C1-inhibitor in Allergic ASThma Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effect of Intravenous Administration of C1-inhibitor on Inflammation and Coagulation After Bronchial Instillation of House Dust Mite Allergen and Lipopolysaccharide in Allergic Asthma Patients

Conditions
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Asthma

Intervention / Treatment
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* Drug: C1-inhibitor
* Other: Saline
* Drug: Antibiotics


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: C1-inhibitor<br>One gift of intravenous administration of C1-inhibitor (Cinryze, 100U/kg) during one hour | Drug: C1-inhibitor<br>* 100 Unit/kg IV, one gift prior to broncho provocation.<br>* Other names: Cinryze;|
| Placebo Comparator: Saline<br>One gift of intravenous administration of 0.9% NaCl during one hour. | Other: Saline<br>* 0.9% NaCl<br>|
| Experimental: Antibiotics<br>broad spectrum antibiotics (vancomycin, ciprofloxacin, metronidazole) for 7 days (washout 36 hours before study day). | Drug: Antibiotics<br>* vancomycin, ciprofloxacin, metronidazole<br>* Other names: vancomycin, ciprofloxacin, metronidazole;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Influx of inflammatory cells in the lung | Most important cell types are the eosinophils and neutrophils in bronchoaveolar fluid | 7 hours after bronchial instillation of house dust mite (HDM) and lipopolyssacharide(LPS) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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C1-inhibitor, house dust mite, complement system