theophylline and Airflow Obstruction, Chronic studies

Research Excerpts

Excerpt	Relevance	Reference
"Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option."	9.05	The effect of doxofylline in asthma and COPD. ( Cazzola, M; Matera, MG, 2020)
"Doxofylline, a methylxanthine derivative, has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analogue, theophylline, indicated for asthma and chronic obstructive pulmonary disease."	8.85	Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. ( Chakraborty, S; Mishra, B; Shukla, D; Singh, S, 2009)
"Despite having been recognized for a long time as a cheap and effective therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD), theophylline is relegated to third-line therapy in the treatment of airway diseases due to the drug's frequent side effects and relatively low efficacy."	8.82	Theophylline: mechanism of action and use in asthma and chronic obstructive pulmonary disease. ( Barnes, PJ; Erin, EM; Hansel, TT; Higgins, LA; Neighbour, H; Tan, AJ; Tennant, RC, 2004)
"Theophylline has been reduced usage in asthma and chronic obstructive pulmonary disease because of the high frequency of side effects and the relatively low efficacy."	8.82	[Development of theophylline in treatment of asthma and chronic obstructive pulmonary disease]. ( Xu, YJ, 2004)
"BACKGROUND The aim of this study was to investigate the effects of doxofylline combined with ceftazidime on clinical efficacy, drug safety, and prognosis in patients with COPD complicated with infection."	8.02	Effects of Doxofylline Combined with Ceftazidime on Clinical Efficacy, Drug Safety, and Prognosis in Patients with Chronic Obstructive Pulmonary Disease Complicated with Infection. ( Wang, Y, 2021)
"Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown."	7.85	Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. ( Aisiku, IP; Chen, RC; Chen, YT; Chu, H; Frendl, G; Hou, PC; Hsu, YT; Ou, SM; Quraishi, SA; Seethala, RR; Shih, CJ; Shih, YN, 2017)
"Both theophylline and doxofylline produced enhancements in PFT at different time intervals in both asthma and COPD patients."	7.81	Comparative study of the efficacy and safety of theophylline and doxofylline in patients with bronchial asthma and chronic obstructive pulmonary disease. ( Kumar, R; Lal, D; Manocha, S; Ray, A; Vijayan, VK, 2015)
"Theophylline is a useful drug for the treatment of asthma."	7.73	A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD. ( Adachi, M; Fukuda, T; Kihara, N; Makino, S; Miyamoto, T; Nakajima, S; Nishima, S; Ohta, K, 2006)
"A large-scale prospective study was conducted in 3810 Japanese elderly (> or =65 years old) patients with asthma or chronic obstructive pulmonary disease (COPD) who had been treated with sustained-release theophylline tablets (THEODUR) at a dose of 400 mg/day for 1-6 months, in principle."	7.72	A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD. ( Fukuchi, Y; Grouse, L; Mizutani, R; Ohta, K; Rabe, KF; Rennard, SI; Zhong, NS, 2004)
"Lomefloxacin is a difluorinated quinolone with excellent activity against a wide range of pathogens including those responsible for acute exacerbations of chronic bronchitis (AECB)."	7.71	Safety and effectiveness of lomefloxacin in patients with acute exacerbation of chronic bronchitis (AECB) chronically treated with oral theophyllines. ( Cantoni, V; Melani, AS; Pirrelli, M; Sarlo, F, 2001)
"Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world."	6.48	Can β2-adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD? ( Advenier, C; Bureau, F; Cambier, C; Cui, YY; Devillier, P; Gustin, P; Rong, WF; Zhang, WH; Zhang, Y, 2012)
"Theophylline has an anti-inflammatory role in COPD."	5.51	Theophylline inhibits cigarette smoke-induced inflammation in skeletal muscle by upregulating HDAC2 expression and decreasing NF-κB activation. ( Bai, J; Bin, Y; He, Z; Huang, D; Liang, Q; Liang, Y; Ma, Z; Xiao, Y; Zhang, J; Zhang, W; Zhong, X, 2019)
"Theophylline is an oral methylxanthine bronchodilator recommended as alternate therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD)."	5.41	Theophylline for the management of respiratory disorders in adults in the 21st century: A scoping review from the American College of Clinical Pharmacy Pulmonary Practice and Research Network. ( Abdalla, M; Bissell, B; Boylan, PM; Malesker, MA; Santibañez, M; Smith, Z, 2023)
"In a 12-week, open-labeled, parallel-group randomized study, pulmonary functions and dyspnea scores were compared between the combination and theophylline alone therapy at baseline, and 4 and 8 weeks after randomization in COPD."	5.13	Effect of add-on therapy of tiotropium in COPD treated with theophylline. ( Aizawa, H; Hoshino, T; Ichiki, M; Iwanaga, T; Kawayama, T; Kinoshita, M; Koga, T; Takata, S; Tsuda, T, 2008)
"Our results indicate that adding theophylline to standard treatment with inhaled bronchodilators provides additional benefits in stable COPD patients by reducing dynamic pulmonary hyperinflation, improving exercise tolerance, dyspnea and QoL."	5.11	[Clinical and functional benefits of adding theophylline to a standard treatment with short acting bronchodilators in patients with COPD]. ( Borzone, G; Díaz, O; Dreyse, J; Lisboa, C; Silva, F, 2005)
"Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option."	5.05	The effect of doxofylline in asthma and COPD. ( Cazzola, M; Matera, MG, 2020)
"Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD)."	4.95	Xanthines and Phosphodiesterase Inhibitors. ( Page, CP; Spina, D, 2017)
"Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD)."	4.90	Phosphodiesterase inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. ( Page, CP, 2014)
"Doxofylline, a methylxanthine derivative, has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analogue, theophylline, indicated for asthma and chronic obstructive pulmonary disease."	4.85	Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease. ( Chakraborty, S; Mishra, B; Shukla, D; Singh, S, 2009)
"Theophylline has been relegated to a second- or even third-line therapy in the treatment of asthma and chronic obstructive pulmonary disease (COPD), behind glucocorticosteroids and beta2-agonists, although recent findings have suggested that theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a bronchodilator."	4.83	Are phosphodiesterase 4 inhibitors just more theophylline? ( Boswell-Smith, V; Cazzola, M; Page, CP, 2006)
"Despite having been recognized for a long time as a cheap and effective therapy for the treatment of asthma and chronic obstructive pulmonary disease (COPD), theophylline is relegated to third-line therapy in the treatment of airway diseases due to the drug's frequent side effects and relatively low efficacy."	4.82	Theophylline: mechanism of action and use in asthma and chronic obstructive pulmonary disease. ( Barnes, PJ; Erin, EM; Hansel, TT; Higgins, LA; Neighbour, H; Tan, AJ; Tennant, RC, 2004)
"Theophylline has been reduced usage in asthma and chronic obstructive pulmonary disease because of the high frequency of side effects and the relatively low efficacy."	4.82	[Development of theophylline in treatment of asthma and chronic obstructive pulmonary disease]. ( Xu, YJ, 2004)
"BACKGROUND The aim of this study was to investigate the effects of doxofylline combined with ceftazidime on clinical efficacy, drug safety, and prognosis in patients with COPD complicated with infection."	4.02	Effects of Doxofylline Combined with Ceftazidime on Clinical Efficacy, Drug Safety, and Prognosis in Patients with Chronic Obstructive Pulmonary Disease Complicated with Infection. ( Wang, Y, 2021)
"Although newer and more efficient medicines to treat asthma and COPD has been developed, theophylline is still prescribed and used in 2016, but the incidence and prevalence have decreased markedly since 1997."	3.88	Nationwide use of theophylline among adults-A 20-year Danish drug utilisation study. ( Davidsen, JR; Henriksen, DP; Laursen, CB, 2018)
"Although theophylline has been shown to have anti-inflammatory effects, the therapeutic use of theophylline before sepsis is unknown."	3.85	Association of pre-hospital theophylline use and mortality in chronic obstructive pulmonary disease patients with sepsis. ( Aisiku, IP; Chen, RC; Chen, YT; Chu, H; Frendl, G; Hou, PC; Hsu, YT; Ou, SM; Quraishi, SA; Seethala, RR; Shih, CJ; Shih, YN, 2017)
"Both theophylline and doxofylline produced enhancements in PFT at different time intervals in both asthma and COPD patients."	3.81	Comparative study of the efficacy and safety of theophylline and doxofylline in patients with bronchial asthma and chronic obstructive pulmonary disease. ( Kumar, R; Lal, D; Manocha, S; Ray, A; Vijayan, VK, 2015)
"Theophylline is a useful drug for the treatment of asthma."	3.73	A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD. ( Adachi, M; Fukuda, T; Kihara, N; Makino, S; Miyamoto, T; Nakajima, S; Nishima, S; Ohta, K, 2006)
"A large-scale prospective study was conducted in 3810 Japanese elderly (> or =65 years old) patients with asthma or chronic obstructive pulmonary disease (COPD) who had been treated with sustained-release theophylline tablets (THEODUR) at a dose of 400 mg/day for 1-6 months, in principle."	3.72	A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD. ( Fukuchi, Y; Grouse, L; Mizutani, R; Ohta, K; Rabe, KF; Rennard, SI; Zhong, NS, 2004)
"Lomefloxacin is a difluorinated quinolone with excellent activity against a wide range of pathogens including those responsible for acute exacerbations of chronic bronchitis (AECB)."	3.71	Safety and effectiveness of lomefloxacin in patients with acute exacerbation of chronic bronchitis (AECB) chronically treated with oral theophyllines. ( Cantoni, V; Melani, AS; Pirrelli, M; Sarlo, F, 2001)
" During the treatment, the remission time of typical respiratory manifestations was recorded, and the adverse reactions were observed."	3.01	Efficacy and safety of combined doxofylline and salbutamol in treatment of acute exacerbation of chronic obstructive pulmonary disease. ( Bao, H; Du, X; Zhao, D, 2021)
"The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries."	3.01	The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial. ( Barnes, PJ; Berend, N; Bradbury, T; Celli, B; Di Tanna, GL; Jenkins, CR; Martin, A; Scaria, A; Wen, FQ; Zheng, JP; Zhong, NS, 2021)
"COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings."	3.01	Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial. ( Alupo, P; Barnes, PJ; Checkley, W; Dowdy, D; Hurst, JR; Jackson, P; Kalyesubula, R; Kirenga, B; Namazzi, E; Padalkar, R; Pollard, SL; Rahman, N; Robertson, NM; Sekitoleko, I; Siddharthan, T; Wise, R; Wosu, AC, 2021)
"Theophylline is a drug that has been around for decades."	2.90	Low-dose oral theophylline combined with inhaled corticosteroids for people with chronic obstructive pulmonary disease and high risk of exacerbations: a RCT. ( Barnes, PJ; Briggs, A; Burns, G; Chaudhuri, R; Chrystyn, H; Cotton, S; Davies, L; Devereux, G; Fielding, S; Gompertz, S; Haughney, J; Innes, K; Kaniewska, J; Lee, A; McMeekin, N; Morice, A; Norrie, J; Price, D; Soyza, A; Sullivan, A; Wilson, A, 2019)
"Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively."	2.87	Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial. ( Barnes, PJ; Briggs, A; Burns, G; Chaudhuri, R; Chrystyn, H; Cotton, S; Davies, L; De Soyza, A; Devereux, G; Fielding, S; Gompertz, S; Haughney, J; Innes, K; Kaniewska, J; Lee, A; McMeekin, N; Morice, A; Norrie, J; Price, D; Sullivan, A; Wilson, A, 2018)
"Tiotropium bromide has been widely used in clinical practice, while theophylline is another treatment option for chronic obstructive pulmonary disease (COPD)."	2.87	Effects of Tiotropium Combined with Theophylline on Stable COPD Patients of Group B, D and its Impact on Small Airway Function: A Randomized Controlled Trial. ( Cheng, DY; Fan, LL; Wu, HX; Xiong, XF; Zhu, M, 2018)
"TCM lung rehabilitation treatment of chronic obstructive pulmonary disease has obvious curative effect, it can improve the function of lung, reduce the occurrence of dyspnea, improve patients' tolerance and have obvious long-term curative effect."	2.84	The study of long term curative effect of chronic obstructive pulmonary disease in remission stage treated with TCM. ( Quanqing, M, 2017)
"COPD is characterized by chronic inflammation."	2.82	Oral Low-dose Theophylline on Top of Inhaled Fluticasone-Salmeterol Does Not Reduce Exacerbations in Patients With Severe COPD: A Pilot Clinical Trial. ( Agusti, A; Barnes, PJ; Córdova, R; Cosío, BG; Gea, J; Iglesias, A; Palou, A; Pascual, S; Peces-Barba, G; Rodriguez-Roisin, R; Shafiek, H; Sibila, O; Yanez, A, 2016)
" Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l."	2.80	Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial. ( Barnes, P; Briggs, A; Burns, G; Chaudhuri, R; Chrystyn, H; Cotton, S; Davies, L; De Soyza, A; Devereux, G; Fielding, S; Gompertz, S; Haughney, J; Lee, AJ; McCormack, K; McPherson, G; Morice, A; Norrie, J; Price, D; Sullivan, A; Wilson, A, 2015)
"The additional use of an SABA by COPD patients improved their pulmonary function, which was accompanied by changes in regional lung air flow."	2.79	Effects of bronchodilators on regional lung sound distribution in patients with chronic obstructive pulmonary disease. ( Matsuoka, S; Mineshita, M; Miyazawa, T, 2014)
"Bu-Fei Yi-Shen granule combined with acupoint sticking therapy has been used in the patients with stable chronic obstructive pulmonary disease (COPD) as major traditional interventions for the treatment of the disease."	2.77	Bu-Fei Yi-Shen granule combined with acupoint sticking therapy in patients with stable chronic obstructive pulmonary disease: a randomized, double-blind, double-dummy, active-controlled, 4-center study. ( Bai, YP; Guo, LX; Li, JS; Li, SY; Li, ZG; Shao, SJ; Wang, MH; Wang, YF; Xie, Y; Yu, XQ; Zhang, NZ; Zhang, YJ; Zhu, L, 2012)
"Theophylline is a widely available medication which may further improve lung function and exercise performance."	2.77	Effect of theophylline on exercise capacity in COPD patients treated with combination long-acting bronchodilator therapy: a pilot study. ( Aaron, SD; Alvarez, GG; Amjadi, K; Sabri, E; Tessier, C; Voduc, N, 2012)
"In patients with COPD who are not on maintenance therapy, tiotropium is associated with significant benefits in disease progression."	2.75	Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. ( Celli, B; Decramer, M; Kesten, S; Lystig, T; Mehra, S; Tashkin, DP; Troosters, T, 2010)
"Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD)."	2.74	Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. ( Agusti, A; Barnes, PJ; Cosio, BG; Iglesias, A; Ito, K; Noguera, A; Rios, A; Sala, E, 2009)
"The regression slope of breathlessness as a function of oxygen consumption (primary outcome), mean ratings of breathlessness throughout exercise and peak ratings of breathlessness were significantly higher with naloxone than normal saline."	2.74	Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. ( Baird, JC; Kraemer, WJ; Mahler, DA; Murray, JA; Ward, J; Waterman, LA; Zhang, X, 2009)
"In those with severe COPD, TS resulted in equal exacerbation rates and slightly lower costs compared with TP."	2.73	Cost effectiveness of therapy with combinations of long acting bronchodilators and inhaled steroids for treatment of COPD. ( Aaron, SD; Fitzgerald, JM; Jones, PW; Marra, CA; Najafzadeh, M; Sadatsafavi, M; Sullivan, SD; Vandemheen, KL, 2008)
"The airway inflammation of chronic obstructive pulmonary disease (COPD) demonstrates a poor response to the anti-inflammatory actions of corticosteroids."	2.73	Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. ( Haruta, Y; Hattori, N; Ishikawa, N; Iwamoto, H; Kanehara, M; Kohno, N; Shiota, N; Taooka, Y; Tomoda, Y; Yokoyama, A, 2008)
"Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects: (Doxofylline 8 and theophylline 25) or number of drop-out side-effects (doxofylline 5 and theophylline 10)."	2.73	Treatment of moderate chronic obstructive pulmonary disease (stable) with doxofylline compared with slow release theophylline--a multicentre trial. ( Santra, CK, 2008)
"Theophylline was administered at 400mg/day."	2.73	Long-term treatment with theophylline reduces neutrophils, interleukin-8 and tumor necrosis factor-alpha in the sputum of patients with chronic obstructive pulmonary disease. ( Ashitani, J; Iiboshi, H; Katoh, S; Matsumoto, N; Mukae, H; Nakazato, M; Sano, A, 2007)
"Treatment of COPD patients with TP is more effective than with theophylline."	2.73	Clinical efficacy of the transdermal tulobuterol patch in patients with chronic obstructive pulmonary disease: a comparison with slow-release theophylline. ( Aizawa, H; Gohara, R; Ichiki, M; Iwanaga, T; Kawayama, T; Kinoshita, M; Koga, H; Minami, S; Nishiyama, M; Sueyasu, Y, 2008)
"In total, 110 participants with COPD were randomly assigned to receive slow-release theophylline (100 mg b."	2.72	Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. ( Liu, S; Qiu, R; Ran, P; Wang, X; Xie, J; Zeng, X; Zheng, J; Zhong, N; Zhou, Y, 2006)
"Sixteen COPD subjects participated in the study."	2.72	Inhibition of reactive nitrogen species production in COPD airways: comparison of inhaled corticosteroid and oral theophylline. ( Akamatsu, K; Gohda, M; Hirano, T; Ichikawa, T; Ichinose, M; Matsunaga, K; Minakata, Y; Nakanishi, M; Ueshima, K; Yamagata, T; Yamagata, Y; Yanagisawa, S, 2006)
" The concentration-to-dose ratio and the relationship between the steady-state plasma concentration at different times during the dosage interval and Css(avg) are described."	2.71	Pharmacokinetics of an ultralong sustained-release theophylline formulation when given twice daily in elderly patients with chronic obstructive pulmonary disease: monitoring implications. ( Arjona, R; Armijo, JA; Cos, MA; Cuadrado, A; González-Ruiz, M; Peralta, FG; Sánchez, BM; Verdejo, A, 2003)
"Eighteen moderate COPD patients (53-77 yr, mean basal FEV(1)=49."	2.71	Salmeterol & fluticasone 50 microg/250 microg bid in combination provides a better long-term control than salmeterol 50 microg bid alone and placebo in COPD patients already treated with theophylline. ( Dal Negro, RW; Micheletto, C; Pomari, C; Tognella, S, 2003)
"Forty stable COPD patients (group C) were randomized into a subgroup receiving oral theophylline 0."	2.71	[Changes of leukotriene B4 in induced sputum and plasma of patients with chronic obstructive pulmonary disease and the effects of theophylline]. ( Ding, YL; Liu, Z; Wang, YZ; Yao, WZ, 2005)
" Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol."	2.70	Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. ( Della Cioppa, G; Kottakis, J; Kristufek, P; Levine, BE; Rossi, A; Thomson, MH; Till, D, 2002)
"Theophylline was well tolerated."	2.70	Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. ( Barnes, PJ; Culpitt, SV; de Matos, C; Donnelly, LE; Rogers, DF; Russell, RE, 2002)
"Two weeks after placebo treatment, the COPD control group did not show such changes."	2.69	Effects of theophylline on plasma levels of interleukin-4, cyclic nucleotides and pulmonary functions in patients with chronic obstructive pulmonary disease. ( Fang, H; Liu, J; Ni, W; Xu, Y; Zhang, N; Zhang, Z, 1999)
"Inflammation is a central feature of asthma and chronic obstructive pulmonary disease (COPD)."	2.61	Transcription inhibitors and inflammatory cell activity. ( Adcock, IM; Cannavò, MF; Caramori, G; Coppolino, I; Mumby, S; Nucera, F; Proietto, A; Ruggeri, P, 2019)
"Doxofylline is an effective bronchodilator for relieving airway obstruction in patients with asthma or chronic obstructive pulmonary disease (COPD), and displays a better safety profile with respect to theophylline."	2.58	Impact of doxofylline in COPD: A pairwise meta-analysis. ( Calzetta, L; Cazzola, M; Matera, MG; Page, C; Rogliani, P, 2018)
" In addition, we assessed the risk of adverse events by normalising data on safety as a function of person-weeks."	2.58	Efficacy and safety profile of xanthines in COPD: a network meta-analysis. ( Barnes, PJ; Calzetta, L; Cazzola, M; Criner, GJ; Gabriella Matera, M; Martinez, FJ; Papi, A, 2018)
"Chronic obstructive pulmonary disease (COPD) is a respiratory disorder characterised by largely irreversible changes in air flow due to irritants such as tobacco smoke."	2.53	Chronic obstructive pulmonary disease: Useful medications for patients with recurrent symptoms. ( , 2016)
"Theophylline has been shown to improve respiratory function and oxygenation in patients with chronic obstruction pulmonary disease (COPD)."	2.53	Chronic Use of Theophylline and Mortality in Chronic Obstructive Pulmonary Disease: A Meta-analysis. ( Horita, N; Inoue, M; Ishigatsubo, Y; Kaneko, T; Kojima, R; Miyazawa, N, 2016)
"Results of an NMA of COPD treatments suggest that SFC and indacaterol may reduce mortality."	2.52	Mortality and drug therapy in patients with chronic obstructive pulmonary disease: a network meta-analysis. ( Calverley, P; Celli, BR; Chambers, M; Clark, JF; Hawkins, N; Scott, DA; Thompson, JC; Woods, B, 2015)
"Chronic obstructive pulmonary disease (COPD) has become a global epidemic disease with an increased morbidity and mortality in the world."	2.48	Can β2-adrenoceptor agonists, anticholinergic drugs, and theophylline contribute to the control of pulmonary inflammation and emphysema in COPD? ( Advenier, C; Bureau, F; Cambier, C; Cui, YY; Devillier, P; Gustin, P; Rong, WF; Zhang, WH; Zhang, Y, 2012)
"COPD is a major cause of chronic morbidity and mortality worldwide."	2.48	Soft drugs for future treatment of chronic obstructive pulmonary disease (COPD). ( Szelenyi, I, 2012)
"Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible."	2.47	Copd. ( McIvor, RA; Todd, DC; Tunks, M, 2011)
" The RR of total adverse events was similar (RR 1."	2.46	[Meta-analysis of efficacy and safety of oral theophylline in chronic obstructive pulmonary disease]. ( Fu, PF; Li, M; Peng, AM; Wang, CH; Yan, ZM; Zhang, GL; Zhang, Q, 2010)
"The inflammation is resistant to steroids, and it is believed that there may be a defect in the anti-inflammatory effects of these drugs in COPD."	2.45	[The pathogenesis of chronic obstructive pulmonary disease, steroid resistance and the place of theophylline in the treatment]. ( Bayram, H, 2009)
"Chronic obstructive pulmonary disease (COPD) and asthma are chronic diseases that are increasing worldwide in incidence, prevalence, and burden."	2.44	Differentiating chronic obstructive pulmonary disease from asthma. ( Balkstra, CR; Buchsel, PC; Kuebler, KK, 2008)
"Chronic obstructive pulmonary disease (COPD) is a disease state characterised by airflow limitation that is not fully reversible."	2.44	Copd. ( Kerstjens, HA; Postma, DS; Ten Hacken, N, 2008)
"Chronic obstructive pulmonary disease (COPD) is a 4(th) major cause of morbidity and mortality worldwide."	2.44	[Histone dependent signalization during pharmacotherapy of chronic obstructive pulmonary disease]. ( Braszko, JJ; Chyczewska, E; Hołownia, A; Mróz, RM; Noparlik, J, 2007)
"Theophylline is a nonspecific phosphodiesterase inhibitor and is usually reserved for patients with ongoing symptoms despite optimum inhaled bronchodilator treatment or when difficulty is encountered with inhaler devices."	2.44	Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment. ( Anderson, WJ; Butler, CA; Currie, GP; Skinner, C, 2008)
" Older people experience more adverse drug effects because of pharmacodynamic and pharmacokinetic changes and particularly drug-drug and drug-disease interactions."	2.44	Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing. ( Gupta, P; O'Mahony, MS, 2008)
"Theophylline has been shown to restore steroid sensitivity in vitro."	2.43	Theophylline in chronic obstructive pulmonary disease: new horizons. ( Barnes, PJ, 2005)
"The benefits of theophylline in stable chronic obstructive pulmonary disease, however, have to be weighed against the risk of adverse effects, particularly nausea."	2.43	Use of theophylline in chronic obstructive pulmonary disease: examining the evidence. ( Ram, FS, 2006)
"Smoking cessation is the only known causative treatment option."	2.43	[Pharmacological treatment of COPD and future of anti-inflammatory therapy]. ( Bitter-Suermann, S; Kanniess, F; Magnussen, H; Watz, H, 2006)
"The treatment of chronic obstructive pulmonary disease (COPD) has improved substantially over recent years, and is increasingly based on evidence from prospective studies."	2.43	[Stage appropriate therapy for COPD]. ( Hamm, H, 2006)
"Inflammatory lung diseases are characterised by increased expression of multiple inflammatory genes that are regulated by proinflammatory transcription factors, such as NF-kappaB."	2.43	Histone deacetylation: an important mechanism in inflammatory lung diseases. ( Adcock, IM; Barnes, PJ; Ito, K, 2005)
"Smoking cessation is the only intervention that has proved effective."	2.43	Pharmacological treatment of chronic obstructive pulmonary disease. ( Montuschi, P, 2006)
"Theophylline is a nonspecific inhibitor of phosphodiesterases that, despite exerting bronchodilator and anti-inflammatory effects, is a third-line therapy rarely used to treat chronic airflow limitation."	2.43	A meta-analysis on the efficacy of oral theophylline in patients with stable COPD. ( Molfino, NA; Zhang, P, 2006)
"COPD is a disease that affects a significant number of residents in nursing facilities."	2.42	Improving COPD management in the nursing home--part 2. ( Beecham, N; Doherty, DE, 2004)
"Chronic obstructive pulmonary disease (COPD) is a major health problem across the world and its medical, societal and economic impacts continue to grow."	2.42	Approaches to slowing the progression of COPD. ( Altose, MD, 2003)
"With very few exceptions, COPD is caused by tobacco smoking, and smoking cessation is the only truly effective treatment of COPD available."	2.42	Pharmacology of airway inflammation in asthma and COPD. ( Adcock, I; Caramori, G, 2003)
"The Cochrane airways review group's COPD register."	2.42	Methylxanthines for exacerbations of chronic obstructive pulmonary disease: meta-analysis of randomised trials. ( Barr, RG; Camargo, CA; Rowe, BH, 2003)
"The care of patients with chronic obstructive pulmonary disease (COPD) has changed radically over the past 2 decades, and novel therapies can not only improve the health status of patients with COPD but also modify its natural course."	2.42	Contemporary management of chronic obstructive pulmonary disease: scientific review. ( Anthonisen, NR; Man, SF; McAlister, FA; Sin, DD, 2003)
"Smoking cessation is a basic standing point for management of COPD."	2.42	[Management of patients with stable COPD]. ( Toyoshima, H; Yoshida, M, 2003)
"Theophylline has weak antiinflammatory effects."	2.42	[New drug therapy of chronic obstructive pulmonary disease]. ( Kino, H, 2003)
"None of the available drugs for chronic obstructive pulmonary disease is able to reduce the progressive decline in lung function which is the hallmark of this disease."	2.42	[Pharmacological therapy of chronic obstructive pulmonary disease]. ( Montuschi, P, 2003)
"Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications."	2.42	PDE4 inhibitors in COPD--a more selective approach to treatment. ( Vignola, AM, 2004)
"Chronic obstructive pulmonary disease (COPD) is a chronic disorder of the lungs and airways that imposes a huge socioeconomic burden on both the patients and society."	2.41	[Medical maintenance treatment of chronic obstructive pulmonary disease (COPD)]. ( Kerstjens, HA; Postma, DS, 2002)
"Theophylline has a modest effect on FEV1 and FVC and slightly improves arterial blood gas tensions in moderate to severe COPD."	2.41	Oral theophylline for chronic obstructive pulmonary disease. ( Atallah, AN; Castro, AA; Cendon, S; De Brito, JA; Goldstein, R; Jones, PW; Lacasse, Y; Mazzini, R; Ram, FS, 2002)
"Chronic obstructive lung disease affects over 15 million people in the United States."	2.39	Management of chronic obstructive pulmonary disease. ( Donohue, JF, 1995)
"Theophylline and CDH5 were exclusively elevated in advanced COPD but not in its mild form."	1.91	Proteomics and metabolomics profiling reveal panels of circulating diagnostic biomarkers and molecular subtypes in stable COPD. ( Chen, L; Fang, Y; He, S; Li, Q; Li, Y; Lin, F; Liu, F; Lu, W; Wang, J; Wei, X; Zhang, Z; Zhou, J, 2023)
"Doxofylline was shown to improve ventilation and air exchange during mechanical ventilation in rats with COPD, reduce the inflammatory response and oxidative stress, and mitigate the degree of pulmonary tissue injury."	1.72	Effect of doxofylline on pulmonary inflammatory response and oxidative stress during mechanical ventilation in rats with COPD. ( Chen, ZY; Chu, SQ; Li, Y; Lin, YM; Wu, JH; Xie, WX; Zhang, XQ; Zhang, Y, 2022)
"Chronic obstructive pulmonary disease (COPD) is characterized by reduced sensitivity of cells to the anti-inflammatory effects of glucocorticoids (GCs)."	1.62	[The effect of glucocorticoids in combination with azithromycin or theophylline on cytokine production by NK and NKT-like blood cells of patients with chronic obstructive pulmonary disease]. ( Kadushkin, AG; Khadasouskaya, AV; Kolesnikova, TS; Movchan, LV; Shman, TV; Tahanovich, AD, 2021)
"The relationship between chronic obstructive pulmonary disease (COPD) and reflux esophagitis (RE) was controversial."	1.62	Reflux esophagitis in patients with chronic obstructive pulmonary disease. ( Ha, SY; Kang, HH; Lee, J; Lee, SH; Oh, JH; Seo, M, 2021)
"Theophylline has an anti-inflammatory role in COPD."	1.51	Theophylline inhibits cigarette smoke-induced inflammation in skeletal muscle by upregulating HDAC2 expression and decreasing NF-κB activation. ( Bai, J; Bin, Y; He, Z; Huang, D; Liang, Q; Liang, Y; Ma, Z; Xiao, Y; Zhang, J; Zhang, W; Zhong, X, 2019)
"Chronic obstructive pulmonary disease (COPD) is common around the world and carries a high morbidity and mortality."	1.48	Medical Treatment of COPD. ( Ficker, JH; Graf, J; Jörres, RA; Lucke, T; Nowak, D; Vogelmeier, CF, 2018)
"Congestive cardiac failure, congestive liver disease and polypharmacy were factors isolated from this case that expedited the patients' development of theophylline toxicity."	1.43	Case Report: The risks associated with chronic theophylline therapy and measures designed to improve monitoring and management. ( Hopkins, ME; MacKenzie-Ross, RV, 2016)
"Theophylline (TP) is a bronchodilator used orally to treat chronic obstructive pulmonary disease (COPD) that has been associated with multiple side effects, tempering its present use."	1.42	The formulation of a pressurized metered dose inhaler containing theophylline for inhalation. ( Goud, M; Haghi, M; Traini, D; Young, PM; Zhu, B, 2015)
"We have shown that COPD patients have increased steroid resistant CD28null (senescent) pro-inflammatory T and NKT-like peripheral blood cells (particularly CD8+ subsets) and we hypothesized that these changes would be associated with a loss of HDAC2 from these senescent pro-inflammatory lymphocytes."	1.42	Lymphocyte senescence in COPD is associated with decreased histone deacetylase 2 expression by pro-inflammatory lymphocytes. ( Hodge, G; Hodge, S; Holmes, M; Jersmann, H; Reynolds, PN; Roscioli, E; Tran, HB, 2015)
"Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids."	1.42	Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD. ( Agustí, A; Busquets, X; Cosío, BG; Iglesias, A; Jahn, A; Shafiek, H, 2015)
"Treatment with theophylline is associated with an elevated incidence of exacerbations and hospitalizations."	1.40	The effects of theophylline on hospital admissions and exacerbations in COPD patients: audit data from the Bavarian disease management program. ( Donnachie, E; Fexer, J; Hofmann, F; Keller, M; Mehring, M; Schneider, A; Wagenpfeil, S, 2014)
"We analyzed COPD subjects with GOLD I-IV disease in the COPDGene® study."	1.38	Demographic, physiologic and radiographic characteristics of COPD patients taking chronic systemic corticosteroids. ( Criner, GJ; Kim, V; Make, BJ; Murphy, JR; Newell, J; Satti, A; Silverman, EK; Steiner, RM; Swift, I; Wilson, C, 2012)
"Chronic obstructive pulmonary disease (COPD) is characterized by the abnormal and chronic lung inflammation."	1.38	Low dose theophylline showed an inhibitory effect on the production of IL-6 and IL-8 in primary lung fibroblast from patients with COPD. ( Feng, MX; Qu, JM; Zhang, J, 2012)
"The Spanish COPD Guidelines (GesEPOC) is an initiative of SEPAR, which, together with the scientific societies involved in COPD patient care, and the Spanish Patient Forum, has developed these new clinical practice guidelines."	1.38	Spanish COPD Guidelines (GesEPOC): pharmacological treatment of stable COPD. Spanish Society of Pulmonology and Thoracic Surgery. ( Almagro, P; Ancochea, J; Calle, M; López-Campos, JL; Miravitlles, M; Molina, J; Piñera, P; Quintano, JA; Riesco, JA; Simón, A; Soler-Cataluña, JJ; Soriano, JB; Trigueros, JA, 2012)
"The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats."	1.38	Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques. ( Chakraborty, S; Mishra, B; Shukla, D, 2012)
"We found that patients with COPD were vulnerable and that factors determining vulnerability were different for men than for women."	1.38	Vulnerability of patients with chronic obstructive pulmonary disease according to gender in China. ( Chen, N; Chen, P; Lou, P; Wu, H; Yu, J; Zhang, L; Zhang, N; Zhang, P; Zhao, J; Zhu, Y, 2012)
"Treatment with ciprofloxacin is associated with a significant increase in the risk of theophylline toxicity."	1.37	Ciprofloxacin-induced theophylline toxicity: a population-based study. ( Antoniou, T; Gomes, T; Juurlink, DN; Mamdani, MM, 2011)
"In the second model, in blood of COPD-patients and healthy controls ex vivo pre-incubated with a physiological concentration of 1,7-dimethylxanthine (10microM), LPS-induced production of the cytokines IL-6 and TNF-alpha was significantly suppressed."	1.36	Inhibition of acute pulmonary and systemic inflammation by 1,7-dimethylxanthine. ( Bast, A; Brauers, K; Geraets, L; Haegens, A; Hageman, GJ; Vernooy, JH; Weseler, AR; Wouters, EF, 2010)
"Theophylline was a potent selective inhibitor of oxidant-activated PI3K-δ, which was up-regulated in peripheral lung tissue of patients with COPD."	1.36	Targeting phosphoinositide-3-kinase-delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. ( Adcock, IM; Barnes, PJ; Elliott, WM; Failla, M; Hogg, JC; Ito, K; Ito, M; Kizawa, Y; Kusama, T; To, Y, 2010)
"Despite increased awareness, COPD remains underdiagnosed."	1.36	[Update on current care guidelines: Chronic obstructive pulmonary disease, diagnosis and treatment]. ( , 2010)
"The study included patients with stable COPD and aged >or= 40 years, evaluated in primary care."	1.35	Characteristics of chronic obstructive pulmonary disease in Spain from a gender perspective. ( Carrasco-Garrido, P; de Miguel, AG; de Miguel-Díez, J; Gobartt-Vázquez, E; Hernandez-Barrera, V; Jimenez-Garcia, R; Martín-Centeno, A; Rejas-Gutierrez, J, 2009)
"Theophylline has a lower efficacy/tolerance ratio than inhaled bronchodilators."	1.35	[Pharmacological treatment of stable chronic obstructive pulmonary disease]. ( Allain, YM; Giraud, F; Huchon, G; Roche, N, 2009)
"Increased FKBP51 in COPD patients treated with formoterol/ budesonide/theophylline may be important in altering signaling from corticosteroid receptors."	1.35	Increased FKBP51 in induced sputum cells of chronic obstructive pulmonary disease patients after therapy. ( Braszko, JJ; Chyczewska, E; Holownia, A; Kolodziejczyk, A; Mroz, RM, 2009)
"A cohort of 36,492 chronic obstructive pulmonary disease (COPD) patients aged > or =50 years was reconstructed from the health administrative databases of the province of Quebec, Canada, between 1 January 1995 and 31 December 2002 to compare users of theophyllines with users of inhaled corticosteroids (ICS) and users of long-acting beta(2)-agonists (LABA) on their rate of moderate to severe COPD exacerbations."	1.35	Effect of theophylline on the rate of moderate to severe exacerbations among patients with chronic obstructive pulmonary disease. ( Beauchesne, MF; Blais, L; Cyr, MC; Lemière, C, 2008)
"Exacerbations of chronic obstructive pulmonary disease (COPD) are an important cause of both morbidity and mortality."	1.34	[Treatment of exacerbations of chronic obstructive pulmonary disease]. ( Luchetti, L; Urso, DL, 2007)
"Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation, measured by the forced expiratory volume in 1 second (FEV1) after the administration of bronchodilator."	1.34	[Diagnosis and management of chronic obstructive pulmonary disease]. ( Kanazawa, M; Sato, N, 2007)
"Concomitant GERD was revealed in 45."	1.33	[Gastroesophageal reflux disease and respiratory apparatus pathology: the evidence of interrelation and unsolved problems]. ( Chereĭskaia, NK; Isakov, VA; Ivanova, OV; Paleev, NR, 2005)
"Treatment with theophylline decreased the percentage of neutrophil and the concentrations of LTB4 in BALF of the COPD rats, attenuated the pathological changes of small airways, such as airway occlusion, goblet-cell metaplasia, inflammatory cell infiltration, and fibrosis and smooth muscle proliferation."	1.33	[Changes of leukotriene B4 in chronic obstructive pulmonary disease and effects of theophylline on leukotriene B4]. ( Ding, YL; Liu, Z; Yao, WZ; Zheng, J; Zhu, YL, 2005)
"Exacerbations in COPD patients are characterized by an acute aggravation of the condition with an increase in symptoms (labored breathing, cough, expectoration, tightness of the chest and, rarely, fever)."	1.33	[COPD--how to deal with an acute exacerbation]. ( Worth, H, 2006)
" It should be noted that these effects were more pronounced in the mean daily theophylline dosage regimen."	1.33	[Effect of theophylline on respiratory function in patients with chronic obstructive lung disease]. ( Altymysheva, AT; Kadyraliev, ZhK; Mirrakhimov, MM; Shabykeeva, SB; Sooronbaev, TM, 2006)
"Thirty stable COPD patients (all smokers) with disease severity ranging from mild to severe."	1.32	Oxidative stress in expired breath condensate of patients with COPD. ( Kostikas, K; Loukides, S; Panagou, P; Papatheodorou, G; Psathakis, K, 2003)
"Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lungs with little or no response to glucocorticoids and a high level of oxidative stress."	1.32	Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. ( Adcock, IM; Barnes, PJ; Cosio, BG; Ito, K; Jazrawi, E; Tsaprouni, L, 2004)
"Theophylline is a drug used in the treatment of obstructive pulmonary disease and a strong immunomodulator and has anti-inflammatory potential."	1.32	[The influence of theophilline on oxygen metabolism of neutrophils in vitro]. ( Puszczewicz, M; Zielińska, M, 2004)
"inhibition: 97."	1.32	Effects of piclamilast, a selective phosphodiesterase-4 inhibitor, on oxidative burst of sputum cells from mild asthmatics and stable COPD patients. ( Beeh, KM; Beier, J; Buhl, R; Lerch, C; Schulz, AK, 2004)
" These results indicate that the treatment with the greater dosage administration of Unifil is effective to improve the physiological function of the respiratory system in elderly patients with COPD, and it may be the treatment of choice for elderly COPD patients."	1.31	[Effect of sustained release of theophylline on pulmonary physiologic function in elderly patients with chronic obstructive pulmonary disease]. ( Teramoto, S, 2002)

Research

Studies (208)

Authors

Clinical Trials (17)

Trial Overview

Trial Outcomes

Change in COPD Assessment Test (CAT) Score

Timeframe	Studies, this research(%)	All Research%
pre-1990	0 (0.00)	18.7374
1990's	2 (0.96)	18.2507
2000's	118 (56.73)	29.6817
2010's	70 (33.65)	24.3611
2020's	18 (8.65)	2.80

Authors	Studies
Kodimuthali, A	1
Jabaris, SS	1
Pal, M	1
Du, X	1
Bao, H	1
Zhao, D	1
Chen, ZY	2
Lin, YM	1
Wu, JH	2
Zhang, XQ	1
Zhang, Y	3
Xie, WX	1
Chu, SQ	1
Li, Y	2
Sevik, OE	1
Canakci, ME	1
Zhang, Z	3
Wang, J	2
Liu, F	1
Chen, L	1
He, S	1
Lin, F	1
Wei, X	1
Fang, Y	1
Li, Q	1
Zhou, J	1
Lu, W	1
Boylan, PM	1
Abdalla, M	1
Bissell, B	1
Malesker, MA	1
Santibañez, M	1
Smith, Z	1
Zhao, X	1
Ma, H	1
Pan, Q	1
Wang, H	1
Qian, X	1
Song, P	1
Zou, L	1
Mao, M	1
Xia, S	1
Ge, G	1
Yang, L	1
Cazzola, M	8
Matera, MG	4
Balakrishnan, S	1
Rakesh, PS	1
Jayasankar, S	1
Sunilkumar, M	1
Krishnaveni, V	1
Gopal, B	1
Manu, MS	1
Achuthan Nair, S	1
Jenkins, CR	1
Wen, FQ	1
Martin, A	1
Barnes, PJ	19
Celli, B	2
Zhong, NS	3
Zheng, JP	2
Scaria, A	1
Di Tanna, GL	1
Bradbury, T	1
Berend, N	1
Siddharthan, T	1
Pollard, SL	1
Jackson, P	1
Robertson, NM	1
Wosu, AC	1
Rahman, N	1
Padalkar, R	1
Sekitoleko, I	1
Namazzi, E	1
Alupo, P	1
Hurst, JR	1
Kalyesubula, R	1
Dowdy, D	1
Wise, R	1
Checkley, W	1
Kirenga, B	1
Roche, N	2
Shuai, T	1
Zhang, C	1
Zhang, M	1
Wang, Y	3
Xiong, H	1
Huang, Q	1
Liu, J	2
Kunisaki, KM	1
Sin, DD	2
Zheng, XF	1
Chen, DD	1
Zhu, XL	1
Le Grange, JM	1
Zhou, LQ	1
Zhang, JN	1
Kadushkin, AG	1
Tahanovich, AD	1
Movchan, LV	1
Kolesnikova, TS	1
Khadasouskaya, AV	1
Shman, TV	1
Liu, CY	1
Huang, CL	1
Lin, AM	1
Xu, XT	1
Gao, XH	1
Kang, HH	1
Seo, M	1
Lee, J	1
Ha, SY	1
Oh, JH	1
Lee, SH	1
Shih, YN	1
Chen, YT	1
Chu, H	1
Shih, CJ	1
Ou, SM	1
Hsu, YT	1
Chen, RC	1
Quraishi, SA	1
Aisiku, IP	1
Seethala, RR	1
Frendl, G	1
Hou, PC	1
Nath, A	1
Khan, A	1
Hashim, Z	1
Toledo-Pons, N	1
Cosío, BG	5
Quanqing, M	1
Page, C	2
Calzetta, L	2
Rogliani, P	1
Criner, GJ	3
Martinez, FJ	2
Papi, A	1
Gabriella Matera, M	2
Ma, Y	1
Xue, L	1
Chen, X	1
Kang, Y	1
Wang, L	1
Pleasants, RA	1
Henriksen, DP	1
Davidsen, JR	1
Laursen, CB	1
Graf, J	1
Jörres, RA	1
Lucke, T	1
Nowak, D	1
Vogelmeier, CF	2
Ficker, JH	1
Celli, BR	2
Devereux, G	3
Cotton, S	3
Fielding, S	3
McMeekin, N	2
Briggs, A	3
Burns, G	3
Chaudhuri, R	3
Chrystyn, H	3
Davies, L	3
De Soyza, A	2
Gompertz, S	3
Haughney, J	3
Innes, K	2
Kaniewska, J	2
Lee, A	2
Morice, A	3
Norrie, J	3
Sullivan, A	3
Wilson, A	3
Price, D	3
Bin, Y	1
Xiao, Y	1
Huang, D	1
Ma, Z	1
Liang, Y	1
Bai, J	1
Zhang, W	1
Liang, Q	1
Zhang, J	2
Zhong, X	1
He, Z	1
Xiong, XF	1
Fan, LL	1
Wu, HX	1
Zhu, M	1
Cheng, DY	1
Caramori, G	3
Coppolino, I	1
Cannavò, MF	1
Nucera, F	1
Proietto, A	1
Mumby, S	1
Ruggeri, P	1
Adcock, IM	7
Meek, P	1
Lareau, S	1
Fahy, B	1
Austegard, E	1
Soyza, A	1
Goodwin, AT	1
Singanayagam, A	1
Jenkins, G	1
Wu, JP	1
Wu, Q	1
Sun, X	1
Sun, HF	1
Gosch, M	1
Dovjak, P	1
Mineshita, M	1
Matsuoka, S	1
Miyazawa, T	1
Al-Alawi, M	1
Hassan, T	1
Chotirmall, SH	1
Kirkham, PA	1
Whiteman, M	1
Winyard, PG	1
Gordon, F	2
Ford, PA	2
Chung, KF	1
Fexer, J	2
Donnachie, E	2
Schneider, A	2
Wagenpfeil, S	2
Keller, M	2
Hofmann, F	2
Mehring, M	2
Windeler, J	1
Page, CP	3
Lal, D	1
Manocha, S	1
Ray, A	1
Vijayan, VK	1
Kumar, R	1
Zhu, B	1
Haghi, M	1
Goud, M	1
Young, PM	1
Traini, D	1
Barnes, P	1
Lee, AJ	1
McCormack, K	1
McPherson, G	1
Hodge, G	1
Jersmann, H	1
Tran, HB	1
Roscioli, E	1
Holmes, M	1
Reynolds, PN	1
Hodge, S	1
Scott, DA	1
Woods, B	1
Thompson, JC	1
Clark, JF	1
Hawkins, N	1
Chambers, M	1
Calverley, P	1
Horita, N	1
Miyazawa, N	1
Kojima, R	1
Inoue, M	1
Ishigatsubo, Y	1
Kaneko, T	1
Jahn, A	1
Iglesias, A	3
Shafiek, H	2
Busquets, X	1
Agustí, A	3
Lahousse, L	1
Verhamme, KM	1
Stricker, BH	1
Brusselle, GG	1
Hopkins, ME	1
MacKenzie-Ross, RV	1
Pomares, X	1
Montón, C	1
Yanez, A	1
Córdova, R	1
Palou, A	1
Rodriguez-Roisin, R	1
Peces-Barba, G	1
Pascual, S	1
Gea, J	1
Sibila, O	1
Spina, D	1
Najafzadeh, M	1
Marra, CA	1
Sadatsafavi, M	1
Aaron, SD	2
Sullivan, SD	1
Vandemheen, KL	1
Jones, PW	2
Fitzgerald, JM	1
Kuebler, KK	1
Buchsel, PC	1
Balkstra, CR	1
Lee, TA	2
Pickard, AS	2
Au, DH	1
Bartle, B	2
Weiss, KB	1
Kanehara, M	1
Yokoyama, A	1
Tomoda, Y	1
Shiota, N	1
Iwamoto, H	1
Ishikawa, N	1
Taooka, Y	1
Haruta, Y	1
Hattori, N	1
Kohno, N	1
Stiefelhagen, P	2
Carrasco-Garrido, P	1
de Miguel-Díez, J	1
Rejas-Gutierrez, J	1
Martín-Centeno, A	1
Gobartt-Vázquez, E	1
Hernandez-Barrera, V	1
de Miguel, AG	1
Jimenez-Garcia, R	1
Rios, A	1
Noguera, A	1
Sala, E	1
Ito, K	5
Allain, YM	1
Giraud, F	1
Huchon, G	1
Beecham, N	1
Doherty, DE	2
Mahler, DA	1
Murray, JA	1
Waterman, LA	1
Ward, J	1
Kraemer, WJ	1
Zhang, X	1
Baird, JC	1
Miravitlles, M	3
Murio, C	2
Tirado-Conde, G	1
Levy, G	1
Muellerova, H	1
Soriano, JB	2
Ramirez-Venegas, A	1
Ko, FW	1
Canelos-Estrella, B	1
Giugno, E	1
Bergna, M	1
Chérrez, I	1
Anzueto, A	1
Santra, CK	1
Kerstjens, HA	3
Postma, DS	3
Ten Hacken, N	4
Bulut, I	1
Arbak, P	1
Coskun, A	1
Balbay, O	1
Annakkaya, AN	1
Yavuz, O	1
Gülcan, E	1
Bayram, H	1
Shukla, D	2
Chakraborty, S	2
Singh, S	1
Mishra, B	2
Schumock, GT	1
Geraets, L	2
Haegens, A	1
Weseler, AR	1
Brauers, K	1
Vernooy, JH	1
Wouters, EF	2
Bast, A	2
Hageman, GJ	2
Mizutani, N	1
Fuchikami, J	1
Takahashi, M	1
Nabe, T	1
Yoshino, S	1
Kohno, S	1
Holownia, A	1
Mroz, RM	2
Kolodziejczyk, A	1
Chyczewska, E	2
Braszko, JJ	2
Troosters, T	1
Lystig, T	1
Kesten, S	1
Mehra, S	1
Tashkin, DP	2
Decramer, M	1
Li, YY	1
Liu, XS	1
Xu, YJ	2
To, Y	1
Kizawa, Y	1
Failla, M	1
Ito, M	1
Kusama, T	1
Elliott, WM	1
Hogg, JC	1
Durham, AL	1
Russell, RE	2
Palamarthy, AB	1
Wang, CH	1
Zhang, Q	1
Li, M	1
Fu, PF	1
Yan, ZM	1
Peng, AM	1
Zhang, GL	1
Uslu, A	1
Ogus, C	1
Ozdemir, T	1
Bilgen, T	1
Tosun, O	1
Keser, I	1
Rabe, KF	3
Hiemstra, PS	1
Antoniou, T	1
Gomes, T	1
Mamdani, MM	1
Juurlink, DN	1
McIvor, RA	1
Tunks, M	1
Todd, DC	1
Schudt, C	1
Hatzelmann, A	1
Beume, R	1
Tenor, H	1
Li, JS	1
Li, SY	1
Yu, XQ	1
Xie, Y	1
Wang, MH	1
Li, ZG	1
Zhang, NZ	1
Shao, SJ	1
Zhang, YJ	1
Zhu, L	1
Guo, LX	1
Bai, YP	1
Wang, YF	1
Wang, T	1
Luo, G	1
Hu, Y	1
Li, F	1
Ma, J	1
Zuo, P	1
Xiong, W	1
Liu, X	1
Zhao, J	2
Xiong, S	1
Li, C	1
Zhao, S	1
Sun, J	1
Xu, Y	2
Zhang, WH	1
Cui, YY	1
Rong, WF	1
Cambier, C	1
Devillier, P	2
Bureau, F	1
Advenier, C	1
Gustin, P	1
Swift, I	1
Satti, A	1
Kim, V	1
Make, BJ	1
Newell, J	1
Steiner, RM	1
Wilson, C	1
Murphy, JR	1
Silverman, EK	1
Feng, MX	1
Qu, JM	1
Soler-Cataluña, JJ	1
Calle, M	1
Molina, J	1
Almagro, P	1
Quintano, JA	1
Riesco, JA	1
Trigueros, JA	1
Piñera, P	1
Simón, A	1
López-Campos, JL	1
Ancochea, J	1
Voduc, N	1
Alvarez, GG	1
Amjadi, K	1
Tessier, C	1
Sabri, E	1
Szelenyi, I	1
Lou, P	1
Zhu, Y	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
The Effect of Low-dose Corticosteroids and Theophylline on the Risk of Acute Exacerbations of COPD: the TASCS Randomised Clinical Trial[NCT02261727]	Phase 4	1,670 participants (Actual)	Interventional	2014-06-30	Completed
Effectiveness of Low-Dose Theophylline for the Management of Biomass-Associated COPD[NCT03984188]	Phase 3	100 participants (Actual)	Interventional	2021-02-23	Completed
Impact of Systemic Manifestations/Comorbidities on Clinical State, Prognosis and Utilisation of Health Care Resources in Patients With COPD[NCT01245933]		2,741 participants (Actual)	Observational	2010-11-30	Active, not recruiting
Enhancement of In-vitro GC Function in Patients With COPD. A Randomised, Double Blind, Placebo Controlled, Parallel-group Study to Investigate the Effect of Theophylline and Fluticasone on Induced Sputum Cells Obtained Form COPD Patients[NCT00241631]	Phase 2	49 participants (Actual)	Interventional	2006-04-30	Completed
Efficacy Of Doxophylline As A Sparing Treatment For Inhaled Corticosteroids In Mexican Children With Asthma[NCT03879590]	Phase 3	60 participants (Anticipated)	Interventional	2019-05-31	Not yet recruiting
Multicenter 52 Weeks Double Blind Placebo-controlled Trial for the Assessment of Theophylline on Top of Combination Therapy in Severe COPD[NCT01599871]	Phase 3	70 participants (Actual)	Interventional	2011-01-31	Completed
Comparative Effectiveness of COPD Assessment and Management Bundle Versus Usual Care in Patients Suspected of Having COPD[NCT01833026]		56 participants (Actual)	Interventional	2013-03-31	Completed
Reducing Diagnostic Error to Improve Patient Safety in COPD and Asthma (REDEFINE Study)[NCT03137303]	Phase 3	402 participants (Actual)	Interventional	2017-07-01	Completed
Molecular Mechanisms of COPD Exacerbations. Effect of Low-Dose Theophylline[NCT00671151]		35 participants (Actual)	Interventional	2005-06-30	Completed
Role of Endorphins in the Perception of Dyspnea in Patients With Chronic Obstructive Pulmonary Disease[NCT00458419]		17 participants (Actual)	Interventional	2005-09-30	Completed
A Randomized, Double-blind, Placebo-controlled, Parallel Group Trial Assessing the Rate of Decline of Lung Function With Tiotropium 18 mcg Inhalation Capsule Once Daily in Patients With Chronic Obstructive Pulmonary Disease (COPD).[NCT00144339]	Phase 3	5,993 participants (Actual)	Interventional	2002-12-31	Completed
Effect of Theophylline on Exercise Capacity and Lung Function in COPD Patients Receiving Long-acting Inhaled Bronchodilator Therapy[NCT00299858]	Phase 2/Phase 3	24 participants (Actual)	Interventional	2006-10-31	Completed
Exhaled Breath Condensate (EBC) Collection and Analysis in Mechanically Ventilated ICU Patients: Monitoring of the Influence of Various Tidal Volumes on Lung Inflammatory Biomarkers[NCT00910026]		20 participants (Anticipated)	Interventional	2009-05-31	Completed
Clinical Implementation and Outcomes Evaluation of Blood-Based Biomarkers for COPD Management: COPD Prednisone Sub-Study[NCT02534402]	Phase 4	40 participants (Actual)	Interventional	2015-08-31	Active, not recruiting
Clinical Implementation and Outcomes Evaluation of Blood-Based Biomarkers for Chronic Obstructive Pulmonary Disease Management[NCT02050022]		522 participants (Actual)	Observational	2013-04-30	Active, not recruiting
Smell in COVID-19 and Efficacy of Nasal Theophylline 3[NCT05947643]	Phase 2	240 participants (Anticipated)	Interventional	2022-11-22	Recruiting
A Randomized, Double-blind, Placebo and Active-controlled, Incomplete Block Cross-over, Dose Ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 1531 pMDI (Formoterol Fumarate) in Asthmatic Subjects[NCT03086460]	Phase 2	67 participants (Actual)	Interventional	2017-09-08	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

The COPD Assessment Test (CAT) is a patient-completed questionnaire assessing globally the impact of COPD (cough, sputum, dysnea, chest tighteness) on health status. The range of CAT scores from 0-40. Higher scores denote a more severe impact of COPD on a patient's life. The outcome measure is assessing the change in score from baseline to 48 weeks. A negative change denotes an improvement in health status. (NCT02261727)
Timeframe: 48 weeks

Hospitalisations

Intervention	Score on a scale (Mean)
Placebo	-2.29
Low-dose Theophylline Arm	-2.77
Theophylline and Prednisone Arm	-2.57

The total number of hospitalisation events within 48 weeks (NCT02261727)
Timeframe: 48 weeks

Post Bronchodilator FEV1

Intervention	Number of hospitalisation events (Number)
Placebo	120
Low-dose Theophylline Arm	101
Theophylline and Prednisone Arm	122

The change in post bronchodilator FEV1 from baseline to 48 weeks (NCT02261727)
Timeframe: Change at 48 weeks

Quality of Life Measured by St. George's Respiratory Questionnaire (SGRQ)

Intervention	L/sec (Mean)
Placebo	-0.02
Low-dose Theophylline Arm	-0.01
Theophylline and Prednisone Arm	-0.02

THe St. George's Respiratory Questionnaire (SGRQ) is a disease-specific instrument designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations. (NCT02261727)
Timeframe: Change over 48 week study duration

Time to First COPD Exacerbation

Intervention	Scores on a scale (Mean)
Placebo	-4.95
Low-dose Theophylline Arm	-6.85
Theophylline and Prednisone Arm	-6.48

The median time (days) from randomisation to first exacerbation per participant (NCT02261727)
Timeframe: Median time (days) from randomisation to first exacerbation over a 48 week period per participant

Total COPD Exacerbation Rate

Intervention	Days (Median)
Placebo	137
Low-dose Theophylline Arm	150
Theophylline and Prednisone Arm	151

The total number of COPD exacerbations reported within 48 weeks (NCT02261727)
Timeframe: 48 weeks observation; rate annualised

Interleukin 8 (IL8)

Sputum Inflammatory Cell Counts

Intervention	Exacerbations per participant year (Number)
Placebo	1.00
Low-dose Theophylline Arm	0.86
Theophylline and Prednisone Arm	0.89

Intervention	ng/mL (Mean)
Placebo	33.3
Steroid	28.3

Supernatant collect, cell pellets count on slides (NCT00241631)
Timeframe: 10 weeks

Total Sputum Eosinophils

Number of Participants With Accurate Classification of Irreversible Airflow Obstruction

Intervention	millions cells/ ml (Mean)
Placebo	5.42
Steroid	3.89

Intervention	millions cells/ml (Mean)
Placebo	0.132
Steroid	0.053

accuracy of diagnosis was the outcome measure. The results of the spirometry test (done in the beginning for the intervention group and ant the end of 1 year for the usual care groups) were reviewed in conjunction with the initial physician diagnosis of COPD and/or asthma to confirm whether the diagnosis was accurate, not accurate, or indeterminate. Accuracy of diagnosis of COPD was determined by spirometry results if the FEV1/FVC ratio was <0.7. (NCT01833026)
Timeframe: spirometry was performed at the first visit for intervention group and at 1 year from recruitment for the usual care group, one time assessment for both groups

Total Number of Healthcare Visits

Intervention	Participants (Count of Participants)
COPD Assessment and Management Recommendations	10
Usual Care	5

Determine differences in healthcare visits which include all-cause and respiratory related, acute care outpatient visits, emergency department visits, and hospitalizations between groups (NCT03137303)
Timeframe: 1 year

Days of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Leading to Hospitalization

Intervention	Participants (Count of Participants)
	Emergency room visit72551318	Emergency room visit72551317	Hospitalization72551317	Hospitalization72551318	Acute outpatient visit72551318	Acute outpatient visit72551317	Routine primary care visits72551317	Routine primary care visits72551318	New diagnostic tests72551318	New diagnostic tests72551317
	No	Missing	Yes
Patient Subject Usual Care	111
Patient-Subject Intervention	76
Patient Subject Usual Care	119
Patient-Subject Intervention	93
Patient Subject Usual Care	1
Patient Subject Usual Care	48
Patient-Subject Intervention	17
Patient Subject Usual Care	182
Patient-Subject Intervention	152
Patient Subject Usual Care	61
Patient-Subject Intervention	35
Patient Subject Usual Care	169
Patient-Subject Intervention	134
Patient Subject Usual Care	198
Patient-Subject Intervention	138
Patient Subject Usual Care	32
Patient-Subject Intervention	31
Patient-Subject Intervention	2
Patient Subject Usual Care	126
Patient-Subject Intervention	72
Patient Subject Usual Care	104
Patient-Subject Intervention	97

Number of days with chronic obstructive pulmonary disease (COPD) exacerbation leading to hospitalization (normalized by treatment exposure) (NCT00144339)
Timeframe: From Day 1 to 4 years

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1

Intervention	days/patient year (Mean)
Placebo	3.13
Tiotropium Bromide Inhalation Capsules 18 mcg	3.17

Estimated forced expiratory volume in one second (FEV1) after bronchodilator at month 1 (NCT00144339)
Timeframe: Month 1

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42

Intervention	L (Mean)
Placebo	1.372
Tiotropium Bromide Inhalation Capsules 18 mcg	1.418

Intervention	L (Mean)
Placebo	1.345
Tiotropium Bromide Inhalation Capsules 18 mcg	1.398

Intervention	L (Mean)
Placebo	1.326
Tiotropium Bromide Inhalation Capsules 18 mcg	1.379

Intervention	L (Mean)
Placebo	1.294
Tiotropium Bromide Inhalation Capsules 18 mcg	1.356

Intervention	L (Mean)
Placebo	1.274
Tiotropium Bromide Inhalation Capsules 18 mcg	1.335

Intervention	L (Mean)
Placebo	1.250
Tiotropium Bromide Inhalation Capsules 18 mcg	1.315

Estimated FEV1 after bronchodilator at Month 42 (NCT00144339)
Timeframe: Month 42

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48

Estimated Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 1

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 12

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 18

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 24

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 30

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 36

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 42

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 48

Estimated Post-bronchodilator Forced Vital Capacity (FVC) at Month 6

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 1

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 12

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 18

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 24

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 30

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 36

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 42

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 48

Estimated Post-bronchodilator Slow Vital Capacity (SVC) at Month 6

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 1

Intervention	L (Mean)
Placebo	1.236
Tiotropium Bromide Inhalation Capsules 18 mcg	1.297

Intervention	L (Mean)
Placebo	1.219
Tiotropium Bromide Inhalation Capsules 18 mcg	1.268

Intervention	L (Mean)
Placebo	1.365
Tiotropium Bromide Inhalation Capsules 18 mcg	1.423

Intervention	L (Mean)
Placebo	3.149
Tiotropium Bromide Inhalation Capsules 18 mcg	3.204

Intervention	L (Mean)
Placebo	3.110
Tiotropium Bromide Inhalation Capsules 18 mcg	3.158

Intervention	L (Mean)
Placebo	3.075
Tiotropium Bromide Inhalation Capsules 18 mcg	3.126

Intervention	L (Mean)
Placebo	3.036
Tiotropium Bromide Inhalation Capsules 18 mcg	3.095

Intervention	L (Mean)
Placebo	3.010
Tiotropium Bromide Inhalation Capsules 18 mcg	3.057

Intervention	L (Mean)
Placebo	2.973
Tiotropium Bromide Inhalation Capsules 18 mcg	3.038

Intervention	L (Mean)
Placebo	2.959
Tiotropium Bromide Inhalation Capsules 18 mcg	3.005

Intervention	L (Mean)
Placebo	2.929
Tiotropium Bromide Inhalation Capsules 18 mcg	2.961

Intervention	L (Mean)
Placebo	3.137
Tiotropium Bromide Inhalation Capsules 18 mcg	3.193

Intervention	L (Mean)
Placebo	3.280
Tiotropium Bromide Inhalation Capsules 18 mcg	3.318

Intervention	L (Mean)
Placebo	3.228
Tiotropium Bromide Inhalation Capsules 18 mcg	3.260

Intervention	L (Mean)
Placebo	3.195
Tiotropium Bromide Inhalation Capsules 18 mcg	3.234

Intervention	L (Mean)
Placebo	3.157
Tiotropium Bromide Inhalation Capsules 18 mcg	3.189

Intervention	L (Mean)
Placebo	3.126
Tiotropium Bromide Inhalation Capsules 18 mcg	3.157

Intervention	L (Mean)
Placebo	3.086
Tiotropium Bromide Inhalation Capsules 18 mcg	3.136

Intervention	L (Mean)
Placebo	3.073
Tiotropium Bromide Inhalation Capsules 18 mcg	3.100

Intervention	L (Mean)
Placebo	3.041
Tiotropium Bromide Inhalation Capsules 18 mcg	3.067

Intervention	L (Mean)
Placebo	3.268
Tiotropium Bromide Inhalation Capsules 18 mcg	3.304

Estimated FEV1 before bronchodilator at Month 1 (NCT00144339)
Timeframe: Month 1

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 12

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 18

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 24

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 30

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 36

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 42

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 48

Estimated Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Month 6

Intervention	L (Mean)
Placebo	1.134
Tiotropium Bromide Inhalation Capsules 18 mcg	1.221

Intervention	L (Mean)
Placebo	1.111
Tiotropium Bromide Inhalation Capsules 18 mcg	1.213

Intervention	L (Mean)
Placebo	1.101
Tiotropium Bromide Inhalation Capsules 18 mcg	1.192

Intervention	L (Mean)
Placebo	1.079
Tiotropium Bromide Inhalation Capsules 18 mcg	1.173

Intervention	L (Mean)
Placebo	1.061
Tiotropium Bromide Inhalation Capsules 18 mcg	1.156

Intervention	L (Mean)
Placebo	1.045
Tiotropium Bromide Inhalation Capsules 18 mcg	1.144

Intervention	L (Mean)
Placebo	1.034
Tiotropium Bromide Inhalation Capsules 18 mcg	1.129

Estimated forced expiratory volume in one second (FEV1) before bronchodilator at month 6 (NCT00144339)
Timeframe: Month 6

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 1

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 12

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 18

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 24

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 30

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 36

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 42

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 48

Estimated Pre-bronchodilator Forced Vital Capacity (FVC) at Month 6

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 1

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 12

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 18

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 24

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 30

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 36

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 42

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 48

Estimated Pre-bronchodilator Slow Vital Capacity (SVC) at Month 6

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 12

"SGRQ total score summarizes the impact of COPD on overall patient's health status.~Total scores are expressed as a percentage of overall impairment where 100 represents worst possible health status and 0 indicates best possible health status.~The scale is continuous.~Rate of decline shows the yearly change of SGRQ total score." (NCT00144339)
Timeframe: Month 12

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 18

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 24

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 30

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 36

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 42

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 48

Estimated St George's Respiratory Questionnaire (SGRQ) Total Score at Month 6

Number of Chronic Obstructive Pulmonary Disease (COPD) Exacerbations Per Patient Year

Number of Exacerbation Days Per Patient Year

Number of exacerbation days normalized by treatment exposure (NCT00144339)
Timeframe: Day 1 to 4 years

Number of Exacerbation Leading to Hospitalization

Estimated number of exacerbations leading to hospitalizations per patient year (NCT00144339)
Timeframe: From Day 1 to 4 years

Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline of forced expiratory volume in one second (FEV1) measured after the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Post-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years

Rate of decline of forced expiratory volume in one second (FEV1) measured after bronchodilation. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1. (NCT00144339)
Timeframe: From day 30 to 4 years

Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline of forced vital capacity (FVC) after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Post-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years

Rate of decline of forced vital capacity (FVC) measured after bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: From day 30 to 4 years

Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline of slow vital capacity (SVC) after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Post-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years

Rate of decline of slow vital capacity (SVC) measured after bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: From day 30 to 4 years

Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline of forced expiratory volume in one second (FEV1) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FEV1 over time, while a positive value indicates increasing FEV1 (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.

Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) Rate of Decline From Day 30 to 4 Years

Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline of forced vital capacity (FVC) before bronchodilation. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days.

Pre-bronchodilator Forced Vital Capacity (FVC) Rate of Decline From Day 30 to 4 Years

Rate of decline of forced vital capacity (FVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing FVC over time, while a positive value indicates increasing FVC (NCT00144339)
Timeframe: From day 30 to 4 years

Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 1 to 30 Days After Completion of Double Blinded Treatment

Rate of decline slow vital capacity (SVC) before bronchodilation. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: Day 1 to 30 days after completion of double blinded treatment between Day 1 and 4 years plus 30 days

Pre-bronchodilator Slow Vital Capacity (SVC) Rate of Decline From Day 30 to 4 Years

Rate of decline of slow vital capacity (SVC) measured before the use of bronchodilators. A negative rate of decline indicates decreasing SVC over time, while a positive value indicates increasing SVC (NCT00144339)
Timeframe: From day 30 to 4 years

Rate of Decline of St George's Respiratory Questionnaire (SGRQ) Total Score

SGRQ total score shows the impact of COPD on patient's health status, and expressed as a percentage of impairment with scale from 0 (best health status) to 100 (worst possible status). A negative rate of decline shows decreasing SGRQ total score (or improved health) over time, while a positive value shows increasing score (or worsen health). (NCT00144339)
Timeframe: From month 6 to 4 years

Time to First COPD Exacerbation Leading to Hospitalization (for 25% Patients)

Time to First Exacerbation

Chronic obstructive pulmonary disease (COPD) exacerbation (NCT00144339)
Timeframe: From Day 1 to 4 years

Incidence Rate of Serious Adverse Event (Preferred Term = Angina)

Descriptive statistics show the number of patients with event, central tendency shows incidence rate. Incidence rate calculated as number of patients with event divided by at-risk years * 100. (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days

Incidence Rate of Serious Adverse Event (Preferred Term = Atrial Fibrillation)

Incidence Rate of Serious Adverse Event (Preferred Term = Bronchitis)

Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure Congestive)

Incidence Rate of Serious Adverse Event (Preferred Term = Cardiac Failure)

Incidence Rate of Serious Adverse Event (Preferred Term = Chronic Obstructive Pulmonary Disease (COPD) Exacerbation)

Incidence Rate of Serious Adverse Event (Preferred Term = Coronary Artery Disease)

Incidence Rate of Serious Adverse Event (Preferred Term = Dyspnoea)

Incidence Rate of Serious Adverse Event (Preferred Term = Myocardial Infarction)

Incidence Rate of Serious Adverse Event (Preferred Term = Pneumonia)

Incidence Rate of Serious Adverse Event (Preferred Term = Respiratory Failure)

Incidence Rate of Serious Adverse Event (System Organ Class = Cardiac Disorders)

Incidence Rate of Serious Adverse Event (System Organ Class = Lower Respiratory System Disorders)

Number and Percentage of Participants With a Lower Respiratory Death (Adjudicated; Including Vital Status Follow-up, Cutoff at 1470 Days)

The primary cause of death was adjudicated by an external committee prior to unblinding; vital status was information followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used (NCT00144339)
Timeframe: Day 1 to day 1470

Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1440 Days)

Number and Percentage of Participants With All Cause Death (Including Vital Status Follow-up, Cutoff at 1470 Days)

All cause mortality vital status information was followed-up after discontinuation; vital status information up to 1470 days after the start of treatment was used. (NCT00144339)
Timeframe: Day 1 to day 1470

Number and Percentage of Participants With All Cause Death and Time to Event Analysis (On-treatment)

On-treatment defined as day 1 to completion of double blinded treatment plus 30 days (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days

Number and Percentage of Participants With Lower Respiratory Death (On-treatment; Adjudicated Primary Cause)

The primary cause of death was adjudicated by an external committee prior to unblinding; on-treatment defined as day 1 to completion of double blinded treatment plus 30 days (NCT00144339)
Timeframe: Day 1 to completion of double blinded treatment plus 30 days between Day 1 and 4 years plus 30 days

Number and Percentage of Patients With at Least on COPD Exacerbation Leading to Hospitalization

Number and Percentage of Patients With at Least One Chronic Obstructive Pulmonary Disease (COPD) Exacerbation

FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14

"Spirometry used to measure FEV1, was performed according to internationally accepted standards. Results show the change from baseline in FEV1 AUC(0-12h), normalized by time on Day 14; it was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Definitions:~AUC=Area under the curve; AUC(0-12h)=AUC between 0 and 12 h; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; FEV1=Forced expiratory volume in the 1st second;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1

"Spirometry used to measure FEV1, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1

"Patients achieving onset of action, defined as a change from baseline in post-dose FEV1 ≥12% and ≥200 mL, on Day 1. These are the subjects who contributed to the results, reported as median and 95% CI for 'Time to onset of action' presented in the Outcome Measure 13, above.~For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment.~Definitions:~Onset of action=Change from baseline in post-dose FEV1 ≥12% and ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose);" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14

"Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14

"Spirometry, used to measure FVC, was performed according to internationally accepted standards.~Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended).~Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

"The primary analysis was repeated, considering patients as randomized and including only the first instance of each treatment.~Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

"The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred.~The number of patients shown represents those with at least one post-baseline assessment available." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14

"Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended).~Patients considered in this analysis are those with at least one available post-baseline assessment." (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1

"Spirometry, used to measure FEV1, was performed according to internationally accepted standards.~For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment.~Definitions:~Time to onset of action=The time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period;" (NCT03086460)
Timeframe: Baseline, Day 1 post-dose

12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Results are shown by treatment group, as change from baseline (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14

Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14

"Heart rate (HR) AUC(0-4h) and HR peak(0-4h), normalized by time (in bpm).~Results are shown as change from pre-dose on Day 14 (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~Definitions:~HR=Heart rate; HR AUC(0-4h)=Area under the curve between 0 and 4 h for heart rate; HR peak(0-4h)=The maximum observed value over 4 h after dosing;" (NCT03086460)
Timeframe: Baseline, Day 14 post-dose

Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Heart rate HR AUC(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm).~The HR AUC(0-4h) normalized by time is calculated based on the actual times, using the linear trapezoidal rule.~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Heart rate (HR) peak(0-4h) normalized by time.~Results are shown by treatment group, as change from baseline (in bpm).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period.~Definitions:~HR=Heart rate; HR peak(0-4h)=The maximum observed value over 4 hours following dosing;" (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14

"Serum glucose level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14

"Serum potassium level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period." (NCT03086460)
Timeframe: Baseline, Day 1, Day 14 post-dose

Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14

"Vital signs -- Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were measured at pre-specified times (at baseline - pre dose and on Day 14 of each treatment period or on the day of early study termination).~Results are shown by treatment group, as change from baseline (in mmHg).~For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation.~Definitions:~For safety variables, the baseline for each treatment period was defined as pre-dose measurements on Day 1 of each treatment period; Day 14=The day of the last dosing of a treatment period. Day 14 of the second, third, and fourth treatment periods (day of last dosing); treatments were separated by a 2-week wash-out interval;" (NCT03086460)
Timeframe: Baseline, Day 1 and Day 14 post-dose

Intervention	L (Mean)
Placebo	1.024
Tiotropium Bromide Inhalation Capsules 18 mcg	1.112

Intervention	L (Mean)
Placebo	1.126
Tiotropium Bromide Inhalation Capsules 18 mcg	1.225

Intervention	L (Mean)
Placebo	2.667
Tiotropium Bromide Inhalation Capsules 18 mcg	2.856

Intervention	L (Mean)
Placebo	2.640
Tiotropium Bromide Inhalation Capsules 18 mcg	2.838

Intervention	L (Mean)
Placebo	2.622
Tiotropium Bromide Inhalation Capsules 18 mcg	2.816

Intervention	L (Mean)
Placebo	2.597
Tiotropium Bromide Inhalation Capsules 18 mcg	2.785

Intervention	L (Mean)
Placebo	2.572
Tiotropium Bromide Inhalation Capsules 18 mcg	2.757

Intervention	L (Mean)
Placebo	2.553
Tiotropium Bromide Inhalation Capsules 18 mcg	2.753

Intervention	L (Mean)
Placebo	2.540
Tiotropium Bromide Inhalation Capsules 18 mcg	2.724

Intervention	L (Mean)
Placebo	2.532
Tiotropium Bromide Inhalation Capsules 18 mcg	2.702

Intervention	L (Mean)
Placebo	2.658
Tiotropium Bromide Inhalation Capsules 18 mcg	2.862

Intervention	L (Mean)
Placebo	2.847
Tiotropium Bromide Inhalation Capsules 18 mcg	3.017

Intervention	L (Mean)
Placebo	2.820
Tiotropium Bromide Inhalation Capsules 18 mcg	2.996

Intervention	L (Mean)
Placebo	2.811
Tiotropium Bromide Inhalation Capsules 18 mcg	2.965

Intervention	L (Mean)
Placebo	2.775
Tiotropium Bromide Inhalation Capsules 18 mcg	2.942

Intervention	L (Mean)
Placebo	2.738
Tiotropium Bromide Inhalation Capsules 18 mcg	2.908

Intervention	L (Mean)
Placebo	2.731
Tiotropium Bromide Inhalation Capsules 18 mcg	2.897

Intervention	L (Mean)
Placebo	2.713
Tiotropium Bromide Inhalation Capsules 18 mcg	2.875

Intervention	L (Mean)
Placebo	2.696
Tiotropium Bromide Inhalation Capsules 18 mcg	2.846

Intervention	L (Mean)
Placebo	2.841
Tiotropium Bromide Inhalation Capsules 18 mcg	3.027

Intervention	Units on a scale (Mean)
Placebo	42.501
Tiotropium Bromide Inhalation Capsules 18 mcg	39.730

Intervention	Units on a scale (Mean)
Placebo	43.067
Tiotropium Bromide Inhalation Capsules 18 mcg	40.474

Intervention	Units on a scale (Mean)
Placebo	43.562
Tiotropium Bromide Inhalation Capsules 18 mcg	41.178

Intervention	Units on a scale (Mean)
Placebo	44.342
Tiotropium Bromide Inhalation Capsules 18 mcg	41.919

Intervention	Units on a scale (Mean)
Placebo	45.280
Tiotropium Bromide Inhalation Capsules 18 mcg	41.935

Intervention	Units on a scale (Mean)
Placebo	45.722
Tiotropium Bromide Inhalation Capsules 18 mcg	42.905

Intervention	Units on a scale (Mean)
Placebo	45.968
Tiotropium Bromide Inhalation Capsules 18 mcg	43.665

Intervention	Units on a scale (Mean)
Placebo	42.289
Tiotropium Bromide Inhalation Capsules 18 mcg	39.409

Intervention	number per patient year (Mean)
Placebo	0.85
Tiotropium Bromide Inhalation Capsules 18 mcg	0.73

Intervention	days/patient year (Mean)
Placebo	13.64
Tiotropium Bromide Inhalation Capsules 18 mcg	12.11