Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of fluticasone furoate vilanterol for COPD in clinical practice. N Engl J Med 216;375: DOI: 1.156/NEJMoa16833 (PDF updated October 6, 216.)

2 Supplementary appendix for Effectiveness of Fluticasone Furoate/Vilanterol in COPD in clinical practice Jørgen Vestbo, 1 David Leather, 2 Nawar Diar Bakerly, 3 John New, 3,4 J. Martin Gibson, 3-5 Sheila McCorkindale, 6,7 Susan Collier, 8 Jodie Crawford, 8 Lucy Frith, 8 Catherine Harvey, 9 Henrik Svedsater, 8 Ashley Woodcock, 1 on behalf of the Salford Lung Study Investigators* Contents: 1. List of investigators 2. Expanded Statistical Methods Section 3. CONSORT diagram 4. Expanded Results Tables 5. Expanded Safety Results Section 6. References 1

3 1. List of investigators Dr J Amin, Dr M Austin, Dr M Sharma, Dr J Borg-Constanzi, Dr N Browne, Dr K Buch, Dr P Budden, Dr A Chaudry, Dr L Cheema, Dr N Chennupati, Dr S Coulson, Dr L Cribbin, Dr D Dillon, Dr B Farooq, Dr N Finnegan, Dr A Fletcher, Dr L Addlestone, Dr B Hope, Dr M Khan, Dr J White, Dr J Behardien, Dr C Mafunga, Dr C Malcolmson, Dr D McCarthy, Dr H Milligan, Dr V Raj, Dr R Salim, Dr H Singh, Dr M Sultan, Dr R Seaton, Dr J Tankel, Dr R Khan, Dr N Tyrell, Dr U Umeadi, Dr S Wright, Dr C Gibbons, Dr C Brunt, Dr L Gill, Dr R Archer, Dr R Howard, Dr G Breen, Dr P Stratford-Smith, Dr R Wilson, Dr H Wilkinson, Dr A El-Kafrawy, Dr P Patel, Dr S Iles, Dr S Frier, Dr A Bakhat, Dr N Smith, Dr D Herron, Dr D Adams-Strump, Dr N Acherakar, Dr D Shah, Dr N Kanumilli, Dr A Afshar, Dr M Stamp, Dr C Westwood, Dr A Wright, Dr K Richardson, Dr P Jackson, Dr M Jarvis, Dr P Fink, Dr N Lord, Dr C Hughes, Dr A Ahuja, Dr V Joshi, Dr D Larah, Dr S Levenson, Dr C Malcomson, Dr R Parveen, Dr A Rahman, Dr N Kassamr, and Dr S Kwok. 2. Expanded Statistical Methods Section Sample size calculations were based on the primary endpoint (mean annual rate of moderate and severe exacerbations). A total of 2,238 patients were required for the study to have 8% power to detect a relative reduction of 12% in the mean annual moderate or severe exacerbation rate, assuming a mean exacerbation rate of 2.3 for the usual care group, based on retrospective analysis of Salford data (1) collected from the linked NWEH database. Calculations were based on a negative binomial regression with a dispersion rate of.7 and use a two-sided 5% significance level. The dispersion rate was based on three previous efficacy trials (2-4). The primary analysis was based on a two-sided hypothesis testing approach. The analysis was performed using a generalized linear model, assuming the Negative Binomial distribution adjusting for randomized treatment, baseline COPD maintenance therapy per randomization stratification, 2

4 number of moderate-severe COPD exacerbations in the year prior to randomization (<2, 2), smoking status at baseline and logarithm of time on treatment as an offset variable. For the incidence of SAEs of pneumonia, the non-inferiority margin for the ratio of the proportions of patients with 1SAE of pneumonia on FF/VI versus usual care was set at 2. Non-inferiority would be demonstrated if the upper limit of the two-sided 95% confidence interval for the incidence ratio FF/VI / usual care was less than 2. The incidence ratio was calculated as the percentage of patients who had 1SAE of pneumonia in the FF/VI group divided by the percentage of patients who had 1SAE of pneumonia in the Usual Care group. The two-sided confidence interval of the incidence ratio was calculated assuming that the natural logarithm of the incidence ratio follows a normal distribution. 3

5 3. CONSORT diagram. 4

6 4. Expanded Results Tables Table s1 Baseline characteristics of study participants Entire study PEA Entire study population population N=2,799 population N=2,269 Usual care N=1,43 FF/VI N=1,396 Age (year) 67±1 67±1 67±1 67±1 Female Sex 1369 (49%) 1122 (49%) 671 (48%) 698 (5%) BMI n kg/m (13%) 241 (13%) 15 (13%) 144 (13%) >21 kg/m (87%) 1567 (87%) 972 (87%) 965 (87%) mean (kg/m 2 ) 28±6 28±6 28±6 28±7 Current Smokers 1289 (46%) 146 (46%) 666 (47%) 623 (45%) Duration of COPD 5 years 148 (53%) 1215 (54%) 748 (53%) 732 (52%) Post-bronchodilator FEV1 (L) 1.62± ± ± ±.64 COPD Severity Category* n GOLD 268 (12%) 25 (12%) 136 (12%) 132 (12%) GOLD 1 or (59%) 129 (58%) 641 (58%) 652 (59%) 5

7 Entire study PEA Entire study population population N=2,799 population N=2,269 Usual care N=1,43 FF/VI N=1,396 GOLD 3 or (29%) 547 (31%) 324 (29%) 314 (29%) CAT Score n <1 286 (1%) 21 (9%) 135 (1%) 151 (11%) (9%) 265 (91%) 1267 (9%) 1243 (89%) Pre-randomization COPD therapy Long-acting bronchodilators, alone or in combination 391 (14%) 276 (12%) 196 (14%) 195 (14%) Inhaled corticosteroids, alone or in combination with a long-acting bronchodilator 958 (34%) 762 (34%) 48 (34%) 478 (34%) Inhaled corticosteroids in combination with two long-acting bronchodilators 145 (52%) 1231 (54%) 727 (52%) 723 (52%) Mean number of exacerbations during the 12 months prior to randomisation 2.1± ± ± ±1.9 Co-morbidities Any 2145 (77%) 1758 (77%) 176 (77%) 169 (77%) 6

8 Entire study PEA Entire study population population N=2,799 population N=2,269 Usual care N=1,43 FF/VI N=1,396 Cardiac 72 (26%) 588 (26%) 367 (26%) 353 (25%) Vascular 1363 (49%) 195 (48%) 675 (48%) 688 (49%) Asthma 69 (22%) 512 (23%) 293 (21%) 316 (23%) Diabetes 438 (16%) 353 (16%) 28 (15%) 23 (16%) Mean±standard deviation or n (%) * based on available forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) PEA Primary effectiveness analysis; FF/VI Fluticasone furoate vilanterol combination; BMI Body mass index; CAT COPD assessment test 7

9 5. Expanded Safety Section A total of 44 patients (29%) in the FF/VI group experienced an on-treatment SAEs compared with a similar incidence (383 [27%]) in the usual care group. There was no notable difference between treatment groups for any AESI (Table 2). There were 94 patients (7%) in the FF/VI group who had 1SAE listed as pneumonia vs. 83 patients (6%) in the usual care group, incidence rate ratio 1.1 (95% CI.9 to 1.5), thus showing non-inferiority. There was a trend towards an increased risk of hospital admission with pneumonia in the strata receiving a treatment regimen without an ICS at randomization, mean annual rate 3.1 (95% CI.97 to 9.33, treatment by baseline maintenance therapy interaction p=.96 for the analysis across the three strata). Thirteen patients (<1%) per group had an event of pneumonia (AESI group) with a fatal outcome. In total, 45 patients in the FF/VI group and 3 patients in the usual care group died during the study; reported causes of fatal events are listed in Table s1. No subgroups with an increased risk of a SAE of pneumonia in the FF/VI group could be identified. 8

10 Table s1 Fatal serious adverse events * Fatal events by SOC (System, Organ, Class) Usual care N=1,43 FF/VI N=1,396 All-cause mortality 3 (2%) 45 (3%) Cause-specific mortality Infections and infestations 18 (1%) 15 (1%) Cardiac disorders Acute myocardial infarction Myocardial ischemia Atrial fibrillation Congestive heart failure Cardiac arrest Arrhythmia Arteriosclerosis coronary artery Cardiac failure Cardiac failure acute Cardiomyopathy Left ventricular dysfunction Left ventricular failure Myocardial infarction 7 (<1%) 2 (<1%) 12 (<1%) 2 (<1%) 2 (<1%) 2 (<1%) 2 (<1%) 9

11 Fatal events by SOC (System, Organ, Class) Usual care N=1,43 FF/VI N=1,396 Respiratory, thoracic and mediastinal disorders 8 (<1%) 9 (<1%) Neoplasms benign, malignant and unspecified (including cysts and polyps) * Malignant lung neoplasm Metastases to liver Metastatic neoplasm Bladder cancer Recurrent chronic lymphocytic leukemia Glioblastoma multiforme Hepatic cancer metastatic Lung adenocarcinoma Lung cancer metastatic Lung squamous cell carcinoma Stage IV Squamous cell carcinoma of lung Ureteric cancer 3 (<1%) 13 (<1%) 5 (<1%) 2 (<1%) Nervous system disorders 3 (<1%) 4 (<1%) Gastrointestinal disorders 3 (<1%) 2 (<1%) Renal and urinary disorders 2 (<1%) 3 (<1%) Vascular disorders 3 (<1%) Hepatobiliary disorders 2 (<1%) 1

12 Fatal events by SOC (System, Organ, Class) Usual care N=1,43 FF/VI N=1,396 Injury, poisoning and procedural complications 2 (<1%) Metabolism and nutrition disorders Blood and lymphatic system disorders General disorders and administration site conditions Immune system disorders n (%) * Patients can have more than one fatal event listed FF/VI Fluticasone furoate vilanterol combination 11

13 6. References: 1. Elkhenini HF, Davis, KJ, Stein ND, New JP, Delderfield MR, Gibson M, Vestbo J, Woodcock A, Bakerly ND. Using an electronic medical record (EMR) to conduct clinical trials: Salford Lung Study feasibility. BMC Med Inform Dec Making 215; 15: 8; DOI: /s z. 2. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 23; 361: Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J, on behalf of the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 27; 356: Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (25/5 microg) or salmeterol (5 microg) on COPD exacerbations. Respir Med 28; 12: