abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis which is part of the clinical study report had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion. The synopsis may include approved and non approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities. A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug. More current information regarding a drug is available in the approved labeling information which may vary from country to country.. Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim s Policy on Transparency and Publication of Clinical Study Data. The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission.
Page: 1 of 7 International GmbH This is the International GmbH Title of study: Investigator: Study centers: Publication (reference): Clinical phase: A Randomised, Double-Blind, Double-Dummy, Placebo- and Active-Controlled, Parallel Group Efficacy and Safety Comparison of 12-Week Treatment of Two Doses [5 μg (2 actuations of 2.5 μg) and 10 μg (2 actuations of 5 μg)] of Tiotropium Inhalation Solution Delivered by the Respimat Inhaler, Placebo and Ipratropium Bromide Inhalation Aerosol (MDI) in Patients with Chronic Obstructive Pulmonary Disease (COPD) Multicentre trial without official designation of a Principal or Coordinating Investigator. BI Responsible Medical Officer: M.D. Multicentre study Data from this study have not been published. III Objectives: The primary objective of this study was to compare the bronchodilator efficacy of two doses (5 μg and 10 μg) of tiotropium inhalation solution delivered by the Respimat inhaler once daily to placebo delivered by the Respimat inhaler and metered dose inhaler (MDI) and to ipratropium bromide inhalation aerosol delivered by MDI four times daily in patients with chronic obstructive pulmonary disease (COPD). The secondary objective was to compare the safety of tiotropium inhalation solution delivered by Respimat inhaler to placebo and ipratropium bromide inhalation aerosol. Methodology: Randomised, double-blinded, double-dummy, placebo-controlled and active-controlled, parallel design No. of subjects: planned: Entered: 336 actual: Enrolled: 429 Entered: 361 Tiotropium Respimat 5 µg: entered: 88 treated: 88 analysed (for primary endpoint): 85 Tiotropium Respimat 10 µg: entered: 93 treated: 93 analysed (for primary endpoint): 89 Ipratropium Bromide MDI 36 µg: entered: 89 treated: 89 analysed (for primary endpoint): 84 Placebo: entered: 91 treated: 91 analysed (for primary endpoint): 87
Page: 2 of 7 This is the Diagnosis and main criteria for inclusion: Test product: dose: mode of admin.: batch no.: Outpatients of either sex, aged 40 years with a diagnosis of COPD (FEV 1 60% predicted [ECCS criteria] and FEV 1 /FVC 70%) Tiotropium inhalation solution 5 μg (2 inhalations of 2.5 μg) and 10 μg (2 inhalations of 5 μg) once a day Oral inhalation by the Respimat inhaler 2.5 μg inhalation solution 202948 with Respimat inhaler WE01070187 5 μg inhalation solution 202821 with Respimat inhaler WE01080199 Duration of treatment: Reference therapy: dose: mode of admin.: batch no.: 12 weeks Placebo Not applicable Oral inhalation by the Respimat inhaler and HFA inhalation aerosol (MDI) Placebo inhalation solution 202942 with Respimat inhaler WE02050101 Placebo inhalation aerosol: 205392 Reference therapy 2: dose: mode of admin.: Ipratropium bromide 36 μg (2 inhalations of 18μg) four times a day Oral inhalation by HFA inhalation aerosol (MDI) batch no.: 202261 Criteria for evaluation: Efficacy: Safety: Statistical methods: FEV 1 (trough, AUC 0-6h; peak, onset and duration of response; percent responders), FVC (trough, AUC 0-6h, peak), twice daily peak expiratory flow rates (PEFR), rescue medication use, COPD symptoms, global evaluations Adverse events, vital signs, laboratory evaluations, ECG testing and physical examinations Analysis of covariance with terms for centre, treatment, smoking status and baseline as covariates; descriptive statistics
Page: 3 of 7 This is the SUMMARY CONCLUSIONS: Efficacy results Overall, the study demonstrated that both doses of tiotropium delivered once-daily by the Respimat device provide effective bronchodilation. In particular, the following may be concluded from the study. FEV 1 and FVC - Both tiotropium inhalation solution groups as well as the ipratropium 36 µg inhalation aerosol group were superior compared to placebo. For the tiotropium 10 µg inhalation solution group, the differences were statistically significant (p<0.05) at all time points on all test-days after the first dose of study medication except for trough on Test Day 8. For the tiotropium 5 µg inhalation solution group the differences were statistically significant (p<0.05) at all time points on all test-days after the first dose of study medication except for most trough values and a few post-dose values. For the ipratropium 36 µg inhalation aerosol group, the differences were statistically significant (p<0.05) at all time points after the first dose of study medication with the exception of the trough measurements taken just prior to dosing and measurements toward the end of the dosing interval. - Both tiotropium inhalation solution groups were superior to the ipratropium 36 µg inhalation aerosol group in trough response on all test-days. The differences were in general statistically significant (p<0.05) for the 10µg group but not statistically significant for the 5 µg group. In terms of AUC(0-6h) response, the tiotropium 10 µg inhalation solution group was directionally superior to the ipratropium 36 µg inhalation aerosol group except for FEV 1 on Test Day 1, but the differences were in general not statistically significant. The tiotropium 5 µg inhalation solution group was comparable to the ipratropium 36 µg inhalation aerosol group. In general, the peak (0-6h) responses for the 10 µg tiotropium inhalation solution group was also directionally superior to the ipratropium 36 µg inhalation aerosol group, but the differences were not statistically significant. The tiotropium 5 µg inhalation solution group was comparable to the ipratropium 36 µg inhalation aerosol group. - The tiotropium 10 µg inhalation solution group showed some improvement over the tiotropium 5 µg inhalation solution group, particularly after Test Day 29, but the differences were in general not statistically significant.
Page: 4 of 7 This is the Efficacy results (cont'd.): Pre-dose morning and evening PEFRs - Both tiotropium inhalation solution groups had higher peak flows compared to the control groups. The treatment differences were highly statistically significant (p<0.01) for the 10 µg group and were in general statistically significant (p<0.05) for the 5 µg group. The ipratropium 36 µg inhalation aerosol group in general had lower pre-dose morning and higher evening peak flows compared to placebo. These differences were in general not statistically significant. - The tiotropium 10 µg inhalation solution group had higher peak flows than the 5 µg inhalation solution group, but the differences were not statistically significant. Rescue salbutamol use - Both tiotropium inhalation solution groups as well as the ipratropium 36 µg inhalation aerosol group were superior compared to placebo. These differences were statistically significant (p<0.05) for all weeks for the tiotropium 10 µg inhalation solution group but were generally not statistically significant for the tiotropium 5 µg inhalation solution and ipratropium 36 µg inhalation aerosol groups. - The differences among the three active treatment groups were small and generally not statistically significant. COPD symptoms - The treatment differences between the tiotropium 10 µg inhalation solution and ipratropium 36 µg inhalation aerosol groups were statistically significant (p<0.05) for the wheezing, shortness of breath and chest tightness, but not the coughing scores. Otherwise, the treatment differences were in general not statistically significant. In all cases the differences were small. Physician's Global Evaluation - The differences among the treatment groups were small. However, they were in general statistically significant (p<0.05) in favour of the tiotropium groups compared to the control groups. Onset of steady state - Pharmacodynamic steady state was not achieved by the first test-day after multiple dosing (Test Day 8), though some levelling off of effect was seen by Test Day 29 (75% and 91% of Test Day 85 trough response seen at Test Days 8 and 29, respectively). -
Page: 5 of 7 This is the Efficacy results (cont'd): Safety results: Onset and duration of therapeutic response - Onset of response on Test Day 1 was comparable for the tiotropium 10 µg inhalation solution and ipratropium 36 µg inhalation aerosol groups (median onset within 28 minutes) and longer for the tiotropium 5 µg inhalation solution group (median onset of 59 minutes). - For the ipratropium 36 µg inhalation aerosol group, both the onset and duration of response were slightly shorter at Test Day 85 compared to Test Day 1. Rebound - There is no indication of a rebound effect (i.e., there was no sudden worsening of condition following the end of treatment) The percentage of patients reporting at least one treatment emergent adverse event was relatively balanced across the four treatment groups. Overall, the most frequently occurring adverse events were in the lower and upper respiratory system and gastrointestinal system organ classes. The most common events were COPD exacerbation, pharyngitis, headache and cough. COPD exacerbation was reported most commonly in the ipratropium 36 μg inhalation aerosol group (13.5%) followed by the tiotropium 10 μg and 5 μg inhalation solution groups (11.8%, 10.2%, respectively) and the placebo group (8.8%). Pharyngitis was reported most commonly in the placebo group (13.2%) followed by the ipratropium 36 μg inhalation aerosol, tiotropium 10 μg and 5 μg inhalation solution groups (9.0%, 8.6%, 8.0%, respectively). Headache was reported most commonly in the placebo group (7.7%) followed by the ipratropium 36 μg inhalation aerosol (4.5%), tiotropium 10 μg inhalation solution (3.2%) and tiotropium 5 μg inhalation solution (2.3%) groups. Cough was reported most commonly in the ipratropium 36 μg inhalation aerosol and tiotropium 10 μg inhalation solution and groups (5.6% and 5.4%, respectively) followed by the tiotropium 5 μg inhalation solution (3.4%) and the placebo (2.2%) groups. The events of mouth dry and pharyngolaryngeal pain were reported more frequently for the two doses of tiotropium inhalation solution compared to the ipratropium 36 μg inhalation aerosol and placebo control groups. The events of diarrhoea, COPD exacerbation and cough were reported more frequently in the three active treatment groups compared to the placebo group. Among these events, diarrhoea and pharyngolaryngeal pain were most frequent in the tiotropium 10 μg inhalation solution group; mouth dry was most frequent in the tiotropium 5 μg inhalation solution group; COPD exacerbation was most
Page: 6 of 7 This is the Safety results (cont'd.): frequent in the ipratropium 36 μg inhalation aerosol group and cough was most common in the tiotropium 10 μg inhalation solution and ipratropium 36 μg inhalation aerosol groups. Overall, 7.5% of the patients reported at least one adverse event which was considered by the investigator as related to treatment with the test medication (related adverse event). The percentage of patients with a related adverse event was greatest in the tiotropium 5 μg inhalation solution group (11.4%) followed by the ipratropium bromide 36 μg inhalation aerosol, tiotropium 10 μg inhalation solution and placebo groups (6.7%, 6.5%, 5.5%, respectively). The most common event reported as related was mouth dry, which was reported by 3 patients (3.2%) in the tiotropium 10 μg inhalation solution group, 2 (2.3% and 2.2%) in the tiotropium 5 μg inhalation solution and placebo groups and 1 (1.1%) in the ipratropium bromide 36 μg inhalation aerosol group. Overall, 7.5% of the patients reported a treatment emergent adverse event for which the action taken with the test medication for the event was recorded as discontinued. The greatest percentage of patients reporting an adverse event that led to treatment discontinuation was in the ipratropium 36 μg inhalation aerosol group (12.4%); followed by the tiotropium 5 μg inhalation solution group (6.8%) and the placebo and tiotropium 10 μg inhalation solution groups (5.5% and 5.4%, respectively). The most common event leading to treatment discontinuation was COPD exacerbation, which was reported by 8 (9.0%) patients in the ipratropium 36 μg inhalation aerosol group, 2 (2.3% and 2.2%) in the tiotropium 5 μg inhalation solution and placebo groups, and 1 (1.1%) in the tiotropium 10 μg inhalation solution group. Overall, 5.3% of the patients reported a treatment emergent serious adverse event. The greatest percentage of patients reporting a serious adverse event was in the ipratropium 36 μg inhalation aerosol group (9.0%); followed by the tiotropium 10 μg inhalation solution (5.4%), placebo (4.4%) and tiotropium 5 μg inhalation solution (2.3%) groups. Nine of the patients reporting a treatment emergent serious adverse event discontinued the test medication due to the event(s) (Tio R 5: 2 patients, Tio R 10: 3 patients, IB MDI 36: 4 patients, placebo: 0 patients). One patient (Tio R 10) reported fatal adverse events. The patient died from a COPD exacerbation and respiratory failure. The events were not considered by the investigator as related to treatment with the test medication.
Page: 7 of 7 This is the Safety results (cont'd.): Conclusions: Evaluation of clinical laboratory values and vital signs (individual patient marked changes, mean changes and shifts from baseline) indicated that changes from baseline were minimal and no effect of treatment was observed. Clinically significant change from baseline in ECGs and physical examination were reported infrequently and all were recorded as adverse events. In summary, evaluation of all of the safety data collected from this trial did not reveal any unexpected safety findings for the tiotropium 5 μg and 10 μg inhalation solution delivered by the Respimat inhaler in comparison ipratropium 36 μg inhalation aerosol or placebo. Furthermore no definitive dose-relationship on the safety findings was noted between the two doses of tiotropium. The data support a favourable safety profile of tiotropium 5 μg and 10 μg inhalation solution delivered by the Respimat inhaler. This study supports that tiotropium inhalation solution delivered by the Respimat inhaler in the doses of 5 µg and 10 µg once daily is a safe and effective long-acting anticholinergic bronchodilator for the long-term maintenance treatment of patients with airflow obstruction due to COPD.