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Download A comparison of the efficacy and safety of once-daily fluticasone... twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD
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A comparison of the efficacy and safety of once-daily fluticasone furoate/vilanterol with twice-daily fluticasone propionate/salmeterol in moderate to very severe COPD Agusti et al Supplementary Information Minimal Important Difference (MID) for Weighted Mean FEV1 This study was designed to provide 90% power to detect a 60 mL difference in wmFEV1 at Week 12 between two active treatments. Although there are no published literature or consensus statements on what constitutes the Minimal Clinically Important Difference (MCID) for wmFEV1 for patients with airflow obstruction, there is some published literature that defines the MCID for trough FEV1 in patients with COPD at 100 mL.1 To estimate a non-inferiority limit and/or MCID, we examined the dose-ranging data obtained with vilanterol (VI) in patients with COPD.2 The difference in wmFEV1 between the minimally effective dose of 3mcg (minimum dose demonstrating >= 100mL mean difference from placebo in trough FEV1) and the dose of 25mcg (plateau of the doseresponse curve) was 53mL. From this method, we estimated a non-inferiority limit in 24-h wmFEV1 between two active treatments as 50 mL. This non-inferiority estimate of 50 mL is further supported by analysis of the data from one of the pivotal studies for fluticasone propionate/salmeterol (FP/SAL),3 in which the difference in trough FEV1 for the comparison of SAL with FP/SAL 500/50 mcg was statistically significant (67 mL, P < 0.05) and the difference in 12-h wm was 50 mL (data on 1 file). Similar differences in trough FEV1 were observed when comparing SAL with FP/SAL 250/50 mcg (69 mL, P = 0.012) in the other pivotal study4; however, 12-h serial FEV1 was not measured in this study. Food and Drug Administration guidance states that a non-inferiority margin should be specified as the proportion of the whole effect of the active control compared with placebo that should be preserved by the new treatment. This is determined as the lower 95% confidence interval (CI) for the difference between the active control and placebo in previous trials. Based on Mahler et al, a non-inferiority limit of 50 mL would preserve 40% of the FP/SAL effect (124mL) and the whole effect of the contribution of SAL to the FP/SAL combination (lower 95% CI for this comparison = 47 mL) . Thus, based on the analysis of the data outlined here, and in the absence of published data on either a non-inferiority limit and/or an MCID for 24-h wmFEV1, we concluded that 50 mL appears as a reasonable estimate for a non-inferiority limit/MCID, and that larger values (eg, 60 mL) are reasonable values on which to power for superiority. 2 Supplementary Table – Medications excluded during run-in and active treatment periods Medication No use within the following time intervals prior to Screening (Visit 1) and thereafter at any time during the study Depot corticosteroids 12 weeks Systemic, oral, parenteral (intra-articular) 6 weeks corticosteroids Antibiotics (for lower respiratory tract 6 weeks infection) Cytochrome P450 3A4 strong inhibitors including but not limited to antiretrovirals (protease inhibitors) (e.g., indinavir, 6 weeks nelfinavir, ritonavir, saquinavir, atazanavir); Grapefruit is allowed up to Visit 1, then limited to imidazole and triazole anti-fungals (e.g., no more than one glass of grapefruit juice (250 ketaconazole, itraconazole, voriconazole); mL/8 ounces) or one grapefruit per day clarithromycin, telithromycin, troleandomycin , mibefradil, cyclosporin , nefazodone. Inhaled corticosteroids 1 week Inhaled ICS/LABA combination products 1 week Long-acting anticholinergics 1 week Oral PDE-4 inhibitors 1 week Theophylline preparations 48 hours Oral leukotriene inhibitors (zafirlukast, 48 hours montelukast, zileuton) Inhaled LABA 48 hours Oral beta-agonists Long-acting 48 hours Short-acting 12 hours Inhaled sodium cromoglycate or 24 hours nedocromil sodium Ipratropium/salbutamol combination 4 hours product Inhaled short-acting beta2-agonists1 4 hours 4 hours (stable dose of ipratropium alone is allowed Short-acting anti-cholinergics during the study but must be withheld 4 hours prior to each study visit) Prior use of study medication/ any other 30 days or 5 half lives, whichever is longer investigational drug 3 SUPPLEMENTAL REFERENCES 1. Donohue JF. Minimal clinically important differences in COPD lung function. COPD. 2005;2(1):111-124. 2. Hanania NA, Feldman G, Zachgo W, et al. The efficacy and safety of the novel longacting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial. Chest. 2012;142(1):119-127. 3. Mahler DA, Wire P, Horstman D, Chang CN, Yates J, Fischer T, Shah T. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166(8):1084-1091. 4. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124(3):834-843. 4