C1-inhibitor in Allergic ASThma Patients (CAST)

• ClinicalTrials.gov Identifier: NCT03051698
• Recruitment Status: Terminated
• First Posted: February 14, 2017
• Last Update Posted: June 24, 2020
• Sponsor: T. van der Poll
• 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

• 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

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 :

1. 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 :

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

Other Outcome Measures:

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

Eligibility Criteria

• 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

Locations

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

• 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.

• 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
• Last Update Posted: June 24, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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