A Randomized, Double-Blind, Cross-Over Study to Demonstrate Superiority of Fluticasone/Salmeterol Over Double the Dose of Fluticasone on Methacholine Hyper-Reactivity in Patients With Persistent, Mild to Moderate Asthma

The objective of pharmacotherapy in the treatment of asthma is restoration of pulmonary function. This is accomplished by reducing airway inflammation, stimulating bronchodilation or a combination of the two. The classes of drug that have proved effective in this regard are anti-inflammatory agents such as corticosteroids and mast cell-stabilising agents, and bronchodilators such as β2 adrenergic agonists.

Inhaled corticosteroids (ICS) are used as a first-line anti-inflammatory prophylactic therapy for asthma. Current guidelines recommend initiating treatment with a medium to high dose, then reducing to the lowest effective dose for long-term maintenance.

Corticosteroids are preferably inhaled from aerosol inhalers (commonly pMDIs: pressurised metered dose inhalers) using large-volume spacer devices for pMDI doses in excess of 800 µg/day of BDP (Beclometasone Dipropionate), or equivalent. CFCs ((Chlorofluorocarbon)) ( propellants in BDP pMDIs are being replaced with non-ozone-depleting propellants such as hydrofluoroalkane-134a (HFA).

Comparison of steroid therapies in patients with asthma is rather difficult using conventional measures such as lung function parameters (FEV1/forced expiratory flow over one sencond or PEF/Peak expiratory flow) when chosen as the primary outcome variable, as these are relatively insensitive to ICS therapy, and are rather distant from the underlying inflammatory process. Measurements of airway responsiveness are frequently used to evaluate asthma treatments and methacholine or histamine challenge testing is recognized and recommended by regulatory authorities.

Airway responsiveness is defined as the relative ease with which airways can be made to constrict when exposed to non-sensitising chemical or physical stimuli such as methacholine, histamine, cold air, exercise or hyperventilation. Methacholine challenge looks at the functional antagonism of long acting bronchodilators (LABA) against increased airway tone; as such there is always more room for potential improvement, and therefore treatment response, with protection against challenge than with spirometry alone. In addition the effect of ICS is more sensitive when measured with methacholine challenge testing than with lung function alone.