The primary objective of this clinical trial is to compare the free elastase concentration in BAL fluid in cystic fibrosis subjects following 28 days treatment with one of the following treatments; 1) 250mg tg-hAAT nebulized once daily, 2) 250mg tg-hAAT nebulized twice daily, 3)placebo nebulized once daily, and 4) placebo nebulized twice daily. Cystic Fibrosis (CF) is a common autosomal recessive genetic disorder characterized by abnormally viscid mucous secretions in the respiratory and gastrointestinal tracts. Respiratory symptoms and signs predominate with chronic respiratory infection, pulmonary inflammation and progressive deterioration in lung function. The underlying defect is in the cystic fibrosis transmembrane conductance regulator gene, which results in abnormal ion channel function and transmembrane exchange of chloride ions. Submucous glands produce viscous mucus which, in the lungs, causes airway obstruction and leads to chronic infection and inflammation. This results in recruitment of large numbers of neutrophils into the airways with the release of a large amount of elastase. Elastase is a powerful inflammatory mediator which causes airway damage directly as well as recruiting still more neutrophils and stimulating further mucus production. Alpha-1 anti-trysin is a naturally occurring serine protease inhibitor whose main substrate is neutrophil elastase. Subjects with CF have normal concentrations of AAT but it is overwhelmed by the amount of neutrophil elastase in the lung. PPL Therauetics Limited have a form of AAT which is produced from transgenic sheep; it is denoted tg-hAAT and is identical to naturally occurring AAT with the exception of some of the side-chain sugars on the molecule. The rationale for the use of AAT in CF is that a reduction in the production/activity of elastase may reduce both the intensity of the cycle of damage and the decline in pulmonary function. There is evidence that plasma derived AAT reduces BAL fluid elastase concentrations in subjects with CF. This study is to investigate whether tg-hAAT also reduces neutrophil elastase activity and if this is translated into clinical benefit for subjects with cystic fibrosis.
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