AsthmaEarly Phase 1NCT02740049
In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma
A Early Phase 1 study testing VR588 in people with Asthma, run by Imperial College London at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 79 years
- Conditions the study is for
- Asthma
- What is being tested?
- VR588
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 27 Jan 2016to 19 Oct 2016
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 79 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- All patients must be able to give informed consent.
- The definition of severe asthma will be on the basis of:
- Treatment: High dose of ICS ± OCS ≥ 1000mcg FP daily or equivalent plus one other controller medication.
- Disease Control: Uncontrolled (GINA guidelines), three or more of the following present in any week in the preceding 4 weeks:
- Daytime symptoms more than twice per week
- Any limitation of activities
Show all 11Show fewer
- Nocturnal symptoms once or more per week
- Need for reliever treatment more than twice per week
- 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).
- 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.
Who cannot join
- Patients with a FEV1 < 1L
- Any other active lung condition
- Subjects unable to give consent
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Brompton & Harefield NHS Foundation Trust
London, SW3 6NP
About this study
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.
Read the 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.
- Conditions
- Asthma
- Being tested
- VR588
- Keywords
- Epithelial Cells
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VR588Drug
Evaluation of the efficacy of a novel JAK/STAT inhibitor, VR588, in isolated epithelial cells from asthma patients
| Study group | Role | What they receive |
|---|---|---|
| Astma patients | Experimental | Participant undergoes a bronchoscopy to isolate epithelial cells Receives: Drug: VR588 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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).
Measured: 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).
Measured: 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2016 (estimated)
- Study start27 Jan 2016
- Primary completion19 Oct 2016
- Study completion19 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for AsthmaStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Collaborators
- Vectura Limited
- Responsible party
- Sponsor
- Investigators
- Fan Chung, MD, Principal investigator, Imperial College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02740049
- Sponsor's protocol ID
- 15IC2844
- Status last verified
- Oct 2019
- First submitted
- 12 Apr 2016
- Last updated
- 28 Oct 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- In Vitro Evaluation of a Novel Drug on Airway Epithelial Cells Obtained From Participants With Severe Asthma
- ClinicalTrials.gov ID
- NCT02740049
- Acronym / sponsor ID
- 15IC2844
- Conditions
- Asthma
- Keywords
- Epithelial Cells
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Collaborators
- Vectura Limited
- Study start
- 27 Jan 2016 (actual)
- Primary completion
- 19 Oct 2016 (actual)
- Study completion
- 19 Oct 2016 (actual)
- First posted
- 15 Apr 2016 (estimated)
- Results
- Posted 9 Oct 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Astma patients | Experimental | Drug: VR588Participant undergoes a bronchoscopy to isolate epithelial cells |
Who may qualify
- Ages
- 18 to 79 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- All patients must be able to give informed consent.
- Treatment: High dose of ICS ± OCS ≥ 1000mcg FP daily or equivalent plus one other controller medication.
- Disease Control: Uncontrolled (GINA guidelines), three or more of the following present in any week in the preceding 4 weeks:
- 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.
Key exclusion criteria (3 listed)
- Patients with a FEV1 < 1L
- Any other active lung condition
- Subjects unable to give consent
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VR588Evaluation of the efficacy of a novel JAK/STAT inhibitor, VR588, in isolated epithelial cells from asthma patients | Drug | Astma patients |
Primary outcome
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).
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).
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).
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fan Chung, MD principal investigator
Imperial College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing VR588 in people with Asthma, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Oct 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2019.