David Young

Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study

BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months. METHODS In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 μg) or tiotropium (18 μg) once-daily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728. FINDINGS Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 difference between the groups was -0.011 L (least squares mean with indacaterol [n=1450] 1.134 L [SE 0.008] vs tiotropium [n=1467] 1.145 L [0.008]; one-sided 97.5% CI lower limit -0.026 L; p<0.0001). The lower limit of the 97.5% CI was above the prespecified non-inferiority margin of -0.055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44). In the safety set, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718 patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients). Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 [43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147 [9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients). INTERPRETATION Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines. FUNDING Novartis Pharma AG.

INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD

The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol (INSTEAD) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease (COPD) exacerbations from salmeterol/fluticasone (SFC; inhaled corticosteroid (ICS) regimen) to indacaterol monotherapy (non-ICS regimen). This 26-week, double-blind, double-dummy, parallel-group, phase IV study, randomised 581 patients with moderate COPD to indacaterol 150 μg once daily or SFC 50/500 μg twice daily. Patients had been receiving SFC 50/500 μg for ≥3 months, with no COPD exacerbations for more than a year before the study (patients for whom ICS is not recommended). The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough forced expiratory volume in 1 second (FEV1) after 12 weeks (non-inferiority margin of 0.06 L). The primary objective was met, with a mean treatment difference of 9 mL (95% CI -45–26 mL). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George’s Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. Safety profiles of both treatments were as expected. This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 μg with no efficacy loss. Moderate COPD patients can switch from salmeterol/fluticasone to indacaterol with no efficacy loss http://ow.ly/CkkDp

Sustained 24-hour efficacy of once daily indacaterol (300 μg) in patients with chronic obstructive pulmonary disease: a randomized, crossover study.

PURPOSE Indacaterol is a novel, once daily, inhaled ultra-long-acting β₂-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Here we compared the 24-h spirometry profile of once daily indacaterol 300 μg with that of placebo and twice daily salmeterol 50 μg in patients with COPD. METHODS This randomized, multicenter, placebo-controlled, crossover study comprised three 14-day treatment periods (with 14-day washouts). Patients (male/female ≥ 40 years) with moderate-to-severe COPD were randomized to receive double-blind indacaterol 300 μg or placebo once daily, or open-label salmeterol 50 μg twice daily. The primary outcome measure was 24-h post-dose (trough) FEV₁ (mean of FEV₁ at 23 h 10 min and 23 h 45 min post-indacaterol dose) after 14 days. FEV₁ was assessed at multiple time points on Days 1 and 14 of each treatment period. Safety and tolerability were also monitored. RESULTS Of 68 randomized patients, 61 completed. Trough FEV₁ (primary endpoint) on Day 14 for indacaterol was 200 mL higher than placebo (p < 0.001), exceeding the prespecified minimum clinically important difference (120 mL), and was 90 mL higher than for salmeterol (p = 0.011). After Day 1, trough FEV(1) for indacaterol was 150 mL higher than placebo (p < 0.001). Indacaterol provided superior bronchodilation compared with placebo (p < 0.001) across the full 24-h assessment period on Days 1 and 14. In addition, on both days, indacaterol provided superior FEV₁ compared with salmeterol (p < 0.05) at many post-baseline time points, including 5 min post-dose. All treatments were well tolerated. CONCLUSIONS Once daily indacaterol 300 μg produced effective sustained 24-h bronchodilation from the first dose, an efficacy profile superior to placebo and twice daily salmeterol. Given its effective bronchodilation with once daily dosing, indacaterol is likely to be a useful treatment option for patients with moderate-to-severe COPD.

Breathlessness or Health Status in Chronic Obstructive Pulmonary Disease: The Impact of Different Definitions

Abstract Objective: The GOLD 2011 report recommends the use of symptoms, exacerbation history, and FEV1% predicted to categorise patients into groups A–D. We investigated the choice of mMRC or CAT on category assignment and characterization of the categories. Methods: Patients were prospectively recruited from tertiary hospitals in China, as part of the INTACT study, with a prior diagnosis of COPD. The GOLD categories were defined using mMRC and CAT, along with exacerbations in the previous year, and FEV1% predicted. Results: 1,465 patients were included. The most prevalent group was group D. However, proportions of patients categorised into groups A to D differed depending on symptom instruments. The use of CAT resulted in more patients being placed into groups B and D. Cardiac co-morbid conditions, particularly ischaemic heart disease, heart failure, and arrhythmia were highly prevalent in groups B and D. Group B appeared to have a similar burden of cardiac co-morbidities to group D, in spite of a higher FEV1 level. Although mMRC assigned a smaller proportion of patients to groups B and D, the patients it did assign had a higher burden of cardiac co-morbidities than patients assigned by CAT. When patients were assessed according to LLN, 14.2% had normal airflow according to ECSC 1993 equations, with 12.6% having normal airflow according to GLI 2012 formulae. Conclusions: The choice of symptom assessment is one potential confounder impacting the patient assignment. Breathlessness may be an important marker of overall disease severity, indicating the presence of cardiac co-morbidities in the GOLD categories.

Monotherapy with indacaterol once daily reduces the rate of exacerbations in patients with moderate-to-severe COPD: Post-hoc pooled analysis of 6 months data from three large phase III trials

BACKGROUND In patients with COPD, exacerbations are associated with poor quality of life and may shorten survival. Prevention of exacerbations is, therefore, a key objective in COPD management. Indacaterol, a once-daily ultra-long-acting β2-agonist, has been shown to reduce exacerbations in various studies. This pooled analysis evaluated the effect of indacaterol on exacerbations versus placebo. METHODS Six-month data were pooled from three randomized, double-blind, and placebo-controlled studies: indacaterol 300 μg versus placebo (1 year); indacaterol 150 μg and 300 μg versus placebo (6 months); and indacaterol 150 μg versus placebo (6 months). All treatments were administered once daily. Data from other treatment groups were excluded. All three studies enrolled patients aged ≥40 years with moderate-to-severe COPD and smoking history ≥20 pack-years. Time to exacerbation and exacerbation rate were analyzed. RESULTS Overall, the pooled data set included 2716 patients (indacaterol 150 μg [n = 746], indacaterol 300 μg [n = 819], placebo [n = 1151]). Both indacaterol doses 150 and 300 μg significantly reduced the COPD exacerbation rates compared with placebo (Rate ratios, RR [95% Confidence Interval, CI]: 0.69 [0.55-0.87], 0.71 [95% CI: 0.57-0.88] respectively; both p = 0.002). Over 6 months, indacaterol 150 and 300 μg also significantly prolonged the time to first moderate-to-severe exacerbation versus placebo (Hazard ratios, HR [95% CI]: 0.74: [0.59-0.93], p = 0.009; 0.73 [0.59-0.90], p = 0.004, respectively). At months 3 and 6, clinically relevant improvements in lung function versus placebo were observed with indacaterol 150 μg (Least squares mean treatment differences: Month 3 = 170 mL; Month 6 = 160 mL) and 300 μg (170 mL at both time-points; all p < 0.001). CONCLUSIONS In this pooled analysis, both indacaterol doses, 150 and 300 μg, were associated with significant reductions in exacerbations and significant improvements in bronchodilation versus placebo. The results suggest once-daily indacaterol is an effective treatment option for providing sustained bronchodilation and preventing exacerbations in patients with COPD.

The revised GOLD 2017 COPD categorization in relation to comorbidities

INTRODUCTION The COPD classification proposed by the Global Initiative for Obstructive Lung Disease was recently revised, and the A to D grouping is now based on symptoms and exacerbations only. Potential associations with comorbidities have not been assessed so far. Thus the aim of the present study was to determine the relationship between the revised (2017) GOLD groups A-D and major comorbidities. METHODS We used baseline data from the COPD cohort COSYCONET. Comorbidities were identified from patient self-reports and disease-specific medication: gastrointestinal disorders, asthma, sleep apnea, hyperuricemia, hyperlipidemia, diabetes, osteoporosis, mental disorders, heart failure, hypertension, coronary artery disease. The A-D groups were based on either the COPD Assessment Test or the modified Medical Research Council scale. Exacerbations were also categorized as per GOLD recommendations. RESULTS Data from 2228 patients were analyzed. Using GOLD group A as a reference, group D was associated with nearly all comorbidities, followed by group B and C. When groups A-D were dichotomized as AC vs. BD (symptoms) and AB vs. CD (exacerbations), all comorbidities correlated with symptoms and/or exacerbations. This was true for both mMRC- and CAT-based categorizations. CONCLUSIONS These findings suggest that the recently modified GOLD categorization is clinically relevant beyond being purely an assessment of symptoms and exacerbations. As the A-D groups correlated with the risk of important comorbidities, with some differences in terms of the correlation with symptoms and exacerbations, the findings underline the importance of identifying comorbidities in COPD, particularly in non-responders to therapy who have high symptoms and/or exacerbation rates.

The impact of treatment with indacaterol in patients with COPD: A post-hoc analysis according to GOLD 2011 categories A to D

BACKGROUND Indacaterol is an inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). We report on the effectiveness of indacaterol and other bronchodilators compared with placebo in patients across the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 categories A to D. METHODS A post-hoc, subgroup pooled analysis of 6-month efficacy data from three randomized, placebo-controlled, parallel-group studies involving 3862 patients was performed across GOLD 2011 categories A to D, according to baseline forced expiratory volume in 1 s (FEV1) % predicted, modified Medical Research Council (mMRC) dyspnea scale, and exacerbation history in the 12 months prior to entry. Efficacy of once-daily indacaterol 150 and 300 μg, open-label tiotropium 18 μg, twice-daily salmeterol 50 μg, and formoterol 12 μg was compared with placebo. End points analysed were trough FEV1, transition dyspnea index (TDI), and St Georges Respiratory Questionnaire (SGRQ) total score, all at Week 26, and mean rescue medication use over 26 weeks. RESULTS Indacaterol 150 and 300 μg significantly improved FEV1, compared with placebo across all GOLD groups. Indacaterol 150 and 300 μg also significantly improved TDI, SGRQ total score, and mean rescue medication use compared with placebo across most GOLD subgroups. CONCLUSIONS Treatment selection according to patients symptoms as well as lung function is an important consideration in maintenance treatment of COPD. Indacaterol 150 and 300 μg effectively improved lung function and symptoms in patients across all GOLD 2011 categories.

The History and Performance of the Breezhaler Device

The device used for marketed indacaterol maleate is a single-dose dry powder inhaler (SDDPI) known as the Onbrez® Breezhaler®. The device was designed such that patients receive immediate feedback that the dose has been taken correctly, as they can hear a distinctive ‘whirring’ noise on correct inhalation, can check that the clear capsule is empty, and most will feel the lactose excipient against the back of their throats.