Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study

Gary T Ferguson, Alberto Papi, Antonio Anzueto, Edward M Kerwin, Christy Cappelletti, Elizabeth A Duncan, Jack Nyberg, Paul Dorinsky, Gary T Ferguson, Alberto Papi, Antonio Anzueto, Edward M Kerwin, Christy Cappelletti, Elizabeth A Duncan, Jack Nyberg, Paul Dorinsky

Abstract

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV1versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.

Conflict of interest statement

Conflict of interest: G.T. Ferguson reports grants, personal fees and non-financial support from AstraZeneca, during the conduct of the study; and grants, personal fees and non-financial support from Boehringer Ingelheim, Novartis, AstraZeneca, Pearl (a member of the AstraZeneca Group) and Sunovion, grants and personal fees from Theravance, and personal fees from Verona, Mylan, Innoviva, GlaxoSmithKline and Circassia, outside the submitted work. Conflict of interest: A. Papi reports board membership, consultancy, payment for lectures, grants for research and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and TEVA, payment for lectures and travel expenses reimbursement from Menarini, Novartis and Zambon, board membership, payment for lectures, grants for research and travel expenses reimbursement from Pfizer, and grants for research from Sanofi, outside the submitted work. Conflict of interest: A. Anzueto reports institutional grants from GSK, and personal fees for consultancy from GSK, AstraZeneca, Novartis and BI, outside the submitted work. Conflict of interest: E.M. Kerwin is an employee of Crisor LLC Research, has served on advisory boards, speaker panels, or received travel reimbursement from Novartis, AstraZeneca, Amphastar, Forest, Pearl (a member of the AstraZeneca Group), Sunovion, Teva and Theravance, has served on a medical advisory board for Mylan, and has undertaken consultancy for GSK, outside the submitted work. Conflict of interest: C. Cappelletti is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: E.A. Duncan is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: J. Nyberg is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: P. Dorinsky is a full-time employee of Pearl (a member of the AstraZeneca Group).

Copyright ©ERS 2018.

Figures

FIGURE 1
FIGURE 1
Patient disposition. BD: budesonide; BFF: budesonide/formoterol fumarate dihydrate; BUD/FORM DPI: budesonide/formoterol dry powder inhaler; FF: formoterol fumarate dihydrate; MDI: metered dose inhaler. #: 19 patients who were randomised were not treated: 14 did not meet baseline stability criteria; one due to chronic obstructive pulmonary disease diagnosis; one due to eDiary compliance; one due to prohibited medication; one was a screen failure (non-specific); and one was a “mistake”. One patient in the BFF MDI 160/10 µg group was identified as a duplicate patient and excluded from the analysis populations, but completed treatment.
FIGURE 2
FIGURE 2
Primary efficacy end-points (efficacy estimand; modified intent-to-treat population). a) Adjusted mean change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over time. b) Adjusted mean change from baseline in FEV1 area under the curve from 0–4 h (AUC0–4) over time. Data are presented as least squares means with standard errors. BD: budesonide; BFF: budesonide/formoterol fumarate dihydrate; BUD/FORM DPI: budesonide/formoterol dry powder inhaler; FF: formoterol fumarate dihydrate; MDI: metered dose inhaler.
FIGURE 3
FIGURE 3
Forest plots of primary lung function end-points by baseline eosinophil count (efficacy estimand; modified intent-to-treat (mITT) population; US approach). a) Change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 24. b) Change from baseline in FEV1 area under the curve from 0–4 h at week 24. Data are presented as least squares mean treatment differences with 95% confidence intervals. mITT population: <150 cells per mm3, n=810; ≥150 cells per mm3, n=1551; all patients, n=2361. BD: budesonide; BFF: budesonide/formoterol fumarate dihydrate; FF: formoterol fumarate dihydrate; MDI: metered dose inhaler.
FIGURE 4
FIGURE 4
Forest plots of rate of moderate/severe chronic obstructive pulmonary disease exacerbations by baseline eosinophil count (efficacy estimand; modified intent-to-treat (mITT) population; US and EU approach). Data are presented as rate ratios with 95% confidence intervals. mITT population: 3, n=810; ≥150 cells per mm3, n=1551; all patients, n=2361. BD: budesonide; BFF: budesonide/formoterol fumarate dihydrate; FF: formoterol fumarate dihydrate; MDI: metered dose inhaler.

References

    1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. . Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Eur Respir J 2017; 49: 1700214.
    1. Calverley PMA, Anderson JA, Celli B, et al. . Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–789.
    1. Ferguson GT, Anzueto A, Fei R, et al. . Effect of fluticasone propionate/salmeterol (250/50 µg) or salmeterol (50 µg) on COPD exacerbations. Respir Med 2008; 102: 1099–1108.
    1. Rennard SI, Tashkin DP, McElhattan J, et al. . Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs 2009; 69: 549–565.
    1. Sharafkhaneh A, Southard JG, Goldman M, et al. . Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir Med 2012; 106: 257–268.
    1. Anzueto A, Ferguson GT, Feldman G, et al. . Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD 2009; 6: 320–329.
    1. Jenkins CR, Jones PW, Calverley PMA, et al. . Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009; 10: 59.
    1. Ferguson GT, Tashkin DP, Skärby T, et al. . Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: the 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. Respir Med 2017; 132: 31–41.
    1. Zhong N, Zheng J, Wen F, et al. . Efficacy and safety of budesonide/formoterol via a dry powder inhaler in Chinese patients with chronic obstructive pulmonary disease. Curr Med Res Opin 2012; 28: 257–265.
    1. Fukuchi Y, Samoro R, Fassakhov R, et al. . Budesonide/formoterol via Turbuhaler® versus formoterol via Turbuhaler® in patients with moderate to severe chronic obstructive pulmonary disease: phase III multinational study results. Respirology 2013; 18: 866–873.
    1. Szafranski W, Cukier A, Ramirez A, et al. . Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003; 21: 74–81.
    1. Pascoe S, Locantore N, Dransfield MT, et al. . Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3: 435–442.
    1. Watz H, Tetzlaff K, Wouters EFM, et al. . Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med 2016; 4: 390–398.
    1. Bafadhel M, Peterson S, De Blas MA, et al. . Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med 2018; 6: 117–126.
    1. Doty A, Schroeder J, Vang K, et al. . Drug delivery from an innovative LAMA/LABA co-suspension delivery technology fixed-dose combination MDI: evidence of consistency, robustness, and reliability. AAPS PharmSciTech 2018; 19: 837–844.
    1. Vehring R, Lechuga-Ballesteros D, Joshi V, et al. . Cosuspensions of microcrystals and engineered microparticles for uniform and efficient delivery of respiratory therapeutics from pressurized metered dose inhalers. Langmuir 2012; 28: 15015–15023.
    1. Taylor G, Warren S, Dwivedi S, et al. . Gamma scintigraphic pulmonary deposition study of glycopyrronium/formoterol metered dose inhaler formulated using co-suspension delivery technology. Eur J Pharm Sci 2018; 111: 450–457.
    1. Kerwin EM, Siler TM, Arora S, et al. . Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis 2018; 13: 1483–1494.
    1. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: 932–946.
    1. AstraZeneca UK Limited. Symbicort® Turbohaler® 200/6 Inhalation Powder: Summary of Product Characteristics . Date last updated: April 27 2018. Date last accessed: June 21 2018.
    1. Mahler DA. Peak inspiratory flow rate as a criterion for dry powder inhaler use in chronic obstructive pulmonary disease. Ann Am Thorac Soc 2017; 14: 1103–1107.
    1. Bosnic-Anticevich S, Chrystyn H, Costello RW, et al. . The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes. Int J Chron Obstruct Pulmon Dis 2017; 12: 59–71.
    1. Tashkin DP, Rennard SI, Martin P, et al. . Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs 2008; 68: 1975–2000.
    1. Kerwin EM, Scott-Wilson C, Sanford L, et al. . A randomised trial of fluticasone furoate/vilanterol (50/25 µg; 100/25 µg) on lung function in COPD. Respir Med 2013; 107: 560–569.
    1. Martinez FJ, Boscia J, Feldman G, et al. . Fluticasone furoate/vilanterol (100/25; 200/25 µg) improves lung function in COPD: a randomised trial. Respir Med 2013; 107: 550–559.
    1. Zhang Y, Morgan RL, Alonso-Coello P, et al. . A systematic review of how patients value COPD outcomes. Eur Respir J 2018; 52: 1800222.
    1. Suissa S, Drazen JM. Making sense of triple inhaled therapy for COPD. N Engl J Med 2018; 378: 1723–1724.
    1. Agustí A, Bafadhel M, Beasley R, et al. . Pavord ID, on behalf of all participants in the seminar. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J 2017; 50: 1701655.
    1. Lipson DA, Barnhart F, Brealey N, et al. . Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018; 378: 1671–1680.
    1. Battisti WP, Wager E, Baltzer L, et al. . Good publication practice for communicating company-sponsored medical research: GPP3. Ann Intern Med 2015; 163: 461–464.

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