Fluticasone Propionate Compared with Budesonide: a Double-Blind Trial in Asthmatic Children Using Powder Devices at a Dosage of 400 Μgæday-1
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Eur Respir J, 1996, 9, 2263–2272 Copyright ERS Journals Ltd 1996 DOI: 10.1183/09031936.96.09112263 European Respiratory Journal Printed in UK - all rights reserved ISSN 0903 - 1936 Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 µgÆday-1 J.C.M. Hoekx*, G. Hedlin**, W. Pedersen+, R. Sorva++, K. Hollingworth#, J. Efthimiou# Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic *Dept of Paediatrics, Groene Hart Zieken- children using powder devices at a dosage of 400 mg·day-1. J.C.M. Hoekx, G. Hedlin, huis, Gouda, The Netherlands. **Dept of W. Pedersen, R. Sorva, K. Hollingworth, J. Efthimiou. ©ERS Journals Ltd 1996. Paediatrics, Karolinska Institutet, Hudd- + ABSTRACT: The aim of this study was to compare fluticasone propionate (FP) inge, Sweden. Paediatric Dept, Centrals- µ -1 ygehuseet Hillerod, Hillerod, Denmark. with budesonide (BUD) at a dose of 400 g·day in the treatment of children with ++Dept of Allergic Diseases, Helsinki Uni- asthma. Two hundred and twenty nine children with mild-to-moderate asthma, versity Central Hospital, Helsinki, Finland. currently receiving 200–400 µg·day-1 of inhaled corticosteroid, were randomized #Dept of Respiratory Medicine, Glaxo to receive either 400 µg·day-1 of FP from the DiskhalerTM (registered trade mark Wellcome Research and Development Ltd, of the Glaxo Group of Companies) or 400 µg·day-1 of BUD from the TurbuhalerTM U.K. (registered trade mark of Astra Pharmaceuticals Ltd) for 8 weeks, in a parallel- group, double-blind, double-dummy study. Primary efficacy was assessed by mea- Correspondence: K. Hollingworth surement of daily peak expiratory flow (PEF). In addition, pulmonary function Glaxo Wellcome Research and Development tests were performed at each clinic visit and a self-administered patient-centred Greenford Road Greenford questionnaire was completed by one parent of each patient at the start and end Middlesex UB6 OHE of study treatment. UK Mean morning PEF increased following treatment both with FP and BUD, but was significantly higher following treatment with FP during Weeks 1–4 (p=0.015) Keywords: Asthma and Weeks 1–8 (p=0.019). Similar results were found for mean evening PEF and budesonide percentage predicted morning and evening PEF. Children receiving FP experi- fluticasone propionate enced significantly less disruption in their physical activities (i.e. sports, games) paediatric because of their asthma compared to children treated with BUD (p=0.03). Mean powder device cortisol levels increased in both groups, but the increase was significantly higher Received: August 8 1995 in the FP group at 4 weeks (p=0.022). Serum and urine markers of bone forma- Accepted after revision July 23 1996 tion and resorption changed very little and showed no consistent pattern of change. Fluticasone propionate at a dosage of 400 µg·day-1 from the DiskhalerTM pro- vided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 µg day-1 from the TurbuhalerTM. Both treatments were well-tolerated, with a similar safety profile. Eur Respir J., 1996, 9, 2263–2272. Early use of inhaled anti-inflammatory treatment is efficiency for either steroid [6–8]. However, several clin- widely recognized as being of key importance in the icopharmacological studies have suggested that BUD treatment of asthma, both in adults and children [1–3] has a more favourable antiasthma to systemic gluco- and inhaled corticosteroids are considered the most corticoid activity ratio than BDP, and BUD may be pre- effective anti-inflammatory agents available [2, 4]. At ferred where high doses of inhaled corticosteroids are high doses, the systemic absorption of inhaled corti- needed to control asthma [9]. PEDERSEN and FUGSLANG costeroids may carry a risk of side-effects in some [10] showed that, in asthmatic children, high-dose inhal- patients [5]. These may include suppression of the hypo- ed BDP resulted in lower urine cortisol excretion than thalamic-pituitary-adrenal (HPA) axis, demineraliza- high-dose BUD, the difference being most pronounced tion of bone and growth retardation, all of which are in children treated with doses of 1,000–1,200 µg daily. particularly undesirable in growing children. It is, there- At standard doses of BDP and BUD (100–400 µg b.i.d.) fore, important for inhaled corticosteroids to have a high other authors have shown little difference in effects on local potency coupled with a low systemic bioavail- adrenal function in asthmatic children [7, 8, 11]. ability, in order to have an acceptable therapeutic ratio Fluticasone propionate (FP) is a new, topically active for use in children. corticosteroid, which has been shown to have an improved Beclomethasone dipropionate (BDP) and budesonide therapeutic ratio in adults [12]. FP has negligible system- (BUD) are inhaled corticosteroids, already widely-used ic availability from the gut due to a combination of poor in the treatment of asthma. Previous clinical studies in gastrointestinal absorption and extensive first pass hep- children have shown no clear advantage in terms of atic metabolism to inactive metabolites [13]. Therefore, 2264 J.C.M. HOEKX ET AL. although the majority of a dose of inhaled corticosteroid and BUD administered by Turbuhaler to treat asthma is swallowed (approximately 80%), for FP almost none in children. The same nominal dose of each product was of this portion enters the systemic circulation. In con- used (400 µg·day-1) and the primary objective was to trast, BUD has an oral bioavailability of approximately compare their efficacy and effects on serum cortisol and 13% [14]. In preclinical and volunteer studies, FP has serum and urinary indices of bone metabolism. been shown to have a greater anti-inflammatory activity at a given microgram dose than the established cortico- steroids [15]. Clinical studies have borne this out, show- Methods ing that FP 200 µg·day-1, is at least as effective as BDP, µ -1 400 g·day , in mild-to-moderate asthma in children [16]. Patients FP may be administered by metered-dose inhaler (MDI) or as a powder via a dose-protected, breath-acti- A total of 285 children with asthma were recruited TM vated Diskhaler (registered trade mark of the Glaxo at 22 centres in four countries. All were out-patients, Group of Companies). The clinical efficacy and safety who were already treated with inhaled corticosteroids of FP administered by MDI or Diskhaler have been at a prescribed dose of 200–400 µg·day-1 and were using shown to be equivalent at doses of 200 µg·day-1 [17], β2-agonists as required. Two hundred and twenty nine µ -1 and 500 g·day [18]. prepubescent patients of mean age 8 yrs (range 4–13 BUD may also be administered by MDI or as a pow- yrs) entered the randomized phase of the study: 119 TM der via the Turbuhaler (registered trade mark of Astra received FP, 400 µg·day-1 by Diskhaler, and 110 received Pharmaceuticals Ltd). Recently it has been reported that BUD, 400 µg·day-1 by Turbuhaler. In the 2 week run- children receiving half the dose of BUD from the Turbu- in period preceding the randomized phase of the study, TM haler compared to the MDI plus Nebuhaler (regis- none of the 229 patients changed the medication they tered trade mark of Astra Pharmaceuticals Ltd), showed were using for asthma and all were required to demon- no difference in their asthma control, implying that strate two of the following four criteria: daytime or BUD is delivered more efficiently to the lungs via the night-time symptoms on four out of seven consecutive Turbuhaler [19]. However, WHITE et al. [20] showed no days; wakening during the night or early morning on difference between the Turbuhaler and the MDI plus one or more occasions; peak expiratory flow (PEF) of Nebuhaler with respect to the delivery of BUD to the ≤75% of predicted value on four out of seven days; or airways. SELROOS and HOLME [21] also showed no dif- µ at least 15% reversibility of the forced expiratory vol- ference in efficacy between BDP, at a dose of 500 g ume in one second (FEV1) or PEF in response to a β - b.i.d. delivered via the MDI plus Volumatic spacer, and 2 µ agonist. BUD, 600 g b.i.d. delivered via the Turbuhaler. They Patients were excluded: if they had received oral or did show, however, that mean serum cortisol and mean parenteral corticosteroids during the 3 months prior to urinary cortisol excretion were significantly higher fol- the run-in period; if they were unable to use the Diskhaler lowing treatment with BDP compared with BUD con- or the Turbuhaler device; if they were unable to use sistent with greater systemic absorption from the latter. the mini-WrightTM (registered trade mark of Clement Comparisons of the Turbuhaler and Diskhaler devices Clarke International Ltd) peak flow meter with or with- have shown that these devices achieved similar clinical out parental help; and if they had suffered infection, efficacy for delivering both beta-agonists [22] and cor- seasonal allergy or any other disease likely to affect ticosteroids [23]. HARVEY and WILLIAMS [24], however, their asthma during the trial. Patients were also exclud- in an open study showed that the Turbuhaler provided ed if they had any known or suspected hypersensitivity more effective bronchodilatation than the Diskhaler and to corticosteroids, and if they had received any other the MDI. investigational drug within the previous month. In adults, there have been several comparative stud- Regulatory and Ethics Committee approval was obtained ies of FP and BUD using both powder and MDI form- prior to the start of the study.