Figures
- 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
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
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
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
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
- TABLE 1
Demographics and baseline characteristics (modified intent-to-treat population)
BFF MDI 320/10 µg BFF MDI 160/10 µg FF MDI 10 µg All patients Patients, n 619 617 607 1843 Age, years 65.3±8.1 64.5±8.4 64.8±8.5 64.9±8.3 Age ≥65 years 347 (56.1) 318 (51.5) 334 (55.0) 999 (54.2) Male 367 (59.3) 345 (55.9) 339 (55.8) 1051 (57.0) White/black/other, % 83.0/4.8/12.1 83.6/3.6/12.8 83.0/4.8/12.2 83.2/4.4/12.4 Current smoker 257 (41.5) 223 (36.1) 245 (40.4) 725 (39.3) Number of pack-years smoked 44.2±26.0 45.8±28.0 44.9±27.4 45.0±27.1 Total CAT score# 21.7±6.4 21.3±6.1 21.2±6.3 21.4±6.3 SGRQ total score 51.4±18.2 51.1±17.8 50.7±17.6 51.1±17.8 History of moderate/severe exacerbations 0 exacerbations 5 (0.8) 2 (0.3) 1 (0.2) 8 (0.4) 1 exacerbation 378 (61.1) 374 (60.6) 374 (61.6) 1126 (61.1) ≥2 exacerbations 236 (38.1) 241 (39.1) 232 (38.2) 709 (38.5) History of severe exacerbations 0 exacerbations 494 (79.8) 510 (82.7) 497 (81.9) 1501 (81.4) 1 exacerbation 108 (17.4) 96 (15.6) 93 (15.3) 297 (16.1) ≥2 exacerbations 17 (2.7) 11 (1.8) 17 (2.8) 45 (2.4) COPD severity Mild 0 (0.0) 1 (0.2) 1 (0.2) 2 (0.1) Moderate 338 (54.6) 330 (53.5) 321 (52.9) 989 (53.7) Severe 241 (38.9) 230 (37.3) 244 (40.2) 715 (38.8) Very severe 37 (6.0) 56 (9.1) 36 (5.9) 129 (7.0) COPD duration, years 8.1±6.4 7.7±5.5 7.9±6.2 7.9±6.1 Prior COPD treatment¶ SABA and/or SAMA only, PRN 4 (0.6) 3 (0.5) 1 (0.2) 8 (0.4) MA only 26 (4.2) 33 (5.3) 30 (4.9) 89 (4.8) BA only 22 (3.6) 37 (6.0) 39 (6.4) 98 (5.3) ICS only 12 (1.9) 14 (2.3) 13 (2.1) 39 (2.1) MA/BA only 83 (13.4) 81 (13.1) 71 (11.7) 235 (12.8) ICS/BA only 272 (43.9) 264 (42.8) 258 (42.5) 794 (43.1) ICS/MA only 13 (2.1) 16 (2.6) 17 (2.8) 46 (2.5) ICS/MA/BA 185 (29.9) 165 (26.7) 177 (29.2) 527 (28.6) ICS use at screening 482 (77.9) 459 (74.4) 465 (76.6) 1406 (76.3) Baseline blood eosinophil count <150 cells·mm−3 197 (31.8) 213 (34.5) 193 (31.8) 603 (32.7) ≥150 cells·mm−3 422 (68.2) 403 (65.3) 413 (68.0) 1238 (67.2) Post-bronchodilator FEV1, % predicted 51.09±13.70 50.59±14.27 50.97±13.46 50.88±13.81 Post-bronchodilator reversibility for FEV1, %+ 12.1±13.0 13.2±14.1 12.9±14.3 12.7±13.8 Rescue medication use, puffs·day-1 3.5±3.2 3.7±3.4 3.6±3.5 3.6±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 μg BFF MDI 160/10μg FF MDI 10 µg Patients, n 619 617 607 Primary endpoint Change from baseline in morning pre-dose trough FEV1 (mL) at week 12# n 542 540 501 LSM±se 72±9.4 69±9.3 37±9.6 LSM difference versus FF MDI (95% CI) 34 (9–60) 32 (7–57) p-value 0.0081 0.0134 Secondary endpoints Change from baseline in morning pre-dose trough FEV1 (mL) at week 12 (attributable estimand)# n 612 612 601 LSM±se 59±9.7 53±9.5 9±10.1 LSM difference versus FF MDI (95% CI) 50 (24–76) 44 (18–70) p-value 0.0002 0.0009 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-value 0.0441 0.0198 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-value 0.0121 0.0002 Change from baseline in mean daily rescue medication use (puffs·day-1) over 12 weeks# n 612 610 599 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-value 0.0097 0.0185 Additional endpoints Rate of moderate/severe exacerbations per year§ Adjusted rate of exacerbations+/−SE 0.93±0.073 0.98±0.076 1.39±0.106 Rate ratio versus FF MDI (95% CI) 0.67 (0.54–0.82) 0.71 (0.58–0.87) p-value 0.0001ƒ 0.0010ƒ 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-value 0.0904 0.1178 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 μg BFF MDI 160/10 μg FF MDI 10 μg All patients Patients, n 619 617 607 1843 ≥1 TEAE 297 (48.0), 819 314 (50.9), 919 305 (50.2), 932 916 (49.7), 2670 Mild 124 (20.0) 116 (18.8) 106 (17.5) 346 (18.8) Moderate 118 (19.1) 135 (21.9) 119 (19.6) 372 (20.2) Severe 55 (8.9) 63 (10.2) 80 (13.2) 198 (10.7) Drug-related TEAEs# 31 (5.0), 43 26 (4.2), 35 24 (4.0), 33 81 (4.4), 111 Serious TEAEs¶ 60 (9.7), 88 78 (12.6), 110 83 (13.7), 151 221 (12.0), 349 Drug-related serious TEAEs 1 (0.2), 2 1 (0.2), 1 1 (0.2), 1 3 (0.2), 4 TEAEs leading to early discontinuation 28 (4.5), 35 21 (3.4), 29 33 (5.4), 42 82 (4.4), 106 Serious TEAEs leading to early discontinuation 17 (2.7), 18 16 (2.6), 17 22 (3.6), 25 55 (3.0), 60 Deaths (all causes) On-treatment 3 (0.5) 4 (0.6) 8 (1.3) 15 (0.8) Post-treatment 3 (0.5) 4 (0.6) 0 (0.0) 7 (0.4) TEAEs occurring in ≥4% of patients in any treatment arm (preferred term) Nasopharyngitis 41 (6.6), 53 53 (8.6), 61 36 (5.9), 43 130 (7.1), 157 COPD 27 (4.4), 32 30 (4.9), 33 50 (8.2), 65 107 (5.8), 130 Upper respiratory tract infection 28 (4.5), 29 14 (2.3), 18 24 (4.0), 28 66 (3.6), 75 Confirmed MACE as determined by CEC 0 (0.0), 0 3 (0.5), 3 6 (1.0), 6 9 (0.5), 9 Confirmed pneumonia as determined by CEC 10 (1.6), 11 15 (2.4), 15 14 (2.3), 15 39 (2.1), 41 Serious confirmed pneumonia events 8 (1.3), 8 11 (1.8), 11 8 (1.3), 9 27 (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.
Supplementary Material
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Online data supplement Hanania_PT009003_SOPHOS_manuscript_RESUBMITTED_SUPPPL_INFO_23Mar20
