Healthy
Conditions
Brief summary
The purpose of this trial is to demonstrate bioequivalence of a newly developed fixed dose combination (FDC) tablet containing linagliptin and metformin extended release compared to the free combination of linagliptin and metformin extended release, both under fed and fasted conditions.
Interventions
1x Linagliptin/Metformin FDC tablet
DRUGLinagliptin
1x Linagliptin tablet
DRUGMetformin ER
2x Metformin ER tablets
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
\- Healthy male or female subjects
Exclusion criteria
\- Any relevant deviation from healthy condition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | AUC 0-72 (area under concentration-time curve of the Linagliptin in plasma from 0 to 72 hours) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
| Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | Cmax (maximum measured concentration of Linagliptin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | AUC 0-t (Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
| Cmax of Metformin in Plasma | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | Cmax (maximum measured concentration of the Metformin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-inf of Metformin in Plasma | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | AUC0-inf(area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
| Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration | AUC0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Linagliptin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively. |
Countries
Germany
Participant flow
Recruitment details
The study is conducted in two parts: Part 1 of the study was conducted in fasting conditions. Part 2 of the study was conducted in fed conditions.
Participants by arm
| Arm | Count |
|---|---|
| FDC 1000 Fast or L+M 1000 Fast The subjects in Part 1 were randomly allocated to 1 of the 2 treatment sequences T fasted\_R fasted or R fasted\_T fasted.
FDC 1000 fast (T fasted): 5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.
L+M 1000 fast (R fasted): 5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after an overnight fast of at least 10 h.
Where, L+M = Linagliptin 5mg+Metformin 1000mg | 52 |
| FDC 1000 Fed or L+M 1000 Fed The subjects in Part 2 were randomly allocated to 1 of the 2 treatment sequences T fed\_R fed or R fed\_T fed.
FDC 1000 fed (T fed): 5 mg linagliptin/1000 mg metformin XR (given as 1 FDC tablet) orally with 240 mL of water after after a high-fat, high-calorie meal.
L+M 1000 fed (R fed): 5 mg linagliptin and 1000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 2 tablets 500 mg metformin XR) oral with 240 mL of water after a high-fat, high-calorie meal.
Where, L+M = Linagliptin 5mg+Metformin 1000mg | 16 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout Period 1 (35 Days) | Adverse Event | 0 | 0 | 1 | 1 |
| Washout Period 1 (35 Days) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | FDC 1000 Fast or L+M 1000 Fast | FDC 1000 Fed or L+M 1000 Fed | Total |
|---|---|---|---|
| Age, Continuous | 34.7 years STANDARD_DEVIATION 10.4 | 36.1 years STANDARD_DEVIATION 11.9 | 35.0 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 29 Participants | 10 Participants | 39 Participants |
| Sex: Female, Male Male | 23 Participants | 6 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 52 | 9 / 52 | 4 / 15 | 4 / 14 |
| serious Total, serious adverse events | 0 / 52 | 0 / 52 | 2 / 15 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72)
AUC 0-72 (area under concentration-time curve of the Linagliptin in plasma from 0 to 72 hours) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 286.639 nmol*h/L | Geometric Coefficient of Variation 11.8 |
| FDC 1000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 287.696 nmol*h/L | Geometric Coefficient of Variation 11.8 |
| L+M 1000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 234.052 nmol*h/L | Geometric Coefficient of Variation 9.2 |
| FDC 1000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 221.644 nmol*h/L | Geometric Coefficient of Variation 9.2 |
p-value: <0.000190% CI: [96.562, 104.326]ANOVA
p-value: 0.000490% CI: [88.712, 101.089]ANOVA
Primary
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
AUC 0-t (Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 7146.61 ng∙h/mL | Geometric Coefficient of Variation 22.2 |
| FDC 1000 Fasted | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 7146.00 ng∙h/mL | Geometric Coefficient of Variation 22.2 |
| L+M 1000 Fed | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 11326.12 ng∙h/mL | Geometric Coefficient of Variation 7.1 |
| FDC 1000 Fed | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 10980.17 ng∙h/mL | Geometric Coefficient of Variation 7.1 |
p-value: <0.000190% CI: [93.03, 107.47]ANOVA
p-value: <0.000190% CI: [92.24, 101.89]ANOVA
Primary
Cmax of Metformin in Plasma
Cmax (maximum measured concentration of the Metformin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | Cmax of Metformin in Plasma | 925.709 ng/mL | Geometric Coefficient of Variation 23.4 |
| FDC 1000 Fasted | Cmax of Metformin in Plasma | 923.543 ng/mL | Geometric Coefficient of Variation 23.4 |
| L+M 1000 Fed | Cmax of Metformin in Plasma | 947.445 ng/mL | Geometric Coefficient of Variation 5.9 |
| FDC 1000 Fed | Cmax of Metformin in Plasma | 937.685 ng/mL | Geometric Coefficient of Variation 5.9 |
p-value: <0.000190% CI: [92.464, 107.645]ANOVA
p-value: <0.000190% CI: [94.95, 103.16]ANOVA
Primary
Maximum Measured Concentration of Linagliptin in Plasma (Cmax)
Cmax (maximum measured concentration of Linagliptin in plasma) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 8.826 nmol/L | Geometric Coefficient of Variation 27.1 |
| FDC 1000 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 9.540 nmol/L | Geometric Coefficient of Variation 27.1 |
| L+M 1000 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 5.791 nmol/L | Geometric Coefficient of Variation 6.1 |
| FDC 1000 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 5.689 nmol/L | Geometric Coefficient of Variation 6.1 |
p-value: 0.003890% CI: [99.022, 117.989]ANOVA
p-value: <0.000190% CI: [94.067, 102.597]ANOVA
Secondary
Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf)
AUC0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Linagliptin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 461.306 nmol*h/L | Geometric Coefficient of Variation 14.3 |
| FDC 1000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 460.009 nmol*h/L | Geometric Coefficient of Variation 14.3 |
| L+M 1000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 397.945 nmol*h/L | Geometric Coefficient of Variation 32.4 |
| FDC 1000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 387.424 nmol*h/L | Geometric Coefficient of Variation 32.4 |
p-value: <0.000190% CI: [95.163, 104.493]ANOVA
p-value: 0.077890% CI: [77.082, 122.963]ANOVA
Secondary
AUC0-inf of Metformin in Plasma
AUC0-inf(area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) for Metformin. The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40min, 1h,1h 30min, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h,34h, 48h and 72h after drug administration
Population: PKS 1000 fast and PKS 1000 fed, included all treated subjects in Part 1 and Part 2, respectively, who provided at least 1 observation for at least 1 primary endpoint, without important protocol violations regarding the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 1000 Fasted | AUC0-inf of Metformin in Plasma | 7607.75 ng∙h/mL | Geometric Coefficient of Variation 21.7 |
| FDC 1000 Fasted | AUC0-inf of Metformin in Plasma | 7540.21 ng∙h/mL | Geometric Coefficient of Variation 21.7 |
| L+M 1000 Fed | AUC0-inf of Metformin in Plasma | 15047.37 ng∙h/mL | Geometric Coefficient of Variation 7.2 |
| FDC 1000 Fed | AUC0-inf of Metformin in Plasma | 14773.59 ng∙h/mL | Geometric Coefficient of Variation 7.2 |
p-value: <0.000190% CI: [92.37, 106.35]ANOVA
p-value: <0.000190% CI: [93.34, 103.27]ANOVA