Effect of BIBT 986 Followed by BIBT 986 Given as IV Infusion on Tissue Factor Triggered Coagulation in Healthy Male Volunteers

Study Overview
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Brief Summary
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To compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation in a model of tissue factor triggered activation of the coagulation system; to examine the safety of BIBT 986 in this setting

Official Title
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Investigation of the Effect of 0.9, 2.25 or 4.5 mg of BIBT 986 Over 1 Hour, Followed by 0.2, 0.5 or 1.0 mg/Hour of BIBT 986 for 7 Hours Given as IV Infusion on Tissue Factor Triggered Coagulation in a Randomised, Placebo Controlled, Dose Escalation Design in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Low dose of BIBT 986 CL, per i.v. infusion
* Drug: Medium dose of BIBT 986 CL, per i.v. infusion
* Drug: High dose of BIBT 986 CL, per i.v. infusion
* Drug: Placebo
* Drug: Lipopolysaccharide (LPS), single i.v. bolus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects as determined by the screening procedure Signed written informed consent form in accordance with good clinical practice (GCP) and local legislation was available Age ≥ 18 and ≤ 40 years Body mass index: BMI ≥ 18 and ≤ 29.9 kg/m2 Normal findings in medical history and physical examination unless the investigator considered an abnormality to be clinically irrelevant Normal laboratory parameters unless the investigator considered an abnormality to be clinically irrelevant Exclusion Criteria: Any finding in the medical examination (including blood pressure, pulse rate, ECG, and laboratory parameters) deviating from normal and of clinical relevance History of or current gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunologic, autoimmune, hormonal disorders, diseases of the central nervous system (such as epilepsy), or psychiatric disorders Symptoms of a clinically relevant illness in the 3 weeks before the first trial day History of orthostatic hypotension, fainting spells, and blackouts Chronic or relevant acute infections History of allergy / hypersensitivity (including drug allergy) which was deemed relevant to the trial as judged by the investigator History of any bleeding disorder including prolonged or habitual bleeding any familial bleeding disorder other haematological disease cerebral bleeding (e.g. after a car accident) commotio cerebri Hereditary deficiency of protein C or S, or a mutation of factor V (Leiden), or any other known abnormality affecting coagulation, fibrinolysis, or platelet function Platelet count < 150000/μL Any ECG value outside of the reference range of clinical relevance (QRS interval > 110 ms or QTcB (QT interval Bazett correction) > 450 ms will be an obligatory exclusion criterion) Intake of drugs with a long half-life (> 24 hours) within 1 month prior to administration Use of any drugs that might influence the results of the trial within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within 2 months prior to administration or during trial Participation in an LPS trial within the last six weeks Smoker (> 10 cigarettes or 3 cigars or 3 pipes/day) or inability to refrain from smoking on study days Concurrent or history of drug, alcohol, tobacco or coffee / tea / cola abuse Blood donation within 1 month prior to administration or during the trial Excessive physical activities within 5 days prior to administration or during the trial Seropositivity for hepatitis B surface antigen (HBs-Ag), hepatitis C virus (HCV), HIV 1, or HIV 2 antibodies Weight over 95 kg

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Low dose of BIBT 986 CL<br> | Drug: Low dose of BIBT 986 CL, per i.v. infusion<br> <br> Drug: Lipopolysaccharide (LPS), single i.v. bolus<br>* Endotoxin derived from E. coli bacteria, used for activation of coagulation<br>|
| Experimental: Medium dose of BIBT 986 CL<br> | Drug: Medium dose of BIBT 986 CL, per i.v. infusion<br> <br> Drug: Lipopolysaccharide (LPS), single i.v. bolus<br>* Endotoxin derived from E. coli bacteria, used for activation of coagulation<br>|
| Experimental: High dose of BIBT 986 CL<br> | Drug: High dose of BIBT 986 CL, per i.v. infusion<br> <br> Drug: Lipopolysaccharide (LPS), single i.v. bolus<br>* Endotoxin derived from E. coli bacteria, used for activation of coagulation<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> Drug: Lipopolysaccharide (LPS), single i.v. bolus<br>* Endotoxin derived from E. coli bacteria, used for activation of coagulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in activated partial thromboplastin time (aPTT) |  | up to 48 hours after start of treatment | 
| Change in international normalized ratio (INR) |  | up to 48 hours after start of treatment | 
| Change in thrombin time (TT) |  | up to 48 hours after start of treatment | 
| Change in ecarin clotting time (ECT) |  | up to 48 hours after start of treatment | 
| Change in prothrombin fragment (F1+2) |  | up to 48 hours after start of treatment | 
| Change in D-dimer |  | up to 48 hours after start of treatment | 
| Change in thrombin anti-thrombin complexes (TAT) |  | up to 48 hours after start of treatment | 
| Change in protein C activity |  | up to 48 hours after start of treatment | 
| Change in antithrombin |  | up to 48 hours after start of treatment | 
| Change in thrombomodulin |  | up to 48 hours after start of treatment | 
| Change in tissue factor messenger RNA (mRNA) |  | up to 48 hours after start of treatment | 
| Change in platelet count |  | up to 48 hours after start of treatment | 
| Change in plasmin antiplasmin complexes (PAP) |  | Pre-dose, up to day 14 after start of treatment | 
| Change in soluble P-selectin |  | up to 48 hours after start of treatment | 
| Change in tumor necrosis factor alpha (TNF alpha) |  | up to 48 hours after start of treatment | 
| Change in interleukin-6 (IL-6) |  | up to 48 hours after start of treatment | 
| Change in primary haemostasis measured by closure times |  | up to 48 hours after start of treatment | 
| Number of subjects with clinically relevant changes in vital signs | blood pressure, pulse rate, body temperature | up to 14 days after start of treatment | 
| Number of subjects with clinically relevant changes in laboratory parameters |  | up to 14 days after start of treatment | 
| Number of subjects with adverse events |  | up to 14 days after start of treatment | 
| Number of subjects with clinically relevant changes in ECG |  | up to 14 days after start of treatment | 
| Change in thrombus precursor protein |  | up to 48 hours after start of treatment | 
| Change in soluble E-selectin |  | up to 48 hours after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve (AUC) |  | up to 48 hours after start of treatment | 
| Maximum concentration in plasma at the end of the infusion (Cgh) |  | up to 48 hours after start of treatment | 
| Apparent terminal half-life of BIBT 986 in plasma (t1/2) |  | up to 48 hours after start of treatment | 
| Mean residence time of BIBT 986 in the body after intravenous bolus administration (MRT) |  | up to 48 hours after start of treatment | 
| Volume of distribution of BIBT 986 in plasma at steady state (Vss) |  | up to 48 hours after start of treatment | 
| Apparent volume of distribution of BIBT 986 during the terminal phase after intravenous infusion (Vz) |  | up to 48 hours after start of treatment |