Diabetes Mellitus, Type 2
Conditions
Brief summary
The objective of this trial is to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of once daily oral administration of BI 10773 administered for 28 days in Japanese patients with T2DM.
Interventions
DRUGPlacebo (middle dose)
Placebo tablets once a day
DRUGPlacebo
Placebo tablets once a day
DRUGBI 10773
BI 10773 middle dose tablets once a day
Placebo tablets once a day
Placebo tablets once a day
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
20 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Japanese male or female patients with T2DM treated with diet and exercise alone or with one hypoglycaemic drug other than glitazones. 2. Hemoglobin A1c (HbA1c) at screening (Visit 1) * For patients treated with 1 other oral antidiabetic drug: HbA1c between 6.5% and 9.0%. * For patients not treated with any antidiabetic drug: HbA1c between 7.0% and 10.0%. 3. Age between 20 and 70 years 4. Body mass index (BMI) between18.0 and 40.0 kg/m2 5. Signed and dated written informed consent before admission to the trial in accordance with the Good Clinical Practice (GCP) and the local legislation.
Exclusion criteria
1. Antidiabetic treatment with insulin or glitazones within 3 months before obtaining informed consent or with more than 1 oral hypoglycaemic agent at the time of informed consent 2. Fasted blood glucose of \>240 mg/dL (\>13.3 mmol/L) or a randomly determined blood glucose level of \>400 mg/dL (22.2 mmol/L) on 2 consecutive days during wash-out period. 3. Myocardial infarction, stroke, or transient ischaemic attack within 6 months before informed consent. 4. Clinically relevant concomitant diseases other than T2DM, hyperlipidaemia, and medically treated hypertension before the first administration such as * Renal insufficiency (calculated estimated glomerular filtration rate \<60) * Cardiac insufficiency of New York Heart Association (NYHA) II-IV or other known cardiovascular diseases including hypertension of \>160/95 mmHg, * Neurological disorders (such as epilepsy) or psychiatric disorders * Acute or clinically relevant chronic infections (e.g., human immunodeficiency virus, hepatitis, repeated urogenital infections) * Any gastrointestinal, hepatic, respiratory, endocrine, or immunological disorder 5. Patients under treatment with any concomitant medication except for the following drugs at the time of informed consent.: * Statins. * Antihypertensives (diuretics not allowed) * alpha-Blockers for benign prostate hypertrophy * Occasional use of acetylsalicylic acid, ibuprofen, or paracetamol 6. Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Urine Glucose Excretion | baseline and 28 days | Change from baseline in Urine glucose excretion to 28 days |
| Change From Baseline in Fasting Plasma Glucose | baseline and 28 days | Change from baseline in Fasting plasma glucose to 28 days |
| Change From Baseline in 8-point Glucose | baseline and 27 days | Change from baseline in 8-point glucose to 27 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Insulin | baseline and 28 days | Change from baseline in Fasting insulin to 28 days |
| Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | baseline and 28 days | Change from baseline in the area under the curve of plasma glucose levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days |
| Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | baseline and 28 days | Change from baseline in the area under the curve of glucagon levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days |
| Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | baseline and 28 days | Change from baseline in the area under the curve of insulin levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days |
| AUCτ,1 | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | Area under the concentration-time curve of the analyte in plasma after administration of the first dose over a uniform dosing interval τ |
| AUC0-tz | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | area under the concentration-time curve of the analyte in plasma over the time interval from 0 to last quantifiable plasma concentration |
| AUC0-∞ | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity |
| Cmax | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | maximum measured concentration of the analyte in plasma |
| t1/2 | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | terminal half-life of the analyte in plasma |
| CL/F | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | apparent clearance of the analyte in plasma after extravascular administration |
| Vz/F | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration | apparent volume of distribution during the terminal phase λz following an extravascular dose |
| Ae0-24 | 0-5, 5-12, 12-24 hour after first drug administration | amount of the analyte that is eliminated in urine over the time interval 0 to 24 |
| Change From Baseline in HbA1c | baseline and 28 days | Change from baseline in HbA1c to 28 days |
| CLR,0-24 | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min, 0-5h, 5-12h, 12-24h after first drug administration | renal clearance of the analyte in plasma after extravascular administration - based on 0-24 hours data |
| AUCτ,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration | area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ at steady state |
| Cmax,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration | maximum measured concentration of the analyte in plasma at steady state |
| t1/2,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration | terminal half-life of the analyte in plasma at steady state |
| CL/F,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration | apparent clearance of the analyte in plasma after extravascular administration at steady state |
| Vz/F,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration | apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state |
| RA,Cmax | Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration | accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on Cmax |
| RA,AUC | Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration | accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on AUCτ |
| Ae0-24,ss | 0-5, 5-12, 12-24 hour after last drug administration | amount of the analyte that is eliminated in urine at steady state over the time interval 0 to 24 |
| fe0-24,ss | 0-5, 5-12, 12-24 hour after last drug administration | fraction of the analyte excreted unchanged in urine at steady state from time interval 0 to 24 |
| CLR,ss | Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 0-5h, 5-12h, 12-24h after last drug administration | renal clearance of the analyte at steady state determined over the dosing interval τ |
| fe0-24 | 0-5, 5-12, 12-24 hour after first drug administration | fraction of the analyte excreted unchanged in urine from time interval 0 to 24 |
| Change From Baseline in Fructosamine | baseline and 28 days | Change from baseline in Fructosamine to 28 days |
| Change From Baseline in 1,5-anhydroglucitol | baseline and 28 days | Change from baseline in 1,5-anhydroglucitol to 28 days |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Treatment with placebo once daily | 21 |
| Empa 1 mg Treatment with Empa 1 mg once daily | 19 |
| Empa 5 mg Treatment with Empa 5 mg once daily | 21 |
| Empa 10 mg Treatment with Empa 10 mg once daily | 20 |
| Empa 25 mg Treatment with Empa 25 mg once daily | 19 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Other reason not defined above | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Empa 1 mg | Empa 5 mg | Empa 10 mg | Empa 25 mg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 10 | 58.6 years STANDARD_DEVIATION 8.2 | 53.9 years STANDARD_DEVIATION 9.9 | 55.8 years STANDARD_DEVIATION 8 | 60.8 years STANDARD_DEVIATION 8.7 | 57.2 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 1 Participants | 3 Participants | 4 Participants | 16 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 20 Participants | 17 Participants | 15 Participants | 84 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 21 | 6 / 19 | 2 / 21 | 5 / 20 | 7 / 19 |
| serious Total, serious adverse events | 0 / 21 | 1 / 19 | 0 / 21 | 0 / 20 | 0 / 19 |
Outcome results
Primary
Change From Baseline in 8-point Glucose
Change from baseline in 8-point glucose to 27 days
Time frame: baseline and 27 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 8-point Glucose | -17.381 mg/dL | Standard Error 3.932 |
| Empa 1 mg | Change From Baseline in 8-point Glucose | -35.263 mg/dL | Standard Error 4.121 |
| Empa 5 mg | Change From Baseline in 8-point Glucose | -39.867 mg/dL | Standard Error 3.903 |
| Empa 10 mg | Change From Baseline in 8-point Glucose | -43.646 mg/dL | Standard Error 4.113 |
| Empa 25 mg | Change From Baseline in 8-point Glucose | -45.721 mg/dL | Standard Error 4.187 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.00395% CI: [-29.529, -6.236]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: <0.000195% CI: [-33.308, -11.665]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: <0.000195% CI: [-37.762, -14.768]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: <0.000195% CI: [-39.665, -17.015]ANCOVA
Primary
Change From Baseline in Fasting Plasma Glucose
Change from baseline in Fasting plasma glucose to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose | -15.436 mg/dL | Standard Error 2.86 |
| Empa 1 mg | Change From Baseline in Fasting Plasma Glucose | -28.116 mg/dL | Standard Error 2.965 |
| Empa 5 mg | Change From Baseline in Fasting Plasma Glucose | -35.355 mg/dL | Standard Error 2.865 |
| Empa 10 mg | Change From Baseline in Fasting Plasma Glucose | -41.643 mg/dL | Standard Error 3.009 |
| Empa 25 mg | Change From Baseline in Fasting Plasma Glucose | -42.670 mg/dL | Standard Error 3.089 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.00395% CI: [-20.936, -4.424]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: <0.000195% CI: [-27.919, -11.921]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: <0.000195% CI: [-34.49, -17.925]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: <0.000195% CI: [-35.586, -18.884]ANCOVA
Primary
Change From Baseline in Urine Glucose Excretion
Change from baseline in Urine glucose excretion to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Urine Glucose Excretion | 599.763 mg | Standard Error 4497.46 |
| Empa 1 mg | Change From Baseline in Urine Glucose Excretion | 43428.245 mg | Standard Error 4598.593 |
| Empa 5 mg | Change From Baseline in Urine Glucose Excretion | 81564.440 mg | Standard Error 4460.086 |
| Empa 10 mg | Change From Baseline in Urine Glucose Excretion | 89189.527 mg | Standard Error 4704.967 |
| Empa 25 mg | Change From Baseline in Urine Glucose Excretion | 86220.111 mg | Standard Error 4828.541 |
Comparison: Difference calculated as empa 1mg minus placebop-value: <0.000195% CI: [29936.586, 55720.378]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: <0.000195% CI: [68437.16, 93492.194]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: <0.000195% CI: [75583.738, 101595.79]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: <0.000195% CI: [72484.181, 98756.515]ANCOVA
Secondary
Ae0-24
amount of the analyte that is eliminated in urine over the time interval 0 to 24
Time frame: 0-5, 5-12, 12-24 hour after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ae0-24 | 338 nmol | Geometric Coefficient of Variation 23.7 |
| Empa 1 mg | Ae0-24 | 1640 nmol | Geometric Coefficient of Variation 56.2 |
| Empa 5 mg | Ae0-24 | 3460 nmol | Geometric Coefficient of Variation 17.5 |
| Empa 10 mg | Ae0-24 | 8550 nmol | Geometric Coefficient of Variation 17 |
Secondary
Ae0-24,ss
amount of the analyte that is eliminated in urine at steady state over the time interval 0 to 24
Time frame: 0-5, 5-12, 12-24 hour after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ae0-24,ss | 479 nmol | Geometric Coefficient of Variation 27.2 |
| Empa 1 mg | Ae0-24,ss | 2250 nmol | Geometric Coefficient of Variation 44.5 |
| Empa 5 mg | Ae0-24,ss | 4780 nmol | Geometric Coefficient of Variation 18.6 |
| Empa 10 mg | Ae0-24,ss | 11500 nmol | Geometric Coefficient of Variation 24.3 |
Secondary
AUC0-∞
area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-∞ | 249 nmol*h/L | Geometric Coefficient of Variation 15.5 |
| Empa 1 mg | AUC0-∞ | 1070 nmol*h/L | Geometric Coefficient of Variation 44.5 |
| Empa 5 mg | AUC0-∞ | 2320 nmol*h/L | Geometric Coefficient of Variation 18.1 |
| Empa 10 mg | AUC0-∞ | 5930 nmol*h/L | Geometric Coefficient of Variation 18.6 |
Secondary
AUC0-tz
area under the concentration-time curve of the analyte in plasma over the time interval from 0 to last quantifiable plasma concentration
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-tz | 216 nmol*h/L | Geometric Coefficient of Variation 18.4 |
| Empa 1 mg | AUC0-tz | 937 nmol*h/L | Geometric Coefficient of Variation 44.2 |
| Empa 5 mg | AUC0-tz | 2040 nmol*h/L | Geometric Coefficient of Variation 19.5 |
| Empa 10 mg | AUC0-tz | 5180 nmol*h/L | Geometric Coefficient of Variation 18.6 |
Secondary
AUCτ,1
Area under the concentration-time curve of the analyte in plasma after administration of the first dose over a uniform dosing interval τ
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUCτ,1 | 216 nmol*h/L | Geometric Coefficient of Variation 18.4 |
| Empa 1 mg | AUCτ,1 | 938 nmol*h/L | Geometric Coefficient of Variation 44.2 |
| Empa 5 mg | AUCτ,1 | 2040 nmol*h/L | Geometric Coefficient of Variation 19.4 |
| Empa 10 mg | AUCτ,1 | 5190 nmol*h/L | Geometric Coefficient of Variation 18.6 |
Secondary
AUCτ,ss
area under the concentration-time curve of the analyte in plasma over a uniform dosing interval τ at steady state
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUCτ,ss | 277 nmol*h/L | Geometric Coefficient of Variation 17 |
| Empa 1 mg | AUCτ,ss | 1270 nmol*h/L | Geometric Coefficient of Variation 15 |
| Empa 5 mg | AUCτ,ss | 2580 nmol*h/L | Geometric Coefficient of Variation 17.3 |
| Empa 10 mg | AUCτ,ss | 6330 nmol*h/L | Geometric Coefficient of Variation 20.3 |
Secondary
Change From Baseline in 1,5-anhydroglucitol
Change from baseline in 1,5-anhydroglucitol to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 1,5-anhydroglucitol | 1.174 ug/mL | Standard Error 0.439 |
| Empa 1 mg | Change From Baseline in 1,5-anhydroglucitol | -3.018 ug/mL | Standard Error 0.581 |
| Empa 5 mg | Change From Baseline in 1,5-anhydroglucitol | -3.435 ug/mL | Standard Error 0.615 |
| Empa 10 mg | Change From Baseline in 1,5-anhydroglucitol | -2.863 ug/mL | Standard Error 0.622 |
| Empa 25 mg | Change From Baseline in 1,5-anhydroglucitol | -3.713 ug/mL | Standard Error 0.982 |
Comparison: Difference calculated as empa 1mg minus placebop-value: <0.000195% CI: [-5.653, -2.731]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: <0.000195% CI: [-6.126, -3.091]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: <0.000195% CI: [-5.565, -2.508]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: <0.000195% CI: [-7.048, -2.726]ANCOVA
Secondary
Change From Baseline in Fasting Insulin
Change from baseline in Fasting insulin to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Insulin | -0.387 uU/mL | Standard Error 0.287 |
| Empa 1 mg | Change From Baseline in Fasting Insulin | -0.866 uU/mL | Standard Error 0.295 |
| Empa 5 mg | Change From Baseline in Fasting Insulin | -0.766 uU/mL | Standard Error 0.287 |
| Empa 10 mg | Change From Baseline in Fasting Insulin | -1.730 uU/mL | Standard Error 0.301 |
| Empa 25 mg | Change From Baseline in Fasting Insulin | -1.643 uU/mL | Standard Error 0.312 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.249895% CI: [-1.302, 0.343]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: 0.354495% CI: [-1.189, 0.43]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: 0.001895% CI: [-2.171, -0.516]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: 0.003795% CI: [-2.094, -0.419]ANCOVA
Secondary
Change From Baseline in Fructosamine
Change from baseline in Fructosamine to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fructosamine | -8.436 umol/L | Standard Error 12.289 |
| Empa 1 mg | Change From Baseline in Fructosamine | 4.091 umol/L | Standard Error 12.663 |
| Empa 5 mg | Change From Baseline in Fructosamine | -2.453 umol/L | Standard Error 12.362 |
| Empa 10 mg | Change From Baseline in Fructosamine | -26.294 umol/L | Standard Error 12.933 |
| Empa 25 mg | Change From Baseline in Fructosamine | -28.275 umol/L | Standard Error 13.282 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.482395% CI: [-22.757, 47.811]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: 0.730595% CI: [-28.422, 40.39]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: 0.321395% CI: [-53.438, 17.721]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: 0.276895% CI: [-55.869, 16.192]ANCOVA
Secondary
Change From Baseline in HbA1c
Change from baseline in HbA1c to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in HbA1c | -0.420 percentage of HbA1c | Standard Error 0.089 |
| Empa 1 mg | Change From Baseline in HbA1c | -0.659 percentage of HbA1c | Standard Error 0.093 |
| Empa 5 mg | Change From Baseline in HbA1c | -0.717 percentage of HbA1c | Standard Error 0.09 |
| Empa 10 mg | Change From Baseline in HbA1c | -0.849 percentage of HbA1c | Standard Error 0.094 |
| Empa 25 mg | Change From Baseline in HbA1c | -0.815 percentage of HbA1c | Standard Error 0.096 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.070595% CI: [-0.498, -0.02]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: 0.020395% CI: [-0.545, -0.047]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: 0.001495% CI: [-0.687, -0.17]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: 0.003395% CI: [-0.654, -0.135]ANCOVA
Secondary
Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)
Change from baseline in the area under the curve of glucagon levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -23.452 hr*pg/mL | Standard Error 9.177 |
| Empa 1 mg | Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -0.785 hr*pg/mL | Standard Error 9.383 |
| Empa 5 mg | Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | 7.124 hr*pg/mL | Standard Error 9.138 |
| Empa 10 mg | Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -17.478 hr*pg/mL | Standard Error 9.635 |
| Empa 25 mg | Change From Baseline in the Area Under the Curve of Glucagon Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -12.437 hr*pg/mL | Standard Error 9.964 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.088395% CI: [-3.47, 48.805]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: 0.020395% CI: [4.859, 56.293]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: 0.654195% CI: [-20.434, 32.382]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: 0.420695% CI: [-16.036, 38.066]ANCOVA
Secondary
Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)
Change from baseline in the area under the curve of insulin levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | 2.948 hr*uU/mL | Standard Error 2.819 |
| Empa 1 mg | Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -5.921 hr*uU/mL | Standard Error 2.896 |
| Empa 5 mg | Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -11.396 hr*uU/mL | Standard Error 2.811 |
| Empa 10 mg | Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -12.695 hr*uU/mL | Standard Error 2.982 |
| Empa 25 mg | Change From Baseline in the Area Under the Curve of Insulin Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -7.170 hr*uU/mL | Standard Error 3.048 |
Comparison: Difference calculated as empa 1mg minus placebop-value: 0.031895% CI: [-16.949, -0.789]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: 0.000595% CI: [-22.225, -6.462]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: 0.000395% CI: [-23.853, -7.432]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: 0.016495% CI: [-18.339, -1.897]ANCOVA
Secondary
Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test)
Change from baseline in the area under the curve of plasma glucose levels until 4 hours after intake of a standardised food (meal tolerance test) to 28 days
Time frame: baseline and 28 days
Population: Full analysis set (FAS)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -81.357 hr*mg/dL | Standard Error 10.481 |
| Empa 1 mg | Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -176.771 hr*mg/dL | Standard Error 10.924 |
| Empa 5 mg | Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -190.837 hr*mg/dL | Standard Error 10.554 |
| Empa 10 mg | Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -212.693 hr*mg/dL | Standard Error 11.023 |
| Empa 25 mg | Change From Baseline in the Area Under the Curve of Plasma Glucose Levels Until 4 Hours After Intake of a Standardised Food (Meal Tolerance Test) | -217.698 hr*mg/dL | Standard Error 11.247 |
Comparison: Difference calculated as empa 1mg minus placebop-value: <0.000195% CI: [-125.995, -64.833]ANCOVA
Comparison: Difference calculated as empa 5mg minus placebop-value: <0.000195% CI: [-138.633, -80.327]ANCOVA
Comparison: Difference calculated as empa 10mg minus placebop-value: <0.000195% CI: [-161.848, -100.824]ANCOVA
Comparison: Difference calculated as empa 25mg minus placebop-value: <0.000195% CI: [-166.86, -105.823]ANCOVA
Secondary
CL/F
apparent clearance of the analyte in plasma after extravascular administration
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CL/F | 149 mL/min | Geometric Coefficient of Variation 15.5 |
| Empa 1 mg | CL/F | 173 mL/min | Geometric Coefficient of Variation 44.5 |
| Empa 5 mg | CL/F | 159 mL/min | Geometric Coefficient of Variation 18.1 |
| Empa 10 mg | CL/F | 156 mL/min | Geometric Coefficient of Variation 18.6 |
Secondary
CL/F,ss
apparent clearance of the analyte in plasma after extravascular administration at steady state
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CL/F,ss | 133 mL/min | Geometric Coefficient of Variation 17 |
| Empa 1 mg | CL/F,ss | 146 mL/min | Geometric Coefficient of Variation 15 |
| Empa 5 mg | CL/F,ss | 143 mL/min | Geometric Coefficient of Variation 17.3 |
| Empa 10 mg | CL/F,ss | 146 mL/min | Geometric Coefficient of Variation 20.3 |
Secondary
CLR,0-24
renal clearance of the analyte in plasma after extravascular administration - based on 0-24 hours data
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min, 0-5h, 5-12h, 12-24h after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CLR,0-24 | 25.7 mL/min | Geometric Coefficient of Variation 21.2 |
| Empa 1 mg | CLR,0-24 | 28.7 mL/min | Geometric Coefficient of Variation 27.3 |
| Empa 5 mg | CLR,0-24 | 28.3 mL/min | Geometric Coefficient of Variation 24.4 |
| Empa 10 mg | CLR,0-24 | 27.5 mL/min | Geometric Coefficient of Variation 23.4 |
Secondary
CLR,ss
renal clearance of the analyte at steady state determined over the dosing interval τ
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 0-5h, 5-12h, 12-24h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | CLR,ss | 28.8 mL/min | Geometric Coefficient of Variation 25.2 |
| Empa 1 mg | CLR,ss | 29.6 mL/min | Geometric Coefficient of Variation 40.5 |
| Empa 5 mg | CLR,ss | 30.9 mL/min | Geometric Coefficient of Variation 28.1 |
| Empa 10 mg | CLR,ss | 30.3 mL/min | Geometric Coefficient of Variation 28.3 |
Secondary
Cmax
maximum measured concentration of the analyte in plasma
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax | 38.5 nmol/L | Geometric Coefficient of Variation 28.8 |
| Empa 1 mg | Cmax | 166 nmol/L | Geometric Coefficient of Variation 47.6 |
| Empa 5 mg | Cmax | 358 nmol/L | Geometric Coefficient of Variation 29.1 |
| Empa 10 mg | Cmax | 844 nmol/L | Geometric Coefficient of Variation 15.7 |
Secondary
Cmax,ss
maximum measured concentration of the analyte in plasma at steady state
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax,ss | 41.4 nmol/L | Geometric Coefficient of Variation 32.3 |
| Empa 1 mg | Cmax,ss | 182 nmol/L | Geometric Coefficient of Variation 31.4 |
| Empa 5 mg | Cmax,ss | 393 nmol/L | Geometric Coefficient of Variation 28 |
| Empa 10 mg | Cmax,ss | 836 nmol/L | Geometric Coefficient of Variation 29.2 |
Secondary
fe0-24
fraction of the analyte excreted unchanged in urine from time interval 0 to 24
Time frame: 0-5, 5-12, 12-24 hour after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | fe0-24 | 15.2 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 23.7 |
| Empa 1 mg | fe0-24 | 14.8 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 56.2 |
| Empa 5 mg | fe0-24 | 15.6 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 17.5 |
| Empa 10 mg | fe0-24 | 15.4 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 17 |
Secondary
fe0-24,ss
fraction of the analyte excreted unchanged in urine at steady state from time interval 0 to 24
Time frame: 0-5, 5-12, 12-24 hour after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | fe0-24,ss | 21.6 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 27.2 |
| Empa 1 mg | fe0-24,ss | 20.3 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 44.5 |
| Empa 5 mg | fe0-24,ss | 21.6 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 18.6 |
| Empa 10 mg | fe0-24,ss | 20.8 percentage of Ae0-24 (to dosage) | Geometric Coefficient of Variation 24.3 |
Secondary
RA,AUC
accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on AUCτ
Time frame: Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | RA,AUC | 1.28 ratio | Geometric Coefficient of Variation 9.21 |
| Empa 1 mg | RA,AUC | 1.32 ratio | Geometric Coefficient of Variation 42.5 |
| Empa 5 mg | RA,AUC | 1.32 ratio | Geometric Coefficient of Variation 13.1 |
| Empa 10 mg | RA,AUC | 1.23 ratio | Geometric Coefficient of Variation 12.7 |
Secondary
RA,Cmax
accumulation ratios of the analyte in plasma after 28 doses (once daily) over a uniform dosing interval τ, based on Cmax
Time frame: Predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration, and predose, 15min, 30min, 45min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | RA,Cmax | 1.08 ratio | Geometric Coefficient of Variation 23.3 |
| Empa 1 mg | RA,Cmax | 1.07 ratio | Geometric Coefficient of Variation 54.2 |
| Empa 5 mg | RA,Cmax | 1.16 ratio | Geometric Coefficient of Variation 34.2 |
| Empa 10 mg | RA,Cmax | 0.998 ratio | Geometric Coefficient of Variation 30.4 |
Secondary
t1/2
terminal half-life of the analyte in plasma
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | t1/2 | 9.55 hour | Geometric Coefficient of Variation 14.8 |
| Empa 1 mg | t1/2 | 9.09 hour | Geometric Coefficient of Variation 15 |
| Empa 5 mg | t1/2 | 9.14 hour | Geometric Coefficient of Variation 13.3 |
| Empa 10 mg | t1/2 | 9.26 hour | Geometric Coefficient of Variation 15.8 |
Secondary
t1/2,ss
terminal half-life of the analyte in plasma at steady state
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | t1/2,ss | 12.2 hour | Geometric Coefficient of Variation 45.5 |
| Empa 1 mg | t1/2,ss | 11.9 hour | Geometric Coefficient of Variation 48 |
| Empa 5 mg | t1/2,ss | 13.4 hour | Geometric Coefficient of Variation 37.7 |
| Empa 10 mg | t1/2,ss | 16.4 hour | Geometric Coefficient of Variation 48.4 |
Secondary
Vz/F
apparent volume of distribution during the terminal phase λz following an extravascular dose
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 23h55min after first drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Vz/F | 123 Liter | Geometric Coefficient of Variation 26.1 |
| Empa 1 mg | Vz/F | 136 Liter | Geometric Coefficient of Variation 46.3 |
| Empa 5 mg | Vz/F | 126 Liter | Geometric Coefficient of Variation 25.5 |
| Empa 10 mg | Vz/F | 125 Liter | Geometric Coefficient of Variation 25.3 |
Secondary
Vz/F,ss
apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state
Time frame: Predose and 15 minutes (min), 30min, 45min, 1 hour (h), 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h 48h, 72h after last drug administration
Population: Pharmacokinetic analysis set: all patients who received at least one dose of BI 10773 and had some pharmacokinetic data
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Vz/F,ss | 141 Liter | Geometric Coefficient of Variation 37.8 |
| Empa 1 mg | Vz/F,ss | 151 Liter | Geometric Coefficient of Variation 48.6 |
| Empa 5 mg | Vz/F,ss | 166 Liter | Geometric Coefficient of Variation 43.6 |
| Empa 10 mg | Vz/F,ss | 208 Liter | Geometric Coefficient of Variation 51.6 |