An Open-label, Randomized, Crossover Study of Comparative Pharmacokinetics and Bioequivalence of Dapagliflozin + Metformin, 10 mg + 1000 mg Versus the Combined Use of Forxiga™, 10 mg and Two Glucophage® Long, ER Tablets, 500 mg Co-administered to Healthy Volunteers Under Standard Fed Conditions

Study Overview
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Brief Summary
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The aim of this study is to demonstrate bioequivalence of fixed dose combination Dapagliflozin + Metformin modified -release, film-coated tablets, 10 mg + 1000 mg, (AstraZeneca AB, Sweden) versus Forxiga™ (Dapagliflozin), film-coated tablets, 10 mg (Bristol Myers Squibb Company, USA) and Glucophage® long (Metformin), ER tablets, 1000 mg (2 x 500 mg) (Merck Santé S.A.S., France) which are already registered in the Russian Federation.

Detailed Description
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Randomised open-label crossover comparative, single center, two periods, clinical study of investigational drug and reference drugs bioequivalence evaluation with a single administration of the study drug (1 modified - release film-coated tablets of Dapagliflozin + Metformin or 1 film-coated tablets of Forxiga™ + 2 tablets ER of Glucophage® long) under fed condition in healthy volunteers.

Official Title
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An Open-label, Randomized, Crossover Study of Comparative Pharmacokinetics and Bioequivalence of Dapagliflozin + Metformin Modified Release Film-coated Tablets, 10 mg + 1000 mg (AstraZeneca AB, Sweden) Versus the Combined Use of Forxiga™ (Dapagliflozin), Film-coated Tablets, 10 mg (Bristol Myers Squibb Company, USA) and Two Glucophage® Long (Metformin), ER Tablets, 500 mg (Merck Santé S.A.S., France), Co-administered to Healthy Volunteers Under Standard Fed Conditions

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Xigduo XR
* Drug: Metformin ER (Glucophage® long)
* Drug: Dapagliflozin (Forxiga)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The volunteer is able to understand the requirements of the study, to sign the informed consent form, and agrees with all the restrictions imposed in the course of the study; Male and female subjects aged 18-45, inclusive; Caucasian race; Body-mass index (BMI) within the range dated 18.5 to 30 kg/m2; Verified diagnosis healthy as confirmed by the results of standard clinical, laboratory, and instrumental evaluations; A negative pregnancy test at the Screening Visit for female subjects of childbearing potential. Postmenopausal (no menses for at least 1 year) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) females are exempted from the requirement. In case of using hormonal contraceptives, these should be withdrawn at least 2 months before the study; Volunteers' with preserved reproductive potential agree to use adequate contraception throughout the study and for 30 days thereafter Exclusion Criteria: Known hypersensitivity or intolerance to dapagliflozin or metformin or any other excipient of the study drugs; History of allergy to Na+ glucose co-transport inhibitor; Complicated allergic history including food intolerance; Lactose intolerance, lactase deficiency, glucose-galactose malabsorption; Chronic diseases of the cardiovascular, bronchopulmonary, nervous, endocrine, or musculoskeletal systems, as well as diseases of the gastrointestinal tract, liver, kidneys, blood, immune system, mental disorders; Deviations from the normal parameters in clinical blood count analysis, biochemical blood analysis, urinalysis; vital signs; Mental, physical and other reasons that do not allow the subjects according to investigator's opinion to assess their behavior adequately, to follow correctly the requirements of the clinical study protocol and to assess the expected risks and possible discomfort; Organic brain damage, history of increased seizure activity; Changes on ECG (clinically significant); Systolic blood pressure (AD) measured in a sitting position, less than 100 mmHg or above 130 mmHg and / or diastolic blood pressure below 70 mm Hg or above 90 mmHg at screening or any time during the study; Heart rate less than 60 or more than 80 beats per minute at screening or prior to administration of the drug in each period of the study; Scheduled radioisotope or radiological examinations using iodinated contrast agents during < 2 days before dosing; Rare hereditary diseases manifestating with fructose or sorbitol intolerance; Gastrointestinal tract surgery (except appendectomy); Acute infectious diseases less than 4 weeks before the start of the study; Regular medication (including dietary supplements and combination herbal medicinal products) and vitamins intake within 2 weeks (or 6 half-lives, whichever is longer) prior inclusion into the study and subject does not give agreement to refuse from this medication until the end of study; Administration of the medicines that have a significant effect on circulatory dynamics, liver function, etc. (barbiturates, omeprazol, zimetidin etc.) less than 30 days before the start of the study; Blood donation (450 ml and more of blood or plasma) less than 2 months before the start of the study; Participation in another clinical study within 3 months before the start of the study; Alcohol intake > 10 units of alcohol per week (1 unit of alcohol - 500 ml of beer, 200 ml of dry wine or 50 ml of strong alcoholic beverages) or history of alcohol abuse, narcomania or other drug abuse. Use of alcohol and/or caffeinated and xanthine containing substances (for example, coffee, tea, colas, energetic drinks), chocolate as well as citrus fruits and cranberry (including juices, fruit drinks, etc.) 72 hours prior and throughout the study. Smoker (>10 cigarettes per day) and/or inability to refrain from smoking on Period I and Period II Special diets (e.g. vegetarians or hypocaloric diet [ less than 1000 cal/day]) or lifestyle (including night work and extreme physical activities, such as sports or weight lifting), which may impede the study conduction and monitoring; Positive screening blood test for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, human immunodeficiency virus (HIV-1or HIV-2 antibodies) and / or syphilis (RW); A positive drug urine screening (cocaine, opiates, cannabis, barbiturates, amphetamines); A positive alcohol breath test; Dehydration due to diarrhea, vomiting or another cause during the last 24 hours before the start of the study; There is any concern by the investigator regarding the safe participation of the subject in the study or for any other reason; the investigator considers the subject ineligible for the study. Breast-feeding period; For women - Use of hormonal contraceptives for 2 months before the study start; Female volunteers with childbearing potential, having unprotected sexual intercourse with any unsterilized male partner (i.e., a man that is not sterilized by vasectomy for at least 6 months) for 30 days before receiving study medication.

Ages Eligible for Study
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Minimum Age: 18 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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T/R<br>Test product (T): a single oral dose of modified release fixed dose combination film-coated tablet consisting of 10 mg dapagliflozin IR and 1000 mg metformin hydrochloride extended release. Volunteers enrolled to group 1, on the first study period will take the study test product (Т), and on the second study period after wash out period of 7 days the volunteers will be given the Reference product (R) | Drug: Xigduo XR<br>* a single oral dose of modified release fixed dose combination film-coated tablet consisting of 10 mg dapagliflozin IR and 1000 mg metformin hydrochloride extended release<br>Drug: Metformin ER (Glucophage® long)<br>* co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).<br>Drug: Dapagliflozin (Forxiga)<br>* co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).<br>|
| Experimental: R/T<br>Reference product (R): co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long). Volunteers from group 2 will be administered with the study drug in reverse order. It means that group 1 will take the study products in sequence T-R and group 2 in the sequence R-T. | Drug: Xigduo XR<br>* a single oral dose of modified release fixed dose combination film-coated tablet consisting of 10 mg dapagliflozin IR and 1000 mg metformin hydrochloride extended release<br>Drug: Metformin ER (Glucophage® long)<br>* co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).<br>Drug: Dapagliflozin (Forxiga)<br>* co-administration of a single oral dose of 10 mg dapagliflozin film-coated tablet (Forxiga™) and two tablets 500 mg metformin hydrochloride extended release tablets (Glucophage® long).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax). |  | Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product. | 
| Area Under the Concentration - Time Curve (AUC0-t) |  | Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product. | 
| Area Under the Concentration - Time Curve (AUC0-∞) |  | Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product. | 
| Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | The drugs are considered bioequivalent if the 90% confidence intervals for the Test : Reference products geometric least squares mean ratios of AUC, Cmax и Cmax/AUC parameters are in the range of 80% - 125%. | Blood sampling 0 h, 30 min, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours after the dosing. Time interval for sampling is provided with pharmacokinetic characteristics of the product. | 
| Adverse Events | Adverse events data for Dapagliflozin + Metformin, modified-release film-coated tablets, 10 mg + 1000 mg (AstraZeneca AB, Sweden) and for co-administered Forxiga™ (Dapagliflozin), film-coated tablets, 10 mg, (Bristol Myers Squibb Company, USA) and Glucophage® long (Metformin), XR tablets, 500 mg/2 tablets (Merck Santé S.A.S, France) | AE information will be collected from the time of the first dosing to the last study procedure made in the hospital, approximately 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Xigduo;, bioequivalence;, crossover;, Russia