In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma

• ClinicalTrials.gov Identifier: NCT02740049
• Recruitment Status: Completed
• First Posted: April 15, 2016
• Results First Posted: October 9, 2019
• Last Update Posted: October 28, 2019
• Sponsor: Imperial College London
• Collaborator: Vectura Limited
• Information provided by (Responsible Party): Imperial College London

Study Description

Brief Summary:

Asthma is a long term disease of the lungs. In asthma patients the sensitive airway tubes narrow in reaction to something that irritates the airways such as allergens or environmental pollutants. There is currently no cure for asthma and new medicines or combinations of medicines are needed that will be of benefit to patients particularly those with a more severe disease.

Activation of certain signal molecules inside the lung cells may participate in the development of asthma and the response to allergens. Blocking these signal molecules specifically with medicines might therefore be beneficial in the treatment of asthma. In this study we want to test a new medicine that specifically targets a subset of signal molecules that are associated with the allergen response in the lung. In particular, we want to test this medicine on cells obtained from the lungs of asthma patients. Understanding the effects of this new medicine on these asthmatic lung cells will give vital information on how this new medicine works before we can test it in asthma patients.

Condition or disease	Intervention/treatment	Phase
Asthma	Drug: VR588	Early Phase 1

Detailed Description:

Asthma and COPD are chronic inflammatory diseases of the airway although the precise cells and mediators involved are distinct. Both diseases are characterised by airway hyperresponsiveness (AHR) in response to exogenous stimuli such as allergens in asthma or environmental pollutants. There is currently no cure for asthma and new drugs or combinations of drugs are needed that will be of benefit to patients particularly those with more severe disease.

Activation of JAK/STAT pathways may participate in the pathogenesis of asthma. STAT1 and STAT6 expression is elevated in animal models of asthma and in the lower airways of some but not all patients. STAT6 is activated by key cytokines involved in asthma such as IL-13 in primary human bronchial epithelial cells. In addition, baseline phospho-STAT1 and phospho-STAT6 levels are increased in systemic T cells from steroid naïve asthmatics and the Th2 cytokines IL-4, IL-13 and TSLP activate STAT1 and STAT6 in a number of airway cells. In animal models of allergen-induced AHR, airway inflammation including CXCL9 and CXCL10 involves STAT1. In addition, STAT6 knockout mice have no response to IL-4, do not develop Th2 cells in response to IL-4, and fail to produce IgE, bronchial hyperresponsiveness or BAL eosinophilia after allergen sensitization. The expression of CCL11, CCL17 and CCL22 also involves STAT6 in these models.

Importantly, STAT1 is a critical signalling molecule involved in the production of type I IFNs (α/β), IFN-γ and for resistance to viral respiratory infections. JAK/STATs inhibitors have proved effective in clinical trials for rheumatoid arthritis and inflammatory bowel disease.

Therefore, we propose to use the primary airway epithelial cell culture model grown at air:liquid interface (ALI culture) to evaluate the efficacy of a novel JAK/STAT inhibitor, VR588, against CP-690550 and fluticasone proprionate (FP) in suppressing inflammatory readouts induced by IL-13 and by TNF/IFN.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma
• Actual Study Start Date: January 27, 2016
• Actual Primary Completion Date: October 19, 2016
• Actual Study Completion Date: October 19, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Astma patients; Participant undergoes a bronchoscopy to isolate epithelial cells	Drug: VR588; Evaluation of the efficacy of a novel JAK/STAT inhibitor, VR588, in isolated epithelial cells from asthma patients

Outcome Measures

Primary Outcome Measures :

1. Concentration (pg/ml) of CXCL8 Cytokine in Cell Supernatant After Stimulation (IFN/TNF or IL13) and Treatment (VR588, FP or CP) Conditions in ALI Cultured Epithelial Cells. [ Time Frame: 21 days ]
   Measurement of cytokine levels in cell supernatant after stimulation of isolated epithelial cells. For this study epithelial cells from severe asthma patients (n = 9) were cultured and stimulated with either IFN/TNF or IL-13 to induce inflammation. Cells are then treated with VR588 (2 concentration) or with Fluticasone Propionate (FP) or with CP690553 (CP; Tofacitinib). The concentrations of drugs are listed in the title (e.g. 10-9M).
2. Percentage of Viable Cells Compared to Baseline After Stimulation (IFN/TNF or IL13) and Treatment (VR588, FP or CP) Conditions in ALI Cultured Epithelial Cells. [ Time Frame: 21 days ]
   Measurement of cell viability after stimulation of isolated epithelial cells. For this study epithelial cells from severe asthma patients (n = 9) were cultured and stimulated with either IFN/TNF or IL-13 to induce inflammation. Cells are then treated with VR588 (2 concentration) or with Fluticasone Propionate (FP) or with CP690553 (CP; Tofacitinib). The concentrations of drugs are listed in the title (e.g. 10-9M).
3. Relative Fluorescence Units of STAT1 Protein Phosphorylation After Stimulation (IFN/TNF or IL13) and Treatment (VR588, FP or CP) Conditions in ALI Cultured Epithelial Cells. [ Time Frame: 21 days ]
   Measurement of activation of phospho-STAT1 member of the JAK/STAT signaltransduction pathway in cell lysates. For this study epithelial cells from severe asthma patients (n = 9) were cultured and stimulated with either IFN/TNF or IL-13 to induce inflammation. Cells are then treated with VR588 (2 concentration) or with Fluticasone Propionate (FP) or with CP690553 (CP; Tofacitinib). The concentrations of drugs are listed in the title (e.g. 10-9M).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 79 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

All patients must be able to give informed consent.

The definition of severe asthma will be on the basis of:

1. Treatment: High dose of ICS ± OCS ≥ 1000mcg FP daily or equivalent plus one other controller medication.

2. Disease Control: Uncontrolled (GINA guidelines), three or more of the following present in any week in the preceding 4 weeks:

   1. Daytime symptoms more than twice per week
   2. Any limitation of activities
   3. Nocturnal symptoms once or more per week
   4. Need for reliever treatment more than twice per week
   5. Prebronchodilator FEV1 <80% predicted or personal best AND/OR Frequent severe exacerbations (≥2 per year requiring high dose OCS or doubling of maintenance dose for at least three days or requiring hospitalisation).
3. Asthma Diagnosis:

Improvement in FEV1 ≥ 12% or 200ml predicted after inhalation of 400mcg salbutamol OR Diurnal variation in PEF: amplitude % mean of twice daily PEF > 8% OR Decrease in FEV1 ≥ 12% and >200ml within 4 weeks after tapering treatment with one or more of the following drugs: ICS, OCS, LABA, SABA PLUS A history of wheeze occurring spontaneously or on exertion.

Exclusion Criteria:

1. Patients with a FEV1 < 1L
2. Any other active lung condition
3. Subjects unable to give consent

Contacts and Locations

Locations

United Kingdom

Royal Brompton & Harefield NHS Foundation Trust

London, United Kingdom, SW3 6NP

Sponsors and Collaborators

Imperial College London

Vectura Limited

Investigators

• Principal Investigator: Fan Chung, MD; Imperial College London

More Information

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT02740049
• Other Study ID Numbers: 15IC2844
• First Posted: April 15, 2016
• Results First Posted: October 9, 2019
• Last Update Posted: October 28, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Imperial College London:

Epithelial Cells

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases