An Early Phase 1 interventional study of VR588 in Asthma, sponsored by Imperial College London. Completed at 1 site in United Kingdom. Open to participants aged 18 Years to 79 Years. Per ClinicalTrials.gov, last updated 2019-10-28.
Sponsored by Imperial College London · Early Phase 1, Interventional, and Basic science
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.
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.
3,921 studies on the registry are indexed under Asthma; 507 are open to participants now.
This study's enrollment of 9 is below the median of 83 across 2,752 interventional studies indexed under Asthma.
Browse Asthma studies →Imperial College London is the lead sponsor of 824 studies on the registry; 178 are open to participants now.
Of its 9 completed or terminated interventional studies of FDA-regulated products, 6 (67%) have results posted.
Counted across the registry records on this site, refreshed daily.
All patients must be able to give informed consent.
The definition of severe asthma will be on the basis of:
Disease Control: Uncontrolled (GINA guidelines), three or more of the following present in any week in the preceding 4 weeks:
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:
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
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.
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).
Time frame: 21 days
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.
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).
Time frame: 21 days
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.
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).
Time frame: 21 days
Participant diagnosed with severe asthma were recruited from clinics at the Royal Brompton hospital between January 2016 and September 2016.
| Milestone | Astma Patients |
|---|---|
| Started | 9 |
| Completed | 8 |
| Not completed | 1 |
| Withdrew: Isolated cells did not grow sufficiently | 1 |
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).
| pg/ml | Astma Patients |
|---|---|
| Non-treated Control | 2090.0 ± 319.7 |
| Non-treated VR588 10-8M | 1835.2 ± 818.1 |
| Non-treated VR588 10-7M | 1863.7 ± 310.9 |
| Non-treated CP 10-7M | 1815.1 ± 605.1 |
| Non-treated FP 10-8M | 1635.1 ± 530.1 |
| IFN/TNF | 7000.5 ± 1047.4 |
| IFN/TNF VR588 10-9M | 5402.1 ± 1427.5 |
| IFN/TNF VR588 10-7M | 3996.4 ± 988.5 |
| IFN/TNF CP 10-7M | 3050.4 ± 924.1 |
| IFN/TNF FP 10-8M | 2558.6 ± 895.5 |
| IL-13 | 8686.3 ± 2024.3 |
| IL-13 VR588 10-9M | 6188.6 ± 734.3 |
| IL-13 VR588 10-7M | 4555.2 ± 1467.9 |
| IL-13 CP 10-7M | 4599.8 ± 1649.7 |
| IL-13 FP 10-8M | 4639.0 ± 905.9 |
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).
| percentage against baseline | Astma Patients |
|---|---|
| Non-treated Control | 100.0 ± 30.1 |
| Non-treated VR588 10-9M | 98.4 ± 23.1 |
| Non-treated VR588 10-7M | 95.4 ± 23.2 |
| Non-treated CP 10-7M | 98.4 ± 14.1 |
| Non-treated FP 10-8M | 102.9 ± 27.1 |
| IFN/TNF | 87.1 ± 10.5 |
| IFN/TNF VR588 10-9M | 92.0 ± 15.0 |
| IFN/TNF VR588 10-7M | 93.3 ± 14.5 |
| IFN/TNF CP 10-7M | 96.6 ± 10.5 |
| IFN/TNF FP 10-8M | 82.2 ± 11.2 |
| IL-13 | 91.4 ± 12.4 |
| IL-13 VR588 10-9M | 86.9 ± 14.2 |
| IL-13 VR588 10-7M | 90.0 ± 10.7 |
| IL-13 CP 10-7M | 89.0 ± 11.7 |
| IL-13 FP 10-8M | 92.7 ± 12.4 |
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).
| Relative Fluorescence Units | Astma Patients |
|---|---|
| Non-treated Control | 0.80 ± 0.11 |
| Non-treated VR588 10-9M | 0.82 ± 0.13 |
| Non-treated VR588 10-7M | 0.74 ± 0.20 |
| Non-treated CP 10-7M | 0.64 ± 0.22 |
| Non-treated FP 10-8M | 0.60 ± 0.28 |
| IFN/TNF | 6.94 ± 1.75 |
| IFN/TNF VR588 10-9M | 4.99 ± 1.82 |
| IFN/TNF VR588 10-7M | 4.15 ± 1.55 |
| IFN/TNF CP 10-7M | 1.56 ± 0.96 |
| IFN/TNF FP 10-8M | 3.20 ± 1.36 |
| IL-13 | 4.24 ± 1.72 |
| IL-13 VR588 10-9M | 1.97 ± 1.37 |
| IL-13 VR588 10-7M | 1.38 ± 0.71 |
| IL-13 CP 10-7M | 0.89 ± 0.36 |
| IL-13 FP 10-8M | 0.96 ± 0.37 |
Collected over 21 days. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Astma Patients | 0/9 (0%) | 0/9 (0%) | 0/9 (0%) |
| Age, Customized(years) | Astma Patients |
|---|---|
| Participants | 51.9 ± 15.5 |
| Sex: Female, Male(Participants) | Astma Patients |
|---|---|
| Female | 5 |
| Male | 4 |
| Race/Ethnicity, Customized(Participants) | Astma Patients |
|---|---|
| Indian | 1 |
| White | 8 |
| Region of Enrollment(participants) | Astma Patients |
|---|---|
| United Kingdom | 9 |
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