Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 1356 BS as Tablet in Patients With Type 2 Diabetes

Study Overview
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Brief Summary
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Study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 1356 BS during 4 week treatment duration

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Oral Doses (2.5, 5, and 10 mg q.d. for 28 Days) of BI 1356 BS as Tablet in Patients With Type 2 Diabetes (Randomised, Double-blind, Placebo-controlled Within the Dose Groups)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: BI 1356 BS, low dose
* Drug: BI 1356 BS, medium dose
* Drug: BI 1356 BS, high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female postmenopausal patients with proven diagnose of type 2 diabetes mellitus treated with diet and exercise only or with one (or two) oral hypoglycaemic agents besides glitazones Glycosylated haemoglobin A1 (HbA1c) ≤ 8.5 % at screening for patients treated with diet and exercise and/or one oral hypoglycaemic agent or ≤ 8.0 % at screening for patients treated with two oral hypoglycaemic agents Male patients: Age ≥21 and Age ≤70 years Female patients: Age ≥60 and Age ≤70 years BMI ≥18.5 and BMI ≤35 kg/m2 (Body Mass Index) Caucasian ethnicity Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice and the local legislation Exclusion Criteria: Any finding of the medical examination (including Blood Pressure, Pulse Rate and Electrocardiogram) deviating from normal and of not acceptable clinical relevance Clinically relevant concomitant diseases like renal insufficiency, cardiac insufficiency NYHA (New York Heart Association) II-IV, known cardiovascular diseases including hypertension > 150/95mmHg, stroke and TIA (transient ischemic attack) Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders besides type 2 diabetes, hyperlipidaemia and medically treated hypertension Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or relevant neurological disorders besides polyneuropathy Chronic or relevant acute infections (e.g. HIV, Hepatitis) History of relevant allergy/hypersensitivity (including allergy to drug or its excipients) Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial except allowed co-medication Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within two months prior to administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 40 g/day = 5 units/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range and the clinical relevance is not acceptable (or the value is more than three times higher than the upper limit of the normal range e.g. liver enzymes) Change of drug dosing of allowed co-medication (anti-hypertensive agents, acetylic salicylic acid and statins) within the last 3 months Fasted blood glucose > 240 mg/dl (=13.3 mmol/L) on two consecutive days during washout Serum creatinine above upper limit of normal at screening Male Patients: Not willing to use adequate contraception (condom use plus another form of contraception e.g. spermicide, oral contraceptive taken by female partner, sterilisation, intrauterine device) during the whole study period from the time of the first intake of study drug until one month after the last intake Female patients: Positive pregnancy test

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: BI 1356 BS, low dose<br> | Drug: BI 1356 BS, low dose<br> <br> |
| Experimental: BI 1356 BS, medium dose<br> | Drug: BI 1356 BS, medium dose<br> <br> |
| Experimental: BI 1356 BS, high dose<br> | Drug: BI 1356 BS, high dose<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of tolerability by investigator on a 4-point scale |  | Day 50 | 
| Incidence of adverse events |  | up to 50 days | 
| Number of patients with abnormal changes in clinical laboratory parameters |  | Baseline, up to day 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum concentration of the analyte in plasma) |  | before and up to 43 days after first study drug administration | 
| tmax (time from dosing to maximum concentration) |  | before and up to 43 days after first study drug administration | 
| AUC (area under the concentration-time curve of the analyte in plasma) for several time points |  | before and up to 43 days after first study drug administration | 
| Cmax,ss (maximum concentration of the analyte in plasma at steady state over a uniform dosing interval) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| Cmin,ss (minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| Cpre,N (predose concentration of the analyte in plasma at steady state immediately before administration of the next dose N) |  | pre-dose on day 28 | 
| tmax,ss (time from dosing to maximum concentration at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| AUCτ,ss (area under the concentration time curve of the analyte in plasma at steady state over a uniform dosing interval) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| λz,ss (terminal rate constant in plasma at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| t1/2,ss (terminal half-life of the analyte in plasma at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| MRTpo,ss (mean residence time of the analyte in the body after 12 administrations at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| CL/F,ss (apparent clearance of the analyte in the plasma after extravascular administration at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| Vz/F,ss (apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| PTF (peak trough fluctuation) |  | before and 0:30 h, 1 h, 1:30 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 hours after last study drug administration | 
| Accumulation ratio (RA) based on Cmax |  | up to 28 days | 
| RA,AUC based on AUCτ |  | up to 28 days | 
| Dipeptidyl-Peptidase IV (DPP-IV) activity for several time points |  | up to day 43 | 
| Change in fasting plasma glucose (AUEC0-3) after MTT (meal tolerance test ) |  | days -1, 1 and 29 | 
| Plasma glucose levels |  | up to day 43 |