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Effect of intrapulmonary recombinant human APC on coagulation and inflammation after LPS.


- candidate number4546
- NTR NumberNTR1544
- ISRCTNISRCTN wordt niet meer aangevraagd
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR18-nov-2008
- Secondary IDsCEMM-APC-01 METC AMC Amsterdam
- Public TitleEffect of intrapulmonary recombinant human APC on coagulation and inflammation after LPS.
- Scientific TitleEffect of Intrapulmonary Administration of Recombinant Human Activated Protein C on Local Coagulation and Inflammation after Bronchial Instillation of Lipopolysaccharide in Humans.
- ACRONYMLPS-APC study
- hypothesisWhat is the effect of locally administered rhAPC on LPS-induced lung inflammation and coagulation.
- Healt Condition(s) or Problem(s) studiedPneumonia, Blood coagulation, Lung disease, Lipopolysaccharide , Recombinant activated protein C, Gram negative infections
- Inclusion criteria1. Male, 18-35 years of age
2. No clinically significant findings during physical examination and hematological and biochemical screening
3. Normal spirometry and ECG
4. Able to communicate well with the investigator and to comply with the requirements of the study
5. No medication
6. Written informed consent
7. No smoking
- Exclusion criteria1. Known diseases
2. A history of smoking within the last six months, or regular consumption of greater than three units of alcohol per day
3. Administration of any investigational drug within 30 days of study initiation
4. Donation of blood within 60 days, or loss of greater than 400 ml of blood within 12 weeks of study initiation
5. History of enhanced bleeding tendency
6. History of heparin-induced thrombocytopenia
7. History of serious drug-related reactions, including hypersensitivity
- mec approval receivedyes
- multicenter trialno
- randomisedyes
- masking/blindingSingle
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-sep-2008
- planned closingdate1-sep-2010
- Target number of participants52
- Interventions1. Dose-escalation study:
Healthy volunteers will be challenged with LPS (4 ng/kg) into a subsegment of both lungs; in one lung segment LPS will be combined with rhAPC, whereas in the contralateral lung segment LPS will be combined with normal saline. Six hours later a bilateral bronchoalveolar lavage (BAL) will be done in order to obtain BAL fluid and cells.
The primary read-out of these dose-escalation studies will be the effect of rhAPC on coagulation. Specifically, we will seek to find an APC dose that inhibits the LPS-induced increase in TAT complexes by at least 30% without causing side effects. We will increase the rhAPC dose 5-fold after each cohort (4 per group) in this part of the project.

2. Follow-up study:
24 subjects will be challenged with LPS in one lung subsegment and with normal saline in a contralateral lung subsegment; in 12 of these subjects LPS will be combined with rhAPC (dose determined in the dose-escalation study), in the other 12 subjects LPS will be combined with saline. In addition, 12 subjects will receive saline in both lung subsegments (not LPS), combined on one side with either rhAPC (n=6) or saline (n=6).
- Primary outcomeTo determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects
- Secondary outcome1. Neutrophil responses
2. Response of alveolar macrophages
3. Activation of the cytokine and chemokine network
4. Activation of coagulation and fibrinolysis
- Timepointst=0: first bronchoscopy
t=6: 6 hours after first bronchoscopy
- Trial web siteN/A
- statusstopped: trial finished
- CONTACT FOR PUBLIC QUERIES Liesbeth Kager
- CONTACT for SCIENTIFIC QUERIESProf. Dr. Tom Poll, van der
- Sponsor/Initiator Academic Medical Center (AMC), Center of Experimental Molecular Medicine
- Funding
(Source(s) of Monetary or Material Support)
ZON-MW, The Netherlands Organization for Health Research and Development
- PublicationsIntrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses.
European Respiratory Journal.
- Brief summaryRecombinant 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.
- Main changes (audit trail)
- RECORD18-nov-2008 - 15-okt-2012


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