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Jadwiga A. Wedzicha – One of the best experts on this subject based on the ideXlab platform.

  • effect of erdosteine on copd Exacerbations in copd patients with moderate airflow limitation
    International Journal of Chronic Obstructive Pulmonary Disease, 2019
    Co-Authors: Peter M A Calverley, Roberto Dal W Negro, Giovanni A Fontana, Clive P Page, Arrigo F G Cicero, Edoardo Pozzi, Mario Cazzola, Jadwiga A. Wedzicha
    Abstract:

    Background: The RESTORE study, a multi-national randomized, placebocontrolled study, showed that erdosteine – a muco-active antioxidant that modulates bacterial adhesiveness – reduced the rate and duration of Exacerbations in moderate and severe COPD with a history of Exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear. Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined Exacerbation rate and duration, time to first Exacerbation, and Exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U-tests, or log rank tests. Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 Exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an Exacerbation. There was a 47% reduction in the mean Exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 Exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild Exacerbation rate (0.23 vs 0.53 mild Exacerbations per-patient per-year, P=0.001). Mean duration of Exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe Exacerbations. Mean time to first Exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P<0.001) and the mean Exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P<0.001). Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, Exacerbations in patients with moderate COPD and a history of Exacerbations.

  • S102 Eosinophil counts as a predictor of future COPD Exacerbations in the DYNAGITO trial
    COPD: inflammation smoking and exacerbations, 2019
    Co-Authors: Peter M A Calverley, Jadwiga A. Wedzicha, Christine Jenkins, A. De La Hoz, Florian Voß, K. F. Rabe, Antonio Anzueto
    Abstract:

    Background There is conflicting evidence from previous studies as to whether eosinophil counts predict the risk of future Exacerbations in COPD. Aims In this post hoc analysis, we investigated the link between baseline eosinophil count and moderate/severe Exacerbation rates during the DYNAGITO trial. Methods DYNAGITO was a 52-week, double-blind, randomised trial in patients with COPD with FEV1 Results At baseline, 81% of patients had an eosinophil count ≤300 cells/µL and 49% had an eosinophil count ≤150 cells/µL. 65–76% of patients were receiving ICS across eosinophil subgroups. Similar rates of moderate/severe Exacerbations were observed across eosinophil subgroups (figure). Rates were similar across eosinophil counts in patient subgroups with low or high Exacerbation history. Conclusions Relatively few patients had an eosinophil count >300 cells/µL, and there was no increase in Exacerbation rates with increasing baseline eosinophil count in the total population, or in patients with low or high Exacerbation history. In this population, many of whom were receiving ICS, Exacerbation history, but not blood eosinophil count, was an important determinant of Exacerbation risk.

  • Eosinophil counts as a predictor of future COPD Exacerbations in the DYNAGITO trial
    Monitoring airway disease, 2019
    Co-Authors: Peter M A Calverley, Jadwiga A. Wedzicha, Klaus F Rabe, Christine Jenkins, A. De La Hoz, Florian Voß, Antonio Anzueto
    Abstract:

    Background: There is conflicting evidence from previous studies as to whether eosinophil counts predict the risk of future Exacerbations in COPD. Aims: In this post hoc analysis, we investigated the link between baseline eosinophil count and moderate/severe Exacerbation rates during the DYNAGITO trial. Methods: DYNAGITO was a 52-week, double-blind, randomised trial in patients with COPD with FEV1 Results: At baseline, 81% of patients had an eosinophil count ≤300 cells/µL and 49% had an eosinophil count ≤150 cells/µL. 65–76% of patients were receiving ICS across eosinophil subgroups. Similar rates of moderate/severe Exacerbations were observed across eosinophil subgroups (Figure). Rates were similar across eosinophil counts in patient subgroups with low or high Exacerbation history. Conclusions: Relatively few patients had an eosinophil count >300 cells/µL, and there was no increase in Exacerbation rates with increasing baseline eosinophil count in the total population, or in patients with low or high Exacerbation history. In this population, many of whom were receiving ICS, Exacerbation history, but not blood eosinophil count, was an important determinant of Exacerbation risk.

Peter M A Calverley – One of the best experts on this subject based on the ideXlab platform.

  • effect of erdosteine on copd Exacerbations in copd patients with moderate airflow limitation
    International Journal of Chronic Obstructive Pulmonary Disease, 2019
    Co-Authors: Peter M A Calverley, Roberto Dal W Negro, Giovanni A Fontana, Clive P Page, Arrigo F G Cicero, Edoardo Pozzi, Mario Cazzola, Jadwiga A. Wedzicha
    Abstract:

    Background: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine – a muco-active antioxidant that modulates bacterial adhesiveness – reduced the rate and duration of Exacerbations in moderate and severe COPD with a history of Exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear. Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted) examined Exacerbation rate and duration, time to first Exacerbation, and Exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U-tests, or log rank tests. Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 Exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an Exacerbation. There was a 47% reduction in the mean Exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 Exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild Exacerbation rate (0.23 vs 0.53 mild Exacerbations per-patient per-year, P=0.001). Mean duration of Exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe Exacerbations. Mean time to first Exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P<0.001) and the mean Exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P<0.001). Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, Exacerbations in patients with moderate COPD and a history of Exacerbations.

  • S102 Eosinophil counts as a predictor of future COPD Exacerbations in the DYNAGITO trial
    COPD: inflammation smoking and exacerbations, 2019
    Co-Authors: Peter M A Calverley, Jadwiga A. Wedzicha, Christine Jenkins, A. De La Hoz, Florian Voß, K. F. Rabe, Antonio Anzueto
    Abstract:

    Background There is conflicting evidence from previous studies as to whether eosinophil counts predict the risk of future Exacerbations in COPD. Aims In this post hoc analysis, we investigated the link between baseline eosinophil count and moderate/severe Exacerbation rates during the DYNAGITO trial. Methods DYNAGITO was a 52-week, double-blind, randomised trial in patients with COPD with FEV1 Results At baseline, 81% of patients had an eosinophil count ≤300 cells/µL and 49% had an eosinophil count ≤150 cells/µL. 65–76% of patients were receiving ICS across eosinophil subgroups. Similar rates of moderate/severe Exacerbations were observed across eosinophil subgroups (figure). Rates were similar across eosinophil counts in patient subgroups with low or high Exacerbation history. Conclusions Relatively few patients had an eosinophil count >300 cells/µL, and there was no increase in Exacerbation rates with increasing baseline eosinophil count in the total population, or in patients with low or high Exacerbation history. In this population, many of whom were receiving ICS, Exacerbation history, but not blood eosinophil count, was an important determinant of Exacerbation risk.

  • Eosinophil counts as a predictor of future COPD Exacerbations in the DYNAGITO trial
    Monitoring airway disease, 2019
    Co-Authors: Peter M A Calverley, Jadwiga A. Wedzicha, Klaus F Rabe, Christine Jenkins, A. De La Hoz, Florian Voß, Antonio Anzueto
    Abstract:

    Background: There is conflicting evidence from previous studies as to whether eosinophil counts predict the risk of future Exacerbations in COPD. Aims: In this post hoc analysis, we investigated the link between baseline eosinophil count and moderate/severe Exacerbation rates during the DYNAGITO trial. Methods: DYNAGITO was a 52-week, double-blind, randomised trial in patients with COPD with FEV1 Results: At baseline, 81% of patients had an eosinophil count ≤300 cells/µL and 49% had an eosinophil count ≤150 cells/µL. 65–76% of patients were receiving ICS across eosinophil subgroups. Similar rates of moderate/severe Exacerbations were observed across eosinophil subgroups (Figure). Rates were similar across eosinophil counts in patient subgroups with low or high Exacerbation history. Conclusions: Relatively few patients had an eosinophil count >300 cells/µL, and there was no increase in Exacerbation rates with increasing baseline eosinophil count in the total population, or in patients with low or high Exacerbation history. In this population, many of whom were receiving ICS, Exacerbation history, but not blood eosinophil count, was an important determinant of Exacerbation risk.

Donald Banerji – One of the best experts on this subject based on the ideXlab platform.

  • late breaking abstract indacaterol glycopyrronium ind gly reduces the risk of Exacerbations versus salmeterol fluticasone sfc in moderate to very severe copd patients irrespective of prior ics laba lama therapy the flame study
    European Respiratory Journal, 2016
    Co-Authors: Jadwiga A. Wedzicha, Karen Mezzi, Tim Ayers, Chau Thach, Robert Fogel, Francesco Patalano, Donald Banerji
    Abstract:

    Introduction FLAME was the first study to show superiority of IND/GLY (LABA/LAMA) in reducing risk of Exacerbations vs. SFC (LABA/ICS) in COPD patients (pts) with history of Exacerbations. We report results regarding effect of IND/GLY vs. SFC on COPD Exacerbations in pts with or without prior ICS/LABA/LAMA triple therapy. Methods FLAME, a 52-week, randomised, double-blind study, compared once-daily IND/GLY 110/50µg vs. twice-daily SFC 50/500μg in pts with moderate-to-very severe COPD with ≥1 Exacerbation in previous year. In this post-hoc analysis, time to first COPD Exacerbation (mild, moderate or severe) and moderate/severe COPD Exacerbation with IND/GLY vs. SFC were analysed. Additionally, treatment effects on rates of Exacerbations were assessed in these pts. Results Of 3354 pts included in this analysis, 1148 (34.2%) were on prior triple therapy. IND/GLY significantly reduced the risk of any Exacerbation and moderate/severe Exacerbation vs. SFC in pts, irrespective of prior triple therapy (table). IND/GLY numerically reduced the rate of any and moderate/severe COPD Exacerbations vs. SFC in pts with/without prior triple therapy (table). Conclusion IND/GLY significantly reduces risk of Exacerbations versus SFC, irrespective of prior triple therapy in exacerbating patients with moderate-to-very severe COPD.

  • indacaterol glycopyrronium ind gly reduces Exacerbations compared with salmeterol fluticasone sfc in various sub groups from the flame study
    European Respiratory Journal, 2016
    Co-Authors: Jadwiga A. Wedzicha, Tim Ayers, Chau Thach, Robert Fogel, Francesco Patalano, Kenneth R Chapman, Angel Fowlertaylor, Petter Olsson, Donald Banerji
    Abstract:

    Introduction LABA/ICS combination and/or LAMA have been the first choice of treatment for COPD patients with high risk of Exacerbation. FLAME is the first study which compared rate and risk of Exacerbations with IND/GLY to SFC in patients with at least one Exacerbation in the previous year. Methods Patients with post-bronchodilator FEV 1 ≥25%- Results In total, 3362 patients were randomised. The rate of all Exacerbations was lower with IND/GLY compared with SFC (Figure 1A) in subgroups defined by age, smoking status, Exacerbation history, and disease severity. IND/GLY also reduced rate of moderate or severe Exacerbations in all subgroups except for <55 years age and GOLD 4, however; the patient number in these subgroups were small (Figure 1B). Similar results were observed for all and moderate or severe Exacerbations for other subgroups. Conclusions IND/GLY significantly reduced all and moderate or severe Exacerbations, compared with SFC in many subgroups, demonstrating a consistent trend to the overall population.

  • qva149 compared with salmeterol fluticasone sfc on Exacerbations and its correlation with baseline blood eosinophils a pooled analysis of lantern and illuminate
    European Respiratory Journal, 2015
    Co-Authors: Jadwiga A. Wedzicha, Karen Mezzi, Robert Fogel, D Price, Donald Banerji
    Abstract:

    Introduction: This pooled analysis compared the incidence of moderate or severe COPD Exacerbations with QVA149 vs SFC. We also investigated if baseline blood eosinophil (EOS) count was a predictor of Exacerbation risk, and magnitude of treatment effect on this risk. Methods: All patients (pts) from two 26-week double-blind studies were included in this analysis. 1263 moderate-to-severe COPD pts with ≤1 Exacerbation in the previous year were randomised (1:1) to QVA149 or SFC. Results: In the overall pool, the rate of moderate or severe Exacerbations was significantly lower with QVA149 vs SFC (RR [95% CI]: 0.67 [0.48-0.94]; p=0.021). There was a trend (p=0.08) towards increased Exacerbation rate with increased baseline blood EOS count. In pts with baseline blood EOS count of 3 and 150-300/mm 3 , QVA149 showed 45% and 43% reduction in the risk of Exacerbations, respectively compared to SFC (Figure 1). In pts with >300/mm 3 blood EOS at baseline (12% of study population), risk of Exacerbations was lower with SFC. Conclusion: QVA 149 was more effective in reducing Exacerbation risk in pts with baseline blood eosinophil 3 (88% of pool) and SFC in pts with >300/mm 3 (12% of pool). These data suggest that baseline blood eosinophil count may be a useful biomarker in assessing potential benefit of QVA149 over SFC in reducing Exacerbations in COPD patients.

Michiaki Mishima – One of the best experts on this subject based on the ideXlab platform.

  • Tiotropium/olodaterol versus tiotropium in Japanese patients with COPD: results from the DYNAGITO study.
    International Journal of Chronic Obstructive Pulmonary Disease, 2018
    Co-Authors: Masakazu Ichinose, Masaharu Nishimura, Manabu Akimoto, Yasuhiro Kurotori, Yihua Zhao, Michiaki Mishima
    Abstract:

    Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe Exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients. Patients and methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe Exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD Exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD Exacerbation, and other secondary endpoints included the annualized rate of Exacerbations leading to hospitalization, time to first COPD Exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively. Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD Exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434). The risk of a first moderate-to-severe COPD Exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; p=0.1379), although this difference was not statistically significant. The annualized rate of COPD Exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; p=0.5654). The adverse event incidence was balanced between treatment arms. Conclusion: In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing Exacerbations. Both treatments were well tolerated.

  • tiotropium olodaterol versus tiotropium in japanese patients with copd results from the dynagito study
    International Journal of Chronic Obstructive Pulmonary Disease, 2018
    Co-Authors: Masakazu Ichinose, Masaharu Nishimura, Manabu Akimoto, Yasuhiro Kurotori, Yihua Zhao, Michiaki Mishima
    Abstract:

    Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe Exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients. Patients and methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe Exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD Exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD Exacerbation, and other secondary endpoints included the annualized rate of Exacerbations leading to hospitalization, time to first COPD Exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively. Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD Exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434). The risk of a first moderate-to-severe COPD Exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; p=0.1379), although this difference was not statistically significant. The annualized rate of COPD Exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; p=0.5654). The adverse event incidence was balanced between treatment arms. Conclusion: In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing Exacerbations. Both treatments were well tolerated.

R Buhl – One of the best experts on this subject based on the ideXlab platform.

  • p296 effect of tiotropium olodaterol therapy on copd Exacerbations in the tonado studies
    Thorax, 2016
    Co-Authors: Eric Derom, Fle M Zcaron, L Gronke, R Buhl
    Abstract:

    Rationale The lung-function efficacy, symptomatic benefits and safety of combined tiotropium (T), a long-acting muscarinic antagonist, and olodaterol (O), a long-acting β 2 –agonist, for the treatment of COPD, was established in the year-long TONADO ® studies (NCT01431274; NCT01431287). It is unknown if these benefits of T/O translate into a reduction in COPD Exacerbation rate. Methods Two replicate, randomised, double-blind, parallel-group trials assessed T/O 2.5/5 μg and T/O 5/5 μg compared to the monocomponents T 5 μg, T 2.5 μg and O 5 µg (all delivered via Respimat ® inhaler) in patients with moderate to very severe COPD. Primary end points included lung function (forced expiratory volume in 1 second [FEV 1 ] area under the curve from 0–3 hours response, trough FEV 1 response) and quality of life (SGRQ). Analysis of the number of Exacerbations and time to Exacerbation was pre-specified using data from the combined TONADO ® studies. We present data from the T/O and T treatment arms. Results 4124 patients were evaluable for the T/O and T treatment arms. Moderate or severe Exacerbations occurred in 27.7% of patients with T/O 5/5 μg, 25.8% of patients with T/O 2.5/5 μg, 28.8% with T 5 μg and 29.6% with T 2.5 μg. Severe Exacerbations occurred in 5.9% of patients receiving T/O 5/5 μg, 4.5% receiving T/O 2.5/5 μg, 4.5% receiving T 5 μg and 5.2% receiving T 2.5 μg. The treatment comparisons for any Exacerbation and moderate/severe Exacerbations were generally consistent between the two studies, except for a higher number of severe Exacerbations with T/O 5/5 μg in TONADO ® 1 only (Table). Conclusions Although there were fewer Exacerbations overall with T/O 2.5/5 µg or 5/5 µg compared to T 2.5 µg or 5 µg, and a numerically longer time to first moderate/severe Exacerbation, the TONADO ® studies did not show a significant difference in the hazard ratios for time to Exacerbation end points. These findings are partially attributable to a higher number of severe Exacerbations with T/O 5/5 µg in TONADO ® 1. TONADO ® was not designed for formal comparison of Exacerbations with T/O versus T; however, a study powered to assess this is ongoing. Funding Boehringer Ingelheim. Please refer to page A273 for declarations of interest in relation to abstract P296.

  • P296 Effect of tiotropium/olodaterol therapy on copd Exacerbations in the tonado® studies
    Thorax, 2016
    Co-Authors: Eric Derom, Florian Voß, L Gronke, M Fle Zcaron, R Buhl
    Abstract:

    Rationale The lung-function efficacy, symptomatic benefits and safety of combined tiotropium (T), a long-acting muscarinic antagonist, and olodaterol (O), a long-acting β 2 –agonist, for the treatment of COPD, was established in the year-long TONADO ® studies (NCT01431274; NCT01431287). It is unknown if these benefits of T/O translate into a reduction in COPD Exacerbation rate. Methods Two replicate, randomised, double-blind, parallel-group trials assessed T/O 2.5/5 μg and T/O 5/5 μg compared to the monocomponents T 5 μg, T 2.5 μg and O 5 µg (all delivered via Respimat ® inhaler) in patients with moderate to very severe COPD. Primary end points included lung function (forced expiratory volume in 1 second [FEV 1 ] area under the curve from 0–3 hours response, trough FEV 1 response) and quality of life (SGRQ). Analysis of the number of Exacerbations and time to Exacerbation was pre-specified using data from the combined TONADO ® studies. We present data from the T/O and T treatment arms. Results 4124 patients were evaluable for the T/O and T treatment arms. Moderate or severe Exacerbations occurred in 27.7% of patients with T/O 5/5 μg, 25.8% of patients with T/O 2.5/5 μg, 28.8% with T 5 μg and 29.6% with T 2.5 μg. Severe Exacerbations occurred in 5.9% of patients receiving T/O 5/5 μg, 4.5% receiving T/O 2.5/5 μg, 4.5% receiving T 5 μg and 5.2% receiving T 2.5 μg. The treatment comparisons for any Exacerbation and moderate/severe Exacerbations were generally consistent between the two studies, except for a higher number of severe Exacerbations with T/O 5/5 μg in TONADO ® 1 only (Table). Conclusions Although there were fewer Exacerbations overall with T/O 2.5/5 µg or 5/5 µg compared to T 2.5 µg or 5 µg, and a numerically longer time to first moderate/severe Exacerbation, the TONADO ® studies did not show a significant difference in the hazard ratios for time to Exacerbation end points. These findings are partially attributable to a higher number of severe Exacerbations with T/O 5/5 µg in TONADO ® 1. TONADO ® was not designed for formal comparison of Exacerbations with T/O versus T; however, a study powered to assess this is ongoing. Funding Boehringer Ingelheim. Please refer to page A273 for declarations of interest in relation to abstract P296.