Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy

Amanda J Oliver, Ronina A Covar, Caroline H Goldfrad, Ryan M Klein, Søren E Pedersen, Christine A Sorkness, Susan A Tomkins, César Villarán, Jonathan Grigg, Amanda J Oliver, Ronina A Covar, Caroline H Goldfrad, Ryan M Klein, Søren E Pedersen, Christine A Sorkness, Susan A Tomkins, César Villarán, Jonathan Grigg

Abstract

Background: Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 μg, 12.5 μg and 25 μg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS.

Methods: This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 μg twice daily. Children were randomised to receive placebo, VI 6.25 μg, VI 12.5 μg or VI 25 μg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations.

Results: In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28-33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period.

Conclusion: VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed.

Trial registration: NCT01573767 (ClinicalTrials.gov).

Keywords: Asthma; Children; Dose response; Efficacy; Fluticasone propionate; Safety; Vilanterol.

Figures

Fig. 1
Fig. 1
Participant flow diagram. Abbreviations: VI, vilanterol
Fig. 2
Fig. 2
LS mean change from baseline in evening PEF averaged over Weeks 1 to 4 (ITT population). Abbreviations: ITT, intention-to-treat; LS, least squares; PEF, peak expiratory flow; SE, standard error, VI, vilanterol

References

    1. Nationwide Frequency and Costs of Potentially Preventable Hospitalizations, 2006: HCUP Statistical Brief #72. 2009. . Accessed September 2015.
    1. British Thoracic Society Scottish Intercollegiate Guidelines Network: British Guideline on the Mangement of Asthma: A national clinical guideline. Thorax. 2014;69:i1–i192.
    1. Guidelines for the Diagnosis and Management of Asthma - Expert Panel Report 3. 2007. . Accessed September 2015.
    1. Zhao Y, Han S, Shang J, Zhao X, Pu R, Shi L. Effectiveness of drug treatment strategies to prevent asthma exacerbations and increase symptom-free days in asthmatic children: a network metaanalysis. J Asthma. 2015;52(8):846–57. doi: 10.3109/02770903.2015.1014101.
    1. Lemanske RF, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med. 2010;362:975–985. doi: 10.1056/NEJMoa1001278.
    1. Ni Chroinin M, Lasserson TJ, Greenstone I, Ducharme FM. Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children. The Cochrane Library 2009, Issue 3. Art. No.: CD007949. DOI: 10.1002/14651858.CD007949.
    1. de Groot EP, Kreggemeijer WJ, Brand PL. Getting the basics right resolves most cases of uncontrolled and problematic asthma. Acta Paediatr. 2015;104(9):916–21. doi: 10.1111/apa.13059.
    1. Stanford RH, Gilsenan AW, Ziemiecki R, Zhou X, Lincourt WR, Ortega H. Predictors of uncontrolled asthma in adult and pediatric patients: analysis of the Asthma Control Characteristics and Prevalence Survey Studies (ACCESS) J Asthma. 2010;47:257–262. doi: 10.3109/02770900903584019.
    1. Price D, Robertson A, Bullen K, Rand C, Horne R, Staudinger H. Improved adherence with once-daily versus twice-daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study. BMC Pulm Med. 2010;10:1–9. doi: 10.1186/1471-2466-10-1.
    1. Toy EL, Beaulieu NU, McHale JM, Welland TR, Plauschinat CA, Swensen A, Duh MS. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105:435–441. doi: 10.1016/j.rmed.2010.09.006.
    1. SYMBICORT® budesonide and formoterol fumarate dihydrate: Highlights of prescribing information. 2010. . Accessed September 2015.
    1. ADVAIR . DISKUS fluticasone propionate and salmeterol: Highlights of prescribing information. 2014.
    1. Bateman ED, O’Byrne P, Busse WW, Lotvall J, Bleecker ER, Andersen L, et al. Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax. 2014;69:312–319. doi: 10.1136/thoraxjnl-2013-203600.
    1. O’Byrne P, Bleecker ER, Bateman ED, Busse WW, Woodcock A, Forth R, et al. Once-daily fluticasone furoate alone or combined with vilanterol in persistent asthma. Eur Respir J. 2014;43:773–782. doi: 10.1183/09031936.00064513.
    1. Lin J, Kang J, Lee SH, Wang C, Zhou X, Crawford J, et al. Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: A randomized trial. Respir Med. 2015;109:44–53. doi: 10.1016/j.rmed.2014.10.012.
    1. Slack RJ, Barrett VJ, Morrison VS, Sturton RG, Emmons AJ, Ford AJ, Knowles RG. In vitro pharmacological characterization of vilanterol, a novel long-acting beta2-adrenoceptor agonist with 24-hour duration of action. J Pharmacol Exp Ther. 2013;344:218–230. doi: 10.1124/jpet.112.198481.
    1. Oliver A, VanBuren S, Allen A, Hamilton M, Tombs L, Inamdar A, Kempsford R. Tolerability of fluticasone furoate/vilanterol combination therapy in children aged 5 to 11 years with persistent asthma. Clin Ther. 2014;36:928–939. doi: 10.1016/j.clinthera.2014.03.014.
    1. Oliver A, VanBuren S, Allen A, Hamilton M, Tombs L, Kempsford R, Qaqundah P. Safety, tolerability, pharmacokinetics, and pharmacodynamics of vilanterol, a novel inhaled long-acting beta-agonist, in children aged 5-11 years with persistent asthma: a randomized trial. Clin Pharmacol Drug Dev. 2014;3:215–221. doi: 10.1002/cpdd.92.
    1. Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med. 2007;175:1304–1345. doi: 10.1164/rccm.200605-642ST.
    1. Quanjer PH, Lebowitz MD, Gregg I, Miller MR, Pedersen OF. Peak expiratory flow: conclusions and recommendations of a working party of the European respiratory society. Eur Respir J Suppl. 1997;24:2S–8S.
    1. Moeller A, Carlsen KH, Sly PD, Baraldi E, Piacentini G, Pavord I, et al. Monitoring asthma in childhood: lung function, bronchial responsiveness and inflammation. Eur Respir Rev. 2015;24:204–215. doi: 10.1183/16000617.00003914.
    1. Moore VC, Parsons NR, Jaakkola MS, Burge CB, Pantin CF, Robertson AS, Burge PS. Serial lung function variability using four portable logging meters. J Asthma. 2009;46:961–966. doi: 10.3109/02770900903229677.
    1. Scott C, Wu W, Ellsworth A. Efficacy and safety of fluticasone propioante/salmeterol DISKUS and fluticasone propionate DISKUS and HFA in children. Eur Respir J. 2005;26 Suppl 161:P1057.
    1. Adams NP, Bestall JC, Lasserson TJ, Jones P, Cates CJ. Fluticasone versus placebo for chronic asthma in adults and children. Cochrane Database Syst Rev. 2008. Issue 4. Art. No.: CD003135. DOI: 10.1002/14651858.CD003135.pub4.
    1. Bush A, Saglani S. Management of severe asthma in children. Lancet. 2010;376:814–825. doi: 10.1016/S0140-6736(10)61054-9.
    1. Clark M, Martin S, Svedsater H, Dale P, Jacques L. Measurement properties of an asthma symptom and rescue medication use diary. J Asthma. 2015;52:88–97. doi: 10.3109/02770903.2014.947430.
    1. Long term effects of budesonide or nedocromil in children with asthma The childhood asthma management program research group. N Engl J Med. 2000;343:1054–1063. doi: 10.1056/NEJM200010123431501.
    1. Hu C, Jia J, Dong K, Luo L, Wu K, Mehta R, et al. Pharmacokinetics and tolerability of inhaled umeclidinium and vilanterol alone and in combination in healthy Chinese subjects: a randomized, open-label, crossover trial. PLoS One. 2015;10:e0121264. doi: 10.1371/journal.pone.0121264.
    1. Chen X, Zheng X, Jiang J, Hu P, Wu K, Zhuang L, et al. Pharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjects. Pharmacotherapy. 2015;35:586–599. doi: 10.1002/phar.1598.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться