Reply to ‘Can a better patient phenotyping predict the efficacy of tiotropium in asthmatic adolescents?’

To the editor,

We thank Liccardi et al. [1] for their intriguing letter concerning our article [2]. They raise several points of interest regarding our report, which we will discuss here.

First, regarding cholinergic tone, this may indeed be a factor predicting positive clinical response to tiotropium Respimat® (Boehringer Ingelheim, Ingelheim am Rhein, Germany) in adolescents, as in any patient with asthma, and as mentioned there are several predictive tools identified by Peters et al. [3]. While many of these tools are difficult to use, of interest in that study is that albuterol was the best predictor of a tiotropium response. Screening for albuterol response could, therefore, be a relatively simple step to include in future analyses. We also acknowledge that it would be, and will be, favorable to perform responder analyses in this patient population. However, the study protocols for these pivotal Phase III trials reviewed in our manuscript [2] were not designed to identify variability in response to tiotropium within patient subsets, but to assess efficacy and safety of tiotropium add-on in patients with symptomatic asthma, across the range of different baseline and disease characteristics. Further analyses are currently ongoing to look more deeply at adult, adolescent, and pediatric responders, which we hope would be of great interest to readers.

Second, regarding the allergic state of the adolescent patients, we agree that this is particularly important in younger patients with asthma, and therefore we have begun to investigate this further. We will shortly be publishing data showing that there is no correlation between the allergic status of children and adolescents included across several trials and the response to tiotropium Respimat®.

Finally, Liccardi et al. [1] suggest that the ‘limited statistical significance’ achieved may be due to insufficient phenotyping and enrolment of non-responders. We maintain that there are numerical and statistically significant improvements in peak and trough forced expiratory volume in 1 s with tiotropium Respimat® across the studies in the endpoints required by the regulatory authorities for this study. Furthermore, as compliance is a key factor in trials with adolescent patients, it is likely that improvements not reaching statistical significance were due to better overall asthma adherence of all participants, including the placebo arm, during the trial. This is indicated by the large placebo effect in these studies, particularly in the shorter study on severe asthma in adolescents [4].

To conclude, tiotropium Respimat® is an effective and safe add-on treatment in patients who remain symptomatic on at least inhaled corticosteroid maintenance therapy. While the efficacy of tiotropium Respimat® has been shown to be independent of a wide range of baseline characteristics, further responder analyses will help predict those patients who will receive the greatest clinical benefit.

Declaration of interest

E Hamelmann has received grants from the Dutch Ministry of Health, and has served as a consultant for Aerocrine, Allergopharma, ALK, Bencard Allergie, Boehringer Ingelheim, HAL Allergy, LETI, Novartis, and Stallergenes. SJ Szefler has received grants from the Colorado Department of Public Health (13-FLA-48556 and 17-FHLA-93211), the National Heart, Lung, and Blood Institute Asthma Clinical Research Network (1 U10 HL098075-01), and GlaxoSmithKline Inner City Asthma School Program Building Bridges (FLV116794). SJ Szefler has also served as a consultant for Aerocrine, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Genentech, GlaxoSmithKline, Hoffmann-La Roche, Merck, Novartis, Roche, Sanofi, and Teva. Medical writing assistance, provided by Helen Moore, PhD, at MediTech Media, was utilized in the preparation and revision of the reply, was supported financially by Boehringer Ingelheim and provided under the authors’ conceptual direction and based on feedback from the authors. Boehringer Ingelheim supported the original studies and manuscript; however, this response is independent by the named authors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Funding

This paper was not funded.