{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T20:56:50Z","timestamp":1771880210472,"version":"3.50.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T00:00:00Z","timestamp":1485993600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T00:00:00Z","timestamp":1485993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["npj Prim Care Resp Med"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chronic obstructive pulmonary disease is associated with significant morbidity and mortality. Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status. Our aim was to investigate the effects of tiotropium\u2009+\u2009olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy. Two pairs of replicate, phase III studies of 12 (OTEMTO 1\u2009+\u20092) and 52 weeks\u2019 (TONADO 1\u2009+\u20092) duration were evaluated, in which patients received either tiotropium\u2009+\u2009olodaterol 2.5\/5 or 5\/5\u2009\u03bcg, tiotropium 2.5 or 5\u2009\u03bcg, olodaterol 5\u2009\u03bcg or placebo, all delivered once daily via Respimat inhaler. Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George\u2019s Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks. Outcomes from the pooled study data are reported. Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively. Significantly larger improvements in St George\u2019s Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George\u2019s Respiratory Questionnaire and transition dyspnoea index) with tiotropium\u2009+\u2009olodaterol compared to either monotherapy or to placebo. Tiotropium\u2009+\u2009olodaterol 5\/5\u2009\u00b5g significantly reduced night-time rescue medication usage.<\/jats:p>","DOI":"10.1038\/s41533-016-0002-x","type":"journal-article","created":{"date-parts":[[2017,2,2]],"date-time":"2017-02-02T11:00:22Z","timestamp":1486033222000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Effect of tiotropium and olodaterol on symptoms and \npatient-reported outcomes in patients with COPD: results from four randomised, double-blind studies"],"prefix":"10.1038","volume":"27","author":[{"given":"Gary T.","family":"Ferguson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill","family":"Karpel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuelle","family":"Clerisme-Beaty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Gr\u00f6nke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Vo\u00df","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Buhl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,2,2]]},"reference":[{"key":"2_CR1","unstructured":"Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Updated 2016. Last accessed on 27 April 2016. Available at http:\/\/www.goldcopd.org\/."},{"key":"2_CR2","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1183\/09059180.00008612","volume":"22","author":"A Cavaill\u00e8s","year":"2013","unstructured":"Cavaill\u00e8s, A., Brinchault-Rabin, G., Dixmier, A., Goupil, F., Gut-Gobert, C. & Marchand-Adam, S. et al. Comorbidities of COPD. Eur. Respir. Rev. \n                           22, 454\u2013475 (2013).","journal-title":"Eur. Respir. Rev."},{"key":"2_CR3","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s12955-015-0241-5","volume":"13","author":"M Wu","year":"2015","unstructured":"Wu, M., Zhao, Q., Chen, Y., Fu, C. & Xu, B. Quality of life and its association with direct medical costs for COPD in urban China. Health Qual. Life Outcomes \n                           13, 57 (2015).","journal-title":"Health Qual. Life Outcomes"},{"key":"2_CR4","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/1471-2466-14-134","volume":"14","author":"ME Wacker","year":"2014","unstructured":"Wacker, M. E., Hunger, M., Karrasch, S., Heinrich, J., Peters, A. & Schulz, H. et al. Health-related quality of life and chronic obstructive pulmonary disease in early stages \u2013 longitudinal results from the population-based KORA cohort in a working age population. BMC Pulm. Med. \n                           14, 134 (2014).","journal-title":"BMC Pulm. Med."},{"key":"2_CR5","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1136\/thx.52.1.67","volume":"52","author":"LM Osman","year":"1997","unstructured":"Osman, L. M., Godden, D. J., Friend, J. A. R., Legge, J. S. & Douglas, J. G. Quality of life and hospital re-admission in patients with chronic obstructive pulmonary disease. Thorax \n                           52, 67\u201371 (1997).","journal-title":"Thorax"},{"key":"2_CR6","doi-asserted-by":"publisher","first-page":"1418","DOI":"10.1164\/ajrccm.157.5.9709032","volume":"157","author":"TAR Seemungal","year":"1998","unstructured":"Seemungal, T. A. R., Donaldson, G. C., Paul, E. A., Bestall, J. C., Jeffries, D. J. & Wedzicha, J. A. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. \n                           157, 1418\u20131422 (1998).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"2_CR7","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1183\/09031936.02.00269802","volume":"19","author":"R Casaburi","year":"2002","unstructured":"Casaburi, R., Mahler, D. A., Jones, P. W., Wanner, A., San Pedro, G. & ZuWallack, R. L. et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. \n                           19, 217\u2013224 (2002).","journal-title":"Eur. Respir. J."},{"key":"2_CR8","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1183\/09031936.04.00116004","volume":"23","author":"DE O\u2019Donnell","year":"2004","unstructured":"O\u2019Donnell, D. E., Fl\u00fcge, T., Gerken, F., Hamilton, A., Webb, K. & Aguilaniu, B. et al. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur. Respir. J. \n                           23, 832\u2013840 (2004).","journal-title":"Eur. Respir. J."},{"key":"2_CR9","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1378\/chest.128.3.1168","volume":"128","author":"F Maltais","year":"2005","unstructured":"Maltais, F., Hamilton, A., Marciniuk, D., Hernandez, P., Sciurba, F. C. & Richter, K. et al. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest \n                           128, 1168\u20131178 (2005).","journal-title":"Chest"},{"key":"2_CR10","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.1056\/NEJMoa0805800","volume":"359","author":"DP Tashkin","year":"2008","unstructured":"Tashkin, D. P., Celli, B., Senn, S., Burkhart, D., Kesten, S. & Menjoge, S. et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N. Engl. J. Med. \n                           359, 1543\u20131554 (2008).","journal-title":"N. Engl. J. Med."},{"key":"2_CR11","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1016\/j.rmed.2010.06.004","volume":"104","author":"ED Bateman","year":"2010","unstructured":"Bateman, E. D., Tashkin, D., Siafakas, N., Dahl, R., Towse, L. & Massey, D. et al. A one-year trial of tiotropium Respimat\u00ae plus usual therapy in COPD patients. Respir. Med. \n                           104, 1460\u20131472 (2010).","journal-title":"Respir. Med."},{"key":"2_CR12","doi-asserted-by":"publisher","first-page":"477","DOI":"10.4187\/respcare.00852","volume":"56","author":"AM Yohannes","year":"2011","unstructured":"Yohannes, A. M., Willgoss, T. G. & Vestbo, J. Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. Respir. Care \n                           56, 477\u2013487 (2011).","journal-title":"Respir. Care"},{"key":"2_CR13","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1056\/NEJMoa1008378","volume":"364","author":"C Vogelmeier","year":"2011","unstructured":"Vogelmeier, C., Hederer, B., Glaab, T., Schmidt, H., Rutten-van M\u00f6lken, M. P. M. H. & Beeh, K. M. et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N. Engl. J. Med. \n                           364, 1093\u20131103 (2011).","journal-title":"N. Engl. J. Med."},{"key":"2_CR14","doi-asserted-by":"publisher","first-page":"629","DOI":"10.2147\/COPD.S61717","volume":"9","author":"GT Ferguson","year":"2014","unstructured":"Ferguson, G. T., Feldman, G. J., Hofbauer, P., Hamilton, A., Allen, L. & Korducki, L. et al. Efficacy and safety of olodaterol once daily delivered via Respimat\u00ae in patients with GOLD 2\u20134 COPD: results from two replicate 48-week studies. Int. J. Chron. Obstruct. Pulmon. Dis. \n                           9, 629\u2013645 (2014).","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"2_CR15","doi-asserted-by":"publisher","first-page":"697","DOI":"10.2147\/COPD.S62502","volume":"9","author":"A Koch","year":"2014","unstructured":"Koch, A., Pizzichini, E., Hamilton, A., Hart, L., Korducki, L. & De Salvo, M. C. et al. Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat\u00ae versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies. Int. J. Chron. Obstruct. Pulmon. Dis \n                           9, 697\u2013714 (2014).","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis"},{"key":"2_CR16","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1186\/2193-1801-3-419","volume":"3","author":"GJ Feldman","year":"2014","unstructured":"Feldman, G. J., Bernstein, J. A., Hamilton, A., Nivens, M. C., Korducki, L. & LaForce, C. The 24-h FEV1 time profile of olodaterol once daily via Respimat\u00ae and formoterol twice daily via Aerolizer\u00ae in patients with GOLD 2\u20134 COPD: results from two 6-week crossover studies. Springerplus \n                           3, 419 (2014).","journal-title":"Springerplus"},{"key":"2_CR17","first-page":"196","volume":"4","author":"P Lange","year":"2014","unstructured":"Lange, P., Aumann, J.-L., Hamilton, A., Tetzlaff, K., Ting, N. & Derom, E. The 24 hour lung function time profile of olodaterol once daily versus placebo and tiotropium in patients with moderate to very severe chronic obstructive pulmonary disease. J. Pulm. Respir. Med. \n                           4, 196 (2014).","journal-title":"J. Pulm. Respir. Med."},{"key":"2_CR18","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1183\/09031936.00136014","volume":"45","author":"R Buhl","year":"2015","unstructured":"Buhl, R., Maltais, F., Abrahams, R., Bjermer, L., Derom, E. & Ferguson, G. et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2\u20134). Eur. Respir. J. \n                           45, 969\u2013979 (2015).","journal-title":"Eur. Respir. J."},{"key":"2_CR19","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1016\/j.rmed.2015.08.002","volume":"109","author":"D Singh","year":"2015","unstructured":"Singh, D., Ferguson, G. T., Bolitschek, J., Gr\u00f6nke, L., Hallmann, C. & Bennett, N. et al. Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Respir. Med. \n                           109, 1312\u20131319 (2015).","journal-title":"Respir. Med."},{"key":"2_CR20","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.pupt.2015.04.002","volume":"32","author":"K-M Beeh","year":"2015","unstructured":"Beeh, K.-M., Westerman, J., Kirsten, A.-M., H\u00e9bert, J., Gr\u00f6nke, L. & Hamilton, A. et al. The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Pulm. Pharmacol. Ther. \n                           32, 53\u201359 (2015).","journal-title":"Pulm. Pharmacol. Ther."},{"key":"2_CR21","doi-asserted-by":"publisher","first-page":"193","DOI":"10.2147\/COPD.S95055","volume":"11","author":"K-M Beeh","year":"2016","unstructured":"Beeh, K.-M., Derom, E., Echave-Sustaeta, J., Gr\u00f6nke, L., Hamilton, A. & Zhai, D. et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat\u00ae is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler\u00ae (ENERGITO\u00ae study). Int. J. Chron. Obstruct. Pulmon. Dis. \n                           11, 193\u2013205 (2016).","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"2_CR22","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1183\/09031936.00200212","volume":"42","author":"ED Bateman","year":"2013","unstructured":"Bateman, E. D., Ferguson, G. T., Barnes, N., Gallagher, N., Green, Y. & Henley, M. et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur. Respir. J. \n                           42, 1484\u20131494 (2013).","journal-title":"Eur. Respir. J."},{"key":"2_CR23","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1016\/j.rmed.2013.06.001","volume":"107","author":"JF Donohue","year":"2013","unstructured":"Donohue, J. F., Maleki-Yazdi, M. R., Kilbride, S., Mehta, R., Kalberg, C. & Church, A. Efficacy and safety of once-daily umeclidinium\/vilanterol 62.5\/25 mcg in COPD. Respir. Med. \n                           107, 1538\u20131546 (2013).","journal-title":"Respir. Med."},{"key":"2_CR24","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1016\/j.rmed.2014.10.002","volume":"108","author":"MR Maleki-Yazdi","year":"2014","unstructured":"Maleki-Yazdi, M. R., Kaelin, T., Richard, N., Zvarich, M. & Church, A. Efficacy and safety of umeclidinium\/vilanterol 62.5\/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Respir. Med. \n                           108, 1752\u20131760 (2014).","journal-title":"Respir. Med."},{"key":"2_CR25","unstructured":"European Medicines Agency. Anoro summary of product characteristics. Updated June 2014. Last accessed on 9 March 2016. Available at http:\/\/www.ema.europa.eu\/ema\/index.jsp?curl=pages\/medicines\/human\/medicines\/002751\/human_med_001754.jsp&mid=WC0b01ac058001d124."},{"key":"2_CR26","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/S2213-2600(14)70065-7","volume":"2","author":"M Decramer","year":"2014","unstructured":"Decramer, M., Anzueto, A., Kerwin, E., Kaelin, T., Richard, N. & Crater, G. et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir. Med. \n                           2, 472\u2013486 (2014).","journal-title":"Lancet Respir. Med."},{"key":"2_CR27","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1183\/09031936.03.00068503a","volume":"21","author":"TJ Witek Jr.","year":"2003","unstructured":"Witek, T. J. Jr. & Mahler, D. A. Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur. Respir. J. \n                           21, 267\u2013272 (2003).","journal-title":"Eur. Respir. J."},{"key":"2_CR28","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.2147\/COPD.S82408","volume":"10","author":"T Perez","year":"2015","unstructured":"Perez, T., Burgel, P. R., Paillasseur, J.-L., Caillaud, D., Desl\u00e9e, G. & Chanez, P. et al. Modified Medical Research Council scale vs Baseline Dyspnea Index to evaluate dyspnea in chronic obstructive pulmonary disease. Int. J. Chron. Obstruct. Pulmon. Dis. \n                           10, 1663\u20131672 (2015).","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"2_CR29","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1183\/09059180.00004311","volume":"20","author":"A Agusti","year":"2011","unstructured":"Agusti, A., Hedner, J., Marin, J. M., Barb\u00e9, F., Cazzola, M. & Rennard, S. Night-time symptoms: a forgotten dimension of COPD. Eur. Respir. Rev. \n                           20, 183\u2013194 (2011).","journal-title":"Eur. Respir. Rev."},{"key":"2_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.4104\/pcrj.2011.00102","volume":"21","author":"T van der Molen","year":"2012","unstructured":"van der Molen, T. & Cazzola, M. Beyond lung function in COPD management: effectiveness of LABA\/LAMA combination therapy on patient-centred outcomes. Prim. Care Respir. J. \n                           21, 101\u2013108 (2012).","journal-title":"Prim. Care Respir. J."},{"key":"2_CR31","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1513\/pats.200509-103SF","volume":"3","author":"DA Mahler","year":"2006","unstructured":"Mahler, D. A. Mechanisms and measurement of dyspnea in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. \n                           3, 234\u2013238 (2006).","journal-title":"Proc. Am. Thorac. Soc."},{"key":"2_CR32","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1378\/chest.85.6.751","volume":"85","author":"DA Mahler","year":"1984","unstructured":"Mahler, D. A., Weinberg, D. H., Wells, C. K. & Feinstein, A. R. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest \n                           85, 751\u2013758 (1984).","journal-title":"Chest"},{"key":"2_CR33","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S2213-2600(14)70038-4","volume":"2","author":"PW Jones","year":"2014","unstructured":"Jones, P. W. Estimation and application of the minimum clinically important difference in COPD. Lancet Respir. Med. \n                           2, 167\u2013169 (2014).","journal-title":"Lancet Respir. Med."}],"container-title":["npj Primary Care Respiratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41533-016-0002-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41533-016-0002-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41533-016-0002-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T01:48:05Z","timestamp":1671760085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41533-016-0002-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,2]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["2"],"URL":"https:\/\/doi.org\/10.1038\/s41533-016-0002-x","relation":{},"ISSN":["2055-1010"],"issn-type":[{"value":"2055-1010","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,2]]},"assertion":[{"value":"15 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2016","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2016","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2017","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"7"}}