A Study to Assess Safety and Efficacy of a Novel Treatment, Keratinocyte Growth Factor (KGF), in Asthmatic Patients

Study Overview
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Brief Summary
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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

Official Title
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Safety and Efficacy of Parenteral KGF in Moderate Asthmatic Subjects

Conditions
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Bronchial Asthma

Intervention / Treatment
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* Drug: Keratinocyte Growth factor
* Drug: Saline placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 60 years, either gender Confirmed diagnosis of asthma for > 1 year as defined by BTS guidelines, requiring treatment with high dose inhaled corticosteroids +/- long acting β2 agonists, with persisting symptoms requiring use of short-acting beta agonist therapy >3x/week. Never-smoker or ex-smoker, having stopped >1 year ago, with <10 pack year history. Subject must understand the procedures of the study and agree to participation in the study by providing written informed consent Subject considered fit enough to undergo lung function testing including provocation tests, and bronchoscopy. Subject must not be participating in another clinical trial or have done so within the last 12 weeks. Exclusion Criteria: Patients requiring regular maintenance oral steroids for their asthma, or those who are adhering to symbicort SMART single inhaler regime. Pregnancy (where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test >5mIU/ml), an intention to become pregnant or breast-feeding (lactating). Subjects with active lung disease other than asthma Significant medical (cardiopulmonary, neurological, renal, endocrine, gastrointestinal, psychiatric, hepatic or haematological)co-morbidity which in the view of the investigator could impact on the interpretation of results or participation in the trial, or which is uncontrolled with standard treatment. Current participation in another clinical trial or previous participation within the last 12 weeks. Alcohol or active drug abuse. Ongoing allergen desensitisation therapy Regular use of sedatives, hypnotics, tranquilisers Cancer or previous history of cancer Inability to understand directions for dosing and study assessment. Inability to be contacted in case of emergency.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Study drug<br>Keratinocyte growth factor (KGF) will be administered intravenously in a 'collapsed dose' regime of 180ug/kg on day 0 and day 11. | Drug: Keratinocyte Growth factor<br>* KGF will be administered intravenously in a 'collapsed dose' regime of 180ug/kg on day 0 and day 11<br>* Other names: Palifermin, rhKGF, Kepivance;|
| Placebo Comparator: Placebo<br>Saline will be used as a placebo comparator | Drug: Saline placebo<br>* Normal (0.9%) saline will be used as a placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate asthmatic, uncontrolled