A randomised, double-blind, four-way, crossover trial comparing the 24-h FEV₁ profile for once-daily versus twice-daily treatment with olodaterol, a novel long-acting β₂-agonist, in patients with chronic obstructive pulmonary disease

Background: This randomised, double-blind, four-way, crossover, Phase II study compared the 24-h forced expiratory volume in 1 s (FEV1) profile of alternative dosing frequencies of two total daily doses of olodaterol (5 and 10 mu g) in patients with chronic obstructive pulmonary disease (COPD). Methods: Patients received olodaterol 2 mu g twice daily (BID), 5 mu g BID, 5 mu g once daily (QD) and 10 mu g QD in a randomised sequence over 3-week treatment periods. Co-primary end points were FEV, area under the curve from 0 to 12 h (AUC(0-12)) and area under the curve from 12 to 24 h (AUC(12-24)) responses. Additional lung-function responses, pharmacokinetics and safety were assessed. Results: 47 patients were treated. All olodaterol doses provided significant increases in FEV, versus baseline (p < 0.001) and FEV, time profiles were nearly identical for olodaterol 5 and 10 mu g QD. Olodaterol 5 pg QD demonstrated improved FEV, AUC(0-12) and similar AUC(12-24) versus 2 mu g BID. Olodaterol 5 mu g QD showed slightly increased FEV, AUC(0-12) but lower AUC(12-24) compared to 5 mu g BID. Bronchodilation over 24 h was similar for olodaterol 5 pg QD and BID. All doses were well tolerated. Conclusions: Olodaterol 5 pg QD is efficacious in COPD, with a superior bronchodilatory profile compared to 2 mu g BID, which is close to the same total daily dose, and a similar degree of bronchodilation over 24 h compared with double the daily dose (administered as 10 pg QD or 5 mu g BID)

Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD

Background: A study was undertaken to record exacerbations and health resource use in patients with COPD during 6 months of treatment with tiotropium, salmeterol, or matching placebos. Methods: Patients with COPD were enrolled in two 6-month randomised, placebo controlled, double blind, double dummy studies of tiotropium 18 µg once daily via HandiHaler or salmeterol 50 µg twice daily via a metered dose inhaler. The two trials were combined for analysis of heath outcomes consisting of exacerbations, health resource use, dyspnoea (assessed by the transitional dyspnoea index, TDI), health related quality of life (assessed by St George's Respiratory Questionnaire, SGRQ), and spirometry. Results: 1207 patients participated in the study (tiotropium 402, salmeterol 405, placebo 400). Compared with placebo, tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation. Fewer COPD exacerbations/patient year occurred in the tiotropium group (1.07) than in the placebo group (1.49, p<0.05); the salmeterol group (1.23 events/year) did not differ from placebo. The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo (not statistically different). For all causes (respiratory and non-respiratory) tiotropium, but not salmeterol, was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group. The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group (tiotropium 8.3 (0.8), salmeterol 11.1 (0.8), placebo 10.9 (0.8), p<0.05). SGRQ total score improved by 4.2 (0.7), 2.8 (0.7) and 1.5 (0.7) units during the 6 month trial for the tiotropium, salmeterol and placebo groups, respectively (p<0.01 tiotropium v placebo). Compared with placebo, TDI focal score improved in both the tiotropium group (1.1 (0.3) units, p<0.001) and the salmeterol group (0.7 (0.3) units, p<0.05). Evaluation of morning pre-dose FEV(1), peak FEV(1) and mean FEV(1) (0–3 hours) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo. Conclusions: Exacerbations of COPD and health resource usage were positively affected by daily treatment with tiotropium. With the exception of the number of hospital days associated with all causes, salmeterol twice daily resulted in no significant changes compared with placebo. Tiotropium also improved health related quality of life, dyspnoea, and lung function in patients with COPD

Efficacy and safety of olodaterol once daily delivered via Respimat&reg; in patients with GOLD 2&ndash;4 COPD: results from two replicate 48-week studies

Gary T Ferguson,1 Gregory J Feldman,2 Peter Hofbauer,3 Alan Hamilton,4 Lisa Allen,5 Lawrence Korducki,5 Paul Sachs6 1Pulmonary Research Institute of Southeast Michigan, Livonia, MI, 2S Carolina Pharmaceutical Research, Spartanburg, SC, USA; 3Pneumologie, Weinheim, Germany; 4Boehringer Ingelheim, Burlington, ON, Canada; 5Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 6Pulmonary Associates of Stamford, Stamford, CT, USA Background: Olodaterol is a long-acting &beta;2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy. Methods: Patients received olodaterol 5 &micro;g or 10 &micro;g or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0&ndash;3) response (change from baseline), and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. Results: Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 &micro;g and 10 &micro;g significantly improved the FEV1 AUC0&ndash;3 response (P&lt;0.0001) and trough FEV1 (study 1222.11, P&lt;0.0001; study 1222.12, P&lt;0.05, post hoc) at week 12, with an incidence of adverse events comparable with that of placebo. Secondary end points supported the efficacy of olodaterol. Conclusion: These studies demonstrate the long-term efficacy and safety of once-daily olodaterol 5 &micro;g and 10 &micro;g in patients with moderate to very severe COPD continuing with usual-care maintenance therapy. Keywords: chronic obstructive pulmonary disease, bronchodilator, olodatero

Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat? versus placebo and formoterol twice daily in patients with GOLD 2-4 COPD: results from two replicate 48-week studies.

Andrea Koch,1 Emilio Pizzichini,2 Alan Hamilton,3 Lorna Hart,3 Lawrence Korducki,4 Maria Cristina De Salvo,5 Pierluigi Paggiaro6 1Medical Clinic III for Pneumology, Allergology, Sleep and Respiratory Medicine, University Hospital Bochum-Bergmannsheil, Bochum, Germany; 2NUPAIVA (Asthma Research Center), Universidade Federal de Santa Catarina, Santa Catarina, Brazil; 3Boehringer Ingelheim, Burlington, Ontario, Canada; 4Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA; 5Centro M&eacute;dico Dra. De Salvo, Fundaci&oacute;n Respirar, Buenos Aires, Argentina; 6Cardio-Thoracic and Vascular Department, University of Pisa, Pisa, Italy Abstract: Two replicate, multicenter, randomized, double-blind, placebo-controlled, parallel-group, Phase III studies investigated the long-term efficacy and safety of once-daily olodaterol via Respimat&reg; versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy. Patients received once-daily olodaterol 5 or 10 &micro;g, twice-daily formoterol 12 &micro;g, or placebo. Co-primary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0&ndash;3 hours response, FEV1 trough response, and Mahler transition dyspnea index total score after 24 weeks; secondary end points included St George&#39;s Respiratory Questionnaire. Overall, 904 (Study 1222.13) and 934 (Study 1222.14) patients received treatment. Olodaterol significantly improved FEV1 area under the curve from 0&ndash;3 hours versus placebo in both studies (with olodaterol 5 &micro;g, 0.151 L and 0.129 L; with olodaterol 10 &micro;g, 0.165 L and 0.154 L; for all comparisons P&lt;0.0001) and FEV1 trough responses versus placebo (0.053&ndash;0.085 L; P&lt;0.01), as did formoterol. Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo. Post hoc analysis using pattern mixture modeling (accounting for discontinuations) demonstrated statistical significance for olodaterol versus placebo. St George&#39;s Respiratory Questionnaire total score was significantly improved with olodaterol, but not formoterol, versus placebo. No safety signals were identified from adverse-event or other safety data. Once-daily olodaterol 5 &micro;g and 10 &micro;g is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy, with a satisfactory safety profile. Keywords: bronchodilator, chronic obstructive pulmonary disease, dyspnea, long-acting beta2-agonis