{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:14:25Z","timestamp":1792005265674,"version":"4.4.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T00:00:00Z","timestamp":1533081600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol\/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol\/glycopyrronium (110\/50 \u03bcg once daily) or continuation of triple therapy (tiotropium [18 \u03bcg] once daily plus combination of salmeterol\/fluticasone propionate [50\/500 \u03bcg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV1. Moderate or severe exacerbations were predefined secondary endpoints.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>A total of 527 patients were randomized to indacaterol\/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of \u221226 ml (95% confidence interval, \u221253 to 1 ml) with confidence limits exceeding the noninferiority margin of \u221250 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with \u2265300 blood eosinophils\/\u03bcl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol\/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with \u2265300 blood eosinophils\/\u03bcl suggests that these patients are likely to benefit from triple therapy.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201803-0405oc","type":"journal-article","created":{"date-parts":[[2018,5,20]],"date-time":"2018-05-20T09:00:55Z","timestamp":1526806855000},"page":"329-339","source":"Crossref","is-referenced-by-count":207,"title":["Long-Term Triple Therapy De-escalation to Indacaterol\/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial"],"prefix":"10.1093","volume":"198","author":[{"given":"Kenneth R.","family":"Chapman","sequence":"first","affiliation":[{"name":"Asthma and Airway Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Hurst","sequence":"additional","affiliation":[{"name":"UCL Respiratory, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan-Marian","family":"Frent","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, University of Medicine and Pharmacy, Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Larbig","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Fogel","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadhg","family":"Guerin","sequence":"additional","affiliation":[{"name":"Novartis Ireland Limited, Dublin, Ireland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Banerji","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation, East Hanover, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Patalano","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Goyal","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Pfister","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kostikas","sequence":"additional","affiliation":[{"name":"Novartis Pharma AG, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadwiga A.","family":"Wedzicha","sequence":"additional","affiliation":[{"name":"Respiratory Clinical Science Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,8,1]]},"reference":[{"key":"2026032023232217500_bib1","author":"Global Initiative for Chronic Obstructive Lung Disease"},{"key":"2026032023232217500_bib2","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S2213-2600(17)30207-2","article-title":"Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort","volume":"5","author":"Han","year":"2017","journal-title":"Lancet Respir Med"},{"key":"2026032023232217500_bib3","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1056\/NEJMoa0909883","article-title":"Susceptibility to exacerbation in chronic obstructive pulmonary disease","volume":"363","author":"Hurst","year":"2010","journal-title":"N Engl J Med"},{"key":"2026032023232217500_bib4","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2147\/COPD.S122013","article-title":"Initiation of triple therapy maintenance treatment among patients with COPD in the US","volume":"12","author":"Simeone","year":"2016","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2026032023232217500_bib5","article-title":"Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical guideline (CG101)","author":"National Institute for Health and Care Excellence"},{"key":"2026032023232217500_bib6","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1164\/rccm.201204-0596PP","article-title":"Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary","volume":"187","author":"Vestbo","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib7","first-page":"10","article-title":"Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease","author":"Kew","year":"2014","journal-title":"Cochrane Database Syst Rev"},{"key":"2026032023232217500_bib8","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.00037-2017","article-title":"The risk of mycobacterial infections associated with inhaled corticosteroid use","volume":"50","author":"Brode","year":"2017","journal-title":"Eur Respir J"},{"key":"2026032023232217500_bib9","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.amjmed.2010.06.019","article-title":"Inhaled corticosteroids and the risks of diabetes onset and progression","volume":"123","author":"Suissa","year":"2010","journal-title":"Am J Med"},{"key":"2026032023232217500_bib10","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.chest.2017.07.002","article-title":"Long-term use of inhaled corticosteroids in COPD and the risk of fracture","volume":"153","author":"Gonzalez","year":"2018","journal-title":"Chest"},{"key":"2026032023232217500_bib11","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1056\/NEJMoa1407154","article-title":"Withdrawal of inhaled glucocorticoids and exacerbations of COPD","volume":"371","author":"Magnussen","year":"2014","journal-title":"N Engl J Med"},{"key":"2026032023232217500_bib12","doi-asserted-by":"crossref","first-page":"196","DOI":"10.7326\/0003-4819-106-2-196","article-title":"Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease","volume":"106","author":"Anthonisen","year":"1987","journal-title":"Ann Intern Med"},{"key":"2026032023232217500_bib13","first-page":"CD006829","article-title":"Combined corticosteroid and long-acting beta-agonist in one inhaler versus long-acting beta-agonists for chronic obstructive pulmonary disease","author":"Nannini","year":"2007","journal-title":"Cochrane Database Syst Rev"},{"key":"2026032023232217500_bib14","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1056\/NEJMoa1303342","article-title":"Tiotropium Respimat inhaler and the risk of death in COPD","volume":"369","author":"Wise","year":"2013","journal-title":"N Engl J Med"},{"key":"2026032023232217500_bib15","first-page":"CD002991","article-title":"Inhaled corticosteroids for stable chronic obstructive pulmonary disease","author":"Yang","year":"2012","journal-title":"Cochrane Database Syst Rev"},{"key":"2026032023232217500_bib16","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1136\/bmj.320.7245.1297","article-title":"Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial","volume":"320","author":"Burge","year":"2000","journal-title":"BMJ"},{"key":"2026032023232217500_bib17","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1056\/NEJMra1510063","article-title":"Challenges in the design and interpretation of noninferiority trials","volume":"377","author":"Mauri","year":"2017","journal-title":"N Engl J Med"},{"key":"2026032023232217500_bib18","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/1465-9921-8-93","article-title":"Withdrawal of inhaled corticosteroids in people with COPD in primary care: a randomised controlled trial","volume":"8","author":"Choudhury","year":"2007","journal-title":"Respir Res"},{"key":"2026032023232217500_bib19","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0954-6111(99)90001-X","article-title":"An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease","volume":"93","author":"Jarad","year":"1999","journal-title":"Respir Med"},{"key":"2026032023232217500_bib20","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1164\/rccm.200206-512OC","article-title":"Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study","volume":"166","author":"van der Valk","year":"2002","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib21","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1136\/thx.2004.034280","article-title":"Withdrawal of fluticasone propionate from combined salmeterol\/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial","volume":"60","author":"Wouters","year":"2005","journal-title":"Thorax"},{"key":"2026032023232217500_bib22","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1183\/09031936.00126814","article-title":"INSTEAD: a randomised switch trial of indacaterol versus salmeterol\/fluticasone in moderate COPD","volume":"44","author":"Rossi","year":"2014","journal-title":"Eur Respir J"},{"key":"2026032023232217500_bib23","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s12931-017-0622-x","article-title":"Efficacy and safety of direct switch to indacaterol\/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial","volume":"18","author":"Vogelmeier","year":"2017","journal-title":"Respir Res"},{"key":"2026032023232217500_bib24","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1183\/13993003.01644-2015","article-title":"Lung function changes over time following withdrawal of inhaled corticosteroids in patients with severe COPD","volume":"47","author":"Magnussen","year":"2016","journal-title":"Eur Respir J"},{"key":"2026032023232217500_bib25","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2147\/COPD.S119908","article-title":"Comparative efficacy of long-acting \u03b22-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis","volume":"12","author":"Donohue","year":"2017","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2026032023232217500_bib26","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.jaci.2012.12.1564","article-title":"Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease","volume":"131","author":"Barnes","year":"2013","journal-title":"J Allergy Clin Immunol"},{"key":"2026032023232217500_bib27","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/S2213-2600(16)00100-4","article-title":"Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial","volume":"4","author":"Watz","year":"2016","journal-title":"Lancet Respir Med"},{"key":"2026032023232217500_bib28","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S2213-2600(15)00106-X","article-title":"Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials","volume":"3","author":"Pascoe","year":"2015","journal-title":"Lancet Respir Med"},{"key":"2026032023232217500_bib29","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1164\/rccm.201502-0235LE","article-title":"Blood eosinophils: a biomarker of response to extrafine beclomethasone\/formoterol in chronic obstructive pulmonary disease","volume":"192","author":"Siddiqui","year":"2015","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib30","doi-asserted-by":"crossref","first-page":"2222","DOI":"10.1056\/NEJMoa1516385","article-title":"Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD","volume":"374","author":"Wedzicha","year":"2016","journal-title":"N Engl J Med"},{"key":"2026032023232217500_bib31","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1164\/rccm.201709-1822LE","article-title":"Dual bronchodilation response by exacerbation history and eosinophilia in the FLAME study","volume":"197","author":"Papi","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib32","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1016\/S0140-6736(17)30188-5","article-title":"Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial","volume":"389","author":"Vestbo","year":"2017","journal-title":"Lancet"},{"key":"2026032023232217500_bib33","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1016\/S0140-6736(16)31354-X","article-title":"Single inhaler triple therapy versus inhaled corticosteroid plus long-acting \u03b22-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial","volume":"388","author":"Singh","year":"2016","journal-title":"Lancet"},{"key":"2026032023232217500_bib34","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1164\/rccm.201703-0449OC","article-title":"FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease","volume":"196","author":"Lipson","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib35","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1016\/S0140-6736(18)30206-X","article-title":"Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial","volume":"391","author":"Papi","year":"2018","journal-title":"Lancet"},{"key":"2026032023232217500_bib36","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1183\/09031936.00035909","article-title":"Predictive accuracy of patient-reported exacerbation frequency in COPD","volume":"37","author":"Quint","year":"2011","journal-title":"Eur Respir J"},{"key":"2026032023232217500_bib37","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1164\/rccm.201701-0009LE","article-title":"Stability of blood eosinophils in patients with chronic obstructive pulmonary disease and in control subjects, and the impact of sex, age, smoking, and baseline counts","volume":"195","author":"Oshagbemi","year":"2017","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032023232217500_bib38","doi-asserted-by":"crossref","first-page":"907","DOI":"10.2147\/COPD.S130482","article-title":"LABA\/LAMA combinations versus LAMA monotherapy or LABA\/ICS in COPD: a systematic review and meta-analysis","volume":"12","author":"Rodrigo","year":"2017","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2026032023232217500_bib39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.4104\/pcrj.2012.00092","article-title":"Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD","volume":"22","author":"Price","year":"2013","journal-title":"Prim Care Respir J"},{"key":"2026032023232217500_bib40","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.chest.2017.05.020","article-title":"Precision medicine urgency: the case of inhaled corticosteroids in COPD","volume":"152","author":"Suissa","year":"2017","journal-title":"Chest"},{"key":"2026032023232217500_bib41","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1186\/s12931-017-0682-y","article-title":"A proposal for the withdrawal of inhaled corticosteroids in the clinical practice of chronic obstructive pulmonary disease","volume":"18","author":"Miravitlles","year":"2017","journal-title":"Respir Res"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/198\/3\/329\/67125166\/ajrccm_198_3_329.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/198\/3\/329\/67125166\/ajrccm_198_3_329.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T03:23:37Z","timestamp":1774063417000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/198\/3\/329\/8498181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,1]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,8,1]]},"published-print":{"date-parts":[[2018,8,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201803-0405oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,8]]},"published":{"date-parts":[[2018,8,1]]}}}