Effect of Intrapulmonary Recombinant Human Activated Protein C (APC) on Coagulation and Inflammation After Lipopolysaccharide (LPS)

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)52 enrolled

Overview

Recombinant human Activated Protein C (rhAPC) has been shown to reduce the mortality of patients with severe sepsis. The biological effects of APC are pleiotropic, and can be roughly divided in anticoagulant and cytoprotective effects. Lung infection and inflammation are associated with reduced bronchoalveolar levels of endogenous APC. Recent evidence derived from animal studies indicates that local administration of rAPC into the lungs exerts local anti-inflammatory and anticoagulant effects. In this study we propose to study the potential of locally administered APC, within a lung subsegment, to inhibit lipopolysaccharide (LPS) induced lung inflammation and coagulation in humans.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

SINGLE

Enrollment

Conditions

Pneumonia Lipopolysaccharides

Interventions

Drotrecogin alpha is given intrabronchially by bronchoscopy at t=0

Saline (NaCl 0.9%)DRUG

Normal saline is given intrabronchially by bronchoscopy at t=0

EndotoxinDRUG

Endotoxin (4 ng/kg body weight) is given intrabronchially in one subsegment at t=0

BronchoscopyPROCEDURE

Bronchoscopies are performed at t=0 (for instillation of LPS and Drotrecogin alpha) and at t=6 (for performing a bronchoalveolar lavage)

Blood samplingPROCEDURE

Blood sampling is done by venapuncture at t=0 and t=6

Eligibility

Sex: MALEMin age: 18 YearsMax age: 35 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Male, 18-35 years of age * No clinically significant findings during physical examination and hematological and biochemical screening * Normal spirometry and ECG * Able to communicate well with the investigator and to comply with the requirements of the study * No medication * Written informed consent * No smoking Exclusion criteria: * Known diseases * A history of smoking within the last six months, or regular consumption of greater than three units of alcohol per day * Administration of any investigational drug within 30 days of study initiation * Donation of blood within 60 days, or loss of greater than 400 ml of blood within 12 weeks of study initiation * History of enhanced bleeding tendency * History of heparin-induced thrombocytopenia * History of serious drug-related reactions, including hypersensitivity

Locations (1)

Academic Medical Center/ University of Amsterdam

Amsterdam, Netherlands

Outcomes

Primary Outcomes

To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects

Time frame: 1 year

Secondary Outcomes

1. Neutrophil responses 2. Response of alveolar macrophages 3. Activation of the cytokine and chemokine network 4. Activation of coagulation and fibrinolysis

Time frame: 1 year

Data from ClinicalTrials.gov

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