Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Doses of BI 10773 Tablets

Study Overview
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Brief Summary
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To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BI 10773 with repeat dosing for eight days and the exploration of the pharmacokinetics and pharmacodynamics of BI 10773 after multiple dosing, including dose proportionality and assessment of steady state.

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of 4 Multiple Rising Oral Doses (2.5 mg to 100 mg) of BI 10773 Tablets in Male and Female Type 2 Diabetic Patients

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI 10773 Placebo
* Drug: BI 10773
* Drug: BI 10773 Placebo
* Drug: BI 10773
* Drug: BI 10773 Placebo
* Drug: BI 10773 Placebo
* Drug: BI 10773
* Drug: BI 10773


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and postmenopausal or hysterectomised 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 thiazolidindiones with at least one agent taken at 50% of its maximum dose or less. Glycosylated haemoglobin A1 (HbA1c) £ 8.5 % at screening. Age >21 and Age <70 years (male and hysterectomised female patients) Age >60 and Age <70 years (postmenopausal female patients) Body Mass Index (BMI) >18.5 and <40 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with GCP and the local legislation Exclusion criteria: Antidiabetic treatment with insulin or glitazones or with more than one oral hypoglycaemic agent (except if 2 agents and at least one of them not taken at more than 50% of its maximum dose) Fasted blood glucose > 240 mg/dl (>13.3 mmol/L) on two consecutive days during washout. Glycosylated haemoglobin A1 (HbA1c) >8.5% at screening Clinically relevant concomitant diseases other than type 2 diabetes, hyperlipidaemia and medically treated hypertension, such as: Any late stage complication of diabetes (e.g. retinopathy, polyneuropathy, vegetative disorders, diabetic foot) Renal insufficiency (calculated creatinine clearance < 80 ml/min/1.73m²) 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 (Transistoric ischaemic attack) Neurological disorders (such as epilepsy) or psychiatric disorders Acute or relevant chronic infections (e.g. HIV, repeated urogenital infections) Any gastrointestinal, hepatic, respiratory, endocrine or immunological disorder History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for TdP (torsade des pointes) (e.g., heart failure, hypokalemia, family history of sudden death before the age of 50)

Ages Eligible for Study
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Minimum Age: 18 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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 10773 (dose group 3)<br>multiple doses as tablet | Drug: BI 10773 Placebo<br>* po taken fasting with 240 mL water<br>Drug: BI 10773<br>* po taken fasting with 240 mL water<br>|
| Experimental: BI 10773 (dose group 4)<br>multiple doses as tablet | Drug: BI 10773<br>* po taken fasting with 240 mL water<br>Drug: BI 10773 Placebo<br>* po taken fasting with 240 mL water<br>|
| Experimental: BI 10773 (dose group 1)<br>multiple doses as tablet | Drug: BI 10773 Placebo<br>* po taken fasting with 240 mL water<br>Drug: BI 10773<br>* po taken fasting with 240 mL water<br>|
| Experimental: BI 10773 (dose group 2)<br>multiple doses as tablet | Drug: BI 10773 Placebo<br>* po taken fasting with 240 mL water<br>Drug: BI 10773<br>* po taken fasting with 240 mL water<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Relevant Findings in Physical Examination, Vital Signs and Clinical Laboratory Tests | Percentage of participants with clinically relevant findings in physical examination, vital signs and clinical laboratory tests. Relevant findings or worsenings of baseline conditions were reported as Adverse Events (cardiac disorders and investigations). | day 1 to day 21 | 
| Percentage of Participants With Clinically Relevant Findings in Electrocardiogram (ECG) Results | Percentage of participants with clinically relevant findings in electrocardiogram (ECG) results | day 1 to day 21 | 
| Micturition Frequency | Micturition frequency is reported as change from pre-treatment to day 9 during the day, the night and total. Baseline is the mean of days 8-3 before drug administration. | Baseline and Day 9 | 
| Assessment of Tolerability by Investigator | Tolerability will be assessed by the investigator according to the categories good, satisfactory, not satisfactory and bad. | day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of the Analyte in Plasma | Maximum concentration of the analyte in plasma (Cmax) after first dose, Maximum, minimum (Cmin) and average (Cavg) concentration of the analyte in plasma at steady-state, Concentration of analyte in plasma at 24 h after administration of the 8th dose (at steady-state) (C24,8) | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval (AUC) | AUC0-∞: from 0 extrapolated to infinity after first dose AUCtau,1: over a uniform dosing interval tau after first dose AUCtau,ss: over a uniform dosing interval tau at steady-state AUCs were computed using the linear up/log down algorithm. If an analyte concentration was equal to or higher than the preceding concentration, the linear trapezoidal method was to be used. If the analyte concentration was smaller than the preceding concentration, the logarithmic method was to be used. | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Time to Maximum Concentration of the Analyte in Plasma | Time from last dosing to maximum concentration of the analyte in plasma (tmax) after first dose and at steady-state | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1.-0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Terminal Rate Constant in Plasma | Terminal rate constant in plasma after first dose and at steady-state | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Half-life and Mean Residence Time of the Analyte in Plasma | Terminal half life of the analyte in plasma (t1/2) and mean residence time of the analyte in the body after single oral administration (MRTpo) after first dose and at steady-state. | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Apparent Volume of Distribution During the Terminal Phase | Apparent volume of distribution during the terminal phase (Vz/F) after first dose and at steady state. Apparent volume is defined as CL/F divided by the terminal rate constant in plasma (either after first dose or at steady-state). | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Amount of Analyte Eliminated in Urine | Amount of analyte that is eliminated in urine after first dose and at steady state from the time interval 0 to 24 h (Ae0-24) and 0 to 48 h (Ae0-48) | 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 hours (h) after dose on day 1 and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 and 48-72 hours (h) after dose on day 9 | 
| Fraction of Analyte Excreted Unchanged in Urine | Fraction of analyte excreted unchanged in urine in the time interval 0 to 12 h (fe0-12) after first dose and at steady-state. The fraction excreted was calculated by dividing Ae0-12 by the Dose and multiply it with 100. Fraction of analyte excreted unchanged in urine in the time interval 0 to 24 h (fe0-24) after first dose and at steady-state. The fraction excreted was calculated by dividing Ae0-24 by the Dose and multiply it with 100. | 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 hours (h) after dose on day 1 and 0-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 and 48-72 hours (h) after dose on day 9 | 
| Apparent and Renal Clearance of the Analyte in Plasma | Apparent clearance of the analyte in plasma (CL/F) after first dose and at steady-state, Renal clearance of the analyte in plasma after extravascular administration (CLR) after first dose and at steady-state. Apparent clearance after first dose is defined as the dose divided by AUC0-∞; apparent clearance at steady-state is defined as the dose divided by AUC0-tau at steady-state. Renal clearance CLR(0-t) is defined as Ae0-t divided by AUC0-t. | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Peak Trough Fluctuation | Peak trough fluctuation (PTF) is defined as the difference between Cmax and Cmin divided by Cavg and multiplied with 100% at steady-state | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Linearity Index | The linearity index is defined as AUC0-tau divided by AUC0-∞ both at steady state. | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Accumulation Ratios | Accumulation ratio based on Cmax (RA,Cmax) and Accumulated ratio based on AUC0-tau (RA,AUC) at steady-state. Accumulation ratio for the respective doses were calculated using below mentioned equations: RA,Cmax = Cmax,ss/Cmax RA,AUC= AUCtau,ss/AUCtau | -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h and 48h after dose on day 1. -0:05 before dose and 0:10,0:20,0:30,0:40,1h,1:30h,2h,3h,4h,6h,8h,12h,16h,24h,30h,36h, 48h,60h and 72h after dose on day 9. | 
| Change From Baseline to Day 8 in Urinary Glucose Excretion | Change from baseline to day 8 in urinary glucose excretion. Baseline is defined as Day -2. | -2-0 hours(h) before drug administration and 0-2, 2-4, 4-6, 6-8, 8-12,12-16 and 16-24 h after drug administration on day -2 and day 8 | 
| Mean Daily Glucose | Change from baseline to Day 8 in mean daily glucose. Baseline is defined as Day -2. | 0:00, 2:00, 5:00, 7:00, 10:00, 12:00,13:30 and 24:00 hours(h) after drug administration on day -2 and -0.05, 2:30, 5:00, 7:00, 10:00, 12.00, 13:30 and 24:00 hours (h) after drug administration on day 8 | 
| Fasting Plasma Glucose | Percentage change from baseline to Day 8 in fasting plasma glucose. Baseline is defined as Day -2. | -0:30 (Pre dose samples) | 
| Serum Insulin | Serum insulin measured for on day -2 and day 8 for AUEC0-5 and AUEC0-12. AUEC0-5: The area under the effect concentration-time curve over the time interval 0 to 5. AUEC0-12: The area under the effect concentration-time curve over the time interval 0 to 12. | 0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8 | 
| Serum Insulin | Serum insulin measured for on day -2 and day 8 for Emax0-5, Emax0-12, Emin0-5 and Emin0-12. Emax: Maximum effect (maximum measured concentration of glucose or insulin in plasma) & Emin: Minimum effect (minimum measured concentration of glucose or insulin in plasma) | 0.0h, 2h, 5h, 7h, 10h, 12h on day -2 & day 8 |