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Significant variability in response to inhaled corticosteroids for persistent asthma,☆☆,

https://doi.org/10.1067/mai.2002.122635Get rights and content

Abstract

Background: A clinical model is needed to compare inhaled corticosteroids (ICSs) with respect to efficacy. Objective: The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs. Methods: A 24-week, parallel, open-label, multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma. Benefit was assessed by improvements in FEV1 and PC20; risk was assessed by overnight plasma cortisol suppression. Thirty subjects were randomized to either beclomethasone dipropionate (BDP) 168, 672, and 1344 μg/day (n = 15) or fluticasone propionate (FP) 88, 352, and 704 μg/day (n = 15), both administered by means of a metered dose inhaler (MDI) with chlorofluorocarbon propellant via a spacer, in 3 consecutive 6-week intervals; this was followed by 3 weeks of FP dry powder inhaler (DPI) 2000 μg/day. Results: Maximum FEV1 response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI. Near-maximum methacholine PC20 improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI. Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression. Responsiveness to ICS treatment was found to vary markedly among subjects. Good (>15%) FEV1 response, in contrast to poor (<5%) response, was found to be associated with high exhaled nitric oxide (median, 17.6 vs 11.1 ppb), high bronchodilator reversibility (25.2% vs 8.8%), and a low FEV1/forced vital capacity ratio (0.63 vs 0.73) before treatment. Excellent (>3 doubling dilutions) improvement in PC20, in contrast to poor (<1 doubling dilution) improvement, was found to be associated with high sputum eosinophil levels (3.4% vs 0.1%) and older age at onset of asthma (age, 20-29 years vs <10 years). Conclusions: Near-maximal FEV1 and PC20 effects occurred with low-medium dose for both ICSs in the subjects studied. High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated, but it did increase the systemic effect measure, overnight cortisol secretion. Significant intersubject variability in response occurred with both ICSs. It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study, such as prevention of asthma exacerbations. (J Allergy Clin Immunol 2002;109:410-8.)

Section snippets

Study population

Study subjects were asthmatic individuals who were 18 to 55 years of age and had a baseline FEV1 of 55% to 85% of predicted, a β2-adrenergic agonist response of ≥12%, an improvement of at least 200 mL in FEV1, a methacholine PC20 value of ≤8 mg/mL, an exercise-induced fall in FEV1 of ≥12%, a morning plasma cortisol value of ≥5 μg/dL, and a smoking history of <10 pack-years; none of the subjects had smoked within the previous year. Subjects were excluded if they had received corticosteroid

Study population

A total of 30 subjects were enrolled (15 in each group); there were no significant differences between the 2 groups at baseline (Table I). Table II presents the results of cohort data with a complete sample set for each parameter. Of the 30 subjects enrolled, 26 completed the study. Of the 4 subjects who stopped participating, 3 withdrew their consent (2 were unwilling to follow the protocol and 1 did not feel the treatment was effective); 1 subject was lost to follow-up.

Cortisol suppression

Overnight plasma

Discussion

This study compared the dose-response effects of 2 ICSs on markers of benefit (FEV1, PC20) and of systemic effect (overnight plasma cortisol) in corticosteroid-naive subjects with persistent asthma. In lieu of more-difficult-to-obtain indicators for significant clinical effects, such as growth, bone density, and cataracts, attention has turned to measures of cortisol suppression as a surrogate marker of systemic effect.14

The 2 ICSs differed in their dose-response profile for both efficacy and

Acknowledgements

We thank Maureen Plourd-Sandoval for assistance with the preparation of this manuscript. Clinical coordinators: J. Burke, RN, E. Freeman, L. Mazzella, C. Connolly, E. Snyder, C. Hong, J. Chang, J. Oliviero (Boston); A. Stevens, J. Derbort, J. Pak (Denver); M. Love-Patton, RN, B. Miller, RN, R. Kelley, R.P.F.T., A. Sexton, MPH (Madison); E. Gilbert, H. Brooks, C. Jimenez, Y. Marcano (New York); P. Ilves-Corressel, RN, C. Czajka, RN, S. Dodds, RN, C. Mitchell, M. Whitsett, D. Campbell, M.

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    Supported by grants U10 HL-51810, U10 HL-51823, U10 HL-51831, U10 HL-51834, U10 HL-51843, U10 HL-51845, and U10 HL-56443 from the National Heart, Lung, and Blood Institute.

    ☆☆

    This study was carried out in part in the General Clinical Research Centers at the University of Wisconsin, Brigham and Women's Hospital, Columbia University, and the University of California San Francisco with funds provided by the National Center for Research Resources (5 M01 RR-00079, M01-RR-00645, M01-RR02635, and M01-RR-03186, US Public Health Service).

    Reprint requests: Stanley J. Szefler, MD, National Jewish Medical and Research Center, Department of Pediatrics, Room B104a, 1400 Jackson Street, Denver, CO 80206.

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