Efficacy and safety of indacaterol 150 μg once-daily in COPD: a double-blind, randomised, 12-week study

Abstract

BackgroundIndacaterol is a novel, once-daily (o.d.) inhaled, long-acting β2-agonist in development for chronic obstructive pulmonary disease (COPD). This 12-week, double-blind study compared the efficacy, safety, and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD.MethodsEfficacy variables included 24-h trough FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose) at Week 12 (primary endpoint) and after Day 1, and the percentage of COPD days with poor control (i.e., worsening symptoms). Safety was assessed by adverse events (AEs), mean serum potassium and blood glucose, QTc (Fridericia), and vital signs.ResultsPatients were randomised (n = 416, mean age 63 years) to receive either indacaterol 150 μg o.d. (n = 211) or placebo (n = 205) via a single-dose dry-powder inhaler; 87.5% completed the study. Trough FEV1 (LSM ± SEM) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo, a clinically relevant difference of 130 ± 24 mL (p < 0.001). Trough FEV1 after one dose was significantly higher with indacaterol than placebo (p < 0.001). Indacaterol demonstrated significantly higher peak FEV1 than placebo, both on Day 1 and at Week 12, with indacaterol-placebo differences (LSM ± SEM) of 190 ± 28 (p < 0.001) and 160 ± 28 mL (p < 0.001), respectively. Standardised AUC measurements for FEV1 (between 5 min and 4 h, 5 min and 1 h, and 1 and 4 h post-dose) at Week 12 were all significantly greater with indacaterol than placebo (p < 0.001), with LSM (± SEM) differences of 170 ± 24, 180 ± 24, and 170 ± 24 mL, respectively. Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5% (p < 0.001) and was also associated with significantly reduced use of rescue medication (p < 0.001). The overall rates of AEs were comparable between the groups (indacaterol 49.3%, placebo 46.8%), with the most common AEs being COPD worsening (indacaterol 8.5%, placebo 12.2%) and cough (indacaterol 6.2%, placebo 7.3%). One patient died in the placebo group. Serum potassium and blood glucose levels did not differ significantly between the two groups, and no patient had QTc >500 ms.ConclusionsIndacaterol 150 μg o.d. provided clinically significant and sustained bronchodilation, reduced rescue medication use, and had a safety and tolerability profile similar to placebo.Trial registrationNCT00624286

Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD

“…Previous study results provided an assumed treatment difference (indacaterol-tiotropium) of 40 mL for trough FEV1 at week 12 [2], with a standard deviation of 225 mL [2,11,12]. A sample size of 666 evaluable patients per treatment group was needed to detect this difference as statistically significant at the 5% level (two-sided) with 90% power.…”

Cardiovascular safety of new inhaled medications for asthma and chronic obstructive pulmonary disease: a critical review from pharmacist perspective

“…40 The incidence of tachycardia and tremor were found to be infrequent (2%), whereas the incidence of QTc prolongation was observed in up to 3.3% (vs. 2.0% in placebo group) of subjects, but they were not deemed to be clinically significant (<500 ms). 15,52,54,55 The study by Kerwin EM et al observed no difference in pulse and QTc intervals, but reported significant lowering in diastolic BP among subjects from the 300 mcg indacaterol group. 54 Increases in blood glucose were also observed during clinical trials.…”

“…However, most studies showed no change in potassium levels during beta-2 agonist treatment, whereas other studies observed small changes but no mention of its relationship with cardiovascular events. 51,[53][54][55] An earlier semi-open label study has reported a decrease in serum potassium levels in ~5% of subjects treated with LABAs, but no statistically significant difference was observed in laboratory values, ECG and vital signs. 38 In addition, one study has found that serum potassium and glucose levels were slightly increased without reaching significance, and incidences of other AEs were lower in the treatment group.…”

“…15,40,49,51,53,54 Additionally, regular daily dosing was not found associated with loss in efficacy or potential beta-2 adrenoceptor down-regulation. 55 A 12-week trial has demonstrated that indacaterol is non-inferior to tiotropium. 15 Furthermore, patients reported immediate symptom relief due to the fast onset of action, which can contribute to better compliance.…”

“…40 Cough was a common AE observed in up to 30% of subjects, but most studies demonstrated no statistically significant increase in cardiovascular AEs among study subjects. 15,40,41,51,[53][54][55] However, manufacturer's warnings of systemic effects included: increased HR, blood pressure (BP), and ECG changes, including flattening of T wave, QTc prolongation and ST segment depression. 15 Although only a small fraction of subjects were involved, incidences of cardiac AEs were reported in some of the studies.…”