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Yasuo To,
Masaharu Kinoshita,
Sang Haak Lee,
Liang-Wen Hang,
Masakazu Ichinose,
Yoshinosuke Fukuchi,
Tetsuji Kitawaki,
Naoko Okino,
Niyati Prasad,
David Lawrence, Benjamin Kramer
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ABSTRACT: This post hoc analysis evaluated the efficacy of indacaterol, a novel inhaled once-daily long-acting β(2)-agonist, by disease severity (GOLD 2005) in patients with moderate-to-severe COPD from six Asian countries/areas (Hong Kong, India, Japan, Korea, Singapore, Taiwan).
Data from a 12-week, double-blind, placebo-controlled, parallel-group study in patients randomized to indacaterol 150 μg, indacaterol 300 μg or placebo once daily were analyzed based on baseline disease severity (moderate or severe). Endpoints were: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) at Week 12. Safety data were collected.
Of 347 patients randomized, 59.7% had moderate, and 40.3% had severe COPD. Least squares means (LSMs) indacaterol-placebo differences in trough FEV(1) at Week 12 exceeded the pre-specified minimal clinically important difference (MCID) of 0.12L and were statistically superior (p < 0.001) for indacaterol (150 μg, 300 μg) versus placebo in the two subgroups [0.19L, 0.20L (moderate); 0.15L, 0.19L (severe) respectively]. LSM TDI scores for both indacaterol doses versus placebo in both subgroups were statistically superior (p < 0.05) and clinically meaningful (≥1 unit). Both indacaterol doses showed improvements in LSM SGRQ total scores at Week 12 which exceeded the MCID (4 units) versus placebo in both subgroups, with indacaterol 300 μg-placebo difference in the severe subgroup being statistically significant (p < 0.01). Overall incidence of adverse events was lower with indacaterol than with placebo across both subgroups.
Indacaterol demonstrated clinically relevant improvements versus placebo in lung function, dyspnea and health status in Asian COPD patients irrespective of disease severity. CLINICAL TRIALS IDENTIFIER: NCT00794157.
Respiratory medicine 10/2012; 106(12):1715-21. · 2.33 Impact Factor
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ABSTRACT: Abstract Indacaterol is an inhaled, once-daily, long-acting ®(2)-agonist for the treatment of COPD. Most previous studies were conducted with doses of 150 and/or 300 μg once-daily, and data with the 75 μg dose are limited. Two identically designed studies were, therefore, conducted to evaluate the efficacy and safety of the 75 μg once-daily dose. In two double-blind studies conducted in the USA, patients with moderate-to-severe COPD were randomized to treatment with indacaterol 75 μg once-daily (n = 163 and 159) or matching placebo (n = 160 and 159) for 12 weeks. The primary variable was forced expiratory volume in 1 s measured 24 h post-dose after 12 weeks (reported elsewhere). This report describes secondary efficacy endpoints, including transition dyspnea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores, and the percentages of patients with improvements of or above the minimal clinically important difference (MCID; ≥1 in TDI score and ≥4 in SGRQ score). Differences between indacaterol and placebo for TDI total score at week 12 were 1.23 (p < 0.001) and 0.45 (p = 0.16), with odds ratios for achieving the MCID of 2.19 (p = 0.002) and 1.58 (p = 0.065). SGRQ total score decreased (improved) from baseline by 5.8 and 4.9 units with indacaterol at week 12 (2.0 and 0.9 with placebo), with odds ratios for achieving the MCID of 1.80 (p = 0.024) and 1.71 (p = 0.031). Patients receiving indacaterol had statistically significant or numerical improvements in diary-derived symptom variables compared with placebo. Treatment with indacaterol 75 μg may provide useful improvements in patient-reported outcomes in patients with moderate-to-severe COPD.
COPD Journal of Chronic Obstructive Pulmonary Disease 09/2012; · 1.79 Impact Factor
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ABSTRACT: Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease (COPD). The authors investigated the approach of dual bronchodilation using indacaterol, a once-daily long-acting β(2) agonist, and the long-acting muscarinic antagonist tiotropium, compared with tiotropium alone.
In two identically designed, double-blind, 12-week studies, patients with moderate to severe COPD were randomised to indacaterol 150 μg once daily or matching placebo. All patients concurrently received open-label tiotropium 18 μg once daily. The primary outcome was standardised area under the curve of forced expiratory volume in 1 s (FEV(1)) from 5 min to 8 h post dose at week 12. The key secondary outcome was 24 h post-dose ('trough') FEV(1) at week 12. Resting inspiratory capacity (IC) was measured in a subgroup.
1134 and 1142 patients were randomised in studies 1 and 2; 94% and 94% completed. Compared with monotherapy, concurrent therapy increased FEV(1) (area under the curve by 130 and 120 ml, trough by 80 and 70 ml; all p<0.001) and trough IC (by 130 and 100 ml, p<0.01). Cough was more common with indacaterol plus tiotropium (10% and 9%) than with tiotropium alone (4% and 4%). Most cases (∼90%) of cough were mild. Other adverse events were similar for the treatment groups.
Compared with tiotropium monotherapy, indacaterol plus tiotropium provided greater bronchodilation and lung deflation (reflected by increased resting IC). Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium. These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action. TRIAL REGISTRATION NUMBERS: NCT00846586 and NCT00877383.
Thorax 04/2012; 67(9):781-8. · 6.84 Impact Factor
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ABSTRACT: Indacaterol is the first once-daily, long-acting, inhaled β(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease (COPD). Two studies (previously reported in a Congress abstract) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 μg once daily, a dose lower than that previously investigated in most studies.
The primary objective was to evaluate the efficacy of indacaterol 75 μg once daily in terms of 24-hour post-dose ("trough") forced expiratory volume in the first second of respiration (FEV(1)) compared with placebo after 12 weeks of treatment.
Patients with moderate to severe COPD were randomized to receive double-blind treatment with indacaterol 75 μg once daily (n = 163 and 159) or placebo (n = 160 and 159) for 12 weeks. In addition to trough FEV(1) after 12 weeks, rescue albuterol use, health status (St. George's Respiratory Questionnaire [SGRQ]), and tolerability were evaluated. Clinically relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1) and a decrease of ≥4 units in SGRQ total score.
Of patients enrolled in the 2 studies, 54% were men, and 90% and 94% were white, with mean age 64 and 61 years. Mean duration of COPD was 7 years; smoking history was 52 pack-years; and 45% and 37% of patients were receiving inhaled corticosteroid therapy. At week 12, indacaterol demonstrated clinically relevant bronchodilator efficacy, increasing trough FEV(1) by ≥120 mL versus placebo (P < 0.001), with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose. Over 12 weeks, relative to placebo, in patients receiving indacaterol therapy, rescue albuterol use was reduced by 1.2 and 0.7 puffs per day (P < 0.01), and the percentage of rescue-free days was increased by 13.7 and 8.4 (P < 0.01). At week 12, the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6, respectively (P ≤ 0.01). Adverse events were reported for 49% and 45% of patients receiving indacaterol therapy, and for 46% and 41% receiving placebo.
Compared with placebo, indacaterol 75 μg once daily provided statistically significant and clinically relevant 24-hour bronchodilation and was well tolerated. In patients receiving indacaterol, the reduction in rescue albuterol use was statistically significant. Changes in health status also were statistically significant compared with placebo, although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance. The results of these studies suggest that indacaterol 75 μg once daily is an effective maintenance treatment in patients with moderate to severe COPD. ClinicalTrials.gov identifiers: NCT01072448 and NCT01068600.
Clinical Therapeutics 12/2011; 33(12):1974-84. · 2.32 Impact Factor
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ABSTRACT: The efficacy and safety of indacaterol, a novel inhaled once daily ultra long-acting β(2) -agonist was evaluated in COPD patients in six Asian countries/areas. This study was primarily designed to obtain the regulatory approval of indacaterol in Japan.
Moderate-to-severe COPD patients were randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily. Efficacy variables: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), health status (St. George's Respiratory Questionnaire) and transition dyspnoea index at week 12. Safety/tolerability was evaluated.
A total of 347 patients were randomized (96.5% male, mean (SD) age 66.7 (8.38) years, post-bronchodilator FEV(1) % predicted: 53.7 (12.50)); 88.8% completed. The least squares means (LSM) trough FEV(1) at week 12 for indacaterol 150 µg, indacaterol 300 µg and placebo were 1.34 L, 1.37 L and 1.17 L, respectively, with differences versus placebo exceeding the prespecified minimal clinically important difference of 0.12 L (0.17 L and 0.20 L for indacaterol 150 µg and 300 µg, respectively, both P < 0.001). The week 12 LSM transition dyspnoea index score was statistically superior for both indacaterol doses versus placebo (differences of 1.30 and 1.26, P < 0.001; both exceeding the minimal clinically important difference of 1). At week 12, both indacaterol doses provided statistically significant (P ≤ 0.005) and clinically meaningful (≥4 units) improvements in LSM St. George's Respiratory Questionnaire total score versus placebo (differences: -4.8 and -5.7 units). Adverse events for indacaterol (49.1%, both doses) were lower than placebo (59.0%) and were mostly mild/moderate in severity; no deaths were reported.
Indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients.
Respirology 11/2011; 17(2):379-89. · 2.42 Impact Factor
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ABSTRACT: Effective bronchodilation is an important part of the management of patients with chronic obstructive pulmonary disease (COPD) and can improve breathlessness and ability to undertake physical activities. Indacaterol is a new once-daily, long-acting inhaled bronchodilator for COPD. We review here the efficacy of indacaterol as a bronchodilator, including its impact upon symptoms and health status. The evidence reviewed comprises four placebo-controlled clinical studies of indacaterol treatment, three of which included treatment arms with one of the other long-acting inhaled bronchodilators (once-daily tiotropium or twice-daily salmeterol or formoterol), in 4,833 patients with moderate-to-severe COPD. Indacaterol had a bronchodilator effect significantly greater than formoterol and salmeterol, and similar to tiotropium. Its effect on symptoms and health status was similar or significantly greater than the other bronchodilators. The safety profile was similar to placebo. Once-daily indacaterol is an effective and beneficial maintenance bronchodilator treatment for patients with moderate-to-severe COPD.
Primary care respiratory journal: journal of the General Practice Airways Group 07/2011; 20(4):380-8.
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ABSTRACT: Indacaterol is a novel, inhaled, once-daily ultra long-acting β(2)-agonist (ultra-LABA) for the treatment of COPD. This study investigated the effect of indacaterol on exercise endurance, and on lung hyperinflation during exercise and at rest in patients with moderate-to-severe COPD.
In this double-blind, placebo-controlled, two-period crossover study (3-week treatment, 3-week washout between treatments), patients were randomized to receive indacaterol 300 μg once-daily or matching placebo. The primary efficacy variable was exercise endurance time after 3 weeks of treatment, measured through constant-load cycle ergometry testing performed at 75% of the peak work rate in a screening incremental exercise test.
Of 90 patients randomized (mean age: 62.8 years; post-bronchodilator FEV(1): 61.2% predicted and FEV(1)/FVC: 51.6%), 74 completed the study. Pre-treatment exercise tolerance averaged 459 s. Improvement in exercise endurance time was higher with indacaterol 300 μg than with placebo both after the first dose (treatment difference: 101 s; p < 0.001) and after 3 weeks (treatment difference: 111 s; p = 0.011). In addition, indacaterol increased end-exercise inspiratory capacity (IC) versus placebo after 3 weeks (0.28 L, p = 0.002). Significant improvements were also observed in resting IC (0.17 L, p = 0.001), FEV(1) (0.25 L, p < 0.001) and FVC (0.26 L, p < 0.001) with indacaterol compared with placebo at 75 min post-dose after 3 weeks.
In conclusion, indacaterol treatment improved the ability of patients with COPD to exercise. In addition, the improvements observed in resting and end-exercise IC indicate reductions in lung hyperinflation after 3 weeks treatment (ClinicalTrials.gov registration number: NCT00620022).
Respiratory medicine 07/2011; 105(7):1030-6. · 2.33 Impact Factor
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ABSTRACT: Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist providing 24-h bronchodilation with once-daily (od) dosing for maintenance use in patients with chronic obstructive pulmonary disease (COPD). This article reviews the bronchodilator properties of indacaterol compared with other treatments used in COPD. Data from five published placebo-controlled studies were reviewed. Two 14-day crossover studies, the first comparing indacaterol 300 µg od with salmeterol 50 µg twice daily (bid), the second comparing indacaterol 150 µg and 300 µg od with tiotropium 18 µg od, assessed forced expiratory volume in 1 s (FEV(1)) at 24 h postdose (trough). Third, a 14-day crossover study evaluated trough FEV(1) following indacaterol 300 µg dosed morning or evening compared with salmeterol 50 µg bid. Fourth, a single-dose study of indacaterol 150 and 300 µg measured FEV(1) at 5 min postdose compared with salmeterol/fluticasone 50/500 µg and salbutamol 200 µg. Finally, data from a 1-year study with indacaterol 300 µg and formoterol 12 µg bid were examined to determine whether bronchodilation was maintained long term. In the first two studies, indacaterol increased trough FEV(1) after 14 days by a statistically significant and clinically relevant margin over placebo; indacaterol had a greater effect than salmeterol and a similar effect to tiotropium. In the third study, indacaterol had the same effect on trough FEV(1) whether dosed in the morning or evening. In the fourth study, the onset of the bronchodilator effect of indacaterol was similar to that of salbutamol. In the fifth study, the bronchodilator effect of indacaterol on trough FEV(1) was maintained at a significant and clinically relevant level over 52 weeks, whereas the bronchodilator effect of formoterol diminished over time. To conclude, indacaterol is a highly effective bronchodilator that is superior to or at least as effective as other available long-acting bronchodilators for COPD.
Therapeutic Advances in Respiratory Disease 06/2011; 5(5):345-57.
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ABSTRACT: Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD. The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status, using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators.
Individual patient data were pooled from three randomized, placebo-controlled studies (NCT00393458; NCT00567996; NCT00463567), conducted in patients with moderate-to-severe COPD. Treatments were double-blind indacaterol 150 μg (n = 746) or 300 μg (n = 853) once-daily, formoterol 12 μg twice-daily (n = 556), salmeterol 50 μg twice-daily (n = 333) and placebo (n = 1185); and open-label tiotropium 18 μg once-daily (n = 415). Evaluation after 6 months' treatment was by transition dyspnoea index (TDI; minimum clinically important difference [MCID] ≥1 point), and St George's Respiratory Questionnaire (SGRQ; MCID ≥4 units).
Differences from placebo in TDI total score were 1.01 (indacaterol 150 μg) 1.28 (indacaterol 300 μg), 0.74 (formoterol), 0.92 (salmeterol) and 0.88 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91, 2.69, 2.02, 1.79 and 1.49 (all p < 0.05). Differences versus placebo in SGRQ total score were -4.4 (indacaterol 150 μg), -3.4 (indacaterol 300 μg), -2.8 (formoterol), -4.0 (salmeterol) and -1.7 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID of 1.95, 1.63, 1.54, 1.82 and 1.29 (all p < 0.05 apart from tiotropium).
Indacaterol provided clinically important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD.
Respiratory medicine 03/2011; 105(6):892-9. · 2.33 Impact Factor
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ABSTRACT: 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.
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.
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.
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.
Pulmonary Pharmacology & Therapeutics 02/2011; 24(1):162-8. · 2.80 Impact Factor
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ABSTRACT: Indacaterol is an inhaled, long-acting β(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD.
Subjects with moderate to severe COPD who completed a 26-week, randomized, double-blind study were eligible for enrollment in an extension, during which treatment with double-blind indacaterol, 150 or 300 μg once daily, or placebo was continued for a further 26 weeks. The primary objective was to evaluate the long-term safety of indacaterol. Efficacy end points included trough (24 h postdose) FEV(1) at 52 weeks, exacerbations, and health status (St. George Respiratory Questionnaire [SGRQ]).
Four hundred fifteen subjects participated in the extension. Adverse events, mostly mild or moderate, occurred in 76%, 77%, and 68% of subjects receiving indacaterol, 150 μg; indacaterol, 300 μg; and placebo, respectively. Serious adverse events occurred in 10.4%, 12.3%, and 10.5%, respectively. Indacaterol had no clinically significant effects on ECG findings (corrected QT interval) or on serum potassium or plasma glucose levels. Indacaterol increased trough FEV(1) relative to placebo throughout the study (difference of ≥ 170 mL at week 52). No tolerance to its bronchodilator effect was detected. Indacaterol treatment was accompanied by significant reductions in COPD exacerbations (rate ratios compared with placebo, 0.62-0.64; P < .05) and as-needed albuterol use (1.2-1.4 puffs/d decrease, P < .001 compared with placebo). Health status improved with indacaterol treatment, with decreases from baseline in mean total SGRQ score generally > 4 units.
During 1 year of treatment, indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes.
ClinicalTrials.gov; No.: NCT00677807; URL: www.clinicaltrials.gov.
Chest 02/2011; 140(1):68-75. · 5.25 Impact Factor
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ABSTRACT: For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients' correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients' correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients' preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by > 77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01).Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.
International Journal of COPD 01/2011; 6:353-63.
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ABSTRACT: Indacaterol is an inhaled, once-daily long-acting β(2)-agonist bronchodilator for regular use in patients with chronic obstructive pulmonary disease (COPD). As indacaterol is the first once-daily β(2)-agonist to be developed, it is relevant to evaluate its bronchodilator efficacy, safety, and tolerability.
Data were pooled from three randomized, double-blind, clinical studies in patients with moderate-to-severe COPD treated with indacaterol 150 μg qd (n = 627) or placebo (n = 1021). Bronchodilator efficacy was assessed as trough (24-hour post-dose) forced expiratory volume in 1 second (FEV(1)) after 12 weeks (primary endpoint in individual studies) and FEV(1) measured serially post-dose. Rescue use of albuterol was monitored.
At week 12, indacaterol increased trough FEV(1) by 160 mL compared with placebo (P < 0.001), exceeding the 120 mL level prespecified as clinically important. FEV(1) during the first 12-hour post-dose at week 12 averaged 210 mL higher with indacaterol than with placebo (P < 0.001). Patients receiving indacaterol recorded 53% of days without use of rescue albuterol, compared with 38% of days in the placebo group (P < 0.001). Adverse events (mostly mild or moderate) were reported for 52% and 46% of patients receiving indacaterol and placebo, respectively, and serious adverse events for 4% and 5%. Worsening of COPD was the most frequent adverse event (10% indacaterol; 15% placebo). Indacaterol had little effect on pulse or blood pressure or measures of systemic β(2)-adrenoceptor activity (blood glucose, serum potassium, and corrected QT interval).
Indacaterol was an effective bronchodilator and was well tolerated, with a good safety profile over 12 weeks of treatment. It should prove a useful treatment for patients with moderate-to-severe COPD.
International Journal of COPD 01/2011; 6:431-8.
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ABSTRACT: Pooled data were analyzed to evaluate the safety and tolerability of indacaterol, a once-daily inhaled long-acting β(2)-agonist for chronic obstructive pulmonary disease (COPD).
Data were pooled from clinical studies of 3-12 months' duration in patients with moderate-to-severe COPD receiving double-blind indacaterol 75 μg (n = 449), 150 μg (n = 2611), 300 μg (n = 1157), or 600 μg once daily (n = 547); formoterol 12 μg twice daily (n = 556); salmeterol 50 μg twice daily (n = 895); placebo (n = 2012); or tiotropium 18 μg once daily, given open label or blinded (n = 1214). Outcomes were adverse events, serious adverse events and deaths, plasma potassium, blood glucose, and QTc interval and vital signs.
The commonest adverse events with indacaterol were COPD worsening, nasopharyngitis, and headache; most cases were mild or moderate and incidence was generally similar to placebo and other active treatments. The risk of acute respiratory serious adverse events (leading to hospitalization, intubation, or death) was not significantly increased with any of the active treatments compared with placebo. COPD exacerbation rates (analyzed in the intent-to-treat population) were significantly reduced with all active treatments versus placebo. Hazard ratios versus placebo for major cardiovascular adverse events were < 1 for all indacaterol doses. Notable values for vital signs and measures of systemic β(2)-adrenoceptor activity were rare with indacaterol. The number of deaths adjusted per patient-year was lower with indacaterol (all doses combined) than with placebo (relative risk 0.21 [95% confidence interval 0.07-0.660], P = 0.008).
Indacaterol has a good profile of safety and tolerability that is appropriate for the maintenance treatment of patients with COPD.
International Journal of COPD 01/2011; 6:477-92.
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ABSTRACT: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations.
To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD.
Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 μg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period.
Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 μg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing indacaterol dose was similar in both populations. All indacaterol doses in both studies demonstrated similar safety profiles.
Indacaterol provided 24-hour bronchodilation with a fast onset of action and similar pharmacokinetic and safety profiles in Caucasian and Japanese patients. These findings suggest that ethnic factors do not influence the treatment of COPD with indacaterol.
Clinical Drug Investigation 12/2010; 31(4):247-55. · 1.82 Impact Factor
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ABSTRACT: Indacaterol is a novel, inhaled once-daily ultra-long-acting beta-2 agonist under development as a fixed-dose combination with an inhaled corticosteroid (ICS) for asthma treatment. This study evaluated the 24-h bronchodilator efficacy of indacaterol in Japanese patients with asthma.
Randomised, placebo-controlled, 5-period crossover study. Patients with persistent asthma (18-75 years, FEV(1) 50-85% predicted, ≥12% and 200 mL FEV(1) reversibility) receiving ICS were randomised to double-blind single dose indacaterol 150, 300, or 600 μg or placebo, with open-label salmeterol 50 μg twice-daily for one day in the 5(th) period. Primary endpoint was FEV(1)AUC(22-24h).
Of 41 randomised patients (48.8% male; mean age: 47.8 years), 39 completed. All indacaterol doses showed significantly higher FEV(1)AUC(22-24h) than placebo (P<0.001), with treatment-placebo differences of 180, 220, and 260 mL for indacaterol 150, 300, and 600 μg, respectively (salmeterol-placebo difference 170 mL; P < 0.001). For individual time-point FEV(1), all indacaterol doses were superior to placebo from 5 min to 24h post-dose (P < 0.001). Compared with salmeterol, all indacaterol doses were superior from 5 to 30 min (P < 0.05); in addition indacaterol 300 μg and 600 μg were superior at a number of subsequent time points. Changes in safety parameters with indacaterol were similar to placebo. All indacaterol doses were well tolerated.
Single dose indacaterol provided sustained 24-h bronchodilation with a faster onset of action than salmeterol and a good overall safety and tolerability profile in Japanese patients with asthma. These results are consistent with data from Caucasian populations.
Respiratory medicine 11/2010; 104(11):1629-37. · 2.33 Impact Factor
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ABSTRACT: Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, double-blind study compared the bronchodilator efficacy of indacaterol with that of placebo and tiotropium in patients with moderate-to-severe COPD.
In an incomplete-block, multi-dose, three-period, crossover design, patients received three of the following four treatments: indacaterol 150 μg, indacaterol 300 μg, tiotropium 18 μg and placebo, each once-daily for 14 days. Each treatment period was separated by a 14-day washout. Study drug was supplied daily by blinded, third party study personnel to maintain blinding of patients and investigators. The primary efficacy variable was trough forced expiratory volume in one second (FEV1) at 24 h post-dose after 14 days. The study was powered to demonstrate non-inferiority of indacaterol to tiotropium for this variable.
A total of 169 patients were randomized (mean age 65 years); 153 (90.5%) completed. Trough FEV1 after 14 days with indacaterol 150 μg and 300 μg was statistically and clinically superior to placebo, with differences (95% CI) of 170 (120-220) and 150 (100-200) mL respectively (both p < 0.001). For this endpoint, both doses of indacaterol not only met the criterion for non-inferiority compared with tiotropium, but also achieved numerically higher values, with differences versus tiotropium of 40 and 30 mL for indacaterol 150 and 300 μg, respectively. At 5 min post-dose on Day 1, the mean FEV1 for both indacaterol doses was significantly higher than placebo (by 120 and 130 mL for indacaterol 150 and 300 μg, respectively; p < 0.001) and tiotropium (by 80 mL for both doses; p < 0.001). Adverse events were reported by similar proportions of patients: 31.4%, 29.5%, 28.3% and 28.5% for indacaterol 150 μg and 300 μg, tiotropium and placebo treatments, respectively.
Once-daily indacaterol provided clinically and statistically significant 24-h bronchodilation. Indacaterol was at least as effective as tiotropium, with a faster onset of action (within 5 min) on the first day of dosing. Indacaterol should prove useful in patients with moderate-to-severe COPD, for whom treatment with one or more classes of long-acting bronchodilator is recommended.
ClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19.
Respiratory research 10/2010; 11:135. · 3.36 Impact Factor
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ABSTRACT: Indacaterol is an investigational, novel, inhaled once-daily ultra-long-acting beta-2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). This study evaluated the 24-h bronchodilatory efficacy and safety of indacaterol in Japanese patients with COPD.
This Phase-II, randomised, placebo-controlled, crossover study comprised four double-blind, single-dose treatment periods (washout between periods: 14-28 days). Japanese patients aged 40-75 years with moderate-to-severe COPD were randomised to receive single doses of indacaterol (150, 300, or 600 microg) or placebo via a single-dose dry-powder inhaler. Efficacy (primary endpoint: standardised FEV(1)AUC(22-24h)) and safety were assessed for 24 h post-dose in each treatment period.
Of the 50 patients randomised (92% male; mean age, 67.2 years), 45 completed the study. Standardised FEV(1)AUC(22-24h) was significantly higher for all indacaterol doses as compared with placebo, with clinically relevant differences of 130, 160, and 170 mL for 150, 300, and 600 microg, respectively (P < 0.001). The improvement in FEV(1) was seen as early as 5 min post-dose with indacaterol and sustained for 24 h (P < 0.001 vs placebo at all time points). All indacaterol doses were well tolerated and showed no clinically meaningful effect on pulse rate, blood pressure, QTc interval, and laboratory parameters when compared with placebo.
In the Japanese COPD population studied, single doses of indacaterol (150, 300, and 600 microg) provided sustained 24-h bronchodilation, with onset of action within 5 min post-dose. All doses were well tolerated. These results are consistent with data from Caucasian populations.
Allergology International 09/2010; 59(3):285-93.
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ABSTRACT: The drug development process can be streamlined by combining the traditionally separate stages of dose-finding (Phase IIb) and confirmation of efficacy and safety (Phase III) using an adaptive seamless design. This approach was used in a clinical study of indacaterol, a novel once-daily (od) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD (chronic obstructive pulmonary disease).
The study comprised a dose-finding stage with dose selection after 14 days of treatment, and a second stage evaluating efficacy and safety during 26 weeks of treatment. The dose-finding stage included seven randomized treatment arms: double-blind indacaterol 75 microg, 150 microg, 300 microg or 600 microg od, the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo, or the anticholinergic tiotropium 18 microg od open-label. An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician. The sponsor, investigators and patients remained blinded to the results. The indacaterol doses were selected using pre-set efficacy criteria for trough (24-h post-dose) and early (1-4 h post-dose) bronchodilator effect after 14 days, and all safety data. To qualify for selection, the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol, whichever was the highest value. Selected doses were continued into the second, 26-week stage. The two other indacaterol doses not selected, and formoterol, were discontinued following dose selection.
801 patients with moderate-to-severe COPD were evaluated. Indacaterol 150 microg was the lowest effective dose, exceeding criteria for trough FEV(1) (reference value 140 mL vs placebo) and FEV(1) AUC(1-4 h) (reference value 220 mL vs placebo). No safety signal was observed with any dose of indacaterol. Thus, indacaterol 150 and 300 microg were selected to continue into the second, 26-week stage.
The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.
Pulmonary Pharmacology & Therapeutics 06/2010; 23(3):165-71. · 2.80 Impact Factor
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James F Donohue,
Charles Fogarty,
Jan Lötvall,
Donald A Mahler,
Heinrich Worth,
Arzu Yorgancioglu,
Amir Iqbal,
James Swales,
Roger Owen,
Mark Higgins, Benjamin Kramer
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ABSTRACT: Indacaterol is the first once-daily, long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).
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.
Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 microg or placebo, or open-label tiotropium 18 microg, 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.
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 < 0.001 vs. placebo). At Week 26, for indacaterol 150/300 microg, 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.
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).
American Journal of Respiratory and Critical Care Medicine 06/2010; 182(2):155-62. · 11.08 Impact Factor
