No registrations found.
ID
Source
Brief title
Health condition
pulmonary inflammation
gram negative pulmonary infections
recombinant activated protein C
pulmonary effects of lipopolysaccharide (LPS)
blood coagulation during pulmonary inflammation
longinflammatie
gramnegatieve longontstekingen
recombinant geactiveerd proteine C
pulmonale effecten van LPS
bloedstolling tijdens pulmonale inflammatie
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine whether direct intrapulmonary delivery of rhAPC can inhibit LPS-induced lung inflammation, thereby avoiding systemic APC effects
Secondary outcome
1. Neutrophil responses
2. Response of alveolar macrophages
3. Activation of the cytokine and chemokine network
4. Activation of coagulation and fibrinolysis
Background 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.
Study objective
What is the effect of locally administered rhAPC on LPS-induced lung inflammation and coagulation.
Study design
t=0: first bronchoscopy
t=6: 6 hours after first bronchoscopy
Intervention
1. 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).
Liesbeth Kager
Amsterdam 1105 AZ
The Netherlands
+31 (0)20 5669111 sein 58526
l.m.kager@amc.uva.nl
Liesbeth Kager
Amsterdam 1105 AZ
The Netherlands
+31 (0)20 5669111 sein 58526
l.m.kager@amc.uva.nl
Inclusion criteria
1. 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 criteria
1. 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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| NTR-new | NL1475 |
| NTR-old | NTR1544 |
| Other | METC AMC Amsterdam : CEMM-APC-01 |
| ISRCTN | ISRCTN wordt niet meer aangevraagd |
Summary results
European Respiratory Journal.