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

Study Overview
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Brief Summary
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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.

Official Title
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Effect of Intrapulmonary Administration of Recombinant Human Activated Protein C on Local Coagulation and Inflammation After Bronchial Instillation of Lipopolysaccharide in Humans

Conditions
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Pneumonia, Lipopolysaccharides

Intervention / Treatment
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* Drug: Drotrecogin alpha
* Drug: Saline (NaCl 0.9%)
* Drug: Endotoxin
* Procedure: Bronchoscopy
* Procedure: Blood sampling


Participation Criteria
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Eligibility Criteria
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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

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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Activated protein C<br> | Drug: Drotrecogin alpha<br>* Drotrecogin alpha is given intrabronchially by bronchoscopy at t=0<br>Drug: Endotoxin<br>* Endotoxin (4 ng/kg body weight) is given intrabronchially in one subsegment at t=0<br>Procedure: Bronchoscopy<br>* Bronchoscopies are performed at t=0 (for instillation of LPS and Drotrecogin alpha) and at t=6 (for performing a bronchoalveolar lavage)<br>Procedure: Blood sampling<br>* Blood sampling is done by venapuncture at t=0 and t=6<br>|
| Placebo Comparator: Saline<br> | Drug: Saline (NaCl 0.9%)<br>* Normal saline is given intrabronchially by bronchoscopy at t=0<br>Drug: Endotoxin<br>* Endotoxin (4 ng/kg body weight) is given intrabronchially in one subsegment at t=0<br>Procedure: Bronchoscopy<br>* Bronchoscopies are performed at t=0 (for instillation of LPS and Drotrecogin alpha) and at t=6 (for performing a bronchoalveolar lavage)<br>Procedure: Blood sampling<br>* Blood sampling is done by venapuncture at t=0 and t=6<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1. Neutrophil responses 2. Response of alveolar macrophages 3. Activation of the cytokine and chemokine network 4. Activation of coagulation and fibrinolysis |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Activated Protein C, Lipopolysaccharides, Inflammation, Pulmonary