Improved Asthma Control After Changing From Low-to-Medium Doses of Other Inhaled Corticosteroids to Low-Dose Fluticasone Propionate

Stuart W. Stoloff, MD, Sharon H. Srebro, MD, Lisa D. Edwards, PhD, Marty C. Johnson, MS, Kathleen A. Rickard, MD

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Materials and Methods

Two separate sets of retrospective analyses were conducted on data from a total of 11 adult and 4 pediatric randomized, double-blind, parallel-group clinical trials (Table 1). These 15 trials were originally performed to compare the efficacy and safety of fluticasone propionate with placebo, other inhaled corticosteroids, or leukotriene modifiers. The adult trials included patients with asthma >= 12 years of age (n = 1453) and ranged from 6-26 weeks in duration, while the pediatric trials included patients with asthma between 4 and 11 years of age (n = 161) and ranged from 12-52 weeks in duration. Informed patient consent and institutional review board approval were obtained prior to commencing each trial. All patients had a history of chronic asthma diagnosed according to American Thoracic Society criteria,[15] which required daily pharmacotherapy for at least 3 months prior to the trials. Adults were required to have a baseline FEV1 of 40% to 90% of Polgar[16] (ages 12-17) and Crapo[17] (>=18 years) predicted values, and to demonstrate FEV1 reversibility of at least 12% after administration of albuterol. Pediatric patients were required to have baseline FEV1 values of 50% to 85% (ages 6-11) or baseline PEF values of <= 85% (ages 4-5) of Polgar[16] predicted values, and were required to demonstrate FEV1 reversibility of >= 15% (ages 6-11) after administration of albuterol.

Major exclusion criteria for the studies included: pregnancy; smoking; systemic administration of corticosteroids; life-threatening asthma or other significant, uncontrolled illness; use of concomitant medications that might affect asthma or interfere with study medications; and chickenpox within the previous 3 weeks (pediatric studies only).

During the trials, patients were required to discontinue all other asthma medications except for supplemental albuterol for control of asthma symptoms (no albuterol within 6 hours prior to study visits), and theophylline and/or salmeterol if taken at stable and approved doses (morning doses withheld prior to study visits). Thus, patients had been treated with an inhaled corticosteroid for at least 3 months prior to changing to fluticasone propionate. Fluticasone propionate doses of 88, 110, and 220 mcg via a metered dose inhaler are equivalent to doses of 100, 125, and 250 mcg, respectively, via a dry powder inhaler. Therefore, fluticasone propionate aerosol was administered via a metered dose inhaler at a dose of 176 mcg daily (88 mcg twice daily), while fluticasone propionate powder was administered via the breath-actuated Diskhaler or the multidose Diskus inhaler at a dose of 200 mcg daily (100 mcg twice daily) in adults and 100 mcg daily (50 mcg twice daily) in children. In the adult trials, patients were receiving low-to-medium doses of beclomethasone dipropionate (168-672 mcg/day), triamcinolone acetonide (400-1200 mcg/day), or flunisolide (>= 1000 mcg/day) prior to changing to fluticasone propionate. Pediatric patients received low doses of triamcinolone acetonide (4-8 puffs/day), or low-to-medium doses of beclomethasone dipropionate (4-8 puffs/day) or flunisolide (2-6 puffs/day), for at least 3 months prior to treatment with fluticasone propionate.

In 3 comparative trials of fluticasone propionate vs beclomethasone dipropionate in this database, some patients were randomized to, and remained on, low-dose beclomethasone dipropionate (336 mcg daily). These patients served as a control arm for the adult studies in this analysis. However, pediatric studies included only placebo controls; therefore, no active comparator data were available for the analysis of pediatric studies.

The primary efficacy parameter in this analysis, FEV1, was measured before the morning dose during clinic visits, which occurred every 1-2 weeks. Secondary evaluations of efficacy in this analysis included a patient's daily diary record of morning and evening PEF using the Mini-Wright® peak flow meter, supplemental albuterol use, self-rated asthma symptoms on a scale of 0 to 100 (0 = none; 100 = most severe), and symptom-free days (defined as days during which patients experienced no asthma symptoms).

Safety evaluations varied between studies but included adverse event monitoring for all studies. Additional assessments included routine clinical laboratory tests, physical examinations, 12-lead electrocardiograms, assessment of HPA-axis integrity as measured by plasma cortisol concentrations in the morning and/or after cosyntropin stimulation, as well as measurement of growth rates in a pediatric trial. In this retrospective analysis of safety data, the incidence of drug-related adverse events in adults treated with low-dose fluticasone propionate was compared with that of patients treated with low-dose beclomethasone dipropionate, and the incidence of these events was also determined in pediatric patients.

Summary analyses were performed on 2 separate sets of combined data, one from a total of 11 adult trials and the other from a total of 4 pediatric trials. Baseline FEV1 was defined as the value obtained immediately prior to first dose of study medication. Baseline values for diary card data (morning and evening PEF, supplemental albuterol use, asthma symptom scores, and symptom-free days) were calculated as the average of values recorded during the 7 days immediately preceding the first dose of study medication. Baseline differences were evaluated by analyses of variance, adjusting for study and investigator. Summaries of all efficacy data are based on percent change from baseline values at end point, where end point is defined as the last available post-baseline measurement for FEV1 and as the last post-baseline week of measurements for diary card evaluations. End point data included the last available measurements obtained from patients who were withdrawn from their respective study. Data from the adult clinical trials were also subjected to subgroup analyses to evaluate the effect of variables such as asthma severity and type of prior inhaled corticosteroid therapy. All within-group change from baseline P values are based on 2-sided t-tests. All between-group change from baseline P values were derived from analyses of covariance, adjusting for study, investigator, and baseline value.

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