The primary objective is to determine the effect of intravenously administered rhAPC on HDM-LPS induced allergic lung inflammation.
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Eight hours after instillation of HDM and LPS (t = 8 hours) a second
bronchoscopy will be performed and the challenged segments will be lavaged.
Primary outcome is leukocyte difference in obtained lavage fluid.
Secondary outcome
In BAL fluid and blood, obtained directly before bronchoscopies, leukocyte
responses, the response of alveolar macrophages, activation of the cytokine and
chemokine network, complement and activation of coagulation and fibrinolysis
will be determined.
Background summary
Allergic lung inflammation is associated with reduced bronchoalveolar levels of
endogenous activated protein C (APC). The biological effects of APC are
pleiotropic, and can be roughly divided in anticoagulant and cytoprotective
effects. Recombinant human Activated Protein C (rhAPC) has been shown to
decrease inflammation and is known for its capability to decrease mortality of
patients with severe sepsis. Recent evidence derived from animal studies, in
part from our laboratory, indicates that APC is also beneficial in allergic
inflammatory conditions. In this study, we will examine whether intravenous
administration of rhAPC is capable to inhibit local inflammation, within a lung
subsegment, induced by combined administration of house dust mite (HDM) and
lipopolysaccharide (LPS) in asthma patients.
Study objective
The primary objective is to determine the effect of intravenously administered
rhAPC on HDM-LPS induced allergic lung inflammation.
Study design
Double-blind, randomized controlled single centre intervention study in 28
asthma patients (18 - 45 years).
Intervention
28 asthma patients will start on intravenous treatment with rhAPC or placebo 4
hours before (t = -4 hours) bronchial instillation of HDM/LPS in a lung
subsegment and bronchial instillation of saline in a contralateral lung
subsegment (t = 0 hours). Intravenous treatment with rhAPC or placebo will be
continued until 1 hour before initiation of the second bronchoscopy.
Study burden and risks
The burden associated with this study includes a screening visit, during which
an intake interview, a physical examination, routine blood tests and spirometry
will be done. After a medication free period of 2 weeks, subjects will stay in
the hospital overnight. At 5.00 AM (t = -4 hours) intravenous infusion of rhAPC
or placebo will be started; two bronchoscopies will be done (at t = 0 hours and
t = 8 hours), which in our own experience is very well tolerated. At t = -4
hours and before each bronchoscopy blood will be obtained (60 ml each).
Bronchial instillation of HDM/ LPS may induce bronchus obstruction in patients.
This will be monitored by spirometry and Salbutamol (Ventolin by inhaler) will
be available as rescue medication during the study for all subjects. Notably,
our department has experience with both LPS challenge and HDM/LPS challenge by
bronchoscope in asthma patients (METC 08/241); these challenges are well
tolerated. RhAPC is registered for intravenous use; the risks associated are
minimal. The low risk and little discomfort outweigh the potential benefit
generated by this proof-of-principle study. The results of this study may be
important for asthma patients as it will shed light on the effect of APC on
allergic inflammation and coagulation in asthma and on a potential new
therapeutic approach for asthma in general. Furthermore, this study will
provide data which could clarify how HDM and LPS exert their effects on lung
inflammation in asthma patients.
Meibergdreef 9
1105 AZ
NL
Meibergdreef 9
1105 AZ
NL
Listed location countries
Age
Inclusion criteria
* Intermittent to mild asthmatics between 18 and 45 years of age according to the Global Initiative for Asthma (GINA) criteria
* Allergy for HDM documented by a positive RAST and a positive skin prick test.
* No clinically significant findings during physical examination and hematological and biochemical screening
* At spirometry FEV1 more than 70% of predicted value
* Able to communicate well with the investigator and to comply with the requirements of the study
* Stable asthma withouth the use of asthma medication 2 weeks prior to the study day.
* Written informed consent
* No current smoking for at least 1 year and less than 10 pack years of smoking history
* Both male and female subjects are eligible for the study. Female subjects of child bearing potential will use adequate anti-conceptive precautions and will be tested for pregnancy.
Exclusion criteria
* Relevant comorbidity, pregnancy and/or recent surgical procedures.
* A history of smoking within the last 12 months, or regular consumption of greater than three units of alcohol per day
* Exacerbation and/ or the use of asthma medication within 2 weeks before start
* 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 or abnormal clotting test results.
* History of heparin-induced thrombocytopenia
* History of serious drug-related reactions, including hypersensitivity
* Inability to maintain stable without the use of asthma medication 2 weeks before start.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-001543-76-NL |
| CCMO | NL36336.018.11 |
| OMON | NL-OMON22425 |