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

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

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 Overview

• Status: Completed
• Conditions: Pneumonia; Lipopolysaccharides
• Intervention / Treatment: Drug: Drotrecogin alpha; Drug: Endotoxin; Procedure: Bronchoscopy; Procedure: Blood sampling; Drug: Saline (NaCl 0.9%)

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1100DD
    • Academic Medical Center/ University of Amsterdam

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Tom Van der Poll, MD PhD, AMC/UvA Amsterdam

Publications and helpful links

General Publications

• Kager LM, de Boer JD, Bresser P, van der Zee JS, Zeerleder S, Meijers JC, van 't Veer C, van der Poll T. Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses. Eur Respir J. 2013 Jul;42(1):188-97. doi: 10.1183/09031936.00057112. Epub 2012 Oct 11.

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): August 1, 2010
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: July 21, 2009
• First Submitted That Met QC Criteria: July 21, 2009
• First Posted (Estimate): July 22, 2009

Study Record Updates

• Last Update Posted (Estimate): March 16, 2011
• Last Update Submitted That Met QC Criteria: March 15, 2011
• Last Verified: July 1, 2009

More Information

Terms related to this study

• Keywords: Activated Protein C; Lipopolysaccharides; Inflammation, Pulmonary
• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Anti-Infective Agents; Drotrecogin alfa activated
• Other Study ID Numbers: CEMM-APC-01; MEC 08/188