NULL HYPOTHESIS

In patients with mild-to-moderate asthma, there are no differences in the systemic effect as measured by suppression of timed plasma cortisol levels among comparable doses (on a ľg per ľg basis) of inhaled beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FLU), fluticasone propionate (FP) (MDI and DPI), and triamcinolone acetonide (TAA) when administered via their respective delivery systems (metered-dose inhaler [MDI] plus chamber for FLU, FP-MDI, and BDP; MDI with spacer built-in for TAA; Turbuhaler^TM dry-powder inhaler [DPI] for BUD; and Diskhaler device for FP-DPI). Additionally, there are no differences in systemic effect between the chlorofluorocarbon (CFC) and dry powder preparations of the same inhaled corticosteroid (FP).

DESIGN

Patients (post-pubertal to 60 years of age) were recruited with mild-to-moderate asthma, defined as reversible airflow obstruction (12% change in FEV₁) or methacholine PC₂₀ <= 8 mg/ml, and baseline forced expiratory volume in 1 second (FEV₁) 65-90% of predicted. Also, AM (prior to 9:30 AM) plasma cortisol concentration of >= 5 mcg/dl needed to be attained at enrollment. After a 1-week run-in period, patients were randomized to one of six active ICS ´ delivery systems (or the corresponding placebo). After each week of treatment, patients visited the hospital for an overnight stay and received a medication supply with a doubled dose for the subsequent week. The primary outcome variable was cortisol suppression, based on data collected during Visits 3-7. Plasma cortisol concentrations were measured every hour from 8 PM to 8 AM, and areas under the concentration vs. time curve were calculated. From these, dose-response relationships (dose vs. % change from the placebo baseline period) were compared between individual inhaled steroids, and equi-systemic effect doses (i.e., those that cause the same or comparable effect) were determined. Twenty-four hour (collected from 8 AM - 8 PM and 8 PM - 8 AM), as well as the two 12-hour collections, urine cortisol excretion were measured, and % change from the placebo baseline period was used to construct dose-response relationships. A secondary marker of systemic effect was serum osteocalcin.

RESULTS

Enrollment for the DICE trial began in September 1998 and the last patient visits occurred in November 1999. There were 156 randomized patients, 24 in each of the 6 active ICS ´ delivery systems and 2 in each of the 6 placebo ICS ´ delivery systems. All of the groups displayed a significant dose-response effect with respect to cortisol suppression, except for the FP-DPI group and the pooled placebo group. The major publication appeared in AJRCCM:

Martin RJ, Szefler, SJ, Chinchilli VM, Kraft M, Dolovich M, Boushey HA, Cherniack RM, Craig TJ, Drazen JM, Fagan JK, Fahy JV, Fish JE, Ford JG, Israel E, Kunselman SJ, Lazarus SC, Lemanske RF, Jr, Peters SP, Sorkness CA. Systemic effect comparisons of six inhaled corticosteroid preparations. American Journal of Respiratory and Critical Care Medicine 2002; 165:1377-1383.