C1-inhibitor in Allergic ASThma Patients (CAST)

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

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

Study Overview

• Status: Terminated
• Conditions: Asthma
• Intervention / Treatment: Other: Saline; Drug: C1-inhibitor; Drug: Antibiotics

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 Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / 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 Names: 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 Names: vancomycin, ciprofloxacin, metronidazole

What is the study measuring?

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	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

Other Outcome Measures

Outcome Measure	Time Frame
C1-inhibitor activity in bronchoalveolar lavage	7 hours after bronchial instillation of HDM and LPS

Collaborators and Investigators

• Sponsor: T. van der Poll
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Prothya Biosolutions
• Investigators: Principal Investigator: Tom vd Poll, Prof, dr, MD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Publications and helpful links

General 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.
• Zhang X, Kohl J. A complex role for complement in allergic asthma. Expert Rev Clin Immunol. 2010 Mar;6(2):269-77. doi: 10.1586/eci.09.84.
• Schmudde I, Laumonnier Y, Kohl 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.
• 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. No abstract available.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2016
• Primary Completion (Actual): October 23, 2019
• Study Completion (Actual): October 23, 2019

Study Registration Dates

• First Submitted: February 7, 2017
• First Submitted That Met QC Criteria: February 9, 2017
• First Posted (Actual): February 14, 2017

Study Record Updates

• Last Update Posted (Actual): June 24, 2020
• Last Update Submitted That Met QC Criteria: June 23, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: house dust mite; C1-inhibitor; complement system
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Genetic Diseases, Inborn; Skin Diseases, Vascular; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Asthma; Angioedemas, Hereditary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Cytochrome P-450 CYP1A2 Inhibitors; Complement Inactivating Agents; Vancomycin; Metronidazole; Anti-Bacterial Agents; Ciprofloxacin; Complement C1 Inhibitor Protein
• Other Study ID Numbers: 2015_024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No