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Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD

Nicola A. Hanania, Alberto Papi, Antonio Anzueto, Fernando J. Martinez, Kimberly A. Rossman, Christy S. Cappelletti, Elizabeth A. Duncan, Jack S. Nyberg, Paul M. Dorinsky
ERJ Open Research 2020 6: 00187-2019; DOI: 10.1183/23120541.00187-2019
Nicola A. Hanania
1Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA
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  • For correspondence: hanania@bcm.edu
Alberto Papi
2Research Centre on Asthma and COPD, Dept of Medical Sciences, University of Ferrara, Ferrara, Italy
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  • ORCID record for Alberto Papi
Antonio Anzueto
3Pulmonary Medicine and Critical Care, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX, USA
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Fernando J. Martinez
4Joan and Sanford I. Weill Dept of Medicine, Weill Cornell Medicine, New York, NY, USA
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Kimberly A. Rossman
5AstraZeneca, Morristown, NJ, USA
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Christy S. Cappelletti
6AstraZeneca, Durham, NC, USA
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Elizabeth A. Duncan
6AstraZeneca, Durham, NC, USA
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Jack S. Nyberg
7Former employee of AstraZeneca, Morristown, NJ, USA
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Paul M. Dorinsky
6AstraZeneca, Durham, NC, USA
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  • FIGURE 1
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    FIGURE 1

    Patient disposition. A total of 21 subjects had participated in multiple sponsor studies and were excluded from the intent to treat (ITT), modified ITT (mITT) and safety populations. BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate.

  • FIGURE 2
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    FIGURE 2

    Primary efficacy endpoint: adjusted mean change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over time (modified intent-to-treat population; efficacy estimand). Error bars represent the standard error. BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate.

  • FIGURE 3
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    FIGURE 3

    Time to first moderate/severe chronic obstructive pulmonary disease (COPD) exacerbation (modified intent-to-treat population; efficacy estimand). BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate.

  • FIGURE 4
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    FIGURE 4

    Change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12, a) and rate of moderate/severe chronic obstructive pulmonary disease (COPD) exacerbations, b) by baseline eosinophil count (modified intent-to-treat population; efficacy estimand). Error bars represent 95% confidence intervals. BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate.

  • FIGURE 5
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    FIGURE 5

    Lung function and exacerbation responses by blood eosinophil counts (efficacy estimand, modified intent-to-treat population). Change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) (mL) at week 12 by blood eosinophil count, for a) budesonide/formoterol fumarate dihydrate (BFF) metered dose inhaler (MDI) 320/10 µg versus formoterol fumarate dihydrate (FF) MDI 10 µg, b) BFF MDI 160/10 µg versus FF MDI 10 µg, and c) BFF MDI 320/10 µg versus BFF MDI 160/10 µg, and rate of moderate/severe COPD exacerbations by blood eosinophil count for d) BFF MDI 320/10 µg versus FF MDI 10 µg, e) BFF MDI 160/10 µg versus FF MDI 10 µg, and f) BFF MDI 320/10 µg versus BFF MDI 160/10 µg. The banded areas represent 95% confidence intervals. COPD: chronic obstructive pulmonary disease.

Tables

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  • TABLE 1

    Demographics and baseline characteristics (modified intent-to-treat population)

    BFF MDI 320/10 µgBFF MDI 160/10 µgFF MDI 10 µgAll patients
    Patients, n6196176071843
    Age, years65.3±8.164.5±8.464.8±8.564.9±8.3
    Age ≥65 years347 (56.1)318 (51.5)334 (55.0)999 (54.2)
    Male367 (59.3)345 (55.9)339 (55.8)1051 (57.0)
    White/black/other, %83.0/4.8/12.183.6/3.6/12.883.0/4.8/12.283.2/4.4/12.4
    Current smoker257 (41.5)223 (36.1)245 (40.4)725 (39.3)
    Number of pack-years smoked44.2±26.045.8±28.044.9±27.445.0±27.1
    Total CAT score#21.7±6.421.3±6.121.2±6.321.4±6.3
    SGRQ total score51.4±18.251.1±17.850.7±17.651.1±17.8
    History of moderate/severe exacerbations
     0 exacerbations5 (0.8)2 (0.3)1 (0.2)8 (0.4)
     1 exacerbation378 (61.1)374 (60.6)374 (61.6)1126 (61.1)
     ≥2 exacerbations236 (38.1)241 (39.1)232 (38.2)709 (38.5)
    History of severe exacerbations
     0 exacerbations494 (79.8)510 (82.7)497 (81.9)1501 (81.4)
     1 exacerbation108 (17.4)96 (15.6)93 (15.3)297 (16.1)
     ≥2 exacerbations17 (2.7)11 (1.8)17 (2.8)45 (2.4)
    COPD severity
     Mild0 (0.0)1 (0.2)1 (0.2)2 (0.1)
     Moderate338 (54.6)330 (53.5)321 (52.9)989 (53.7)
     Severe241 (38.9)230 (37.3)244 (40.2)715 (38.8)
     Very severe37 (6.0)56 (9.1)36 (5.9)129 (7.0)
    COPD duration, years8.1±6.47.7±5.57.9±6.27.9±6.1
    Prior COPD treatment¶
     SABA and/or SAMA only, PRN4 (0.6)3 (0.5)1 (0.2)8 (0.4)
     MA only26 (4.2)33 (5.3)30 (4.9)89 (4.8)
     BA only22 (3.6)37 (6.0)39 (6.4)98 (5.3)
     ICS only12 (1.9)14 (2.3)13 (2.1)39 (2.1)
     MA/BA only83 (13.4)81 (13.1)71 (11.7)235 (12.8)
     ICS/BA only272 (43.9)264 (42.8)258 (42.5)794 (43.1)
     ICS/MA only13 (2.1)16 (2.6)17 (2.8)46 (2.5)
     ICS/MA/BA185 (29.9)165 (26.7)177 (29.2)527 (28.6)
    ICS use at screening482 (77.9)459 (74.4)465 (76.6)1406 (76.3)
    Baseline blood eosinophil count
     <150 cells·mm−3197 (31.8)213 (34.5)193 (31.8)603 (32.7)
     ≥150 cells·mm−3422 (68.2)403 (65.3)413 (68.0)1238 (67.2)
    Post-bronchodilator FEV1, % predicted51.09±13.7050.59±14.2750.97±13.4650.88±13.81
    Post-bronchodilator reversibility for FEV1, %+12.1±13.013.2±14.112.9±14.312.7±13.8
    Rescue medication use, puffs·day-13.5±3.23.7±3.43.6±3.53.6±3.4

    Data are presented as mean±standard deviation or n (%), unless otherwise stated. BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate; CAT: Chronic Obstructive Pulmonary Disease (COPD) Assessment Test; SGRQ: St George's Respiratory Questionnaire; SABA: short-acting β2-agonist; SAMA: short-acting muscarinic antagonist; PRN: as needed; MA: muscarinic antagonist; BA: β2-agonist; ICS: inhaled corticosteroid; FEV1: forced expiratory volume in 1 s. #: total CAT score was the sum of eight CAT item scores and could range from 0 to 40; ¶: scheduled use of a SAMA and/or SABA was included in all categories except PRN; +: reversibility is defined as (change from pre-bronchodilator to post-bronchodilator for FEV1)×100/pre-bronchodilator FEV1.

    • TABLE 2

      Primary, secondary and additional efficacy endpoints (modified intent-to-treat population; efficacy estimand unless stated otherwise)

      BFF MDI 320/10 μgBFF MDI 160/10μgFF MDI 10 µg
      Patients, n619617607
      Primary endpoint
       Change from baseline in morning pre-dose trough FEV1 (mL) at week 12#
        n542540501
        LSM±se72±9.469±9.337±9.6
        LSM difference versus FF MDI (95% CI)34 (9–60)32 (7–57)
        p-value0.00810.0134
      Secondary endpoints
       Change from baseline in morning pre-dose trough FEV1 (mL) at week 12 (attributable estimand)#
        n612612601
        LSM±se59±9.753±9.59±10.1
        LSM difference versus FF MDI (95% CI)50 (24–76)44 (18–70)
        p-value0.00020.0009
       Time to first moderate/severe COPD exacerbation¶
        Patients with exacerbation n (%)220 (35.5)223 (36.1)241 (39.7)
        HR versus FF MDI (95% CI)0.827 (0.688–0.995)0.803 (0.668–0.966)
        p-value0.04410.0198
       SGRQ responder rate at week 12+
        Responders n (%)315 (51.98)331 (54.00)262 (43.96)
        Difference versus FF MDI % (95% CI)7.55 (1.67–13.43)11.05 (5.18–16.91)
        p-value0.01210.0002
       Change from baseline in mean daily rescue medication use (puffs·day-1) over 12 weeks#
        n612610599
        LSM±se−0.9±0.09−0.9±0.09−0.6±0.09
        LSM difference versus FF MDI (95% CI)−0.32 (−0.56 to −0.08)−0.29 (−0.53 to −0.05)
        p-value0.00970.0185
      Additional endpoints
       Rate of moderate/severe exacerbations per year§
        Adjusted rate of exacerbations+/−SE0.93±0.0730.98±0.0761.39±0.106
        Rate ratio versus FF MDI (95% CI)0.67 (0.54–0.82)0.71 (0.58–0.87)
        p-value0.0001ƒ0.0010ƒ
       Time to first moderate/severe COPD exacerbation in patients with a history of ≥2 COPD exacerbations in the last 12 months§
        Patients with exacerbation, n (%)93 (39.4)97 (40.2)106 (45.7)
        HR versus FF MDI (95% CI)0.783 (0.590–1.039)0.799 (0.603–1.059)
        p-value0.09040.1178

      BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate; FEV1: forced expiratory volume in 1 s; LSM: least squares mean; HR: hazard ratio; SGRQ: St George's Respiratory Questionnaire; COPD: chronic obstructive pulmonary disease. #: analysed by repeated measures linear mixed model; ¶: analysed by Cox regression; +: analysed by logistic regression model; §: analysed by negative binomial regression. Rate of exacerbations per year=total number of exacerbations / total years of exposure across all patients for the treatment. ƒ: p-values for this endpoint are considered nominal since these analyses were not under Type I error control.

      • TABLE 3

        Treatment-emergent adverse events (TEAEs) (safety population)

        BFF MDI 320/10 μgBFF MDI 160/10 μgFF MDI 10 μgAll patients
        Patients, n6196176071843
        ≥1 TEAE297 (48.0), 819314 (50.9), 919305 (50.2), 932916 (49.7), 2670
         Mild124 (20.0)116 (18.8)106 (17.5)346 (18.8)
         Moderate118 (19.1)135 (21.9)119 (19.6)372 (20.2)
         Severe55 (8.9)63 (10.2)80 (13.2)198 (10.7)
        Drug-related TEAEs#31 (5.0), 4326 (4.2), 3524 (4.0), 3381 (4.4), 111
        Serious TEAEs¶60 (9.7), 8878 (12.6), 11083 (13.7), 151221 (12.0), 349
        Drug-related serious TEAEs1 (0.2), 21 (0.2), 11 (0.2), 13 (0.2), 4
        TEAEs leading to early discontinuation28 (4.5), 3521 (3.4), 2933 (5.4), 4282 (4.4), 106
        Serious TEAEs leading to early discontinuation17 (2.7), 1816 (2.6), 1722 (3.6), 2555 (3.0), 60
        Deaths (all causes)
         On-treatment3 (0.5)4 (0.6)8 (1.3)15 (0.8)
         Post-treatment3 (0.5)4 (0.6)0 (0.0)7 (0.4)
        TEAEs occurring in ≥4% of patients in any treatment arm (preferred term)
         Nasopharyngitis41 (6.6), 5353 (8.6), 6136 (5.9), 43130 (7.1), 157
         COPD27 (4.4), 3230 (4.9), 3350 (8.2), 65107 (5.8), 130
         Upper respiratory tract infection28 (4.5), 2914 (2.3), 1824 (4.0), 2866 (3.6), 75
        Confirmed MACE as determined by CEC0 (0.0), 03 (0.5), 36 (1.0), 69 (0.5), 9
        Confirmed pneumonia as determined by CEC10 (1.6), 1115 (2.4), 1514 (2.3), 1539 (2.1), 41
         Serious confirmed pneumonia events8 (1.3), 811 (1.8), 118 (1.3), 927 (1.5), 28

        Data are presented as n (%), events or n (%), unless otherwise stated. BFF: budesonide/formoterol fumarate dihydrate; MDI: metered dose inhaler; FF: formoterol fumarate dihydrate; COPD: chronic obstructive pulmonary disease; MACE: major adverse cardiovascular event; CEC: Clinical Endpoint Committee. #: relationship determined by investigator assessment; ¶: TEAE leading to death, hospitalisation or a life-threatening TEAE.

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        Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD
        Nicola A. Hanania, Alberto Papi, Antonio Anzueto, Fernando J. Martinez, Kimberly A. Rossman, Christy S. Cappelletti, Elizabeth A. Duncan, Jack S. Nyberg, Paul M. Dorinsky
        ERJ Open Research Apr 2020, 6 (2) 00187-2019; DOI: 10.1183/23120541.00187-2019

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        Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD
        Nicola A. Hanania, Alberto Papi, Antonio Anzueto, Fernando J. Martinez, Kimberly A. Rossman, Christy S. Cappelletti, Elizabeth A. Duncan, Jack S. Nyberg, Paul M. Dorinsky
        ERJ Open Research Apr 2020, 6 (2) 00187-2019; DOI: 10.1183/23120541.00187-2019
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