Sarah Cockle

Comparative efficacy of combination bronchodilator therapies in COPD: a network meta-analysis

Background Several new fixed-dose combination bronchodilators have been recently launched, and assessing their efficacy relative to each other, and with open dual combinations is desirable. This network meta-analysis (NMA) assessed the efficacy of umeclidinium and vilanterol (UMEC/VI) with that of available dual bronchodilators in single/separate inhalers. Methods A systematic literature review identified randomized controlled trials of ≥10 weeks among chronic obstructive pulmonary disease patients (≥40 years), assessing the efficacy of combination bronchodilators in single or separate inhalers. Comparative assessment was conducted on change from baseline in trough forced expiratory volume in 1 second (FEV1), St George’s Respiratory Questionnaire (SGRQ) total scores, transitional dyspnea index (TDI) focal scores, and rescue medication use at 12 weeks and 24 weeks using an NMA within a Bayesian framework. Results A systematic literature review identified 77 articles of 26 trials comparing UMEC/VI, indacaterol/glycopyrronium (QVA149), formoterol plus tiotropium (TIO) 18 μg, salmeterol plus TIO, or indacaterol plus TIO, with TIO and placebo as common comparators at 12 weeks and approximately 24 weeks. The NMA showed that at 24 weeks, efficacy of UMEC/VI was not significantly different compared with QVA149 on trough FEV1 (14.1 mL [95% credible interval: −14.2, 42.3]), SGRQ total score (0.18 [−1.28, 1.63]), TDI focal score (−0.30 [−0.73, 0.13]), and rescue medication use (0.02 [−0.27, 0.32]); compared with salmeterol plus TIO on trough FEV1 (67.4 mL [−25.3, 159.4]), SGRQ total score (−0.11 [−1.84, 1.61]), and TDI focal score (0.58 [−0.33, 1.50]); and compared with formoterol plus TIO 18 μg on SGRQ total score (−0.68 [−1.77, 0.39]). Results at week 12 were consistent with week 24 outcomes. Due to lack of availability of evidence, no comparison was made with formoterol plus TIO on FEV1 or TDI at 24 weeks. Conclusion UMEC/VI has comparable efficacy to other dual-bronchodilator combinations on available efficacy endpoints.

Biologic treatment eligibility for real-world patients with severe asthma: The IDEAL study

ABSTRACT Objectives: Severe asthma comprises several distinct phenotypes. Consequently, patients with severe asthma can be eligible for more than one biologic treatment targeting Th2 inflammation, such as anti-interleukin (IL)-5 and anti-immunoglobulin (Ig) E. The objective of this study was to describe treatment eligibility and overlap in treatment eligibility for mepolizumab (anti-IL-5), omalizumab (anti-IgE) and reslizumab (anti-IL-5) in patients with severe asthma, who were recruited from clinical practice. Methods: This cross-sectional, single-visit, observational study in six countries enrolled patients with severe asthma (defined by American Thoracic Society/European Respiratory Society guidelines). Assessable patients were analysed as a total cohort and a sub-cohort, who were not currently receiving omalizumab. Treatment eligibility was defined according to the local prescribing information or protocol-defined inclusion/exclusion criteria. Patients currently receiving omalizumab were automatically categorised as omalizumab-eligible. Results: The total cohort comprised 670 patients who met the analysis criteria, of whom 20% were eligible for mepolizumab, 31–41% were eligible for omalizumab (depending on eligibility criteria used), and 5% were eligible for reslizumab. In patients not currently receiving omalizumab (n = 502), proportions eligible for each biologic were similar (mepolizumab: 20%, reslizumab 6%) or lower (omalizumab 7–21%) than those for the total cohort. Overlap in treatment eligibility varied; in mepolizumab-eligible patients not currently receiving omalizumab (n = 101), 27–37% were omalizumab-eligible and 18% were reslizumab-eligible. Conclusions: Treatment eligibility for mepolizumab and omalizumab was higher than that for reslizumab. Although there was some overlap in treatment eligibility, the patient groups eligible for treatment with anti-IL-5 or anti-IgE therapies were often distinct, emphasising the different phenotypes and endotypes in severe asthma.

Comparison of laboratory- and field-based exercise tests for COPD: a systematic review.

Exercise tests are often used to evaluate the functional status of patients with COPD. However, to the best of our knowledge, a comprehensive systematic comparison of these tests has not been performed. We systematically reviewed studies reporting the repeatability and/or reproducibility of these tests, and studies comparing their sensitivity to therapeutic intervention. A systematic review identified primary manuscripts in English reporting relevant data on the following exercise tests: 6-minute walk test (6MWT) and 12-minute walk test, incremental and endurance shuttle walk tests (ISWT and ESWT, respectively), incremental and endurance cycle ergometer tests, and incremental and endurance treadmill tests. We identified 71 relevant studies. Good repeatability (for the 6MWT and ESWT) and reproducibility (for the 6MWT, 12-minute walk test, ISWT, ESWT, and incremental cycle ergometer test) were reported by most studies assessing these tests, providing patients were familiarized with them beforehand. The 6MWT, ISWT, and particularly the ESWT were reported to be sensitive to therapeutic intervention. Protocol variations (eg, track layout or supplemental oxygen use) affected performance significantly in several studies. This review shows that while the validity of several tests has been established, for others further study is required. Future work will assess the link between these tests, physiological mechanisms, and patient-reported measures.

Qualitative evaluation of the St George's Respiratory Questionnaire in patients with severe asthma

PURPOSE Content validity is the extent to which a patient-reported outcome measure evaluates the concepts most relevant to a patients condition and treatment. The St Georges Respiratory Questionnaire (SGRQ) has been validated in a range of respiratory conditions. This study evaluated the content validity of the SGRQ in patients with severe asthma. METHODS A qualitative study, guided by a protocol, which included concept elicitation and cognitive debriefing of the SGRQ, was conducted in patients aged ≥18 years with history of severe asthma and blood eosinophil counts of ≥150/μL (past month) or ≥300/μL (past 12 months). Patients were recruited until saturation for concept elicitation was achieved (i.e. no additional concepts identified). Concepts identified by the patients were then mapped to the SGRQ. RESULTS 18 patient interviews provided concept saturation. Concept elicitation confirmed that the SGRQ includes the commonly reported asthma symptoms and their impact on daily life. In total, 89-100% of patients routinely experienced cough, nighttime awakenings, shortness of breath, chest tightness, sleep difficulty, phlegm/mucus, and wheezing. Patients reported asthma impacting daily and physical activities, mood and sleep. Cognitive interviewing confirmed that patients understood the instructions, items and response options in the SGRQ. Nearly half of the concepts in the SGRQ were endorsed by ≥12 patients; of the 17 items with scoring weights ≥85, 11 were mentioned by ≥12 patients. CONCLUSIONS This study demonstrates that the SGRQ is a relevant, comprehensive and content-valid instrument to assess health status in patients with severe asthma.

P15 Cost effectiveness of mepolizumab for severe eosinophilic asthma from the uk perspective

Introduction Severe asthma patients have limited therapeutic options. These patients remain at risk of exacerbations, their quality of life is negatively impacted and they place a significant burden on the health service. Mepolizumab is licensed for use in patients with severe eosinophilic asthma. As reimbursement authorities expect evidence of health economic benefits, this study aimed to estimate the cost-utility of mepolizumab as an add-on therapy to standard of care (SOC) versus SOC alone. Methods A de novo Markov cost-utility model was produced which compared the costs and outcomes of mepolizumab vs. SOC over a lifetime horizon. Primary analysis was based on data from the MENSA clinical trial (NCT01691521). Patients entering the model were assigned to mepolizumab or SOC and experienced treatment-specific probabilities of exacerbation events with an associated risk of mortality and disutility. The model included a continuation criteria where patients on mepolizumab who failed to demonstrate an exacerbation reduction were transitioned to the SOC arm. Costs and health outcomes were discounted annually at 3.5%. The model did not account for indirect costs or value in steroid reduction. Results In the basecase analysis (patients with ≥300 eosinophil cells/µL and ≥4 exacerbations in the previous 12 months) the incremental cost-effectiveness ratio (ICER) of add-on mepolizumab compared with SOC was £30,268/QALY gained. Scenario analyses showed that the ICER was sensitive to the starting age of the cohort, the source of utility and asthma-related mortality. Conclusion Mepolizumab represents a clinically efficacious and cost-effective alternative to SOC.

Characteristics of adult onset vs. late onset asthma - a multinational database cohort study

Background: Although early onset asthma has been well characterised, data on adult onset asthma are scarce. Aims: To describe characteristics of adult onset asthma using data from 5 European electronic health record (EHR) databases in the study period 2008-2013. Methods: Asthma patients aged ≥18 yrs at diagnosis (COPD excluded) and with ≥1 year of follow-up were identified in EHR databases from the Netherlands (IPCI), Italy (HSD), UK (CPRD), Denmark (AUH) and Spain (SIDIAP). Patients were categorised into early adult onset asthma (>=18-39 yrs) or late onset asthma (>=40 yrs) based on the age at diagnosis. Characteristics were assessed at study start. Differences were tested with Chi-Square and Mann Whitney U test. The analysis was repeated in severe asthma only (use of high dose ICS + controller therapy for ≥120 days). Results: We included 504,745 patients (median age from 44.5-48.0 yrs) with asthma of whom 40,193 (8.0%) had severe asthma. The proportion of late onset asthma was 56.8% (range 56-60.1% across database) which increased to 70.4% (range 66.5-91.6%) in severe asthma. Compared to early adult onset asthma, patients with late onset asthma were less frequently atopic (range 9.2-28.7% across database vs. 21.5-39.5%), suffered more frequently from chronic rhinosinusitis (0.4-11.2% vs. 0.2-8.0%) and/or nasal polyposis (0.6-4.6% vs. 0.3-1.7%), GERD (2.8-14.3% vs. 0.9-7.5%) and obesity (10.5-72.2% vs. 9.3-54.7%) and had lower median IgE levels (63-91 vs. 108-226 IU/L)(all significant). Similar patterns were observed among severe asthma only. Conclusion: Differences in comorbidity in late onset vs. early adult onset asthma may be important for asthma management. GSK funded (PRJ2284)

Predictors of respiratory health status in patients with severe asthma

Rationale: Patients with severe asthma experience substantial impact on health related quality of life. Characterization of predictors of worse health status in severe asthma may help identify patients requiring additional interventions. This post-hoc analysis of the IDEAL study (201722; NCT02293265) evaluated predictors of respiratory health status, measured by the St George9s Respiratory Questionnaire (SGRQ). Methods: The IDEAL study was a cross-sectional, non-interventional study in 6 countries, and included subjects ≥12 years with severe asthma (ATS/ERS guidelines) treated with high-dose ICS plus additional controller(s) for ≥12 months. Assessments included a blood sample, spirometry, and PRO, including the SGRQ. Clinical and demographic characteristics predictive of SGRQ score in the total cohort were evaluated with univariate analysis and multivariate linear regression. Results: In univariate analysis, predictors of SGRQ included gender, pre-bronchodilator FEV 1 %predicted, bronchodilator reversibility, smoking status, use of maintenance oral corticosteroids (OCS), history of clinically significant exacerbations (prior 12 months), and blood eosinophil level. Total IgE and use of omalizumab were not associated with SGRQ. In multivariate regression, predictors of lower health status score included history of clinically significant exacerbations, lower FEV 1 %predicted, OCS use, female gender, and current or a history of smoking. Conclusions: Among patients with severe asthma, there are clinical and demographic characteristics associated with an impact on respiratory health status measured by the SGRQ, that could be addressed by targeted intervention. Funding: GSK (NCT02293265).

Clinical characteristics and burden of illness in a cohort of severe asthma patients

Objectives: Describe demographic and clinical traits among patients with severe asthma (SA) and a subset of patients with inadequately controlled severe eosinophilic asthma (SEA). Methods: IDEAL study (201722; NCT02293265) is a cross-sectional cohort of SA patients (age ≥12 years, high-dose ICS + additional controller/s for ≥12 months) recruited from specialist clinics in 6 countries. Inadequately controlled SEA was defined as (1) blood eosinophil count of ≥300 cells/μL in the past 12 months prior to study visit OR ≥150 cells/μL at study visit AND (2) ≥2 or more severe exacerbations of asthma (requiring systemic corticosteroid and/or emergency room (ER) visit and/or hospitalization) in the past 12 months. Extensive medical history supplemented with existing medical records and a blood sample were collected. Results: The cohort consisted of 670 SA patients, of whom 137 (20%) had SEA. Compared to the total SA cohort, the subset with SEA had equal proportion of females (62%), was slightly younger (mean: 48 vs. 51 yrs) and had more significant smoking history (45% vs. 36%). Mean of severe exacerbations was 3.2 vs. 1.2/patient-year and 23% vs 9% had ≥1 asthma hospitalization, with more frequent regular OCS use (20% vs. 14%). Further, higher levels of IgE (179 vs. 155 KU/L), lower FEV 1 values (64 vs. 68 FEV 1 % pred.) and more frequent comorbidities were observed. Conclusions: The IDEAL study shows a considerable disease burden in a cohort of patients with severe asthma, with impaired lung function and on average more than one exacerbation/yr. The subset with inadequately controlled severe eosinophilic asthma with more than 3 exacerbations/yr seems to drive much of this disease burden. Funded by GSK.

P40 Systematic review of the repeatability, reproducibility, sensitivity and comparability of key exercise capacity tests used in chronic obstructive pulmonary disease (COPD)

Introduction and Objectives Various exercise tests are used as endpoints to evaluate the functional status of patients with COPD. While individual studies have compared different tests, a systematic assessment of this data has not been performed. We therefore aimed to review the repeatability (variation in tests performed on the same day), reproducibility (variation in tests performed on different days), sensitivity and comparability between and within exercise tests in adult patients with COPD. Methods A systematic review of Embase, MEDLINE® and the Cochrane Library identified primary manuscripts in English reporting relevant data on the following exercise tests: six- and twelve-minute walk tests (6MWTs and 12MWTs), incremental and endurance shuttle walk tests (ISWTs and ESWTs), treadmill test (TT), and incremental and endurance cycle ergometer tests (ICETs and ECETs). Comparability within exercise tests was assessed by examining studies that compared different protocols of the same test type. Results We identified 90 relevant studies (Figure 1). The majority of studies exploring repeatability and/or reproducibility examined the 6MWT, 12MWT and ISWT; no studies examined repeatability in treadmill and cycle tests. Only four studies reported the intraclass correlation coefficient (ICC); two examined repeatability and reproducibility of the 6MWT (ICCs = 0.94 and 0.88, respectively), and a further two reported reproducibility of the ECET and endurance TT (ICCs = 0.85 and 0.84, respectively). These data indicate good repeatability/reproducibility, but other studies contradict these findings. Prior familiarisation consistently improved repeatability and reproducibility of tests. Most relevant studies reported that exercise tests were sensitive to interventions, but the magnitude of response varied between test types and depended on the intervention and outcome assessed. Protocol variations, such as in track layout or supplemental oxygen use, affected performance in the majority of studies identified. Studies with pair-wise comparisons between walk tests, cycle tests, and walk and cycle tests reported inconsistent comparability between test types. Abstract P40 Figure 1. Breakdown of the relevant studies. Numbers of studies that contain data examining the repeatability, reproducibility, sensitivity and comparability (within and between different tests) for the different exercise tests. As some studies fall into more than one category, the combined number of studies in this figure exceeds 90. Conclusion This review found varied repeatability, reproducibility and sensitivity of exercise tests often resulting from inconsistencies in protocol administration (e.g. variations in protocols used, outcomes analysed, or protocol familiarisation). Such within- and between-test variations make comparisons difficult, even between studies ostensibly reporting the same test.