Diabetes Mellitus, Type 2
Conditions
Brief summary
Primary objective: safety and tolerability of BI 10773 in male and female patients with type 2 diabetes Secondary objective: pharmacokinetics and pharmacodynamics of BI 10773
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Male and postmenopausal or hysterectomised female patients with type 2 diabetes * Age \>18 and \< 70 years * BMI \>18.5 and \<40 kg/m2
Exclusion criteria
* Antidiabetic treatment with insulin or glitazones or with more than one oral hypoglycaemic agent; * Fasted blood glucose \> 240 mg/dl (\>13.3 mmol/L) or a blood glucose level above 400 mg/dl (22.2 mmol/L) postprandially; * HbA1c \> 8.5 %
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Drug Related Adverse Events | from drug administration up to 6 weeks | number of subjects with investigator-defined drug-related adverse events. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | from drug administration up to 6 weeks | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 of Empagliflozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28 | terminal half-life of the analyte in plasma after first dose (Day 1), denoted by t1/2; and at steady state (Day 28), denoted by t1/2,ss. |
| AUC0-∞ of Empagliflozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) and over a uniform dosing interval τ at steady state (AUCτ,ss) |
| CL/F of Empaglifozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28 | apparent clearance of the analyte in plasma after first dose (CL/F) and at steady state (CL/F,ss) |
| fe0-24 of Empagliflozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28 | Fraction of analyte eliminated in urine from time point 0 to 24h after first dose (fe0-24) and at steady state (fe0-24,ss) |
| LI (Linearity Index). | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 after drug administration on day 1 and 28 | The linearity index is defined as AUC0-τ divided by AUC0-∞ both at steady state. |
| Ae0-24 of Glucose | Day -2 and 27: -2 to 0, 0 to 5, 5 to 12 and 12 to 24h; Day -1 and 1: 0 to 5, 5 to 12 and 12 to 24; Day 28: 0 to 5, 5 to 12, 12 to 24, 24 to 36, 36 to 48 and 48 to 72h | Amount of glucose eliminated in urine over the time interval 0 to 24h on day -2, -1, 1, 27 and 28. (Urinary Glucose Excretion) |
| Fasting Plasma Glucose (FPG) | in the morning of days -1 and 28 | fasting plasma glucose on day -1 (baseline) and change from baseline to day 28 |
| Cmax of Empagliflozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 hours(h) after drug administration on day 1 and 28 | maximum concentration of the analyte in plasma after first dose (Cmax, Day 1 ) and at steady state over a uniform dosing interval (Cmax,ss, Day 28). |
| Insulin AUEC0-5 | 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28. | change in AUEC0-5 from baseline on day 28. Baseline is defined as day -1. |
| Insulin Emax (Maximum Measured Effect) | 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28. | change in Emax from baseline on day 28. Baseline is defined as day -1 |
| Fasting Insulin | in the morning of days -1( baseline), 1, 7, 14, 21 and 28 | Change from baseline to the days 1, 7, 14, 21 and 28. Baseline is defined as day -1. |
| Glucagon Emax (Maximum Measured Effect) | 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 24:00 h after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28. | Change from baseline (day -1) in Emax on day 28. |
| Glucagon AUEC0-5 | 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28. | Change from baseline (day -1) in AUEC0-5 on day 28. |
| Fructosamine | day -1 (baseline), 14 and 28 | change from baseline to days 14 and 18. Baseline is defined as day -1. |
| HbA1c | in the morning of days -1 and 28 | change from baseline on day 28. Baseline is defined as day -1. |
| Mean Daily Glucose (MDG) Measured in Blood | 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day -2. 0:05 h before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day 1, 7, 14, 21 and 27 | change from baseline in MDG on the days 1, 7, 14, 21 and 27. Baseline is defined as day -2. |
| Tmax of Empagliflozin | 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28 | time from last dosing to maximum concentration of the analyte in plasma after first dose (Day 1), denoted by tmax; and at steady state (Day 28), denoted by tmax,ss. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo oral administration in the fasted state once daily. | 16 |
| 10mg Empagliflozin oral administration in the fasted state once daily. | 16 |
| 25mg Empagliflozin oral administration in the fasted state once daily. | 16 |
| 100mg Empagliflozin oral administration in the fasted state once daily. | 30 |
| Total | 78 |
Baseline characteristics
| Characteristic | Placebo | 10mg Empagliflozin | 25mg Empagliflozin | 100mg Empagliflozin | Total |
|---|---|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 10.4 | 56.8 years STANDARD_DEVIATION 8.7 | 56.1 years STANDARD_DEVIATION 8.5 | 56.5 years STANDARD_DEVIATION 8.2 | 56.7 years STANDARD_DEVIATION 8.7 |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 11 Participants |
| Sex: Female, Male Male | 15 Participants | 13 Participants | 12 Participants | 27 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 10 / 16 | 8 / 16 | 9 / 16 | 18 / 30 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 16 | 0 / 30 |
Outcome results
Primary
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG
Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events.
Time frame: from drug administration up to 6 weeks
Population: treated set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Lipase increased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood triglycerides increased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood creatine phosphokinase increased | 0 participants |
| Placebo | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Ventricular extrasystoles | 0 participants |
| 10mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood triglycerides increased | 1 participants |
| 10mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood creatine phosphokinase increased | 0 participants |
| 10mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Ventricular extrasystoles | 1 participants |
| 10mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Lipase increased | 0 participants |
| 25mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood creatine phosphokinase increased | 0 participants |
| 25mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood triglycerides increased | 0 participants |
| 25mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Ventricular extrasystoles | 0 participants |
| 25mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Lipase increased | 1 participants |
| 100mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Ventricular extrasystoles | 0 participants |
| 100mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood triglycerides increased | 0 participants |
| 100mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Lipase increased | 2 participants |
| 100mg Empagliflozin | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Blood creatine phosphokinase increased | 1 participants |
Primary
Number of Subjects With Drug Related Adverse Events
number of subjects with investigator-defined drug-related adverse events.
Time frame: from drug administration up to 6 weeks
Population: treated set: comprised all 78 patients who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Subjects With Drug Related Adverse Events | 7 participants |
| 10mg Empagliflozin | Number of Subjects With Drug Related Adverse Events | 3 participants |
| 25mg Empagliflozin | Number of Subjects With Drug Related Adverse Events | 4 participants |
| 100mg Empagliflozin | Number of Subjects With Drug Related Adverse Events | 14 participants |
Secondary
Ae0-24 of Glucose
Amount of glucose eliminated in urine over the time interval 0 to 24h on day -2, -1, 1, 27 and 28. (Urinary Glucose Excretion)
Time frame: Day -2 and 27: -2 to 0, 0 to 5, 5 to 12 and 12 to 24h; Day -1 and 1: 0 to 5, 5 to 12 and 12 to 24; Day 28: 0 to 5, 5 to 12, 12 to 24, 24 to 36, 36 to 48 and 48 to 72h
Population: PD analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Ae0-24 of Glucose | Ae0-24 on day 27 (N=14,13,14,27) | 3790 mg | Geometric Coefficient of Variation 296 |
| Placebo | Ae0-24 of Glucose | Ae0-24 on day -1 (N=13,15,16,25) | 6490 mg | Geometric Coefficient of Variation 136 |
| Placebo | Ae0-24 of Glucose | Ae0-24 on day 28 (N=13,13,11,23) | 6310 mg | Geometric Coefficient of Variation 230 |
| Placebo | Ae0-24 of Glucose | Ae0-24 on day 1 (N=15,15,16,29) | 3970 mg | Geometric Coefficient of Variation 197 |
| Placebo | Ae0-24 of Glucose | Ae0-24 on day -2 (N=15,16,15,26) | 4270 mg | Geometric Coefficient of Variation 185 |
| 10mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 1 (N=15,15,16,29) | 81500 mg | Geometric Coefficient of Variation 35.7 |
| 10mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 27 (N=14,13,14,27) | 78000 mg | Geometric Coefficient of Variation 44.1 |
| 10mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 28 (N=13,13,11,23) | 75400 mg | Geometric Coefficient of Variation 44.6 |
| 10mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -1 (N=13,15,16,25) | 8450 mg | Geometric Coefficient of Variation 114 |
| 10mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -2 (N=15,16,15,26) | 7760 mg | Geometric Coefficient of Variation 161 |
| 25mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 1 (N=15,15,16,29) | 95700 mg | Geometric Coefficient of Variation 30.4 |
| 25mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -2 (N=15,16,15,26) | 5340 mg | Geometric Coefficient of Variation 123 |
| 25mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -1 (N=13,15,16,25) | 8150 mg | Geometric Coefficient of Variation 91 |
| 25mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 27 (N=14,13,14,27) | 82900 mg | Geometric Coefficient of Variation 32.9 |
| 25mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 28 (N=13,13,11,23) | 83400 mg | Geometric Coefficient of Variation 26.4 |
| 100mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 27 (N=14,13,14,27) | 81300 mg | Geometric Coefficient of Variation 50.1 |
| 100mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -1 (N=13,15,16,25) | 6190 mg | Geometric Coefficient of Variation 134 |
| 100mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day -2 (N=15,16,15,26) | 6050 mg | Geometric Coefficient of Variation 190 |
| 100mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 1 (N=15,15,16,29) | 87000 mg | Geometric Coefficient of Variation 36.9 |
| 100mg Empagliflozin | Ae0-24 of Glucose | Ae0-24 on day 28 (N=13,13,11,23) | 73900 mg | Geometric Coefficient of Variation 61.6 |
Secondary
AUC0-∞ of Empagliflozin
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) and over a uniform dosing interval τ at steady state (AUCτ,ss)
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC0-∞ of Empagliflozin | AUC0-∞ | 1740 nmol*h/L | Geometric Coefficient of Variation 16.4 |
| Placebo | AUC0-∞ of Empagliflozin | AUCτ,ss | 1870 nmol*h/L | Geometric Coefficient of Variation 15.9 |
| 10mg Empagliflozin | AUC0-∞ of Empagliflozin | AUC0-∞ | 4340 nmol*h/L | Geometric Coefficient of Variation 23.1 |
| 10mg Empagliflozin | AUC0-∞ of Empagliflozin | AUCτ,ss | 4740 nmol*h/L | Geometric Coefficient of Variation 21.2 |
| 25mg Empagliflozin | AUC0-∞ of Empagliflozin | AUC0-∞ | 18000 nmol*h/L | Geometric Coefficient of Variation 24.3 |
| 25mg Empagliflozin | AUC0-∞ of Empagliflozin | AUCτ,ss | 18700 nmol*h/L | Geometric Coefficient of Variation 25.2 |
Secondary
CL/F of Empaglifozin
apparent clearance of the analyte in plasma after first dose (CL/F) and at steady state (CL/F,ss)
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | CL/F of Empaglifozin | CL/F | 218 mL/min | Geometric Coefficient of Variation 15.3 |
| Placebo | CL/F of Empaglifozin | CL/F,ss | 202 mL/min | Geometric Coefficient of Variation 15.9 |
| 10mg Empagliflozin | CL/F of Empaglifozin | CL/F | 223 mL/min | Geometric Coefficient of Variation 21.2 |
| 10mg Empagliflozin | CL/F of Empaglifozin | CL/F,ss | 203 mL/min | Geometric Coefficient of Variation 21.4 |
| 25mg Empagliflozin | CL/F of Empaglifozin | CL/F | 215 mL/min | Geometric Coefficient of Variation 20.8 |
| 25mg Empagliflozin | CL/F of Empaglifozin | CL/F,ss | 208 mL/min | Geometric Coefficient of Variation 22 |
Secondary
Cmax of Empagliflozin
maximum concentration of the analyte in plasma after first dose (Cmax, Day 1 ) and at steady state over a uniform dosing interval (Cmax,ss, Day 28).
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 hours(h) after drug administration on day 1 and 28
Population: Pharmacokinetic (PK) analysis set: comprised all 62 patients who received Empagliflozin and had evaluable PK parameter data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax of Empagliflozin | Cmax | 309 nmol/L | Geometric Coefficient of Variation 45.2 |
| Placebo | Cmax of Empagliflozin | Cmax,ss | 259 nmol/L | Geometric Coefficient of Variation 24.8 |
| 10mg Empagliflozin | Cmax of Empagliflozin | Cmax | 722 nmol/L | Geometric Coefficient of Variation 20 |
| 10mg Empagliflozin | Cmax of Empagliflozin | Cmax,ss | 687 nmol/L | Geometric Coefficient of Variation 18.4 |
| 25mg Empagliflozin | Cmax of Empagliflozin | Cmax | 2630 nmol/L | Geometric Coefficient of Variation 25.8 |
| 25mg Empagliflozin | Cmax of Empagliflozin | Cmax,ss | 2390 nmol/L | Geometric Coefficient of Variation 28.1 |
Secondary
Fasting Insulin
Change from baseline to the days 1, 7, 14, 21 and 28. Baseline is defined as day -1.
Time frame: in the morning of days -1( baseline), 1, 7, 14, 21 and 28
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fasting Insulin | baseline (day -1) (N=12,12,14,23) | 10 µU/mL | Standard Deviation 4.37 |
| Placebo | Fasting Insulin | change from baseline to day 1 (N=11,12,14,22) | -1.08 µU/mL | Standard Deviation 2.9 |
| Placebo | Fasting Insulin | change from baseline to day 7 (N=9,10,9,18) | 0.48 µU/mL | Standard Deviation 2.56 |
| Placebo | Fasting Insulin | change from baseline to day 14 (N=12,11,14,22) | 2.32 µU/mL | Standard Deviation 4.68 |
| Placebo | Fasting Insulin | change from baseline to day 21 (N=10,11,14,21) | 1.84 µU/mL | Standard Deviation 4.76 |
| Placebo | Fasting Insulin | change from baseline to day 28 (N=11,11,12,20) | -1.2 µU/mL | Standard Deviation 1.74 |
| 10mg Empagliflozin | Fasting Insulin | change from baseline to day 28 (N=11,11,12,20) | -2.89 µU/mL | Standard Deviation 4.68 |
| 10mg Empagliflozin | Fasting Insulin | change from baseline to day 14 (N=12,11,14,22) | -1.16 µU/mL | Standard Deviation 4.58 |
| 10mg Empagliflozin | Fasting Insulin | baseline (day -1) (N=12,12,14,23) | 11.43 µU/mL | Standard Deviation 6.23 |
| 10mg Empagliflozin | Fasting Insulin | change from baseline to day 7 (N=9,10,9,18) | -2.49 µU/mL | Standard Deviation 6.01 |
| 10mg Empagliflozin | Fasting Insulin | change from baseline to day 1 (N=11,12,14,22) | -1.56 µU/mL | Standard Deviation 3.97 |
| 10mg Empagliflozin | Fasting Insulin | change from baseline to day 21 (N=10,11,14,21) | -0.17 µU/mL | Standard Deviation 6.35 |
| 25mg Empagliflozin | Fasting Insulin | change from baseline to day 1 (N=11,12,14,22) | -1.1 µU/mL | Standard Deviation 2.29 |
| 25mg Empagliflozin | Fasting Insulin | change from baseline to day 7 (N=9,10,9,18) | -1 µU/mL | Standard Deviation 3.36 |
| 25mg Empagliflozin | Fasting Insulin | change from baseline to day 14 (N=12,11,14,22) | 0.18 µU/mL | Standard Deviation 2.74 |
| 25mg Empagliflozin | Fasting Insulin | change from baseline to day 28 (N=11,11,12,20) | -1.73 µU/mL | Standard Deviation 3.64 |
| 25mg Empagliflozin | Fasting Insulin | change from baseline to day 21 (N=10,11,14,21) | -1.21 µU/mL | Standard Deviation 2.85 |
| 25mg Empagliflozin | Fasting Insulin | baseline (day -1) (N=12,12,14,23) | 8.74 µU/mL | Standard Deviation 4.13 |
| 100mg Empagliflozin | Fasting Insulin | change from baseline to day 21 (N=10,11,14,21) | 1.53 µU/mL | Standard Deviation 5.87 |
| 100mg Empagliflozin | Fasting Insulin | change from baseline to day 28 (N=11,11,12,20) | -2.1 µU/mL | Standard Deviation 4.46 |
| 100mg Empagliflozin | Fasting Insulin | change from baseline to day 1 (N=11,12,14,22) | 0.15 µU/mL | Standard Deviation 4.51 |
| 100mg Empagliflozin | Fasting Insulin | change from baseline to day 14 (N=12,11,14,22) | 1.37 µU/mL | Standard Deviation 4.75 |
| 100mg Empagliflozin | Fasting Insulin | baseline (day -1) (N=12,12,14,23) | 9.3 µU/mL | Standard Deviation 5.14 |
| 100mg Empagliflozin | Fasting Insulin | change from baseline to day 7 (N=9,10,9,18) | -0.2 µU/mL | Standard Deviation 6.58 |
Secondary
Fasting Plasma Glucose (FPG)
fasting plasma glucose on day -1 (baseline) and change from baseline to day 28
Time frame: in the morning of days -1 and 28
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fasting Plasma Glucose (FPG) | baseline (day -1) | 153.87 mg/dL | Standard Deviation 40.53 |
| Placebo | Fasting Plasma Glucose (FPG) | change from baseline to day 28 (N=15, 15, 16, 28) | -4.08 mg/dL | Standard Deviation 27.08 |
| 10mg Empagliflozin | Fasting Plasma Glucose (FPG) | change from baseline to day 28 (N=15, 15, 16, 28) | -43.7 mg/dL | Standard Deviation 81.81 |
| 10mg Empagliflozin | Fasting Plasma Glucose (FPG) | baseline (day -1) | 186.18 mg/dL | Standard Deviation 92.96 |
| 25mg Empagliflozin | Fasting Plasma Glucose (FPG) | baseline (day -1) | 167.49 mg/dL | Standard Deviation 39.61 |
| 25mg Empagliflozin | Fasting Plasma Glucose (FPG) | change from baseline to day 28 (N=15, 15, 16, 28) | -34.22 mg/dL | Standard Deviation 26.44 |
| 100mg Empagliflozin | Fasting Plasma Glucose (FPG) | baseline (day -1) | 149.92 mg/dL | Standard Deviation 31.65 |
| 100mg Empagliflozin | Fasting Plasma Glucose (FPG) | change from baseline to day 28 (N=15, 15, 16, 28) | -28.69 mg/dL | Standard Deviation 18.25 |
Secondary
fe0-24 of Empagliflozin
Fraction of analyte eliminated in urine from time point 0 to 24h after first dose (fe0-24) and at steady state (fe0-24,ss)
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28
Population: PK analysis set for patients who have fe data at day 1 and day 28
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | fe0-24 of Empagliflozin | fe0-24 (N=14,16,30) | 12.5 percentage of Empagliflozin | Geometric Coefficient of Variation 24 |
| Placebo | fe0-24 of Empagliflozin | fe0-24,ss | 18.3 percentage of Empagliflozin | Geometric Coefficient of Variation 25 |
| 10mg Empagliflozin | fe0-24 of Empagliflozin | fe0-24 (N=14,16,30) | 13.3 percentage of Empagliflozin | Geometric Coefficient of Variation 24.5 |
| 10mg Empagliflozin | fe0-24 of Empagliflozin | fe0-24,ss | 17.8 percentage of Empagliflozin | Geometric Coefficient of Variation 17.8 |
| 25mg Empagliflozin | fe0-24 of Empagliflozin | fe0-24 (N=14,16,30) | 13.7 percentage of Empagliflozin | Geometric Coefficient of Variation 34.1 |
| 25mg Empagliflozin | fe0-24 of Empagliflozin | fe0-24,ss | 17.5 percentage of Empagliflozin | Geometric Coefficient of Variation 28.3 |
Secondary
Fructosamine
change from baseline to days 14 and 18. Baseline is defined as day -1.
Time frame: day -1 (baseline), 14 and 28
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Fructosamine | baseline (day -1) | 237.27 µmol/L | Standard Deviation 33.97 |
| Placebo | Fructosamine | change from baseline to day 28 (N=14, 15, 16, 28) | -23.57 µmol/L | Standard Deviation 28.67 |
| Placebo | Fructosamine | change from baseline to day 14 (N=14, 16, 15, 29) | 19.57 µmol/L | Standard Deviation 24.67 |
| 10mg Empagliflozin | Fructosamine | baseline (day -1) | 251.88 µmol/L | Standard Deviation 39.19 |
| 10mg Empagliflozin | Fructosamine | change from baseline to day 28 (N=14, 15, 16, 28) | -24.33 µmol/L | Standard Deviation 29.98 |
| 10mg Empagliflozin | Fructosamine | change from baseline to day 14 (N=14, 16, 15, 29) | 24.75 µmol/L | Standard Deviation 21.55 |
| 25mg Empagliflozin | Fructosamine | change from baseline to day 14 (N=14, 16, 15, 29) | 13.07 µmol/L | Standard Deviation 20.83 |
| 25mg Empagliflozin | Fructosamine | baseline (day -1) | 257.88 µmol/L | Standard Deviation 53.64 |
| 25mg Empagliflozin | Fructosamine | change from baseline to day 28 (N=14, 15, 16, 28) | -22.06 µmol/L | Standard Deviation 32.89 |
| 100mg Empagliflozin | Fructosamine | baseline (day -1) | 237.07 µmol/L | Standard Deviation 41.48 |
| 100mg Empagliflozin | Fructosamine | change from baseline to day 28 (N=14, 15, 16, 28) | -26.29 µmol/L | Standard Deviation 31.04 |
| 100mg Empagliflozin | Fructosamine | change from baseline to day 14 (N=14, 16, 15, 29) | 18.31 µmol/L | Standard Deviation 22 |
Secondary
Glucagon AUEC0-5
Change from baseline (day -1) in AUEC0-5 on day 28.
Time frame: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.
Population: Pharmacodynamic (PD) analysis set: All patients who receive at least one dose of study medication (active drug or placebo) and had some PD data were included in the pharmacodynamic analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Glucagon AUEC0-5 | baseline (day -1) | 290.66 ng*h/L | Standard Deviation 74.99 |
| Placebo | Glucagon AUEC0-5 | change from baseline to day 28 (N=14, 14, 16, 28) | 9.01 ng*h/L | Standard Deviation 81.1 |
| 10mg Empagliflozin | Glucagon AUEC0-5 | change from baseline to day 28 (N=14, 14, 16, 28) | 59.69 ng*h/L | Standard Deviation 89.52 |
| 10mg Empagliflozin | Glucagon AUEC0-5 | baseline (day -1) | 310.76 ng*h/L | Standard Deviation 72.1 |
| 25mg Empagliflozin | Glucagon AUEC0-5 | baseline (day -1) | 291.09 ng*h/L | Standard Deviation 104.11 |
| 25mg Empagliflozin | Glucagon AUEC0-5 | change from baseline to day 28 (N=14, 14, 16, 28) | 33.6 ng*h/L | Standard Deviation 73.09 |
| 100mg Empagliflozin | Glucagon AUEC0-5 | baseline (day -1) | 303.06 ng*h/L | Standard Deviation 75.4 |
| 100mg Empagliflozin | Glucagon AUEC0-5 | change from baseline to day 28 (N=14, 14, 16, 28) | 40.65 ng*h/L | Standard Deviation 75.72 |
Secondary
Glucagon Emax (Maximum Measured Effect)
Change from baseline (day -1) in Emax on day 28.
Time frame: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 24:00 h after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Glucagon Emax (Maximum Measured Effect) | baseline (day -1) | 80.35 ng/L | Standard Deviation 18.01 |
| Placebo | Glucagon Emax (Maximum Measured Effect) | change from baseline to day 28 (N=14, 14, 16, 28) | 12.44 ng/L | Standard Deviation 28.69 |
| 10mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | change from baseline to day 28 (N=14, 14, 16, 28) | 13.69 ng/L | Standard Deviation 23.96 |
| 10mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | baseline (day -1) | 90.58 ng/L | Standard Deviation 19.63 |
| 25mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | baseline (day -1) | 82.75 ng/L | Standard Deviation 17.79 |
| 25mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | change from baseline to day 28 (N=14, 14, 16, 28) | 7.84 ng/L | Standard Deviation 16.66 |
| 100mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | baseline (day -1) | 86.98 ng/L | Standard Deviation 22.51 |
| 100mg Empagliflozin | Glucagon Emax (Maximum Measured Effect) | change from baseline to day 28 (N=14, 14, 16, 28) | 6.84 ng/L | Standard Deviation 21.45 |
Secondary
HbA1c
change from baseline on day 28. Baseline is defined as day -1.
Time frame: in the morning of days -1 and 28
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | HbA1c | baseline (day -1) | 6.89 percentage of hemoglobin | Standard Deviation 0.91 |
| Placebo | HbA1c | change from baseline to day 28 (N=13, 13, 15, 28) | -0.18 percentage of hemoglobin | Standard Deviation 0.62 |
| 10mg Empagliflozin | HbA1c | change from baseline to day 28 (N=13, 13, 15, 28) | -0.27 percentage of hemoglobin | Standard Deviation 0.36 |
| 10mg Empagliflozin | HbA1c | baseline (day -1) | 7.15 percentage of hemoglobin | Standard Deviation 0.67 |
| 25mg Empagliflozin | HbA1c | baseline (day -1) | 7.45 percentage of hemoglobin | Standard Deviation 0.8 |
| 25mg Empagliflozin | HbA1c | change from baseline to day 28 (N=13, 13, 15, 28) | -0.22 percentage of hemoglobin | Standard Deviation 0.32 |
| 100mg Empagliflozin | HbA1c | baseline (day -1) | 7.1 percentage of hemoglobin | Standard Deviation 0.88 |
| 100mg Empagliflozin | HbA1c | change from baseline to day 28 (N=13, 13, 15, 28) | -0.36 percentage of hemoglobin | Standard Deviation 0.31 |
Secondary
Insulin AUEC0-5
change in AUEC0-5 from baseline on day 28. Baseline is defined as day -1.
Time frame: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Insulin AUEC0-5 | baseline (day -1) | 108.16 µU*h/mL | Standard Deviation 70.85 |
| Placebo | Insulin AUEC0-5 | change from baseline to day 28 (N=16, 16, 16, 29) | 24.37 µU*h/mL | Standard Deviation 99.44 |
| 10mg Empagliflozin | Insulin AUEC0-5 | change from baseline to day 28 (N=16, 16, 16, 29) | 3.24 µU*h/mL | Standard Deviation 91.07 |
| 10mg Empagliflozin | Insulin AUEC0-5 | baseline (day -1) | 117.34 µU*h/mL | Standard Deviation 54.36 |
| 25mg Empagliflozin | Insulin AUEC0-5 | baseline (day -1) | 102.44 µU*h/mL | Standard Deviation 65.8 |
| 25mg Empagliflozin | Insulin AUEC0-5 | change from baseline to day 28 (N=16, 16, 16, 29) | 3.8 µU*h/mL | Standard Deviation 73.66 |
| 100mg Empagliflozin | Insulin AUEC0-5 | baseline (day -1) | 121.53 µU*h/mL | Standard Deviation 101.07 |
| 100mg Empagliflozin | Insulin AUEC0-5 | change from baseline to day 28 (N=16, 16, 16, 29) | 8.83 µU*h/mL | Standard Deviation 67.79 |
Secondary
Insulin Emax (Maximum Measured Effect)
change in Emax from baseline on day 28. Baseline is defined as day -1
Time frame: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day -1. 0:05 before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00 after drug administration on day 28.
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Insulin Emax (Maximum Measured Effect) | baseline (day -1) | 50.78 µU/mL | Standard Deviation 28.35 |
| Placebo | Insulin Emax (Maximum Measured Effect) | change from baseline to day 28 (N=16, 16, 16, 29) | 7.77 µU/mL | Standard Deviation 30.73 |
| 10mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | change from baseline to day 28 (N=16, 16, 16, 29) | 0.55 µU/mL | Standard Deviation 36.94 |
| 10mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | baseline (day -1) | 48.09 µU/mL | Standard Deviation 23.38 |
| 25mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | baseline (day -1) | 46.13 µU/mL | Standard Deviation 24.7 |
| 25mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | change from baseline to day 28 (N=16, 16, 16, 29) | -0.46 µU/mL | Standard Deviation 28.46 |
| 100mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | baseline (day -1) | 53.06 µU/mL | Standard Deviation 43.3 |
| 100mg Empagliflozin | Insulin Emax (Maximum Measured Effect) | change from baseline to day 28 (N=16, 16, 16, 29) | 2.92 µU/mL | Standard Deviation 32.52 |
Secondary
LI (Linearity Index).
The linearity index is defined as AUC0-τ divided by AUC0-∞ both at steady state.
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 after drug administration on day 1 and 28
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | LI (Linearity Index). | 1.09 ratio | Geometric Coefficient of Variation 11.1 |
| 10mg Empagliflozin | LI (Linearity Index). | 1.1 ratio | Geometric Coefficient of Variation 12.5 |
| 25mg Empagliflozin | LI (Linearity Index). | 1.04 ratio | Geometric Coefficient of Variation 9.21 |
Secondary
Mean Daily Glucose (MDG) Measured in Blood
change from baseline in MDG on the days 1, 7, 14, 21 and 27. Baseline is defined as day -2.
Time frame: 0:00, 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day -2. 0:05 h before drug administration and 2:30, 5:00, 7:00, 10:00, 12:00, 13:30, 24:00 h after drug administration on day 1, 7, 14, 21 and 27
Population: PD analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | baseline (day -2) | 152.06 mg/dL | Standard Deviation 41.49 |
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 1 | 2.13 mg/dL | Standard Deviation 18.37 |
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 7 | -2.4 mg/dL | Standard Deviation 15.78 |
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 14 | 2.68 mg/dL | Standard Deviation 28.05 |
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 21 | -3.41 mg/dL | Standard Deviation 30.46 |
| Placebo | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 27 | -4.69 mg/dL | Standard Deviation 32.01 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 27 | -19.57 mg/dL | Standard Deviation 28 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 14 | -26.97 mg/dL | Standard Deviation 27.9 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | baseline (day -2) | 164.83 mg/dL | Standard Deviation 43.18 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 7 | -25.45 mg/dL | Standard Deviation 23.2 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 1 | -14.69 mg/dL | Standard Deviation 15.81 |
| 10mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 21 | -26.47 mg/dL | Standard Deviation 31.71 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 1 | -23.51 mg/dL | Standard Deviation 17.26 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 7 | -28.58 mg/dL | Standard Deviation 17.6 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 14 | -20.43 mg/dL | Standard Deviation 24.69 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 27 | -26.37 mg/dL | Standard Deviation 18.74 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 21 | -19.68 mg/dL | Standard Deviation 24.94 |
| 25mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | baseline (day -2) | 166.26 mg/dL | Standard Deviation 35.86 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 21 | -13.93 mg/dL | Standard Deviation 24.46 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 27 | -23.87 mg/dL | Standard Deviation 18.44 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 1 | -23.02 mg/dL | Standard Deviation 16.72 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 14 | -12.03 mg/dL | Standard Deviation 28.51 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | baseline (day -2) | 149.43 mg/dL | Standard Deviation 34.94 |
| 100mg Empagliflozin | Mean Daily Glucose (MDG) Measured in Blood | change from baseline to day 7 | -21.17 mg/dL | Standard Deviation 21.95 |
Secondary
t1/2 of Empagliflozin
terminal half-life of the analyte in plasma after first dose (Day 1), denoted by t1/2; and at steady state (Day 28), denoted by t1/2,ss.
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28
Population: PK analysis set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | t1/2 of Empagliflozin | t1/2 | 8.69 hours | Geometric Coefficient of Variation 12.9 |
| Placebo | t1/2 of Empagliflozin | t1/2,ss | 12.20 hours | Geometric Coefficient of Variation 41.4 |
| 10mg Empagliflozin | t1/2 of Empagliflozin | t1/2 | 8.16 hours | Geometric Coefficient of Variation 14.5 |
| 10mg Empagliflozin | t1/2 of Empagliflozin | t1/2,ss | 12.70 hours | Geometric Coefficient of Variation 32.7 |
| 25mg Empagliflozin | t1/2 of Empagliflozin | t1/2 | 8.53 hours | Geometric Coefficient of Variation 18.5 |
| 25mg Empagliflozin | t1/2 of Empagliflozin | t1/2,ss | 15.00 hours | Geometric Coefficient of Variation 44.3 |
Secondary
Tmax of Empagliflozin
time from last dosing to maximum concentration of the analyte in plasma after first dose (Day 1), denoted by tmax; and at steady state (Day 28), denoted by tmax,ss.
Time frame: 0:05 before drug administration and 0:15 0:30 0:45 1:00 1:30 2:00 2:30 3:00 4:00 6:00 8:00 10:00 12:00 16:00 24:00 h after drug administration on day 1 and 28
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Tmax of Empagliflozin | tmax | 1.50 hours | Full Range 29.8 |
| Placebo | Tmax of Empagliflozin | tmax,ss | 1.50 hours | Full Range 13 |
| 10mg Empagliflozin | Tmax of Empagliflozin | tmax | 1.50 hours | Full Range 28.7 |
| 10mg Empagliflozin | Tmax of Empagliflozin | tmax,ss | 1.50 hours | Full Range 14.9 |
| 25mg Empagliflozin | Tmax of Empagliflozin | tmax | 1.50 hours | Full Range 30.9 |
| 25mg Empagliflozin | Tmax of Empagliflozin | tmax,ss | 1.50 hours | Full Range 18.7 |