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

Pneumonia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00943267
• Other study ID #: CEMM-APC-01
• Secondary ID: MEC 08/188
• Status: Completed
• Phase: N/A
• First received: July 21, 2009
• Last updated: March 15, 2011
• Start date: October 2008
• Est. completion date: March 2011

Study information

• Verified date: July 2009
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: March 2011
• Est. primary completion date: August 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 35 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject)

Related Conditions & MeSH terms

• Inflammation
• Lipopolysaccharides
• Pneumonia

Intervention

Drug:
• Drotrecogin alpha
Drotrecogin alpha is given intrabronchially by bronchoscopy at t=0
• Saline (NaCl 0.9%)
Normal saline is given intrabronchially by bronchoscopy at t=0
• 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)
• Blood sampling
Blood sampling is done by venapuncture at t=0 and t=6

Locations

Country	Name	City	State
Netherlands	Academic Medical Center/ University of Amsterdam	Amsterdam

Sponsors (1)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects		1 year	No
Secondary	1. Neutrophil responses 2. Response of alveolar macrophages 3. Activation of the cytokine and chemokine network 4. Activation of coagulation and fibrinolysis		1 year	No