DOSE OF INHALED CORTICOSTEROID WITH EQUISYSTEMIC EFFECTS (DICE)--PILOT STUDY

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Prior to the initiation of the formal protocol, Dose of Inhaled Corticosteroids with Equisystemic Effect (DICE), a pilot study described below is to be performed employing beclomethasone (BDP) at 84 mcg/puff and fluticasone (FP) at 44 mcg/puff. Approximately five subjects will be studied at each of six centers (final total of 27) to obtain preliminary data on the variability of systemic absorption of inhaled corticosteroids (ICS) among subjects with mild-moderate asthma and to ensure all techniques are working appropriately at each center prior to initiation of the formal protocol. Additionally, for both BDP and FP we will establish at what dose adrenal suppression is first demonstrated. The results of the pilot study will guide dosing, sample size and techniques for the formal protocol. Background and Rationale Inhaled corticosteroids (ICS) are being recommended for use in asthma treatment both more frequently and at higher doses than previously). Since corticosteroids have multiple potential adverse systemic effects, it is essential to be able to compare the different available inhaled steroids and delivery systems with respect to both systemic effects and efficacy as an asthma treatment. While several inhaled steroids (with differing in vitro potencies and pharmacokinetic characteristics) and inhaled delivery systems are presently available, and others expected to be introduced in coming years, in vivo systemic effects data comparing these inhaled steroids and delivery systems are lacking. In this DICE study we propose an experimental paradigm in which inhaled steroids and delivery systems are characterized in terms of systemic effects so that "equi-systemic" doses can be subsequently compared in future efficacy trials, including the Asthma Clinical Research Network (ACRN) efficacy trial entitled "Measuring Inhaled Corticosteroid Efficacy" (MICE). In the DICE trial, adrenal suppression will be used as the primary index of systemic absorption. As a network we acknowledge that growth in children and connective tissue parameters are important indicators of systemic absorption, but due to the slow rate of change in these outcome measures, they do not lend themselves to rapid evaluation. We therefore propose to use plasma cortisol profiles (determined over time) which are a sensitive and reproducible indicator of basal adrenal function as our index of systemic steroid absorption. Urine cortisol excretion will be a secondary measure of adrenal suppression. Markers of bone remodelling which are sensitive to steroids, specifically serum osteocalcin and urinary N-telopeptide, will also be incorporated as secondary indices of systemic absorption and effect.