Trial Outcomes & Findings for 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 (NCT NCT02722239)
NCT ID: NCT02722239
Last Updated: 2018-02-19
Results Overview
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
40 participants
Primary outcome timeframe
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.
Results posted on
2018-02-19
Participant Flow
Participants recruited from one medical clinic located in Moscow, Russia in March and April 2016.
46 subjects were screened, 40 randomized (2 did not meet inclusion criteria and 4 were back-up volunteers).
Participant milestones
| Measure |
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)
|
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.
|
|---|---|---|
|
Overall Study
STARTED
|
20
|
20
|
|
Overall Study
First Intervention (1 Day)
|
20
|
20
|
|
Overall Study
Washout (7 Days)
|
20
|
20
|
|
Overall Study
Second Intervention (1 Day)
|
20
|
20
|
|
Overall Study
COMPLETED
|
20
|
20
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
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
Baseline characteristics by cohort
| Measure |
T Drug First / Then Drug R
n=20 Participants
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)
|
R Drug First / Then Drug T
n=20 Participants
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.
|
Total
n=40 Participants
Total of all reporting groups
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|---|---|---|---|
|
Age, Continuous
Age (years): Mean ± Standard Deviation
|
29.6 years
STANDARD_DEVIATION 7.7 • n=99 Participants
|
30.8 years
STANDARD_DEVIATION 8.7 • n=107 Participants
|
30.2 years
STANDARD_DEVIATION 8.1 • n=206 Participants
|
|
Age, Customized
<18 years
|
0 participants
n=99 Participants
|
0 participants
n=107 Participants
|
0 participants
n=206 Participants
|
|
Age, Customized
between 18 and 45 years (inclusive)
|
20 participants
n=99 Participants
|
20 participants
n=107 Participants
|
40 participants
n=206 Participants
|
|
Age, Customized
>45 years
|
0 participants
n=99 Participants
|
0 participants
n=107 Participants
|
0 participants
n=206 Participants
|
|
Sex: Female, Male
Female
|
9 Participants
n=99 Participants
|
10 Participants
n=107 Participants
|
19 Participants
n=206 Participants
|
|
Sex: Female, Male
Male
|
11 Participants
n=99 Participants
|
10 Participants
n=107 Participants
|
21 Participants
n=206 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
White
|
20 Participants
n=99 Participants
|
20 Participants
n=107 Participants
|
40 Participants
n=206 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
PRIMARY outcome
Timeframe: 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.Outcome measures
| Measure |
Test Product (T)
n=40 Participants
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.
|
Reference Product (R)
n=40 Participants
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).
|
|---|---|---|
|
Maximum Concentration (Cmax).
Dapagliflozin Cmax [ug/ml]: Mean (± SD)
|
90.883 ug/ml
Standard Deviation 25.302
|
95.975 ug/ml
Standard Deviation 25.135
|
|
Maximum Concentration (Cmax).
Metformin Cmax [ug/ml]: Mean (± SD)
|
1030.83 ug/ml
Standard Deviation 258.910
|
986.93 ug/ml
Standard Deviation 255.277
|
PRIMARY outcome
Timeframe: 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.Outcome measures
| Measure |
Test Product (T)
n=40 Participants
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.
|
Reference Product (R)
n=40 Participants
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).
|
|---|---|---|
|
Area Under the "Concentration - Time" Curve (AUC0-t)
Dapagliflozin AUC0-t [ug/mL*h]: Mean (± SD)
|
505.964 ug/mL*h
Standard Deviation 130.420
|
511.293 ug/mL*h
Standard Deviation 127.715
|
|
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
|
9286.92 ug/mL*h
Standard Deviation 3222.38
|
PRIMARY outcome
Timeframe: 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.Outcome measures
| Measure |
Test Product (T)
n=40 Participants
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.
|
Reference Product (R)
n=40 Participants
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).
|
|---|---|---|
|
Area Under the "Concentration - Time" Curve (AUC0-∞)
Dapagliflozin AUC0-∞ [ug/mL*h]: Mean (± SD)
|
521.295 ug/mL*h
Standard Deviation 136.036
|
532.556 ug/mL*h
Standard Deviation 144.768
|
|
Area Under the "Concentration - Time" Curve (AUC0-∞)
Metformin AUC0-∞ [ug/mL*h]: Mean (± SD)
|
9408.51 ug/mL*h
Standard Deviation 3373.65
|
9612.23 ug/mL*h
Standard Deviation 3440.33
|
PRIMARY outcome
Timeframe: 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.
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%.
Outcome measures
| Measure |
Test Product (T)
n=40 Participants
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.
|
Reference Product (R)
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).
|
|---|---|---|
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Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios
Dapagliflozin AUC0-t %
|
99.0829 Geometric least squares mean ratio (%)
Interval 95.943 to 102.326
|
—
|
|
Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios
Dapagliflozin Cmax %
|
94.7712 Geometric least squares mean ratio (%)
Interval 87.887 to 102.194
|
—
|
|
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 (%)
Interval 89.102 to 102.675
|
—
|
|
Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios
Metformin AUC0-t %
|
95.9105 Geometric least squares mean ratio (%)
Interval 89.492 to 102.79
|
—
|
|
Bioequivalence Consideration: 90% Confidence Intervals for the Test:Reference Geometric Least Squares Mean Ratios
Metformin Cmax %
|
104.3772 Geometric least squares mean ratio (%)
Interval 98.492 to 110.614
|
—
|
|
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 (%)
Interval 101.607 to 116.561
|
—
|
PRIMARY outcome
Timeframe: AE information will be collected from the time of the first dosing to the last study procedure made in the hospital, approximately 1 monthAdverse 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)
Outcome measures
| Measure |
Test Product (T)
n=40 Participants
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.
|
Reference Product (R)
n=40 Participants
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).
|
|---|---|---|
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Adverse Events
|
34 adverse event
|
31 adverse event
|
Adverse Events
Test Product (T)
Serious events: 0 serious events
Other events: 20 other events
Deaths: 0 deaths
Reference Product (R)
Serious events: 0 serious events
Other events: 19 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Test Product (T)
n=40 participants at risk
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.
|
Reference Product (R)
n=40 participants at risk
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).
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|---|---|---|
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Investigations
Glucose urine present
|
32.5%
13/40 • Number of events 13 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
22.5%
9/40 • Number of events 9 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
|
Investigations
Haematocrit increased in hematology
|
0.00%
0/40 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
5.0%
2/40 • Number of events 2 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
|
Investigations
Specific gravity urine decreased
|
12.5%
5/40 • Number of events 5 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
20.0%
8/40 • Number of events 8 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
|
Investigations
pH urine decreased
|
37.5%
15/40 • Number of events 15 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
25.0%
10/40 • Number of events 10 • 1 month
According to the local regulatory authorities request any (even clinically insignificant) laboratory abnormalities have been interpreted as adverse event.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee PI signed the Protocol and agreed to conform fully to the Protocol requirements. According to the Protocol the PI should inform the Sponsor in writing beforehand and provide the sponsor with all manuscripts or abstracts before submitting them to the editorial office or scientific expert board, and obtain a written permission from the Sponsor. The period is not mentioned.
- Publication restrictions are in place
Restriction type: OTHER