Abstract
Rationale: Indacaterol is the first once-daily, long-acting inhaled β2-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).
Objectives: To demonstrate greater efficacy of indacaterol versus placebo on FEV1 at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks.
Measurements: Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 μg or placebo, or open-label tiotropium 18 μg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV1 at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.
Results: A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV1, 56% predicted; FEV1/FVC, 0.53) were randomized to the four treatment arms. Trough FEV1 at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P < 0.001 vs. placebo). At Week 26, for indacaterol 150/300 μg, respectively, versus placebo, TDI increased (1.00/1.18, P < 0.001) and SGRQ total score decreased (−3.3/−2.4, P < 0.01); corresponding results with tiotropium were 0.87 (P < 0.001) for TDI and (−1.0, P = not significant) for SGRQ total score. The incidence of adverse events, low serum potassium, high blood glucose, and prolonged QTc interval was similar across treatments.
Conclusions: Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD.
Clinical trial registered with clinicaltrials.gov (NCT 00463567).
Patients with chronic obstructive pulmonary disease (COPD) can benefit from regular treatment with long-acting bronchodilators. The once-daily anticholinergic bronchodilator tiotropium is an effective bronchodilator and is widely used for the maintenance therapy of COPD.
When the once-daily β2-agonist bronchodilator indacaterol was compared with tiotropium, both treatments were effective in providing 24-hour bronchodilation, and indacaterol was at least as effective as tiotropium in its effect on symptoms and health status. The availability of two once-daily bronchodilators with different modes of action may provide patients and physicians with more flexibility in treating COPD.
Indacaterol was previously evaluated for its bronchodilator effect and safety in early-phase studies of up to 4 weeks (8–10). The primary objective of this 26-week study was to compare indacaterol (150 and 300 μg once daily) with placebo in its effect on trough FEV1 (measured 24 h post dose) after 12 weeks of treatment. The key secondary aim was to demonstrate that indacaterol performed as well as tiotropium in its effect on trough FEV1. The safety of the treatments and their effects on a range of clinical outcomes were also evaluated. Some of the results of this study have been previously reported in abstract form (11–16).
More details are provided in the online supplement.
Patients aged 40 years or older with a smoking history of 20 pack-years or more and a diagnosis of moderate-to-severe COPD (17) were enrolled.
This study was performed in two stages in an adaptive seamless design (Figure 1). In stage 1, patients were randomized to receive indacaterol 75, 150, 300, or 600 μg once daily, formoterol 12 μg twice daily, or placebo, all double-blind, or open-label tiotropium 18 μg once daily. An independent committee used predefined efficacy criteria to select two indacaterol doses based on 2-week efficacy and safety data. As reported elsewhere, the two indacaterol doses selected were 150 and 300 μg (18). In stage 2, the four treatment groups were the two selected doses of indacaterol, tiotropium, and placebo. Treatment continued to 26 weeks, with additional patients recruited and randomized.
Patients received double-blind indacaterol 150 or 300 μg or placebo via single-dose dry powder inhaler, or open-label tiotropium 18 μg via HandiHaler (Boehringer Ingelheim, Ridgefield, CT). (Blinded tiotropium was not available.) Treatments were taken once daily at 08:00 to 10:00.
Spirometry was performed at each visit (19), and a subset of patients had more frequent measurements post dose (see Methods section in the online supplement). Dyspnea was assessed with the transition dyspnea index (TDI) (20), and health status was assessed with the St. George's Respiratory Questionnaire (SGRQ) (21). Patients used diary cards to record symptoms, albuterol use, peak expiratory flow (premedication) and adverse events. COPD exacerbations were defined as onset or worsening of one or more respiratory symptoms (dyspnea, cough, sputum purulence/volume, or wheeze) for 3 or more consecutive days, plus intensified treatment (e.g., systemic steroids, antibiotics, oxygen) and/or hospitalization or emergency room visit.
Adverse events and serious adverse events (including hospitalization and deaths) were collected, along with vital signs, ECGs including Fridericia's correction of QT interval (QTc interval), and the incidence of clinically notable laboratory values, including reduced serum potassium (<3.0 mmol/L) and elevated blood glucose (>9.99 mmol/L).
The primary objective was to test whether at least one indacaterol dose was more effective than placebo on 24 hours post-dose (trough) FEV1 (mean of 23 h 10 min and 23 h 45 min post-dose measurements) at Week 12 (the minimum period required for FEV1 as a primary endpoint for a pivotal registration study). The key secondary objective was to demonstrate noninferiority of at least one indacaterol dose to tiotropium for trough FEV1 at Week 12 (and, if met, to demonstrate superiority). Results out to 26 weeks were to evaluate continued efficacy, particularly clinical outcomes, and safety.
Efficacy was evaluated for the intention-to-treat population, comprising all randomized patients who received at least one dose of study drug. The safety population comprised all patients who received at least one dose of study drug.
Primary and key secondary objectives were analyzed by mixed model with treatment, smoking status, and country as fixed effects and baseline FEV1 and reversibility as covariates. Missing values at Week 12 were replaced with the previous value (from Week 2 or later).
Exploratory analysis of the primary variable was performed in subgroups according to baseline status of age less than 65 or greater than or equal to 65 years, smoking status (ex-smokers or current smokers), and ICS use. Changes in smoking status during study treatment were recorded but not quantified or used in the analysis. The time to first COPD exacerbation was analyzed by Cox regression model and exacerbation rates by Poisson regression model. Unless otherwise stated, efficacy data are given as least squares means with standard error (SE) or 95% confidence interval (CI).
Patients were recruited from 23 April 2007, with the last completing on 23 August 2008. The patients' characteristics at baseline are shown in Table 1. The disposition of patients during the study is shown in Figure E1 in the online supplement. Of 2,059 patients randomized into stages 1 and 2, 1,683 were involved in stage 2 and 1,291 (77%) completed the study (indacaterol 150 μg, 77%; indacaterol 300 μg, 82%; tiotropium, 79%; placebo, 69%). The subset of patients with additional spirometry measurements comprised 96, 102, 103, and 107 patients receiving indacaterol 150 μg or 300 μg, tiotropium, and placebo, respectively.
Indacaterol 150 μg | Indacaterol 300 μg | Tiotropium | Placebo | |
|---|---|---|---|---|
| n | 416 | 416 | 415 | 418 |
| Age, yr, mean (SD) | 63.4 (9.40) | 63.3 (9.32) | 64.0 (8.77) | 63.6 (8.92) |
| Male sex, n (%) | 259 (62.3) | 263 (63.2) | 269 (64.8) | 255 (61.0) |
| BMI, mean (SD) | 27.0 (6.25) | 26.7 (6.00) | 26.9 (6.33) | 26.3 (5.60) |
| ICS users, n (%) | 159 (38.2) | 155 (37.3) | 145 (34.9) | 165 (39.5) |
| Smoking history, pack-years, mean (SD) | 48.3 (23.42) | 50.8 (27.74) | 50.0 (25.07) | 49.7 (23.94) |
| FEV1, L, mean (SD)† | 1.52 (0.497) | 1.53 (0.521) | 1.45 (0.505) | 1.51 (0.490) |
| FEV1, % predicted, mean (SD)† | 56.1 (14.47) | 56.3 (14.50) | 53.9 (15.56) | 56.1 (14.27) |
| FEV1/FVC, %, mean (SD)† | 53.0 (9.97) | 52.6 (10.07) | 52.7 (10.14) | 53.4 (10.11) |
| Reversibility (β2-agonist), %, mean (SD)† | 15.6 (15.43) | 15.2 (15.44) | 15.6 (17.64) | 15.5 (18.03) |
| Reversibility (anticholinergic), %, mean (SD)‡ | 15.3 (15.37) | 15.9 (21.85) | 14.8 (16.05) | 15.9 (18.28) |
Treatment differences in trough (24-h post-dose) FEV1 at Day 2, Week 12, and Week 26 are shown in Table 2. At Week 12, the differences versus placebo were 180 ml for both indacaterol doses and 140 ml for tiotropium, all exceeding the prespecified minimum clinically important difference of 120 ml. The 40- to 50-ml differences between indacaterol and tiotropium were significant when tested for superiority (P ≤ 0.01) and noninferiority (P < 0.001). The effects of indacaterol and tiotropium on trough FEV1 were maintained over the course of the study, in terms of both difference from placebo (adjusted means from analysis of covariance; Table 2) and change from baseline (unadjusted means from summary statistics; Table E1).
Least Squares Mean ± SE (L) Placebo | Treatment Difference Vs Placebo (L): Least Squares Mean and 95% CI* | |||||
|---|---|---|---|---|---|---|
| Indacaterol 150 μg | Indacaterol 300 μg | Tiotropium | ||||
| Day 2 | 1.34 (0.011) | 0.11 (0.08, 0.13) | 0.14 (0.12, 0.16)‡ | 0.10 (0.07, 0.12) | ||
| n | 391 | 400 | 396 | 395 | ||
| Week 2 | 1.29 (0.013) | 0.17 (0.14, 0.20)† | 0.18 (0.15, 0.21)‡ | 0.14 (0.11, 0.17) | ||
| n | 377 | 389 | 391 | 393 | ||
| Week 12 | 1.28 (0.015) | 0.18 (0.14, 0.22)‡ | 0.18 (0.14, 0.22)‡ | 0.14 (0.10, 0.18) | ||
| n | 376 | 389 | 389 | 393 | ||
| Week 26 | 1.26 (0.017) | 0.16 (0.12, 0.19) | 0.18 (0.14, 0.22)† | 0.14 (0.10, 0.18) | ||
| n | 317 | 349 | 361 | 356 | ||
Results for Week 12 trough FEV1 in patient subgroups are shown in Figure 2. Indacaterol and tiotropium retained their effects relative to placebo at a similar level in each subgroup (all P < 0.001).
Figure 2. Trough FEV1 at 12 weeks: differences between active and placebo treatments in patient subgroups divided according to baseline status for age, smoking status, and inhaled corticosteroid (ICS) use. All contrasts versus placebo significant at P < 0.001. Indacaterol (both doses) was noninferior to tiotropium (P ≤ 0.005) in all subgroups.
[More] [Minimize]Serial measurements of FEV1 and FVC at Week 26 (in the subset of patients with 12-h serial spirometry) are depicted in Figure 3. At Week 26, peak FEV1 in this subset was increased by indacaterol 150 μg and 300 μg relative to placebo by 210 ml (95% CI, 130–280 ml) and 240 ml (95% CI, 170–320 ml), and by 180 ml (95% CI, 100–250 ml) with tiotropium (all P < 0.001 vs. placebo). These values corresponded to increases from baseline (unadjusted means) of 290 ml (22%), 330 ml (25%), and 250 ml (22%), respectively; the increase on placebo was 70 ml (5%). At Day 1 in the whole population, FEV1 at 5 minutes post dose was increased relative to placebo by 120 ml (95% CI, 100–140 ml) with both indacaterol doses and by 60 ml (95% CI, 30–80 ml) with tiotropium (all P < 0.001 vs. placebo and for indacaterol vs. tiotropium).
Figure 3. Serial measurements of (a) FEV1 and (b) FVC from −50 min to 23 hours 45 minutes post dose measured in subset with 12-hour serial spirometry at Week 26. Data are least squares means ± SE. Treatment differences for FEV1: P < 0.05 for indacaterol (both doses) and tiotropium versus placebo at all time points; P < 0.05 for indacaterol 300 μg versus tiotropium at −50, −15, and 5 minutes, 2 hours, 4 hours, and 23 hours 10 minutes. Treatment differences for FVC: P < 0.05 for indacaterol (both doses) and tiotropium versus placebo at all time points; P < 0.05 for indacaterol 300 μg versus 150 μg at 2 hours, 4 hours, 23 hours 10 minutes, and 24 hours 45 minutes.
[More] [Minimize]The TDI total score increased relative to placebo (P < 0.001) at all assessments with indacaterol and at Weeks 4, 12, and 16 with tiotropium, with differences between indacaterol 300 μg and tiotropium (P < 0.05) at Weeks 4, 8, and 12 (Figure 4a; Tables E3 and E4). Differences between indacaterol 300 μg and placebo were above the level of clinical importance (≥1 point) at all assessments (Table E3). The proportions of patients with a clinically important improvement from baseline (≥1) in TDI total score (22) followed a similar pattern and were highest with indacaterol 300 μg (P < 0.001 vs. placebo; P ≤ 0.01 vs. tiotropium) (Figure 4b; Table E4).
Figure 4. (a) transition dyspnea index (TDI) total score and (b) the proportions of patients with a clinically important improvement from baseline in TDI total score (≥ 1 point) (intention-to-treat population). Data for TDI total score are least squares means ± 95% confidence interval. **P < 0.01 and ***P < 0.001 versus placebo; †P < 0.05, ††P ≤ 0.01, and †††P < 0.001 versus tiotropium.
[More] [Minimize]Over the 26-week study, the use of as-needed albuterol was lower during active treatments than placebo, and lower with indacaterol than with tiotropium (Table 3). Table 3 also shows other symptom-based diary data and peak expiratory flow. SGRQ total scores were decreased (improved) relative to placebo with both doses of indacaterol at all assessments (P < 0.01) but not with tiotropium (Table E5). The proportions of patients with a clinically relevant improvement (≥4 points) in SGRQ total score followed a similar pattern (Table E6). Total and component health status scores at Week 26 are shown in Table 4.
Indacaterol 150 μg | Indacaterol 300 μg | Tiotropium | Placebo | |
|---|---|---|---|---|
| Change from baseline in mean daily number of puffs of as-needed albuterol | −1.5 (0.13)*† | −1.6 (0.13)*† | −1.0 (0.13)* | −0.4 (0.14) |
| % of days with no use of as-needed albuterol | 56.7 (1.97)*† | 57.8 (1.97)*† | 46.1 (1.96) | 41.8 (2.01) |
| Change from baseline in morning PEF, L/min | 30.8 (2.46)*† | 34.0 (2.44)*† | 19.8 (2.45)* | 3.0 (2.49) |
| Change from baseline in evening PEF, L/min | 31.2 (2.42)*‡ | 33.4 (2.42)*§ | 25.5 (2.42)* | 3.2 (2.46) |
| % of nights with no awakenings | 72.5 (1.49)‖ | 72.6 (1.49)‖ | 70.7 (1.48) | 67.5 (1.52) |
| % of days with no daytime symptoms | 11.8 (1.13)¶ | 11.7 (1.13)¶ | 10.6 (1.13) | 8.6 (1.15) |
| % of days able to perform usual activities | 48.7 (1.71)* | 49.6 (1.72)* | 46.8 (1.71)¶ | 41.6 (1.74) |
Least Squares Mean (SE) Placebo | Treatment Difference Vs. Placebo: Least Squares Mean (95% CI) | |||||
|---|---|---|---|---|---|---|
| Indacaterol 150 μg | Indacaterol 300 μg | Tiotropium | ||||
| n | 346 | 346 | 360 | 357 | ||
| Total score | 40.4 (0.79) | −3.3 (−5.1 to −1.5)*† | −2.4 (−4.2 to −0.6)‡ | −1.0 (−2.8 to 0.8) | ||
| Symptoms component | 49.0 (1.18) | −4.0 (−6.8 to −1.3)‡§ | −4.3 (−7.0 to −1.6)‡§ | −1.3 (−4.0 to 1.5) | ||
| Activity component | 56.7 (1.01) | −4.8 (−7.1 to −2.5)*§ | −3.1 (−5.3 to −0.8)‡ | −2.2 (−4.5 to 0.1) | ||
| Impacts component | 27.8 (0.85) | −2.3 (−4.3 to −0.3)‖§ | −1.5 (−3.5 to 0.4) | −0.2 (−2.2 to 1.8) | ||
Exacerbation-free rates at 6 months are presented in Table E7. Analysis of time to first COPD exacerbation showed a reduced risk relative to placebo for indacaterol 150 μg (hazard ratio 0.69 [95% CI, 0.51–0.94]; P = 0.019). Numerical reductions compared with placebo were observed for indacaterol 300 μg (0.74 [95% CI, 0.55–1.01]; P = 0.054) and tiotropium (0.76 [95% CI, 0.56–1.03]; P = 0.080). Similarly, the rate of exacerbations relative to placebo was lower for indacaterol 150 μg (rate ratio 0.67 [95% CI, 0.46–0.99]; P = 0.044) but not for indacaterol 300 μg (0.75 [95% CI, 0.51–1.08]; P = 0.125) or tiotropium (0.70 [95% CI, 0.48–1.03]; P = 0.070). Rates of exacerbations per year were 0.50, 0.53, 0.53, and 0.72 for indacaterol 150 μg, 300 μg, tiotropium, and placebo, respectively. With imputation for patients discontinuing prematurely, these rates increased to 0.95, 0.86, 0.93, and 1.33, respectively, whereas the rate ratios of exacerbations versus placebo remained similar but not statistically significant, at 0.71 (P = 0.185) for indacaterol 150 μg, 0.65 (P = 0.108) for indacaterol 300 μg, and 0.69 (P = 0.157) for tiotropium.
Table 5 shows adverse events and serious adverse events and the most common examples of each. Three patients died during study treatment (a sudden death with indacaterol 150 μg in a patient diagnosed with cardiac failure, a death due to an unspecified event secondary to arteriosclerosis, and another due to severe acute bronchopneumonia with tiotropium); none of the deaths was considered related to treatment by the investigators.
Indacaterol 150 μg | Indacaterol 300 μg | Tiotropium | Placebo | |
|---|---|---|---|---|
| n | 416 | 416 | 415 | 418 |
| Any adverse event | 277 (66.6) | 273 (65.6) | 279 (67.2) | 266 (63.6) |
| COPD worsening | 73 (17.5) | 76 (18.3) | 81 (19.5) | 91 (21.8) |
| Upper respiratory tract infection | 35 (8.4) | 27 (6.5) | 31 (7.5) | 31 (7.4) |
| Nasopharyngitis | 33 (7.9) | 39 (9.4) | 36 (8.7) | 36 (8.6) |
| Cough | 30 (7.2) | 30 (7.2) | 26 (6.3) | 28 (6.7) |
| Headache | 28 (6.7) | 18 (4.3) | 19 (4.6) | 14 (3.3) |
| Serious adverse events | 35 (8.4) | 32 (7.7) | 34 (8.2) | 35 (8.4) |
| COPD worsening | 11 (2.6) | 7 (1.7) | 7 (1.7) | 10 (2.4) |
| Pneumonia | 2 (0.5) | 3 (0.7) | 4 (1.0) | 4 (1.0) |
| Adverse events leading to discontinuation | 30 (7.2) | 24 (5.8) | 17 (4.1) | 45 (10.8) |
| COPD worsening | 7 (1.7) | 7 (1.7) | 2 (0.5) | 11 (2.6) |
Within the classification of cardiac disorders, the incidence of adverse events was 5.7% of patients for the two indacaterol doses combined and 5.6% for tiotropium, compared with 3.8% for placebo; these were serious in 1.7, 1.9, and 1.4% of patients and led to discontinuation of study treatment in 1.4, 1.0, and 1.4%, respectively. Of the adverse events that might be regarded as typical of their class, tremor was reported in 0.5% of patients in both indacaterol groups. Tachycardia was reported in 1.2 and 0.2% of patients in the indacaterol 150 and 300 μg groups, respectively, and in 1.4% of the tiotropium group and 0.7% of placebo. Dry mouth was reported in 4.6% of tiotropium patients and in 1.0 to 1.2% of the other three groups.
The rate of cough as an adverse event did not differ across the treatment groups (Table 5). Aside from this, investigators were asked to record any instances of cough occurring within 5 minutes of drug administration at clinic visits, regardless of whether they considered it to be an adverse event. This was observed in an average of 16.6 and 21.3% of patients per visit in the indacaterol 150 and 300 μg groups, in 0.8% of the tiotropium group, and in 2.4% of the placebo group. This cough typically started within 15 seconds of inhalation and had a median duration of 6 seconds. It was not associated with bronchospasm or with increased study discontinuation rates.
Incidences of clinically notable values for the indacaterol 150 μg, indacaterol 300 μg, tiotropium, and placebo groups, respectively, were 9.9, 7.5, 7.5, and 6.0% of patients with blood glucose greater than 9.99 mmol/L; 0.2, 0.5, 0.2, and 0.5% with serum potassium less than 3.0 mmol/L; and 0.2, 0.2, 0.5, and 0.7% with increases from baseline in QTc interval of greater than 60 milliseconds. Notably high values were observed for pulse rate (>130 bpm, or ≥120 plus ≥15 bpm increase from baseline) in 0 to 0.2% of patients, for systolic blood pressure (>200 mm Hg, or ≥180 and ≥20 mm Hg increase from baseline) in 1.2 to 1.7%, and for diastolic blood pressure (>115 mm Hg, or ≥105 and ≥15 mm Hg increase from baseline) in 0.7 to 1.7%.
This study is noteworthy in combining dose selection and efficacy evaluation in one major trial, and is to our knowledge unique in the respiratory field in this respect. The two-stage design provides a seamless experience for patients and trialists, makes efficient use of valuable patient resources and, by incorporating an interim analysis by independent statisticians and clinicians against preset efficacy criteria, provided a robust validation of the dose selection for efficacy evaluation in the second stage (18). The second stage of the study confirmed the bronchodilator efficacy of indacaterol compared with placebo. The statistically significant and clinically relevant effects on trough FEV1 at 24 hours post dose (180 ml above placebo at Week 12) (23) demonstrate the suitability of this agent for once-daily dosing. The 40- to 50-ml difference in trough FEV1 for indacaterol beyond that achieved with the established bronchodilator, tiotropium, is similar to the margin tiotropium has previously achieved over twice-daily β2-agonists (4, 7). Any additional improvement in FEV1 in the early morning is potentially beneficial, this being a time when lung function is at its lowest in COPD (24) and patients are most limited by their disease (25). Indacaterol maintained its bronchodilator efficacy over time, as also observed elsewhere (26), with efficacy (in terms of the primary endpoint) retained in subgroups of patients divided according to baseline age, ICS use, and smoking status. The fast onset of action of indacaterol on initial dosing may help patients feel an immediate symptomatic benefit (27). Both indacaterol doses improved dyspnea (TDI) by margins over placebo that were generally close to the 1-point difference regarded as clinically relevant (22), although the indacaterol 300-μg dose was the only treatment that consistently exceeded this threshold. The improvement in dyspnea may be explained by reduced hyperinflation, which in turn may allow patients greater activity and improved health status (28, 29). To support this hypothesis, it would have been useful if this study had assessed treatment effects on inspiratory capacity. Recent reports that indacaterol increased inspiratory capacity at rest (30) and during exercise, in association with increased exercise endurance and reduced dyspnea (31), provide indirect support. For health status, the likelihood of patients achieving a clinically relevant change was greatest with indacaterol, although none of the active treatments met the 4-point difference in mean SGRQ score versus placebo that is regarded as clinically relevant (32). It is rare for a 4-point difference to be obtained in placebo-controlled studies of drug treatments (but not pulmonary rehabilitation or lung volume reduction surgery).
Usually, studies of 1 year or longer are required to show an effect on exacerbations, but the indacaterol 150-μg dose was associated with a statistically significant improvement over placebo in the time to first exacerbation and rate of exacerbations despite the relatively short duration of this study. The indacaterol 300-μg dose and tiotropium showed a trend toward reduced exacerbations but did not reach statistical significance relative to placebo. The study was not powered for exacerbations, so this lack of statistical significance is not surprising, especially in view of the low overall rate of exacerbations in the study (annual exacerbation rate of 0.72 in the placebo arm of this study, compared with 1.13 reported elsewhere (33, 34)). It should be noted that a history of repeated exacerbations was not required for study entry. However, the way in which exacerbations were defined in this study means that some episodes could have been missed, either through incomplete diary card reporting or, conceivably, through rapid resolution of symptoms (although a definition based on a combination of symptoms and resource use was believed to be both conservative and appropriate). More meaningful conclusions regarding an effect on exacerbations are expected from future longer-term studies with indacaterol in patients with a history of more frequent exacerbations.
There was an approximately 10% higher rate of dropout of placebo patients compared with other groups, with a larger proportion of placebo dropouts due to adverse events, withdrawal of consent, or lack of therapeutic effect. The high placebo dropout rate is typical for COPD studies (3, 33). The resulting loss of patient numbers over the course of the study (data could only be carried forward for a specified period) and the higher rate of placebo dropouts could have reduced the power to detect differences between treatments at Week 26, and it is therefore of note that the results were similar with or without imputation.
The design of this study was limited by the inability to blind the tiotropium treatment, raising the possibility of bias in comparing the indacaterol results with those of tiotropium. Given the difficulties in blinding tiotropium, double-dummy blinded comparisons are being conducted (35). The effect of tiotropium on trough FEV1 (140 ml vs. placebo) in this study was very close to previously reported differences (140 ml or 120–150 ml vs. placebo) in studies using blinded tiotropium (4, 36, 37). Effects of tiotropium on dyspnea (0.4–0.9 vs. placebo) were similar to or a little lower than previous reports (0.8–1.0 vs. placebo) (4, 37).
Additionally, because the efficacy outcomes (other than the primary and key secondary endpoints) were analyzed without allowances for multiplicity, it cannot be excluded that apparently significant differences have arisen by chance, with a 5 in 100 chance of a spurious positive finding for any comparison. However, the consistency in these results over time and the magnitude of the uncontrolled P values in showing the greater efficacy of indacaterol and tiotropium over placebo, with indacaterol performing at least as well as tiotropium, argue that these are very unlikely to be purely random findings. Despite the limitations, we believe the results of this study provide a strong indication that indacaterol has beneficial effects on clinical outcomes compared with placebo and is at least as effective as tiotropium.
The overall incidence of adverse events and the most commonly occurring adverse events were similar across the treatment groups, including placebo. Respiratory tract infections and respiratory events, as might be expected for a population of patients with COPD, were the most common type of adverse events, serious events, and those leading to withdrawal of study treatment. Other than these, headache was the most commonly reported adverse event. Most cases (89%) of headache during indacaterol treatment were mild or moderate, and none was serious, although it resulted in discontinuation for one patient in the indacaterol 150 μg group. Tremor, a typical side effect of β2-adrenoceptor agonists, was rarely reported. Tachycardia was more commonly reported with the lower dose of indacaterol and with tiotropium but the incidence of serious adverse cardiac events was similar across the treatment groups, and there were very few notable QTc interval increases with either indacaterol or tiotropium. Other work has demonstrated a low arrhythmogenic potential for indacaterol (38). Results for blood glucose and serum potassium show that indacaterol had little impact on known β2-adrenoceptor–mediated systemic effects, and there were no marked differences between groups in vital signs. The safety results with the 300-μg dose of indacaterol showed no increase in adverse events or worsening of other safety variables compared with the lower dose.
Investigators were specifically asked to observe if patients coughed after inhaling their study treatment. This was observed in up to one-fifth of patients taking indacaterol. However, the cough did not reduce the efficacy of indacaterol. In a preplanned analysis of trough FEV1 at 12 weeks, the change from baseline in trough FEV1 was similar between the groups of patients with and without cough after inhalation (changes from baseline of, respectively, 120 and 130 ml with the 150-μg dose, and 150 and 150 ml with the 300-μg dose). The underlying mechanism of this cough after inhalation is unknown, but it did not appear bothersome to patients because it did not result in discontinuation, nor did it present any safety concerns. As an adverse event, cough was reported at a similar level for indacaterol and placebo patients (7.2 and 6.7%, respectively).
In conclusion, once-daily indacaterol provides clinically and statistically significant bronchodilation compared with placebo at 24 hours post dose after 12 weeks of treatment, demonstrating its suitability for once-daily dosing. Relative to tiotropium, the effect on trough FEV1 met prespecified requirements for statistical noninferiority. Although other comparisons in this study were not controlled for multiplicity, the consistent order of treatment effect and the magnitude of the uncontrolled P values when indacaterol and open-label tiotropium were compared provide evidence that this new bronchodilator is likely to be at least as effective as tiotropium for bronchodilation and other clinical outcomes, such as dyspnea and health status.
The authors thank the patients and staff at the participating centers in the study. Sarah Filcek of ACUMED wrote the first draft of the manuscript and coordinated input from authors into subsequent drafts. This support was funded by Novartis. David Young of Novartis reviewed the manuscript.
| 1. | Global initiative for chronic obstructive lung disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease (accessed September, 2009). Updated 2009. Available from www.goldcopd.com. |
| 2. | Barr RG, Bourbeau J, Camargo CA, Ram FS. Tiotropium for stable chronic obstructive pulmonary disease: a meta-analysis. Thorax 2006;61:854–862. [Published erratum appears in Thorax 2007;62:191.] |
| 3. | Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543–1554. |
| 4. | Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ Jr, Kesten S, Towse L. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002;122:47–55. |
| 5. | Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399–404. (Erratum in: Thorax 2005;60:105). |
| 6. | Vogelmeier C, Kardos P, Harari S, Gans SJ, Stenglein S, Thirlwell J. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Respir Med 2008;102:1511–1520. |
| 7. | van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B, Mueller A, Cornelissen PJ. Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005;26:214–222. |
| 8. | Rennard S, Bantje T, Centanni S, Chanez P, Chuchalin A, D'Urzo A, Kornmann O, Perry S, Jack D, Owen R, et al. A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison. Respir Med 2008;102:1033–1044. |
| 9. | Beier J, Chanez P, Martinot JB, Schreurs AJ, Tkácová R, Bao W, Jack D, Higgins M. Safety, tolerability and efficacy of indacaterol, a novel once-daily beta(2)-agonist, in patients with COPD: a 28-day randomised, placebo controlled clinical trial. Pulm Pharmacol Ther 2007;20:740–749. |
| 10. | Bauwens O, Ninane V, Van de Maele B, Firth R, Dong F, Owen R, Higgins M. 24-hour bronchodilator efficacy of single doses of indacaterol in subjects with COPD: comparison with placebo and formoterol. Curr Med Res Opin 2009;25:463–470. |
| 11. | Fogarty C, Worth H, Hebert J, Iqbal A, Owen R, Higgins M, Kramer B. Sustained 24-h bronchodilation with indacaterol once-daily in COPD: a 26-week efficacy and safety study [abstract]. Am J Respir Crit Care Med 2009;179:A4547. |
| 12. | Fogarty C, Hebert J, Iqbal A, Owen R, Kramer B, Higgins M. Indacaterol once-daily provides effective 24-h bronchodilation in COPD patients: a 26-week evaluation vs placebo and tiotropium [abstract]. Eur Respir J 2009;34:2025. |
| 13. | Lötvall J, Cosio BG, Iqbal A, Swales J, Owen R, Kramer B, Higgins M. Indacaterol once-daily improves day and night-time symptom control in COPD patients: a 26-week study versus placebo and tiotropium [abstract]. Eur Respir J 2009;34:2029. |
| 14. | Yorgancioğlu A, Mahler D, Iqbal A, Owen R, Higgins M, Kramer B. Indacaterol once-daily improves health-related quality of life in COPD patients: a 26-week comparison with placebo and tiotropium [abstract]. Eur Respir J 2009;34:2028. |
| 15. | Mahler D, Palange P, Iqbal A, Owen R, Higgins M, Kramer B. Indacaterol once-daily improves dyspnoea in COPD patients: a 26-week placebo-controlled study with open-label tiotropium comparison [abstract]. Eur Respir J 2009;34:E4360. |
| 16. | Worth H, Kleerup E, Iqbal A, Owen R, Higgins M, Kramer B. Safety and tolerability of indacaterol once-daily in COPD patients versus placebo and tiotropium: a 26-week study [abstract]. Eur Respir J 2009;34:2030. |
| 17. | Global Initiative for chronic obstructive lung disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease [updated 2005; accessed 2009 24 February]. Available from www.goldcopd.com. |
| 18. | Barnes PJ, Pocock SJ, Magnussen H, Iqbal A, Kramer B, Higgins M, Lawrence D. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther 2010;23:165–171. |
| 19. | Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al.; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005;26:319–338. |
| 20. | Mahler DA, Weinberg DH, Wells CK, Feinstein AR. The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984;85:751–758. |
| 21. | Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327. |
| 22. | Witek TJ Jr, Mahler DA. Minimal important difference of the transition dyspnoea index in a multinational clinical trial. Eur Respir J 2003;21:267–272. |
| 23. | Cazzola M, MacNee W, Martinez FJ, Rabe KF, Franciosi LG, Barnes PJ, Brusasco V, Burge PS, Calverley PM, Celli BR, et al.; American Thoracic Society. European Respiratory Society Task Force on outcomes of COPD. Outcomes for COPD pharmacological trials: from lung function to biomarkers. Eur Respir J 2008;31:416–469. |
| 24. | Calverley PM, Lee A, Towse L, van Noord J, Witek TJ, Kelsen S. Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease. Thorax 2003;58:855–860. |
| 25. | Partridge MR, Karlsson N, Small IR. Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin 2009;25:2043–2048. |
| 26. | Dahl R, Kolman P, Jack D, Owen R, Kramer B, Higgins M. Indacaterol once-daily provides sustained 24-h bronchodilation over 52 weeks of treatment in COPD [abstract]. Am J Respir Crit Care Med 2009;179:A4545. |
| 27. | Donohue JF. Minimal clinically important differences in COPD lung function. COPD 2005;2:111–124. |
| 28. | Cooper CB. Airflow obstruction and exercise. Respir Med 2009;103:325–334. |
| 29. | Hanania NA, Donohue JF. Pharmacologic interventions in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2007;4:526–534. |
| 30. | Beier J, Beeh KM, Brookman L, Peachey G, Hmissi A, Pascoe S. Bronchodilator effects of indacaterol and formoterol in patients with COPD. Pulm Pharmacol Ther 2009;22:492–496. |
| 31. | Beeh KM, Khindri S, Eeg M, Drollman AF. Effect of indacaterol maleate on dynamic lung hyperinflation in patients with COPD [abstract]. Eur Respir J 2009;34:4357. |
| 32. | Jones PW. St. George's Respiratory Questionnaire: MCID. COPD 2005;2:75–79. |
| 33. | Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775–789. |
| 34. | Vestbo J, Hurst J, Muellerova H, Locantore N, Wedzicha J, Anzueto A. One-year exacerbation frequency and treatment in the ECLIPSE study cohort [abstract P3464]. Eur Respir J 2009;34:604s. |
| 35. | Vogelmeier C, Ramos-Barbon D, Jack D, Piggott S, Owen R, Higgins M, Kramer B. Once-daily indacaterol provides effective 24-hour bronchodilation in COPD: a double-blind comparison with tiotropium [abstract]. Chest 2009;136:4S-g–5S-g. |
| 36. | Casaburi R, Briggs DD Jr, Donohue JF, Serby CW, Menjoge SS, Witek TJ Jr. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Chest 2000;118:1294–1302. |
| 37. | Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, Menjoge SS, Serby CW, Witek T Jr. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19:217–224. |
| 38. | Khindri S, Sabo R, Harris S, Jennings S, Drollmann AF. A thorough QT study on the effect of indacaterol on cardiac safety in healthy subjects [abstract]. Am J Respir Crit Care Med 2009;179:A2463. |
