Diabetes Mellitus, Type 2
Conditions
Brief summary
the pharmacokinetics, pharmacodynamics and safety and tolerability of single and multiple oral doses of BI 10773 at low dose once daily (q.d.) and high dose q.d. administered to Chinese female and male patients with type 2 diabetes will be investigated.
Interventions
DRUGBI10773
patient to receive a tablet containing high dose BI10773 p.o. plus one placebo
DRUGPlacebo
patient to receive two placebos
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Chinese male and female patients with proven diagnosis of type 2 diabetes mellitus treated with diet and exercise only or on a maximum of two oral antidiabetic agents except thiazolidinediones with at least one agent taken at 50% of its maximum dose or less, unchanged for at least 12 weeks before randomization 2. Glycosylated haemoglobin A1(HbA1c)\<=8.5% and \>=7.0% at screening,age\>=21 and age\<=70 years (male and female patients),BMI\>=19 and \<=40 kg/m2 3. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation.
Exclusion criteria
1. Patient who did not discontinue the antidiabetic treatment with insulin or glitazones, DPP-IV at least before 12 weeks before randomization 2. Uncontrolled hyperglycaemia with a glucose level \>240 mg/dl (\>13.3 mmol/L) after an overnight fast at screening visit 3. Clinically relevant concomitant diseases other than type 2 diabetes, hyperlipidaemia and medically treated hypertension, such as: 4 Any late stage complication of diabetes (e.g. retinopathy, polyneuropathy, vegetative disorders, diabetic foot) 5 Renal insufficiency (calculated creatinine clearance \< 80 ml/min/1.73m²) 6 Cardiac insufficiency NYHA II-IV, myocardial infarction, other known cardiovascular diseases including hypertension \> 160/95mmHg (measured at training visit and each of the timepoints of Day -1), stroke and TIA 7 Neurological disorders (such as epilepsy) or psychiatric disorders 8 Acute or relevant chronic infections (e.g. HIV, repeated urogenital infections) 9 Any gastrointestinal, hepatic, respiratory, endocrine or immunological disorder 10. History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) 11. A marked baseline prolongation of QT/QTc interval (e.g., ECG demonstration of a QTc interval \>450 ms ) at screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose (FPG) Change From Baseline | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Fasting Plasma Glucose (FPG) change from baseline between day 1 and day 9. |
| Maximum Measured Concentration (Cmax) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Maximum measured concentration of the analyte in plasma after the first dose on day 1. |
| Time to Maximum Measured Concentration (Tmax) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Time from dosing to the maximum measured concentration of the analyte in plasma, after the first dose on day 1. |
| Area Under the Curve 0 to Infinity (AUC0-∞) After Single Dosing | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity, after the first dose on day 1 |
| Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the time of the last quantifiable data point, after the first dose on day 1. |
| Terminal Rate Constant (λz) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Terminal Rate Constant in Plasma (λz), after the first dose on day 1 |
| Terminal Half-life (t1/2) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Terminal half-life of empagliflozin (empa) in plasma after the first dose on day 1 |
| Mean Residence Time (MRTpo) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Mean residence time of empagliflozin (empa) in the body after the first dose on day 1. |
| Apparent Clearance of Empagliflozin After Extravascular Administration (CL/F) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Apparent clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1. |
| Apparent Volume of Distribution During the Terminal Phase λz (Vz/F) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Apparent volume of distribution during the terminal phase λz, after the first dose on day 1. |
| Amount of Empagliflozin Eliminated in Urine in the Time Interval 0 Hours to 24 Hours (Ae 0-24) | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Amount of empagliflozin (empa) eliminated in urine in the time interval 0 hours to 24 hours, after the first dose on day 1. |
| Fraction of Empagliflozin Excreted Unchanged in Urine in the Time Interval 0 Hours to 24 Hours (fe 0-24). | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Fraction of empagliflozin (empa) excreted unchanged in urine in the time interval 0 hours to 24 hours, after the first dose on day 1. |
| Renal Clearance After Extravascular Administration (CL R,0-48) | 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration | Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1. |
| Maximum Measured Concentration Over a Uniform Dosing Interval (Cmax,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Maximum measured concentration of empagliflozin (empa) in plasma at steady state over a uniform dosing interval. |
| Time From Last Dosing to Maximum Measured Concentration Over a Uniform Dosing Interval at Steady State (Tmax,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Time from last dosing to maximum measured concentration of empagliflozin (empa) in plasma over a uniform dosing interval at steady state, after multiple dosing. |
| Area Under the Concentration-time Curve in Plasma at Steady State Over a Uniform Dosing Interval (AUCτ,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Area under the concentration-time curve of empagliflozin (empa) in plasma at steady state over a uniform dosing interval, after multiple dosing |
| Terminal Rate Constant in Plasma at Steady State (λz,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Terminal rate constant in plasma at steady state, after multiple dosing. |
| Terminal Half-life in Plasma at Steady State (t1/2,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Terminal half-life of empagliflozin (empa) in plasma at steady state, after multiple dosing. |
| Mean Residence Time at Steady State (MRTpo,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Mean residence time of empagliflozin (empa) in the body at steady state after multiple oral administrations |
| Apparent Clearance of Empagliflozin After Extravascular Administration (CL/Fss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Apparent clearance of empagliflozin (empa) in the plasma at steady state following multiple oral dose administration. |
| Apparent Volume of Distribution During the Terminal Phase λz (Vz/Fss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Apparent volume of distribution during the terminal phase λz at steady state following oral administration after multiple dosing |
| Amount of Analyte Eliminated in Urine at Steady State in Time Interval 0 Hours to 24 Hours (Ae 0-24,ss) | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Amount of empagliflozin (empa) eliminated in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing. |
| Fraction of Empagliflozin Excreted Unchanged in Urine at Steady State in the Time Interval 0 Hours to 24 Hours (fe 0-24,ss) | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Fraction of empagliflozin (empa) excreted unchanged in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing. |
| Renal Clearance at Steady State (CL R,ss) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9 | Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after multiple dosing. |
| Accumulation Ratio Based on AUC (R A,AUC) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration on days 1 and 9 | Accumulation ratio of empagliflozin (empa) based on AUC, after multiple dosing |
| Accumulation Ratio Based on Cmax (R A,Cmax) | 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration between days 5 and 9 | Accumulation ratio of empagliflozin (empa) based on Cmax, after multiple dosing |
| Predose Plasma Concentration Before Planned Dose x (Cpre,x) | 5 minutes before drug administration | Predose plasma concentration of empagliflozin (empa) before planned dose by day. This endpoint in steady state is identical to Cmin,ss. |
| Urinary Glucose Excretion (UGE) Change From Baseline | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | Change from day -1 in urinary glucose excretion in a 24 hour collection period per time point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference | Drug administration until end of trial, up to 21 days | Clinically relevant abnormalities for protocol-specified significant adverse events, hypoglycaemic events, vital signs, blood chemistry, use of rescue therapy, change in body weight and change in waist circumference. Results shown are for hypoglycaemic events, as this was the only event that occurred for this endpoint. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo tablets, one matching the empa 10mg tablet and one matching the empa 25mg tablet, taken orally either as a single dose (single dose period) or for 7 consecutive days (multiple dose period). | 6 |
| Empa 10 mg 10 mg Empagliflozin (empa) taken orally either as a single dose (single dose period) or for 7 consecutive days (multiple dose period). Along with this a placebo tablet matching the 25mg empa tablet was taken at each drug administration. | 9 |
| Empa 25 mg 25 mg Empagliflozin (empa) taken orally either as a single dose (single dose period) or for 7 consecutive days (multiple dose period). Along with this a placebo tablet matching the 10mg empa tablet was taken at each drug administration. | 9 |
| Total | 24 |
Baseline characteristics
| Characteristic | Placebo | Empa 10 mg | Empa 25 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 9.6 | 54.1 years STANDARD_DEVIATION 7.9 | 52.7 years STANDARD_DEVIATION 9.9 | 53.4 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 4 Participants | 7 Participants | 3 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 6 | 4 / 9 | 2 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Accumulation Ratio Based on AUC (R A,AUC)
Accumulation ratio of empagliflozin (empa) based on AUC, after multiple dosing
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration on days 1 and 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Accumulation Ratio Based on AUC (R A,AUC) | 1.14 Ratio | Geometric Coefficient of Variation 12 |
| Empa 25 mg | Accumulation Ratio Based on AUC (R A,AUC) | 1.17 Ratio | Geometric Coefficient of Variation 11.2 |
Primary
Accumulation Ratio Based on Cmax (R A,Cmax)
Accumulation ratio of empagliflozin (empa) based on Cmax, after multiple dosing
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, and16h after drug administration between days 5 and 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Accumulation Ratio Based on Cmax (R A,Cmax) | 1.12 Ratio | Geometric Coefficient of Variation 32 |
| Empa 25 mg | Accumulation Ratio Based on Cmax (R A,Cmax) | 1.15 Ratio | Geometric Coefficient of Variation 30.8 |
Primary
Amount of Analyte Eliminated in Urine at Steady State in Time Interval 0 Hours to 24 Hours (Ae 0-24,ss)
Amount of empagliflozin (empa) eliminated in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Amount of Analyte Eliminated in Urine at Steady State in Time Interval 0 Hours to 24 Hours (Ae 0-24,ss) | 4420 nmol | Geometric Coefficient of Variation 14.6 |
| Empa 25 mg | Amount of Analyte Eliminated in Urine at Steady State in Time Interval 0 Hours to 24 Hours (Ae 0-24,ss) | 11600 nmol | Geometric Coefficient of Variation 23.3 |
Primary
Amount of Empagliflozin Eliminated in Urine in the Time Interval 0 Hours to 24 Hours (Ae 0-24)
Amount of empagliflozin (empa) eliminated in urine in the time interval 0 hours to 24 hours, after the first dose on day 1.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Amount of Empagliflozin Eliminated in Urine in the Time Interval 0 Hours to 24 Hours (Ae 0-24) | 4030 nmol | Geometric Coefficient of Variation 18.9 |
| Empa 25 mg | Amount of Empagliflozin Eliminated in Urine in the Time Interval 0 Hours to 24 Hours (Ae 0-24) | 9940 nmol | Geometric Coefficient of Variation 23.8 |
Primary
Apparent Clearance of Empagliflozin After Extravascular Administration (CL/F)
Apparent clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Apparent Clearance of Empagliflozin After Extravascular Administration (CL/F) | 144 mL/min | Geometric Coefficient of Variation 12.3 |
| Empa 25 mg | Apparent Clearance of Empagliflozin After Extravascular Administration (CL/F) | 127 mL/min | Geometric Coefficient of Variation 24.4 |
Primary
Apparent Clearance of Empagliflozin After Extravascular Administration (CL/Fss)
Apparent clearance of empagliflozin (empa) in the plasma at steady state following multiple oral dose administration.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Apparent Clearance of Empagliflozin After Extravascular Administration (CL/Fss) | 139 mL/min | Geometric Coefficient of Variation 15.4 |
| Empa 25 mg | Apparent Clearance of Empagliflozin After Extravascular Administration (CL/Fss) | 123 mL/min | Geometric Coefficient of Variation 21.4 |
Primary
Apparent Volume of Distribution During the Terminal Phase λz (Vz/F)
Apparent volume of distribution during the terminal phase λz, after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Apparent Volume of Distribution During the Terminal Phase λz (Vz/F) | 115 L | Geometric Coefficient of Variation 31.8 |
| Empa 25 mg | Apparent Volume of Distribution During the Terminal Phase λz (Vz/F) | 115 L | Geometric Coefficient of Variation 30.1 |
Primary
Apparent Volume of Distribution During the Terminal Phase λz (Vz/Fss)
Apparent volume of distribution during the terminal phase λz at steady state following oral administration after multiple dosing
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Apparent Volume of Distribution During the Terminal Phase λz (Vz/Fss) | 150 L | Geometric Coefficient of Variation 55.1 |
| Empa 25 mg | Apparent Volume of Distribution During the Terminal Phase λz (Vz/Fss) | 125 L | Geometric Coefficient of Variation 29.9 |
Primary
Area Under the Concentration-time Curve in Plasma at Steady State Over a Uniform Dosing Interval (AUCτ,ss)
Area under the concentration-time curve of empagliflozin (empa) in plasma at steady state over a uniform dosing interval, after multiple dosing
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Area Under the Concentration-time Curve in Plasma at Steady State Over a Uniform Dosing Interval (AUCτ,ss) | 2650 nmol*h/L | Geometric Coefficient of Variation 15.4 |
| Empa 25 mg | Area Under the Concentration-time Curve in Plasma at Steady State Over a Uniform Dosing Interval (AUCτ,ss) | 7520 nmol*h/L | Geometric Coefficient of Variation 21.4 |
Primary
Area Under the Curve 0 to Infinity (AUC0-∞) After Single Dosing
Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 extrapolated to infinity, after the first dose on day 1
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Area Under the Curve 0 to Infinity (AUC0-∞) After Single Dosing | 2560 nmol*h/L | Geometric Coefficient of Variation 12.3 |
| Empa 25 mg | Area Under the Curve 0 to Infinity (AUC0-∞) After Single Dosing | 7250 nmol*h/L | Geometric Coefficient of Variation 24.4 |
Primary
Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of empagliflozin (empa) in plasma over the time interval from 0 to the time of the last quantifiable data point, after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) | 2510 nmol*h/L | Geometric Coefficient of Variation 12.3 |
| Empa 25 mg | Area Under the Curve 0 to the Last Quantifiable Data Point (AUC0-tz) | 7070 nmol*h/L | Geometric Coefficient of Variation 24.1 |
Primary
Fasting Plasma Glucose (FPG) Change From Baseline
Fasting Plasma Glucose (FPG) change from baseline between day 1 and day 9.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacodynamic analysis (PD) set included all patients documented to have taken at least one dose of investigational treatment, who received at least one dose of empagliflozin or placebo and who provided at least one baseline and post-treatment observation for at least one PD endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Fasting Plasma Glucose (FPG) Change From Baseline | -3.67 mg/dL | Standard Deviation 7.45 |
| Empa 25 mg | Fasting Plasma Glucose (FPG) Change From Baseline | -25.56 mg/dL | Standard Deviation 20.74 |
| Empa 25 mg | Fasting Plasma Glucose (FPG) Change From Baseline | -31.44 mg/dL | Standard Deviation 26.92 |
Primary
Fraction of Empagliflozin Excreted Unchanged in Urine at Steady State in the Time Interval 0 Hours to 24 Hours (fe 0-24,ss)
Fraction of empagliflozin (empa) excreted unchanged in urine at steady state in the time interval 0 hours to 24 hours, after multiple dosing.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Fraction of Empagliflozin Excreted Unchanged in Urine at Steady State in the Time Interval 0 Hours to 24 Hours (fe 0-24,ss) | 19.9 percentage of empa | Geometric Coefficient of Variation 14.6 |
| Empa 25 mg | Fraction of Empagliflozin Excreted Unchanged in Urine at Steady State in the Time Interval 0 Hours to 24 Hours (fe 0-24,ss) | 20.9 percentage of empa | Geometric Coefficient of Variation 23.3 |
Primary
Fraction of Empagliflozin Excreted Unchanged in Urine in the Time Interval 0 Hours to 24 Hours (fe 0-24).
Fraction of empagliflozin (empa) excreted unchanged in urine in the time interval 0 hours to 24 hours, after the first dose on day 1.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Fraction of Empagliflozin Excreted Unchanged in Urine in the Time Interval 0 Hours to 24 Hours (fe 0-24). | 18.2 percentage of empa | Geometric Coefficient of Variation 18.9 |
| Empa 25 mg | Fraction of Empagliflozin Excreted Unchanged in Urine in the Time Interval 0 Hours to 24 Hours (fe 0-24). | 17.9 percentage of empa | Geometric Coefficient of Variation 23.8 |
Primary
Maximum Measured Concentration (Cmax)
Maximum measured concentration of the analyte in plasma after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Maximum Measured Concentration (Cmax) | 436 nmol/L | Geometric Coefficient of Variation 14.1 |
| Empa 25 mg | Maximum Measured Concentration (Cmax) | 1090 nmol/L | Geometric Coefficient of Variation 29.2 |
Primary
Maximum Measured Concentration Over a Uniform Dosing Interval (Cmax,ss)
Maximum measured concentration of empagliflozin (empa) in plasma at steady state over a uniform dosing interval.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Maximum Measured Concentration Over a Uniform Dosing Interval (Cmax,ss) | 489 nmol/L | Geometric Coefficient of Variation 27.4 |
| Empa 25 mg | Maximum Measured Concentration Over a Uniform Dosing Interval (Cmax,ss) | 1250 nmol/L | Geometric Coefficient of Variation 32.1 |
Primary
Mean Residence Time at Steady State (MRTpo,ss)
Mean residence time of empagliflozin (empa) in the body at steady state after multiple oral administrations
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Mean Residence Time at Steady State (MRTpo,ss) | 10.5 hours | Geometric Coefficient of Variation 18.5 |
| Empa 25 mg | Mean Residence Time at Steady State (MRTpo,ss) | 10.2 hours | Geometric Coefficient of Variation 19.1 |
Primary
Mean Residence Time (MRTpo)
Mean residence time of empagliflozin (empa) in the body after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Mean Residence Time (MRTpo) | 9.29 hours | Geometric Coefficient of Variation 16.4 |
| Empa 25 mg | Mean Residence Time (MRTpo) | 10.2 hours | Geometric Coefficient of Variation 13.2 |
Primary
Predose Plasma Concentration Before Planned Dose x (Cpre,x)
Predose plasma concentration of empagliflozin (empa) before planned dose by day. This endpoint in steady state is identical to Cmin,ss.
Time frame: 5 minutes before drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Empa 10 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 6 | 25.70 nmol/L | Geometric Coefficient of Variation 1.23 |
| Empa 10 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 8 | 26.10 nmol/L | Geometric Coefficient of Variation 1.22 |
| Empa 10 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 7 | 25.24 nmol/L | Geometric Coefficient of Variation 1.24 |
| Empa 10 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 9 | 27.21 nmol/L | Geometric Coefficient of Variation 1.23 |
| Empa 10 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 5 | 24.64 nmol/L | Geometric Coefficient of Variation 1.24 |
| Empa 25 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 9 | 76.02 nmol/L | Geometric Coefficient of Variation 1.42 |
| Empa 25 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 5 | 70.54 nmol/L | Geometric Coefficient of Variation 1.48 |
| Empa 25 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 6 | 80.27 nmol/L | Geometric Coefficient of Variation 1.42 |
| Empa 25 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 7 | 78.96 nmol/L | Geometric Coefficient of Variation 1.57 |
| Empa 25 mg | Predose Plasma Concentration Before Planned Dose x (Cpre,x) | Treatment Day 8 | 72.74 nmol/L | Geometric Coefficient of Variation 1.43 |
Primary
Renal Clearance After Extravascular Administration (CL R,0-48)
Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Renal Clearance After Extravascular Administration (CL R,0-48) | 28.9 mL/min | Geometric Coefficient of Variation 22.6 |
| Empa 25 mg | Renal Clearance After Extravascular Administration (CL R,0-48) | 25.6 mL/min | Geometric Coefficient of Variation 31.8 |
Primary
Renal Clearance at Steady State (CL R,ss)
Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after multiple dosing.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Renal Clearance at Steady State (CL R,ss) | 27.8 mL/min | Geometric Coefficient of Variation 15.8 |
| Empa 25 mg | Renal Clearance at Steady State (CL R,ss) | 26.1 mL/min | Geometric Coefficient of Variation 30 |
Primary
Terminal Half-life in Plasma at Steady State (t1/2,ss)
Terminal half-life of empagliflozin (empa) in plasma at steady state, after multiple dosing.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Terminal Half-life in Plasma at Steady State (t1/2,ss) | 12.4 hours | Geometric Coefficient of Variation 52.5 |
| Empa 25 mg | Terminal Half-life in Plasma at Steady State (t1/2,ss) | 11.8 hours | Geometric Coefficient of Variation 24.6 |
Primary
Terminal Half-life (t1/2)
Terminal half-life of empagliflozin (empa) in plasma after the first dose on day 1
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Terminal Half-life (t1/2) | 9.25 hours | Geometric Coefficient of Variation 30.3 |
| Empa 25 mg | Terminal Half-life (t1/2) | 10.4 hours | Geometric Coefficient of Variation 22.2 |
Primary
Terminal Rate Constant in Plasma at Steady State (λz,ss)
Terminal rate constant in plasma at steady state, after multiple dosing.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Terminal Rate Constant in Plasma at Steady State (λz,ss) | 0.0559 1/h | Geometric Coefficient of Variation 52.5 |
| Empa 25 mg | Terminal Rate Constant in Plasma at Steady State (λz,ss) | 0.0588 1/h | Geometric Coefficient of Variation 24.6 |
Primary
Terminal Rate Constant (λz)
Terminal Rate Constant in Plasma (λz), after the first dose on day 1
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Terminal Rate Constant (λz) | 0.0749 1/h | Geometric Coefficient of Variation 30.3 |
| Empa 25 mg | Terminal Rate Constant (λz) | 0.0664 1/h | Geometric Coefficient of Variation 22.2 |
Primary
Time From Last Dosing to Maximum Measured Concentration Over a Uniform Dosing Interval at Steady State (Tmax,ss)
Time from last dosing to maximum measured concentration of empagliflozin (empa) in plasma over a uniform dosing interval at steady state, after multiple dosing.
Time frame: 5 minutes (min) before drug administration and 10min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 36h 48h, 60h, 72h and 96h after drug administration on day 9
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Time From Last Dosing to Maximum Measured Concentration Over a Uniform Dosing Interval at Steady State (Tmax,ss) | 1.17 hours | Geometric Coefficient of Variation 43.8 |
| Empa 25 mg | Time From Last Dosing to Maximum Measured Concentration Over a Uniform Dosing Interval at Steady State (Tmax,ss) | 1.37 hours | Geometric Coefficient of Variation 35 |
Primary
Time to Maximum Measured Concentration (Tmax)
Time from dosing to the maximum measured concentration of the analyte in plasma, after the first dose on day 1.
Time frame: 5 minutes (min) before drug administration and 10 min, 20min, 30min, 40min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h, 16h after drug administration
Population: Pharmacokinetic (PK) analysis set included all evaluable patients documented to have taken at least one dose of investigational treatment and who provided at least one observation for at least one PK endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Empa 10 mg | Time to Maximum Measured Concentration (Tmax) | 1.13 hours | Geometric Coefficient of Variation 33.3 |
| Empa 25 mg | Time to Maximum Measured Concentration (Tmax) | 1.50 hours | Geometric Coefficient of Variation 40.8 |
Primary
Urinary Glucose Excretion (UGE) Change From Baseline
Change from day -1 in urinary glucose excretion in a 24 hour collection period per time point.
Time frame: Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration
Population: Pharmacodynamic analysis (PD) set included all patients documented to have taken at least one dose of investigational treatment, who received at least one dose of empagliflozin or placebo and who provided at least one baseline and post-treatment observation for at least one PD endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Empa 10 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 1 | -988.38 mg | Standard Deviation 2791.68 |
| Empa 10 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 9 | -4106.10 mg | Standard Deviation 6428.12 |
| Empa 25 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 1 | 87680.85 mg | Standard Deviation 22924.91 |
| Empa 25 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 9 | 95765.72 mg | Standard Deviation 24133.47 |
| Empa 25 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 1 | 82791.86 mg | Standard Deviation 18752.81 |
| Empa 25 mg | Urinary Glucose Excretion (UGE) Change From Baseline | Day 9 | 82633.88 mg | Standard Deviation 34757.02 |
Secondary
Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference
Clinically relevant abnormalities for protocol-specified significant adverse events, hypoglycaemic events, vital signs, blood chemistry, use of rescue therapy, change in body weight and change in waist circumference. Results shown are for hypoglycaemic events, as this was the only event that occurred for this endpoint.
Time frame: Drug administration until end of trial, up to 21 days
Population: Treated set (TS) includes all patients who were documented to have taken at least one dose of investigational treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Empa 10 mg | Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference | 0 participants |
| Empa 25 mg | Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference | 1 participants |
| Empa 25 mg | Clinical Relevant Abnormalities for Protocol-Specified Significant Adverse Events, Hypoglycaemic Events, Vital Signs, Blood Chemistry, Rescue Therapy, Body Weight and Waist Circumference | 0 participants |