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
Linagliptin
DRUGMetformin
Metformin
Linagliptin/Metformin FDC
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 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 metformin 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 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 linagliptin 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 metformin 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
This study was conducted in two parts. Part 1: Fasting study Part 2: Fed Study
Participants by arm
| Arm | Count |
|---|---|
| FDC 2000 Fasted or L+M 2000 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 2000 fasted (T fasted): 2X2.5 mg linagliptin/1000 mg metformin XR (given as FDC tablet) orally with 240 mL of water after an overnight fast of at least 10 h.
L+M 2000 fasted (R fasted): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fasted) orally with 240 mL of water after an overnight fast of at least 10 h.
Where, L+M = Linagliptin 5mg+Metformin XR 2000mg | 58 |
| FDC 2000 Fed or L+M 2000 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 2000 fed (T fed): 2X2.5 mg linagliptin/1000 mg metformin XR (given as FDC tablet) orally with 240 mL of water after a high-fat, high-calorie meal.
L+M 2000 fed (R fed): 5 mg linagliptin and 2000 mg metformin XR (given as 1 tablet 5 mg linagliptin and 4 tablets 500 mg metformin XR; R fed) orally with 240 mL of water after a high-fat, high-calorie meal.
Where, L+M = Linagliptin 5mg+Metformin XR 2000mg | 16 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 (4 Days) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
| Washout Period 1 (35 Days) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | FDC 2000 Fasted or L+M 2000 Fasted | FDC 2000 Fed or L+M 2000 Fed | Total |
|---|---|---|---|
| Age, Continuous | 33.1 years STANDARD_DEVIATION 9.8 | 32.6 years STANDARD_DEVIATION 8.2 | 33.0 years STANDARD_DEVIATION 9.4 |
| Sex: Female, Male Female | 38 Participants | 7 Participants | 45 Participants |
| Sex: Female, Male Male | 20 Participants | 9 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 | 20 / 56 | 24 / 58 | 8 / 16 | 5 / 16 |
| serious Total, serious adverse events | 0 / 56 | 0 / 58 | 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 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: PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 2000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 278.460 nmol*h/L | Geometric Coefficient of Variation 9.1 |
| FDC 2000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 288.709 nmol*h/L | Geometric Coefficient of Variation 9.1 |
| L+M 2000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 264.509 nmol*h/L | Geometric Coefficient of Variation 12.7 |
| FDC 2000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 268.814 nmol*h/L | Geometric Coefficient of Variation 12.7 |
p-value: <0.000190% CI: [100.703, 106.747]ANOVA
p-value: 0.000390% CI: [93.721, 110.202]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 metformin 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: PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 2000 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) | 12028.27 ng*h/mL | Geometric Coefficient of Variation 17.6 |
| FDC 2000 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) | 11601.19 ng*h/mL | Geometric Coefficient of Variation 17.6 |
| L+M 2000 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) | 20411.01 ng*h/mL | Geometric Coefficient of Variation 11.7 |
| FDC 2000 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) | 19952.61 ng*h/mL | Geometric Coefficient of Variation 11.7 |
p-value: <0.000190% CI: [91.23, 101.97]ANOVA
p-value: 0.000290% CI: [90.47, 105.63]ANOVA
Primary
Cmax of Metformin in Plasma
Cmax (maximum measured concentration of 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: PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 2000 Fasted | Cmax of Metformin in Plasma | 1516.558 ng/mL | Geometric Coefficient of Variation 19.9 |
| FDC 2000 Fasted | Cmax of Metformin in Plasma | 1485.642 ng/mL | Geometric Coefficient of Variation 19.9 |
| L+M 2000 Fed | Cmax of Metformin in Plasma | 1571.040 ng/mL | Geometric Coefficient of Variation 13.8 |
| FDC 2000 Fed | Cmax of Metformin in Plasma | 1662.954 ng/mL | Geometric Coefficient of Variation 13.8 |
p-value: <0.000190% CI: [92.046, 104.257]ANOVA
p-value: 0.00390% CI: [96.705, 115.861]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: PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 2000 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 8.274 nmol/L | Geometric Coefficient of Variation 19.6 |
| FDC 2000 Fasted | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 9.480 nmol/L | Geometric Coefficient of Variation 19.6 |
| L+M 2000 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.729 nmol/L | Geometric Coefficient of Variation 20.1 |
| FDC 2000 Fed | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.613 nmol/L | Geometric Coefficient of Variation 20.1 |
p-value: 0.011390% CI: [107.687, 121.908]ANOVA
p-value: 0.006490% CI: [86.543, 111.609]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 linagliptin 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: PKS2000 Fast and PKS2000 Fed, consists of the subjects who provided at least 1 observation for at least 1 primary endpoint without Important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| L+M 2000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 457.780 nmol*h/L | Geometric Coefficient of Variation 15.8 |
| FDC 2000 Fasted | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 473.704 nmol*h/L | Geometric Coefficient of Variation 15.8 |
| L+M 2000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 445.884 nmol*h/L | Geometric Coefficient of Variation 16.7 |
| FDC 2000 Fed | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-inf) | 451.888 nmol*h/L | Geometric Coefficient of Variation 16.7 |
p-value: <0.000190% CI: [98.426, 108.79]ANOVA
p-value: 0.001990% CI: [91.13, 112.708]ANOVA
Secondary
AUC0-inf of Metformin in Plasma
AUC0-inf(area under the concentration-time curve of the metformin 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 2000 fast and PKS 2000 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 2000 Fasted | AUC0-inf of Metformin in Plasma | 12736.87 ng*h/mL | Geometric Coefficient of Variation 19.7 |
| FDC 2000 Fasted | AUC0-inf of Metformin in Plasma | 12162.37 ng*h/mL | Geometric Coefficient of Variation 19.7 |
| L+M 2000 Fed | AUC0-inf of Metformin in Plasma | 20721.20 ng*h/mL | Geometric Coefficient of Variation 11.9 |
| FDC 2000 Fed | AUC0-inf of Metformin in Plasma | 20346.34 ng*h/mL | Geometric Coefficient of Variation 11.9 |
p-value: <0.000190% CI: [89.73, 101.62]ANOVA
p-value: 0.000290% CI: [90.73, 106.27]ANOVA