Mark Higgins

Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium.

RATIONALE Indacaterol is the first once-daily, long-acting inhaled beta(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 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 Georges 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 < 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. 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).

Efficacy of a new once-daily long-acting inhaled β2-agonist indacaterol versus twice-daily formoterol in COPD

Background Indacaterol is a long-acting inhaled β2-agonist (LABA) for the treatment of chronic obstructive pulmonary disease (COPD). In previous studies, indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action. This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year. Methods Patients with moderate to severe COPD were randomised to receive once-daily indacaterol 300 μg (n=437) or 600 μg (n=428), twice-daily formoterol 12 μg (n=435) or placebo (n=432) for 52 weeks in a double-blind double-dummy parallel group study. The primary efficacy variable was forced expiratory volume in 1 s (FEV1) measured 24 h postdose after 12 weeks (indacaterol vs placebo). Other outcomes included dyspnoea (transition dyspnoea index, TDI), use of as-needed salbutamol, symptom-based measures recorded on diary cards, exacerbations, health status (St Georges Respiratory Questionnaire), BODE index (body mass index, obstruction, dyspnoea, exercise), safety and tolerability. Results Indacaterol increased 24 h postdose FEV1 after 12 weeks by 170 ml (both doses) versus placebo and by 100 ml versus formoterol (all p<0.001). These significant differences were maintained at 52 weeks. Symptomatic outcomes were improved compared with placebo with all active treatments, and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol. Indacaterol was well tolerated and had a good overall safety profile, including minimal impact on QTc interval and systemic β2-mediated events. Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD. Trial registration number NCT 00393458.

Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial

BACKGROUND A light-porous-particle, dry-powder formulation of tobramycin was developed, using PulmoSphere® technology, to improve airway delivery efficiency, substantially reduce delivery time, and improve patient convenience and satisfaction. We evaluated the safety, efficacy and convenience of tobramycin inhalation powder (TIP™) versus tobramycin inhalation solution (TIS, TOBI®) for treating Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients aged ≥6 years. METHODS In this open-label study, 553 patients were randomized 3:2 to TIP (total 112mg tobramycin) via the Novartis T-326 Inhaler or TIS 300mg/5mL via PARI LC® PLUS nebulizer twice daily for three treatment cycles (28 days on-drug, 28 days off-drug). Safety, efficacy, and treatment satisfaction outcomes were evaluated. RESULTS TIP was generally well-tolerated; adverse events were similar in both groups. The rate of cough suspected to be study drug related was higher in TIP-treated patients (TIP: 25.3%; TIS: 4.3%), as was the overall discontinuation rate (TIP: 26.9%; TIS: 18.2%). Increases in FEV(1)% predicted from baseline to Day 28 of Cycle 3 were similar between groups; the mean reduction in sputum P. aeruginosa density (log(10) CFU/g) on Day 28 of Cycle 3 was also comparable between groups. Administration time was significantly less for TIP (mean: 5.6 versus 19.7min, p<0.0001). Treatment satisfaction was significantly higher for TIP for effectiveness, convenience, and global satisfaction. CONCLUSIONS TIP has a safety and efficacy profile comparable with TIS, and offers a far more convenient treatment option for pseudomonas lung infection in CF.

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

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

A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison.

This dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled beta2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected. In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV(1)40% of predicted and > or =1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400microg or placebo via multi-dose dry powder inhaler, or indacaterol 400microg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18microg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC(22-24h)) on Day 1. Clinically relevant improvements versus placebo in FEV1 AUC(22-24h) were seen for 400 and 200microg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200microg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension. The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled beta2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile.

Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium

BackgroundIndacaterol 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.MethodsIn 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.ResultsA 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.ConclusionsOnce-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.Trial registrationClinicalTrials.gov: NCT00615459, EudraCT number: 2007-004071-19

Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design

BACKGROUND 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). METHODS 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. RESULTS 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. CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial.

Indacaterol, a novel inhaled β2-agonist, provides sustained 24-h bronchodilation in asthma

The present study examined the bronchodilator and safety profiles of single-dose indacaterol in intermittent or persistent asthma. In the present double-blind crossover study, 42 patients were randomised to receive single doses of indacaterol (50, 100, 200 and 400 µg) or placebo via a hydrofluoroalkane pressurised metered-dose inhaler. The primary efficacy comparisons were the per cent changes in forced expiratory volume in one second (FEV1 ) between indacaterol and placebo 30 min and 21 h post-dose. All doses resulted in prolonged bronchodilation, with indacaterol 200 and 400 µg meeting pre-specified efficacy criteria. The mean percentage increases in FEV1 from placebo with indacaterol 200 and 400 µg were 7.6 and 14.9%, respectively, at 30 min, and 7.5 and 10.4%, respectively, at 21 h post-dose. At these doses, changes in mean FEV1 relative to placebo were statistically significant from 5 min to 25 h, inclusive. At 5 min, the geometric least squares mean values for FEV1 were 3.08 and 3.22 L for the 200 and 400 µg doses, respectively, compared with 2.99 L for placebo. At 24 h after dosing, the baseline-adjusted geometric least square mean FEV1 was 3.13, 3.11, 3.24 and 3.30 L for indacaterol 50, 100, 200 and 400 µg, respectively, and 2.98 L for placebo. All treatments were well tolerated. Once-daily indacaterol at doses of 200 and 400 µg provided sustained 24-h bronchodilation, with a rapid onset and a good tolerability and safety profile.

24-hour bronchodilator efficacy of single doses of indacaterol in subjects with COPD: comparison with placebo and formoterol

ABSTRACT Objective: To assess the bronchodilator efficacy, safety and tolerability of indacaterol, a novel, once-daily inhaled β2-agonist bronchodilator, in patients with chronic obstructive pulmonary disease (COPD). Methods: This crossover, double-blind, double-dummy study was conducted to evaluate the 24-h bronchodilator effect of a range of single doses of indacaterol (150 µg, 300 µg and 600 µg), given in the morning via single-dose dry powder inhaler (SDDPI) in subjects with COPD, compared with placebo and with the daily therapeutic dose of formoterol (two 12 µg doses 12 h apart, via an SDDPI). Tolerability and safety were also assessed. Results: Fifty-one subjects with moderate-to-severe COPD received each of the five treatments on separate study days in randomised sequence. The 24-h trough FEV1 (primary endpoint; mean [95% CI]) was 1.46 (1.43, 1.49) L with indacaterol 600 µg (p < 0.001 vs. placebo, p < 0.01 vs. formoterol, p < 0.05 vs. indacaterol 150 µg), 1.45 (1.42, 1.48) L with indacaterol 300 µg (p < 0.001 vs. placebo, p < 0.05 vs. formoterol), 1.42 (1.39, 1.45) L with indacaterol 150 µg (p < 0.001 vs. placebo), 1.41 (1.38, 1.43) L with formoterol (p < 0.001 vs. placebo) and 1.28 (1.25, 1.31) L with placebo. All treatments were well tolerated and there was little effect on serum potassium, blood glucose or QTc interval. Conclusion: All doses of indacaterol were effective in providing 24-h bronchodilation and were well-tolerated in subjects with COPD. The bronchodilator efficacy of indacaterol (150, 300 and 600 μg) at 24 h post-dose was at least as efficacious as formoterol 12 µg twice daily.

Onset of action of indacaterol in patients with COPD: Comparison with salbutamol and salmeterol-fluticasone

Background: Indacaterol is a novel, inhaled once-daily ultra-long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease (COPD). Objectives: This study compared the onset of action of single doses of indacaterol 150 and 300 μg with salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo in moderate-to-severe COPD patients. Methods: This was a multicenter, randomized, double-blind, placebo-controlled crossover study. The primary variable was forced expiratory volume in one second (FEV1) at five minutes postdose. Results: Out of 89 patients randomized (mean age 62 years), 86 completed the study. At five minutes postdose, both indacaterol doses were statistically and clinically superior to placebo (P < 0.001), with treatment–placebo differences in FEV1 of 100 (95% confidence interval [CI] 70–130) mL and 120 (95% CI 90–150) mL for indacaterol 150 and 300 μg, respectively. FEV1 at five minutes postdose with both indacaterol doses was numerically higher than for salbutamol (10 and 30 mL for indacaterol 150 and 300 μg, respectively) and significantly higher than for salmeterol-fluticasone (50 mL, P = 0.003; 70 mL, P < 0.001, respectively). Moreover, both indacaterol doses showed significantly higher FEV1 than placebo (P < 0.001) at all postdose time points. The numbers of patients with an FEV1 increase of at least 12% and 200 mL at five minutes postdose were 16 (18.8%), 24 (27.6%), 20 (23.3%), 8 (9.1%), and 3 (3.4%) for indacaterol 150 and 300 μg, salbutamol 200 μg, salmeterol-fluticasone 50/500 μg, and placebo, respectively. Conclusions: Single doses of indacaterol 150 and 300 μg demonstrated a fast onset of action similar to that for salbutamol and faster than that for salmeterol-fluticasone.