Changing patterns in long-acting bronchodilator trials in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Developments in the understanding of COPD have led to standard guidelines for diagnosis, treatment, and spirometry assessments, which have in turn influenced trial designs and inclusion criteria. Substantial clinical evidence has been gained from clinical trials and supports a positive approach to COPD management. However, there appear to be changing trends in recent trials. Large bronchodilator studies have reported lower improvements in trough forced expiratory volume in 1 second (FEV1) values versus placebo than were observed in earlier studies, while the rate of FEV1 decline seems to be lower in more recent trials. In addition, recent evidence has called into question the usefulness of bronchodilator reversibility testing as a trial inclusion criterion. Baseline patient populations and use of concomitant medications have also changed over recent years due to increased treatment options. The impact of these many variables on clinical trial results is explored, with a particular focus on changes in inclusion criteria and patient baseline demographics

A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease

Peer reviewedPublisher PD

A retrospective study of two populations to test a simple rule for spirometry

Abstract Background Chronic lung disease is common and often under-diagnosed. Methods To test a simple rule for conducting spirometry we reviewed spirograms from two populations, occupational medicine evaluations (OME) conducted by Saint Louis and Wake Forest Universities at 3 sites (n = 3260, mean age 64.14 years, 95 % CI 58.94–69.34, 97 % men) and conducted by Wake Forest University preop clinic (POC) at one site (n = 845, mean age 62.10 years, 95 % CI 50.46–73.74, 57 % men). This retrospective review of database information that the first author collected prospectively identified rates, types, sensitivity, specificity and positive and negative predictive value for lung function abnormalities and associated mortality rate found when conducting spirometry based on the 20/40 rule (≥20 years of smoking in those aged ≥ 40 years) in the OME population. To determine the reproducibility of the 20/40 rule for conducting spirometry, the rule was applied to the POC population. Results A lung function abnormality was found in 74 % of the OME population and 67 % of the POC population. Sensitivity of the rule was 85 % for an obstructive pattern and 77 % for any abnormality on spirometry. Positive and negative predictive values of the rule for a spirometric abnormality were 74 and 55 %, respectively. Patients with an obstructive pattern were at greater risk of coronary heart disease (odds ratio (OR) 1.39 [confidence interval (CI) 1.00–1.93] vs. normal) and death (hazard ratio (HR) 1.53, 95 % CI 1.20–1.84) than subjects with normal spirometry. Restricted spirometry patterns were also associated with greater risk of coronary disease (odds ratio (OR) 1.7 [CI 1.23–2.35]) and death (Hazard ratio 1.40, 95 % CI 1.08–1.72). Conclusions Smokers (≥ 20 pack years) age ≥ 40 years are at an increased risk for lung function abnormalities and those abnormalities are associated with greater presence of coronary heart disease and increased all-cause mortality. Use of the 20/40 rule could provide a simple method to enhance selection of candidates for spirometry evaluation in the primary care setting

Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and health care expenditure worldwide. Relaxation of airway smooth muscle with inhaled bronchodilators is the cornerstone of treatment for stable COPD, with inhaled corticosteroids reserved for those with a history of exacerbations. Tiotropium has occupied center stage in COPD treatment for over 10 years and improves lung function, quality of life, exercise endurance, and reduces the risk of COPD exacerbation. Long-acting β2-agonists (LABAs) improve lung function, reduce dynamic hyperinflation, increase exercise tolerance, health-related quality of life, and reduce acute exacerbation of COPD. The combination of long-acting muscarinic antagonists (LAMAs) and LABAs is thought to leverage different pathways to induce bronchodilation using submaximal drug doses, increasing the benefits and minimizing receptor-specific side effects. Umeclidinium/vilanterol is the first combination of LAMA/LABA to be approved for use in stable COPD in USA and Europe. Additionally, indacaterol/glycopyrronium and aclidinium/formoterol have been approved in Europe and in numerous locations outside USA. Several other agents are in the late stages of development, most of which offer once-daily dosing. The benefits of new LAMA/LABA combinations include improved pulmonary function, dyspnea, and health-related quality of life, and in some cases, reduced exacerbations. These evolving treatments will provide new opportunities and challenges in the management of COPD

Clinical trial design in chronic obstructive pulmonary disease: current perspectives and considerations with regard to blinding of tiotropium

Abstract Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open-label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting β2-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non-blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George’s Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy

Clinical trial design in chronic obstructive pulmonary disease: current perspectives and considerations with regard to blinding of tiotropium

Randomised, double-blind, controlled trials are considered the gold standard for evaluating a pharmacological agent, as they minimise any potential bias. However, it is not always possible to perform double-blind trials, particularly for medications delivered via specific devices, e.g. inhalers. In such cases, open-label studies can be employed instead. Methods used to minimise any potential bias introduced by open-label study design include randomisation, crossover study design, and objective measurements of primary efficacy and safety variables. Concise reviews analysing the effect of blinding procedures of comparator drugs on outcomes in respiratory trials are limited. Here, we compare data from different chronic obstructive pulmonary disease trials with once-daily indacaterol versus a blinded or non-blinded comparator. The clinical trial programme for indacaterol, a once-daily, long-acting β2-agonist, used tiotropium as a comparator either in an open-label or blinded fashion. Data from these studies showed that the effects of tiotropium were consistent for forced expiratory volume in 1 second, an objective measure, across blinded and non-blinded studies. The data were consistent with previous studies of double-blind tiotropium, suggesting that the open-label use of tiotropium did not introduce treatment bias. The effect of tiotropium on subjective measures (St George’s Respiratory Questionnaire; transition dyspnoea index) varied slightly across blinded and non-blinded studies, indicating that minimal bias was introduced by using open-label tiotropium. Importantly, the studies used randomised, open-label tiotropium patients to treatment allocation, a method shown to minimise bias to a greater degree than blinding. In conclusion, it is important when reporting a clinical trial to be transparent about who was blinded and how the blinding was performed; if the design is open-label, additional efforts must be made to minimise risk of bias. If these recommendations are followed, and the data are considered in the full knowledge of any potential sources of bias, results with tiotropium suggest that data from open-label studies can provide valuable and credible evidence of the effects of therapy

Inhaler Devices for Delivery of LABA/LAMA Fixed-Dose Combinations in Patients with COPD

Published 13th March 2019. Issue Date June 2019. Funding. The preparation of this manuscript was funded by Novartis Pharma AG. No funding or sponsorship was recieved for the publication of this article. Medical Writing and Editorial Assistance The authors thank David Prefontaine, PhD and Rahul Lad, PhD (Novartis), and Praveen Kaul, PhD for providing medical writing and editorial support, which was funded by Novartis Pharma AG in accordance with Good Publication Practice (GPP3) guidelines.Peer reviewedPublisher PD

Indacaterol vs tiotropium in COPD patients classified as GOLD A and B

SummaryIntroductionAccording to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two.MethodsIn this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1 s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use.ResultsIn ‘GOLD A’ patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05 L; rescue medication use −0.41 puffs/day; TDI total score 0.94 points; SGRQ total score −3.13 units, all p < 0.01). In ‘GOLD B, no ICS’ patients, compared with tiotropium, indacaterol treatment increased trough FEV1 (0.055 L, p < 0.05) and permitted a larger reduction in rescue medication use (−0.81 puffs/day, p = 0.004). In all patients, and in patients not using ICS, differences favored indacaterol for all variables.ConclusionsOur findings suggest that patients in GOLD groups A and B may experience greater benefits with indacaterol than with tiotropium