Reduced Exacerbation Rates Research Articles

Real-world study in severe eosinophilic asthma patients refractory to anti-IL5 biological agents treated with benralizumab in Spain (ORBE study)

BackgroundBenralizumab, a monoclonal antibody targeting the human interleukin-5 (IL-5) receptor (IL-5R), was used before marketing authorisation in Spain in a real world setting as part of an early-access programme (EAP) to treat patients with severe eosinophilic asthma with prior insufficient response or intolerance to anti-IL5 treatment (mepolizumab or reslizumab). The objective of this study is to describe the patient profile candidate for treatment and to assess benralizumab effectiveness.MethodsThis is an observational, retrospective, multicentre study in severe eosinophilic asthma patients refractory to other biological agents targeting the IL-5 pathway. Baseline characteristics included closest data, from the previous 12 months, to benralizumab treatment onset (index date). Patients were followed until the last treatment dosage while EAP was active (March to December 2018). Effectiveness was evaluated versus baseline, in patients who received at least three doses, with asthma control test (ACT), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), annual severe exacerbation rate, oral corticosteroids treatment (OCS) and asthma-related healthcare resources utilization.ResultsTwenty-seven patients treated with benralizumab were included in the analysis. Effectiveness was assessed in 19 patients. Both questionnaires showed clinically meaningful differences, i.e. ACT score ≥ 3 and MiniAQLQ score ≥ 0.5, compared with baseline [mean (SD), 3.3 (6.8) and 1.2 (1.9), respectively]. Patients treated with OCS decreased during follow-up from 88.9% (n = 24/27) at baseline to 78.9% (n = 15/19) and 31.6% (n = 6/19) had an OCS dose reduction ≥ 50%. The difference in annual severe exacerbation rate during follow-up showed a significant reduction vs. baseline (2.12 per patient-year, 95% CI 0.99–3.24, p = 0.002). The differences in annual rate of non-scheduled primary care and specialist visits during follow-up indicated a significant decrease [2.28 per patient-year (95% CI 1.55–3.01; p < 0.001) and 1.47 per patient-year (95% CI 0.65–2.30; p = 0.004), respectively], as well as the difference in annual rate of number of emergency department visits [1.18 per patient-year (95% CI 0.51–1.85; p = 0.007)].ConclusionsThese results suggest that severe eosinophilic asthma patients receiving benralizumab, presented clinically meaningful improvement in asthma control and asthma-related QoL as well as OCS dose reduction. Results also aim to significant reductions in annual severe exacerbation rates, non-scheduled primary care and specialist visits, and emergency department visits rates.

Benefit–harm analysis of azithromycin for the prevention of acute exacerbations of chronic obstructive pulmonary disease

BackgroundLow-dose oral azithromycin therapy is recommended as a preventive treatment for acute exacerbations of COPD. However, the overall benefit–harm balance of this treatment has not been well studied.MethodsA probabilistic Markov...

Macrolides versus placebo for chronic asthma.

Macrolides versus placebo for chronic asthma.

Small airways targeted treatment with smart nebulizer technology could improve severe asthma in children: a retrospective analysis

Objective Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients ‘individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). Methods We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC — Sophia Children’s Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. Results Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). Conclusion Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment.

Inhaled Phosphodiesterase Inhibitors for the Treatment of Chronic Obstructive Pulmonary Disease.

Phosphodiesterase (PDE) 4 inhibitors prevent the metabolism of cyclic adenosine monophosphate, thereby reducing inflammation. Inhaled PDE4 inhibitors aim to restrict systemic drug exposure to enhance the potential for clinical benefits (in the lungs) versus adverse events (systemically). The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. CHF6001 is an inhaled PDE4 inhibitor, while inhaled ensifentrine is an inhibitor of both PDE3 and PDE4; antagonism of PDE3 facilitates smooth muscle relaxation and hence bronchodilation. These inhaled PDE inhibitors have both reported positive findings from early phase clinical trials, and have been well tolerated. Longer term trials are needed to firmly establish the clinical benefits of these drugs.

REAL-WORLD STUDY ON THE USE OF AZITHROMYCIN IN ASTHMA: EXPERIENCE FROM A DISTRICT TEACHING HOSPITAL

TOPIC: Allergy and Airway TYPE: Original Investigations PURPOSE: Asthma affects approximately 300 million people world-wide with the global burden of disease estimated to be 15 million disability-adjusted life-years. Azithromycin exhibits anti-inflammatory effects in addition to antibiotic properties. The British Thoracic Society guidelines recommends long-term macrolides use in adult asthmatics to reduce exacerbation rate. Azithromycin has been associated with side effects like prolonged QTc, ventricular arrhythmias, hearing impairment and diarrhoea. Real world studies are important for clinical decision making. This study aimed to determine if there is an improvement in the number exacerbations in asthmatic patients on long-term azithromycin in addition to other aspects of prescription METHODS: An observational study looking at 34 asthmatic patients on azithromycin was done. The patient data sets were anonymised and analysed on an Excel 2010 Spread sheet. Asthmatic patients aged 18 and over were included. This study excluded patients with non-tuberculosis mycobacterium, overlap conditions such as COPD and bronchiectasis, and patients on nebulised antibiotics or monoclonal antibodies.Data collected included: age, sex, respiratory diagnosis, co-morbidities, and immune status, number of infections and hospitalisations prior to and after staring azithromycin, lung function, corrected QT intervals, hearing issues, liver function test and gastrointestinal symptoms. RESULTS: 34 asthmatic patients (9 male, 25 female) with a median age of 58 (Range: 23-81) years were commenced on prophylactic azithromycin at the dose of 250mg Three times a week. The average BMI was 31.66 (S.D. 7.83). There were 8 smokers, 9 ex-smokers and 17 non-smokers. 7 patients were immunosuppressed. The dose prescribed was 250 mg three times a week. Mean duration was 39.83 (S.D. 24.04). Treatment was stopped in 13 patients: 7/13 for ineffectiveness, 4/13 for side effects (gastrointestinal problems 2/13 and hearing issues in 2/13), and 2/13 for other reasons not documented. Approximately 5.8 % hearing impairment exclusively due to azithromycin. Additionally, 2/34 patients (1 male, 1 female) had prolonged QTc before starting and 5/34 patients (3 female, 2 male) had prolonged QTc after starting azithromycin. No statistical significance (p>0.05) in the FEV1: FVC ratio before and after starting azithromycin. The average number of infections in the pre-treatment group was 6.44 (S.D. 2.80) versus 1.52 (S.D. 2.20) in the post azithromycin phase. The reduction in the number of infections and hospitalisations over the 12 months following treatment was significant with p<0.001 and p<0.034, respectively. 12/34 patients experienced a 100% reduction in the number of infections. Information on number of infections pre and post treatment were based on patients recalling and may pose a recall bias CONCLUSIONS: Long-term prophylactic azithromycin has been shown to correlate with a significant reduction the number of infections and hospitalisations in asthmatic patients. Our study did not show any lung function improvements with azithromycin use and the adverse effect hearing loss similar to previous studies of 5% CLINICAL IMPLICATIONS: Azithromycin is a safe and effective prophylactic drug in reducing exacerbations in this cohort of asthma patients our real world experience is in keeping with studies done so far DISCLOSURES: No relevant relationships by Hanan Ajay, source=Web Response No relevant relationships by Tanya Gordon, source=Web Response No relevant relationships by Nargis Khatoon, source=Web Response No relevant relationships by Aravind Ponnuswamy, source=Web Response

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial

IntroductionRecurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether...

Anti-Interleukin-5 in the Management of Eosinophilic Asthma: A Review of Effectiveness, Safety, and Budgetary Impact From the Perspective of the Brazilian Health System

ObjectivesTo evaluate the efficacy and safety of anti-interleukin-5 class therapy agents in the treatment of eosinophilic asthma and the financial impact of these drugs on the Brazilian and Mato Grosso public health systems. MethodsThe literature review in important databases was guided by a structured research question including patient or population, intervention, comparator, outcome and type of study. The retrieved studies went through a screening, selection, data extraction, and methodological quality assessment process. A model with two scenarios, one with mepolizumab and the other with benralizumab, was created for budget impact analysis. ResultsEvidence indicated that anti-interleukins-5 have an acceptable safety profile and can reduce exacerbation rates by up to 50% in the population with eosinophilic asthma; however, they showed no significant difference in quality of life. The adoption of these drugs in the Brazilian health system can impact the budget from R$ 40,379,731.50 to R$ 140,301,211.34 depending on the drug incorporated, considering a time horizon of 5 years. From the perspective of the state of Mato Grosso, the budget impact may reach, in the fifth year, an amount of R$ 1,301,210.58 and R$ 2,050.687.62 for the scenarios with mepolizumab and benralizumab, respectively. ConclusionAnti-interleukins-5 are promising treatments for eosinophilic asthma because they minimise exacerbations and are well tolerated and safe. The financial impact is large, implying that technology costs may be a barrier to accessing this treatment class.

The Benefit of Benralizumab Monoclonal Antibody Treatment for Severe Eosinophilic Asthma in a Case Series (Pulmonology Clinic Târgu Mureș, Romania)

Abstract Background: Monoclonal antibody therapy is currently an additional treatment option to reduce exacerbations and improve symptom control in patients with severe eosinophilic asthma (SEA) that is uncontrolled despite treatment with high-dose inhaled corticosteroids and long-acting beta-2 agonists. Benralizumab, a monoclonal antibody that binds to the interleukin-5 receptor (IL-5), significantly reduces symptoms and annual exacerbations, as well as the use of systemic corticosteroids in patients with SEA. However, few studies are available on the effectiveness of this biological treatment in real life. The aim of this case series was to evaluate the efficacy of benralizumab by analyzing changes in clinical parameters and blood eosinophils in patients with SEA. Methods: We analyzed four patients with SEA who started treatment with benralizumab. The history of symptoms and exacerbations, eosinophil counts, data regarding the oral corticosteroid dose, need for rescue treatment, spirometry measurements and asthma control questionnaires (ACT) regarding the level of asthma control were recorded. A positive response to treatment was defined by a significant reduction in eosinophil counts, increased ACT scores, and lower rates of exacerbations. Results and conclusions: Benralizumab monoclonal antibody was effective in all four patients. This was shown by a reduction in exacerbation rates, symptom severity, and lower dose of oral corticosteroids and rescue medication. This novel treatment was well tolerated by the analyzed patients, thus indicating that benralizumab is an attractive choice for patients due to eosinophilic count reduction as well as the less frequent dosing schedule. However, further studies are required, on larger populations.

Tezepelumab normalizes serum interleukin-5 and -13 levels in patients with severe, uncontrolled asthma

Asthma is a chronic, heterogeneous disease of the airways that involves a multitude of inflammatory processes triggered by various airborne stimuli. Thymic stromal lymphopoietin (TSLP)—an epithelial cell–derived cytokine produced in response to triggers such as allergens, viruses, or pollutants—has a central role in activating and maintaining downstream inflammatory processes in asthma.1 Tezepelumab is an anti-TSLP human monoclonal antibody. In the PATHWAY phase 2b (NCT02054130) and NAVIGATOR phase 3 (NCT03347279) studies, tezepelumab significantly reduced exacerbation rates vs placebo in patients with severe, uncontrolled asthma.

Efficacy of Roflumilast in Bronchiectasis Patients with Frequent Exacerbations: A Double-Blinded, Randomized, Placebo-Controlled Pilot Clinical Trial.

BackgroundBronchiectasis patients with neutrophilic airway inflammation develop symptoms of chronic cough, sputum production, and recurrent exacerbations. Roflumilast has anti-inflammatory actions via decreased neutrophilic airway inflammation. The effectiveness of roflumilast to reduce bronchiectasis exacerbation has never been evaluated.MethodsWe conducted a double-blinded, randomized, placebo-controlled trial. Our primary objective was to assess the effect of roflumilast compared with that of a placebo in reducing exacerbation rates in bronchiectasis patients. The secondary objectives were the changes in forced expiratory volume in 1 second (FEV1) and St. George’s Respiratory Questionnaire (SGRQ). Bronchiectasis patients older than 18 years who had had two exacerbations during the previous 12 months were randomly assigned to receive either 500 μg of either roflumilast or a placebo once daily for 6 months in a 1:1 ratio.ResultsForty bronchiectasis patients who had experienced exacerbations were screened. Thirty patients completed the study after 6 months of treatment: roflumilast group (n=15) and placebo group (n=15). The rates of exacerbations were 0.57 and 0.59 per patient in the roflumilast and placebo groups, respectively. Prebronchodilator FEV1 increased by 0.07 L from baseline in the roflumilast group and decreased by 0.015 L in the placebo group, but the difference was not significant. No significant differences were observed in the change of SGRQ scores between the roflumilast and placebo groups. Roflumilast had significant side effects, including loss of appetite and headache.ConclusionRoflumilast did not significantly affect the rate of exacerbations or quality of life. However, FEV1 tended to improve more in the roflumilast group than in the placebo group.

Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial

Genetic data implicate IL-33 in asthma susceptibility. Itepekimab, a monoclonal antibody targeting IL-33, demonstrated clinical activity in asthma, with potential in chronic obstructive pulmonary disease (COPD). In this study we first aimed to test the hypothesis that genetic variants in the IL-33 pathway were also associated with COPD. On the basis of the strong association of IL-33 pathway genes with pulmonary diseases like asthma and COPD, we conducted this phase 2a trial to assess the safety and efficacy of itepekimab in patients with moderate-to-severe COPD on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy. In this two-part study, genetic analyses of loss-of-function and gain-of-function variants in the IL-33 pathway, previously associated with asthma risk, were initially characterised for COPD. We then did a double-blind, phase 2a trial comparing itepekimab with placebo in patients with moderate-to-severe COPD despite standard therapy, at 83 study sites in ten countries. Patients aged 40-75 years who were current or former smokers, had been diagnosed with COPD for at least 1 year, and were on a stable regimen of triple-inhaled or double-inhaled background maintenance therapy, were randomly assigned (1:1) to receive itepekimab 300 mg or placebo, administered as two subcutaneous injections every 2 weeks for 24-52 weeks. The primary endpoint of the phase 2a trial was annualised rate of moderate-to-severe acute exacerbations of COPD during the treatment period. The key secondary outcome was change in prebronchodilator FEV1 from baseline to weeks 16-24. Prespecified subgroup analyses were done for each of the endpoints, including by smoking status. Efficacy and safety analyses were done in all participants who received at least one dose of assigned treatment (modified intention-to-treat population). This trial is registered at ClinicalTrials.gov (NCT03546907). Genetic analyses demonstrated association of loss of function in IL33 with reduced COPD risk, and gain of function in IL33 and IL1RL1 variants with increased risk. Subsequent to this, in the phase 2 trial, 343 patients were randomly assigned to placebo (n=171) or itepekimab (n=172) from July 16, 2018, to Feb 19, 2020. Annualised rates of acute exacerbations of COPD were 1·61 (95% CI 1·32-1·97) in the placebo group and 1·30 (1·05-1·61) in the itepekimab group (relative risk [RR] 0·81 [95% CI 0·61-1·07], p=0·13), and least squares mean prebronchodilator FEV1 change from baseline to weeks 16-24 was 0·0 L (SD 0·02) and 0·06 L (0·02; difference 0·06 L [95% CI 0·01-0·10], p=0·024). When analysis was restricted to former smokers, treatment with itepekimab was associated with nominally significant reductions in acute exacerbations of COPD (RR 0·58 [95% CI 0·39-0·85], p=0·0061) and FEV1 improvement (least squares mean difference 0·09 L [0·02-0·15], p=0·0076) compared with placebo. Current smokers treated with itepekimab showed no treatment benefit versus placebo for exacerbations (RR 1·09 [0·74-1·61], p=0·65) or FEV1 (least squares mean difference 0·02 [-0·05 to 0·09], p=0·54). Treatment-emergent adverse events (TEAEs) occurred in 135 (78%) patients in the itepekimab group and 136 (80%) in the placebo group. The most common TEAEs were nasopharyngitis (28 [16%] in the itepekimab group vs 29 [17%] in the placebo group), bronchitis (18 [10%] vs 14 [8%]), headache (14 [8%] vs 23 [13%]), and upper respiratory tract infection (13 [8%] vs 15 [9%]). The primary endpoint in the overall population was not met, subgroup analysis showed that itepekimab reduced exacerbation rate and improved lung function in former smokers with COPD. Two phase 3 clinical studies are ongoing to confirm the efficacy and safety profile of itepekimab in former smokers with COPD. Sanofi and Regeneron Pharmaceuticals.

Population Decline in COPD Admissions During the COVID-19 Pandemic Associated with Lower Burden of Community Respiratory Viral Infections

BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has led to widespread implementation of public health measures, such as stay-at-home orders, social distancing, and masking mandates. In addition to decreasing spread of severe acute respiratory syndrome coronavirus 2, these measures also impact the transmission of seasonal viral pathogens, which are common triggers of chronic obstructive pulmonary disease (COPD) exacerbations. Whether reduced viral prevalence mediates reduction in COPD exacerbation rates is unknown. MethodsWe performed retrospective analysis of data from a large, multicenter health care system to assess admission trends associated with community viral prevalence and with initiation of COVID-19 pandemic control measures. We applied difference-in-differences analysis to compare season-matched weekly frequency of hospital admissions for COPD prior to and after implementation of public health measures for COVID-19. Community viral prevalence was estimated using regional Centers for Disease Control and Prevention test positivity data and correlated to COPD admissions. ResultsData involving 4422 COPD admissions demonstrated a season-matched 53% decline in COPD admissions during the COVID-19 pandemic, which correlated to community viral burden (r = 0.73; 95% confidence interval, 0.67-0.78) and represented a 36% greater decline over admission frequencies observed in other medical conditions less affected by respiratory viral infections (incidence rate ratio 0.64; 95% confidence interval, 0.57-0.71, P < .001). The post-COVID-19 decline in COPD admissions was most pronounced in patients with fewer comorbidities and without recurrent admissions. ConclusionThe implementation of public health measures during the COVID-19 pandemic was associated with decreased COPD admissions. These changes are plausibly explained by reduced prevalence of seasonal respiratory viruses.

Exacerbation Rate Reduction With Mepolizumab Stratified by Maintenance Oral Corticosteroids Use and Eosinophil Levels: A Post Hoc Analysis of the DREAM and MENSA Studies.

Exacerbation Rate Reduction With Mepolizumab Stratified by Maintenance Oral Corticosteroids Use and Eosinophil Levels: A Post Hoc Analysis of the DREAM and MENSA Studies.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

A Single Inhaler Combining a Corticosteroid and Long-Acting Beta-2 Agonist for Maintenance with Additional Doses for Reliever Therapy (SMART): Obstacles for Asthma Patients in the USA.

Monoclonal antibodies in type 2 asthma: an updated network meta-analysis.

Novel treatments target eosinophilic inflammation in type 2 asthma. We aimed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate. PubMed and Embase were searched for phase II and phase III randomized clinical trials with monoclonal antibodies targeting key mediators of type 2-associated asthma between 2019 and 2021 to update our previous meta-analysis covering studies published from 2005 to 2018. Five-hundred and sixty six publications have been identified, of which six recent trials (on top of 30 previously identified) involving mepolizumab, benralizumab, reslizumab and dupilumab met our inclusion criteria. As no head-to-head trials were retrieved from literature, we performed an arm-based network meta-analysis including a total of 19 RCTs to compare effects on exacerbation rate between the different treatments. Benralizumab significantly reduced the risk of exacerbations compared to the pooled placebo in our network meta-analysis (median effect difference: -0.520, 95% CI [-1.010- -0.048]). No biologic showed superiority over the others in indirect comparisons. Large reductions in exacerbation rates were observed compared to placebo, though only benralizumab was sufficiently powered (N.=2564) to demonstrate significantly decreased exacerbation rates both in the overall population and in the subgroup analysis of IL-5 acting agents compared to placebo. Monoclonal antibodies have proven their benefit to reduce exacerbation rates in severe persistent eosinophilic asthma in the published trials. No biological showed superiority over the others emphasizing the need for clearly defined endotypes indicating those patients who will optimally benefit for each treatment.

Inhaled antibiotics for treatment of adults with non-cystic fibrosis bronchiectasis: A systematic review and meta-analysis

BackgroundInhaled antibiotics (IA) in non-cystic fibrosis bronchiectasis (NCFB) are recommended by some clinical practice guidelines for prevention or treatment of NCFB exacerbations. MethodsWe performed a systematic review and meta-analysis to evaluate the efficacy and safety of IA use for treatment of adults with NCFB and Pseudomonas aeruginosa chronic bronchial infection. The search was performed in the Cochrane Library, PubMed, and Web of Science databases from 2000 to 2019. Studies of IA for treatment of stable or exacerbated NCFB adults (≥18 years) with P. aeruginosa infection were considered eligible. PROSPERO Registration number: CRD42019136154. ResultsTwelve trials (2476 participants) were included. IA therapy increased P. aeruginosa eradication from sputum in patients with exacerbations (OR: 3.19, 95%CI: 1.70–5.99) with similar effects on stable patients (OR: 7.22, 95%CI: 2.81–18.59), and a trend to reduced emergence of new respiratory pathogens (OR: 0.58, 95%CI: 0.28–1.18). IA achieved significant reduced exacerbation rates (RR: 0.90; 95%CI: 0.82–0.98) in stable patients, with a number needed to treat (NNT) of 59, but no significant changes in FEV1, mortality, hospitalizations or quality of life were identified. In stable patients, IA use increased antimicrobial resistance (RR: 2.10, 95%CI: 1.35–3.27) at the end of therapy, with a number needed to treat of 6. ConclusionsIA therapy achieved a statistically significant eradication of P. aeruginosa from sputum, with a 10% reduction of exacerbations in stable patients. This effect has to be balanced with significant increases in antimicrobial resistance. Our meta-analysis failed to show a significant benefit in terms of patient-centered outcomes.

Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol Fumarate versus Other Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 μg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01703-z.

Seasonal variation in COPD exacerbation rates: budesonide/glycopyrronium/formoterol metered dose inhaler (BGF MDI) at two ICS dose levels in the ETHOS trial

Background: In the Phase III, 52-week ETHOS study (NCT02465567), BGF MDI triple fixed-dose combination, reduced moderate/severe COPD exacerbation rate vs dual therapies; however, rates are known to vary by season. Objective: To assess exacerbation rates by season in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 μg or 160/14.4/10 μg, glycopyrronium/formoterol (GFF) MDI 14.4/10 μg or budesonide/formoterol (BFF) MDI 320/10 μg twice-daily via a single Aerosphere inhaler. Annualised exacerbation rates were assessed using negative binomial regression. Results: In the mITT population (n=8509), 56.5% of patients had ≥2 exacerbations in the previous year. BGF MDI 320/14.4/10 µg and 160/14.4/10 µg reduced exacerbation rate vs GFF MDI and BFF MDI (Figure); rate ratios vs GFF MDI for winter, spring, summer and fall were 0.83, 0.77, 0.71, 0.77 and 0.82, 0.82, 0.81, 0.66, respectively (all p Conclusions: In patients with moderate-to-very severe COPD and an exacerbation history, seasonal variation in exacerbation rate occurred in each treatment group. A reduction in exacerbation rate was generally observed across all seasons for BGF MDI (both dose levels) vs LAMA/LABA and ICS/LABA.

Effect of compliance with GOLD treatment recommendations on COPD health care resource utilization, cost, and exacerbations among patients with COPD on maintenance therapy.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report for the management of chronic obstructive pulmonary disease (COPD) focuses on reducing existing symptoms, decreasing the risk of future exacerbations, and improving health status by recommending specific drug therapy based on exacerbation risk and symptoms. However, disparities exist between evidence-based recommendations and clinical practice. Research that quantifies the real-world effect of COPD regimen alignment with the GOLD recommendations on clinical and economic outcomes is needed. OBJECTIVE: To compare COPD-related health care resource utilization (HRU) and costs, as well as exacerbation rates, among patients with COPD on maintenance therapy based on 2017 GOLD treatment recommendation compliance status per GOLD ABCD risk group classification in a U.S. commercially insured/Medicare Advantage population. METHODS: This retrospective cohort study utilized administrative claims data in the HealthCore Integrated Research Database. The COPD population was identified using a previously validated claims-based predictive model. Among this population, patients with ≥ 1 claim for a COPD maintenance medication (earliest maintenance fill-date = index date) between January 1, 2014, and March 31, 2017, were identified. Patients were required to be aged ≥ 40 years, have ≥ 12 months of pre-index and ≥ 30 days of post-index health plan enrollment, with no diagnosis for asthma, cystic fibrosis, and/or lung cancer at any time from January 1, 2013, to March 31, 2018. Patients were categorized into exacerbation risk/symptomatology groups according to the 2017 GOLD ABCD assessment recommendations and were then classified into treatment-compliance status based on their maintenance therapy. Multivariable analyses were conducted to examine post-index COPD-related HRU, costs, and exacerbations by compliance status. RESULTS: The primary analytical study sample included 38,382 patients in the GOLD A/B group and 6,525 in the GOLD C/D group. Patients were further categorized into GOLD A (n = 19,345), B (n = 19,037), C (n = 1,865), and D (n = 4,670). GOLD-compliant regimens were observed in 32.9% of patients in the GOLD A/B group and in 58.9% of patients in the GOLD C/D group. Inhaled corticosteroid-containing regimens were the most commonly observed noncompliant regimen. Patients on compliant regimens had significantly fewer COPD-related inpatient and emergency department visits and therefore had significantly lower COPD-related medical costs in both the GOLD A/B and C/D cohorts. Similar results were observed for individual GOLD cohorts B, C, and D. These savings were offset by increased pharmacy expenditures. Being on GOLD guideline-compliant regimens significantly reduced the risk of exacerbation by 8% (hazard ratio [HR] = 0.92; P < 0.0001) in the GOLD A/B cohort and by 12% (HR = 0.88; P = 0.0005) in the GOLD C/D cohort, and was also associated with a significantly reduced exacerbation rate in the GOLD A/B (rate ratio [RR] = 0.93; P < 0.0001) and GOLD C/D (RR = 0.93; P = 0.0129) groups. CONCLUSIONS: This study suggests a continuing trend of high prevalence of suboptimal prescriber compliance to GOLD treatment recommendations. Treatment regimens compliant with GOLD recommendations were associated with improvement in exacerbations, reduced COPD-related HRU, and COPD-related medical cost offsets. DISCLOSURES: This study was funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. Palli and Shaikh are employees of BIPI. Willey is an employee of HealthCore, which was contracted by BIPI to conduct this study. Zhou was an employee of HealthCore at the time of study execution. Data were presented in part during an AMCP webinar (recording not made public) held in lieu of the Spring 2020 AMCP conference, which was canceled due to the COVID-19 pandemic.