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Page 2 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 2 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Table 1: Patients entered, treated, and analysed (primary endpoint) Entered Treated Analysed Placebo 202 202 199 Tiotropium 5 µg 203 203 2 Tio+Olo 2.5/5 µg 202 202 200 Tio+Olo 5/5 µg 202 202 200 Diagnosis: Main Criteria for Inclusion: BI Investigational Product: Dose: Mode of Admin.: Batch No.: BI Investigational Product: Dose: Mode of Admin.: Batch No.: COPD Outpatients with COPD 40 years old, smoking history of >10 pack years, postbronchodilator FEV 1 30% and <80% of predicted normal, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II III, and post-bronchodilator FEV 1 / forced vital capacity (FVC) <70%. Tiotropium+Olodaterol (Tio+Olo) inhalation solution - RESPIMAT 2.5 μg tiotropium / 5 μg olodaterol (1.25 μg + 2.5 µg, respectively, per actuation Oral inhalation B132000060 Tio+Olo inhalation solution - RESPIMAT 5 μg tiotropium / 5 μg olodaterol (2.5 µg each per actuation) Oral inhalation B132000059
Page 3 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 3 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Comparator Product: Dose: Mode of Admin.: Batch No.: Comparator Product: Dose: Mode of Admin.: Batch No.: Duration of Treatment: Criteria for Evaluation: Efficacy: Safety: Tiotropium inhalation solution - RESPIMAT 5 μg (2.5 µg per actuation) Oral inhalation B132000026 Placebo inhalation solution RESPIMAT Oral inhalation B122000078 12 weeks. The duration of the trial for each patient was 18 weeks: 1-week run-in period, 2-week screening period, 12-week treatment period, and 3-week follow-up period Primary efficacy endpoints: FEV 1 area under the curve (AUC) 0-3h response (change from baseline) after 12 weeks of treatment Trough FEV 1 response (change from baseline) after 12 weeks of treatment SGRQ total score after 12 weeks of treatment Secondary efficacy endpoints: Transitional Dyspnoea Index (TDI) focal score after 12 weeks of treatment FVC AUC 0-3h response (change from baseline) after 12 weeks of treatment Trough FVC response (change from baseline) after 12 weeks of treatment Further (non-secondary) endpoints are not presented here. The assessment of safety was based on routine safety monitoring and reporting through adverse events, serious adverse events, physical examination, pulse rate and blood pressure pre-dose and post-dose at Visits 2 and 5, and treatment exposure.
Page 4 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 4 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Statistical Methods: SUMMARY - CONCLUSIONS: Trial Subjects and Compliance with Trial Protocol: The primary analysis was performed on the full analysis set (FAS). Comparisons between treatment groups for change from baseline in FEV 1 AUC 0-3h, change from baseline in trough FEV 1, and SGRQ total score were analysed using a restricted maximum likelihood (REML)-based mixed effects model for repeated measures (MMRM) approach. The MMRM model included treatment, test day and treatment by test day interaction as fixed, categorical effects, baseline and baseline-by-test day interaction as continuous fixed covariates, and patient as random effect. A spatial power (co)variance structure was used to model the within-patient errors. The Kenward-Roger approximation was used to estimate denominator degrees of freedom. Adjusted mean values were presented together with p-values and 95% confidence intervals (CI). The empirical sandwich estimator approach was used as sensitivity analysis. For the 3 primary endpoints, Tio+Olo 5/5 µg and Tio+Olo 2.5/5 µg were tested vs. placebo in a pre-defined sequential testing scheme. For the third primary endpoint, SGRQ total score, the data from this trial (1237.26) were also combined with data from the replicate trial (1237.25). The primary treatment comparison was the contrast between treatment groups after 12 weeks of treatment. Statistical significance was declared if 2-sided hypothesis tests were rejected at the 0.05 significance level, the treatment effect favoured the Tio+Olo fixed dose combination (FDC) vs. placebo, and all previous hypothesis tests in the pre-defined hierarchy had shown statistical significance. Further comparisons between treatment groups (i.e. Tio+Olo 5/5 µg and Tio+Olo 2.5/5 µg vs. Tio 5 µg, Tio 5 µg vs. placebo, and Tio+Olo 5/5 µg vs. Tio+Olo 2.5/5) were performed as descriptive analyses (i.e. not protected by the overall type I error at the 0.05 level). A total of 809 patients were randomised and treated. Of these, 764 patients (94.4%) completed the trial and 45 patients (5.6%) discontinued study medication prematurely. The only reason for premature discontinuation reported for >1% of patients was occurrence of adverse events (AEs, 2.8% overall). Premature study medication discontinuation was more frequent in the placebo group (9.9%) than in the active treatment groups (tiotropium [Tio] 5 µg: 5.9%, tiotropium + olodaterol
Page 5 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 5 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Efficacy Results: [T+O] 5/5 µg: 2.0%, T+O 2.5/5 µg: 4.5%). Twenty-two of the 809 treated patients (2.7%) had at least 1 important protocol violation (IPV) during the trial. The incidence of IPVs was similar in all treatment groups (2.0 to 3.5%). Demographic characteristics were generally well balanced among the 4 treatment groups. The majority of patients were White (96.3%) and male (62.5%). The percentage of male patients was slightly lower in the placebo group (57.9%) than in the active treatment groups (62.4% to 65.8%). The overall mean age was 64.6 years (standard deviation 8.4 years). In line with the inclusion criteria, all patients were aged 40 years (range 41 to 92 years), and all were ex-smokers (54.5%) or current smokers (45.5%). The overall mean smoking history was 49.3 pack-years (range 11 to 208 pack-years). Efficacy results from lung function endpoints presented in this report are based on analyses of the data from trial 1237.26. Efficacy results from SGRQ and Mahler TDI score endpoints presented in this report are based on both the individual dataset from trial 1237.26 and the combined dataset from 1237.25 and 1237.26. Primary efficacy endpoints: The primary lung function endpoints for this trial were the FEV 1 AUC 0-3h response (change from baseline) and trough FEV 1 response assessed after 12 weeks of treatment (based on the individual data from this trial). The primary symptomatic endpoint was the SGRQ total score after 12 weeks of treatment based on the individual data from this trial as well as the combined data from this trial and the replicate trial 1237.25. The Tio+Olo FDCs were superior to placebo for both primary lung function endpoints and for the primary symptomatic endpoint (p<0.05, 2-sided) based on all pre-defined hypothesis tests. Sensitivity analyses yielded similar results to those of the primary analyses. The adjusted mean FEV 1 AUC 0-3h responses after 12 weeks were larger for the Tio+Olo FDCs than for placebo or Tio 5 µg (placebo: -0.006 [standard error [SE] [ 0.4] L, Tio 5 μg: 0.188 [0.3] L, T+O 2.5/5 μg: 0.279 [0.4] L, T+O 5/5 μg: 0.293 [0.3] L). The improvement over placebo after 12 weeks was 0.299 L for Tio+Olo 5/5 µg and 0.284 L for Tio+Olo 2.5/5 µg (p<0.00 for both
Page 6 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 6 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. comparisons). The adjusted mean trough FEV 1 responses after 12 weeks were also larger for the Tio+Olo FDCs than for placebo or Tio 5 µg (placebo: -0.003 [SE 0.4] L, Tio 5 μg: 0.124 [0.3] L, T+O 2.5/5 μg: 0.166 [0.3] L, T+O 5/5 μg: 0.163 [0.3] L). The improvement over placebo was 0.166 L for Tio+Olo 5/5 μg and 0.169 L for Tio+Olo 2.5/5 μg (p<0.00 for both comparisons). The adjusted mean SGRQ total score after 12 weeks of treatment was lower (better) for the Tio+Olo FDCs than for placebo or Tio 5 µg in both, the individual trial data from 1237.26 (placebo: 42.575, [SE 0.711] points, Tio 5 μg: 39.729 [0.694] points, T+O 2.5/5 μg: 38.909 [0.691] points, T+O 5/5 μg: 38.1 [0.683] points) and the combined trial data (placebo: 42.265 [0.511] points, Tio 5 μg: 39.694 [0.498] points, T+O 2.5/5 μg: 38.419 [0.494] points, T+O 5/5 μg: 37.597 [0.492] points). The scores obtained from both data sources (individual and combined data) were comparable. Based on the data from trial 1237.26, the treatment difference in the adjusted mean SGRQ total score was -4.564 points for Tio+Olo 5/5 μg vs. placebo and -3.666 points for Tio+Olo 2.5/5 μg vs. placebo (p<0.00 and p = 0.0002, respectively). Based on the combined data, the treatment difference in the adjusted mean SGRQ total score was -4.668 points for Tio+Olo 5/5 μg vs. placebo and -3.846 points for Tio+Olo 2.5/5 μg vs. placebo (p<0.00 for both comparisons). Consequently, all confirmatory hypotheses were met in this trial. The type I error was protected only for the above comparisons. The following comparisons were not included in the hierarchical testing sequence and were therefore considered descriptive (nominal p-values). The treatment difference for Tio 5 µg vs. placebo was 0.194 L for FEV 1 AUC 0-3h response and 0.127 L for trough FEV 1 response ( p<0.00 for both lung function endpoints). The treatment difference for the adjusted mean SGRQ total score for Tio 5 µg vs. placebo was -2.846 points based on individual trial data from 1237.26 and -2.571 points based on combined data (p = 0.0042 and p = 0.0003, respectively). Treatment differences in favour of the FDCs compared with Tio 5 µg were observed for FEV 1 AUC 0-3h response (0.105 L for T+O 5/5 µg and 0.091 L for T+O 2.5/5 µg vs. Tio 5 µg, p<0.00 for both comparisons) and for trough FEV 1
Page 7 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 7 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. response (0.039 L for T+O 5/5 µg and 0.042 L for T+O 2.5/5 µg vs. Tio 5 µg, p = 0.0395 and p = 0.0269, respectively). Treatment differences in favour of the FDCs compared with Tio 5 µg were also observed for the SGRQ total score for both, the individual trial data from 1237.26 (-1.717 points for T+O 5/5 µg and -0.820 points for T+O 2.5/5 µg vs. Tio 5 µg, p = 0.0780 and p = 0.4028, respectively) and the combined data( -2.097 points for Tio+Olo 5/5 µg and -1.274 points for Tio+Olo 2.5/5 µg vs. Tio 5 µg, p = 0.0028 and p = 0.0696, respectively). Secondary efficacy endpoints: The analyses of secondary endpoints are descriptive, and p-values for treatment comparisons are nominal. TDI focal score after 12 weeks of treatment The adjusted mean TDI focal score after 12 weeks of treatment was higher (better) for the Tio+Olo FDCs than for placebo or Tio 5 µg in both, the individual trial data from 1237.26 (placebo: 0.337 [SE 0.195] points, Tio 5 μg: 0.950 [0.191] points, T+O 2.5/5 μg: 1.599 [0.189] points, T+O 5/5 μg: 1.531 [0.187] points) and the combined trial data (placebo: 0.111 [0.139] points, Tio 5 μg: 1.140 [0.136] points, T+O 2.5/5 μg: 1.722 [0.134] points, T+O 5/5 μg: 1.734 [0.134] points). The scores obtained from both data sources (individual and combined data) were comparable. Based on individual trial data from 1237.26, the treatment difference was 1.195 points for Tio+Olo 5/5 µg vs. placebo and 1.263 points for Tio+Olo 2.5/5 µg vs. placebo (p<0.00 for both comparisons). The treatment difference for Tio 5 µg vs. placebo was 0.613 points (p = 0.0248). Based on combined data, the treatment difference was 1.623 points for Tio+Olo 5/5 µg vs. placebo and 1.611points for Tio+Olo 2.5/5 µg vs. placebo; the treatment difference for Tio 5 µg vs. placebo was 1.029 points (p<0.00 for all comparisons). Treatment differences in favour of the FDCs compared with Tio 5 µg were observed for both, the individual trial data from 1237.26 (0.582 points for T+O 5/5 µg and 0.650 points for T+O 2.5/5 µg vs. Tio 5 µg, p = 0.0296 and p = 0.59, respectively) and the combined data (0.594 points for T+O 5/5 µg and
Page 8 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 8 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Safety Results: 0.582 points for T+O 2.5/5 µg vs. Tio 5 µg, p = 0.09 and p = 0.0023, respectively). FVC AUC 0-3h response and trough FVC response (changes from baseline) after 12 weeks of treatment The results for the adjusted mean FVC AUC 0-3h responses after 12 weeks of treatment were in line with the FEV 1 data and were clearly larger for the 2 FDCs than for placebo and Tio 5 µg (placebo: -0.8, [SE 0.025] L, Tio 5 μg: 0.266 [0.023] L, T+O 2.5/5 μg: 0.436 [0.024] L, T+O 5/5 μg: 0.414 [0.023] L). The difference to placebo was 0.432 L for Tio+Olo 5/5 μg and 0.455 L for Tio+Olo 2.5/5 µg (p<0.00 for both comparisons). The adjusted mean trough FVC responses showed a similar pattern (placebo: -0.021 [SE 0.024] L, Tio 5 μg: 0.170 [0.023] L, T+O 2.5/5 μg: 0.284 [0.023] L, T+O 5/5 μg: 0.231 [0.023] L). The difference to placebo was 0.252 L for Tio+Olo 5/5 μg and 0.305 L for Tio+Olo 2.5/5 μg (p<0.00 for both comparisons). The treatment differences for Tio 5 µg vs. placebo were 0.284 L for the FVC AUC 0-3h response and 0.191 L for the trough FVC response (p<0.00 for both lung function endpoints). Treatment differences in favour of the FDCs compared with Tio 5 µg were observed for FVC AUC 0-3h response (0.148 L for Tio+Olo 5/5 µg and 0.171 L for Tio+Olo 2.5/5 µg vs. Tio 5 µg, p<0.00 for both comparisons) and for trough FVC response (0.061 L for Tio+Olo 5/5 µg and 0.114 L for Tio+Olo 2.5/5 µg vs. Tio 5 µg, p = 0.0614 and p = 0.0005, respectively). Further (non-secondary) endpoints are not presented here. Overall, 45.1% of patients reported at least 1 AE during the trial, and the incidence was similar between the treatment groups (placebo: 46.0%, Tio 5 μg: 45.8%, T+O 2.5/5 μg: 45.5%, T+O 5/5 μg: 43.1%). Consistent with the population under study, the most frequently reported AEs by SOC were respiratory, thoracic and mediastinal disorders (16.2% overall) and infections and infestations (15.7% overall). AEs reported for more than 2.0% of patients overall were COPD (lowest level term COPD exacerbation; 6.2%), nasopharyngitis (4.3%), cough (3.1%), dyspnoea (3.0%), and upper respiratory
Page 9 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 9 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. tract infection (2.3%). The incidence of cough and dyspnoea was higher in the placebo group than in the active treatment groups; for other common AEs, incidences were generally comparable across the treatment groups, and there was no indication of a tiotropium dose relationship for the combination therapies. The majority of AEs were mild to moderate in intensity; severe AEs were reported for 22 patients (2.7%) overall, with similar frequencies in the T+O 5/5 μg and placebo groups. Drug-related AEs (as assessed by the investigator) were reported for 35 patients (4.3%) overall. The most commonly reported related AEs were cough, reported for 6 patients (0.7%), and dyspnoea and COPD, each reported for 4 patients (0.5%). There were no noteworthy differences between the treatment groups with regard to specific drug-related AEs. One patient died during the trial (T+O 5/5 µg group). The fatal AE (myocardial infarction) was not considered to be drug-related by the investigator. Overall, 26 patients (3.2%) experienced at least 1 serious adverse event (SAE) during the treatment period (placebo: 2.0%, Tio 5 μg: 5.9%, T+O 2.5/5 μg: 2.0%, T+O 5/5 μg: 3.0%). The most frequent SAEs by SOC were cardiac disorders, reported for a total of 7 patients (0.9%): 3 patients each in the Tio 5 µg and Tio+Olo 5/5 µg groups, and 1 patient in the placebo group. SAEs that were reported for more than 2 patients overall were myocardial infarction, COPD, and musculoskeletal chest pain (3 patients each). One case of myocardial infarction in the Tio+Olo 5/5 µg group was fatal. All but one of the patients with cardiac SAEs had pre-existing coronary heart disease and/or cardiovascular risk factors. There were no notable differences between the treatment groups with regard to specific SAEs. SAEs reported for 2 patients (T+O 2.5/5 μg group) were considered to be drug-related by the investigator (cellulitis in 1 patient and rash in 1 patient). A total of 22 patients (2.7%) experienced AEs that led to discontinuation of study medication, with the highest incidence being observed in the placebo group (placebo: 5.0%, Tio 5 μg: 3.4%, T+O 2.5/5 μg: 2.0%, T+O 5/5 μg: 0.5%). AEs leading to treatment discontinuation that were reported for more than 2 patients overall were COPD (7 patients), dyspnoea (5 patients), and cough (3 patients). Vital signs measurements were similar between treatment groups. No dose- or time- related trends or patterns were observed.
Page 10 of 10 BI Trial No.: 1237.26 c03025733-25 International GmbH or one or more of its affiliated companies 10 of 10 25 International GmbH or one or more of its affiliated companies. All rights reserved. Conclusions: With respect to the lung function primary endpoints (FEV 1 AUC 0-3h response, trough FEV 1 response after 12 weeks), trial 1237.26 confirmed the benefit of Tio+Olo 5/5 μg and Tio+Olo 2.5/5 μg compared with placebo. With respect to the symptomatic primary endpoint (SGRQ total score after 12 weeks), trial 1237.26 and the combined dataset from 1237.25 and 1237.26 confirmed the benefit of Tio+Olo 5/5 μg compared with placebo, with an effect size greater than the minimum clinically important difference (MCID) of 4.0 points. A benefit of Tio+Olo 2.5/5 μg compared with placebo for the SGRQ total score was also confirmed, however, with an effect size that was below the MCID for both trial 1237.26 and the combined dataset. Tio+Olo 5/5 μg and Tio+Olo 2.5/5 μg were well tolerated; no safety concerns were identified in the trial.