Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple, Rising Oral Doses of BI 11634 Oral 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 after multiple-dose administration (no primary endpoint in a statistical sense defined)

Official Title
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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple, Rising Oral Doses of 2.5 mg, 5 mg, 7.5 mg, and 10 mg BI 11634 Oral Solution Administered t.i.d. for 5 Days to Healthy Male Volunteers; Randomised, Doubleblind, Placebo-controlled at Each Dose Level

Conditions
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Healthy

Intervention / Treatment
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* Drug: BI 11634
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Caucasian males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (blood pressure, pulse rate), 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 and chronic 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 Smoker (>10 cigarettes or >3 cigars or >3 pipes/day) Inability to refrain from smoking on trial days as judged by the investigator 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 six weeks of closed-head or torso trauma or deceleration injury such as an automobile accident or fall from a significant height Inability to comply with dietary regimen of the study centre Inability to understand the protocol requirements, instructions and study-related restrictions; the nature, scope and possible consequences of the study Subjects (including those who have had a vasectomy) who do not agree to use two methods of contraception, including barrier contraception (latex condoms with spermicide plus intrauterine device) when engaging in sexual activity with women of child bearing potential during the study and for 60 days after completion of the study

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<br>multiple rising dose | Drug: BI 11634<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 |
| --- | --- | --- |
| Number of subjects with adverse events |  | up to 10 days after last drug administration | 
| Number of subjects with clinically significant findings in vital signs (blood pressure, pulse rate) |  | up to 10 days after last drug administration | 
| Number of subjects with clinically significant findings in ECG |  | up to 10 days after last drug administration | 
| Number of subjects with clinically significant findings laboratory tests |  | up to 10 days after last drug administration | 
| Assessment of tolerability by investigator on a 4-point scale |  | up to 10 days after last drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration of analyte in plasma) |  | up to 144 hours after first drug administration | 
| tmax (time from dosing to maximum measured concentration) |  | up to 144 hours after first drug administration | 
| AUCτ,n (area under the concentration-time curve of analyte in plasma over a uniform dosing interval τ after administration of the n-th dose) |  | up to 144 hours after first drug administration | 
| Aet1-t2 (amount of analyte eliminated in urine from the time point t1 to time point t2) |  | up to 144 hours after first drug administration | 
| fet1-t2 (fraction of analyte eliminated in urine from time point t1 to time point t2) |  | up to 144 hours after first drug administration | 
| CLR,t1-t2 (renal clearance of analyte from the time point t1 until the time point t2) |  | up to 144 hours after first drug administration | 
| Cmin,ss (minimum measured concentration of analyte in plasma at steady state over a uniform dosing interval τ) |  | up to 144 hours after first drug administration | 
| Cpre,ss (predose concentration of analyte in plasma at steady state immediately before administration of the next dose) |  | up to 144 hours after first drug administration | 
| λz,ss (terminal rate constant in plasma at steady state) |  | up to 144 hours after first drug administration | 
| t1/2,ss (terminal half-life of analyte in plasma at steady state) |  | up to 144 hours after first drug administration | 
| MRTpo,ss (mean residence time of analyte in the body after multiple oral administrations at steady state) |  | up to 144 hours after first drug administration | 
| CL/F,ss (apparent clearance of analyte in the plasma at steady state following extravascular multiple dose administration) |  | up to 144 hours after first drug administration | 
| Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following extravascular administration) |  | up to 144 hours after first drug administration | 
| PTF (peak-trough fluctuation) |  | up to 144 hours after first drug administration | 
| Cavg (average concentration of analyte in plasma at steady state) |  | up to 144 hours after first drug administration | 
| RA,Cmax (Accumulation ratio of analyte in plasma based on Cmax) |  | up to 144 hours after first drug administration | 
| RA,AUC (Accumulation ratio of analyte in plasma based on AUC) |  | up to 144 hours after first drug administration | 
| Cpre,N (predose concentration of analyte in plasma immediately before administration of the Nth dose after N-1 doses were administered ) |  | up to 144 hours after first drug administration | 
| Activated partial thromboplastin time (aPTT) ratios between groups |  | up to 144 hours after first drug administration | 
| Maximum aPTT prolongation |  | up to 144 hours after first drug administration | 
| Maximum international normalized ratio (INR) |  | up to 144 hours after first drug administration | 
| % inhibition of endogenous Factor Xa | by Russel's Viper Venom test (RVV) | up to 144 hours after first drug administration | 
| Maximum prolongation of blood coagulation time | by HepTest® (Haemachem Inc.) | up to 144 hours after first drug administration | 
| Percent inhibition of FXa | by COAMATIC© Heparin test (Chromogenix) | up to 144 hours after first drug administration | 
| Percent inhibition of thrombin generation by BI 11634 |  | up to 144 hours after first drug administration | 
| Percent peak inhibition of thrombin generation |  | up to 144 hours after first drug administration | 
| Time to maximum inhibition of thrombin generation BI 11634 |  | up to 144 hours after first drug administration | 
| Percent prolongation of lag time |  | up to 144 hours after first drug administration |