Healthy
Conditions
Brief summary
The purpose of the trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combination (FDC) tablets containing linagliptin & metformin and the single tablets of linagliptin and metformin when administered singularly.
Interventions
DRUG2x500 mg Metformin (Glumetza)
2 tablets
DRUG5 mg Linagliptin/1000 mg Metformin FDC
FDC tablet
DRUG5 mg Linagliptin (Tradjenta)
1 tablet
DRUG3x500 mg Metformin (Glumetza)
3 tablets
DRUG2 x 500 mg Metformin (Glumetza)
2 tablets
DRUG5 mg Linagliptin/1000mg Metformin FDC
FDC Tablet
DRUG2 x 2.5 mg Linagliptin/750 mg Metformin FDC
2 FDC 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 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy males or females 2. Age 18 -50 years (incl) 3. Body Mass Index (BMI) 18.5 to 29.9 kg/m2 (incl.) 4. Subjects must be able to understand and comply with study requirements
Exclusion criteria
Any deviation from healthy condition
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-72 of Linagliptin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval 0 to 72 Hours (AUC0-72). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
| Cmax of Linagliptin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Maximum Measured Concentration (Cmax) of Linagliptin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
| AUC0-tz of Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
| Cmax of Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Maximum Measured Concentration (Cmax) of Metformin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-infinity of Linagliptin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
| AUC0-infinity of Metformin | 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total 1000 Fasted Patients were administered 1 fixed dose combination (FDC) tablet 5 mg linagliptin/1000 mg metformin extended release (XR) orally in the morning under fasted conditions in one treatment period and 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR orally in the morning under fasted conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days. | 24 |
| Total 1000 Fed Patients were administered 1 FDC tablet 5 mg linagliptin/1000 mg metformin XR orally in the morning under fed conditions in one treatment period and 1 tablet linagliptin 5 mg and 2 tablets metformin 500 mg XR orally in the morning under fed conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days. | 24 |
| Total 1500 Fasted Patients were administered 2 FDC tablets 2.5 mg linagliptin/750 mg metformin XR orally in the morning under fasted conditions in one treatment period and 1 tablet linagliptin 5 mg and 3 tablets metformin 500 mg XR orally in the morning under fasted conditions in the other treatment period. Both periods lasted 4 days, separated by a washout period of at least 35 days. | 24 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout Period | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 |
| Washout Period | elevated lab values (not clinic. sign.) | 0 | 0 | 1 | 0 | 0 | 0 |
| Washout Period | Lost to Follow-up | 0 | 1 | 0 | 1 | 0 | 1 |
| Washout Period | Protocol Violation | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total 1000 Fasted | Total 1000 Fed | Total 1500 Fasted | Total |
|---|---|---|---|---|
| Age, Continuous | 34.8 years STANDARD_DEVIATION 9.3 | 30.6 years STANDARD_DEVIATION 9 | 28.4 years STANDARD_DEVIATION 7.1 | 31.3 years STANDARD_DEVIATION 8.8 |
| Sex: Female, Male Female | 8 Participants | 8 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 10 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 23 | 1 / 23 | 1 / 22 | 0 / 23 | 3 / 23 | 2 / 23 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 | 0 / 22 | 1 / 23 | 0 / 23 | 0 / 23 |
Outcome results
Primary
AUC0-72 of Linagliptin
Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval 0 to 72 Hours (AUC0-72). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | AUC0-72 of Linagliptin | 317.0 nmol*h/L | Geometric Coefficient of Variation 8 |
| L+M1000 Fasted | AUC0-72 of Linagliptin | 319.2 nmol*h/L | Geometric Coefficient of Variation 8 |
| FDC1000 Fed | AUC0-72 of Linagliptin | 309.6 nmol*h/L | Geometric Coefficient of Variation 5.5 |
| L+M1000 Fed | AUC0-72 of Linagliptin | 304.9 nmol*h/L | Geometric Coefficient of Variation 5.5 |
| FDC1500 Fasted | AUC0-72 of Linagliptin | 325.8 nmol*h/L | Geometric Coefficient of Variation 5.1 |
| L+M1500 Fasted | AUC0-72 of Linagliptin | 322.9 nmol*h/L | Geometric Coefficient of Variation 5.1 |
90% CI: [95.3, 103.5]ANOVA
Comparison: One patient was excluded from this analysis due to the lack of the 72h sample for the L+M1000 fed treatment.90% CI: [98.4, 104.7]ANOVA
90% CI: [98.2, 103.7]ANOVA
Primary
AUC0-tz of Metformin
Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | AUC0-tz of Metformin | 8629.0 ng*h/mL | Geometric Coefficient of Variation 21.8 |
| L+M1000 Fasted | AUC0-tz of Metformin | 8913.7 ng*h/mL | Geometric Coefficient of Variation 21.8 |
| FDC1000 Fed | AUC0-tz of Metformin | 13772.0 ng*h/mL | Geometric Coefficient of Variation 7.4 |
| L+M1000 Fed | AUC0-tz of Metformin | 13851.1 ng*h/mL | Geometric Coefficient of Variation 7.4 |
| FDC1500 Fasted | AUC0-tz of Metformin | 10472.9 ng*h/mL | Geometric Coefficient of Variation 18.5 |
| L+M1500 Fasted | AUC0-tz of Metformin | 10543.5 ng*h/mL | Geometric Coefficient of Variation 18.5 |
90% CI: [86.6, 108.2]ANOVA
90% CI: [95.6, 103.4]ANOVA
90% CI: [90.1, 109.5]ANOVA
Primary
Cmax of Linagliptin
Maximum Measured Concentration (Cmax) of Linagliptin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | Cmax of Linagliptin | 10.1 nmol/L | Geometric Coefficient of Variation 17.1 |
| L+M1000 Fasted | Cmax of Linagliptin | 10.6 nmol/L | Geometric Coefficient of Variation 17.1 |
| FDC1000 Fed | Cmax of Linagliptin | 7.7 nmol/L | Geometric Coefficient of Variation 13 |
| L+M1000 Fed | Cmax of Linagliptin | 7.9 nmol/L | Geometric Coefficient of Variation 13 |
| FDC1500 Fasted | Cmax of Linagliptin | 11.6 nmol/L | Geometric Coefficient of Variation 16.5 |
| L+M1500 Fasted | Cmax of Linagliptin | 10.7 nmol/L | Geometric Coefficient of Variation 16.5 |
90% CI: [86.8, 103.6]ANOVA
90% CI: [90.2, 103.8]ANOVA
90% CI: [99.5, 118.5]ANOVA
Primary
Cmax of Metformin
Maximum Measured Concentration (Cmax) of Metformin in plasma. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | Cmax of Metformin | 1047.4 ng/mL | Geometric Coefficient of Variation 25.5 |
| L+M1000 Fasted | Cmax of Metformin | 1085.6 ng/mL | Geometric Coefficient of Variation 25.5 |
| FDC1000 Fed | Cmax of Metformin | 1119.0 ng/mL | Geometric Coefficient of Variation 8.1 |
| L+M1000 Fed | Cmax of Metformin | 1084.5 ng/mL | Geometric Coefficient of Variation 8.1 |
| FDC1500 Fasted | Cmax of Metformin | 1347.0 ng/mL | Geometric Coefficient of Variation 29.3 |
| L+M1500 Fasted | Cmax of Metformin | 1250.6 ng/mL | Geometric Coefficient of Variation 29.3 |
90% CI: [84.8, 109.8]ANOVA
90% CI: [98.9, 107.7]ANOVA
90% CI: [92.5, 125.4]ANOVA
Secondary
AUC0-infinity of Linagliptin
Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | AUC0-infinity of Linagliptin | 546.1 nmol*h/L | Geometric Coefficient of Variation 12.8 |
| L+M1000 Fasted | AUC0-infinity of Linagliptin | 526.5 nmol*h/L | Geometric Coefficient of Variation 12.8 |
| FDC1000 Fed | AUC0-infinity of Linagliptin | 537.1 nmol*h/L | Geometric Coefficient of Variation 9.6 |
| L+M1000 Fed | AUC0-infinity of Linagliptin | 510.0 nmol*h/L | Geometric Coefficient of Variation 9.6 |
| FDC1500 Fasted | AUC0-infinity of Linagliptin | 562.9 nmol*h/L | Geometric Coefficient of Variation 13.5 |
| L+M1500 Fasted | AUC0-infinity of Linagliptin | 581.1 nmol*h/L | Geometric Coefficient of Variation 13.5 |
90% CI: [97.1, 110.8]ANOVA
90% CI: [99.9, 111]ANOVA
90% CI: [90.2, 104.1]ANOVA
Secondary
AUC0-infinity of Metformin
Area under the concentration-time curve of Metformin in plasma over the time interval from 0 extrapolated to infinity based on predicted last concentration values. The shown geometric coefficients of variation (gCV) are the pooled intra-individual gCV - each over 2 treatment groups (FDC1000 fasted and L+M1000 fasted, FDC1000 fed and L+M1000 fed, FDC1500 fasted and L+M1500 fasted). The geometric means are actually adjusted geometric means.
Time frame: 1 hour (h) before drug administration and 20 minutes (min), 40 min, 1h, 1:30h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72h after drug administration at Day 1 of each treatment period
Population: Pharmacokinetic set including all subjects of the TS 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 |
|---|---|---|---|
| FDC1000 Fasted | AUC0-infinity of Metformin | 9037.6 ng*h/mL | Geometric Coefficient of Variation 21.5 |
| L+M1000 Fasted | AUC0-infinity of Metformin | 9326.5 ng*h/mL | Geometric Coefficient of Variation 21.5 |
| FDC1000 Fed | AUC0-infinity of Metformin | 14031.3 ng*h/mL | Geometric Coefficient of Variation 7 |
| L+M1000 Fed | AUC0-infinity of Metformin | 14069.7 ng*h/mL | Geometric Coefficient of Variation 7 |
| FDC1500 Fasted | AUC0-infinity of Metformin | 11037.7 ng*h/mL | Geometric Coefficient of Variation 19.1 |
| L+M1500 Fasted | AUC0-infinity of Metformin | 11512.2 ng*h/mL | Geometric Coefficient of Variation 19.1 |
90% CI: [86.8, 108.2]ANOVA
90% CI: [96.1, 103.5]ANOVA
90% CI: [86.7, 106]ANOVA