C1-inhibitor in Allergic ASThma Patients (CAST)

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ClinicalTrials.gov Identifier: NCT03051698

Recruitment Status : Terminated (Interim analysis showed no differences between groups)

First Posted : February 14, 2017

Last Update Posted : June 24, 2020

Sponsor:

Collaborators:

ZonMw: The Netherlands Organisation for Health Research and Development

Sanquin Plasma Products BV

Information provided by (Responsible Party):

T. van der Poll, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Study Description

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

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: C1-inhibitor Other: Saline Drug: Antibiotics	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	37 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
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
Actual Study Start Date :	November 16, 2016
Actual Primary Completion Date :	October 23, 2019
Actual Study Completion Date :	October 23, 2019

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Allergic asthma Hereditary angioedema

MedlinePlus related topics: Asthma

Genetic and Rare Diseases Information Center resources: Hereditary Angioedema

U.S. FDA Resources

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

Influx of inflammatory cells in the lung [ Time Frame: 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 Outcome Measures :

Interleukin-4 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
Interleukin-5 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
IL-13 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
IL-10 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
IFN-Y in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
TNF-α in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
CCL11 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
Interleukin-6 in pg/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
C4bc u/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
C3bc u/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
iC3b u/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
C5a ng/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
C5b-9 u/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
C3a in ng/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
FXIIa activity in OD [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
FXIa in OD [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
FXIIa- C1-inhibitor complexes u/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
kallikrein-C1-inhibitor complexes u/ml [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
high-molecular weight kininogen in AU [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]
thrombin-antithrombin complexes in ng/ml. [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]

Other Outcome Measures:

C1-inhibitor activity in bronchoalveolar lavage [ Time Frame: 7 hours after bronchial instillation of HDM and LPS ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 45 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03051698

Locations

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Netherlands
Academic Medical Center
Amsterdam, Noord-Holland, Netherlands, 1105 AZ

Sponsors and Collaborators

T. van der Poll

ZonMw: The Netherlands Organisation for Health Research and Development

Sanquin Plasma Products BV

Investigators

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Principal Investigator:	Tom vd Poll, Prof, dr, MD	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

More Information

Publications:

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.

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

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.

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.

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

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.

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Responsible Party:	T. van der Poll, Prof. dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:	NCT03051698
Other Study ID Numbers:	2015_024
First Posted:	February 14, 2017 Key Record Dates
Last Update Posted:	June 24, 2020
Last Verified:	June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by T. van der Poll, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):


C1-inhibitor house dust mite complement system

Additional relevant MeSH terms:

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Asthma Angioedemas, Hereditary Bronchial Diseases Respiratory Tract Diseases Lung Diseases, Obstructive Lung Diseases Respiratory Hypersensitivity Hypersensitivity, Immediate Hypersensitivity Immune System Diseases Angioedema Vascular Diseases Cardiovascular Diseases Genetic Diseases, Inborn Urticaria	Skin Diseases, Vascular Skin Diseases Anti-Bacterial Agents Metronidazole Vancomycin Ciprofloxacin Anti-Infective Agents Antiprotozoal Agents Antiparasitic Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Cytochrome P-450 CYP1A2 Inhibitors

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