Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Oral Doses of BI 11634 Solution in Healthy Male Volunteers

Study Overview
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Brief Summary
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First evaluation of safety, tolerability, pharmacokinetics and the pharmacodynamic effect of BI 11634 on coagulation parameters

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Oral Doses of 5, 10, 25, 50, 100, 200 and 400 mg BI 11634 Solution Administered to Healthy Male Volunteers. Randomised, Double-blind, Placebo Controlled at Each Dose Level. Intra-individual Comparison of Solution to an Immediate Release Tablet Formulation at One Dose Level (50 mg)

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 11634 drinking solution
* Drug: BI 11634 tablet
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests Age ≥18 and ≤50 years Haemoglobin within the normal ranges Body Mass Index (BMI) ≥18.5 and BMI ≤29.9 kg/m2 Signed and dated written informed consent prior to admission to the study in accordance with Good clinical practice (GCP) and the local legislation Exclusion Criteria: Relevant gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Relevant surgery of gastrointestinal tract History of any bleeding disorder or acute blood coagulation defect, for the subject itself or any person of his family as far as known History of gastric ulcera and cholecystectomy Occult blood in feces Relevant diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Relevant chronic or acute infections History of allergy/hypersensitivity (including drug allergy) which is deemed relevant to the trial as judged by the investigator 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 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 Use of acetylsalicylic acid or any other non-steroidal anti-inflammatory drugs (NSAID) within 2 weeks of study start until the end of study Participation in another trial with an investigational drug within two months prior to administration or during the trial Alcohol abuse (more than 40 g/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 that is of clinical relevance Vulnerable subjects (e.g. persons kept in detention) The subject is not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions Subjects with a history within the past 2 weeks of closed head or torso trauma or deceleration injury such as an automobile accident or fall from a significant height

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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 11634 drinking solution<br>single rising dose | Drug: BI 11634 drinking solution<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |
| Experimental: BI 11634 tablet<br> | Drug: BI 11634 tablet<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with adverse events |  | up to 10 days after drug administration | 
| Number of subjects with clinically significant findings in vital signs (blood pressure, pulse rate) |  | up to 10 days after drug administration | 
| Number of subjects with clinically significant findings in ECG |  | up to 10 days after drug administration | 
| Number of subjects with clinically significant findings laboratory tests |  | up to 10 days after drug administration | 
| Assessment of tolerability by investigator on a 4-point scale |  | up to 10 days after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration of the analyte in plasma) |  | up to 72 hours after drug administration | 
| tmax (time from dosing to maximum measured concentration) |  | up to 72 hours after drug administration | 
| AUC0-inf (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) |  | up to 72 hours after drug administration | 
| AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 up to the last quantifiable data point) |  | up to 72 hours after drug administration | 
| λz (terminal rate constant in plasma) |  | up to 72 hours after drug administration | 
| t1/2 (terminal half-life of the analyte in plasma) |  | up to 72 hours after drug administration | 
| MRTpo (mean residence time of the analyte in the body after oral administration) |  | up to 72 hours after drug administration | 
| CL/F (apparent clearance of the analyte in plasma after extravascular administration) |  | up to 72 hours after drug administration | 
| Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose) |  | up to 72 hours after drug administration | 
| Aet1-t2 (amount of analyte eliminated in urine from the time point t1 to time point t2) |  | up to 48 hours after drug administration | 
| fet1-t2 (fraction of analyte eliminated in urine from time point t1 to time point t2) |  | up to 48 hours after drug administration | 
| CLR,t1-t2 (renal clearance of the analyte from the time point t1 until the time point t2) |  | up to 48 hours after drug administration | 
| Activated partial thromboplastin time (aPTT) ratios between groups |  | up to 72 hours after drug administration | 
| Maximum aPTT prolongation | compared between groups | up to 72 hours after drug administration | 
| Maximum international normalized ratio (INR) | compared between groups | up to 72 hours after drug administration | 
| % inhibition of endogenous Factor Xa | by Russel's Viper Venom test (RVV) | up to 72 hours after drug administration | 
| Percent inhibition of thrombin generation by BI 11634 |  | up to 24 hours after drug administration | 
| Percent peak inhibition of thrombin generation |  | up to 24 hours after drug administration | 
| Time to maximum inhibition of thrombin generation BI 11634 |  | up to 24 hours after drug administration | 
| Percent prolongation of lag time |  | up to 24 hours after drug administration | 
| Area under the inhibition of the endogenous thrombin generation-time curve |  | up to 24 hours after drug administration | 
| Maximum prolongation of blood coagulation time | by HepTest® (Haemachem Inc.) and COAMATIC® Heparin test (Chromogenix) | up to 72 hours after drug administration |