Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Empagliflozin in Chinese Female and Male Patients With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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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.

Official Title
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Pharmacokinetics and Pharmacodynamics of BI 10773 After Single and Multiple Oral Dose of 10 mg and 25 mg BI 10773 in Chinese Male and Female Type 2 Diabetic Patients

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI10773
* Drug: Placebo
* Drug: Placebo
* Drug: Placebo
* Drug: BI10773


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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 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 Signed and dated written informed consent by date of Visit 1 in accordance with GCP and local legislation. Exclusion criteria: Patient who did not discontinue the antidiabetic treatment with insulin or glitazones, DPP-IV at least before 12 weeks before randomization Uncontrolled hyperglycaemia with a glucose level >240 mg/dl (>13.3 mmol/L) after an overnight fast at screening visit 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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI10773 low dose Per Os(p.o.)<br>patient to receive a tablet containing low dose BI10773 Per Os(p.o.) plus one placebo | Drug: Placebo<br>* patient to receive two placebos<br>Drug: BI10773<br>* patient to receive a tablet containing low dose BI10773 p.o. plus one placebo<br>|
| Placebo Comparator: Placebo<br>patient to receive two placebos | Drug: Placebo<br>* patient to receive two placebos<br>|
| Experimental: BI10773 high dose Per Os(p.o.)<br>patient to receive a tablet containing high dose BI10773 Per Os(p.o.) plus one placebo | Drug: BI10773<br>* patient to receive a tablet containing high dose BI10773 p.o. plus one placebo<br>Drug: Placebo<br>* patient to receive two placebos<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Measured Concentration (Cmax) | Maximum measured concentration of the analyte in plasma after the first dose on day 1. | 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 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. | 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 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 | 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 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. | 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 (λz) | Terminal Rate Constant in Plasma (λz), after the first dose on day 1 | 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 (t1/2) | Terminal half-life of empagliflozin (empa) in plasma after the first dose on day 1 | 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 (MRTpo) | Mean residence time of empagliflozin (empa) in the body after the first dose on day 1. | 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 After Extravascular Administration (CL/F) | Apparent clearance of empagliflozin (empa) in plasma after extravascular administration, after the first dose on day 1. | 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 (Vz/F) | Apparent volume of distribution during the terminal phase λz, after the first dose on day 1. | 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 | 
| 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. | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | 
| 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. | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | 
| 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. | 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 Over a Uniform Dosing Interval (Cmax,ss) | Maximum measured concentration of empagliflozin (empa) in plasma at steady state over a uniform dosing interval. | 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 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. | 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 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 | 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 (λz,ss) | Terminal rate constant in plasma at steady state, after multiple dosing. | 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 in Plasma at Steady State (t1/2,ss) | Terminal half-life of empagliflozin (empa) in plasma at steady state, after multiple dosing. | 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 at Steady State (MRTpo,ss) | Mean residence time of empagliflozin (empa) in the body at steady state after multiple oral administrations | 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 After Extravascular Administration (CL/Fss) | Apparent clearance of empagliflozin (empa) in the plasma at steady state following multiple oral dose administration. | 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 (Vz/Fss) | Apparent volume of distribution during the terminal phase λz at steady state following oral administration after multiple dosing | 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 | 
| 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. | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | 
| 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. | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | 
| Renal Clearance at Steady State (CL R,ss) | Renal clearance of empagliflozin (empa) in plasma after extravascular administration, after multiple dosing. | 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 | 
| Accumulation Ratio Based on AUC (R A,AUC) | Accumulation ratio of empagliflozin (empa) based on AUC, after multiple dosing | 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 Based on Cmax (R A,Cmax) | Accumulation ratio of empagliflozin (empa) based on Cmax, after multiple dosing | 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 | 
| 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. | 5 minutes before drug administration | 
| Urinary Glucose Excretion (UGE) Change From Baseline | Change from day -1 in urinary glucose excretion in a 24 hour collection period per time point. | 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 | Fasting Plasma Glucose (FPG) change from baseline between day 1 and day 9. | Sampling intervals were 0-2 hours (h), 2-4h, 4-8h, 8-12h and 12-24h after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Drug administration until end of trial, up to 21 days |