Non-inferiority Trial between Two Dry-powder Inhalers Containing Fluticasone/Salmeterol in Asthmatic Patients

Abstract

Asthma is an increasing pathology with poor compliance. Achievement of control is possible but under intensive treatment. In this setting, fluticasone/salmeterol association delivered by dry powder inhalers is a valuable and proved option. A prospective, parallel, open-label, phase IV, multicentre non-inferiority study was conducted to determine therapeutic similarity between 2 different inhalers: Generic DPI and Diskus^®, which both deliver a fluticasone/salmeterol association (CAS 80474-14-2/CAS 89365-50-4). A 103 uncontrolled asthmatic patients were randomly assigned in 2 groups, Generic (G) and Diskus^® (D), and received the association for 18 weeks through the appropriate device. They were evaluated according to Asthma Quality of Life Questionnaire and GINA/NIH guidelines. To demonstrate non-inferiority, the estimation of the Relative Risk between the Global Score Rate per group with its 95% confidence interval was calculated and compared against a non-inferiority margin obtained from a previous study. The Global Score Rate was 82% for G Group and 83% for D Group. The RR was 1.0124 (95% CI: 0.847–1.210). The margin set at 0.832 was not reached by the lower 95% CI (z=−2.097; p=0.018) pointing out non-inferiority. The results have demonstrated non-inferiority between groups. Thus, the 2 products are therapeutically similar.

Key words

non-inferiority trials - anti-asthma/COPD drugs - dry-powder inhaler devices

• References

• 1 Myers TR, Tomasio L. Asthma: 2015 and beyond. Respir Care 2011; 56: 1389-1407
• 2 Yeh KW, Chen SH, Chiang LC et al. Survey of asthma care in Taiwan: a comparison of asthma specialists and general practitioners. Ann Allergy Asthma Immunol 2006; 96: 593-599
• 3 Chapman KR, Boulet LP, Rea RM et al. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J 2008; 31: 320-325
• 4 Shapiro G, Lumry W, Wolfe J et al. Combined salmeterol 50 μg and fluticasone propionate 250 μg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med 2000; 161: 527-534
• 5 Adams RJ, Fuhlbrigge A, Guilbert T et al. Inadequate use of asthma medication in the United States: results of the Asthma in America national population survey. J Allergy Clin Immunol 2002; 110: 58-64
• 6 Adams WP, Arhens RC, Chen ML et al. Demonstrating bioequivalence of locally acting orally inhaled drug products (OIPs): workshop summary report. J Aerosol Med Pulm Drug Deliv 2010; 23: 1-29
• 7 Daley-Yates PT, Parkins DA, Thomas MJ et al. Pharmacokinetic, pharmacodynamic, efficacy, and safety data from two randomized, double blind studies in patients with asthma and in vitro study comparing two dry-powder inhalers delivering a combination of salmeterol 50 μg and fluticasone propionate 250 μg: implications for establishing bioequivalence of inhaled products. Clin Ther 2009; 31: 370-385
• 8 Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med 2006; 145: 62-69
• 9 D’Agostino Sr RB, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues – the encounters of academic consultants in statistics. Stat Med 2003; 22: 169-186
• 10 Bateman ED, Boushey HA, Bousquet J et al. GOAL Investigators Group . Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma controL study. Am J Respir Crit Care Med 2004; 170: 836-844
• 11 Global Initiative for Asthma (GINA) . Global strategy for asthma management and prevention. NHLBI/WHO workshop report. NIH publication number 95-3659. Bethesda: National Institutes of Health, National Heart, Lung and Blood Institute; 1995
• 12 Jones B, Jarvis P, Lewis JA et al. Trials to assess equivalence: the importance of rigorous methods. BMJ 1996; 313: 36-39
• 13 Nunn AJ, Gregg I. New regression equations for predicting peak expiratory flow in adults. BMJ 1989; 298: 1068-1070
• 14 Almendra-Arao F, Sotres-Ramos D. Comparison of some non-inferiority asymptotic statistical tests for two independent proportions. Agrociencia 2009; 43: 163-172
• 15 Hasselblad V, Kong DF. Statistical methods for comparison to placebo in active-control trials. Drug Inf J 2001; 35: 435-449
• 16 Armitage P, Berry G. Estadística para investigación biomédica. Barcelona: Doyma; 1992: 146-154
• 17 Garcia Garcia ML, Wahn U, Gilles L et al. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study. Pediatrics 2005; 116: 360-369
• 18 Bousquet J, Aubier M, Sastre J et al. Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma. Allergy 2006; 61: 72-78
• 19 Boulet LP, Bateman ED, Voves R et al. A randomized study comparing ciclesonide and fluticasone propionate in patients with moderate persistent asthma. Respir Med 2007; 101: 1677-1686
• 20 Vermeulen JH, Gyurkovits K, Rauer H et al. Randomized comparison of the efficacy and safety of ciclesonide and budesonide in adolescents with severe asthma. Respir Med 2007; 101: 2182-2191
• 21 von Berg A, Engelstätter R, Minic P et al. Comparison of the efficacy and safety of ciclesonide 160 μg once daily vs. budesonide 400 μg once daily in children with asthma. Pediatr Allergy Immunol 2007; 18: 391-400
• 22 Bateman ED, Linnhof AE, Homik L et al. Comparison of Twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma. Pulm Pharmacol Ther 2008; 21: 264-275
• 23 Harnest U, Price D, Howes T et al. Comparison of mometasone furoate dry powder inhaler and fluticasone propionate dry powder inhaler in patients with moderate to severe persistent asthma requiring high-dose inhaled corticosteroid therapy: findings from a noninferiority trial. J Asthma 2008; 45: 215-220
• 24 Vincken W, Bantje T, Middle MV et al. Long-term efficacy and safety of ipratropium bromide plus fenoterol via Respimat^® soft misttrade mark inhaler (SMI) versus pressurized metered-dose inhaler in asthma. Clin Drug Investig 2004; 24: 17-28
• 25 Chopra N, Williams M, Rimmer M et al. SMO30006 and SMO30007 International Study Teams. Salmeterol HFA is as effective as salmenterol CFC in children and adults with persistent asthma. Respir Med 2005; 99 (Suppl) S1-S10
• 26 Dusser D, Vicaut E, Lefrançois G. Formoterol HFA group . Double-blind, double-dummy, multinational, multicenter, parallel-D Groupesign clinical trial of clinical non-inferiority of formoterol 12 μg/unit dose in a b.i.d. regimen administered via an HFA-propellant-pMDI or a dry powder inhaler in a 12-week treatment period of moderate to severe stable persistent asthma in adult patients. Respiration 2005; 72 (Suppl. 01) 20-27
• 27 Escribano A, Tutuncu A, Löhr I et al. Clinical comparability between the CFC and HFA budesonide pressurized metered-dose inhalers in paediatric patients with asthma: a randomized controlled trial. Curr Med Res Opin 2006; 22: 1085-1092
• 28 Engelstätter R, Szlávik M, Gerber C et al. Once-daily ciclesonide via metered-dose inhaler: Similar efficacy and safety with or without spacer. Respir Med 2009; 103: 1643-1650
• 29 Kavuru M, Melamed J, Gross G et al. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2000; 105: 1108-1116
• 30 Johansson G, McIvor RA, D’Ambrosio FP et al. Comparison of salmeterol/fluticasone propionate combination with budesonide in patients with mild-to-moderate asthma. Clin Drug Invest 2001; 21: 633-642
• 31 Papi A, Paggiaro P, Nicolini G et al. Beclomethasone/formoterol vs. fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy 2007; 62: 1182-1188
• 32 Hanania NA, King MJ, Braman SS et al. Asthma in Elderly workshop participants . Asthma in the elderly: current understanding and future research needs – a report of a National Institute on Aging (NIA) workshop. J Allergy Clin Immunol 2011; 128 (3 Suppl) S4-S24
• 33 Nguyen K, Zaharan H, Igbal S et al. Factors associated with asthma control among adults in five New England states, 2006-2007. J Asthma 2011; 48: 581-588
• 34 Rabe KF, Vermiere PA, Soriano JB et al. Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J 2000; 16: 802-807