C1-inhibitor in Allergic ASThma Patients

Asthma Clinical Trial

— CAST  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03051698
• Other study ID #: 2015_024
• Status: Terminated
• Phase: Phase 4
• Start date: November 16, 2016
• Est. completion date: October 23, 2019

Study information

• Verified date: June 2020
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 37
• Est. completion date: October 23, 2019
• Est. primary completion date: October 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• C1-inhibitor
100 Unit/kg IV, one gift prior to broncho provocation.

Other:
• Saline
0.9% NaCl

Drug:
• Antibiotics
vancomycin, ciprofloxacin, metronidazole

Locations

Country	Name	City	State
Netherlands	Academic Medical Center	Amsterdam	Noord-Holland

Sponsors (3)

Lead Sponsor	Collaborator
T. van der Poll	Sanquin Plasma Products BV, ZonMw: The Netherlands Organisation for Health Research and Development

Country where clinical trial is conducted

Netherlands, 

References & Publications (6)

Bel EH. Mild asthma. N Engl J Med. 2013 Dec 12;369(24):2362. doi: 10.1056/NEJMc1313111. — View Citation

de Boer JD, Berger M, Majoor CJ, Kager LM, Meijers JC, Terpstra S, Nieuwland R, Boing AN, Lutter R, Wouters D, van Mierlo GJ, Zeerleder SS, Bel EH, van't Veer C, de Vos AF, van der Zee JS, van der Poll T. Activated protein C inhibits neutrophil migration in allergic asthma: a randomised trial. Eur Respir J. 2015 Dec;46(6):1636-44. doi: 10.1183/13993003.00459-2015. Epub 2015 Sep 17. — View Citation

Krug N, Tschernig T, Erpenbeck VJ, Hohlfeld JM, Köhl 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. — View Citation

Schmudde I, Laumonnier Y, Köhl J. Anaphylatoxins coordinate innate and adaptive immune responses in allergic asthma. Semin Immunol. 2013 Feb;25(1):2-11. doi: 10.1016/j.smim.2013.04.009. Epub 2013 May 19. Review. — View Citation

Zeerleder S. C1-inhibitor: more than a serine protease inhibitor. Semin Thromb Hemost. 2011 Jun;37(4):362-74. doi: 10.1055/s-0031-1276585. Epub 2011 Jul 30. Review. — View Citation

Zhang X, Köhl J. A complex role for complement in allergic asthma. Expert Rev Clin Immunol. 2010 Mar;6(2):269-77. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	C1-inhibitor activity in bronchoalveolar lavage		7 hours after bronchial instillation of HDM and LPS
Primary	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	Interleukin-4 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	Interleukin-5 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	IL-13 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	IL-10 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	IFN-Y in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	TNF-a in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	CCL11 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	Interleukin-6 in pg/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	C4bc u/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	C3bc u/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	iC3b u/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	C5a ng/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	C5b-9 u/ml.		7 hours after bronchial instillation of HDM and LPS
Secondary	C3a in ng/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	FXIIa activity in OD		7 hours after bronchial instillation of HDM and LPS
Secondary	FXIa in OD		7 hours after bronchial instillation of HDM and LPS
Secondary	FXIIa- C1-inhibitor complexes u/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	kallikrein-C1-inhibitor complexes u/ml		7 hours after bronchial instillation of HDM and LPS
Secondary	high-molecular weight kininogen in AU		7 hours after bronchial instillation of HDM and LPS
Secondary	thrombin-antithrombin complexes in ng/ml.		7 hours after bronchial instillation of HDM and LPS