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Elisabeth J Adams,1 Alexander van Doornewaard,1 Yixuan Ma,1 Nurilign Ahmed,1 Man Ki Cheng,1 Henrik Watz,2 Masakazu Ichinose,3 Tom Wilkinson,4 Mohit Bhutani,5 Christopher J Licskai,6– 8 Katy M E Turner1 1Aquarius Population Health, London, UK; 2Pulmonary Research Institute at Lungen Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany; 3Academic Center of Osaki Citizen Hospital, Osaki, Japan; 4Southampton University Faculty of Medicine, Southampton, UK; 5University of Alberta, Edmonton, Alberta, Canada; 6London Health Sciences Centre, Western University, London, Ontario, Canada; 7Lawson Health Research Institute, London, Ontario, Canada; 8Asthma Research Group Windsor Essex County Inc., Windsor, Ontario, CanadaCorrespondence: Elisabeth J Adams, Aquarius Population Health, Unit 29 Tileyard Studios, London, N7 9AH, UK, Tel +44 207 993 2930, Email Elisabeth.adams@aquariusph.comIntroduction: COPD is a leading cause of morbidity and mortality globally. Management is complex and costly. Although international quality standards for diagnosis and management exist, opportunities remain to improve outcomes, especially in reducing avoidable hospitalisations.Objective: To estimate the potential health and economic impact of improved adherence to guideline-recommended care for prevalent, on-treatment COPD populations in four high-income settings.Methods: A disease simulation model was developed to evaluate the impact of theoretical improvements to COPD management, comparing outcomes for usual care and policy scenarios for interventions that reduce avoidable hospitalisations: 1) increased attendance (50% vs 31– 38%) of early follow-up review after severe exacerbation hospitalisation; 2) increased access (30% vs 5– 10%) to an integrated disease management (IDM) programme that provides guideline adherent care.Results: For cohorts of 100,000 patients, Policy 1 yielded additional life years (England: 523; Germany: 759; Canada: 1316; Japan: 512) and lifetime cost savings (-£ 2.89 million; -€ 6.58 million; -$40.08 million; -¥ 735.58 million). For Policy 2, additional life years (2299; 3619; 3656) and higher lifetime total costs (£ 38.15 million; € 35.58 million; ¥ 1091.53 million) were estimated in England, Germany and Japan, and additional life years (4299) and cost savings (-$20.52 million) in Canada. Scenarios found that the cost impact depended on the modelled intervention effect size.Conclusion: Interventions that reduce avoidable hospitalisations are estimated to improve survival and may generate cost savings. This study provides evidence on the theoretical impact of policies to improve COPD care and highlights priority areas for further research to support evidence-based policy decisions.Keywords: health intervention, exacerbations, re-admission, integrated care, economic evaluation

Itaru Miura,1 Sho Horikoshi,1,2 Mizue Ichinose,1,3 Yuhei Suzuki,1 Kenya Watanabe4 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 3Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 4Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru Miura, Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, Tel +81-24-547-1331, Fax +81-24-548-6735, Email itaru@fmu.ac.jpAbstract: This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.Keywords: schizophrenia, lurasidone, serotonin-dopamine antagonist, antipsychotics

Shu Hashimoto1,2 ,† Yuri Yoshida,3 Naoyuki Makita,3 Ryoko Sorimachi,3 Satoko Sugaya,4 Yoshifumi Arita,3 Nobuya Hayashi,4 Naoki Tashiro,3 Masakazu Ichinose5,6 1Nihon University, Tokyo, Japan; 2Hibiya Kokusai Clinic, Tokyo, Japan; 3Medical Department, AstraZeneca K.K., Osaka, Japan; 4R&D, AstraZeneca K.K., Osaka, Japan; 5Academic Center of Osaki Citizen Hospital, Miyagi, Japan; 6Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan†Dr Shu Hashimoto passed away on July 03, 2022Correspondence: Masakazu Ichinose, Academic Center of Osaki Citizen Hospital, 3-8-1 Honami, Furukawa, Osaki, 989-6183, Japan, Tel +81-229-23-3311, Fax +81-229-23-5380, Email ichinose@h-osaki.jpIntroduction: The ACO Japan Cohort Study, a multicenter observational study, investigated the proportion of patients with chronic obstructive pulmonary disease (COPD) who met the Japanese Respiratory Society (JRS) asthma–COPD overlap (ACO) diagnostic criteria, characteristics of ACO and non-ACO patients, and the patient transitions between ACO/non-ACO diagnosis over 2 years.Patients and Methods: Patients with COPD were consecutively enrolled between June and December 2018 and followed up continuously for 2 years. All participating study sites were medical institutions where respiratory specialists routinely conducted medical examinations/tests required for ACO diagnosis.Results: Among 708 patients with COPD, 101 (14.3%), 118 (16.7%), and 125 (17.7%) were diagnosed with ACO at registration, 1 year, and 2 years, respectively. In total, 22.6% of patients lacked the data necessary for ACO diagnosis throughout the 2 years. Among patients who had the necessary data for ACO diagnosis, 24.7% were diagnosed with ACO at 2 years. More ACO patients had moderate or severe exacerbations in the past year than non-ACO patients at registration (15.8% vs 6.3%, p = 0.049) and 1 year (19.4% vs 7.6%, p = 0.025). ACO patients had a greater decrease in mean forced expiratory volume in one second over 2 years than non-ACO patients (− 92.0 vs 43.4 mL). Among patients diagnosed with ACO at registration, 21.4% transitioned to non-ACO after 1 year. Conversely, almost all non-ACO patients at registration remained non-ACO after 1 year.Conclusion: COPD patients with ACO determined by the JRS criteria had a high risk of exacerbations and a rapid decline in respiratory function, indicating that the JRS criteria for ACO are useful for identifying high-risk COPD patients. Testing necessary for ACO diagnosis is insufficiently performed even in real-world clinical practice of COPD specialists.Keywords: asthma, chronic obstructive pulmonary disease, exacerbation, FEV1 decline, inhaled corticosteroid

Anne Meiwald,1 Rupert Gara-Adams,1 Aleix Rowlandson,1 Yixuan Ma,1 Henrik Watz,2 Masakazu Ichinose,3 Jane Scullion,4 Tom Wilkinson,5,6 Mohit Bhutani,7 Georgie Weston,1 Elisabeth J Adams1 1Aquarius Population Health, London, UK; 2Pulmonary Research Institute, LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Schleswig-Holstein, Germany; 3Academic Center, Osaki Citizen Hospital, Miyagi, Japan; 4Bush & Co, Northamptonshire, UK; 5Faculty of Medicine, Southampton University, Southampton, Hampshire, UK; 6Respiratory and Allergy, NIHR Southampton Biomedical Research Centre, Southampton, Hampshire, UK; 7Department of Medicine, University of Alberta, Edmonton, Alberta, CanadaCorrespondence: Elisabeth J Adams, Aquarius Population Health, Unit 29 Tileyard Studios, London, N7 9AH, UK, Tel +44 (0)207 993 2930, Email elisabeth.adams@aquariusph.comBackground: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. A comprehensive and detailed understanding of COPD care pathways from pre-diagnosis to acute care is required to understand the common barriers to optimal COPD care across diverse health systems.Methods: Country-specific COPD care pathways were created for four high-income countries using international recommendations and country-specific guidelines, then populated with published epidemiological, clinical, and economic data. To refine and validate the pathways, semi-structured interviews using pre-prepared discussion guides and country-specific pathway maps were held with twenty-four primary and secondary care respiratory healthcare professionals. Thematic analysis was then performed on the interview transcripts.Results: The COPD care pathway showed broad consistency across the countries. Three key themes relating to barriers in optimal COPD management were identified across the countries: journey to diagnosis, treatment, and the impact of COVID-19. Common barriers included presentation to healthcare with advanced COPD, low COPD consideration, and sub-optimal acute and chronic disease management. COVID-19 has negatively impacted disease management across the pathway but presents opportunities to retain virtual consultations. Structural factors such as insurance and short duration of appointments also impacted the diagnosis and management of COPD.Conclusion: COPD is an important public health issue that needs urgent prioritization. The use of Evidenced Care Pathways with decision-makers can facilitate evidence-based decision making on interventions and policies to improve care and outcomes for patients and reduce unnecessary resource use and associated costs for the healthcare provider/payer.Keywords: health policy, COPD management, COPD diagnosis, exacerbations, qualitative, pathway mapping

Rie Tanaka,1 Akira Koarai,1 Mitsuhiro Yamada,1 Naoya Fujino,1 Tomohiro Ichikawa,1 Tadahisa Numakura,1 Katsuhiro Onodera,2 Yorihiko Kyogoku,1 Tsutomu Tamada,1 Motohiko Miura,3 Yoshiaki Minakata,4 Masakazu Ichinose,5 Hisatoshi Sugiura1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Mizusawa Hospital, Oshu, Japan; 3Department of Respiratory Medicine, Tohoku Rosai Hospital, Sendai, Japan; 4Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama, Japan; 5Academic Center, Osaki Citizen Hospital, Osaki, JapanCorrespondence: Akira KoaraiDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8539Fax +81-22-717-8549Email koarai@rm.med.tohoku.ac.jpBackground: Daily physical activity is reduced in patients with chronic obstructive pulmonary disease (COPD) and a reduced level of physical activity has been shown to be an important predictor for the prognosis, such as increased risk of exacerbation and mortality. However, there has not yet been a useful biomarker of the physical activity. In our previous cross-sectional study, we showed that the level of one of the possible myokines, which is an anti-aging factor, growth differentiation factor 11 (GDF11), was decreased in the plasma from patients with COPD and correlated with the physical activity. To clarify this relationship, we conducted a longitudinal evaluation of such factors.Patients and Methods: Twenty-four COPD patients were enrolled and prospectively followed. We measured the levels of plasma GDF11 and systemic inflammatory markers with immunoblotting or ELISA, respectively. We also evaluated lung function and daily physical activity using a triaxial accelerometer and the incidence of exacerbation.Results: The change in the plasma level of GDF11, but not systemic inflammatory markers, was positively correlated with the change in the physical activity in an intensity-dependent manner (between the change in the number of steps and GDF11; r = 0.41, p = 0.047). In the multiple regression analysis, the relationship was confirmed (β = 0.93, p < 0.001). In addition, patients who maintained their plasma level of GDF11 showed a significantly lower incidence in exacerbations of COPD than those with decreased levels of GDF11 (p = 0.041).Conclusion: The longitudinal change in the plasma level of GDF11 was positively correlated with the change in the daily physical activity in COPD. GDF11 could be a useful humoral factor that reflects the physical activity in COPD.Keywords: chronic obstructive pulmonary disease, physical activity, growth differentiation factor 11, exacerbation, longitudinal study

Mizue Ichinose,1,2 Itaru Miura,1 Sho Horikoshi,1,3 Shinnosuke Yamamoto,1,4 Keiko Kanno-Nozaki,1 Kenya Watanabe,5 Hirooki Yabe1 1Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Neuropsychiatry, Hoshigaoka Hospital, Koriyama, Japan; 3Department of Psychiatry, Horikoshi Psychosomatic Clinic, Fukushima, Japan; 4Department of Psychiatry, Fukushima Red Cross Hospital, Fukushima, Japan; 5Department of Pharmacy, Fukushima Medical University Hospital, Fukushima, JapanCorrespondence: Itaru MiuraDepartment of Neuropsychiatry, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, 960-1295, JapanTel +81-24-547-1331Fax +81-24-548-6735Email itaru@fmu.ac.jpObjective: Although switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia.Methods: The antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters.Results: Switching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p< 0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores.Conclusion: Switching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.Keywords: brexpiprazole, extrapyramidal symptoms, EPS, homovanillic acid, prolactin, schizophrenia, switching

Masakazu Ichinose,1 Yoshiaki Minakata,2 Takashi Motegi,3 Tsuneyuki Takahashi,4 Munehiro Seki,5 Satoko Sugaya,5 Nobuya Hayashi,6 Ichiro Kuwahira7 1Academic Center of Osaki Citizen Hospital, Osaki 989-6183, Japan; 2Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama 644-0044, Japan; 3Respiratory Care Clinic Tokyo, Institute of Clinical Respirology, Tokyo 104-0031, Japan; 4Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Sendai 984-8560, Japan; 5Medical Department, AstraZeneca K.K., Osaka 530-0011, Japan; 6Biometrics Department, AstraZeneca K.K., Osaka 530-0011, Japan; 7Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokyo 151-0053, JapanCorrespondence: Masakazu Ichinose Email ichinose@h-osaki.jpPurpose: Patients with chronic obstructive pulmonary disease (COPD) have decreased physical activity (PA) compared with healthy adults. As lower PA is associated with increased mortality, improving PA is an important objective for COPD management. This large-scale, multicenter, non-interventional, cross-sectional study examined the activity status of COPD patients in Japan and explored factors related to PA.Patients and Methods: Outpatients aged ≥ 40 years with confirmed COPD diagnosis and pulmonary function test data were enrolled. Primary study outcomes were measurement of daily steps (over 14 consecutive days, using an activity monitor), assessment of activity time by activity intensity (using metabolic equivalents [METs]), and evaluation of correlation between PA and patient characteristics. Secondary outcomes included further investigation of the influence of patient characteristics on PA.Results: Data from 417 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I (29.5%), II (43.9%), III (23.5%), and IV (3.1%) were evaluated. Median (Q1, Q3) daily step count was 3440.8 (1831.3, 5709.3). Median (Q1, Q3) durations of PA at ≥ 3 (moderate-to-vigorous) and ≥ 2 METs (light-to-vigorous) were 18.7 (6.5, 41.3) and 186.9 (126.9, 259.2) minutes, respectively. For > 30% of patients, time spent in ≥ 3 METs activity was ≤ 10 minutes. Unemployment was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs) and step count. Severe GOLD stage was significantly correlated with reduced activity time (≥ 3 and ≥ 2 METs). High modified Medical Research Council (mMRC) dyspnea score was significantly correlated with reduced activity time (≥ 3 METs) and step count. Patients tended to overestimate the time spent in activities requiring ≥ 2 METs in their subjective reports compared with activity monitor measurements.Conclusion: Reduced PA was observed in the Japanese COPD patients with the majority of them being GOLD stage I/II. Employment status, GOLD stage, and mMRC dyspnea score could help identify patients at risk of reduced PA.Clinical Trial Registration: NCT03642613 (ClinicalTrials.gov); UMIN000032962 (UMIN-CTR, umin.ac.jp).Keywords: COPD, physical activity, pulmonary function, activity monitor, step counts

Mutsuo Yamaya,1 Osamu Usami,2 Shoichi Nakayama,3 Naoki Tode,4 Aya Yamada,5 Shunsuke Ito,2 Fumiya Omata,2 Haruki Momma,5 Masakatsu Funakubo,6 Masakazu Ichinose4 1Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; 2Department of Respiratory Medicine, Kurihara Central Hospital, Kurihara 987-2205, Japan; 3Department of Medicine, Kurihara Central Hospital, Kurihara 987-2205, Japan; 4Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; 5Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; 6Department of Radiology, Kurihara Central Hospital, Kurihara 987-2205, JapanCorrespondence: Mutsuo YamayaDepartment of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai 980-8575, JapanTel +81-22-717-7184Fax +81-22-717-7576Email myamaya@med.tohoku.ac.jpBackground: Different characteristics of patients with chronic obstructive pulmonary disease (COPD) between Western and Japanese populations have been reported. Risk factors for COPD exacerbation have been reported in Western countries but have not been studied in Japan.Patients and Methods: We retrospectively examined risk factors for COPD exacerbation. A total of 156 Japanese patients were enrolled, and the records of 136 patients were analyzed.Results: In the exacerbation group (n=60), body mass index, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), the FEV1/FVC ratio (FEV1/FVC), the percent predicted values of FEV1 (%FEV1), and serum total protein (TP) and albumin concentrations were lower, and age, mortality rate, frequency of common cold and pneumonia, COPD severity rankings, modified Medical Research Council (mMRC) dyspnea score, and proportions of patients with severe emphysema (> 50% of low attenuation area) and receiving long-term oxygen therapy were higher than those in the nonexacerbation group (n=76). However, the proportion of patients with a greater number of eosinophils (≥ 200/μL and/or ≥ 2%) and the exhaled nitric oxide concentration did not differ between the two groups. In the univariate analysis, the risk factors for exacerbation were age; long-term oxygen therapy; low FVC, FEV1, FEV1/FVC and %FEV1; high COPD severity ranking and mMRC score; severe emphysema; hypoproteinemia (< 6.5 g/dL); hypoalbuminemia (< 3.5 g/dL); leukocytosis; lymphocytopenia; and anemia. In the multivariate analysis, the risk factors were hypoalbuminemia, hypoproteinemia and low FEV1. Additionally, in patients in the exacerbation-induced mortality subgroup, age, exacerbation frequency, mMRC score and the proportion of patients with lymphocytopenia were higher, and FVC, %FVC, FEV1, serum TP concentration and the lymphocyte number were lower than those in the exacerbation survival subgroup.Conclusion: Malnutrition, airflow limitation and severe emphysema were risks for exacerbation and mortality associated with infection in Japanese patients with COPD.Keywords: malnutrition, chronic obstructive pulmonary disease, exacerbation, severe emphysema, airflow limitation

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Paul Dorinsky,8 Colin Reisner9 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS.Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12–24. Symptoms, quality of life, exacerbations, and safety were also assessed.Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV1 over Weeks 12–24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated.Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Colin Reisner,9 Paul Dorinsky8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Großhansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Kentaro Machida,1,* Tomotaka Kawayama,2,* Masaharu Kinoshita,3,* Masakazu Ichinose,4 Tohru Tsuda,5 Shohei Takata,6 Hiroshi Koto,7 Makoto Yoshida,8 Yoshinori Ashihara,9 Masaru Kawashima,10 Hideaki Suna,10 Hiromasa Inoue1 1Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; 2Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; 3Nagata Hospital, Yanagawa 832-0059, Japan; 4Department of Respiratory Medicine, Tohoku University, Graduate School of Medicine, Sendai 980-8574, Japan; 5Kirigaoka Tsuda Hospital, Kitakyushu 802-0052 Japan; 6Division of Respiratory Medicine, National Hospital Organization Fukuoka-Higashi Medical Center, Koga 811-3195, Japan; 7Division of Respiratory Medicine, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka 815-8588, Japan; 8Division of Respiratory Medicine, National Hospital Organization Fukuoka Hospital, Fukuoka 811-1394, Japan; 9Division of Respiratory Medicine, Oita Nakamura Hospital, Oita 870-0022, Japan; 10ONO Pharmaceutical Co. Ltd., Osaka 541-8564, Japan*These authors contributed equally to this workCorrespondence: Hiromasa InoueDepartment of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, JapanTel +81 99 275 6481Fax +81 99 275 6482Email inoue-pulm@umin.netBackground: Although long-acting muscarinic receptor antagonists are central to the management of chronic obstructive pulmonary disease (COPD), inhaled medicines may have technical difficulty in some patients and adherence barriers.Methods: A multicenter, randomized, double-blind, placebo-controlled 3×3 crossover Phase II trial was performed to evaluate the efficacy and safety of oral administration of the antimuscarinic agent imidafenacin in patients with COPD. Twenty-seven male COPD patients with % forced expiratory volume in 1 s (FEV1) ≥30% and

Minakata Y, Motegi T, Ueki J, et al. Int J Chron Obstruct Pulmon Dis. 2019;14:1789–1801.During the publication process there was an operator error where the supplementary materials, mentioned on pages 1790 and 1793, were omitted from the manuscript. Please see the supplementary materials in the attached PDF document. We apologize for this oversight.Read the original article.

Ataru Igarashi,1 Yoshinosuke Fukuchi,2 Kazuto Hirata,3 Masakazu Ichinose,4 Atsushi Nagai,5 Masaharu Nishimura,6 Hajime Yoshisue,7 Kenichi Ohara,8 Jean-Bernard Gruenberger9 1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan; 2Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; 3Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan; 4Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 5Research Institute for Respiratory Diseases, Shin-Yurigaoka General Hospital, Kawasaki City, Japan; 6Department of Pulmonary Medicine, Faculty School of Medicine, Hokkaido University, Hokkaido, Japan; 7Medical Division, Novartis Pharma K.K., Tokyo, Japan; 8Market Access Division, Novartis Pharma K.K., Tokyo, Japan; 9Market Access Division, Novartis Pharma AG, Basel, Switzerland Background: COPD remains a major health problem in Japan. Patients with COPD experience a reduced quality of life (QoL) and have a higher chance of work impairment and productivity loss. However, there is a lack of data on the impact of COPD in terms of QoL and work activity impairment in Japan. This study assessed the socioeconomic burden of COPD in Japan and the impact it may have on the working age population. Patients and methods: This was a 2-year retrospective chart review in COPD patients aged ≥40 years, with at least one health care visit to clinic or hospital in the previous 12 months. Patients were required to have available medical charts for at least the previous 24 months. Symptoms were assessed using COPD assessment test score; EuroQoL Group 5 Dimension (EQ-5D-5L) and work productivity and activity impairment general health questionnaires were used to evaluate health-related QoL and work productivity, and health care resource utilization data were obtained from clinical charts. Results: In total, 71 patients aged

Masakazu Ichinose,1 Masaharu Nishimura,2 Manabu Akimoto,3 Yasuhiro Kurotori,3 Yihua Zhao,4 Alberto de la Hoz,5 Michiaki Mishima6 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Pulmonary Medicine, Faculty School of Medicine, Hokkaido University, Sapporo, Japan; 3Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan; 4Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 5Boehringer Ingelheim International GmbH, Ingelheim, Germany; 6Osaka Saiseikai Noe Hospital, Osaka, Japan Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients. Patients and methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively. Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434). The risk of a first moderate-to-severe COPD exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; p=0.1379), although this difference was not statistically significant. The annualized rate of COPD exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; p=0.5654). The adverse event incidence was balanced between treatment arms. Conclusion: In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations. Both treatments were well tolerated. Keywords: all-cause mortality, COPD, fixed-dose combination therapy, hospitalization, moderate-to-severe exacerbations, monotherapy

Masakazu Ichinose,1 Yoshiaki Minakata,2 Takashi Motegi,3 Jun Ueki,4 Yasuhiro Gon,5 Tetsuo Seki,6 Tatsuhiko Anzai,7 Shuhei Nakamura,6 Kazuto Hirata8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 2Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Wakayama, 3Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, 4Clinical Research Unit of Respiratory Pathophysiology, Juntendo University Graduate School of Health Care and Nursing, Chiba, 5Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, 6Medical Division, Nippon Boehringer Ingelheim Co., Ltd, 7Clinical Information Division Data Science Center, Statistics Analysis Department 1, EPS Corporation, Tokyo, 8Osaka City University, Osaka, Japan Purpose: This study evaluated the efficacy of tiotropium/olodaterol vs tiotropium on lung function, exercise capacity, and physical activity in patients with COPD.Patients and methods: A total of 184 patients aged ≥40 years with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II–IV) received tiotropium/olodaterol for 6 weeks, then tiotropium for 6 weeks, or vice versa. The primary endpoint was inspiratory capacity (IC) at peak post-dose.Results: Adjusted mean IC after 6-week treatment was 1.990 L with tiotropium/olodaterol vs 1.875 L with tiotropium (difference: 115 mL; 95% CI: 77, 153; p

Rie Tanaka,1 Hisatoshi Sugiura,1 Mitsuhiro Yamada,1 Tomohiro Ichikawa,1 Akira Koarai,1 Naoya Fujino,1 Satoru Yanagisawa,1 Katsuhiro Onodera,1 Tadahisa Numakura,1 Kei Sato,1 Yorihiko Kyogoku,1 Hirohito Sano,1 Shun Yamanaka,1 Tatsuma Okazaki,1 Tsutomu Tamada,1 Motohiko Miura,2 Tsuneyuki Takahashi,3 Masakazu Ichinose1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan; 2Department of Respiratory Medicine, Tohoku Rosai Hospital, Aoba-ku, Sendai, Japan; 3Department of Internal Medicine, Tohoku Medical and Pharmaceutical University Wakabayashi Hospital, Wakabayashi-ku, Sendai, Japan Background: Growth differentiation factor 11 (GDF11) is reported to possess anti-aging and rejuvenating effects, including muscle regeneration and to be highly expressed in skeletal muscle. Recently, we demonstrated that the levels of plasma GDF11 were decreased in COPD. However, the effect of decreased circulating GDF11 in the pathophysiology of COPD remains unknown. The aim of this study is to investigate the association between the plasma GDF11 levels and various clinical parameters in patients with COPD. Patients and methods: Eighteen ex-smokers as control subjects and 70 COPD patients participated in the current study. We measured the levels of plasma GDF11 using immunoblotting, lung function, physical activity using a triaxial accelerometer, quadriceps strength, exercise capacity, and systemic inflammatory markers. We investigated the association between the levels of plasma GDF11 and these clinical parameters. Results: The levels of plasma GDF11 in the COPD patients had significant positive correlations with the data of lung function. Furthermore, the levels of plasma GDF11 were significantly correlated with the physical activity, quadriceps strength, and exercise capacity. Moreover, the levels of plasma GDF11 were significantly correlated with the data of inflammatory markers. Although various factors were related to GDF11, the multiple regression analysis showed that physical activity was significantly associated with the levels of plasma GDF11. Conclusion: Physical inactivity was significantly related to the decreased GDF11 levels in COPD, which might be useful for understanding the pathogenesis of COPD. Clarifying the relationships between the physical inactivity and GDF11 may reveal a potentially attractive therapeutic approach in COPD via increasing the plasma levels of GDF11. Keywords: physical activity, muscle strength, rejuvenating factor, COPD

Chunxue Bai,1 Masakazu Ichinose,2 Sang Haak Lee,3 Kwan Ho Lee,4 Olaf Jöns,5 Ulrich Bothner,6 Yihua Zhao,7 Roland Buhl8 1Department of Pulmonary Medicine, Shanghai Respiratory Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China; 2Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 3Department of Internal Medicine, St Paul’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 4Department of Internal Medicine, Yeungnam University Medical Center, Daegu, South Korea; 5Department of Medicine TA Respiratory Diseases, 6Department of Pharmacovigilance, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 7Department of Biostatistics and Data Sciences, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 8Pulmonary Department, Mainz University Hospital, Mainz, Germany Background and purpose: While the efficacy and safety of combined tiotropium and olodaterol in patients with COPD was established in a large clinical trial program, it is important to assess whether clinical data can be applied to geographic patient groups, particularly for East Asian patients who may have a different phenotypic profile to the global trial population. This study aimed to compare the lung function and safety profiles of tiotropium/olodaterol and monocomponents in East Asian and global populations from the TONADO® trials.Materials and methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase III TONADO studies, patients received tiotropium/olodaterol, tiotropium, or olodaterol. We assessed the forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response and trough FEV1 response at 24 weeks for the approved doses, tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, and olodaterol 5 µg. Treatment-emergent adverse events were recorded throughout treatment and ≤21 days after study medication.Results: In the East Asian population, 1,152 patients were randomized (5,163 overall). After 24 weeks, FEV1 AUC0–3 and trough FEV1 responses were greater (P

Hiromasa Inoue,1 Takahide Nagase,2 Satoshi Morita,3 Atsushi Yoshida,4 Tatsunori Jinnai,4 Masakazu Ichinose5 1Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 2Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 3Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, 4Medical Department, AstraZeneca K.K., Osaka, 5Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan Background and objective: There is increasing recognition of asthma–COPD overlap syndrome (ACOS), which shares some features of both asthma and COPD; however, the prevalence and characteristics of ACOS are not well understood. The aim of this study was to investigate the prevalence of ACOS among patients with COPD and its characteristics using a stepwise approach as stated in the recent report of the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Methods: This multicenter, cross-sectional, observational study enrolled outpatients who were receiving medical treatment for COPD. Clinical data, including spirometry results, were retrieved from medical records. For symptom assessment, patients were asked to complete the Clinical COPD questionnaire and the modified British Medical Research Council questionnaire. Results: Of the 1,008 patients analyzed, 167 (16.6%) had syndromic features of ACOS. Of the total number of patients, 93 and 42 (9.2% and 4.2%) also had a predefined clinical variability of ≥12%/≥200 mL and ≥12%/≥400 mL in forced expiratory volume in 1 second (FEV1), respectively, and therefore were identified as having ACOS. Conversely, the number of patients who had either syndromic or spirometric feature of ACOS was 595 (59.0%, ≥12%/≥200 mL FEV1 clinical variability), and 328 patients (32.5%, ≥12%/≥400 mL FEV1 clinical variability) had both the features. Patients identified as having ACOS were of significantly younger age, had a shorter duration of COPD, lower number of pack-years, better lung function, milder dyspnea symptoms, and higher peripheral blood eosinophil values compared with patients with COPD alone. The rate of exacerbations in the previous year was not significantly different between the ACOS and COPD groups. Conclusion: Using a stepwise approach, as stated in the GINA/GOLD report, the proportions of patients identified as having ACOS were found to be 9.2% and 4.2% (depending on the FEV1 variability cutoff used) among the 1,008 outpatients medically treated for COPD in a real-life clinical setting. Keywords: obstructive lung diseases, airway hyperresponsiveness, respiratory function tests, differential diagnosis

Jadwiga A Wedzicha,1 Nanshan Zhong,2 Masakazu Ichinose,3 Michael Humphries,4 Robert Fogel,5 Chau Thach,5 Francesco Patalano,6 Donald Banerji5 1National Heart and Lung Institute, Imperial College London, London, UK; 2State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 4Beijing Novartis Pharma Co. Ltd., Shanghai, People’s Republic of China; 5Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 6Novartis Pharma AG, Basel, Switzerland Background: The FLAME study demonstrated that indacaterol/glycopyrronium (IND/GLY), the fixed-dose combination of a long-acting β2-agonist (LABA, IND) and a long-acting muscarinic antagonist (LAMA, GLY), was superior to salmeterol/fluticasone combination (SFC) in preventing exacerbations in COPD patients with a high risk of exacerbations. In this study, we report a prespecified analysis of the efficacy and safety of IND/GLY versus SFC in Asian patients from the FLAME study.Patients and methods: Patients from Asian centers with moderate-to-very severe COPD and ≥1 exacerbation in the previous year from the 52-week, randomized FLAME study were included. IND/GLY was compared versus SFC for effects on exacerbations, lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), health status (St George’s Respiratory Questionnaire [SGRQ]), rescue medication use, and safety.Results: A total of 510 Asian patients (IND/GLY, n=250 or SFC, n=260) were included. Compared to the overall FLAME population, the Asian cohort had more males, a shorter duration of COPD, fewer patients using inhaled corticosteroid (ICS) at screening, fewer current smokers, and more patients with very severe COPD. IND/GLY significantly reduced the rate of moderate/severe exacerbations (rate ratio: 0.75; 95% confidence interval: 0.58–0.97; P=0.027) and prolonged time to first moderate/severe exacerbation versus SFC (hazard ratio: 0.77; 95% confidence interval: 0.59–1.01; P=0.055). Predose trough FEV1 and FVC significantly improved in Asian patients (P

Masakazu Ichinose,1 Hiroyuki Taniguchi,2 Ayako Takizawa,3 Lars Grönke,4 Lazaro Loaiza,4 Florian Voß,4 Yihua Zhao,5 Yoshinosuke Fukuchi61Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Respiratory Medicine and Allergy, Tosei General Hospital, Aichi, Japan; 3Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 5Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA; 6Juntendo University School of Medicine, Tokyo, JapanBackground: The efficacy and safety of once-daily tiotropium + olodaterol (T+O) maintenance treatment was demonstrated in the large, multinational, replicate, randomized, Phase III, Tonad® 1 (NCT01431274) and 2 (NCT01431287) studies in patients with moderate to very severe COPD. However, there may be racial differences in the effects of T+O on lung function in patients with COPD.Methods: In this Tondao® subgroup analysis, we assessed efficacy and safety of T+O in Japanese participants.Results: Versus the overall population, the 413 Japanese patients randomized and treated were slightly older, with more men, lower body mass index, lower baseline St George’s Respiratory Questionnaire (SGRQ) scores, fewer current smokers, but with higher pack-year smoking history. A lower proportion of Japanese patients used inhaled corticosteroids, short-acting muscarinic antagonists, or short- or long-acting β-adrenergic agonists at baseline, but use of long-acting muscarinic antagonists was higher. At Week 24, mean improvements with T+O 5/5 µg in forced expiratory volume in 1 second area under the curve from 0–3 hours response were 151 mL versus olodaterol and 134 mL versus tiotropium 5 µg; mean improvements with T+O 2.5/5 µg were 87 mL versus olodaterol and 70 mL versus tiotropium 2.5 µg. Mean improvements with T+O 5/5 µg in trough forced expiratory volume in 1 second were 131 mL versus olodaterol and 108 mL versus tiotropium 5 µg; mean improvements with T+O 2.5/5 µg were 60 mL versus olodaterol and 47 mL versus tiotropium 2.5 µg. SGRQ scores improved from baseline to a greater extent with both doses of T+O versus monotherapies. Responses were similar in the overall population. Adverse-event incidence was generally balanced across treatment groups.Conclusion: Consistent with results from the overall population, T+O 5/5 µg was superior to each monotherapy for lung function and SGRQ in the Japanese sub-population of patients with COPD in Tonado®.Keywords: COPD, bronchodilators, maintenance treatment

Hana Müllerová,1 Sarah H Landis,1 Zaurbek Aisanov,2 Kourtney J Davis,3 Masakazu Ichinose,4 David M Mannino,5 Joe Maskell,1 Ana M Menezes,6 Thys van der Molen,7 Yeon-Mok Oh,8 Maggie Tabberer,9 MeiLan K Han10 1GSK, Worldwide Epidemiology, Uxbridge, UK; 2Pulmonology Research Institute, Moscow, Russia; 3GSK, Worldwide Epidemiology, Upper Providence, PA, USA; 4Tohoku University Graduate School of Medicine, Sendai, Japan; 5University of Kentucky College of Public Health, Lexington, KY, USA; 6Federal University of Pelotas, Pelotas, Brazil; 7University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 8University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 9GSK, Value Evidence Outcomes, Uxbridge, UK; 10Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA Background and aims: We used data from the Continuing to Confront COPD International Patient Survey to test the hypothesis that patients with COPD who report less engagement with their disease management are also more likely to report greater impact of the disease. Methods: This was a population-based, cross-sectional survey of 4,343 subjects aged ≥40 years from 12 countries, fulfilling a case definition of COPD based on self-reported physician diagnosis or symptomatology. The impact of COPD was measured with COPD Assessment Test, modified Medical Research Council Dyspnea Scale, and hospital admissions and emergency department visits for COPD in the prior year. The 13-item Patient Activation Measure (PAM-13) instrument and the 8-item Morisky Medication Adherence Scale (MMAS-8) were used to measure patient disease engagement and medication adherence, respectively. Results: Twenty-eight percent of subjects reported being either disengaged or struggling with their disease (low engagement: PAM-13 levels 1 and 2), and 35% reported poor adherence (MMAS-8

Yoshinosuke Fukuchi,1 Koichiro Tatsumi,2 Hiromasa Inoue,3 Yukinori Sakata,4 Kai Shibata,4 Hideaki Miyagishi,4 Yasuhiro Marukawa,4 Masakazu Ichinose5 1Department of Respiratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, 2Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, 3Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, 4Eisai Co., Ltd., Tokyo, 5Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan Background/aim: Lysozyme (mucopeptide N-acetyl-muramyl hydrolase) is widely used as a mucolytic and anti-inflammatory agent in Japan. We evaluated the effects of long-term lysozyme administration on COPD exacerbation. Methods: In a 1-year, randomized, double-blind, placebo-controlled, parallel trial, patients with moderate-to-severe COPD and one or more episodes of COPD exacerbation in the previous year before enrollment were selected. Lysozyme (270 mg) or placebo was administered orally for 52 weeks as an add-on to the standard therapies such as bronchodilators. COPD exacerbation, pulmonary function, and COPD assessment test scores were analyzed. An exacerbation was defined as worsening of more than one symptom of COPD (cough, sputum volume, purulent sputum, or breathlessness) leading to a change in medication. The primary endpoint was exacerbation rate. Results: A total of 408 patients were randomly assigned to the lysozyme and placebo groups. The baseline characteristics were similar between the two groups. The exacerbation rate was not significantly different between the two groups (1.4 vs 1.2; P=0.292, Poisson regression). However, a subgroup analysis showed that lysozyme might reduce exacerbation rate in patients with airway-dominant phenotype (1.2 vs 1.6). Moreover, the median time to first exacerbation was longer in patients with airway-dominant phenotype in the lysozyme group than that in the placebo group. The levels of improvement in forced expiratory volume in 1 second and COPD assessment test scores were not statistically different between the groups, but were always greater in the lysozyme group than in the placebo group over the 52 weeks of the study. Conclusion: The effects of using lysozyme as an add-on to standard COPD therapy were not significantly different compared with placebo and were insufficient to prevent COPD exacerbation. Keywords: lysozyme, COPD exacerbation, forced expiratory volume in 1 second, COPD assessment test

Tsutomu Tamada,1 Hisatoshi Sugiura,1 Tsuneyuki Takahashi,2 Kazuto Matsunaga,3 Keiji Kimura,4 Uichiro Katsumata,5 Daisuke Takekoshi,1 Toshiaki Kikuchi,1 Ken Ohta,6 Masakazu Ichinose1 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, 2Nippon Telegraph and Telephone East Corporation Tohoku Hospital, Sendai, 3Division of Respiratory Medicine and Infectious Disease, Graduate School of Medicine, Yamaguchi University, Ube, 4Hiraka General Hospital, Yokote, 5Iwate Prefectural Isawa Hospital, Oshu, 6National Hospital Organization, Tokyo National Hospital, Kiyose, Tokyo, Japan Abstract: Asthma–chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) was proposed by the science committees of both Global Initiative for Asthma (GINA) and Global Initiative for Chronic Obstructive Lung Disease (GOLD). However, the definition of ACOS has remained unclear all over the world, and the prevalence rate of ACOS is basically dependent on the patient’s symptoms or the physician’s opinion, based on questionnaire testing. In the current case report, we investigated the prevalence rate of COPD patients with high levels of fractional exhaled nitric oxide (FENO) or immunoglobulin E (IgE) as candidate markers of ACOS in COPD, as a multicenter, cross-sectional study. Outpatients with COPD were enrolled from Tohoku University Hospital, Sendai, Japan, and five hospitals (Tohoku University Hospital, Sendai, Japan; NTT East Tohoku Hospital, Sendai, Japan; Wakayama Medical University Hospital, Kimiidera, Japan; Hiraka General Hospital, Yokote, Japan; Iwate Prefectural Isawa Hospital, Oshu, Japan) with pulmonary physicians from March 1, 2013 to February 28, 2014. When they were estimated using 35 ppb as the cutoff value of FENO, the prevalence rate of ACOS was 16.3% in COPD. When estimated by both FENO and IgE, the high-FENO/high-IgE group was 7.8% in COPD. To the best of our knowledge, this study is the first to detect the prevalence rate of ACOS in COPD populations by using objective biomarkers. The results from the current study should be useful to identify the subgroup requiring early intervention by inhaled corticosteroids/long-acting beta agonist combination in COPD in order to improve the long-term management for ACOS. Keywords: FENO, IgE, ICS, LABA, airway inflammation, atopic factors

Masakazu Ichinose,1 Ayako Takizawa,2 Toshiyasu Izumoto,2 Yusuke Tadayasu,2 Alan L Hamilton,3 Christina Kunz,4 Yoshinosuke Fukuchi51Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan; 3Boehringer Ingelheim, Burlington, Ontario, Canada; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany; 5Juntendo University School of Medicine, Tokyo, JapanBackground: Olodaterol is a novel long-acting β2-agonist with proven ≥24-hour duration of action in preclinical and clinical studies.Objective: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the dose response of once-daily (QD) olodaterol based on bronchodilator efficacy, safety, and pharmacokinetics over 4 weeks in Japanese patients with chronic obstructive pulmonary disease (COPD).Methods: All eligible patients were randomized to receive 2 µg, 5 µg, or 10 µg of olodaterol or placebo for 4 weeks via the Respimat® Soft Mist™ inhaler. The primary end point was the change from baseline in trough forced expiratory volume in 1 second (FEV1) after 4 weeks of olodaterol treatment. Secondary end points included trough FEV1 after 1 week and 2 weeks of treatment, FEV1 area under the curve from 0 hour to 3 hours (AUC0–3), peak FEV1 from 0 hour to 3 hours (peak FEV1), and corresponding forced vital capacity (FVC) responses. Rescue medication use, COPD symptoms, physician global evaluation, pharmacokinetics, and safety were also assessed.Results: A total of 328 patients with COPD were randomized to receive treatment. All olodaterol doses assessed in the study showed statistically significant increases in trough FEV1 compared to placebo at Day 29 (P

Yoshiaki Minakata,1 Yukiko Morishita,2 Tomohiro Ichikawa,3 Keiichiro Akamatsu,3 Tsunahiko Hirano,3 Masanori Nakanishi,3 Kazuto Matsunaga,3 Masakazu Ichinose41Department of Respiratory Medicine, National Hospital Organization Wakayama Hospital, Mihama-cho, Hidaka-gun, Wakayama, Japan; 2Department of Respiratory Medicine, Naga Municipal Hospital, Kinokawa, Wakayama, Japan; 3Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Wakayama, Japan; 4Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanBackground: Improvement in the daily physical activity (PA) is important for the management of chronic obstructive pulmonary disease (COPD). However, the effects of pharmacologic treatment on PA are not well understood. We evaluated the effects of additional medications, including bronchodilator with or without inhaled corticosteroid, based on airflow limitation and breathlessness on the PA in COPD patients and the factors that could predict or affect the improvement in PA.Methods: A prospective non-randomized observational study was employed. Twenty-one COPD subjects without any other diseases that might reduce PA were recruited. The PA was measured with a triaxial accelerometer for 2 weeks, and pulmonary function tests and incremental shuttle walking tests were administered before and after 4-week treatment with an additional medication.Results: Bronchodilation was obtained by additional medication. The mean values of PA evaluated by metabolic equivalents (METs) at ≥3.0 METs and the duration of PA at ≥3.0 METs and ≥3.5 METs were improved by medication. The % change in the duration of PA at ≥3.5 METs was significantly correlated with the baseline functional residual capacity (FRC), residual volume, and inspiratory capacity/total lung capacity. However, the % change in the duration of PA at any intensity was not correlated with the % changes of any values of the pulmonary function tests or incremental shuttle walking test except the PA at ≥2.5 METs with FRC.Conclusion: Medication could improve the PA in patients with COPD, especially at a relatively high intensity of activity when medication was administered based on airflow limitation and breathlessness. The improvement was seen in the patients with better baseline lung volume, but was not correlated with the improvements in the pulmonary function tests or exercise capacity.Keywords: COPD, accelerometer, bronchodilator, pulmonary function, predictor

Ana M Menezes,1 Sarah H Landis,2 MeiLan K Han,3 Hana Muellerova,2 Zaurbek Aisanov,4 Thys van der Molen,5 Yeon-Mok Oh,6 Masakazu Ichinose,7 David M Mannino,8 Kourtney J Davis9 1Federal University of Pelotas, Pelotas, Brazil; 2Worldwide Epidemiology, GlaxoSmithKline, Uxbridge, UK; 3Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 4Pulmonology Research Institute, Moscow, Russia; 5University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 6University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 7Tohoku University Graduate School of Medicine, Sendai, Japan; 8University of Kentucky College of Public Health, Lexington, KY, USA; 9Worldwide Epidemiology, GlaxoSmithKline, Wavre, Belgium Purpose: Using data from the Continuing to Confront COPD International Physician and Patient Surveys, this paper describes physicians’ attitudes and beliefs regarding chronic obstructive pulmonary disease (COPD) prognosis, and compares physician and patient perceptions with respect to COPD. Methods: In 12 countries worldwide, 4,343 patients with COPD were identified through systematic screening of population samples, and 1,307 physicians who regularly saw patients with COPD were sampled from in-country professional databases. Both patients and physicians completed surveys about their COPD knowledge, beliefs, and perceptions; physicians answered further questions about diagnostic methods and treatment choices for COPD. Results: Most physicians (79%) responded that the long-term health outlook for patients with COPD has improved over the past decade, largely attributed to the introduction of better medications. However, patient access to medication remains an issue in many countries, and some physicians (39%) and patients (46%) agreed/strongly agreed with the statement “there are no truly effective treatments for COPD”. There was strong concordance between physicians and patients regarding COPD management practices, including the use of spirometry (86% of physicians and 76% of patients reporting they used/had undergone a spirometry test) and smoking cessation counseling (76% of physicians reported they counseled their smoking patients at every clinic visit, and 71% of smoking patients stated that they had received counseling in the past year). However, the groups differed in their perception about the role of smoking in COPD, with 78% of physicians versus 38% of patients strongly agreeing with the statement “smoking is the cause of most cases of COPD”. Conclusion: The Continuing to Confront COPD International Surveys demonstrate that while physicians and patients largely agreed about COPD management practices and the need for more effective treatments for COPD, a gap exists about the causal role of smoking in COPD. Keywords: chronic obstructive pulmonary disease, physician survey, patient survey, beliefs, perceptions

Kourtney J Davis,1 Sarah H Landis,2 Yeon-Mok Oh,3 David M Mannino,4 MeiLan K Han,5 Thys van der Molen,6 Zaurbek Aisanov,7 Ana M Menezes,8 Masakazu Ichinose,9 Hana Muellerova11Worldwide Epidemiology, GlaxoSmithKline, Wavre, Belgium; 2Worldwide Epidemiology, GlaxoSmithKline, Uxbridge, UK; 3University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 4University of Kentucky College of Public Health, Lexington, KY, USA; 5Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 6University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 7Pulmonology Research Institute, Moscow, Russia; 8Federal University of Pelotas, Pelotas, Brazil; 9Tohoku University Graduate School of Medicine, Sendai, JapanAim: Utilizing data from the Continuing to Confront COPD (chronic obstructive pulmonary disease) International Physician Survey, this study aimed to describe physicians’ knowledge and application of the GOLD (Global initiative for chronic Obstructive Lung Disease) Global Strategy for the Diagnosis, Management and Prevention of COPD diagnosis and treatment recommendations and compare performance between primary care physicians (PCPs) and respiratory specialists.Materials and methods: Physicians from 12 countries were sampled from in-country professional databases; 1,307 physicians (PCP to respiratory specialist ratio three to one) who regularly consult with COPD, emphysema, or chronic bronchitis patients were interviewed online, by telephone or face to face. Physicians were questioned about COPD risk factors, prognosis, diagnosis, and treatment, including knowledge and application of the GOLD global strategy using patient scenarios.Results: Physicians reported using spirometry routinely (PCPs 82%, respiratory specialists 100%; P

Phase equilibrium was investigated in the pseudo-ternary system of Na2MoO4-MoO3-La2O3 at 1073 K in air.

Sarah H Landis,1 Hana Muellerova,1 David M Mannino,2 Ana M Menezes,3 MeiLan K Han,4 Thys van der Molen,5 Masakazu Ichinose,6 Zaurbek Aisanov,7 Yeon-Mok Oh,8 Kourtney J Davis,9 1Worldwide Epidemiology, GlaxoSmithKline, Uxbridge, UK; 2University of Kentucky College of Public Health, Lexington, KY, USA; 3Federal University of Pelotas, Pelotas, Brazil; 4Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 5University Medical Center Groningen, Groningen, Netherlands; 6Tohoku University Graduate School of Medicine, Sendai, Japan; 7Pulmonology Research Institute, Moscow, Russia; 8University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; 9Worldwide Epidemiology, GlaxoSmithKline, Wavre, Belgium Purpose: The Continuing to Confront COPD International Patient Survey aimed to estimate the prevalence and burden of COPD globally and to update findings from the Confronting COPD International Survey conducted in 1999–2000. Materials and methods: Chronic obstructive pulmonary disease (COPD) patients in 12 countries worldwide were identified through systematic screening of population samples. Telephone and face-to-face interviews were conducted between November 2012 and May 2013 using a structured survey that incorporated validated patient-reported outcome instruments. Eligible patients were adults aged 40 years and older who were taking regular respiratory medications or suffered with chronic respiratory symptoms and reported either 1) a physician diagnosis of COPD/emphysema, 2) a physician diagnosis of chronic bronchitis, or 3) a symptom-based definition of chronic bronchitis. The burden of COPD was measured with the COPD Assessment Test (CAT) and the modified Medical Research Council (mMRC) Dyspnea Scale. Results: Of 106,876 households with at least one person aged ≥40 years, 4,343 respondents fulfilled the case definition of COPD and completed the full survey. COPD prevalence ranged from 7% to 12%, with most countries falling within the range of 7%–9%. In all countries, prevalence increased with age, and in all countries except the US was greater among men (range 6%–14%) than among women (range 5%–11%). A significant disease burden was observed when considering COPD symptoms or health status, and showed wide variations across countries. Prevalence of moderate-to-severe dyspnea (mMRC scale ≥2) ranged from 27% to 61%, and mean CAT score ranged from 16.0 to 24.8, indicating medium-to-high impairment. Conclusion: This survey, representing 12 countries, showed similar rates of estimated COPD prevalence across countries that were higher than those reported a decade ago in the original Confronting COPD International Survey. A significant burden of COPD was demonstrated by symptoms and health care-resource use, similar to that reported in the original survey. Keywords: chronic obstructive pulmonary disease, patient perspective, prevalence, patient-reported outcomes

Müllerová H, Landis SH, Aisanov Z, et al. Int J Chron Obstruct Pulmon Dis. 2016;11:881–890.On page 882, right column, second paragraph, the sentence “The primary hypotheses were addressed using the PAM-13,2 and Morisky Medication Adherence Scale (MMAS)-8.18 should have read “The primary hypotheses were addressed using the PAM-13,2 and Morisky Medication Adherence Scale (MMAS)-8.18,40,41On page 882, right column, last paragraph, the sentence “Adherence is classified as low (score 1–5), medium (score 6–7), or high (score 8) according to the overall score.” should read “Adherence is classified as low (score ,6), medium (score 6 to ,8), or high (score 8) according to the overall score.”On page 886, Table 3, the copyright statement “Use of the ©MMAS is protected by US copyright laws. Permission for use is required. A license agreement is available from: Donald E Morisky, ScD, ScM, MSPH, Professor, Department of Community Health Sciences, UCLA School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA 90095-1772.18,40,41” was not included in the Note section.Read the original article