Trial Outcomes & Findings for This Study Tests Whether Taking the Medicines Empagliflozin, Linagliptin, and Metformin Together in 1 Pill is the Same as Taking Them in Separate Pills. The Study is Done in Healthy Men and Women and Measures the Amount of Each Medicine in the Blood (NCT NCT03259490)
NCT ID: NCT03259490
Last Updated: 2020-03-05
Results Overview
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) * A predose concentration was \>5% Cmax value of that subject * Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.
Recruitment status
COMPLETED
Study phase
PHASE1
Target enrollment
30 participants
Primary outcome timeframe
Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dose
Results posted on
2020-03-05
Participant Flow
It was planned to include healthy male and female subjects in this randomised, open label study. They were recruited from the volunteers' pool of the study site.
This trial was a two-way crossover study. All subjects received the 2 treatments in randomised order.
Participant milestones
| Measure |
Test/ Reference (TR)
Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.
|
Reference/ Test (RT)
Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.
|
|---|---|---|
|
Period 1
STARTED
|
15
|
15
|
|
Period 1
COMPLETED
|
15
|
14
|
|
Period 1
NOT COMPLETED
|
0
|
1
|
|
Period 2
STARTED
|
15
|
14
|
|
Period 2
COMPLETED
|
14
|
14
|
|
Period 2
NOT COMPLETED
|
1
|
0
|
Reasons for withdrawal
| Measure |
Test/ Reference (TR)
Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.
|
Reference/ Test (RT)
Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.
|
|---|---|---|
|
Period 1
Withdrawal by Subject
|
0
|
1
|
|
Period 2
Protocol Violation
|
1
|
0
|
Baseline Characteristics
TS
Baseline characteristics by cohort
| Measure |
Test/ Reference (TR)
n=15 Participants
Subjects were orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast.
|
Reference/ Test (RT)
n=15 Participants
Subjects were orally administered the free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered a single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast.
|
Total
n=30 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
37.1 years
STANDARD_DEVIATION 12.2 • n=5 Participants • TS
|
43.5 years
STANDARD_DEVIATION 8.0 • n=7 Participants • TS
|
40.3 years
STANDARD_DEVIATION 10.7 • n=5 Participants • TS
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants • TS
|
8 Participants
n=7 Participants • TS
|
13 Participants
n=5 Participants • TS
|
|
Sex: Female, Male
Male
|
10 Participants
n=5 Participants • TS
|
7 Participants
n=7 Participants • TS
|
17 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
Asian
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
Black or African American
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
White
|
15 Participants
n=5 Participants • TS
|
15 Participants
n=7 Participants • TS
|
30 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants • TS
|
0 Participants
n=7 Participants • TS
|
0 Participants
n=5 Participants • TS
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) for empagliflozin. Plasma concentrations and/or parameters of a subject were to be considered as non-evaluable,if for example: * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subjects experiencing emesis) * A predose concentration was \>5% Cmax value of that subject * Missing samples/concentration data at important phases of pharmacokinetic (PK) disposition curve. Pharmacokinetic parameter set (PKS): This subject set included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded according to the description above. Thus, a subject was to be included in the PKS even if he/she contributed only one PK parameter value for one period to the statistical assessment.
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) for Empagliflozin
|
5656.07 nanomoles*hours/ litres (nmol*h/L)
Standard Error 1.04
|
5488.31 nanomoles*hours/ litres (nmol*h/L)
Standard Error 1.04
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
AUC0-tz for metformin.
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
AUC0-tz for Metformin.
|
12455.82 nanogram*hours/ millilitres (ng*h/mL)
Standard Error 1.05
|
12412.57 nanogram*hours/ millilitres (ng*h/mL)
Standard Error 1.05
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours (AUC0-72) for Linagliptin
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) for Linagliptin
|
238.84 nmol*h/L
Standard Error 1.04
|
238.11 nmol*h/L
Standard Error 1.04
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Maximum measured concentration of the empagliflozin in plasma (Cmax)
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
|
540.01 nmol/L
Standard Error 1.04
|
540.26 nmol/L
Standard Error 1.04
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Cmax for metformin in plasma.
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Cmax for Metformin in Plasma
|
1237.16 ng/mL
Standard Error 1.04
|
1147.88 ng/mL
Standard Error 1.04
|
PRIMARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Cmax for linagliptin in plasma.
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Cmax for Linagliptin in Plasma
|
5.69 nmol/L
Standard Error 1.04
|
5.86 nmol/L
Standard Error 1.04
|
SECONDARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Empagliflozin (AUC(0-∞)
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) for Empagliflozin (AUC(0-∞)
|
5727.20 nmol*h/L
Standard Error 1.04
|
5554.37 nmol*h/L
Standard Error 1.04
|
SECONDARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
AUC(0-∞) for Metformin
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
AUC(0-∞) for Metformin
|
12745.62 ng*h/mL
Standard Error 1.05
|
12724.27 ng*h/mL
Standard Error 1.05
|
SECONDARY outcome
Timeframe: Pharmacokinetic samples were collected at 1:30 hours: minutes pre dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 hours:minutes post dosePopulation: PKS
AUC(0-∞) for Linagliptin
Outcome measures
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 Participants
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 Participants
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
AUC(0-∞) for Linagliptin
|
384.27 nmol*h/L
Standard Error 1.05
|
394.95 nmol*h/L
Standard Error 1.05
|
Adverse Events
Empagliflozin/Linagliptin/Metformin FDC (Test)
Serious events: 0 serious events
Other events: 11 other events
Deaths: 0 deaths
Empagliflozin/Linagliptin/Metformin FC (Reference)
Serious events: 0 serious events
Other events: 6 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Empagliflozin/Linagliptin/Metformin FDC (Test)
n=29 participants at risk
Subjects were orally administered a single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast
|
Empagliflozin/Linagliptin/Metformin FC (Reference)
n=29 participants at risk
Subjects were orally administered a single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin XR tablets with 240 mL of water after a high-fat, high-calorie breakfast
|
|---|---|---|
|
Gastrointestinal disorders
Nausea
|
3.4%
1/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
6.9%
2/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
|
Infections and infestations
Oral herpes
|
6.9%
2/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
0.00%
0/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
|
Nervous system disorders
Headache
|
27.6%
8/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
6.9%
2/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
3.4%
1/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
6.9%
2/29 • All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP); up to 50 days
REP for the combined treatment with empagliflozin, linagliptin, and metformin, when measurable drug levels or pharmacodynamic effects were still likely to be present, was defined as 7 days after the last administration of trial medication.
|
Additional Information
Boehringer Ingelheim, Call Center
Boehringer Ingelheim
Phone: 1-800-243-0127
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place