Clinical trial NCT03051698: C1-inhibitor in Allergic ASThma Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Asthma
Keywords: C1-inhibitor
house dust mite
complement system
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Prothya Biosolutions
First posted: 2017-02-14
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Influx of inflammatory cells in the lung
timeFrame: 7 hours after bronchial instillation of house dust mite (HDM) and lipopolyssacharide(LPS)
Secondary outcomes:
measure: Interleukin-4 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: Interleukin-5 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: IL-13 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: IL-10 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: IFN-Y in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: TNF-α in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: CCL11 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: Interleukin-6 in pg/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: C4bc u/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: C3bc u/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: iC3b u/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: C5a ng/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: C5b-9 u/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: C3a in ng/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: FXIIa activity in OD
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: FXIa in OD
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: FXIIa- C1-inhibitor complexes u/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: kallikrein-C1-inhibitor complexes u/ml
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: high-molecular weight kininogen in AU
timeFrame: 7 hours after bronchial instillation of HDM and LPS
measure: thrombin-antithrombin complexes in ng/ml.
timeFrame: 7 hours after bronchial instillation of HDM and LPS
Other outcomes:
measure: C1-inhibitor activity in bronchoalveolar lavage
timeFrame: 7 hours after bronchial instillation of HDM and LPS
Locations:
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
state: Noord-Holland
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Tom vd Poll, Prof, dr, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Kohl J. Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1841-3. doi: 10.1164/ajrccm.164.10.2010096.
citation: Van Engelen TSR, Yang J, Haak BW, Bonta PI, Van Der Poll T, Wiersinga WJ; CAST study group. Gut Microbiome Modulation by Antibiotics in Adult Asthma: A Human Proof-of-Concept Intervention Trial. Clin Gastroenterol Hepatol. 2022 Jun;20(6):1404-1407.e4. doi: 10.1016/j.cgh.2021.07.030. Epub 2021 Jul 22.