title: Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function, part I: general overview of HPA axis study design.
abstract: Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (<6 weeks) for adult trials and blinded, placebo controlled, and long term (≥6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained.
authors.affiliation: Division of Clinical Pharmacology II, Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Lian
authors.initials: L
authors.lastname: Ma
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pippins
authors.forename: Susan
authors.initials: S
authors.lastname: Limb
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.forename: Chandrahas G
authors.initials: CG
authors.lastname: Sahajwalla
mesh_terms: D000280:Administration, Inhalation; D000281:Administration, Intranasal / Q000379:methods; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects*; D010913:Pituitary-Adrenal System / Q000187:drug effects*; D012107:Research Design
chemical_list: D000305:Adrenal Cortex Hormones
keywords: hypothalamic-pituitary-adrenal axis; inhaled corticosteroids; intranasal corticosteroids; pharmacodynamics; pulmonary; regulatory science; study design