Open access Research BMJ Open: first published as 10.1136/bmjopen-2018-024114 on 26 July 2019. Downloaded from Clinical benefit of two-times-per-day aclidinium bromide compared with once-a-day tiotropium bromide hydrate in COPD: a multicentre, open-label, randomised study Tadashi Kamei, 1 Hiroyuki Nakamura,2 Nobuki Nanki,3 Yoshiaki Minakata,4 Kazuto Matsunaga,5 Yoshihiro Mori,6 for Command Study Group To cite: Kamei T, Nakamura H, ABSTRACT Strengths and limitations of this study Nanki N, et al. Clinical Objective Chronic obstructive pulmonary disease (COPD) benefit of two-times-per-day is mainly treated pharmaceutically with bronchodilators. ► This was the first study to evaluate the clinical ben- aclidinium bromide compared The purpose of this study was to evaluate the clinical with once-a-day tiotropium efit of two-times-per-day aclidinium bromide com- benefits of two-times-per-day aclidinium bromide (Acli- bromide hydrate in COPD: pared with once-a-day tiotropium bromide hydrate, BID) compared with once-a-day tiotropium bromide a multicentre, open-label, assessed through evaluation of pulmonary function hydrate (Tio-QD) in patients with COPD. randomised study. BMJ Open and physical activity. 2019;9:e024114. doi:10.1136/ Design This study was a multicentre, open-label, ► Physical activity was evaluated objectively using the randomised study. bmjopen-2018-024114 triaxial accelerometer as well as subjectively using Setting Fourcentres in Kagawa prefecture, Japan. Pre-publication history and self-reported questionnaires. ► Participant Patients who were diagnosed to have COPD additional material is published ► Because we conducted this study in a real-life set- Grade 2–3 according to the Global Initiative for Chronic online only. To view please visit ting, the inclusion and exclusion criteria were not Obstructive Lung Disease 2015 criteria were enrolled. the journal online (http:// dx. doi. very stringent. org/ 10. 1136/ bmjopen- 2018- Interventions Patients were randomly assigned to receive ► This was an exploratory study, and as such, it is a Acli-BID or Tio-QD at a 1:1 ratio, and followed for 8 weeks. 024114). small open-label study with a short period of fol- Acli-BID was administered in the morning and night, and Data included in this paper low-up and without placebo. http://bmjopen.bmj.com/ were presented at the American Tio-QD was administered in the night. Thoracic Society International Primary and secondary outcome measures Primary Conference, 19-24 May 2017, outcome was forced expiratory volume in one second area Washington, DC as a poster under the curve (FEV1AUC0-3), and secondary outcomes Trial registration number UMIN 000020020. presentation, and the abstract were pulmonary function, physical activity, St George’s was published in "American Respiratory Questionnaire (SGRQ), modified Medical Thoracic Society International Conference Abstracts", Research Council (mMRC), the 8-item Short-Form Health INTRODUCTION Am J Respir Crit Care Med Survey (SF-8) and COPD exacerbations. Adverse events Chronic obstructive pulmonary disease were evaluated during the study. on January 13, 2020 by guest. Protected copyright. 2017;195:A5471. (COPD) is a major chronic respiratory disease. Results 44 patients were included in this study. Received 10 May 2018 It is a progressive and irreversible pathological FEV1AUC0-3 at week 8 was 4.62±1.43 L·hour in Acli- Revised 13 June 2019 BID and 4.73±1.60 L·hour in Tio-QD (mean difference condition and is among the leading causes of Accepted 14 June 2019 (MD) −0.11 L·hour; 95% CI), −1.04 to 0.83). Significant death worldwide. To improve the quality of improvement was observed in activity-related subscales life (QoL) of patients with COPD, particu- of SGRQ (MD −7.78; 95% CI −14.61 to −0.94) and SF-8 larly in ageing societies such as Japan, Europe (MD 4.01; 95% CI 0.37 to 7.65), mMRC (MD −0.66; 95% CI and the USA, inhibiting disease progression −1.19 to −0.13) and rate ratio (0.52, 95% CI 0.27 to 0.99) by early therapeutic intervention with bron- © Author(s) (or their of exacerbations in the Acli-BID compared with the Tio- chodilators is considered to be increasingly employer(s)) 2019. Re-use QD. Acli-BID and Tio-QD significantly improved sedentary important.1 The recommendation of the permitted under CC BY-NC. No behaviour (MD −35.20 min; 95% CI −67.41 to −2.94 and Global Initiative for Chronic Obstructive commercial re-use. See rights MD −55.40 min; 95% CI −98.15 to −12.77) within each and permissions. Published by Lung Disease (GOLD) was changed in the BMJ. group, but there was no significant difference between the two groups. 2017 report to select treatment plans for indi- For numbered affiliations see Conclusion Acli-BID as with Tio-QD could be one of the vidual patients considering the severity based end of article. therapeutic options for patients with COPD to improve on pulmonary function and the evaluation of Correspondence to pulmonary function. Also, our results suggest that subjective symptoms, including COPD assess- Dr Tadashi Kamei; intervention with bronchodilators enhanced physical ment test, and the frequency of acute exacer- t- kamei@ mail. netwave. or. jp activity in patients with COPD. bation, reflecting the increasing importance Kamei T, et al. BMJ Open 2019;9:e024114. doi:10.1136/bmjopen-2018-024114 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-024114 on 26 July 2019. Downloaded from of achieving symptomatic control and increasing QoL 2015. Patients were eligible if they had had spirometry 2 in patients with COPD. GOLD 2017 also recommends performed in the previous year and had predicted FEV1 increasing the level of physical activity, because reduced ( 30% and <80%) and FEV1/forced vital capacity <70%. physical activity is a strong predictor of fatality.3 Patients were also only eligible if they had a smoking ≧ Inhalation therapy, including long-acting β2 agonists history of at least 10 pack-years and had been controlled (LABA) and long-acting muscarinic antagonists (LAMA), by medicines other than LAMA for at least 4 weeks before is one of the main treatment options for COPD. Acli- enrolment. Patients were excluded if they had inhaled dinium, a novel, long-acting, inhaled muscarinic agent, corticosteroid (ICS); if their ICS/LABA treatment was for which a Genuair inhaler is used as an inhalation changed in the previous 4 weeks; had concurrent bron- device, has been approved as a COPD treatment drug chial asthma; if they were clearly diagnosed as having for two-times-per-day administration in Japan, Europe pulmonary fibrosis by CT or high-resolution (HR) CT; and the USA. Aclidinium demonstrated equal efficacy had contracted upper or lower airway infection in the to tiotropium for pulmonary function after 6 weeks of previous 4 weeks; had been hospitalised due to exacer- inhalation in phase IIIb study comparing aclidinium bation of COPD in the previous 3 months; or if they were and tiotropium (LAMA).4 Post hoc analysis of this study judged ineligible by the investigator or subinvestigators. reported that aclidinium improved COPD symptoms in Other eligibility criteria, including treatment transition the early morning and at night.5 criteria, are shown in the study protocol (see online Our speculation was that providing two peaks of forced supplementary study protocol). expiratory volume in one second (FEV1) with two-times- Participants were recruited from four study centres per-day administration might be more beneficial in Kagawa prefecture between December 2015 and compared with one peak of FEV1 with once-a-day admin- March 2016. The study was conducted in compliance istration for the improvement of morning symptoms with the Declaration of Helsinki (revised in October and daytime physical activity. Although once a day is the 2013), Ethical Principles for Medical Research Involving preferred frequency of inhalation from the point of view Human Subjects. Ethical principles, selection of study of treatment adherence, it is also important to consider sites, storing of documents, monitoring and audit were administering inhalation therapy when it is needed the conducted based on the International Conference on most (ie, during time of day when the COPD symptoms Harmonization-Good Clinical Practice. are worse and when physically most active). However, it has not yet been clarified whether there is a difference in Intervention the therapeutic effect of LAMAs on early morning symp- At visit 1 (week −4), informed consent was obtained. Enrol- toms and physical activity, depending on the difference in ment and randomisation were conducted at visit 2 (week the number of doses per day. 0), and the investigator enrolled patients who fulfilled the criteria. The patients were randomly assigned either to an http://bmjopen.bmj.com/ aclidinium group (Acli-BID) or a tiotropium group (Tio- OBJECTIVE QD) using block randomisation, comprising four patients Given this background, we compared once-a-day inhala- per block using a 1:1 allocation scheme. The block randomi- tion therapy of tiotropium bromide hydrate and two-times- sation was conducted with the support of a clinical research per-day inhalation therapy of aclidinium bromide in terms organisation, Mebix. A third-party blinding committee of pulmonary function, health-related QoL (HRQoL), was commissioned by the study organisation. The patients and dyspnoea, and also studied their effects on physical were sequentially assigned from visit 2, with stratification activity measured by a validated GT3X-BT (ActiGraph) according to the centre from which they were recruited. on January 13, 2020 by guest. Protected copyright. triaxial accelerometer, as recommended in the European For 8 weeks, aclidinium bromide 400 µg was administered Respiratory Society statement.6 two times per day (in the morning between 9:00 and 11:00 hours and in the night between 21:00 and 23:00 hours), and tiotropium bromide hydrate 5 µg was administered METHODS once-a-day (in the night between 20:00 and 22:00 hours).