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This study will look at the permeability, or 'leakiness' of the airway epithelium (the inner lining of the lung) in asthmatic patients. Increased leakiness of this lining has been shown in asthmatic patients by other studies, not only in the lung but also possibly in the gut, perhaps reflecting a widespread defect. This leakiness may underline the interaction between the environment and a person's genetic make up, and may contribute to why some people get asthma, and how severe it is. Increased leakiness may allow increased exposure to inhaled allergic substances, helping to perpetuate the inflammation in the lungs that is a hallmark of asthma.
Specifically, this study will attempt to modify and reduce this permeability through the use of a substance called 'keratinocyte growth factor', or 'kgf'. KGF is a naturally occuring human protein, which is involved in stimulating the growth of cells lining the layers of the skin and gut, helping to repair damage and maintain their structure. It has been manufactured in a laboratory as the commercial compound 'Palifermin', which has already been used in humans to reduce damage to the lining of the mouth after chemotherapy. The study will see if Palifermin can similarly improve the lining of the lung in asthma patients and improve their symptoms. To date no treatments have been used in this area in asthma, and if successful the study will open up a whole new area of therapy
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Study drug | Active Comparator | Keratinocyte growth factor (KGF) will be administered intravenously in a 'collapsed dose' regime of 180ug/kg on day 0 and day 11. |
|
| Placebo | Placebo Comparator | Saline will be used as a placebo comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Keratinocyte Growth factor | Drug | KGF will be administered intravenously in a 'collapsed dose' regime of 180ug/kg on day 0 and day 11 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in PD15 Mannitol | A standard bronchoprovocation test, the mannitol test, will be used to assess airway hyperreactivity (measured as the dose required to drop FEV1 (forced expiratory volume in 1 second) by 15%, PD15) | Baseline (7 days prior to drug), during drug administration period (3 days after first dose of drug), and short/intermediate term post drug period (3, 6 and 24 days after second drug administration) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in PC20 Metacholine | A standard bronchoprovocation test, metacholine challenge, will be used to assess airway hyperreactivity (by measuring the concentration needed to drop FEV1 by 20%, PC20) | Baseline (6 days prior to drug) and short/intermediate term post drug period (7 and 25 days after second drug administration) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Peter H Howarth, BSc, MBBS | Reader in Medicine and Honorary Consultant Physician, Southampton General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Biomedical Research Unit (Respiratory) | Southampton | Hampshire | SO16 6YD | United Kingdom |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| D051523 | Fibroblast Growth Factor 7 |
| ID | Term |
|---|---|
| D005346 | Fibroblast Growth Factors |
| D036341 | Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
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| Saline placebo | Drug | Normal (0.9%) saline will be used as a placebo. |
|
| Change in asthma symptoms |
Symptoms will be assessed using standardised questionnaires, Asthma control questionnaire (ACQ) and Asthma Quality of Life questionnaire (AQLQ) |
| ACQ is measured weekly during study. AQLQ is measured at baseline screening visit, and on day 35 (35 days post first administration of drug). |
| Short acting beta-agonist use/PEFR variability | A diary card will be used throughout the study for participants to record beta-agonist use and morning/evening peak expiratory flow rates (PEFR), from the latter PEFR variability will be calculated | Throughout study |
| Adverse event reporting | Adverse events will be recorded if they occur | Throughout study |
| Epithelial integrity/activation | Bronchial biopsies, brush specimens and lavage fluid before and after intervention will be analysed to determine markers of activation, inflammation and epithelial integrity | Specimens are taken at 2 bronchoscopies, the first before the drug (4 days prior to the first drug administration) and the second after the drug (21 days after the first drug administration) |
| Epithelial proliferation | Bronchial biopsy specimens will be analysed for markers of proliferation e.g. Ki67 before and after treatment | Specimens are taken at 2 bronchoscopies, the first before the drug (4 days prior to the first drug administration) and the second after the drug (21 days after the first drug administration) |
| Exhaled nitric Oxide | Exhaled nitric oxide, as a surrogate marker of eosinophilic inflammation, will be measured before/during and after intervention | This is measured on the same days as PD15 mannitol, with an additional baseline measurement at the screening visit |
| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D011506 | Proteins |
| D001685 | Biological Factors |