Effect of Single Oral Dose BIRB 796 BS on Endotoxin-induced Inflammatory Responses in Healthy Human Subjects

Study Overview
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Brief Summary
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Study to determine the effect of a single dose BIRB 796 BS on systemic inflammatory responses induced by endotoxin in healthy humans

Official Title
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The Effect of Single Oral Dose BIRB 796 BS (50 and 600 mg) on Endotoxin-induced Inflammatory Responses in Healthy Human Subjects. A Placebo-controlled, Randomised, Parallel, Double-blinded Study.

Conditions
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Healthy

Intervention / Treatment
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* Drug: BIBR 796 BS, low dose
* Drug: BIBR 796 BS, high dose
* Drug: Placebo
* Drug: Lipopolysaccharide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects as determined by results of screening Signed written informed consent in accordance with Good Clinical Practice and local legislation Age ≥18 and ≤ 35 years Broca ≥- 20 % and ≤ + 20% Able to communicate well with the investigator and to comply with study requirements Exclusion Criteria: Any finding of the medical examination (including blood pressure, pulse rate and EKG) deviating from normal and of clinical relevance Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of gastrointestinal tract (except appendectomy) Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections within 14 days of enrolment 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) (< 1 month prior to administration or during the trial) Use of any drugs, which might influence the results of the trial (< 10 days prior to administration or during the trial) Participation in another trial with an investigational drug (< 3 months prior to administration or during trial) Smoker (> 10 cigarettes or >3 cigars or >3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (> 60 g/day) Drug abuse Blood donation or loss > 400 ml (< 2 month prior to administration or during the trial) Excessive physical activities (< 24 hours prior to administration or during the trial) Any laboratory value outside the reference range of clinical relevance History of any familial bleeding disorder Weight > 150 kg Prior confirmed or suspected receipt of a monoclonal antibody

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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: BIBR 796 BS, low dose<br> | Drug: BIBR 796 BS, low dose<br> <br> Drug: Lipopolysaccharide<br>* Lipopolysaccharide (LPS) for endotoxin challenge<br>|
| Experimental: BIBR 796 BS, high dose<br> | Drug: BIBR 796 BS, high dose<br> <br> Drug: Lipopolysaccharide<br>* Lipopolysaccharide (LPS) for endotoxin challenge<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> Drug: Lipopolysaccharide<br>* Lipopolysaccharide (LPS) for endotoxin challenge<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of tumour necrosis factor alpha (TNFα) concentration |  | up to 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of pro-inflammatory cytokines (IL-6, IL-8, G-CSF) |  | up to 2 days | 
| Reduction of anti-inflammatory cytokine and cytokine inhibitors (IL-10, IL-12p40, soluble TNF receptor (sTNFr) type 1, IL-1ra) |  | up to 2 days | 
| Reduction of Acute Phase Proteins (C-reactive protein, Haptoglobin) |  | up to 2 days | 
| Reduction of Endothelial Activation Markers (von Willebrand Factor, soluble E-selectin) |  | up to 2 days | 
| Reduction of Granulocyte Responses (white blood cell (WBC) count with differential, elastase, elastase-á1-antitrypsin complexes) |  | up to 2 days | 
| Reduction of flow Cytometry Cell Surface Markers (Mac-1 (macrophage-1 antigen), L-Selectin) |  | up to 2 days | 
| Reduction of ex vivo p38 mitogen-activated protein kinase (MAPK) phosphorylation activity |  | up to 2 days | 
| Occurence and severity of with chills, nausea, vomiting, abdominal pain, backache, headache, myalgia, fever |  | up to 2 days | 
| Number of patients with clinically significant changes in vital signs (pulse rate, systolic and diastolic blood pressure, temperature) |  | up to 14 days | 
| Number of patients with abnormal changes in laboratory parameters |  | up to 14 days | 
| Number of patients with adverse events |  | up to 14 days | 
| Assessment of Global Clinical Tolerability on a 4-point scale |  | after 14 days | 
| Maximum plasma concentration (Cmax) |  | up to 27 hours after drug administration | 
| Time at which Cmax occurred (tmax) |  | up to 27 hours after drug administration | 
| Elimination half life (t1/2), |  | up to 27 hours after drug administration | 
| Area under the plasma concentration-time curve for different time points(AUC) |  | up to 27 hours after drug administration | 
| Apparent clearance (CL/F) |  | up to 27 hours after drug administration | 
| Elimination rate constant (λz) |  | up to 27 hours after drug administration | 
| Mean residence time (MRT) |  | up to 27 hours after drug administration | 
| Apparent volume of distribution (Vz/F) |  | up to 27 hours after drug administration |