A trial of beclomethasone/formoterol in COPD using EXACT-PRO to measure exacerbations

Combination inhalers containing corticosteroids and long acting beta agonists are used to reduce exacerbation rates in patients with severe COPD. The FORWARD (FOsteR 48-Week trial to reduce exAceRbations in COPD) clinical trial in severe COPD patients is a comparison of extrafine beclomethasone dipropionate and formoterol (BDP/F) in a combination inhaler with extrafine F ; the co-primary endpoints are exacerbation rates over 48 weeks and improvement in FEV1 over 12 weeks. The traditional physician diagnosis of exacerbations is a co-primary outcome, and the EXACT means of collecting patient-reported outcome (PRO) data is also being used to enhance the detection of exacerbation events. EXACT data is being collected using a novel application of a digital platform technology. FORWARD is therefore expected to provide information on the ability of EXACT to detect and measure exacerbations in a large clinical trial setting. The study design of FORWARD is described in this paper

Effect of Erdosteine on COPD Exacerbations in COPD Patients with Moderate Airflow Limitation

Background: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine - a muco-active antioxidant that modulates bacterial adhesiveness - reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear. Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV1] 50\u201279% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U-tests, or log rank tests. Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P=0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P=0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P=0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P<0.001) and the mean exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P<0.001). Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, exacerbations in patients with moderate COPD and a history of exacerbations

Tiotropium/Olodaterol Delays Clinically Important Deterioration Compared with Tiotropium Monotherapy in Patients with Early COPD:a Post Hoc Analysis of the TONADO® Trials

Introduction Since chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, a composite endpoint of clinically important deterioration (CID) may provide a more holistic assessment of treatment efficacy. We compared long-acting muscarinic antagonist/long-acting beta(2)-agonist combination therapy with tiotropium/olodaterol versus tiotropium alone using a composite endpoint for CID. CID was evaluated overall and in patients with low exacerbation history (at most one moderate exacerbation in the past year [not leading to hospitalisation]), Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2 patients and maintenance-naive patients with COPD. We assessed whether early treatment optimisation is more effective with tiotropium/olodaterol versus tiotropium in delaying and reducing the risk of CID. Methods Data were analysed from 2055 patients treated with either tiotropium/olodaterol 5/5 mu g or tiotropium 5 mu g (delivered via Respimat(R)) in two replicate, 52-week, parallel-group, double-blind studies (TONADO(R) 1/2). CID was defined as a decline of at least 0.1 L from baseline in trough forced expiratory volume in 1 s, increase from baseline of at least 4 units in St. George's Respiratory Questionnaire score, or moderate/severe exacerbation. Time to first occurrence of one of these events was recorded as time to first CID. Results Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P <0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P <0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P <0.0001) and maintenance-naive patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030). Conclusion In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naive patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy. PLAIN LANGUAGE SUMMARY COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called "clinically important deterioration" (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible

Metformin in severe exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial

Background Severe exacerbations of COPD are commonly associated with hyperglycaemia, which predicts adverse outcomes. Metformin is a well-established anti-hyperglycaemic agent in diabetes mellitus, possibly augmented with anti-inflammatory effects, but its effects in COPD are unknown. We investigated accelerated metformin therapy in severe COPD exacerbations, primarily to confirm or refute an anti-hyperglycaemic effect, and secondarily to explore its effects on inflammation and clinical outcome. Methods This was a multicentre, randomised, double-blind, placebo-controlled trial testing accelerated metformin therapy in non-diabetic patients, aged ≥35 years, hospitalised for COPD exacerbations. Participants were assigned in a 2:1 ratio to 1 month of metformin therapy, escalated rapidly to 2 g/day, or matched placebo. The primary end point was mean in-hospital blood glucose concentration. Secondary end points included the concentrations of fructosamine and C reactive protein (CRP), and scores on the COPD Assessment Test and Exacerbations of Chronic Pulmonary Disease Tool. Results 52 participants (mean (±SD) age 67±9 years) were randomised (34 to metformin, 18 to placebo). All were included in the primary end point analysis. The mean blood glucose concentrations in the metformin and placebo groups were 7.1±0.9 and 8.0±3.3 mmol/L, respectively (difference −0.9 mmol/L, 95% CI −2.1 to +0.3; p=0.273). No significant between-group differences were observed on any of the secondary end points. Adverse reactions, particularly gastrointestinal effects, were more common in metformin-treated participants. Conclusion Metformin did not ameliorate elevations in blood glucose concentration among non-diabetic patients admitted to hospital for COPD exacerbations, and had no detectable effect on CRP or clinical outcomes. Trial registration number ISRCTN66148745 and NCT01247870

The Effect of Maintenance Treatment with Erdosteine on Exacerbation Treatment and Health Status in Patients with COPD: A Post-Hoc Analysis of the RESTORE Dataset.

PurposeTo explore the effect of erdosteine on COPD exacerbations, health-related quality of life (HRQoL), and subjectively assessed COPD severity.Patients and methodsThis post-hoc analysis of the RESTORE study included participants with COPD and spirometrically moderate (GOLD 2; post-bronchodilator forced expiratory volume in 1 second [FEV1] 50‒79% predicted; n = 254), or severe airflow limitation (GOLD 3; post-bronchodilator FEV1 30‒49% predicted; n = 191) who received erdosteine 300 mg twice daily or placebo added to usual maintenance therapy for 12 months. Antibiotic and oral corticosteroid use was determined together with patient-reported HRQoL (St George's Respiratory Questionnaire, SGRQ). Patient and physician subjective COPD severity scores (scale 0‒4) were rated at baseline, 6 and 12 months. Data were analyzed using descriptive statistics for exacerbation severity, COPD severity, and treatment group. Comparisons between treatment groups used Student's t-tests or ANCOVA as appropriate.ResultsAmong GOLD 2 patients, 43 of 126 erdosteine-treated patients exacerbated (7 moderate-to-severe exacerbations), compared to 62 of 128 placebo-treated patients (14 moderate-to-severe exacerbations). Among those with moderate-to-severe exacerbations, erdosteine-treated patients had a shorter mean duration of corticosteroid treatment (11.4 days vs 13.3 days for placebo, P = 0.043), and fewer patients required antibiotic treatment with/without oral corticosteroids (71.4% vs 85.8% for placebo, P ConclusionAdding erdosteine to the usual maintenance therapy of COPD patients with moderate airflow limitation reduced the number of exacerbations, the duration of treatment with corticosteroids and the episodes requiring treatment with antibiotics. Additionally, treatment with erdosteine improved HRQoL and patient-reported disease severity

Metabolic Effects Associated with ICS in Patients with COPD and Comorbid Type 2 Diabetes: A Historical Matched Cohort Study

Background Management guidelines for chronic obstructive pulmonary disease (COPD) recommend that inhaled corticosteroids (ICS) are prescribed to patients with the most severe symptoms. However, these guidelines have not been widely implemented by physicians, leading to widespread use of ICS in patients with mild-to-moderate COPD. Of particular concern is the potential risk of worsening diabetic control associated with ICS use. Here we investigate whether ICS therapy in patients with COPD and comorbid type 2 diabetes mellitus (T2DM) has a negative impact on diabetic control, and whether these negative effects are dose-dependent. Methods and Findings This was a historical matched cohort study utilising primary care medical record data from two large UK databases. We selected patients aged >= 40 years with COPD and T2DM, prescribed ICS (n = 1360) or non-ICS therapy (n = 2642) between 2008 and 2012. The primary endpoint was change in HbA(1c) between the baseline and outcome periods. After 1:1 matching, each cohort consisted of 682 patients. Over the 12-18-month outcome period, patients prescribed ICS had significantly greater increases in HbA1c values compared with those prescribed non-ICS therapies; adjusted difference 0.16% (95% confidence interval [Cl]: 0.05-0.27%) in all COPD patients, and 0.25% (95% Cl: 0.10-0.40%) in mild-to-moderate COPD patients. Patients in the ICS cohort also had significantly more diabetes-related general practice visits per year and received more frequent glucose strip prescriptions, compared with those prescribed non-ICS therapies. Patients prescribed higher cumulative doses of ICS (> 250 mg) had greater odds of increased HbA(1c) and/or receiving additional antidiabetic medication, and increased odds of being above the Quality and Outcomes Framework (QOF) target for HbA1c levels, compared with those prescribed lower cumulative doses ( Conclusion For patients with COPD and comorbid T2DM, ICS therapy may have a negative impact on diabetes control. Patients prescribed higher cumulative doses of ICS may be at greater risk of diabetes progression

Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis

<p>Abstract</p> <p>Background</p> <p>International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency.</p> <p>Methods</p> <p>Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes.</p> <p>Results</p> <p>Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting β₂-agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.</p> <p>The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium.</p> <p>Conclusions</p> <p>Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present.</p

One-year treatment with mometasone furoate in chronic obstructive pulmonary disease

Many patients with chronic obstructive pulmonary disease (COPD) are treated with twice daily (BID) inhaled corticosteroids (ICS). This study evaluated whether daily PM mometasone furoate administered via a dry powder inhaler (MF-DPI) was equally effective compared to twice daily dosing

Targeting IL-1β and IL-17A driven inflammation during influenza-induced exacerbations of chronic lung inflammation.

For patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), exacerbations are life-threatening events causing acute respiratory distress that can even lead to hospitalization and death. Although a great deal of effort has been put into research of exacerbations and potential treatment options, the exact underlying mechanisms are yet to be deciphered and no therapy that effectively targets the excessive inflammation is available. In this study, we report that interleukin-1β (IL-1β) and interleukin-17A (IL-17A) are key mediators of neutrophilic inflammation in influenza-induced exacerbations of chronic lung inflammation. Using a mouse model of disease, our data shows a role for IL-1β in mediating lung dysfunction, and in driving neutrophilic inflammation during the whole phase of viral infection. We further report a role for IL-17A as a mediator of IL-1β induced neutrophilia at early time points during influenza-induced exacerbations. Blocking of IL-17A or IL-1 resulted in a significant abrogation of neutrophil recruitment to the airways in the initial phase of infection or at the peak of viral replication, respectively. Therefore, IL-17A and IL-1β are potential targets for therapeutic treatment of viral exacerbations of chronic lung inflammation