Diabetes Mellitus, Type 2
Conditions
Keywords
Xigduo;, bioequivalence;, crossover;, Russia
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.
Interventions
DRUGXigduo XR
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
DRUGMetformin ER (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).
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).
Sponsors
Biocard
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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) |
Countries
Russia
Participant flow
Recruitment details
Participants recruited from one medical clinic located in Moscow, Russia in March and April 2016.
Pre-assignment details
46 subjects were screened, 40 randomized (2 did not meet inclusion criteria and 4 were back-up volunteers).
Participants by arm
| Arm | Count |
|---|---|
| T Drug First / Then Drug 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 took the study test product (Т), and on the second study period after wash out period of 7 days the volunteers were given the Reference product (R) | 20 |
| R Drug First / Then Drug 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 were administered with the study drug in reverse order. It means that group 1 took the study products in sequence T-R and group 2 in the sequence R-T. | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | T Drug First / Then Drug R | R Drug First / Then Drug T | Total |
|---|---|---|---|
| Age, Continuous Age (years): Mean ± Standard Deviation | 29.6 years STANDARD_DEVIATION 7.7 | 30.8 years STANDARD_DEVIATION 8.7 | 30.2 years STANDARD_DEVIATION 8.1 |
| Age, Customized <18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >45 years | 0 participants | 0 participants | 0 participants |
| Age, Customized between 18 and 45 years (inclusive) | 20 participants | 20 participants | 40 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Female | 9 Participants | 10 Participants | 19 Participants |
| Sex: Female, Male Male | 11 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 20 / 40 | 19 / 40 |
| serious Total, serious adverse events | 0 / 40 | 0 / 40 |
Outcome results
Primary
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)
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Test Product (T) | Adverse Events | 34 adverse event |
| Reference Product (R) | Adverse Events | 31 adverse event |
Primary
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Test Product (T) | Area Under the Concentration - Time Curve (AUC0-∞) | Dapagliflozin AUC0-∞ [ug/mL*h]: Mean (± SD) | 521.295 ug/mL*h | Standard Deviation 136.036 |
| Test Product (T) | Area Under the Concentration - Time Curve (AUC0-∞) | Metformin AUC0-∞ [ug/mL*h]: Mean (± SD) | 9408.51 ug/mL*h | Standard Deviation 3373.65 |
| Reference Product (R) | Area Under the Concentration - Time Curve (AUC0-∞) | Dapagliflozin AUC0-∞ [ug/mL*h]: Mean (± SD) | 532.556 ug/mL*h | Standard Deviation 144.768 |
| Reference Product (R) | Area Under the Concentration - Time Curve (AUC0-∞) | Metformin AUC0-∞ [ug/mL*h]: Mean (± SD) | 9612.23 ug/mL*h | Standard Deviation 3440.33 |
Primary
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Test Product (T) | Area Under the Concentration - Time Curve (AUC0-t) | Dapagliflozin AUC0-t [ug/mL*h]: Mean (± SD) | 505.964 ug/mL*h | Standard Deviation 130.42 |
| Test Product (T) | Area Under the Concentration - Time Curve (AUC0-t) | Metformin AUC0-t [ug/mL*h]: Mean (± SD) | 8858.52 ug/mL*h | Standard Deviation 2998.49 |
| Reference Product (R) | Area Under the Concentration - Time Curve (AUC0-t) | Dapagliflozin AUC0-t [ug/mL*h]: Mean (± SD) | 511.293 ug/mL*h | Standard Deviation 127.715 |
| Reference Product (R) | Area Under the Concentration - Time Curve (AUC0-t) | Metformin AUC0-t [ug/mL*h]: Mean (± SD) | 9286.92 ug/mL*h | Standard Deviation 3222.38 |
Primary
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%.
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.
Population: The Arms/Groups are combined because the main study goal was to compare the bioequivalence of the study drug and the reference drug which were intaken by all volunteers regardless of the group.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Dapagliflozin AUC0-t % | 99.0829 Geometric least squares mean ratio (%) |
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Dapagliflozin Cmax % | 94.7712 Geometric least squares mean ratio (%) |
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Dapagliflozin Cmax/AUC0-t % | 95.6484 Geometric least squares mean ratio (%) |
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Metformin AUC0-t % | 95.9105 Geometric least squares mean ratio (%) |
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Metformin Cmax % | 104.3772 Geometric least squares mean ratio (%) |
| Test Product (T) | Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios | Metformin Cmax/AUC0-t % | 108.8277 Geometric least squares mean ratio (%) |
Primary
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Test Product (T) | Maximum Concentration (Cmax). | Dapagliflozin Cmax [ug/ml]: Mean (± SD) | 90.883 ug/ml | Standard Deviation 25.302 |
| Test Product (T) | Maximum Concentration (Cmax). | Metformin Cmax [ug/ml]: Mean (± SD) | 1030.83 ug/ml | Standard Deviation 258.91 |
| Reference Product (R) | Maximum Concentration (Cmax). | Dapagliflozin Cmax [ug/ml]: Mean (± SD) | 95.975 ug/ml | Standard Deviation 25.135 |
| Reference Product (R) | Maximum Concentration (Cmax). | Metformin Cmax [ug/ml]: Mean (± SD) | 986.93 ug/ml | Standard Deviation 255.277 |