Author's response to reviews

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1 Author's response to reviews Title:Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial Authors: Kai M Beeh (k.beeh@insaf-wi.de) Henrik Watz (H.Watz@pulmoresearch.de) Luis Puente-Maestu (lpuente@separ.es) Luis de Theresa (deteresa.luis@gmail.com) Diana Jarreta (diana.jarreta@almirall.com) Cynthia Caracta (ccaracta15@gmail.com) Esther Garcia Gil (esther.garciagil@almirall.com) Helgo Magnussen (magnussen@pulmoresearch.de) Version:3Date:21 November 2014 Author's response to reviews: see over

2 Pulmonary Research Institute at LungClinic Grosshansdorf Woehrendamm 80 D Grosshansdorf Germany Tel: Fax: November 2014 Dr Victor Kim Associate Editor BMC Pulmonary Medicine Dear Dr Kim Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized placebo-controlled crossover trial (manuscript id: ) On behalf of my co-authors, I would like to thank you for reviewing our manuscript and providing an opportunity for us to resubmit a revised draft to BMC Pumonary Medicine. We thank the reviewers and editor for their comments and have provided a revised copy of the manuscript, along with revised figures and additional files. We have also provided a point-by-point response to the reviewers comments below, describing the action we have taken within the manuscript. In addition, in response to the editorial request, we have also made minor edits throughout the manuscript to improve clarity. Reviewer 1 Comment 1: Were patients preselected by having dyspnea such as an mmrc score over 2. It s not clear if there is an enrichment but I may have missed it. Response: Dyspnea severity was not a selection criterion in the study. We have added text to the methods to clarify this (page 7, paragraph 2, lines ). Comment 2: Statistical Methods if in your hierarchal statistical plan, after endurance time delta between aclidinium was 5%, using a step down approach, did you use descriptive stats if the hierarchical standard wasn't met for the secondary endpoints. Response: We can confirm that, based on the statistical analyses plan, if the comparison between aclidinium and placebo was not significant for the primary endpoint, then descriptive statistics were to be used to describe the secondary endpoints. As the comparison between aclidinium and placebo was significant for the primary endpoint, we have not included this information in the methods. Comment 3: Treatment effect by baseline PAL is really hard to follow since classifying as inactive verses sedentary while based on the standard score, leaves one confused and

3 this paragraph lines are hard to follow. Again this is the Pal score based terms so you may not be able to do much with it. Response: We thank the reviewer for their comment. To improve clarity we now describe the criteria used to categorize patients as extremely inactive, sedentary, and at least moderately active in the study assessments and endpoints section of the methods (page 10, paragraph 1, lines ). We have also revised the text in the results section to make the text easier to follow (page 14, paragraph 5 and page 15, paragraphs 1 and 2). Comment 4: Static Lung Function; the results in the IC here are less robust a when compared to prior studies by the first author with indacaterol. The IC change seems a little weak. Please comment Response: We thank the reviewer for their comment. While the improvement in static lung function (as assessed by IC at rest) observed with aclidinium 400 µg BID in this study was lower than that previously seen with indacaterol 300 µg QD, it was comparable to that obtained with other LAMAs in patients with COPD. Similarly, improvements in dynamic lung function (assessed as IC at isotime) were also comparable between LAMAs. However, indirect comparisons of treatment effects across studies are not straightforward as, in addition to differences in the mechanism of action of LAMAs and LABAs, the study populations or other aspects of the study design may differ between studies. Therefore, comparisons of results between studies are included for illustrative purposes. For consistency, we have revised the text to put the improvements observed in exercise tolerance, IC at isotime, and IC at rest observed with aclidinium 400 µg BID in context with published data for other LAMAs (page 16, paragraph 2, lines ). Reviewer 2 comments: The authors have presented a well written paper on the effect of aclidinium on exercise, lung volumes, dyspnea, and physical activity in patients with moderate to severe COPD. The study design was randomized, double blind crossover. Patients were treated with aclidinium 400 ug twice daily (or placebo twice daily) for three weeks. There was a 2 week washout period between treatments (placebo vs aclidinium). The primary outcome was exercise time during constant work rate cycle ergometry at 75% max work rate on a previously obtained maximal cardiopulmonary exercise test. Constant work cycle ergometry was performed pre-dose and at 3 hours post dose after 3 weeks of treatment. This is an accepted endpoint when studying the effect of a medication on exercise performance. Important secondary endpoints were static lung volumes, dyspnea, change in IC at isotime and end exercise, physical activity measured by an arm band device, spirometry and COPD symptoms. The authors should be commended for looking at the effect of aclidinium on daily activity outside of the exercise lab. This is a strength of the paper. The authors found that there was a significant increase in endurance time. Additionally, static and dynamic lung volumes were lower. Subjects had less dyspnea as well. Subjects had improvements in duration of at least moderately intense physical activity and daily active energy expenditure but there was not a significant improvement in number of steps taken. I feel that this paper does add to the available literature on

4 improving exercise and physical activity in COPD and should be accepted with revisions. My comments are listed below. Response: We thank the reviewer for their comments. We have revised the manuscript as outlined below to address the reviewer s comments. Major comment 1: The title is misleading and should be adjusted. The title suggests that this is a randomized placebo controlled study when in reality it was done with a crossover study design. While this approach can provide valuable data it is not as ideal as a true placebo controlled trial. Response: We have revised the title as follows: Aclidinium improves exercise endurance, dyspnea, lung hyperinflation, and physical activity in patients with COPD: a randomized, placebo-controlled, crossover trial (see page 1, line 3). Major comment 2: Demonstrating improvement in dynamic hyperinflation can be difficult. Any intervention that lowers static lung volumes at rest will invariably lower lung volumes during exercise. No intervention is likely to completely eliminate dynamic hyperinflation in subjects with moderate severe COPD unless airflow obstruction is completely reversed. The authors should be able to create a plot of lung volumes during exercise that will likely demonstrate a downward and rightward shift. This will be beneficial to the readers and enhance understanding of the data. I would recommend recreating the following figures with the aclidinium data. O Donnell et al ERJ 23: ;2004. Response: We thank the reviewer for their comment. All of the data needed to reproduce the plots the reviewer suggested were not collected during the study. To address the reviewer s comment, and using the available data, we have included a new figure reporting end-expiratory lung volumes (EELV) at baseline and at Week 3 in patients receiving placebo or aclidinium 400 µg BID (please see new Figure 5). These data show that EELV was reduced during exercise following 3 weeks treatment with aclidinium 400 µg BID. In contrast, there was no reduction in EELV with placebo. We have added text to the methods (see page 9, paragraph 1, lines and page 11, paragraph 1, line 203) and results (see page 13, paragraph 1, lines ) to describe these data. Furthermore, while the reviewer is correct, exercise-induced dyspnea depends on how much EILV approaches to TLC. Therefore, even if the effect was a decrease in resting FRC and a corresponding increase in resting IC, with no change in IC during exercise, the result would be a reduction in isotime EILV and consequently a reduction in dyspnea and an increase in exercise tolerance. Major comment 3: I would find it useful to report the change in IC (from beginning to end exercise) during exercise while on placebo and aclidinium separately. I would predict that there would not be a difference in the amount of IC drop since subjects with COPD will stop exercise one reaching a critical IRV (O Donnel J applied physiol 101: ;2006). If space is limited then it could be presented in an online supplement.

5 Additionally, how many subjects did not develop dynamic hyperinflation during exercise? Likely there were subjects that did not have a drop in IC during exercise. Response: We have added data to the results to describe the change from baseline in IC every 2 minutes during exercise at Week 3 (page 12, paragraph 4, lines and page 13, paragraph 1, lines ). We have also included a figure reporting these data as an additional file (Additional File 3). Data for the proportion of patients in the ITT population who developed dynamic hyperinflation during exercise at baseline (pre-dose at Visit 1) have also been added to the results section (page 12, paragraph 2, lines ). Major comment 4: If the improvement in exercise endurance time is related to the decrease in static and dynamic lung volumes then there should be significant correlations between change in static lung volumes (especially RV and IC) with endurance time. These analyses should be provided. Response: We have included analyses of the correlation between changes from baseline in static lung volumes and endurance time. When both treatment groups were combined, there was a weak correlation between improved exercise endurance and reduced postdose RV, post-dose FRC, and trough FRC. There was also a weak positive relationship between changes from baseline in endurance time and IC at rest. In the aclidinium-only treatment period, the correlations between changes from baseline in endurance time and lung volumes did not reach statistical significance. We have revised the methods (page 11, paragraph 2, lines ) and the results (page 13, paragraph 5 and page 14, paragraph 1) to reflect the inclusion of these data and provided further discussion of the data on page 16, paragraph 4, lines and page 17, paragraph 1, lines Major comment 5: There is no mention of whether or not participants participated in pulmonary rehab previous to the trial or if they were currently enrolled in rehab. This should be addressed in the paper if these data are available. Response: We have added text to the methods to clarify that patients who, in the investigator s opinion, may have needed to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to the screening visit were excluded (page 7, paragraph 3, lines ). Minor comment 1: Lung function variable should be reported as %-predicted in table 1 for spirometry, FRC, RV and TLC. Response: We have added data for % predicted FEV 1, FVC, FRC, RV, and TLC at baseline to Table 1 (see Table 1 rows 21, 23, 25, 28, 30, and 32). Data for % predicted IC were not collected. Minor comment 2: Was there significant desaturation in any patients during exercise? This will contribute to exercise limitation and not be helped by bronchodilator therapy.

6 Response: Only two patients did not achieve 85% oxygen saturation at any visit during the study. We have revised the methods section to reflect that SpO 2 levels were assessed during exercise (page 9, paragraph 1, lines ) and we have reported the number of patients who did not achieve 85% oxygen saturation at any visit during the study in the results section (page 13, paragraph 2). Minor comment 3: If possible please provide a table (maybe in supplementary section) of medication use. It is surprising that patients were not on LABA therapy given the severity of airflow obstruction in the trial. Response: The use of LABAs was not permitted during the study. Treatment with twicedaily LABAs (eg, formoterol or salmeterol) must have been discontinued at least 48 h prior to the screening visit; treatment with once-daily LABAs (eg, indacaterol) must have been discontinued at least 7 days prior to screening. We have added text to the methods to clarify this (page 6, paragraph 4, lines ). In addition, we have provided details of COPD medication use prior to the study in Additional File 2. Minor comment 4: Try to shorten the abstract if possible. Response: We have revised the abstract to shorten it. The abstract is now 246 words long which is within the guidelines of 350 words (pages 3 and 4). Thank you for considering our revised manuscript and we look forward to your favourable response. Yours sincerely Professor Helgo Magnussen, MD