Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease Indacaterol Versus Tiotropium

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1 Once-Daily Bronchodilators for Chronic Obstructive Pulmonary Disease Indacaterol Versus Tiotropium James F. Donohue 1, Charles Fogarty 2, Jan Lötvall 3, Donald A. Mahler 4, Heinrich Worth 5, Arzu Yorgancioğlu 6, Amir Iqbal 7, James Swales 7, Roger Owen 7, Mark Higgins 7, and Benjamin Kramer 8, for the INHANCE* Study Investigators 1 Division of Pulmonary and Critical Care Medicine, University of North Carolina, Chapel Hill, North Carolina; 2 Spartanburg Medical Research, Spartanburg, South Carolina; 3 Sahlgrenska Academy, Göteborg University, Göteborg, Sweden; 4 Section of Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 5 Medical Department I, Klinikum der Stadt, Fuerth, Germany; 6 Department of Pulmonology, Celal Bayar University, Manisa, Turkey; 7 Novartis Horsham Research Centre, Horsham, West Sussex, United Kingdom; and 8 Respiratory Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey Rationale: Indacaterol is the first once-daily, long-acting inhaled b 2 - agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD). Objectives: To demonstrate greater efficacy of indacaterol versus placebo on FEV 1 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 mg or placebo, or open-label tiotropium 18 mg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV 1 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 FEV 1, 56% predicted; FEV 1 /FVC, 0.53) were randomized to the four treatment arms. Trough FEV 1 at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P, vs. placebo). At Week 26, for indacaterol 150/300 mg, respectively, versus placebo, TDI increased (1.00/1.18, P, 0.001) and SGRQ total score decreased (23.3/22.4, P, 0.01); corresponding results with tiotropium were 0.87 (P, 0.001) for TDI and (21.0, P 5 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 ). Keywords: COPD; long-acting b 2 -agonists; bronchodilator agents; clinical trial Current guidelines recommend regular treatment with longacting inhaled bronchodilators for patients with symptomatic moderate and severe chronic obstructive pulmonary disease (COPD), with the addition of inhaled corticosteroids (ICS) for (Received in original form October 8, 2009; accepted in final form May 11, 2010) Supported by Novartis Pharma AG. A.I., J.S., R.O., M.H., and B.K. are employees of Novartis. * INdacaterol [versus tiotropium] to Help Achieve New COPD treatment Excellence. Correspondence and requests for reprints should be addressed to James F. Donohue, M.D., University of North Carolina, 4125 BioInformatics Building, 130 Mason Farm Road, CB 7020, Chapel Hill, NC. james_donohue@med.unc. edu This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 182. pp , 2010 Originally Published in Press as DOI: /rccm OC on June 3, 2010 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Patients with chronic obstructive pulmonary disease (COPD) can benefit from regular treatment with longacting bronchodilators. The once-daily anticholinergic bronchodilator tiotropium is an effective bronchodilator and is widely used for the maintenance therapy of COPD. What This Study Adds to the Field When the once-daily b 2 -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 oncedaily bronchodilators with different modes of action may provide patients and physicians with more flexibility in treating COPD. those patients with severe disease who experience repeated exacerbations (1). Currently available long-acting inhaled bronchodilators are the once-daily anticholinergic tiotropium and the twice-daily long-acting b 2 -agonists, formoterol and salmeterol. Tiotropium is a widely used and effective treatment (2, 3), and has generally been shown to provide better bronchodilation and clinical outcomes than the twice-daily b 2 -agonists (4 7). The development of the once-daily b 2 -agonist indacaterol provides the opportunity to compare the effects of two once-daily bronchodilators with different mechanisms of action. 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 mg once daily) with placebo in its effect on trough FEV 1 (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 FEV 1. 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). METHODS More details are provided in the online supplement. Patients 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.

2 156 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 1. Schematic of study design. Study Design 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 mg once daily, formoterol 12 mg twice daily, or placebo, all double-blind, or open-label tiotropium 18 mg 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 mg (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. Study Medications Patients received double-blind indacaterol 150 or 300 mg or placebo via single-dose dry powder inhaler, or open-label tiotropium 18 mg via HandiHaler (Boehringer Ingelheim, Ridgefield, CT). (Blinded tiotropium was not available.) Treatments were taken once daily at 08:00 to 10:00. Assessments 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). Objectives The primary objective was to test whether at least one indacaterol dose was more effective than placebo on 24 hours post-dose (trough) FEV 1 (mean of 23 h 10 min and 23 h 45 min post-dose measurements) at Week 12 (the minimum period required for FEV 1 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 FEV 1 at Week 12 (and, if met, to demonstrate superiority). Results out to 26 weeks were to evaluate continued efficacy, particularly clinical outcomes, and safety. Statistical Methods 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. TABLE 1. PATIENTS CHARACTERISTICS AT BASELINE Indacaterol 150 mg Indacaterol 300 mg Tiotropium Placebo n 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) FEV 1, L, mean (SD) 1.52 (0.497) 1.53 (0.521) 1.45 (0.505) 1.51 (0.490) FEV 1, % predicted, mean (SD) 56.1 (14.47) 56.3 (14.50) 53.9 (15.56) 56.1 (14.27) FEV 1 /FVC, %, mean (SD) 53.0 (9.97) 52.6 (10.07) 52.7 (10.14) 53.4 (10.11) Reversibility (b 2 -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) Definition of abbreviations: BMI 5 body mass index; ICS 5 inhaled corticosteroid. * COPD severity based on Global Initiative for Chronic Obstructive Lung Disease 2005 criteria. Measured 30 minutes after albuterol 360 mg inhalation. Measured 1 hour after ipratropium 42 mg inhalation.

3 Donohue, Fogarty, Lötvall, et al.: Indacaterol Versus Tiotropium for COPD 157 TABLE 2. DIFFERENCES BETWEEN ACTIVE AND PLACEBO TREATMENTS IN EFFECT ON TROUGH FEV 1 Least Squares Treatment Difference Vs Placebo (L): Least Squares Mean and 95% CI* Mean 6 SE (L) Placebo Indacaterol 150 mg Indacaterol 300 mg Tiotropium Day (0.011) 0.11 (0.08, 0.13) 0.14 (0.12, 0.16) 0.10 (0.07, 0.12) n Week (0.013) 0.17 (0.14, 0.20) 0.18 (0.15, 0.21) 0.14 (0.11, 0.17) n Week (0.015) 0.18 (0.14, 0.22) 0.18 (0.14, 0.22) 0.14 (0.10, 0.18) n Week (0.017) 0.16 (0.12, 0.19) 0.18 (0.14, 0.22) 0.14 (0.10, 0.18) n Definition of abbreviation: CI 5 confidence interval. * Week 12 CIs are 98.75%. All treatment differences versus placebo significant for superiority at P, Both indacaterol doses significant for noninferiority versus tiotropium at P, P, P < 0.01 for superiority comparison versus tiotropium. Primary and key secondary objectives were analyzed by mixed model with treatment, smoking status, and country as fixed effects and baseline FEV 1 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). RESULTS Patients were recruited from 23 April 2007, with the last completing on 23 August 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 mg, 77%; indacaterol 300 mg, 82%; tiotropium, 79%; placebo, 69%). The subset of patients with additional spirometry measurements comprised 96, 102, 103, and 107 patients receiving indacaterol 150 mg or 300 mg, tiotropium, and placebo, respectively. Spirometry Treatment differences in trough (24-h post-dose) FEV 1 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 FEV 1 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). Results for Week 12 trough FEV 1 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). Serial measurements of FEV 1 and FVC at Week 26 (in the subset of patients with 12-h serial spirometry) are depicted in Figure 3. At Week 26, peak FEV 1 in this subset was increased by indacaterol 150 mg and 300 mg relative to placebo by 210 ml (95% CI, ml) and 240 ml (95% CI, ml), and by 180 ml (95% CI, ml) with tiotropium (all P, 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, FEV 1 at 5 minutes post dose was increased relative to placebo by 120 ml (95% CI, ml) with both indacaterol doses and by 60 ml (95% CI, ml) with tiotropium (all P, vs. placebo and for indacaterol vs. tiotropium). Other Efficacy Data 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 mg and tiotropium (P, 0.05) at Weeks 4, 8, and 12 (Figure 4a; Tables E3 and E4). Differences between indacaterol 300 mg and Figure 2. Trough FEV 1 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, Indacaterol (both doses) was noninferior to tiotropium (P < 0.005) in all subgroups.

4 158 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL Figure 3. Serial measurements of (a) FEV 1 and (b) FVC from 250 min to 23 hours 45 minutes post dose measured in subset with 12-hour serial spirometry at Week 26. Data are least squares means 6 SE. Treatment differences for FEV 1 : P, 0.05 for indacaterol (both doses) and tiotropium versus placebo at all time points; P, 0.05 for indacaterol 300 mg versus tiotropium at 250, 215, 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 mg versus150mg at 2 hours, 4 hours, 23 hours 10 minutes, and 24 hours 45 minutes. 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 mg (P, vs. placebo; P < 0.01 vs. tiotropium) (Figure 4b; Table E4). 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. 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 mg (hazard ratio 0.69 [95% CI, ]; P ). Numerical reductions compared with placebo were observed for indacaterol 300 mg (0.74 [95% CI, ]; P ) and tiotropium (0.76 [95% CI, ]; P ). Similarly, the rate of exacerbations 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 6 95% confidence interval. **P, 0.01 and ***P, versus placebo; P, 0.05, P < 0.01, and P, versus tiotropium. relative to placebo was lower for indacaterol 150 mg (rate ratio 0.67 [95% CI, ]; P ) but not for indacaterol 300 mg (0.75 [95% CI, ]; P ) or tiotropium (0.70 [95% CI, ]; P ). Rates of exacerbations per year were 0.50, 0.53, 0.53, and 0.72 for indacaterol 150 mg, 300 mg, 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 ) for indacaterol 150 mg, 0.65 (P ) for indacaterol 300 mg, and 0.69 (P ) for tiotropium. Safety 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 mg 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. 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%

5 Donohue, Fogarty, Lötvall, et al.: Indacaterol Versus Tiotropium for COPD 159 TABLE 3. EFFECT OF TREATMENTS ON DIARY CARD DERIVED SYMPTOM VARIABLES Indacaterol 150 mg Indacaterol 300 mg Tiotropium Placebo Change from baseline in mean daily number of puffs of as-needed albuterol 21.5 (0.13)* 21.6 (0.13)* 21.0 (0.13)* 20.4 (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)* x 25.5 (2.42)* 3.2 (2.46) % of nights with no awakenings 72.5 (1.49) k 72.6 (1.49) k 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) Definition of abbreviation: PEF 5 peak expiratory flow. Data (averaged over 26 weeks) are least squares means (SE). Numbers of patients included in the analyses of the different variables were 380 to 385 (indacaterol 150 mg), 377 to 383 (indacaterol 300 mg), 382 to 390 (tiotropium), and 348 to 358 (placebo). * P, for treatment contrast versus placebo. P < for treatment contrast versus tiotropium. P, 0.05 for treatment contrast versus tiotropium. x P, 0.01 for treatment contrast versus tiotropium. k P, 0.01 for treatment contrast versus placebo. { P, 0.05 for treatment contrast versus placebo. of patients in both indacaterol groups. Tachycardia was reported in 1.2 and 0.2% of patients in the indacaterol 150 and 300 mg 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 mg 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 mg, indacaterol 300 mg, 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%. DISCUSSION 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 FEV 1 at 24 hours post dose (180 ml above placebo at Week 12) (23) demonstrate the suitability of this agent for oncedaily dosing. The 40- to 50-ml difference in trough FEV 1 for indacaterol beyond that achieved with the established bronchodilator, tiotropium, is similar to the margin tiotropium has previously achieved over twice-daily b 2 -agonists (4, 7). Any additional improvement in FEV 1 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 TABLE 4. HEALTH STATUS ASSESSED BY ST GEORGE S RESPIRATORY QUESTIONNAIRE SCORES AT WEEK 26 Treatment Difference Vs. Placebo: Least Squares Mean (95% CI) Least Squares Mean (SE) Placebo Indacaterol 150 mg Indacaterol 300 mg Tiotropium n Total score 40.4 (0.79) 23.3 (25.1 to 21.5)* 22.4 (24.2 to 20.6) 21.0 (22.8 to 0.8) Symptoms component 49.0 (1.18) 24.0 (26.8 to 21.3) x 24.3 (27.0 to 21.6) x 21.3 (24.0 to 1.5) Activity component 56.7 (1.01) 24.8 (27.1 to 22.5)* x 23.1 (25.3 to 20.8) 22.2 (24.5 to 0.1) Impacts component 27.8 (0.85) 22.3 (24.3 to 20.3) kx 21.5 (23.5 to 0.4) 20.2 (22.2 to 1.8) See Table 2 for definition of abbreviation. * P, versus placebo. P < 0.01 versus tiotropium. P, 0.01 versus placebo. x P, 0.01 versus tiotropium. k P, 0.05 versus placebo.

6 160 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 5. ADVERSE EVENTS OVERALL AND THOSE MOST COMMONLY OCCURRING Indacaterol 150 mg Indacaterol 300 mg Tiotropium Placebo n 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) Definition of abbreviation: COPD 5 chronic obstructive pulmonary disease. Data are given as n (%). Events occurred in more than 5% of any treatment group for adverse events and more than 1% of any group for serious adverse events and adverse events leading to discontinuation. margins over placebo that were generally close to the 1-point difference regarded as clinically relevant (22), although the indacaterol 300-mg 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-mg 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-mg 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 FEV 1 (140 ml vs. placebo) in this study was very close to previously reported differences (140 ml or ml vs. placebo) in studies using blinded tiotropium (4, 36, 37). Effects of tiotropium on dyspnea ( vs. placebo) were similar to or a little lower than previous reports ( 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 mg group. Tremor, a typical side effect of b 2 -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

7 Donohue, Fogarty, Lötvall, et al.: Indacaterol Versus Tiotropium for COPD 161 blood glucose and serum potassium show that indacaterol had little impact on known b 2 -adrenoceptor mediated systemic effects, and there were no marked differences between groups in vital signs. The safety results with the 300-mg 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 FEV 1 at 12 weeks, the change from baseline in trough FEV 1 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-mg dose, and 150 and 150 ml with the 300-mg 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 FEV 1 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. Conflict of Interest Statement: J.F.D. received $5,001 $10,000 from Novartis, $10,001 $50,000 from GlaxoSmithKline, $5,001 $10,000 from Forest Labs, $10,001 $50,000 from AstraZeneca, and $1,001 $5,000 from Sepracor in consultancy fees; $5,001 $10,000 from Novartis, $5,001 $10,000 from GlaxoSmithKline, $5,001 $10,000 from Almiral Forest, $5,001 $10,000 from AstraZeneca, and $1,001 $5,000 from Sepracor in advisory board fees; $10,001 $50,000 from GlaxoSmithKline, $10,001 $50,000 from AstraZeneca, and $5,001 $10,000 from Boehringer Ingelheim/Pfizer in lecture fees; and $5,001 $10,000 from Boehringer Ingelheim with UNC in industry-sponsored grants. J.F.D. s dependent received $10,001 $50,000 from Centeon with UNC in industry-sponsored grants. C.F. received more than $100,001 from Novartis, more than $100,001 from Roche, more than $100,001 from GlaxoSmithKline, more than $100,001 from Boehringer Ingelheim, and more than $100,001 from Forest in industry-sponsored grants; and more than $100,001 from Pearl, more than $100,001 from Osiris, more than $100,001 from Novo-Nordisk, more than $100,001 from Altana, and more than $100,001 from Alcon in research grants. J.L. received $5,001 $10,000 from GlaxoSmithKline for consultancy per annum, $1,001 $5,000 from Novartis for serving on an advisory board, $5,001 $10,000 from AstraZeneca, and $5,001 $10,000 from Merck/MSD for lectures; more than $100,001 from GlaxoSmithKline, more than $100,001 from AstraZeneca, and more than $100,001 from Novartis in sponsored grants for clinical studies and university fees; has a patent pending on exosomes as vectors for gene therapy; received up to $1,000 from studentlitteratur in royalties for a book produced 20 years ago; and received up to $1,000 from EAACI for serving on an advisory board. D.A.M. received $1,001 $5,000 from Boehringer Ingelheim, $1,001 $5,000 from DeepBreeze, $1,001 $5,000 from Forest, $5,001 $10,000 from GlaxoSmithKline, and $5,001 $10,000 from Novartis in advisory board fees; $10,001 $50,000 from Advanced Health Media in (promotional) lecture fees, and $50,001 $100,000 from Boehringer Ingelheim, more than $100,001 from GlaxoSmithKline, more than $100,001 from Novartis, and $10,001 $50,000 from Sepracor in institutional grants. H.W. received $1,001 $5,000 from AstraZeneca, $1,001 $5,000 from Novartis, $1,001 $5,000 from Nycomed, and $1,001 $5,000 from Janssen-Cilag in advisory board fees; $5,001 $10,000 from GlaxoSmithKline for trainer seminars on Asthma/COPD; $5,001 $10,000 from Pfizer for trainer seminars on COPD; $1,001 $5,000 from Boehringer Ingelheim, $1,001 $5,000 from Chiesi, and $1,001 $5,000 from Nycomed as an invited lecturer; and $1,001 $5,000 from Novartis as a clinical trial grant for his institution. A.Y. received $1,001 $5,000 from GlaxoSmithKline, $1,001 $5,000 from Merck Sharpe & Dohme, $1,001 $5,000 from UCB, and up to $1,000 from AstraZeneca in advisory board fees; $1,001 $5,000 from GlaxoSmithKline, $1,001 $5,000 from AstraZeneca, $1,001 $5,000 from Novartis, $1,001 $5,000 from UCB, and $1,001 $5,000 from Chiesi as an invited lecturer; and $5,001 $10,000 from Novartis and $1,001 $5,000 from AstraZeneca as a clinical trial grant for his institution. A.I. is an employee of Novartis. J.S. is a full-time employee of Novartis and is currently a full-time employee of MHRA, UK. R.O. is a full-time employee of Novartis. M.H. is an employee of Novartis Pharma and holds $50,001 $100,000 as part of the employee stock option scheme. B.K. is an employee of Novartis. Acknowledgment: 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. 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