Asthma
Conditions
Keywords
C1-inhibitor, house dust mite, complement system
Brief summary
The purpose of this proof-of-concept study is to determine the effect of Intestinal Microbiota Depletion or Intravenous Administration of C1-inhibitor on Inflammation and Coagulation after Bronchial Instillation of House Dust Mite Allergen and Lipopolysaccharide in Allergic Asthma Patients
Detailed description
Intravenous administration of C1-inhibitor (n=20) or vehicle (n=20). One group of patients (n=20) will receive broad spectrum antibiotics (vancomycin, ciprofloxacin, metronidazole) for 7 days (washout 36 hours before study day). This group will receive the same vehicle as the control group 2 hours prior to challenge. HDM will be administered together with the environmental pollutant LPS in a lung subsegment via a bronchoscope (mimicking environmental exposure to HDM); a contralateral lung subsegment will be administered with saline (control side). After 7 hours, bronchoalveolar lavage (BAL) fluid will be harvested by a second bronchoscopy. Blood samples will be collected before administration of C1-inhibitor or vehicle, and before both bronchoscopies. Faeces will be collected prior to antibiotic administration as well as prior to HDM+LPS challenge.
Interventions
DRUGC1-inhibitor
100 Unit/kg IV, one gift prior to broncho provocation.
OTHERSaline
0.9% NaCl
DRUGAntibiotics
vancomycin, ciprofloxacin, metronidazole
Sponsors
ZonMw: The Netherlands Organisation for Health Research and Development
Prothya Biosolutions
T. van der Poll
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Intermittent to mild asthma 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 * A PC20 between 0.3 - 9.6 mg/ml (corresponding with increased airway hyperreactivity) * Able to communicate well with the investigator and to comply with the requirements of the study * Stable asthma without the use of asthma medication 2 weeks prior to the study day. As documented by the Juniper's Asthma control questionnaire (ACQ) score \< 1,2. * Written informed consent * No current smoking for at least 1 year and less than 10 pack years of smoking history
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 venous or arterial thromboembolic disease * History of enhanced bleeding tendency or abnormal clotting test results. * History of serious drug-related reactions, including hypersensitivity * Inability to maintain stable without the use of asthma medication 2 weeks before start of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Influx of inflammatory cells in the lung | 7 hours after bronchial instillation of house dust mite (HDM) and lipopolyssacharide(LPS) | Most important cell types are the eosinophils and neutrophils in bronchoaveolar fluid |
Secondary
| Measure | Time frame |
|---|---|
| IL-10 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| IFN-Y in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| Interleukin-4 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| Interleukin-5 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| IL-13 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| TNF-α in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| CCL11 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| Interleukin-6 in pg/ml. | 7 hours after bronchial instillation of HDM and LPS |
| C4bc u/ml | 7 hours after bronchial instillation of HDM and LPS |
| C3bc u/ml | 7 hours after bronchial instillation of HDM and LPS |
| iC3b u/ml | 7 hours after bronchial instillation of HDM and LPS |
| C5a ng/ml | 7 hours after bronchial instillation of HDM and LPS |
| C5b-9 u/ml. | 7 hours after bronchial instillation of HDM and LPS |
| C3a in ng/ml | 7 hours after bronchial instillation of HDM and LPS |
| FXIIa activity in OD | 7 hours after bronchial instillation of HDM and LPS |
| FXIa in OD | 7 hours after bronchial instillation of HDM and LPS |
| FXIIa- C1-inhibitor complexes u/ml | 7 hours after bronchial instillation of HDM and LPS |
| kallikrein-C1-inhibitor complexes u/ml | 7 hours after bronchial instillation of HDM and LPS |
| high-molecular weight kininogen in AU | 7 hours after bronchial instillation of HDM and LPS |
| thrombin-antithrombin complexes in ng/ml. | 7 hours after bronchial instillation of HDM and LPS |
Other
| Measure | Time frame |
|---|---|
| C1-inhibitor activity in bronchoalveolar lavage | 7 hours after bronchial instillation of HDM and LPS |
Countries
Netherlands
Outcome results
None listed