Fluticasone propionate powder and lack of clinically significant effects on hypothalamic-pituitary-adrenal axis and bone mineral density over 2 years in adults with mild asthma,☆☆,

Portions of this manuscript were previously presented at the Annual Meeting of the American College of Allergy, Asthma, and Immunology (Boston, Mass; November 1996) and the American Thoracic Society (San Francisco, Calif; May 1997).
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Abstract

Background: Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking. Objective: This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy. Methods: Fluticasone propionate powder, 500 μg, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-group study. Primary safety variables were measured at baseline and every 6 months thereafter. Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals. Results: Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L1 to L4 ) bone density at week 104 was not significantly different between fluticasone propionate (–0.006 ± 0.008 g/cm2) and placebo (–0.007 ± 0.010 g/cm2). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations (P = .021) and 8-hour plasma cortisol area under the curve values (P = .020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment. Conclusion: Fluticasone propionate powder, 500 μg twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma. (J Allergy Clin Immunol 1999;103:1062-8.)

Section snippets

Patients

Male (18 to 50 years) and female (18 to 40 years) patients, diagnosed with asthma according to the American Thoracic Society definition,14 were enrolled in the study if they had a medical history of asthma for at least 6 months before enrollment, an FEV1 of at least 60% of predicted value, and limited previous corticosteroid therapy (ie, none during the month before the study, ≤4 weeks of cumulative oral therapy, and ≤1 year of cumulative total therapy from any route). Historical medical

Study population

Demography and pulmonary function of the 64 randomized patients were similar across treatment groups (Table I).

. Demographics, disposition, and pulmonary function of patients at baseline

Empty CellPlaceboFP 500 μg BID
No. of patients3232
Sex, M/F (%)81/1991/9
Age, y (mean ± SEM)31.1 ± 1.328.0 ± 1.2
 Range18-4918-41
Height, in (mean ± SEM)69.2 ± 0.769.7 ± 0.5
 Range62-7665-80
Weight, lbs (mean ± SEM)187 ± 4.9177 ± 5.7
 Range126-261125-238
No. completed17 (53%)21 (66%)
No. withdrawn15 (47%)11 (34%)
Reasons for withdrawal
 

DISCUSSION

Few studies have prospectively evaluated the effects of long-term administration of high doses of inhaled corticosteroids on the HPA axis. Prior use of systemic corticosteroids has been a confounding issue in many studies. This trial was designed to evaluate the effect of treatment over 2 years with 1000 μg of fluticasone propionate on adrenal function (at baseline and after stimulation with exogenous adrenocorticotrophic hormone) in patients with minimal prior use of systemic corticosteroids.

Acknowledgements

We thank the following for their contributions to the study: J. Kemp, MD, San Diego, Calif; M. Mass, MD, FACP, Jacksonville, Fla; and J. Pinnas, MD. We would also like to thank Shehnaz Gangjee for writing this manuscript.

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    Supported by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC.

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    Reprint requests: James T. C. Li, MD, Mayo Clinic, 200 1st St SW, Rochester, MN 55905.

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