A Study to Assess the Bioequivalence of Dapagliflozin/Metformin XR Fixed-dose Combination Tablets in Healthy Subjects

Study Overview
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Brief Summary
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This is a bioequivalence study to compare 2 fixed-dose combination tablets of dapagliflozin/metformin XR manufactured at 2 different plants in healthy subjects under fasting and fed conditions

Detailed Description
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This is a Phase 1, 2-part, open-label, randomized, 4-period, 4-treatment, crossover study in healthy subjects (males and females of non-childbearing potential)

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

Conditions
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Bioequivalence, Fixed Dose Combination Tablets, Healthy Male and Female Subjects

Intervention / Treatment
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* Drug: dapagliflozin/metformin XR 5/500 mg test drug (Mount Vernon)
* Drug: dapagliflozin/metformin XR 5/500 mg reference drug (Humacao)
* Drug: dapagliflozin/metformin XR 10/1000 mg test drug (Mount Vernon)
* Drug: dapagliflozin/metformin XR 10/1000 mg reference drug (Humacao)


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 - 55 years with suitable veins for cannulation or repeated venipuncture Females must have a negative serum pregnancy test at screening and 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 and 30 kg/m2 inclusive and weigh at least 50 kg and no more than 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 investigational medicinal product 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 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 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. 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, cotinine 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 Known or suspected history of alcohol abuse or excessive intake of alcohol as judged by the investigator Involvement 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: 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: Treatment A<br>Under fed conditions, subjects will receive single doses of dapagliflozin/metformin XR test drug (Mount Vernon) 5/500 mg dose | Drug: dapagliflozin/metformin XR 5/500 mg test drug (Mount Vernon)<br>* single fixed-combination dose tablets<br>|
| Active Comparator: Treatment B<br>Under fed conditions, subjects will receive single doses of dapagliflozin/metformin XR reference drug (Humacao) 5/500 mg dose | Drug: dapagliflozin/metformin XR 5/500 mg reference drug (Humacao)<br>* single fixed-dose combination tablets<br>|
| Experimental: Treatment C<br>Under fasted conditions, subjects will receive single doses of dapagliflozin/metformin XR test drug (Mount Vernon) 5/500 mg dose | Drug: dapagliflozin/metformin XR 5/500 mg test drug (Mount Vernon)<br>* single fixed-combination dose tablets<br>|
| Active Comparator: Treatment D<br>Under fasted conditions, subjects will receive single doses of dapagliflozin/metformin XR reference drug (Humacao) 5/500 mg dose | Drug: dapagliflozin/metformin XR 5/500 mg reference drug (Humacao)<br>* single fixed-dose combination tablets<br>|
| Experimental: Treatment E<br>Under fed conditions, subjects will receive single doses of dapagliflozin/metformin XR test drug (Mount Vernon) 10/1000 mg dose | Drug: dapagliflozin/metformin XR 10/1000 mg test drug (Mount Vernon)<br>* single fixed-dose combination tablets<br>|
| Active Comparator: Treatment F<br>Under fed conditions, subjects will receive single doses of dapagliflozin/metformin XR reference drug (Humacao) 10/1000 mg dose | Drug: dapagliflozin/metformin XR 10/1000 mg reference drug (Humacao)<br>* single fixed-dose combination tablets<br>|
| Experimental: Treatment G<br>Under fasted conditions, subjects will receive single doses of dapagliflozin/metformin XR test drug (Mount Vernon) 10/1000 mg dose | Drug: dapagliflozin/metformin XR 10/1000 mg test drug (Mount Vernon)<br>* single fixed-dose combination tablets<br>|
| Active Comparator: Treatment H<br>Under fasted conditions, subjects will receive single doses of dapagliflozin/metformin XR reference drug (Humacao) 10/1000 mg dose | Drug: dapagliflozin/metformin XR 10/1000 mg reference drug (Humacao)<br>* single fixed-dose combination tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Plasma Concentration-time Curve [AUC] Under Fasted or Fed State | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 
| AUC From Time Zero to Time of Last Quantifiable Concentration [AUC (0-t)] Under Fasted or Fed State. | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 
| Observed Maximum Plasma Concentration [Cmax] Under Fasted or Fed State | To evaluate the Bioequivalence for Dapagliflozin and Metformin following administration Dapagliflozin/Metformin XR 5/500 mg and 10/1000 mg Manufactured at Mt. Vernon plant, US, Compared to Humacao plant, Puerto Rico, in the Fasted or Fed state | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Reach Maximum Plasma Concentration (t Max) | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 
| Half-life Associated With Terminal Slope (λz) of a Semi-logarithmic Concentration-time Curve [t½λz] | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 
| Apparent Total Body Clearance After Extravascular Administration Estimated as Dose Divided by AUC [CL/F] | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 
| Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration [Vz/F] | To characterize and compare the pharmacokinetic profiles of dapagliflozin and metformin when administered as the 2 fixed-dose combination formulations and in the fed and fasted states. | Days 1 to 3: pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 hours post-dose for each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dapagliflozin/metformin XR 5/500 mg, dapagliflozin/metformin XR10/1000 mg, bioequivalence, fixed dose combination tablets, pharmacokinetic, type 2 Diabetes Mellitus (T2DM), safety