Short-Term Lower Leg Growth in 5- to 11-Year-Old Asthmatic Children Using Beclomethasone Dipropionate Inhalers With Chlorofluorocarbon or Hydrofluoroalkane Propellants: A 9-Week, Open-Label, Randomized, Crossover, Noninferiority Study

Abstract

Background

Beclomethasone dipropionate–hydrofluoroalkane (BDP-HFA) is a non–chlorofluorocarbon (CFC)-propelled metered dose inhaler. Data is needed to support the registration of BDP-HFA in pediatric populations for countries in the European Union.

Objective

The aim of the study was to assess short-term lower leg growth in children with asthma during treatment with BDP-HFA 100 μg BID compared with BDP-CFC 200 μg BID.

Methods

Children with asthma were included in this open-label, randomized, crossover study with 2-week run-in, active treatment, and washout periods. Lower leg length was measured every second week. As a secondary outcome parameter, 24-hour urine was collected for assessment of free cortisol. Interventions were inhaled BDP-HFA 100 μg BID with AeroChamber Plus spacer and BDP-CFC 200 μg BID with Volumatic spacer.

Results

In 63 patients with asthma aged 5 to 11 years, BDP-HFA 100 μg BID was noninferior to BDP-CFC 200 μg BID, as the lower margin of CI (–0.03 to 0.10 mm/wk) of the estimated difference (0.03 mm/wk) was greater than the prespecified lower limit for noninferiority of –0.12 mm/wk. Mean (SD) lower leg growth rate during run-in, BDP-HFA 100 μg BID, and BDP-CFC 200 μg BID was 0.36 (0.17), 0.27 (0.21), and 0.23 (0.18) mm/wk, respectively (BDP-HFA estimate of difference, –0.09 [95% CI, –0.16 to –0.03 mm/wk; P < 0.01]; BDP-CFC estimate of difference, –0.13 [95% CI, –0.19 to –0.06 mm/wk; P < 0.001]). No statistically significant differences were seen in urinary free cortisol assessments. Eight and 6 mild to moderate adverse events in 10 children were reported during treatment with BDP-HFA and BDP-CFC, respectively. One event in each group was judged to be probably related to the study medication; no others were judged to be related.

Conclusions

No statistically significant differences were found in lower leg growth between BDP-HFA 100 μg BID with AeroChamber Plus spacer and BDP-CFC 200 μg BID with Volumatic spacer during 2-week treatment. Evidence of differences in systemic activity between the treatments was not found. EudraCT registration: 2007-007455-14.

Introduction

Beclomethasone dipropionate (BPD) is a topically active synthetic corticosteroid widely used in the treatment of asthma in children.¹ As with other inhaled corticosteroids, during the past decade or so increasing focus has been placed on the risk of systemic activity of the drug and suppressive effects on growth and hypothalamic-pituitary-adrenal function.1, 2 For many years BDP was delivered via the Volumatic volume spacer (Allen & Hanburys, Stockley Park, United Kingdom) from a pressurized metered dose inhaler (pMDI) containing BDP and chlorofluorocarbon (CFC) as propellant.³ During the past 15 years, however, pMDIs containing CFC have been phased out owing to the deleterious effects of CFC on the ozone layer. The alternative propellant hydrofluroroalkane-134a (HFA) does not affect the ozone layer.⁴ BDP-HFA^⁎ is an inhalation aerosol containing BDP as active principle and hydrofluoroalkane (HFA-134a; norflurane; 1,1,1,2-tetrafluoroethane) as propellant.⁵ BDP-HFA was launched in 1998 in the United Kingdom for the prophylactic management of mild, moderate, or severe asthma. It is delivered via a pMDI with an AeroChamber Plus volume spacer (Trudell Medical International, London, Ontario, Canada). Because the particle size of BDP-HFA is considerably smaller than that of the CFC formulation^† (mass median aerodynamic diameter [MMAD] of 1.1 μm [BPD-HFA] vs 3.4 μm [BPD-CFC]), concern has been raised that an increased pulmonary deposition rate may be associated with an increase in systemic bioavailability and, hence, effects on growth and cortisol secretion.⁶ In accordance with this, to support the registration for BDP-HFC in children with asthma, comparative data on short-term growth in children with asthma treated with BDP-HFA 100 μg BID with AeroChamber Plus spacer and BDP-CFC 200 μg BID with Volumatic spacer were requested. As a secondary aim, hypothalamic-pituitary-adrenal function was also assessed in the present study.