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

This study has been completed.
Sponsor:
Information provided by:
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT00943267
First received: July 21, 2009
Last updated: March 15, 2011
Last verified: July 2009
  Purpose

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 Intervention
Pneumonia
Lipopolysaccharides
Drug: Drotrecogin alpha
Drug: Saline (NaCl 0.9%)
Drug: Endotoxin
Procedure: Bronchoscopy
Procedure: Blood sampling

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Official Title: Effect of Intrapulmonary Administration of Recombinant Human Activated Protein C on Local Coagulation and Inflammation After Bronchial Instillation of Lipopolysaccharide in Humans

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects [ Time Frame: 1 year ] [ Designated as safety issue: No ]

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 [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Estimated Enrollment: 52
Study Start Date: October 2008
Study Completion Date: March 2011
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00943267

Locations
Netherlands
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
  More Information

No publications provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Tom van der Poll MD PhD, Center for Experimental Molecular Medicine, AMC-UvA, Amsterdam, The Netherlands
ClinicalTrials.gov Identifier: NCT00943267     History of Changes
Other Study ID Numbers: CEMM-APC-01, MEC 08/188
Study First Received: July 21, 2009
Last Updated: March 15, 2011
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Activated Protein C
Lipopolysaccharides
Inflammation, Pulmonary

Additional relevant MeSH terms:
Inflammation
Pathologic Processes
Drotrecogin alfa activated
Protein C
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Anticoagulants
Hematologic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Cardiovascular Agents

ClinicalTrials.gov processed this record on October 19, 2014