Healthy
Conditions
Brief summary
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
Interventions
DRUGLow dose of BIBT 986 CL, per i.v. infusion
DRUGMedium dose of BIBT 986 CL, per i.v. infusion
DRUGHigh dose of BIBT 986 CL, per i.v. infusion
DRUGPlacebo
DRUGLipopolysaccharide (LPS), single i.v. bolus
Endotoxin derived from E. coli bacteria, used for activation of coagulation
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 40 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in soluble E-selectin | 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 | up to 14 days after start of treatment | blood pressure, pulse rate, body temperature |
| 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 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
Outcome results
None listed