Healthy
Conditions
Brief summary
The objective of the current study is to demonstrate bioequivalence of two 2.5 mg linagliptin/500 mg metformin fixed dose combination tablets compared to the free combination of the linagliptin 5 mg and metformin 1000 mg in healthy male and female volunteers.
Interventions
DRUGMetformin
Free combination
DRUGLinagliptin
Fixed dose combination
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation * Healthy males and females according to the following criteria: Based upon a complete medical history, including physical examination, vital signs (BP, PR), 12-lead ECG and clinical laboratory tests (haematology, clinical chemistry and urinalysis). * Age 18 to 45 years (incl.) * Body mass index by Quetelet between 18.50 to 24.99 kg/m2 (incl.) * Female subjects of childbearing potential who agree on using double-barrier contraception during the study. If a female is postmenopausal (no menses for at least 2 years) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) she will be exempt from the requirement. In case of using oral contraceptives, these should be withdrawn at least 2 months before the first drug dosing. * Male subjects who agree on using effective contraception during the study (barrier contraceptive methods)
Exclusion criteria
* Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance * Any laboratory value outside the reference range that is of clinical relevance * Any evidence of a clinically relevant concomitant disease * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Positive results of blood tests for infections (HIV, syphilis, hepatitis B or C) * A positive urine drug screening test at screening and on admission to the trial site in each treatment period. * A positive alcohol breath test at screening and on admission to the trial site in each treatment period. * Surgery of the gastrointestinal tract (except appendectomy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Linagliptin: AUC 0-72 (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Linagliptin: AUC 0-72 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours) |
| Metformin: AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Metformin: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point) |
| Linagliptin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Linagliptin: Cmax (maximum measured concentration of the analyte in plasma) |
| Metformin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Metformin: Cmax (maximum measured concentration of the analyte in plasma) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metformin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Metformin: AUC 0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |
| Linagliptin: AUC 0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Linagliptin: AUC 0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point) |
| Linagliptin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration | Linagliptin: AUC 0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |
Countries
Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Subjects All subjects treated with 5 mg linagliptin / 1000 mg metformin as fixed dose combination or as free dose combination. | 36 |
| Total | 36 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Continuous | 25.0 years STANDARD_DEVIATION 6.2 |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 36 | 4 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Linagliptin: AUC 0-72 (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours)
Linagliptin: AUC 0-72 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 72 hours)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: subject set for the evaluation of pharmacokinetic endpoints of linagliptin (PKS-L): includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for linagliptin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of linagliptin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Linagliptin: AUC 0-72 (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours) | 293 nmol*h/L | Geometric Coefficient of Variation 23.4 |
| Free Combination | Linagliptin: AUC 0-72 (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 72 Hours) | 288 nmol*h/L | Geometric Coefficient of Variation 22.9 |
p-value: <0.000190% CI: [98.37, 107.688]ANOVA
Primary
Linagliptin: Cmax (Maximum Measured Concentration of the Analyte in Plasma)
Linagliptin: Cmax (maximum measured concentration of the analyte in plasma)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS-L: includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for linagliptin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of linagliptin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Linagliptin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 10.3 nmol/L | Geometric Coefficient of Variation 36.4 |
| Free Combination | Linagliptin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 9.57 nmol/L | Geometric Coefficient of Variation 36.2 |
p-value: 0.001490% CI: [98.299, 120.968]ANOVA
Primary
Metformin: AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point)
Metformin: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: The subject set for the evaluation of pharmacokinetic endpoints of metformin (PKS-M): includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for metformin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of metformin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Metformin: AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 13000 ng*h/mL | Geometric Coefficient of Variation 27.3 |
| Free Combination | Metformin: AUC0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 12100 ng*h/mL | Geometric Coefficient of Variation 24.2 |
p-value: <0.000190% CI: [99.645, 110.941]ANOVA
Primary
Metformin: Cmax (Maximum Measured Concentration of the Analyte in Plasma)
Metformin: Cmax (maximum measured concentration of the analyte in plasma)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS-M: includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for metformin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of metformin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Metformin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 1840 ng/mL | Geometric Coefficient of Variation 28.2 |
| Free Combination | Metformin: Cmax (Maximum Measured Concentration of the Analyte in Plasma) | 1700 ng/mL | Geometric Coefficient of Variation 27 |
p-value: <0.000190% CI: [98.471, 113.692]ANOVA
Secondary
Linagliptin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
Linagliptin: AUC 0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS-L: includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for linagliptin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of linagliptin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Linagliptin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 467 nmol*h/L | Geometric Coefficient of Variation 25.8 |
| Free Combination | Linagliptin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 479 nmol*h/L | Geometric Coefficient of Variation 29.5 |
p-value: <0.000190% CI: [92.177, 105.208]ANOVA
Secondary
Linagliptin: AUC 0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point)
Linagliptin: AUC 0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the time of the last quantifiable data point)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS-L: includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for linagliptin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of linagliptin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Linagliptin: AUC 0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 293 nmol*h/L | Geometric Coefficient of Variation 23.4 |
| Free Combination | Linagliptin: AUC 0-tz (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Data Point) | 288 nmol*h/L | Geometric Coefficient of Variation 22.9 |
p-value: <0.000190% CI: [98.37, 107.688]ANOVA
Secondary
Metformin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
Metformin: AUC 0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity)
Time frame: 2 hours (h) before drug administration and 20 minutes (min), 40min, 1h, 1h 30min, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h, 34h, 48h and 72h after drug administration
Population: PKS-M: includes all subjects of the TS who provided at least 1 observation for at least 1 primary endpoint for metformin and had no important protocol violations with respect to the statistical evaluation of pharmacokinetic endpoints of metformin
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Fixed Dose Combination | Metformin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 13400 ng*h/mL | Geometric Coefficient of Variation 26.8 |
| Free Combination | Metformin: AUC 0-inf (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 12500 ng*h/mL | Geometric Coefficient of Variation 24.1 |
p-value: <0.000190% CI: [99.274, 110.254]ANOVA