Peak Plasma Concentration (Cmax) for each analyte and each state | To demonstrate the bioequivalence of dapagliflozin/metformin XR 10/1000 mg manufactured at Mount Vernon plant and dapagliflozin/metformin XR 10/1000 mg manufactured at Humacao plant in metformin and in dapagliflozin plasma concentrations for the fed state and, separately, the fasted state. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under plasma concentration - time curve from time zero to infinity (AUC) | Measurements of AUC from time zero to infinity for dapagliflozin and metformin when administered as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Adverse events | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing the number of subjects with adverse events. | 10,5 weeks | 
| Blood pressure | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in mmHg of systolic and diastolic blood pressure. | 10,5 weeks | 
| Electrocardiogram (ECG) | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in overall ECG evaluation. | 10,5 weeks | 
| Time to reach maximum plasma concentration (tmax) | Measurements of tmax for dapagliflozin and metformin when administered in both fed and fasted states as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t½λz) | Measurements of half-life associated with terminal slope (t½λz) for dapagliflozin and metformin when administered in both fed and fasted states as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Terminal elimination rate constant (λz) | Measurements of terminal elimination rate constant (λz) for dapagliflozin and metformin when administered in both fed and fasted states as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Apparent total body clearance after extravascular administration (CL/F) | Measurements of apparent total body clearance after extravascular administration (CL/F) for dapagliflozin and metformin when administered in both fed and fasted states as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) | Measurements of apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) for dapagliflozin and metformin when administered in both fed and fasted states as single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants. | Based on pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose sampling times | 
| Laboratory assessments - hematology | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in hematology. | 10,5 weeks | 
| Heart rate | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in heart rate measured as beats per minute. | 10,5 weeks | 
| Laboratory assessments - clinical chemistry | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in clinical chemistry. | 10,5 weeks | 
| Laboratory assessments - urinalysis | To evaluate the safety of single doses of dapagliflozin/metformin 5/500 mg or 10/1000 mg formulation from both the Mount Vernon and Humacao plants both fed and fasted states by assessing changes from baseline in urinalysis. | 10,5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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healthy,, fasted,, fed