Helen Finnigan

Withdrawal of inhaled glucocorticoids and exacerbations of COPD.

BACKGROUND Treatment with inhaled glucocorticoids in combination with long-acting bronchodilators is recommended in patients with frequent exacerbations of severe chronic obstructive pulmonary disease (COPD). However, the benefit of inhaled glucocorticoids in addition to two long-acting bronchodilators has not been fully explored. METHODS In this 12-month, double-blind, parallel-group study, 2485 patients with a history of exacerbation of COPD received triple therapy consisting of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the inhaled glucocorticoid fluticasone propionate (500 μg twice daily) during a 6-week run-in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone in three steps over a 12-week period. The primary end point was the time to the first moderate or severe COPD exacerbation. Spirometric findings, health status, and dyspnea were also monitored. RESULTS As compared with continued glucocorticoid use, glucocorticoid withdrawal met the prespecified noninferiority criterion of 1.20 for the upper limit of the 95% confidence interval (CI) with respect to the first moderate or severe COPD exacerbation (hazard ratio, 1.06; 95% CI, 0.94 to 1.19). At week 18, when glucocorticoid withdrawal was complete, the adjusted mean reduction from baseline in the trough forced expiratory volume in 1 second was 38 ml greater in the glucocorticoid-withdrawal group than in the glucocorticoid-continuation group (P<0.001); a similar between-group difference (43 ml) was seen at week 52 (P=0.001). No change in dyspnea and minor changes in health status occurred in the glucocorticoid-withdrawal group. CONCLUSIONS In patients with severe COPD receiving tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar among those who discontinued inhaled glucocorticoids and those who continued glucocorticoid therapy. However, there was a greater decrease in lung function during the final step of glucocorticoid withdrawal. (Funded by Boehringer Ingelheim Pharma; WISDOM ClinicalTrials.gov number, NCT00975195.).

Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial

BACKGROUND Blood eosinophil counts might predict response to inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) and a history of exacerbations. We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn. METHODS WISDOM was a 12-month, randomised, parallel-group trial in which patients received 18 μg tiotropium, 100 μg salmeterol, and 1000 μg fluticasone propionate daily for 6 weeks and were then randomly assigned (1:1) electronically to receive either continued or reduced ICS over 12 weeks. We did a post-hoc analysis after complete ICS withdrawal (months 3-12) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels. The WISDOM trial is registered at ClinicalTrials.gov, number NCT00975195. FINDINGS In the 2296 patients receiving treatment after ICS withdrawal, moderate or severe exacerbation rate was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts (out of total white blood cell count) of 2% or greater (rate ratio 1·22 [95% CI 1·02-1·48]), 4% or greater (1·63 [1·19-2·24]), and 5% or greater (1·82 [1·20-2·76]). The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose, with significant treatment-by-subgroup interaction reached for 4% and 5% only. Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL, and mutually exclusive subgroups. INTERPRETATION Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations. Our data suggest that counts of 4% or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal, an effect not seen in most patients with eosinophil counts below these thresholds. FUNDING Boehringer Ingelheim.

A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma

Background Studies in adults and adolescents have demonstrated that tiotropium is efficacious as an add‐on therapy to inhaled corticosteroids (ICSs) with or without other maintenance therapies in patients with moderate or severe symptomatic asthma. Objective We sought to assess the efficacy and safety of once‐daily tiotropium Respimat add‐on therapy to high‐dose ICS with 1 or more controller medications, or medium‐dose ICS with 2 or more controller medications, in the first phase III trial of tiotropium in children with severe symptomatic asthma. Methods In this 12‐week, double‐blind, placebo‐controlled, parallel‐group trial, 401 participants aged 6 to 11 years were randomized to receive once‐daily tiotropium 5 &mgr;g (2 puffs of 2.5 &mgr;g) or 2.5 &mgr;g (2 puffs of 1.25 &mgr;g), or placebo (2 puffs), administered through the Respimat device as add‐on to background therapy. Results Compared with placebo, tiotropium 5 &mgr;g, but not 2.5 &mgr;g, add‐on therapy improved the primary end point, peak FEV1 within 3 hours after dosing (5 &mgr;g, 139 mL [95% CI, 75‐203; P < .001]; 2.5 &mgr;g, 35 mL [95% CI, −28 to 99; P = .27]), and the key secondary end point, trough FEV1 (5 &mgr;g, 87 mL [95% CI, 19‐154; P = .01]; 2.5 &mgr;g, 18 mL [95% CI, −48 to 85; P = .59]). The safety and tolerability of tiotropium were comparable with those of placebo. Conclusions Once‐daily tiotropium Respimat 5 &mgr;g improved lung function and was well tolerated as add‐on therapy to ICS with other maintenance therapies in children with severe symptomatic asthma. Graphical abstract Figure. No Caption available.

Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale

Long-acting bronchodilators in combination with inhaled corticosteroids (ICS) are recommended to decrease the risk of recurrent exacerbations in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3-4 chronic obstructive pulmonary disease (COPD). There is increasing concern about the clinical benefit and long-term safety of ICS use in COPD patients. The WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) study (NCT00975195) aims to evaluate the need for ICS use via stepwise withdrawal of ICS in COPD patients (GOLD 3-4 with a history of at least one exacerbation during the 12-month period prior to screening) receiving dual bronchodilation. During the 6-week run-in period, 2456 patients receive tiotropium 18 μg once daily, salmeterol 50 μg twice daily and fluticasone 500 μg twice daily. In a randomized, double-blind, parallel-group, active-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms and safety are also assessed. A sub-study aims to identify sub-populations and markers of steroid need. This study will determine the benefit of continued ICS therapy in combination with dual long-acting bronchodilators in COPD.

Eosinophilia, Frequent Exacerbations, and Steroid Response in Chronic Obstructive Pulmonary Disease

4 Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 5 Department of Metabolic Medicine, University of Modena & Reggio Emilia, Modena, Italy; 6 Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research (DZL), Grosshansdorf, Germany; 7 Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; 8 Department of Biostatistics and Data Sciences, Boehringer Ingelheim, Bracknell, UK

Lung-function changes over time following withdrawal of inhaled corticosteroids in patients with severe COPD

The combination of an inhaled long-acting β2-agonist with an inhaled corticosteroid (ICS) is widely used in the management of chronic obstructive pulmonary disease (COPD), primarily to prevent exacerbations [1]. Concerns about the increased risk of pneumonia, even with newer ICS [2], have generated interest in whether the ICS can be safely withdrawn from patients with COPD. We recently reported, in the WISDOM (Withdrawal of inhaled steroids during optimized bronchodilator management) study (clinicaltrials.gov identifier number: NCT00975195), that patients who continued treatment with a long-acting β2-agonist plus a long-acting muscarinic antagonist did not have an increased risk of exacerbations [3]. However, we observed a statistically significant difference in forced expiratory volume in 1 s (FEV1) after complete ICS withdrawal and at the end of the study in favour of continued ICS treatment. Decreased FEV1 after complete ICS withdrawal in severe COPD was not progressive and did not predict clinical changes http://ow.ly/TtYDV

A randomised, open-label phase II trial of afatinib versus cetuximab in patients with metastatic colorectal cancer

PURPOSE This randomised phase II trial aimed to compare efficacy of the irreversible ErbB family blocker, afatinib, with cetuximab in patients with KRAS wild-type metastatic colorectal adenocarcinoma (mCRC) with progression following oxaliplatin- and irinotecan-based regimens. Efficacy in patients with KRAS mutations was also evaluated. PATIENTS AND METHODS Patients with KRAS wild-type tumours were randomised 2:1 to afatinib (40 mg/day, increasing to 50 mg/day if minimal toxicity) or cetuximab weekly (400 mg/m2 loading dose, then 250 mg/m2/week) according to number of previous chemotherapy lines. All patients with KRAS-mutated tumours received afatinib. Primary end-points were objective response (OR) for the wild-type group and disease control for the KRAS-mutated group. Secondary end-points were progression-free survival (PFS) and overall survival (OS). RESULTS Patients with KRAS wild-type tumours (n=50) received afatinib (n=36) or cetuximab (n=14). Unconfirmed and confirmed ORs were 3% and 0% for afatinib versus 20% and 13% for cetuximab (odds ratio: 0.122 [P=0.0735] and <0.001, respectively). Median PFS was 46.0 and 144.5 days for afatinib and cetuximab, respectively. Median OS was 355 days with afatinib but not reached for cetuximab. In the KRAS-mutated group (n=41), five (12%) patients achieved confirmed disease control (stable disease; P=0.6394 [comparison versus 10%]); no ORs were reported. Median PFS and OS were 41.0 and 173days, respectively. Most frequent treatment-related adverse events were diarrhoea and rash across groups. CONCLUSIONS The efficacy of afatinib was inferior to cetuximab in patients with KRAS wild-type mCRC. In patients with KRAS-mutated tumours, disease control was modest with afatinib. Afatinib had a manageable safety profile.

Daily home-based spirometry during withdrawal of inhaled corticosteroid in severe to very severe chronic obstructive pulmonary disease

The WISDOM study (NCT00975195) reported a change in lung function following withdrawal of fluticasone propionate in patients with severe to very severe COPD treated with tiotropium and salmeterol. However, little is known about the validity of home-based spirometry measurements of lung function in COPD. Therefore, as part of this study, following suitable training, patients recorded daily home-based spirometry measurements in addition to undergoing periodic in-clinic spirometric testing throughout the study duration. We subsequently determined the validity of home-based spirometry for detecting changes in lung function by comparing in-clinic and home-based forced expiratory volume in 1 second in patients who underwent stepwise fluticasone propionate withdrawal over 12 weeks versus patients remaining on fluticasone propionate for 52 weeks. Bland–Altman analysis of these data confirmed good agreement between in-clinic and home-based measurements, both across all visits and at the individual visits at study weeks 6, 12, 18, and 52. There was a measurable difference between the forced expiratory volume in 1 second values recorded at home and in the clinic (mean difference of −0.05 L), which may be due to suboptimal patient effort in performing unsupervised recordings. However, this difference remained consistent over time. Overall, these data demonstrate that home-based and in-clinic spirometric measurements were equally valid and reliable for assessing lung function in patients with COPD, and suggest that home-based spirometry may be a useful tool to facilitate analysis of changes in lung function on a day-to-day basis.

Safety of tiotropium in pre-school children with symptomatic persistent asthma

Introduction and objectives Asthma is the most common chronic disease of childhood (GINA 2015). For pre-school children whose asthma symptoms are not well controlled on inhaled corticosteroids, limited options are available for further treatment. Here, we evaluated the safety of once-daily (QD) tiotropium Respimat® (tioR) in patients aged 1–5 years with symptomatic persistent asthma. Methods A Phase II/III, randomised, double-blind, placebo-controlled, parallel-group trial (NCT01634113) of tioR 5 μg, tioR 2.5 μg or placebo Respimat® (pboR), administered QD in the afternoon for 12 weeks, each as add-on to usual maintenance therapy. Safety data, including post hoc analysis of a composite exacerbation end point derived from adverse events (AEs), are reported. Results No AEs leading to treatment discontinuation or death were reported. The proportion of patients with any AEs was higher with pboR (73.5%) than with tioR 5 μg (58.1%) and 2.5 μg (55.6%). Two patients each in the tioR 5 μg (6.5%) and pboR (5.9%) groups were reported with drug-related AEs. Three patients, all in the pboR group, were reported with serious AEs. Asthma exacerbation/worsening was reported by fewer patients in the tioR 5 μg and tioR 2.5 μg groups compared with the pboR group (Table). Conclusion Once-daily tiotropium Respimat® add-on to maintenance therapy is well tolerated and may reduce exacerbations in pre-school children with symptomatic persistent asthma. Abstract P154 Table 1 Composite asthma endpoint: Asthma exacerbation (broad) with pneumonia plus asthma worsening Composite end pointMedDRA preferred terms Patients, n (%) Tiotropium Respimat® 5 µg QD (n = 31) Tiotropium Respimat® 2.5 µg QD (n = 36) Placebo Respimat® QD (n = 34) Asthma exacerbation (broad)/worsening + pneumonia 9 (29.0) 12 (33.3) 19 (55.9) Asthma 2 (6.5) 5 (13.9) 10 (29.4) Bronchitis 2 (6.5) 1 (2.8) 4 (11.8) Bronchopneumonia 0 0 1 (2.9) Cough 2 (6.5) 4 (11.1) 3 (8.8) Dyspnoea 1 (3.2) 0 0 Pneumonia 0 1 (2.8) 2 (5.9) Viral respiratory tract infection 3 (9.7) 3 (8.3) 4 (11.8) Wheezing 0 2 (5.6) 0 Treated set. Percentages calculated using total number of patients per treatment as denominator. AE preferred terms defined by Medical Dictionary for Regulatory Activities version 17.1. Please refer to page A272 for declarations of interest in relation to abstract P154.