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pISSN 2092-7355   eISSN 2092-7363
    Allergy Asthma Immunol Res. 2017 Mar;9(2):116-125. English.
    Published online Oct 11, 2016.
    https://doi.org/10.4168/aair.2017.9.2.116
    Copyright © 2017 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease
    Original Article

    Asthma-Related Outcomes in Patients Initiating Extrafine Ciclesonide or Fine-Particle Inhaled Corticosteroids

    Dirkje S. Postma,1 Richard Dekhuijzen,2 Thys van der Molen,1 Richard J. Martin,3 Wim van Aalderen,4 Nicolas Roche,5 Theresa W. Guilbert,6 Elliot Israel,7 Daniela van Eickels,8 Javaria Mona Khalid,9 Ron M.C. Herings,10 Jetty A. Overbeek,10 Cristiana Miglio,11 Victoria Thomas,11 Catherine Hutton,11 Elizabeth V. Hillyer,11 and David B. Price11,12
      • 1University of Groningen, Department of Pulmonology, University Medical Center Groningen, Groningen, The Netherlands.
      • 2Radboud University Medical Center, Nijmegen, The Netherlands.
      • 3Department of Medicine, National Jewish Health, and University of Colorado Denver, Denver, CO, USA.
      • 4Emma's Children Hospital AMC, Amsterdam, The Netherlands.
      • 5University Paris Descartes (EA2511), Cochin Hospital Group (AP-HP), Paris, France.
      • 6Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, USA.
      • 7Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
      • 8Takeda Pharmaceuticals International GmbH, Zurich, Switzerland.
      • 9Takeda Development Centre Europe Ltd, London, UK.
      • 10PHARMO Institute for Drug Outcomes Research, The Netherlands.
      • 11Research in Real Life, Cambridge, UK.
      • 12Academic Primary Care, University of Aberdeen, Aberdeen, UK.
    • Correspondence to: David B. Price, FRCGP, Academic Primary Care, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK. Tel: +44-1224-554588; Fax: +44-1224-550683; Email: dprice@rirl.org
    Received May 09, 2016; Accepted July 04, 2016.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Extrafine-particle inhaled corticosteroids (ICS) have greater small airway deposition than standard fine-particle ICS. We sought to compare asthma-related outcomes after patients initiated extrafine-particle ciclesonide or fine-particle ICS (fluticasone propionate or non-extrafine beclomethasone).

    Methods

    This historical, matched cohort study included patients aged 12-60 years prescribed their first ICS as ciclesonide or fine-particle ICS. The 2 cohorts were matched 1:1 for key demographic and clinical characteristics over the baseline year. Co-primary endpoints were 1-year severe exacerbation rates, risk-domain asthma control, and overall asthma control; secondary endpoints included therapy change.

    Results

    Each cohort included 1,244 patients (median age 45 years; 65% women). Patients in the ciclesonide cohort were comparable to those in the fine-particle ICS cohort apart from higher baseline prevalence of hospitalization, gastroesophageal reflux disease, and rhinitis. Median (interquartile range) prescribed doses of ciclesonide and fine-particle ICS were 160 (160-160) µg/day and 500 (250-500) µg/day, respectively (P<0.001). During the outcome year, patients prescribed ciclesonide experienced lower severe exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]), and higher odds of risk-domain asthma control (adjusted odds ratio [95% CI], 1.62 [1.27-2.06]) and of overall asthma control (2.08 [1.68-2.57]) than those prescribed fine-particle ICS. The odds of therapy change were 0.70 (0.59-0.83) with ciclesonide.

    Conclusions

    In this matched cohort analysis, we observed that initiation of ICS with ciclesonide was associated with better 1-year asthma outcomes and fewer changes to therapy, despite data suggesting more difficult-to-control asthma. The median prescribed dose of ciclesonide was one-third that of fine-particle ICS.

    Keywords
    Anti-asthmatic agents; comparative effectiveness research; disease exacerbation; small airway

    INTRODUCTION

    Asthma management guidelines recommend anti-inflammatory controller therapy to attenuate chronic airway inflammation in persistent asthma.1, 2, 3 Inhaled corticosteroids (ICSs) are available inpressurized metered dose inhalers (pMDI) using a hydrofluoroalkane propellant as both fine-particle formulations with a particle mass median aerodynamic diameter (MMAD) of 2-4 µm and as aerosols of extrafine particles with an MMAD-1 µm.4, 5, 6

    Ciclesonide is an extrafine-particle ICS (MMAD 1.0 µm) that shows both high lung deposition and peripheral lung distribution in healthy volunteers and patients with asthma.7, 8 Results of small studies in patients with mild-to-moderate asthma indicate that ciclesonide improves inflammation and patency of small airways9 and, compared to fluticasone (MMAD 2.4-2.6 µm), provides greater improvement in small airway function, inflammation, and hyperresponsiveness to small-particle aerosolized adenosine monophosphate (MMAD 1.04 µm).10, 11 As small airways dysfunction may be involved in unstable asthma, 4, 12, 13, 14 these findings raise the question whether there are differences ineffectiveness between extrafine- and fine-particle ICSs.

    In clinical trials to date, ciclesonide showed similar efficacy as compared with fine-particle ICSs, such as fluticasone and budesonide (MMAD ~3 µm) at similar nominal doses for patients with persistent asthma.10, 15, 16 However, these trials were generally 8-12 weeks in duration and focused on short-term improvement of lung function outcomes, thus they were unable to assess longer term fluctuations in asthma control and events, such as exacerbations. Moreover, smokers and patients with unstable asthma, who may both have more prominent small airways disease,4, 17 were typically excluded, as were patients with poor inhaler techniques, who might also benefit from extrafine-particle ICSs.18 Thus, the question remains whether ICS particle size plays a role in long-term effectiveness of ICS therapy.

    Non-interventional observational studies using high-quality databases can capture prescribing and medical record information to assess long-term outcomes for patients with asthma often excluded from clinical trials but commonly seen by clinicians, such as smokers, patients with poor inhaler techniques, patients at high risk of exacerbation, and those with comorbidities. 14, 17, 19, 20 Previous database studies in the UK and USA have found in matched cohort analyses that the prescription of extrafine-particle beclomethasone was associated with equal, or better, asthma-related outcomes over a 1-year period, at significantly lower prescribed ICS doses, than standard fine-particle fluticasone.21, 22 The aim of the current historical cohort study was to compare 1-year asthma-related outcomes between extrafine particle ciclesonide and 2 standard fine-particle ICS, fluticasone and non-extrafine beclomethasone, for patients in the Netherlands prescribed their first ICS.

    MATERIALS AND METHODS

    Data source

    This was a historical, matched cohort effectiveness study of patients registered from September 2005 through December 2012 in the PHARMO Database Network (PHARMO Institute, Utrecht, The Netherlands), which links outpatient pharmacy and hospital discharge records for a catchment area representing 3.6 million residents (additional detail is provided in the Online Supplement).23, 24, 25 The study was conducted to standards suggested for observational research, including an independent advisory group, use of an a priori analysis plan, and study registration.26, 27, 28

    Patients and study design

    Patients eligible for this study were aged 12-60 years, had ≥1 full year of baseline and ≥1 full year of outcome data before and after their first recorded prescription of ICS (initiation date), and had received 2 or more prescriptions for asthma at any time in their records in addition to the first ICS prescription, including at least 1 more ICS prescription during outcome (but no ICS during the baseline year); therefore, all patients included received at least 2 ICS prescriptions. We excluded patients >60 years old, those with any other recorded chronic respiratory disease, and those prescribed long-acting muscarinic antagonists or maintenance oral corticosteroid therapy during the baseline year.

    At the initiation date, patients received a first prescription of ICS delivered using a pMDI as the extrafine-particle ICS ciclesonide (Alvesco®, Takeda Pharmaceuticals International GmbH, Zurich, Switzerland) or a pMDI fine-particle ICS, either fluticasone propionate (Flixotide®, GlaxoSmithKline, Brentford, Middlesex, UK) or non-extrafine beclomethasone dipropionate (Supplementary Fig. 1).

    Study endpoints

    Co-primary endpoints were assessed during 1 outcome year after initiation of ICS therapy and included (1) the rate of severe exacerbations, defined as asthma-related hospital admission or acute oral corticosteroid prescription (based on the American Thoracic Society/European Respiratory Society definition29 excluding emergency department attendance, not available in the database); (2) risk-domain asthma control, defined as the absence of severe exacerbations; and (3) overall asthma control, defined as achieving risk-domain asthma control plus mean daily dose of albuterol of ≤200 µg. Secondary endpoints included the change in therapy and mean daily dose of short-acting β2-agonists (SABA) during the outcome period (additional detail in the Online Supplement).

    Statistical analysis

    Analyses were carried out using IBM SPSS Statistics version 22, Microsoft Office EXCEL 2007, and SAS version 9.3. Statistical significance was defined as P<0.05. Chi-square or Mann Whitney U-tests (unmatched data) and conditional logistic regression (matched data) were used to compare treatment cohorts at baseline.

    Patients in the 2 cohorts were matched using 1:1 exact-matching methods,30 described in the Online Supplement. Matching variables were sex, age, baseline risk-domain asthma control, prescribed long-acting β2-agonist, SABA daily dose, prescribed leukotriene receptor antagonist, prescribed antifungal medication for oral candidiasis, and year of ICS therapy initiation.

    A conditional Poisson regression model was used to compare the rates of severe exacerbations and hospitalizations for matched patients. Conditional binary logistic regression was used to compare the odds of achieving asthma control, being prescribed higher doses of SABA, and changing therapy. Rate ratios and odds ratios, with 95% confidence intervals, were adjusted for appropriate non-collinear confounders.

    RESULTS

    Patients

    There were 4,064 eligible patients identified in the database during the study period; 1,382 (34%) were prescribed extrafine-particle ciclesonide, and 2,682 (66%) fine-particle ICS. Applying the matching criteria led to 1,244 patients being selected in each treatment cohort (Supplementary Fig. 2).

    After matching, baseline asthma control measures, SABA daily dose, and prior maintenance asthma therapy were comparable between the cohorts (Table 1). Asthma-related hospital admissions during the baseline year, while generally infrequent, were significantly more prevalent in the ciclesonide cohort (Table 1); significantly more patients who received ciclesonide had evidence of rhinitis (43% vs 38%; P=0.004) and were prescribed proton pump inhibitors (41% vs 34%; P<0.001) than those who received fine-particle ICS.

    Table 1
    Demographic and clinical characteristics of the matched patients

    At the initiation date, ciclesonide was prescribed at significantly lower doses than fine-particle ICS (median [interquartile range] 160 [160-160] vs 500 [250-500] µg; P<0.001). The distribution of doses at initiation (Fig. 1) shows clear separation between ciclesonide (mostly 160 µg/day) and fine-particle ICS (mostly ≥500 µg/day, especially for fluticasone) (Supplementary Table 1).

    Fig. 1
    Dose of inhaled corticosteroids prescribed at the initiation date. The doses of ciclesonide and fluticasone are reported as actual doses; the beclomethasone doses were halved and thus reported as fluticasone-equivalents, as per recommendations regarding corticosteroid equivalence.1, 2, 3, 6

    Co-primary endpoints

    During the outcome year, patients prescribed ciclesonide had significantly lower severe asthma exacerbation rates (adjusted rate ratio [95% CI], 0.69 [0.53-0.89]) and significantly greater odds of achieving risk-domain asthma control (defined as absence of asthma-related hospital admissions and of prescriptions of acute oral corticosteroids) and overall asthma control (defined as risk-domain asthma control plus average daily dose of ≤200 µg albuterol) than those receiving fine-particle ICS therapy, after adjusting for baseline confounders (Table 2 and Fig. 2).

    Fig. 2
    Adjusted rate ratios (RRs) and odds ratios (ORs) for ciclesonide relative to fine-particle ICS during the 1 outcome year for the co-primary endpoints (severe exacerbation RR, risk domain asthma control OR, and overall asthma control OR) and secondary endpoints (change in therapy OR and daily short-acting β2-agonist [SABA] use OR).
    *Adjusted for prescriptions of proton-pump inhibitors (yes/no) and baseline severe exacerbations (categorized); †Adjusted for age and prescriptions of proton-pump inhibitors (yes/no); ‡Adjusted for baseline overall asthma control and prescriptions of proton pump inhibitors (yes/no); §Adjusted for prescriptions of nasal corticosteroid preparations (yes/no); IIAdjusted for age and baseline SABA daily dose.

    Table 2
    Outcome measures during a 1-year period after ICS initiation

    Secondary endpoints and other outcomes

    Patients in the ciclesonide cohort received fewer prescriptions of other respiratory drugs and had significantly lower ICS daily dose exposure than the fine-particle ICS cohort during the outcome year (Table 3). The odds of a change in therapy during the outcome year were significantly lower for patients prescribed ciclesonide than those prescribed fine-particle ICS (adjusted odds ratio [95% confidence interval], 0.70 [0.59-0.83]). Similarly, the odds of being prescribed a higher SABA dose during the outcome period significantly favored the ciclesonide cohort (Table 2 and Fig. 2). Subanalysis results for the patients with evidence of rhinitis (prescribed nasal corticosteroids) were similar to those of the main analysis (Supplementary Table 2).

    Table 3
    Respiratory drugs prescribed during the outcome year

    During the outcome year, patients prescribed ciclesonide received a significantly higher ratio of controller-to-total medication than those prescribed fine-particle ICS (Table 2). Although patients in the ciclesonide cohort had higher hospital admissions during the baseline year compared with those receiving fine-particle ICS (1.9% vs 0.5%; P=0.002), this difference was no longer observed during the outcome year after ICS initiation (0.7% vs 0.6% patients prescribed fine-particle ICS; P=0.81; Table 2).

    Prescriptions of oral antifungal medications for treating oral candidiasis were similar in both treatment cohorts at baseline and during the outcome year.

    DISCUSSION

    In our population-based matched cohort study, we observed that patients prescribed extrafine-particle ciclesonide experienced significantly lower rates of severe exacerbations, i.e., hospitalizations or acute oral corticosteroid courses, in the first year after initiating ICS treatment than those prescribed fine-particle ICS, and ciclesonide prescribing was associated with better odds of achieving asthma control. Patients prescribed ciclesonide were also significantly less likely to require a change in therapy or higher doses of reliever medication than those prescribed fine-particle ICS. Notably, the prescribed doses of ciclesonide were one-third those of fine-particle ICS at the initiation date despite matching for patient characteristics (median dose, 160 vs 500 µg/day); and ICS dose exposure during the outcome year was also significantly lower for the ciclesonide cohort (median, 126 vs 332 µg/day). The drop in the dose of both ICS from the initial prescribed dose was likely the result of incomplete adherence during the outcome year, a common finding in real life.31

    We matched the cohorts for important clinical asthma parameters, including baseline risk-domain asthma control status (capturing asthma-related hospitalizations and oral corticosteroid bursts during the baseline year), baseline SABA dose, and demographic characteristics (sex and age). Nevertheless, the ciclesonide cohort presented with signs of more difficult-to-control asthma at baseline in the form of greater frequency of nasal corticosteroid and proton pump inhibitor prescriptions.1, 32 This would presumably favor better asthma control in the outcome year for the fine-particle ICS cohort. Moreover, despite higher baseline hospital admissions in the ciclesonide than in the fine-particle ICS cohort, there was no difference in outcome hospitalizations. These findings suggest a clinically significant improvement in asthma control for patients prescribed ciclesonide who had unstable disease and thus would classically be excluded from randomized controlled trials.

    Possible mechanisms to explain better effectiveness of ciclesonide include (1) improved airway drug distribution, including small airways;4, 7, 8, 10 (2) decreased impact of errors in inhalation techniques (especially poor coordination or too fast inhalation flow rate) on lung deposition;33, 34 and (3) improved adherence, promoted by greater perception of treatment effects, once daily dosing, or reassurance as to the dose of corticosteroid. Moreover, compared to those prescribed fine-particle ICS, more patients prescribed ciclesonide had a controller-to-total medication ratio of ≥0.5, a finding associated with improved asthma-related quality of life, better disease control, and reduced symptoms.35

    There are several limitations to this study. Exclusion of patients without data during a 1-year period before and 1 year after ICS initiation meant that patients who moved or died were not represented. The requirement that all patients have 1-year outcome data predisposed the study to survivor bias. However, this may not have had a major effect, given the median age of 45 years and because patients prescribed their first ICS are unlikely to have severe asthma. Other limitations are those common to observational studies: biases deriving from unmeasured confounders that may particularly affect 1 of the 2 treatment strategies, non-random assignment of drug treatment, and potential misclassification bias and under-reporting if medical attention was not sought.

    During the study period, ciclesonide was not the most common ICS prescribed in the Netherlands, although it was prescribed for 34% of patients. Thus, there may be unrecorded reasons physicians chose to prescribe ciclesonide, resulting in prescription bias. This channeling phenomenon was suggested given that patients prescribed ciclesonide had signs of difficult-to-treat asthma (rhinitis and gastroesophageal reflux),32 find-ings potentially reducing positive effects of ciclesonide versus fine-particle ICS on asthma outcomes, which was not the case. While 1,244/1,382 (90%) eligible patients initiating ciclesonide were matched, only 1,244/2,682 (46%) of those initiating fine-particle ICS were matched, suggesting the possibility that patients in the fine-particle cohort were not representative of those who initiate fine-particle ICS therapy in the Netherlands.

    Finally, our analyses were limited by data availability; for example, smoking history, which may have some impact on effectiveness of ICS,17, 36 was not available, and nor were body mass index and lung function data. Diagnostic information was inferred from prescribing data. This meant that patients were selected as having asthma based on prescribed therapy, potentially leading to diagnostic misclassification. To mitigate this, we excluded patients with only 1 ICS prescription, which could have been a therapy trial. We were not able to assess current clinical control, but SABA dose (based on prescriptions) served as an indication of symptom control: 83% and 64% of patients in the ciclesonide and fine-particle ICS cohorts, respectively, were prescribed ≤1 puff/day (≤100 µg/day) of SABA on average, well within the definition of good control of asthma from an administrative database.37 The actual use of SABA was likely lower, as patients tend to have multiple inhalers and do not use all of the prescribed canisters.

    This study also has several strengths. Patients were drawn from a large diverse population with subsequent 1:1 exact matching on key baseline characteristics to ensure that the 2 cohorts were as comparable as possible with respect to demographic and clinical characteristics.30 Outcome measures were adjusted for appropriate non-collinear baseline confounders. The 1-year baseline and outcome periods enabled us to identify measurable changes in endpoints, such as hospitalizations, severe exacerbations, and asthma control, and also to allow for seasonal changes in respiratory conditions. All patients were prescribed the same inhaler type for ICS (pMDI), minimizing outcome differences associated with inhalation techniques for ICS or mixing inhaler devices (most SABA inhalers prescribed in the Netherlands are pMDIs).6, 38

    The residual baseline differences between treatment cohorts after matching (i.e., greater frequency of rhinitis and gastroesophageal reflux prescriptions in the ciclesonide treatment cohort) were addressed in the statistical models. Nasal corticosteroid prescriptions were not significant in the statistical model for the co-primary endpoints, suggesting that these did not affect the results, and the subgroup analysis of patients receiving nasal corticosteroid prescriptions corroborated the main findings. The co-primary endpoints were all adjusted for proton pump inhibitor prescriptions.

    Guidelines recommend that fluticasone and ciclesonide be prescribed at similar nominal doses1, 2, 3, 6, 15 based on equipotence in formal testing in randomized trials. Despite these recommendations, we found that in practice, ciclesonide was prescribed at lower doses than fluticasone and that fluticasone was typically prescribed at higher than recommended doses, corroborating findings from prior studies in the Netherlands, as well as New Zealand, the UK, and the USA.21, 22, 39, 40 Lower doses of ICS may be associated with reduced adverse events;41, 42 further research is required to determine whether the lower prescribed doses of ciclesonide and of extrafine-particle beclomethasone in prior studies21, 22 are associated with fewer adverse events in real-life populations, an important consideration for long-term asthma controller therapies and one that requires further studies, as we could not capture drug-related adverse events from our data source. Extrafine-particle ICS have relatively low oropharyngeal deposition, which could potentially lead to fewer oral side effects than with larger particle ICS.8, 15, 18, 43 However, we found that the proportion of patients prescribed antifungal medication for oral candidiasis was low and similar in the ciclesonide and fine-particle ICS treatment cohorts (2.3% vs 1.5%).

    In conclusion, the results of this matched cohort analysis suggest that initiation of ICS with ciclesonide is associated with better 1-year asthma outcomes and fewer changes to therapy in that year, at one-third of the prescribed dose than with fine-particle ICS. The study drew on reliable dispensing and hospitalization data for a real-life Dutch population—presumably including smokers and non-smokers, patients with good and bad inhaler techniques, stable and unstable asthma, and good and bad adherence. The association of better outcomes with cicle-sonide therapy was present, even though asthma was somewhat more severe in those prescribed ciclesonide. More real-life observational or randomized controlled studies of other patient populations and different extrafine-particle ICS are needed to further explore these findings.

    Supplemental Materials

    Supplemental Methods

    Click here to view.(185K, pdf)

    Supplementary Fig. 1

    Study design.

    Click here to view.(176K, pdf)

    Supplementary Fig. 2

    Flow chart showing selection of patients in the database.

    Click here to view.(533K, pdf)

    Supplementary Table 1

    Inhaled corticosteroid doses* prescribed on the initiation date

    Click here to view.(132K, pdf)

    Supplementary Table 2

    Possible rhinitis* subgroup analysis: odds ratios and rate ratios for co-primary and secondary endpoints

    Click here to view.(113K, pdf)

    Notes

    Study registration: European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP, study no. 6148).

    The University of Groningen has received money for Professor Dirkje S. Postma regarding an unrestricted educational grant for research from Astra Zeneca, Chiesi. Travel to ERS and/or ATS has been partially funded by AstraZeneca, Chiesi, GSK, Takeda. Fees for consultancies were given to the University of Groningen by AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda, and TEVA. Travel and lectures in China paid by Chiesi.

    Richard Dekhuijzen has received over the past 3 years (i) fees for speaking, organising education, participation in advisory boards or consulting from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Mundipharma, Novartis, Pfizer, Teva, Zambon; (ii) research grants from Novartis, Boehringer Ingelheim, AstraZeneca.

    Thys van der Molen has received grants for research, travel, reimbursement for presentations and advisory boards from AstraZeneca, GlaxoSmithKline, Almirall, Mundipharma, Boehringer Ingelheim, Chiesi, Teva and Novartis.

    Richard J. Martin has done consultancy work and/or received travel support and/or honoraria for attendance at advisory boards for Teva, AstraZeneca, MedImmune, and Merck; received research grants from MedImmune and the NHLBI; received royalties from UpToDate.

    Nicolas Roche has received over the past 3 years (i) fees for speaking, organising education, participation in advisory boards or consulting from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, MSD-Chibret, Mundipharma, Novartis, Pfizer, Stallergenes, Takeda, Teva; (ii) research grants from Novartis, Boehringer Ingelheim and Pfizer.

    Wim van Aalderen is a member of Medical Advisory Board of Astra-Zeneca.

    Theresa Guilbert reports personal fees from American Board of Pediatrics; Pediatric Pulmonary Subboard, grants and personal fees from Teva, personal fees from GSK and MERCK, personal fees from Regeneron Pharmaceuticals, grants from CDC, grants from DHHS, grants from NIH, grants from UW-Madison Medical and Education Research Committee, grants from Abbott Laboratories, grants from Array Biopharma, grants from Mylan, grants from Forest Research Institute, grants from F. Hoffman-LaRoche, grants from Medimmune, grants from KaloBios Pharmaceuticals, grants from Vertex Pharmaceuticals, grants from Roxane Laboratories and CompleWare Corporation, grants from CF Foundation Therapeutics, grants from Roche/Genetech, personal fees and other from Sanofi, personal fees and other from Novartis, and royalities from UpToDate.

    Elliot Israel reports receiving consulting fees from AstraZeneca, Bird Rock Bio, Cowen & Co, Novartis, Nuvelution Pharmaceutical, Philips Respironics, Regeneron Pharmaceuticals, and TEVA Specialty Pharmaceuticals, and Vitaeris, Inc.; fees for expert testimony from Campbell, Campbell, Edwards & Conroy, Crammer, Bishop & O'Brien, Fox Rothschild, and Ryan Ryan Deluca LLP; travel grant support from Research in Real-Life (RiRL), TEVA Specialty Pharmaceuticals; royalties from UpToDate, Deputy Editor fees from the American Thoracic Society, DSMB Member for Novartis with no compensation, and having grant support paid to his Institution from Genentech, Sanofi, and the NIH.

    Daniela van Eickels and Javaria Mona Khalid are employees of Takeda.

    Ron M.C. Herings and Jetty A. Overbeek are employees of the PHARMO Institute. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies.

    Cristiana Miglio, Victoria Thomas, and Catherine Hutton are employees of Research in Real-Life (RiRL), which conducted this study and which has conducted paid research in respiratory disease on behalf of the following other organizations in the past 5 years: Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva, a Sanofi company.

    Elizabeth V. Hillyer is a consultant to RiRL and has received payment for writing and editorial support to Merck.

    David B. Price has Board Membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva.

    Consultancy: Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva, and Zentiva; Grants/Grants Pending with UK National Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and Zentiva; Payments for lectures/speaking: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma, Novartis, Pfizer, SkyePharma, Takeda, and Teva; Payment for manuscript preparation: Mundipharma and Teva; Patents (planned, pending or issued): AKL Ltd.; Payment for the development of educational materials: GlaxoSmithKline, Novartis; Stock/Stock options: Shares in AKL Ltd which produces phytopharmaceuticals and owns 80% of Research in Real Life Ltd and its subsidiary social enterprise Optimum Patient Care; received Payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva; Funding for patient enrolment or completion of research: Almirral, Chiesi, Teva, and Zentiva; Peer reviewer for grant committees: Medical Research Council (2014), Efficacy and Mechanism Evaluation programme (2012), HTA (2014); and Received unrestricted funding for investigator-initiated studies from Aerocrine, AKL Ltd, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis, Orion, Takeda, Teva, and Zentiva.

    There are no financial or other issues that might lead to conflict of interest.

    ACKNOWLEDGMENTS

    Funds to acquire the dataset from the PHARMO Institute were provided by Research in Real-Life, Ltd (RiRL). The study data were provided to the Small Airways Study Group (SASG), which received financial support to conduct the analyses from Takeda Pharmaceuticals International GmbH, Zurich, Switzerland. Two Takeda employees (D.vE. and J.M.K.) are authors of the paper and participated in developing the study protocol and the manuscript. Members of the SASG were reimbursed for travel expenses to attend meetings to discuss this together with several other projects; they were not otherwise compensated for their advisory role.

    The authors acknowledge with gratitude the contributions of Dr. Gene Colice to study design and interpretation. We acknowledge Dr. Matthias Binek for contributions to the study design. The authors thank Jenny Fanstone of Fanstone Medical Communications Ltd., UK, for medical writing support for the initial draft, funded by Research in Real-Life.

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    MeSH Terms
    Adrenal Cortex Hormones*
    Anti-Asthmatic Agents
    Asthma
    Cohort Studies
    Comparative Effectiveness Research
    Diethylpropion
    Disease Progression
    Gastroesophageal Reflux
    Hospitalization
    Humans
    Odds Ratio
    Prevalence
    Rhinitis
    Metrics
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