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
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus, Type 2
Intervention: Xigduo XR; Metformin ER (Glucophage® long); Dapagliflozin (Forxiga)
Intervention description: 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; 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).; 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).
Intervention MeSH terms: Metformin; Dapagliflozin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Xigduo;; bioequivalence;; crossover;; Russia

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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;

          2. Male and female subjects aged 18-45, inclusive;

          3. Caucasian race;

          4. Body-mass index (BMI) within the range dated 18.5 to 30 kg/m2;

          5. Verified diagnosis "healthy" as confirmed by the results of standard clinical,
             laboratory, and instrumental evaluations;

          6. 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;

          7. Volunteers' with preserved reproductive potential agree to use adequate contraception
             throughout the study and for 30 days thereafter

        Exclusion Criteria:

          1. Known hypersensitivity or intolerance to dapagliflozin or metformin or any other
             excipient of the study drugs;

          2. History of allergy to Na+ glucose co-transport inhibitor;

          3. Complicated allergic history including food intolerance;

          4. Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

          5. 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;

          6. Deviations from the normal parameters in clinical blood count analysis, biochemical
             blood analysis, urinalysis; vital signs;

          7. 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;

          8. Organic brain damage, history of increased seizure activity;

          9. Changes on ECG (clinically significant);

         10. 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;

         11. 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;

         12. Scheduled radioisotope or radiological examinations using iodinated contrast agents
             during < 2 days before dosing;

         13. Rare hereditary diseases manifestating with fructose or sorbitol intolerance;

         14. Gastrointestinal tract surgery (except appendectomy);

         15. Acute infectious diseases less than 4 weeks before the start of the study;

         16. 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;

         17. 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;

         18. Blood donation (450 ml and more of blood or plasma) less than 2 months before the
             start of the study;

         19. Participation in another clinical study within 3 months before the start of the study;

         20. 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.

         21. 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.

         22. Smoker (>10 cigarettes per day) and/or inability to refrain from smoking on Period I
             and Period II

         23. 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;

         24. 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);

         25. A positive drug urine screening (cocaine, opiates, cannabis, barbiturates,
             amphetamines);

         26. A positive alcohol breath test;

         27. Dehydration due to diarrhea, vomiting or another cause during the last 24 hours before
             the start of the study;

         28. 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.

         29. Breast-feeding period;

         30. For women - Use of hormonal contraceptives for 2 months before the study start;

         31. 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.