Dear editor
We read with great interest the letter from Tamura and Satoh and would like to provide answers to their queries. The first question related to our method of excluding patients with bronchial asthma. We can clarify that, in addition to the exclusion criteria documented in Table S1, a history of asthma was defined in the protocol as a specific exclusion criterion. Furthermore, for patients with allergic rhinitis, atopy, or a total blood eosinophil count of ≥600/mm3, source documentation was required to verify that the patient did not have asthma. Therefore, we consider it unlikely that any patients with bronchial asthma were included in the study.
Regarding the question on the number of patients who failed to be randomized in the study following enrollment, 59 out of 288 patients (~20%) were screened but not randomized to treatment in the study. These 59 individuals did not meet the inclusion and/or exclusion criteria and were, therefore, not randomized and did not receive any treatment. This proportion of patients is in line with – and, in fact, smaller than – several large Phase III studies, such as ILLUMINATE, where 37% of patients screened were not randomized,1 SHINE, where 41% of patients were not randomized to treatment,2 and SPARK, where 42% of patients were screening failures.3
The third question related to the method of randomization to treatment groups and whether the sequence of treatments affected the outcome. Patients were randomized to one of four possible treatment sequences via a computer program. The order of the administration of each treatment was not expected to affect the outcome since each treatment was followed by a 21-day washout period and a Williams design was selected, such that each treatment occurred only once within each sequence and once within each period.
Footnotes
Disclosure
The institution where KMB is employed has received compensation for organizing or participating in advisory boards for Almirall Hermal, Cytos, Chiesi, Boehringer Ingelheim, AstraZeneca, Mundipharma, Novartis, and Revotar Biopharmaceuticals, and for participation in scientific meetings or courses supported by various pharmaceutical companies (Almirall Hermal, AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, and Takeda) in the past 3 years. KMB’s institution has also received consulting fees from Ablynx, Apellis Pharmaceuticals, Chiesi, and Cytos. The institution has received compensation for the design, performance, or participation in single or multicenter clinical trials in the past 3 years from several companies, including Almirall, Boehringer Ingelheim, Cytos, GSK, Mundipharma, Novartis, Pfizer, Revotar Biopharmaceuticals, Sterna AG, and TEVA. ED reports consultancy fees from Actelion, Boehringer, AstraZeneca, and Cipla, advisory board fees for Chiesi, AstraZeneca, and CSL Behring, and speaker fees for GlaxoSmithKline and Boehringer. LG and AH are employees of Boehringer Ingelheim. JES, DZ, and LB report no conflicts of interest in this communication.
References
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1.Vogelmeier CF, Bateman ED, Pallante J, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med. 2013;1(1):51–60. doi: 10.1016/S2213-2600(12)70052-8. [DOI] [PubMed] [Google Scholar]
-
2.Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42(6):1484–1494. doi: 10.1183/09031936.00200212. [DOI] [PMC free article] [PubMed] [Google Scholar]
-
3.Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1(3):199–209. doi: 10.1016/S2213-2600(13)70052-3. [DOI] [PubMed] [Google Scholar]
