Comparative efficacy of aclidinium bromide 400 µg BID versus tiotropium 18 µg and 5 µg QD as maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD): a network meta-analysis Andreas Karabis,1 Leandro Lindner,2 Michelle Mocarski,3 Walter Bouwmeester,1 Caglar Karakurum,2 Mercedes Prior,2 Gert Bergman1 1MAPI Consultancy, Houten, The Netherlands; 2Almirall S.A., Barcelona, Spain; 3Forest Research Institute, Jersey City, NJ, USA
Introduction Table 1. Reported data in individual studies included in the network meta-analysis (difference in change from baseline and standard error)
C Chronic obstructive pulmonary disease (COPD) is characterized by the progressive AB400 TIO5 TIO18
development of airway obstruction, which manifests as an accelerated decline in FEV1 SGRQ TDI FEV1 SGRQ FEV1 SGRQ TDI lung function, with symptoms such as breathlessness on physical exertion, trough (L) total score focal score trough (L) total score trough (L) total score focal score deteriorating health status and exacerbations. 12 weeks
25 C Treatment aims to prevent and control symptoms, reduce exacerbations and Voshaar 0.12 (0.02) improve health status. Covelli14 0.18 (0.04) Casaburi11 0.15 (0.01) C Current GOLD and NICE guidelines1,2 recommend the use of long-acting Niewoehener18 0.10 (0.01) bronchodilators because they are more effective at producing maintained symptom Moita17 0.10 (0.03) relief than short-acting bronchodilators. Chan13 0.10 (0.02) C Aclidinium bromide is a new long-acting muscarinic antagonist (LAMA) indicated Verkindre21 0.11 (0.04) -6.50 (2.80) 1.28 (0.89) in Europe as a maintenance bronchodilator treatment to relieve symptoms in adult Casaburi12 0.11 (0.02) 0.95 (0.18) patients with COPD. Donohue16 0.14 (0.02) -1.10 (0.85) 0.72 (0.22) C Aclidinium bromide has a clean safety profile3-5 and is administered by inhalation Tonnel20 (TIPHON) -3.51 (1.30) through a user-friendly multidose dry powder inhaler device.6 Kerwin3 0.12 (0.02) -2.50 (1.10) 1.00 (0.31) C The availability of this new medicine poses the question of what its long-term Jones4 (ATTAIN) 0.10 (0.02) -3.97 (0.96) 0.88 (0.27) relative efficacy would be in comparison to other LAMA treatment options, such as LAS 38 CSR5 (ACCORD COPD II) 0.07 (0.02) -1.10 (1.38) 1.00 (0.36) tiotropium. However, only short-term, randomized, controlled trials (RCTs) 24 weeks 7,8 comparing Aclidinium bromide to tiotropium are available and there is a lack of Bateman24 0.10 (0.01) -2.20 (0.46) long-term (>12 weeks) RCTs. Bateman23 0.12 (0.01) c Network meta-analysis (NMA) is a valuable method to synthesize all relevant Niewoehener18 0.10 (0.01) evidence and allows for comparisons between competing interventions in the Tashkin19 (UPLIFT) 0.09 (0.01) -2.86 (0.40) absence of head-to-head evidence. Casaburi12 0.12 (0.02) -3.08 (0.93) 0.84 (0.17) Brusasco10 0.12 (0.02) -2.70 (0.99) 1.10 (0.30) Donohue15 0.14 (0.02) -2.71 (1.20) 1.02 (0.40) Objective Donohue16 0.14 (0.01) -1.00 (0.65) 0.87 (0.23) Tonnel20 (TIPHON) -3.51 (1.30) C To estimate the long-term relative efficacy of aclidinium bromide 400 µg twice daily Vogelmeier22 -2.09 (1.20) (AB400; equivalent to 322 µg aclidinium delivered dose) to tiotropium bromide Jones4 (ATTAIN) 0.13 (0.02) -4.62 (1.16) 1.00 (0.29) 18 µg (TIO18) and 5 µg (TIO5) once daily in patients with COPD. AB400, aclidinium bromide 400 µg twice daily; CSR, clinical study report; FEV1, forced expiratory volume in 1 second; SGRQ, St George’s Respiratory Questionnaire; TDI, Transitional Dyspnoea Index; TIO5, tiotropium bromide 5 µg once daily; TIO18, tiotropium bromide 18 µg once daily
Identification and selection of studies Figure 3. Relative treatment effect of aclidinium bromide 400 µg twice daily (AB400) versus tiotropium bromide 18 µg once daily (TIO18) and 5 µg once daily (TIO5) at 12 and 24 weeks C A systematic literature review was conducted searching Medline®, EMBASE™, MEDLINE® In-Process and the Cochrane Library (clinical trials) for the period of FEV trough (litres) January 1989 to July 2012 (Figure 1). The following inclusion criteria, 1 Difference in change from baseline 12 weeks 24 weeks Difference in change from baseline characterized by population, intervention, outcomes and study design, were used
to select the articles of interest: Estimate 95% Crl Estimate 95% Crl c Population of interest: adults with moderate to severe COPD, as defined by 0.11 ( 0.07, 0.16) AB400 vs placebo 0.13 ( 0.06, 0.19) GOLD guidelines -0.01 (-0.06, 0.04) AB400 vs TIO18 0.01 (-0.06, 0.08) c Interventions: AB400, TIO18 and TIO5 -0.01 (-0.09, 0.07) AB400 vs TIO5 0.02 (-0.06, 0.09) c Comparators: studies that compare any of the interventions above to each other -0.2 -0.1 0.0 0.1 0.2 -0.2 -0.1 0.0 0.10.2 or to placebo Favours comparator Favours AB400 Favours comparator Favours AB400 c Outcomes: trough forced expiratory volume in 1 second (FEV1); St George’s Respiratory Questionnaire (SGRQ) total score; Transitional Dyspnoea Index (TDI) SGRQ total score focal score; all measured at 12 and 24 weeks Estimate 95% Crl Estimate 95% Crl c Study design: RCTs of at least 12 weeks’ duration. -3.27 (-7.00, 0.49) AB400 vs placebo -4.63 (-6.85, -2.43) -0.63 (-5.07, 4.99) AB400 vs TIO18 -2.13 (-4.42, 0.14) C For the studies identified that met the inclusion criteria, the difference in change AB400 vs TIO5 -2.43 (-4.83, -0.05) from baseline (CFB) for the reported outcomes was extracted where reported. If the difference was not reported, it was calculated by subtracting the CFB of -8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0 6.0 8.0 -8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0 6.0 8.0 placebo from the CFB of the active treatment arm (Table 1). Favours AB400 Favours comparator Favours AB400 Favours comparator
TDI focal score Figure 1. Flow diagram of study selection Estimate 95% Crl Estimate 95% Crl 0.93 ( 0.53,1.33) AB400 vs placebo 1.00 ( 0.43, 1.57) 0.06 (-0.42, 0.55) AB400 vs TIO18 0.10 (-0.52, 0.71) Search strategy MEDLINE®, EMBASE™, MEDLINE® In-Process, Cochrane 965 abstracts retrieved -2.0 -1.0 0.0 1.0 2.0 -2.0 -1.0 0.0 1.0 2.0 Favours comparator Favours AB400 Favours comparator Favours AB400 Exclusion of duplicates 212 abstracts CrI, credible interval; SGRQ, St George's Respiratory Questionnaire; TDI, Transitional Dyspnoea Index
Title / abstract screening 753 abstracts Results Conclusion Excluded: 664 abstracts (PICOs, duplicates, conference abstracts <2009) C The systematic literature search identified 965 abstracts, of which 19 unique placebo-controlled RCTs3-5,10-25 were eligible for inclusion (38 publications and This NMA suggests that maintenance treatment with AB400 (322 µg Full text screening 1 clinical study report). aclidinium delivered dose, the licensed dose) results in similar 89 publications C These 19 studies enrolled 20,654 subjects with similar study design and patient improvements in lung function, health status and breathlessness 1 aclidinium bromide CSR Excluded: 52 characteristics across trials. compared with TIO18 and TIO5 in adult patients with moderate to (ACCORD COPD II) (PICOs, not available n=2, 1 ahead of print C If the necessary data was not reported in the text or the tables of the publication severe COPD. language n=5) Jones 2012 (ATTAIN)* but in graphs, the software Digitzelt v1.5 was used to extract them. If the standard error was not reported, it was estimated using other reported measures of 19 studies (38 publications + 1 CSR aclidinium bromide) uncertainty (e.g. confidence intervals). References C In line with the pivotal trials, AB400 was shown to be more efficacious than 1. http://www.goldcopd.org. 2011. *Full citation now available4 placebo on all evaluated endpoints with a higher than 95% probability of 2. http://www.lincolnshire.nhs.uk/en/Commissioning/pacef/Previous-PACE-Bulletins/. 2010. CSR, clinical study report; PICO, population intervention, comparison and outcome model 3. Kerwin EM et al. COPD 2012; 2: 90-101. AB400 being a better treatment. 4. Jones PW et al. Eur Respir J 2012; 40: 830-836. C Compared with TIO18, AB400 resulted in comparable improvements at 12 weeks 5. Almirall, data on file. 6. van der Palen J et al. European Respiratory Society Annual Congress, Vienna, Austria, in trough FEV1 (difference in CFB [95% credible interval] -0.01 L [-0.06, 0.04]), and demonstrated more favourable improvements in SGRQ total score 1-5 September 2012. 7. Fuhr R et al. Chest 2012; 141: 745-752. Statistical analysis (-0.63 [-5.07, 4.99]) and TDI focal score (0.06 [-0.42, 0.55]). 8. Almirall, data on file. C Similar, but numerically greater differences, were also seen for AB400 versus 9. Dias S et al. NICE 2011. C The results of the individual studies were analyzed simultaneously with a Bayesian NMA. TIO18 at 24 weeks in trough FEV (0.01 L [-0.06, 0.08]), SGRQ total score 10. Brusasco V et al. Thorax 2003; 58: 399-404. 1 11. Casaburi R et al. Chest 2000; 118: 1294-1302. C An NMA is an extension of a traditional meta-analysis and allows the relative efficacy (-2.13 [-4.42, 0.14]) and TDI focal score (0.10 [-0.52, 0.71]). 12. Casaburi R et al. Eur Respir J 2002; 19: 217-224. of a particular intervention to be obtained versus competing interventions through 13. Chan C et al. Can Respir J 2007; 14: 465-472. C AB400 demonstrated comparable efficacy with TIO5 in trough FEV1 (-0.007 L indirect comparisons in the absence of head-to-head comparisons (Figure 2). [-0.09, 0.07]) at 12 weeks and (0.002 L [-0.06, 0.09]) at 24 weeks. Regarding 14. Covelli H et al. Pharmacotherapy 2005; 25: 1708-1718. 15. Donohue J et al. Chest 2002; 122: 47-55. C A regression model with a normal likelihood distribution was used.9 the SGRQ total score at 24 weeks, AB400 is expected to be more efficacious 16. Donohue JF et al. Am J Respir Crit Care Med 2010; 182: 155-162. with a difference in CFB (-2.43 [-4.83, -0.05]). For SGRQ at 12 weeks and for TDI, C Both fixed and random effects models were evaluated and the selection was 17. Moita J et al. Pulm Pharmacol Ther 2008; 21: 146-151. no data are available for TIO5. based on goodness-of-fit estimates (deviance information criterion). 18. Niewoehner DE et al. Ann Intern Med 2005; 143: 317-326. c Scenario 1: The AClidinium in Chronic Obstructive Respiratory Disease (ACCORD) 19. Tashkin D et al. N Engl J Med 2008; 359: 1543-1554. C Statistical analysis was performed with WinBUGS software, version 1.4.1. 20. Tonnel AB et al. Int J Chron Obstruct Pulmon Dis 2008; 3: 301-310. COPD II trial5 was excluded from the base case analysis due to a chance 21. Verkindre C et al. Respiration 2006; 73: 420-427. C Outcomes of analysis were trough FEV , SGRQ total score and TDI focal score, 1 imbalance in patients’ baseline characteristics in favour of the placebo group. 22. Vogelmeier C et al. Respir Med 2008; 102: 1511-1520. all measured at 12 and 24 weeks. A scenario analysis including the ACCORD COPD II trial showed comparable 23. Bateman E et al. Int J Chron Obstruct Pulmon Dis 2010; 5: 197-208. 24. Bateman ED et al. Respir Med 2010;104: 1460-1472. improvements for AB400 in trough FEV1 (-0.02 L [-0.07, 0.02]), SGRQ total score ( 0.01 [-3.68, 4.92]) and TDI focal score (0.08 [-0.36, 0.52]), compared with TIO18 25. Voshaar T et al. Respir Med 2008; 102: 32-41. Figure 2. Network of studies 25 at 12 weeks. Regarding TIO5, only trough FEV1 was reported at 12 weeks. The difference in CFB of AB400 versus TIO5 for this outcome is (-0.02 L [-0.09, 0.06]). Acknowledgements These studies were supported by Almirall S.A., Barcelona, Spain and Forest Laboratories, Inc., c Scenario 2: Long-acting b -agonist (LABA) treatment was permitted as concomitant New York, USA. Editorial assistance, funded by Almirall S.A., was provided by Caroline Hewitt, PhD, 13 trials 3 trials 2 Tiotropium bromide Placebo Aclidinium bromide medication in six tiotropium studies.13,14,17-19,24 The information about concomitant at Complete Medical Communications. 18 µg QD 400 µg BID LABA treatment was missing in two studies.10,12 A scenario analysis excluding the six tiotropium studies allowing LABA treatment was performed. Based on NMA 3 trials results, AB400 is expected to be comparable to TIO5 and TIO18 for FEV1 at both Use your Smartphone to scan the QR code to obtain a link to a PDF of timepoints, but more efficacious than TIO18 at 24 weeks with respect to SGRQ this poster. You may have to download a QR reader app from your app store in order to use this code. Alternatively, you can download the poster at Tiotropium bromide score. Compared with TIO18 at 24 weeks, the difference in CFB for trough FEV was 5 µg QD 1 http://www.almirallrespiratory.com/publications (-0.003 L [-0.05, 0.04]) and for SGRQ total score was (-2.47 [-4.81, -0.13]). None of
BID, twice daily; QD, once daily the excluded studies reported TDI focal score, so there was no need to reassess TDI Poster presented at ISPOR 15th Annual European Congress, in Scenario 2. Berlin, Germany, 3–7 November 2012
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