Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial.

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Efficacy and safety of omalizumab in Chinese patients with anti-histamine refractory chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is characterized by the spontaneous development of wheals, itching, and/or angioedema, for ≥6 weeks. In China, non-sedating H1-antihistamines (H1AH) are the recommended first-line treatment, with escalation up to 4× the standard dose in symptomatic patients to achieve control. Treatment options for Chinese patients who remain symptomatic on H1AH treatment are limited. This 20-week randomized, double blind, placebo-controlled, parallel-group study investigated the efficacy and safety of omalizumab as an add-on therapy for the treatment of patients with CSU who remained symptomatic despite H1AH treatment in China. Adult patients (N = 418) diagnosed with refractory CSU for ≥6 months were randomized (2:2:1) to receive omalizumab 300 mg (OMA300), omalizumab 150 mg (OMA150) or placebo, subcutaneously, every 4 weeks. Primary outcome was change from baseline to week 12 in weekly itch severity score (ISS7). Safety was assessed by rates of adverse events (AEs). Demographic and disease characteristics at baseline were comparable across treatment groups. At week 12, statistically significant greater decreases from baseline were observed in ISS7 with OMA300 (least square mean difference [LSM]: -4.23; 95% confidence interval [CI]: -5.70, -2.77; p < 0.001) and OMA150 (LSM: -3.79; 95% CI: -5.24, -2.33; p < 0.001) versus placebo. Incidence of treatment-emergent AEs over 20 weeks was slightly higher with OMA300 (71.3%) compared to OMA150 and placebo groups (64.7% and 63.9%, respectively). The incidences of serious AEs were balanced between groups. This study demonstrated the efficacy and safety of omalizumab in Chinese adult patients with CSU who remained symptomatic despite H1AH therapy.

Efficacy and safety of omalizumab in patients with moderate-to-severe asthma: An analytic comparison of data from randomized controlled trials between Chinese and Caucasians.

BACKGROUND: Omalizumab has > 15 years of real-world evidence of effectiveness in Caucasian patients. In August 2017, it was approved as an add-on therapy for the management of moderate-to-severe asthma in China. OBJECTIVE: To compare the efficacy and safety of omalizumab in Chinese and Caucasian patients. METHODS: This analysis included clinical trial data from a Chinese study (NCT01202903) and four studies with predominantly Caucasian patients (008, 009, EXTRA and INNOVATE). The following outcomes were analyzed: change from baseline in morning peak expiratory flow (mPEF), percentage predicted forced expiratory volume in one second (FEV1), patient-reported outcomes (PROs), asthma exacerbation and safety. Further, a population pharmacokinetic/pharmacodynamic (PK/PD) was also assessed. RESULTS: In the Chinese study, omalizumab significantly improved the mPEF from baseline vs placebo at Weeks > 4-8 through > 16-20; however, the change in mPEF did not reach statistical significance at Week 24. A similar trend towards improvement in mPEF was observed in the studies with Caucasians (INNOVATE, 008 and 009). In all studies, omalizumab showed greater improvement in %predicted FEV1, AQLQ score, and GETE score vs placebo. In addition, asthma symptom scores and seasonal exacerbations were lower, especially during winter, in the Chinese study, and was comparable to studies in Caucasians. PK/PD analyses showed that steady-state PK of omalizumab; free or total immunoglobulin E levels were similar in all studies. CONCLUSIONS: The clinical efficacy and safety of omalizumab was comparable among Chinese and Caucasian patients with moderate-to-severe asthma supporting therapeutic effectiveness, irrespective of race, ethnicity and geographical factors.

Protocol design and synopsis: Omalizumab as Monotherapy and as Adjunct Therapy to Multiallergen OIT in Children and Adults with Food Allergy (OUtMATCH).

Background: Food allergy is common and causes substantial morbidity and even mortality. Safe and effective treatments for food allergy would therefore be highly desirable, especially for individuals with multiple food allergies. Objectives: Our aim was to describe a phase 3 study on treatment of patients with multiple food allergies with omalizumab. Methods: The study was developed as a collaboration between the Consortium for Food Allergy Research, the National Institute of Allergy and Infectious Diseases, and 2 industry sponsors (Genentech and Novartis). Results: The study is currently under way, enrolling participants from age 1 year to age 55 years who are allergic to peanut and at least 2 other foods (including milk, egg, wheat, cashew, hazelnut, and walnut). The study is designed to address 3 major questions. First, stage 1 will study the potential value of omalizumab for the treatment of patients with peanut allergy and at least 2 other common food allergens. Second, stage 2 will directly compare treatment of patients with multifood allergies using omalizumab as monotherapy versus treatment with omalizumab-facilitated multiallergen oral immunotherapy in which omalizumab is used as an adjunctive treatment. Third, stage 3 will address the longer-term outcomes following these treatment approaches, including the introduction of dietary forms of the study foods to induce or maintain desensitization. Conclusions: This phase 3 study will provide important information on the potential of omalizumab to treat patients with multiple food allergies.

Clinical Impact and Healthcare Resource Utilization Associated with Early versus Late COPD Diagnosis in Patients from UK CPRD Database.

Purpose: Previous studies have shown that opportunities to diagnose chronic obstructive pulmonary disease (COPD) early are often missed in primary care. This retrospective study aimed to utilize secondary data from the United Kingdom (UK) healthcare system to understand the impact of early versus late diagnosis of COPD. Patients and Methods: Newly diagnosed COPD patients were identified in the UK Clinical Practice Research Database from 2011 to 2014. Patients whose 5-year medical data before diagnosis revealed ≥3 counts of eight indicators of early COPD were deemed as late-diagnosed, whereas others were deemed as early-diagnosed. We assessed patients' characteristics; time-to-first, risk, and rates of exacerbation; and healthcare resource utilization (COPD-related clinic visits, Accident and Emergency visits, and hospitalizations) in late- versus early-diagnosed patients. Results: Of 10,158 patients included in the study, 6783 (67%) were identified as late-diagnosed and 3375 (33%) as early-diagnosed. The median time-to-first exacerbation was shorter in late-diagnosed (14.5 months) versus early-diagnosed (29.0 months) patients, with a significant risk of exacerbation (hazard ratio 1.46 [95% confidence interval: 1.38-1.55]). Additionally, the exacerbation rate (per 100 person-years) over 3 years was higher in late (108.9) versus early (57.2) diagnosed patients. Late-diagnosed patients had a significantly higher rate of COPD hospitalizations (per 1000 patient years) compared with early-diagnosed patients during 2 and 3 years of follow-ups (P = 0.0165 and P < 0.0001, respectively). Conclusion: Results showed that a significant percentage of COPD patients in UK primary care are diagnosed late. A late COPD diagnosis is associated with a shorter time-to-first exacerbation and a higher rate and risk of exacerbations compared with early diagnosis. Additionally, late diagnosis of COPD is associated with a higher rate of COPD-related hospitalizations compared with early diagnosis.

Adequacy of Therapy for People with Both COPD and Heart Failure in the UK: Historical Cohort Study.

PURPOSE: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) often occur concomitantly, presenting diagnostic and therapeutic challenges for clinicians. We examined the characteristics of patients prescribed adequate versus inadequate therapy within 3 months after newly diagnosed comorbid COPD or HF. PATIENTS AND METHODS: Eligible patients in longitudinal UK electronic medical record databases had pre-existing HF and newly diagnosed COPD (2017 GOLD groups B/C/D) or pre-existing COPD and newly diagnosed HF. Adequate COPD therapy was defined as long-acting bronchodilator(s) with/without inhaled corticosteroid; adequate HF therapy was defined as beta-blocker plus angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker. RESULTS: Of 2439 patients with HF and newly diagnosed COPD (mean 75 years, 61% men), adequate COPD therapy was prescribed for 726 (30%) and inadequate for 1031 (42%); 682 (28%) remained untreated for COPD. Adequate (vs inadequate) COPD therapy was less likely for women (35%) than men (45%), smokers (36%) than ex-/non-smokers (45%), and non-obese (41%) than obese (47%); spirometry was recorded for 57% prescribed adequate versus 35% inadequate COPD therapy. Of 12,587 patients with COPD and newly diagnosed HF (mean 75 years, 60% men), adequate HF therapy was prescribed for 2251 (18%) and inadequate for 5332 (42%); 5004 (40%) remained untreated for HF. Adequate (vs inadequate) HF therapy was less likely for smokers (27%) than ex-/non-smokers (32%) and non-obese (30%) than obese (35%); spirometry was recorded for 65% prescribed adequate versus 39% inadequate HF therapy. CONCLUSION: Many patients with comorbid COPD/HF receive inadequate therapy after new diagnosis. Improved equity of access to integrated care is needed for all patient subgroups.

Add-On Omalizumab for Inadequately Controlled Severe Pollinosis Despite Standard-of-Care: A Randomized Study.

BACKGROUND: Cedar pollinosis (CP), a common form of seasonal allergic rhinitis (AR), is a substantial medical problem in Japan due to its high prevalence and severe symptoms. Omalizumab (anti-IgE therapy) has previously proven to be effective in CP/AR, but no studies for inadequately controlled severe CP/AR despite standard-of-care (SoC) have been conducted. OBJECTIVE: To determine the efficacy of omalizumab added to SoC in patients with inadequately controlled severe CP in a randomized, double-blinded, placebo-controlled, phase III study. METHODS: Adult/adolescent patients with severe CP whose symptoms were inadequately controlled despite nasal corticosteroids plus 1 or more oral medications in the previous 2 seasons were randomized to receive omalizumab (n = 162) or placebo (n = 175). All patients received concomitant antihistamines and nasal corticosteroids as SoC. The primary endpoint was the mean nasal symptom score during the severe symptom period. Secondary endpoints included mean ocular symptom score, quality of life (QoL), and safety. RESULTS: The SoC + omalizumab treatment had statistically significantly and clinically important lower nasal (least squares mean difference, -1.03, P < .001) and ocular (-0.87, P < .001) symptom scores compared with SoC + placebo, respectively. Differences in scores for individual components of nasal and ocular symptoms were also statistically and clinically significant. SoC + omalizumab also improved QoL scores as overall and in all domains. No unexpected safety signals were observed. CONCLUSIONS: In patients with severe CP, omalizumab added to SoC demonstrated consistent efficacy in improving symptoms and QoL, and was well tolerated. These results indicate that omalizumab could be a promising therapeutic option for severe CP/AR.

Efficacy predictors of omalizumab in Chinese patients with moderate-to-severe allergic asthma: Findings from a post-hoc analysis of a randomised phase III study.

BACKGROUND: Omalizumab has demonstrated efficacy as an add-on therapy in Chinese patients with moderate-to-severe allergic asthma. This post-hoc analysis assessed the potential predictors for the efficacy of omalizumab in these patients. METHODS: A post-hoc analysis was performed on a Phase III, randomised, controlled study conducted in Chinese patients with moderate-to-severe persistent allergic asthma (NCT01202903). We evaluated if levels of pre-treatment serum total immunoglobulin-E (IgE) and blood eosinophil (EOS), asthma severity, allergen profile, history of perennial allergic rhinitis (PAR), and free IgE level during omalizumab treatment were predictive of omalizumab's efficacy. RESULTS: This analysis included 608 patients (omalizumab, N = 306; placebo, N = 302). Improvements in forced expiratory volume in 1 s (FEV1), standardized Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Questionnaire (ACQ), and Global Evaluation of Treatment Effectiveness (GETE) scores with omalizumab treatment compared with placebo were observed in patients with baseline IgE levels ≥76 IU/mL (irrespective of the EOS count). Relatively greater improvements with omalizumab treatment was also noted in patients with both moderate or severe allergic asthma (regardless of asthma severity), and patients sensitised to >3 allergens and with a history of PAR. All patients who were treated with omalizumab achieved free IgE levels below 50 ng/mL by Week 1. Similar clinical outcomes were observed in the subset of patients who achieved free IgE levels of <25 and ≥ 25 ng/mL. CONCLUSIONS: In Chinese patients with moderate-to-severe allergic asthma, baseline IgE and allergen profile (number/PAR history) are potential predictors of treatment response to omalizumab. TRIAL REGISTRATION: NCT01202903 (www.clinicaltrials.gov).

Pregnancy outcomes in the omalizumab pregnancy registry and a disease-matched comparator cohort.

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

Inhaled corticosteroids in COPD and onset of type 2 diabetes and osteoporosis: matched cohort study.

Some studies suggest an association between onset and/or poor control of type 2 diabetes mellitus and inhaled corticosteroid (ICS) therapy for chronic obstructive pulmonary disease (COPD), and also between increased fracture risk and ICS therapy; however, study results are contradictory and these associations remain tentative and incompletely characterized. This matched cohort study used two large UK databases (1983-2016) to study patients (≥ 40 years old) initiating ICS or long-acting bronchodilator (LABD) for COPD from 1990-2015 in three study cohorts designed to assess the relation between ICS treatment and (1) diabetes onset (N = 17,970), (2) diabetes progression (N = 804), and (3) osteoporosis onset (N = 19,898). Patients had ≥ 1-year baseline and ≥ 2-year outcome data. Matching was via combined direct matching and propensity scores. Conditional proportional hazards regression, adjusting for residual confounding after matching, was used to compare ICS vs. LABD and to model ICS exposures. Median follow-up was 3.7-5.6 years/treatment group. For patients prescribed ICS, compared with LABD, the risk of diabetes onset was significantly increased (adjusted hazard ratio 1.27; 95% CI, 1.07-1.50), with overall no increase in risk of diabetes progression (adjusted hazard ratio 1.04; 0.87-1.25) or osteoporosis onset (adjusted hazard ratio 1.13; 0.93-1.39). However, the risks of diabetes onset, diabetes progression, and osteoporosis onset were all significantly increased, with evident dose-response relationships for all three outcomes, at mean ICS exposures of 500 µg/day or greater (vs. < 250 µg/day, fluticasone propionate-equivalent). Long-term ICS therapy for COPD at mean daily exposure of ≥ 500 µg is associated with an increased risk of diabetes, diabetes progression, and osteoporosis.

Evaluation of exacerbations and blood eosinophils in UK and US COPD populations.

BACKGROUND: Blood eosinophil counts and history of exacerbations have been proposed as predictors of patients with chronic obstructive pulmonary disease (COPD) who may benefit from triple therapy (inhaled corticosteroid, long-acting ß2-agonist and long-acting muscarinic antagonist). METHODS: In a retrospective cohort analysis we examined the profiles of COPD patients from the UK Clinical Practice Research Datalink (CPRD) and US Optum Clinformatics™ Data Mart (Optum) databases with reference to exacerbation frequency and blood eosinophil distribution. RESULTS: Of the 31,437 (CPRD) and 383,825 (Optum) patients with COPD, 15,364 (CPRD) and 139,465 (Optum) met the eligibility criteria and were included. Among patients with ≥2 exacerbations and available eosinophil counts in the baseline period (CPRD, n = 3089 and Optum, n = 13414), 17.0 and 13.3% respectively had eosinophil counts ≥400 cells/µL. Patients with ≥2 exacerbations or eosinophil count ≥400 cells/µL during first year, exacerbated at least once (CPRD, 82.8% vs Optum, 80.6%) or continued to have eosinophil count ≥300 cells/µL (76.8% vs 76.5%), respectively in the follow-up year. In both years, a higher variability in the number of exacerbations and eosinophil count was observed in patients with one exacerbation and eosinophil counts between 300 and 400 cells/µL; patients with eosinophil count < 150 cells/µL had the lowest variability. Approximately 10% patients had both ≥2 exacerbations and eosinophil count ≥300 cells/µL across the databases. CONCLUSION: A high variability in blood eosinophil counts over two consecutive years was observed in UK and US patients with COPD and should be considered while making treatment decisions. A small proportion of COPD patients had frequent exacerbations and eosinophil count ≥300 cells/µL.

Inhaled corticosteroid use by exacerbations and eosinophils: a real-world COPD population.

Background: Blood eosinophils may predict response to inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) where ICS is recommended in patients at high risk of exacerbations. The proportion of patients who may benefit the most from ICS-based therapy was quantified in a real-world population. Materials and methods: European data from the Adelphi Real World Respiratory Disease Specific Programme™ 2017 survey were collected from consecutive COPD patients by participating physicians. Overall, 1,528 patients were assessable for Global Initiative for COPD (GOLD) 2017 status and were included in the analysis. Results: More GOLD D patients had elevated eosinophil counts compared with GOLD B. The proportions of GOLD D patients with a history of ≥2 exacerbations and eosinophil counts of ≥150, ≥300, and ≥400 cells/µL were 81.2%, 39.4%, and 24.6%, respectively. In total, 10.6% of the patients had ≥300 eosinophils/µL and a history of ≥2 exacerbations. ICS-based therapy was received by 41.5% of GOLD B and 68.0% of GOLD D patients. Conclusion: There was no apparent relation between ICS use and eosinophil blood count. There are differences in the distributions of patients with frequent exacerbations and/or high blood eosinophil counts and the use of ICS in COPD. These data may provide information for the implementation of future treatment recommendations.

Differences in COPD Exacerbation Risk Between Women and Men: Analysis From the UK Clinical Practice Research Datalink Data.

BACKGROUND: Historically, COPD has been considered to affect mostly older men with a history of smoking; however, in recent times, its prevalence and mortality rates have steadily increased among women. OBJECTIVES: The goal of this study was to systematically assess differences in COPD expression between women and men in UK primary care clinics who were newly diagnosed with COPD. METHODS: This retrospective cohort study compared women and men with an incident diagnosis of COPD by using electronic medical records data from the Clinical Practice Research Datalink and linked Hospital Episode Statistics data. The overall study period was between January 1, 2006, and February 28, 2016; patients with an incident diagnosis of COPD between January 1, 2010, and February 28, 2015, were analyzed. RESULTS: A cohort of 22,429 patients were identified as incident patients and included in the study; 48% of patients with COPD were women. The risk of first moderate or severe exacerbation was 17% greater in women than in men (hazard ratio, 1.17; 95% CI, 1.12-1.23), with a median time to first exacerbation of 504 days for women and 637 days for men. These differences were more prominent in the younger age group (≥ 40 years to < 65 years), as well as in Global Initiative for Chronic Obstructive Lung Disease 2016 groups B, C, and D and in individuals with moderate to severe airflow obstruction. The annual rate of moderate or severe exacerbations was higher in women compared with men in the first, second, and third year of follow-up. CONCLUSIONS: These results highlight the unmet need for appropriate identification and management of women with COPD in clinical practice.

Treatment response to indacaterol/glycopyrronium versus salmeterol/fluticasone in exacerbating COPD patients by gender: a post-hoc analysis in the FLAME study.

BACKGROUND: The burden of chronic obstructive lung disease (COPD) is increasing in women, with recent evidence suggesting gender differences in disease characteristics and potentially in treatment outcomes. METHODS: FLAME was a 52-week randomized controlled trial in patients with severe-to-very-severe COPD and a history of exacerbations. In this post-hoc analysis, gender-based baseline differences and treatment outcomes between indacaterol/glycopyrronium 110/50 µg once daily (IND/GLY) and salmeterol/fluticasone 50/500 twice daily (SFC) were assessed in terms of rate of exacerbations, time-to-first exacerbation, lung function, health status, and rescue medication use. RESULTS: This post-hoc analysis included 2557 men and 805 women. Baseline characteristics differed between genders, with women being younger, having better lung function and more often experiencing ≥2 exacerbations in the previous year. Compared with SFC, IND/GLY treatment was associated with reductions in the annualized rates of moderate/severe exacerbations (rate ratio [95% CI]: 0.81 [0.73-0.91], 0.89 [0.74-1.07] in men and women, respectively). Similarly, time-to-first moderate/severe exacerbation was also delayed (hazard ratio [95% CI]: 0.79 [0.70-0.89] and 0.76 [0.63-0.91] in men and women, respectively). Results were similar for all (mild/moderate/severe) exacerbations. Improvements in lung function, health status and rescue medication use with IND/GLY vs SFC were comparable between men and women. The smaller sample size for women may account for some observed discrepancies in treatment responses. CONCLUSIONS: Although there were gender differences in baseline characteristics, IND/GLY demonstrated similar trends for exacerbation prevention and lung function improvement in men and women with moderate-to-very-severe COPD and a history of exacerbations compared with SFC. Small differences in the effects seen between genders may be attributed to the different sizes of the two groups and need to be further evaluated in randomized trials that are appropriately powered for gender analysis. TRIAL REGISTRATION: Post hoc analysis of the FLAME study. ClinicalTrials.gov number: NCT01782326 . Registered 1 February 2013.

Capturing Exacerbations of Chronic Obstructive Pulmonary Disease with EXACT. A Subanalysis of FLAME.

RATIONALE: Chronic obstructive pulmonary disease exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n = 457) from the FLAME (Effect of Indacaterol Glycopyrronium vs. Fluticasone Salmeterol on COPD Exacerbations) study used the Exacerbations of COPD Tool (EXACT) to capture symptom-defined exacerbations. OBJECTIVES: To evaluate the effect of indacaterol/glycopyrronium versus salmeterol/fluticasone on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU). METHODS: All patients in FLAME used an electronic diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery, and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time to first symptom-defined (EXACT) exacerbation and assessed differences between symptom-defined and HCRU events in terms of number, severity, and concordance. MEASUREMENTS AND MAIN RESULTS: A nonsignificant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio, 0.83; 95% confidence interval [CI], 0.60-1.14; P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with indacaterol/glycopyrronium versus salmeterol/fluticasone (hazard ratio, 0.76; 95% CI, 0.56-1.03; P = 0.075). These results were consistent with data from the overall FLAME population. Of the symptom-defined (EXACT) events, 23.5% corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (κ index, 0.24; 95% CI, 0.15-0.33). CONCLUSIONS: Regardless of the exacerbation definition used, our findings support the use of long-acting ß2 agonists/long-acting muscarinic receptor antagonists as the preferred treatment option for patients at risk of future exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).

Indacaterol/glycopyrronium versus salmeterol/fluticasone in the prevention of clinically important deterioration in COPD: results from the FLAME study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive disease and a composite endpoint could be an indicator of treatment effect on disease worsening. This post-hoc analysis assessed whether indacaterol/glycopyrronium (IND/GLY) 110/50 µg once daily reduced the risk of clinically important deterioration (CID) versus salmeterol/fluticasone (SFC) 50/500 µg twice daily in moderate-to-very severe COPD patients from the FLAME study. METHODS: CID was defined as ≥100 mL decrease in forced expiratory volume in 1 s (FEV1) or ≥ 4-unit increase in St. George's Respiratory Questionnaire (SGRQ) total score or a moderate-to-severe COPD exacerbation. Changes from baseline in the rate of moderate and severe exacerbations, time to first moderate-to-severe exacerbation, and change from baseline in the SGRQ score, measured after Week 12 up to Week 52, were assessed by presence of early CID (CID+) or absence of CID (CID-) at Week 12. RESULTS: IND/GLY significantly delayed the time to CID (hazard ratio [HR] (95% confidence interval [CI]), 0.72 [0.67-0.78]; P < 0.0001), and reduced the incidences of CID versus SFC. Additionally, IND/GLY delayed the time to CID in all patient subgroups. After 12 weeks until 52 weeks, CID+ patients had a significantly higher rate of moderate-to-severe exacerbations versus CID- patients (P < 0.0001); moreover, CID+ patients experienced moderate-to-severe exacerbations significantly earlier versus CID- patients (P < 0.0001). CID+ patients had a comparable change in the SGRQ total score versus CID- patients. CONCLUSIONS: IND/GLY reduced the risk of CID versus SFC. CID had a significant impact on long-term exacerbation outcomes in patients with moderate-to-very severe COPD and a history of ≥1 exacerbations in the previous year. TRIAL REGISTRATION: Clinicaltrials.gov NCT01782326 .

Long-Term Triple Therapy De-escalation to Indacaterol/Glycopyrronium in Patients with Chronic Obstructive Pulmonary Disease (SUNSET): A Randomized, Double-Blind, Triple-Dummy Clinical Trial.

RATIONALE: There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations. OBJECTIVES: To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD). METHODS: This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 µg once daily) or continuation of triple therapy (tiotropium [18 µg] once daily plus combination of salmeterol/fluticasone propionate [50/500 µg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV1. Moderate or severe exacerbations were predefined secondary endpoints. MEASUREMENTS AND MAIN RESULTS: A total of 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of -26 ml (95% confidence interval, -53 to 1 ml) with confidence limits exceeding the noninferiority margin of -50 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with ≥300 blood eosinophils/µl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups. CONCLUSIONS: In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/µl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).

Gender-specific estimates of COPD prevalence: a systematic review and meta-analysis.

Rationale: COPD has been perceived as being a disease of older men. However, >7 million women are estimated to live with COPD in the USA alone. Despite a growing body of literature suggesting an increasing burden of COPD in women, the evidence is limited. Objectives: To assess and synthesize the available evidence among population-based epidemiologic studies and calculate the global prevalence of COPD in men and women. Materials and methods: A systematic review and meta-analysis reporting gender-specific prevalence of COPD was undertaken. Gender-specific prevalence estimates were abstracted from relevant studies. Associated patient characteristics as well as custom variables pertaining to the diagnostic method and other important epidemiologic covariates were also collected. A Bayesian random-effects meta-analysis was performed investigating gender-specific prevalence of COPD stratified by age, geography, calendar time, study setting, diagnostic method, and disease severity. Measurements and main results: Among 194 eligible studies, summary prevalence was 9.23% (95% credible interval [CrI]: 8.16%-10.36%) in men and 6.16% (95% CrI: 5.41%-6.95%) in women. Gender prevalences varied widely by the World Health Organization Global Burden of Disease subregions, with the highest female prevalence found in North America (8.07% vs 7.30%) and in participants in urban settings (13.03% vs 8.34%). Meta-regression indicated that age ≥40 and bronchodilator testing contributed most significantly to heterogeneity of prevalence estimates across studies. Conclusion: We conducted the largest ever systematic review and meta-analysis of global prevalence of COPD and the first large gender-specific review. These results will increase awareness of COPD as a critical woman's health issue.

Indacaterol/glycopyrronium reduces the risk of clinically important deterioration after direct switch from baseline therapies in patients with moderate COPD: a post hoc analysis of the CRYSTAL study.

PURPOSE: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting ß2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID. METHODS: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334. RESULTS: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]). CONCLUSION: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice.