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.
Interventions
DRUGLinagliptin
1 x Linagliptin tablet
2 x Linagliptin/Metformin ER FDC tablet
DRUGMetformin ER
3 x 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 the 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-tz (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 |
|---|---|---|
| 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. |
| 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. |
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 1500 Fasted or L+M 1500 Fasted 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 1500 fasted (T fasted): 5 mg linagliptin/1500 mg metformin XR (given as 2\*2.5mg linagliptin/750mg metformin XR FDC tablets) orally with 240 mL of water after an overnight fast of at least 10 h.
L+M 1500 fasted (R fasted): 5 mg linagliptin and 1500 mg metformin XR (given as 1 tablet 5 mg linagliptin and 3 tablets 500 mg metformin XR) orally with 240 mL of water after an overnight fast of at least 10 h.
Where, L+M = Linagliptin 5mg+Metformin XR 1500mg | 58 |
| FDC 1500 Fed or L+M 1500 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 1500 fed (T fed): 5 mg linagliptin/1500 mg metformin XR (given as 2\*2.5mg linagliptin/750mg metformin XR FDC tablets) orally with 240 mL of water after after a high-fat, high-calorie meal.
L+M 1500 fed (R fed): 5 mg linagliptin and 1500 mg metformin XR (given as 1 tablet 5 mg linagliptin and 3 tablets 500 mg metformin XR) orally with 240 mL of water after a high-fat, high-calorie meal.
Where, L+M = Linagliptin 5mg+Metformin XR 1500mg | 16 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Washout Period (35 Days) | Adverse Event | 1 | 1 | 0 | 0 |
| Washout Period (35 Days) | elevated AST and ALT levels | 1 | 0 | 0 | 0 |
| Washout Period (35 Days) | Withdrawal by Subject | 0 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | FDC 1500 Fasted or L+M 1500 Fasted | FDC 1500 Fed or L+M 1500 Fed | Total |
|---|---|---|---|
| Age, Continuous | 39.0 years STANDARD_DEVIATION 9.6 | 42.8 years STANDARD_DEVIATION 10.1 | 39.8 years STANDARD_DEVIATION 9.8 |
| Sex: Female, Male Female | 30 Participants | 9 Participants | 39 Participants |
| Sex: Female, Male Male | 28 Participants | 7 Participants | 35 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 | 15 / 56 | 22 / 54 | 8 / 16 | 3 / 16 |
| serious Total, serious adverse events | 0 / 56 | 0 / 54 | 0 / 16 | 0 / 16 |
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 the 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: PKS1500 Fast and PKS1500 Fed, included all treated subjects in Part 1 and Part 2, 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 1500 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 298.982 nmol*h/L | Geometric Coefficient of Variation 11.5 |
| FDC 1500 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 307.320 nmol*h/L | Geometric Coefficient of Variation 11.5 |
| L+M 1500 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 257.932 nmol*h/L | Geometric Coefficient of Variation 6.6 |
| FDC 1500 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 261.680 nmol*h/L | Geometric Coefficient of Variation 6.6 |
p-value: <0.000190% CI: [98.938, 106.789]ANOVA
p-value: <0.000190% CI: [96.99, 106.121]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-tz (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 1500 fast and PKS 1500 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 1500 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) | 10414.62 ng*h/mL | Geometric Coefficient of Variation 25.5 |
| FDC 1500 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) | 10626.51 ng*h/mL | Geometric Coefficient of Variation 25.5 |
| L+M 1500 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) | 19434.46 ng*h/mL | Geometric Coefficient of Variation 10.7 |
| FDC 1500 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) | 18727.47 ng*h/mL | Geometric Coefficient of Variation 10.7 |
p-value: 0.000190% CI: [94.03, 110.72]ANOVA
p-value: 0.000290% CI: [89.96, 103.22]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 1500 fast and PKS 1500 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 1500 Fasted | Cmax of Metformin in Plasma | 1245.262 ng/mL | Geometric Coefficient of Variation 29.4 |
| FDC 1500 Fasted | Cmax of Metformin in Plasma | 1308.777 ng/mL | Geometric Coefficient of Variation 29.4 |
| L+M 1500 Fed | Cmax of Metformin in Plasma | 1526.907 ng/mL | Geometric Coefficient of Variation 7.2 |
| FDC 1500 Fed | Cmax of Metformin in Plasma | 1739.311 ng/mL | Geometric Coefficient of Variation 7.2 |
p-value: 0.001390% CI: [95.829, 115.269]ANOVA
p-value: 0.001890% CI: [108.749, 119.318]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 1500 fast and PKS 1500 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 1500 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 8.909 nmol/L | Geometric Coefficient of Variation 23.5 |
| FDC 1500 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 9.464 nmol/L | Geometric Coefficient of Variation 23.5 |
| L+M 1500 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.729 nmol/L | Geometric Coefficient of Variation 13.3 |
| FDC 1500 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 7.181 nmol/L | Geometric Coefficient of Variation 13.3 |
p-value: 0.000490% CI: [98.449, 114.614]ANOVA
p-value: 0.00490% CI: [97.614, 116.658]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 1500 fast and PKS 1500 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 1500 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 499.020 nmol*h/L | Geometric Coefficient of Variation 17.5 |
| FDC 1500 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 506.245 nmol*h/L | Geometric Coefficient of Variation 17.5 |
| L+M 1500 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 430.765 nmol*h/L | Geometric Coefficient of Variation 8.7 |
| FDC 1500 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 458.042 nmol*h/L | Geometric Coefficient of Variation 8.7 |
p-value: <0.000190% CI: [95.748, 107.487]ANOVA
p-value: 0.000290% CI: [100.268, 112.763]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 1500 fast and PKS 1500 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 1500 Fasted | AUC0-inf of Metformin in Plasma | 10831.52 ng*h/mL | Geometric Coefficient of Variation 25 |
| FDC 1500 Fasted | AUC0-inf of Metformin in Plasma | 11055.51 ng*h/mL | Geometric Coefficient of Variation 25 |
| L+M 1500 Fed | AUC0-inf of Metformin in Plasma | 19706.52 ng*h/mL | Geometric Coefficient of Variation 10.7 |
| FDC 1500 Fed | AUC0-inf of Metformin in Plasma | 19073.16 ng*h/mL | Geometric Coefficient of Variation 10.7 |
p-value: <0.000190% CI: [94.2, 110.59]ANOVA
p-value: 0.000190% CI: [90.33, 103.7]ANOVA