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

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

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: Low dose of BIBT 986 CL, per i.v. infusion; Drug: Lipopolysaccharide (LPS), single i.v. bolus; Drug: Medium dose of BIBT 986 CL, per i.v. infusion; Drug: High dose of BIBT 986 CL, per i.v. infusion

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Drug: Lipopolysaccharide (LPS), single i.v. bolus; Endotoxin derived from E. coli bacteria, used for activation of coagulation
Experimental: Low dose of BIBT 986 CL	Drug: Low dose of BIBT 986 CL, per i.v. infusion; Drug: Lipopolysaccharide (LPS), single i.v. bolus; Endotoxin derived from E. coli bacteria, used for activation of coagulation
Experimental: Medium dose of BIBT 986 CL	Drug: Lipopolysaccharide (LPS), single i.v. bolus; Endotoxin derived from E. coli bacteria, used for activation of coagulation; Drug: Medium dose of BIBT 986 CL, per i.v. infusion
Experimental: High dose of BIBT 986 CL	Drug: Lipopolysaccharide (LPS), single i.v. bolus; Endotoxin derived from E. coli bacteria, used for activation of coagulation; Drug: High dose of BIBT 986 CL, per i.v. infusion

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): May 1, 2003

Study Registration Dates

• First Submitted: October 7, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimate): October 9, 2014

Study Record Updates

• Last Update Posted (Estimate): October 9, 2014
• Last Update Submitted That Met QC Criteria: October 7, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Other Study ID Numbers: 1192.11