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

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)

Overall Status

Completed

CT.gov ID

NCT00943267

Collaborator

(none)

Enrollment

Location

Arms

28.9

Duration (Months)

1.8

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia Lipopolysaccharides	Drug: Drotrecogin alpha Drug: Saline (NaCl 0.9%) Drug: Endotoxin Procedure: Bronchoscopy Procedure: Blood sampling	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Participant)

Official Title:

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

Study Start Date :

Oct 1, 2008

Actual Primary Completion Date :

Aug 1, 2010

Actual Study Completion Date :

Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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
Placebo Comparator: Saline	Drug: Saline (NaCl 0.9%) Normal saline 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

Arm

Intervention/Treatment

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

Placebo Comparator: Saline

Drug: Saline (NaCl 0.9%)

Normal saline 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

Outcome Measures

Primary Outcome Measures

To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects [1 year]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 35 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Academic Medical Center/ University of Amsterdam	Amsterdam		Netherlands	1100DD

Sponsors and Collaborators

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

Investigators

Principal Investigator: Tom Van der Poll, MD PhD, AMC/UvA Amsterdam

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

, ,

ClinicalTrials.gov Identifier:

NCT00943267

Other Study ID Numbers:

CEMM-APC-01
MEC 08/188

First Posted:

Jul 22, 2009

Last Update Posted:

Mar 16, 2011

Last Verified:

Jul 1, 2009

Keywords provided by , ,

Activated Protein C

Lipopolysaccharides

Inflammation, Pulmonary

Additional relevant MeSH terms:

Inflammation

Drotrecogin alfa activated

Study Results

No Results Posted as of Mar 16, 2011