Healthy
Conditions
Brief summary
The primary objective of this trial is to establish the bioequivalence of two empagliflozin/linagliptin/metformin extended release (XR) fixed dose combination (FDC) tablets (Test, T) compared with the same doses of the individual components given in separate tablets (Reference, R) when administered together after a high-fat, high-calorie meal. The assessment of safety and tolerability will be the secondary objective of this trial.
Interventions
DRUGEmpagliflozin, Metformin HCl, Linagliptin (fixed dose combination)
single dose
DRUGEmpagliflozin
single dose
DRUGLinagliptin
single dose
DRUGMetformin HCl
single dose
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 according to the assessment of the investigator, based on a complete medical history including a physical examination, vital signs (Blood pressure (BP), Pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests * Age of 18 to 55 years (incl.) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and local legislation * Female subjects of childbearing potential willing to use adequate contraception. * Further inclusion criteria apply
Exclusion criteria
* Any finding in the medical examination (including Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (ECG)) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (bpm) * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Concentration of the Metformin in Plasma (Cmax) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | Cmax, maximum measured concentration of the metformin in plasma is presented. SE is a geometric SE. |
| Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-tz, Area under the concentration-time curve of the metformin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE. |
| Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-72, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 to 72 h is presented. SE is a geometric SE. |
| Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | Cmax, maximum measured concentration of the empagliflozin in plasma is presented. SE is a geometric SE. |
| Maximum Measured Concentration of the Linagliptin in Plasma (Cmax) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | Cmax, maximum measured concentration of the linagliptin in plasma is presented. SE is a geometric SE. |
| Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-tz, Area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-∞, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE. |
| Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-∞, area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE. |
| Percentage of Patients With Drug-related Adverse Events (AEs) | All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP), up to 7 days. | Percentage of patients with investigator defined drug-related AEs are presented. |
| Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration. | AUC0-∞, area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE. |
Countries
Germany
Participant flow
Recruitment details
It was planned to include healthy participants in this randomised, open-label, two-way crossover trial with 2 treatments (test treatment (T) and reference treatment (R)) and 2 treatment sequences (TR or RT) in order to compare the treatment T to the treatment R under fed conditions. They were recruited from the volunteers' pool of the study site.
Pre-assignment details
All participants were screened for eligibility to participate in the trial and to ensure that all participants met all inclusion/exclusion criteria. Participants were not to be included in the trial if any of the specific exclusion criteria were met.
Participants by arm
| Arm | Count |
|---|---|
| Test Treatment (T)/ Reference Treatment (R) Participants were administered 2 fixed dose combination (FDC) coated tablet of 5 milligram(mg) empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin extended release (XR) orally in the fed state in period 1, followed by free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days. | 15 |
| Reference Treatment (R)/ Test Treatment (T) Participants were administered the free combination of 1 film-coated tablet of 10 mg empagliflozin, 1 film-coated tablet of 5 mg linagliptin and 4 film-coated tablets of 500 mg metformin XR orally as single dose in the fed state in period 1 and followed by 2 FDC coated tablets of 5 mg empagliflozin/ 2.5 mg linagliptin/ 1000 mg metformin XR orally as a single dose in the fed state in period 2. The T and R treatments were separated by a washout period of at least 35 days. | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 2 (4 Days) | Not treated | 0 | 1 |
Baseline characteristics
| Characteristic | Reference Treatment (R)/ Test Treatment (T) | Total | Test Treatment (T)/ Reference Treatment (R) |
|---|---|---|---|
| Age, Continuous | 41.5 Years STANDARD_DEVIATION 9.7 | 44.2 Years STANDARD_DEVIATION 9 | 46.9 Years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 30 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Female | 5 Participants | 11 Participants | 6 Participants |
| Sex: Female, Male Male | 10 Participants | 19 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 30 |
| other Total, other adverse events | 8 / 29 | 6 / 30 |
| serious Total, serious adverse events | 0 / 29 | 0 / 30 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
AUC0-tz, Area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.
Time frame: Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: Pharmacokinetic parameter set (PKS): PKS included all subjects in the treated set (TS) who provided at least one primary or secondary PK parameter that was not excluded due to protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2134.53 nanomole*hour/litre (nmol*h/L) | Standard Error 1.03 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2125.57 nanomole*hour/litre (nmol*h/L) | Standard Error 1.03 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [98.17, 102.72]ANOVA
Primary
Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72)
AUC0-72, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 to 72 h is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72) | 270.19 nmol*h/L | Standard Error 1.03 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (h) (AUC0-72) | 269.77 nmol*h/L | Standard Error 1.03 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [96.17, 104.31]ANOVA
Primary
Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
AUC0-tz, Area under the concentration-time curve of the metformin in plasma over the time interval from 0 to the last quantifiable data point is presented. Standard error (SE) is a geometric SE.
Time frame: Pharmacokinetic (PK) samples were collected 1:30 hours:minutes (h:m) pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 21687.12 nanogram*h/mL (ng*h/mL) | Standard Error 1.04 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 22748.21 nanogram*h/mL (ng*h/mL) | Standard Error 1.04 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [91.58, 99.24]ANOVA
Primary
Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax)
Cmax, maximum measured concentration of the empagliflozin in plasma is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | 209.67 nanomole/Litre (nmol/ L) | Standard Error 1.05 |
| Reference Treatment (R) | Maximum Measured Concentration of the Empagliflozin in Plasma (Cmax) | 226.50 nanomole/Litre (nmol/ L) | Standard Error 1.05 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: 0.002990% CI: [85.21, 100.57]ANOVA
Primary
Maximum Measured Concentration of the Linagliptin in Plasma (Cmax)
Cmax, maximum measured concentration of the linagliptin in plasma is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Maximum Measured Concentration of the Linagliptin in Plasma (Cmax) | 7.02 nanomole/Litre (nmol/ L) | Standard Error 1.05 |
| Reference Treatment (R) | Maximum Measured Concentration of the Linagliptin in Plasma (Cmax) | 7.21 nanomole/Litre (nmol/ L) | Standard Error 1.05 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: 0.000190% CI: [89.99, 105.26]ANOVA
Primary
Maximum Measured Concentration of the Metformin in Plasma (Cmax)
Cmax, maximum measured concentration of the metformin in plasma is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Maximum Measured Concentration of the Metformin in Plasma (Cmax) | 1853.03 nanogram/ millilitre (ng/ mL) | Standard Error 1.04 |
| Reference Treatment (R) | Maximum Measured Concentration of the Metformin in Plasma (Cmax) | 1767.69 nanogram/ millilitre (ng/ mL) | Standard Error 1.04 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [98.56, 111.5]ANOVA
Secondary
Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
AUC0-∞, area under the concentration-time curve of the empagliflozin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2182.26 nmol*h/L | Standard Error 1.03 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Empagliflozin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2166.54 nmol*h/L | Standard Error 1.03 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [98.33, 103.18]ANOVA
Secondary
Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
AUC0-∞, area under the concentration-time curve of the linagliptin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 471.40 nmol*h/L | Standard Error 1.05 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Linagliptinin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 455.13 nmol*h/L | Standard Error 1.05 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [96.9, 110.71]ANOVA
Secondary
Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
AUC0-∞, area under the concentration-time curve of the metformin in plasma over the time interval from 0 extrapolated to infinity is presented. SE is a geometric SE.
Time frame: PK samples were collected 1:30 h:m pre-dose and 0:30, 1:00, 1:30, 2:00, 2:30, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00, 24:00, 34:00, 48:00 and 72:00 h:m after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test Treatment (T) | Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 22288.72 ng*h/mL | Standard Error 1.04 |
| Reference Treatment (R) | Area Under the Concentration-time Curve of the Metformin Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 23280.48 ng*h/mL | Standard Error 1.04 |
Comparison: An ANOVA model on the logarithmic scale including fixed effects for 'sequence', 'period' and 'treatment' and random effect for 'subject within sequence'.p-value: <0.000190% CI: [92.29, 99.32]ANOVA
Secondary
Percentage of Patients With Drug-related Adverse Events (AEs)
Percentage of patients with investigator defined drug-related AEs are presented.
Time frame: All adverse events (AEs) which occurred through the treatment phase and throughout the residual effect period (REP), up to 7 days.
Population: TS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Test Treatment (T) | Percentage of Patients With Drug-related Adverse Events (AEs) | 7 Participants |
| Reference Treatment (R) | Percentage of Patients With Drug-related Adverse Events (AEs) | 6 Participants |