Blood Eosinophils and Response to Maintenance COPD Treatment: Data from the FLAME Trial. Online Data Supplement

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1 Blood Eosinophils and Response to Maintenance COPD Treatment: Data from the FLAME Trial Nicolas Roche, Kenneth R. Chapman, Claus F. Vogelmeier, Felix JF Herth, Chau Thach, Robert Fogel, Petter Olsson, Francesco Patalano, Donald Banerji and Jadwiga A. Wedzicha Online Data Supplement

2 METHODS Following a 1-week screening period and 4-week run-in period (in which patients received tiotropium 18 μg once daily) patients discontinued tiotropium and were randomized 1:1 to indacaterol/glycopyrronium (IND/GLY) 110/50 μg once daily or salmeterol/fluticasone propionate combination (SFC) 50/500 μg twice daily for 52 weeks, followed by a 30-day follow-up (Figure E1). Patients were provided with a salbutamol inhaler for use as rescue medication during the study. The study was conducted according to the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all patients. Assessments and Variables Patients recorded their daily symptoms in an electronic diary. When exacerbation criteria were met, patients received an alert and were advised to contact the site. All exacerbation events were documented using the chronic obstructive pulmonary disease (COPD) exacerbation electronic case report form (ecrf), including those which required healthcare utilization, with exacerbation severity determined by the type of treatment provided. Health status was assessed using the St George s Respiratory Questionnaire (SGRQ-C) on Weeks 4, 12, 26, 38, and 52 (or at treatment discontinuation). Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were recorded at 45 and 15 min pre-dose, and 30 min and 1 hour post-dose on Day 1 and Weeks 4, 12, 26, 38, and 52 (or at treatment discontinuation) using centralized spirometry. Rescue medication use was captured using the ediary. E2

3 Safety was assessed through recording adverse events and serious adverse events, including regular monitoring of hematology, blood chemistry, and urine, and regular assessments of vital signs, physical condition, and body weight. A pneumonia diagnosis required radiographic imaging via chest x-ray or computed tomography scan. All deaths, serious cardio- and cerebrovascular events, and atrial fibrillation/flutter events that occurred during the study were assessed by an independent adjudication committee. Statistical Analyses Efficacy analyses were performed on the modified intention-to-treat set which included all patients who underwent randomization, received at least one dose of a drug during the treatment period, and did not have major violations of compliance with Good Clinical Practice guidelines before unblinding occurred. Exacerbation rate was analyzed using a negative binomial model, including terms for treatment, baseline smoking status, prior inhaled corticosteroid (ICS) use, airflow limitation, region, subgroup term and treatment by subgroup interaction as fixed effects, with baseline total symptom score and COPD exacerbation history as covariates. Time to first exacerbation was analyzed using a Cox regression model, utilizing the same terms as the negative binomial model. Change from baseline in SGRQ-C total score was analyzed using a mixed model for repeated measures, with terms of treatment, baseline measurements, smoking status at baseline, baseline ICS use, airflow limitation, region, visit (as a factor), subgroup term, treatment-by-visit interaction, baseline-by-visit interaction, treatment- E3

4 by-subgroup term interaction, visit-by-subgroup term interaction, treatment-by-visitby-subgroup term interaction and an unstructured variance covariance structure. The proportion of patients who achieved a 4 unit reduction in total SGRQ-C score (1) was analyzed using repeated measurements logistic regression model with the same terms as the analysis of SGRQ-C score. Change from baseline in trough FEV1 and FVC were analyzed using a similar model as described for SGRQ-C measures, using appropriate baseline values. Change from baseline in daily rescue medication use over the 52-week treatment period was analyzed using a mixed model, with terms of treatment, baseline mean daily use of rescue medication, smoking status at baseline, baseline ICS use, airflow limitation, region, subgroup term and a treatment by subgroup interaction as fixed effects, with center nested within region as a random effect. The full pre-specified statistical analysis plan can be found in the Supplementary Appendix of Wedzicha JA, et al. N Engl J Med 2016 (2). Table E1 lists the pre-specified and post-hoc analyses discussed in this manuscript. Safety endpoints were assessed using the safety set (all patients who received at least one dose of study drug), and patients were analyzed according to the treatment they received. Further information on safety assessment has been published previously (2). E4

5 RESULTS Patient Demographics Baseline blood eosinophil percentage was similar in the IND/GLY and SFC treatment arms, as were mean and median baseline absolute cell count (Figure E2 and Table E2). 60.9% of patients had blood eosinophils 2% at baseline (Table E3). Health Status IND/GLY significantly improved mean SGRQ-C score compared with SFC at Week 52 in the < 2% subgroup, and provided a slight numerical improvement versus SFC in the 2% subgroup (Table E4). IND/GLY also significantly improved the proportion of patients achieving a 4-unit change in SGRQ-C total score compared with SFC at Week 52 in the < 2% subgroup and provided a numerical improvement versus SFC in the 2% subgroup (Table E4). Similarly, IND/GLY significantly improved mean SGRQ-C score and the proportion of SGRQ-C responders compared with SFC at Week 52 in the < 150 and < 300 cells/μl subgroups. Numerical improvements with IND/GLY versus SFC were observed in the 150 subgroup for both endpoints. IND/GLY provided similar improvements to SFC in the 300 cells/µl subgroup (Table E4). Lung Function IND/GLY significantly improved trough FEV1 and FVC compared with SFC at Week 52 in both the < 2% and 2% subgroups. IND/GLY also significantly improved E5

6 trough FEV1 and FVC compared with SFC at Week 52 in the < 150 and 150 cells/μl, and < 300 and 300 cells/μl subgroups (Table E5). Rescue Medication Use IND/GLY significantly reduced rescue medication use over 52 weeks compared with SFC in both the < 2% and 2% subgroups. IND/GLY also significantly reduced rescue medication use compared with SFC over 52 weeks in the < 150 and 150 cells/μl, and < 300 cells/μl subgroups. IND/GLY numerically reduced rescue medication use versus SFC in the 300 cells/μl subgroup (Table E6). Safety The incidence of adverse events and serious adverse events was similar between both treatment arms and between the <2% and 2% subgroups (Table E7). The number of adjudicated major adverse cardiac events and/or cardiovascular deaths was low, and was similar between both treatment arms (Table E8). Change in Blood Eosinophils Between Run-in Visit and Baseline by ICS Use In the total population, there was a small increase in mean (0.3%; 21 cells/μl) and median (0.1%; 0 cells/μl) blood eosinophils between screening and baseline (Table E9). E6

7 SUPPLEMENTARY FIGURES Figure E1. Timing of blood eosinophil measurements during FLAME Definition of abbreviations: b.i.d. = twice daily; Blood eos = blood eosinophils; GLY = glycopyrronium; IND = indacaterol; OL = open label; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. From The New England Journal of Medicine, Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier CF; FLAME Investigators. Indacaterol Glycopyrronium versus Salmeterol Fluticasone for COPD, 2016;9;374(23): Copyright E7

8 (notice year) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society." E8

9 Figure E2. Box plot of baseline blood eosinophils by A) percentage (%) and B) absolute cell count (cells/µl) A B Box-whisker plot with minimum, median, 25th and 75th percentiles and maximum is shown. The values represent baseline blood eosinophils, measured at randomization. Subjects with 600 cell/µl blood eosinophils were excluded before the run-in period at the run-in visit (Visit 101). Baseline is defined as the pre-dose value at randomization (scheduled Day 1, 45 to 20 min pre-dose) or, if missing, as last value measured prior to first dose. The ranges in B exceed 600 cells/µl as a patient with <600 cells/µl blood eosinophils at the run-in visit could theoretically have blood eosinophils 600 cell/µl at baseline, either due to natural variability or exposure to allergens. Definition of abbreviations: GLY = glycopyrronium; IND = indacaterol; SFC = salmeterol/fluticasone propionate combination. E9

10 SUPPLEMENTARY TABLES Table E1. Pre-specified and post-hoc statistical analyses Demographics Efficacy Endpoint Baseline demographic and clinical characteristics Rate of exacerbation (mild, moderate, severe) Statistical analysis Pre-specified in analysis plan Post-hoc analysis Summaries by blood eosinophil <2% and 2% Subgroup analysis by blood eosinophil <2% and 2% <3% and 3% <5% and 5% <150 cells/µl, 150 to <300 cells/µl, and 300 cells/µl Relationship with blood eosinophils as a continuous variable Rate of moderate/severe exacerbation Subgroup analysis by blood eosinophil <2% and 2% <3% and 3% <5% and 5% <150 cells/µl, 150 to <300 cells/µl, and 300 cells/µl Time to first exacerbation (mild, moderate, severe) Subgroup analysis by blood eosinophil <2% and 2% <3% and 3% <5% and 5% <150 cells/µl, 150 to <300 cells/µl, and 300 cells/µl E10

11 Time to first moderate/severe exacerbation SGRQ-C Change from baseline Proportion with 4- unit improvement Trough FEV 1 FVC Daily mean number of puffs or rescue medication Subgroup analysis by blood eosinophil <2% and 2% <3% and 3% <5% and 5% <150 cells/µl, 150 to <300 cells/µl, and 300 cells/µl Subgroup analysis by blood eosinophil <2% and 2% <150 cells/µl and 150 cells/μl <300 cells/µl and 300 cells/µl Subgroup analysis by blood eosinophil <2% and 2% <150 cells/µl and 150 cells/μl <300 cells/µl and 300 cells/µl Subgroup analysis by blood eosinophil <2% and 2% <150 cells/µl and 150 cells/μl <300 cells/µl and 300 cells/µl Safety Adverse event incidences MACE and/or CV deaths Subgroup analysis by blood eosinophil <2% and 2% Blood eosinophils Change between baseline and Weeks 26 and 52 Change between run-in and baseline visits * *Summary statistics (mean, median, etc.) for the change from baseline were pre-specified in the statistical analysis plan. The analysis using the mixed model for repeated measures was post-hoc. Definition of abbreviations: CV = cardiovascular; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; MACE = Major Adverse Cardiovascular Event; SGRQ-C = St George s Respiratory Questionnaire C E11

12 Table E2. Mean and median blood eosinophils at baseline Blood Eosinophils at Baseline IND/GLY 110/50 μg q.d. (n = 1,678) SFC 50/500 μg b.i.d. (n = 1,680) Percentage (%) Mean Q Median Q Absolute cell count (cells/μl) Mean cells/μl Q Median Q Analysis of the safety set (all patients who received at least one dose of study drug). Definition of abbreviations: b.i.d. = twice daily; GLY = glycopyrronium; IND = indacaterol; Q = quartile; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. E12

13 Table E3. Proportion of patients in blood eosinophil subgroups at baseline Proportion of Patients in Blood Eosinophil Subgroups at Baseline, n (%) IND/GLY SFC Blood Eosinophils 110/50 μg q.d. 50/500 μg b.i.d. Total at Baseline (n = 1,680) (n = 1,682) (N = 3,362) < 2% 629 (37.4) 672 (40.0) 1301 (38.7) 2% 1043 (62.1) 1005 (59.8) 2048 (60.9) < 3% 1056 (62.9) 1053 (62.6) 2109 (62.7) 3% 616 (36.7) 624 (37.1) 1240 (36.9) < 5% 1466 (87.3) 1463 (87.0) 2929 (87.1) 5% 206 (12.3) 214 (12.7) 420 (12.5) < 150 cells/μl 634 (37.7) 664 (39.5) 1298 (38.6) 150 to < 300 cells/μl 663 (39.5) 640 (38.0) 1303 (38.8) 300 cells/μl 375 (22.3) 373 (22.2) 748 (22.2) Definition of abbreviations: b.i.d. = twice daily; GLY = glycopyrronium; IND = indacaterol; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. E13

14 Table E4. Change in mean SGRQ-C total score from baseline to Week 52 and the proportion of patients with a 4-unit improvement in SGRQ- C total score from baseline to Week 52 by blood eosinophil subgroup Change in Mean SGRQ-C Total Score from Baseline to Week 52 Proportion of Patients with 4-unit Improvement in SGRQ-C Total Score from Baseline to Week 52 Blood Eosinophil IND/GLY SFC LSM Treatment IND/GLY SFC Subgroup 110/50 μg q.d. 50/500 μg b.i.d. Difference P value 110/50 μg q.d. 50/500 μg b.i.d. OR P value < 2% 3.4 (n = 604) 1.0 (n = 635) 2.4 < % (n = 604) 41.4% (n = 635) % 2.9 (n = 993) 2.4 (n = 954) % (n = 993) 45.2% (n = 954) < 150 cells/μl 3.3 (n = 610) 1.2 (n = 629) % (n = 610) 41.7% (n = 629) cells/μl 2.9 (n = 987) 2.3 (n = 960) % (n = 987) 45.0% (n = 960) E14

15 < 300 cells/μl 3.1 (n = 1,251) 1.6 (n = 1,236) % (n = 1,251) 43.3% (n = 1,236) cells/μl 2.9 (n = 346) 2.6 (n = 353) % (n = 346) 45.3% (n = 353) Definition of abbreviations: b.i.d. = twice daily; GLY = glycopyrronium; IND = indacaterol; LSM = least squares mean; OR = odds ratio; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination; SGRQ-C = St George s Respiratory Questionnaire C. E15

16 Table E5. Change in pre-dose trough FEV 1 and FVC from baseline to Week 52 by blood eosinophil subgroup Change in Pre-dose Trough FEV 1 from Baseline to Week 52 (ml) Change in Pre-dose Trough FVC from Baseline to Week 52 (ml) Blood LSM Eosinophil IND/GLY SFC LSM Treatment IND/GLY SFC Treatment Subgroup 110/50 μg q.d. 50/500 μg b.i.d. Difference P value 110/50 μg q.d. 50/500 μg b.i.d. Difference P value < 2% 4 (n = 601) 68 (n = 636) 72 < (n = 601) 156 (n = 636) 151 < % 21 (n = 991) 35 (n = 955) 56 < (n = 991) 127 (n = 955) 165 < < 150 cells/μl 4 (n = 607) 64 (n = 631) 68 < (n = 607) 154 (n = 631) 159 < cells/μl 21 (n = 985) 37 (n = 960) 59 < (n = 985) 128 (n = 960) 161 < E16

17 < 300 cells/μl 7 (n = 1,246) 60 (n = 1,237) 67 < (n = 1,246) 149 (n = 1,237) 163 < cells/μl 41 (n = 346) 8 (n = 354) (n = 346) 103 (n = 354) 152 < Definition of abbreviations: b.i.d. = twice daily; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GLY = glycopyrronium; IND = indacaterol; LSM = least squares mean; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. E17

18 Table E6. Change in mean daily numbers of puffs of rescue medication from baseline to Week 52 by blood eosinophil subgroup Change in Mean Daily Numbers of Puffs of Rescue Medication from Baseline to Week 52 (Puffs/Day) LSM Blood Eosinophil IND/GLY SFC Treatment Subgroup 110/50 μg q.d. 50/500 μg b.i.d. Difference P value < 2% (n = 608) (n = 648) % 0.99 (n = 996) 0.78 (n = 972) < 150 cells/μl 1.04 (n = 612) 0.70 (n = 643) cells/μl 0.98 (n = 992) 0.80 (n = 977) < 300 cells/μl 0.99 (n = 1,254) 0.73 (n = 1,257) 0.26 < cells/μl 1.05 (n = 350) 0.85 (n = 363) Definition of abbreviations: b.i.d. = twice daily; GLY = glycopyrronium; IND = indacaterol; LSM = least squares mean; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. E18

19 TABLE E7. Adverse and serious adverse events by <2% and 2% blood eosinophils <2% Blood Eosinophils at Baseline 2% Blood Eosinophils at Baseline IND/GLY SFC IND/GLY SFC 110/50 μg q.d. 50/500 μg b.i.d. 110/50 μg q.d. 50/500 μg b.i.d. Variable, n (%) (n = 629) (n = 672) (n = 1,044) (n = 1,004) Patients with at least one AE 535 (85.1) 593 (88.2) 919 (88.0) 902 (89.8) Adverse events in 3% in any treatment group Chronic obstructive pulmonary disease 478 (76.0) 546 (81.3) 817 (78.3) 825 (82.2) Nasopharyngitis 78 (12.4) 64 (9.5) 119 (11.4) 131 (13.0) Viral upper respiratory tract infection 49 (7.8) 51 (7.6) 83 (8.0) 87 (8.7) Upper respiratory tract infection bacterial 46 (7.3) 67 (10.0) 79 (7.6) 101 (10.1) Lower respiratory tract infection 29 (4.6) 44 (6.5) 53 (5.1) 54 (5.4) Pneumonia 26 (4.1) 37 (5.5) 27 (2.6) 43 (4.3) Upper respiratory tract infection 22 (3.5) 33 (4.9) 59 (5.7) 50 (5.0) E19

20 Hypertension 19 (3.0) 15 (2.2) 27 (2.6) 27 (2.7) Cough 17 (2.7) 27 (4.0) 33 (3.2) 24 (2.4) Influenza 15 (2.4) 23 (3.4) 20 (1.9) 33 (3.3) Oral candidiasis 10 (1.6) 30 (4.5) 10 (1.0) 41 (4.1) Dyspnea 9 (1.4) 21 (3.1) 39 (3.7) 30 (3.0) Bronchitis 9 (1.4) 13 (1.9) 20 (1.9) 31 (3.1) Serious AEs or AE discontinuations Death 6 (1.0) 14 (2.1) 17 (1.6) 9 (0.9) SAE(s) 113 (18.0) 136 (20.2) 194 (18.6) 196 (19.5) Discontinuation due to AE(s) 36 (5.7) 65 (9.7) 89 (8.5) 76 (7.6) Discontinuation due to SAE(s) 24 (3.8) 40 (6.0) 60 (5.7) 45 (4.5) Discontinuation due to non-sae(s) 15 (2.4) 33 (4.9) 34 (3.3) 36 (3.6) AEs requiring dose adjustment AEs requiring dose interruption 19 (3.0) 30 (4.5) 29 (2.8) 35 (3.5) AEs requiring additional therapy 397 (63.1) 451 (67.1) 681 (65.2) 705 (70.2) E20

21 The data are based on two different sources, adverse event ecrf and COPD exacerbation episode ecrf. A patient with multiple AEs is counted only once in the "at least one AE" row. A patient with multiple AEs with the same preferred term is counted only once for that preferred term. All adverse events starting on or after the time of first administration of double-blind drug but not later than 7 days (30 days in case of an SAE) after the last administration are included. Definition of abbreviations: AE = adverse event; b.i.d. = twice daily; COPD = chronic obstructive pulmonary disease; ecrf = COPD exacerbation electronic case report form; GLY = glycopyrronium; IND = indacaterol; q.d. = once daily; SAE = serious adverse event; SFC = salmeterol/fluticasone propionate combination. E21

22 Table E8. Number of adjudicated MACE and/or CV deaths <2% Blood Eosinophils at Baseline 2% Blood Eosinophils at Baseline MACE and/or IND/GLY SFC IND/GLY SFC Cardiovascular Death, 110/50 μg q.d. 50/500 μg b.i.d. 110/50 μg q.d. 50/500 μg b.i.d. n (%) (n = 629) (n = 672) (n = 1,044) (n = 1,004) MACE and/or cardiovascular death 9 (1.43) 8 (1.19) 22 (2.11) 22 (2.19) MACE 8 (1.27) 2 (0.30) 16 (1.53) 19 (1.89) Non-fatal myocardial infarction Non-fatal unstable angina 3 (0.48) 1 (0.15) 8 (0.77) 4 (0.40) Non-fatal stroke 2 (0.32) 1 (0.15) 4 (0.38) 7 (0.70) Heart failure requiring hospitalization 1 (0.16) 0 3 (0.29) 4 (0.40) Coronary revascularization 3 (0.48) 1 (0.15) 6 (0.57) 7 (0.70) (CABG or PCI) Cardiovascular death 1 (0.16) 6 (0.89) 7 (0.67) 4 (0.40) Classification was determined by an independent adjudication committee. All deaths were adjudicated. All MACE events and deaths on or after the time of first administration of double-blind drug but not later than 30 days after the last administration are included. Definition of abbreviations: b.i.d. = twice daily; CABG = coronary artery bypass graft; CV = cardiovascular; GLY = glycopyrronium; IND = indacaterol; MACE = Major Adverse Cardiovascular E22

23 Event; PCI = percutaneous coronary intervention; q.d. = once daily; SFC = salmeterol/fluticasone propionate combination. E23

24 Table E9. Change in blood eosinophils between run-in visit and baseline by ICS use ICS Use (n = 1,863) No ICS Use (n = 1,437) Total (n = 3,300) Run-in Visit Baseline Change Run-in Visit Baseline Change Run-in Visit Baseline Change Mean eosinophils, % (SD) 2.6 (1.64) 2.9 (2.12) 0.3 (1.77) 2.6 (1.70) 2.8 (2.02) 0.2 (1.63) 2.6 (1.66) 2.9 (2.08) 0.3 (1.71) Median ICS Use (n = 1,862) No ICS Use (n = 1,437) Total (n = 3,299) Run-in Visit Baseline Change Run-in Visit Baseline Change Run-in Visit Baseline Change Mean eosinophils, cells/μl (SD) 199 (122) 223 (176) 24 (148) 195 (124) 213 (159) 18 (130) 197 (123) 219 (169) 21 (140) Median Definition of abbreviations: b.i.d. = twice daily; GLY = glycopyrronium; ICS = inhaled corticosteroid; IND = indacaterol; q.d. = once daily; SD = standard deviation; SFC = salmeterol/fluticasone propionate combination. E24

25 REFERENCES 1. Jones PW. St. George's Respiratory Questionnaire: MCID. COPD 2005;2: Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier C. Indacaterol-glycopyrronium versus salmeterolfluticasone for COPD. N Engl J Med 2016;374: E25