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
Overview
- Phase
- Phase 1
- Intervention
- Xigduo XR
- Conditions
- Diabetes Mellitus, Type 2
- Sponsor
- AstraZeneca
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Maximum Concentration (Cmax).
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief 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.
Detailed Description
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.
Investigators
Eligibility Criteria
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 In case of using hormonal contraceptives, these should be withdrawn at least 2 months before the study;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;
Arms & Interventions
T/R
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)
Intervention: Xigduo XR
T/R
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)
Intervention: Metformin ER (Glucophage® long)
T/R
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)
Intervention: Dapagliflozin (Forxiga)
R/T
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.
Intervention: Xigduo XR
R/T
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.
Intervention: Metformin ER (Glucophage® long)
R/T
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.
Intervention: Dapagliflozin (Forxiga)
Outcomes
Primary Outcomes
Maximum Concentration (Cmax).
Time Frame: 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)
Time Frame: 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-∞)
Time Frame: 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
Time Frame: 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.
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%.
Adverse Events
Time Frame: AE information will be collected from the time of the first dosing to the last study procedure made in the hospital, approximately 1 month
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)