INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD.

The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol (INSTEAD) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease (COPD) exacerbations from salmeterol/fluticasone (SFC; inhaled corticosteroid (ICS) regimen) to indacaterol monotherapy (non-ICS regimen). This 26-week, double-blind, double-dummy, parallel-group, phase IV study, randomised 581 patients with moderate COPD to indacaterol 150 µg once daily or SFC 50/500 µg twice daily. Patients had been receiving SFC 50/500 µg for ≥3 months, with no COPD exacerbations for more than a year before the study (patients for whom ICS is not recommended). The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough forced expiratory volume in 1 second (FEV1) after 12 weeks (non-inferiority margin of 0.06 L). The primary objective was met, with a mean treatment difference of 9 mL (95% CI -45-26 mL). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George's Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. Safety profiles of both treatments were as expected. This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 µg with no efficacy loss.

Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study.

BACKGROUND: We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease (COPD) and a history of at least one moderate to severe exacerbation in the previous 12 months. METHODS: In this multicentre, randomised, blinded, double-dummy, parallel group study, we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year. We used a computer-generated sequence to randomly allocate patients (1:1; stratified by baseline inhaled corticosteroid use, with the balance of treatments maintained at country level) to receive either indacaterol (150 µg) or tiotropium (18 µg) once-daily for 52 weeks. Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium for trough forced expiratory volume in 1 s (FEV1) at week 12 (primary endpoint), and for rate of exacerbations at week 52 (secondary endpoint). Analysis populations for the primary and key secondary endpoints were per-protocol sets. The safety set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00845728. FINDINGS: Between March 16, 2009, and July 5, 2012, we enrolled and randomly allocated 3444 patients: 1723 to indacaterol and 1721 to tiotropium. At week 12, the estimated least squares mean trough FEV1 difference between the groups was -0.011 L (least squares mean with indacaterol [n=1450] 1.134 L [SE 0.008] vs tiotropium [n=1467] 1.145 L [0.008]; one-sided 97.5% CI lower limit -0.026 L; p<0.0001). The lower limit of the 97.5% CI was above the prespecified non-inferiority margin of -0.055 L, suggesting that indacaterol was non-inferior to tiotropium. Indacaterol did not show non-inferiority in terms of annualised exacerbation rates: 0.79 (indacaterol, n=1529) versus 0.61 (tiotropium, n=1543); ratio 1.29 (one-sided 97.5% CI upper limit 1.44). In the safety set, we recorded no between-group difference in the number of patients who had adverse events (indacaterol 1119 [65%] of 1721 patients vs tiotropium 1065 [62%] of 1718 patients) or serious adverse events (indacaterol, 263 [15%] of 1721 patients vs tiotropium, 255 [15%] of 1718 patients). Respiratory disorders, particularly worsening of COPD, were the most common adverse events (COPD: indacaterol, 747 [43%] of 1721 patients and tiotropium, 665 [39%] of 1718 patients) and serious adverse events (COPD: indacaterol, 147 [9%] of 1721 patients and tiotropium, 121 [7%] of 1718 patients). INTERPRETATION: Indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles. Tiotropium afforded greater protection from exacerbations, although the absolute number of events was small and the difference between treatments is of uncertain clinical importance. The present data offer evidence consistent with current guidelines. FUNDING: Novartis Pharma AG.

Efficacy and safety of indacaterol, a new 24-hour beta2-agonist, in patients with asthma: a dose-ranging study.

BACKGROUND: Indacaterol is a new once-daily inhaled beta(2)-agonist in clinical development for asthma as a component of a fixed-dose combination with an inhaled corticosteroid. OBJECTIVES: To investigate the efficacy and safety of indacaterol in patients with chronic persistent asthma. METHODS: A total of 115 patients were randomized in a double-blind, incomplete-block cross-over design to sequences of four 7-day treatment periods (separated by 7-day washouts) with indacaterol 100, 200, 300, 400, or 600 micro g or placebo, once daily, via single-dose dry-powder inhaler. After the fourth washout, patients received 1 day of open-label formoterol 12 mu g twice daily. Forced expiratory volume in 1 second (FEV(1)) was measured for 24 hours post-dose on days 1 and 7. RESULTS: For standardized (with respect to time) FEV(1) area under the curve at 22 to 24 hours (AUC(22-24h)) on day 1, indacaterol doses >or=200 micro g were superior to placebo (p < 0.05) and similar or greater than formoterol 12 micro g twice daily. By day 7, mean differences from placebo in FEV(1) standardized AUC(22-24h) were 0.08, 0.16, 0.15, 0.11, and 0.16 L for indacaterol 100, 200, 300, 400, and 600 micro g, respectively (all p < 0.05 vs. placebo). Mean FEV(1) for indacaterol doses >or= 200 micro g on day 7 was higher than placebo (p < 0.05) pre-dose and at all post-dose time points. AEs were generally mild in severity; no serious AEs occurred. No clinically meaningful differences were observed between treatments in any safety assessments. CONCLUSIONS: Once-daily indacaterol demonstrated sustained 24-hour bronchodilator efficacy, with similar efficacy on days 1 and 7, and was generally well tolerated.

Safety and tolerability of indacaterol in asthma: a randomized, placebo-controlled 28-day study.

The safety and tolerability of indacaterol, a novel once-daily beta(2)-agonist bronchodilator with a fast onset of action, were assessed in 156 asthma patients in a multicentre, randomized, double-blind, placebo-controlled study. Patients received indacaterol 200, 400 or 600 microg or placebo once daily for 28 days. Adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, spirometry and physical examinations were monitored. Indacaterol pharmacokinetics were assessed. There was no evidence of dose-related increases in AE incidence or clinically significant hypokalaemia or hyperglycaemia in indacaterol-treated patients. Mean pulse rate changes were minor in any group, with maximum 1-h post-dose changes from baseline of -3.7, -3.3 and -2.2 bpm for indacaterol 200, 400 and 600 microg, respectively, and -2.9 bpm for placebo. Mean QTc interval was similar between groups; change from baseline >60 ms occurred in only two patients. Mean FEV(1) increased after the first indacaterol dose; baseline-adjusted pre-dose (trough) values remained >or=166 mL higher than placebo at all subsequent visits, supporting a 24-h bronchodilator effect. Pre-dose (but not post-dose) serum indacaterol concentrations indicated a slight trend for accumulation. Once-daily indacaterol 200-600 microg has a favourable therapeutic index. It is well tolerated, and is not associated with any adverse cardiac or metabolic effects, while providing effective 24-h bronchodilation.

Tolerability of indacaterol, a novel once-daily beta2-agonist, in patients with asthma: a randomized, placebo-controlled, 28-day safety study.

BACKGROUND: Indacaterol is a novel, inhaled, once-daily beta2-agonist. OBJECTIVE: To investigate the safety and tolerability of indacaterol at doses of 400 and 800 microg/d. METHODS: Randomized, double-blind, placebo-controlled, parallel-group, multicenter, 28-day study. Patients with persistent asthma (forced expiratory volume in 1 second [FEV1] > or =-60% predicted, < or =1,600 microg of beclomethasone dipropionate or equivalent daily) received indacaterol, 400 microg (n = 59) or 800 microg (n = 59), or placebo (n = 26) once daily via a single-dose dry powder inhaler. Safety assessments were performed before and after dosing on days 1, 14, and 28, with particular attention to key beta2-agonist safety variables. RESULTS: A total of 144 patients were randomized, with 135 (93.8%) completing the study. Indacaterol was well tolerated: the incidence of adverse events (AEs) was similar between the active and placebo groups, and AEs, when they occurred, were mild or moderate for most (98.2%). There was no dose-response relationship between indacaterol and the incidence of AEs (400 microg, 40.7%; 800 microg, 37.3%; and placebo, 38.5%). Few AEs considered as beta2-agonist class effects occurred (none leading to withdrawal). Small differences between indacaterol and placebo in mean serum potassium (< or =-0.29 mmol/L) and glucose (< or =0.93 mmol/L) levels were occasionally statistically significant (P < .05) but not regarded as clinically meaningful. As expected for a beta2-agonist, there was some indication of a trend in QTc prolongation with increasing exposure (maximum mean change, 8.9 milliseconds; P < .05 vs placebo). Significant increases in FEV1 (P < .05) were seen at all postbaseline time points for both indacaterol doses vs placebo, with indacaterol-placebo differences 30 minutes after dosing of 0.21 to 0.25 L and before dosing on days 14 and 28 (approximately 24 hours after the previous dose) of 0.15 to 0.23 L. CONCLUSION: Indacaterol had a good overall safety profile and was well tolerated at both doses, with predose FEV1 results on days 14 and 28 indicating 24-hour bronchodilator efficacy.

Enteric Bacterial and Viral Pathogens and Indicator Bacteria in Hard Shell Clams.

Enteric bacteria and virus levels were determined in hard shell clams, Mercenaria mercenaria , harvested from areas open or closed for commercial shellfishing on the basis of total coliform levels in water. Four pairs of open and closed stations were sampled seasonally over a 1-year period. Enteric viruses were isolated from 3 of 13 100-g clam samples from open beds and 6 of 15 samples from closed beds. Salmonella was found in 1 of 15 samples from closed areas, but not in any samples from open areas. No Shigella or Yersinia were isolated from clams taken from either open or closed beds. Levels of Vibrio parahaemolyticus , an indigenous estuarine microorganism, were similar in clams from open and closed areas. No statistically significant difference was found in the occurrence of enteric viruses in clams from open and closed areas. Product-moment correlations between concentrations of enteric viruses and bacteria in clams or water demonstrated no statistically significant correlations between virus concentrations in clams and total coliforms or fecal coliforms in water or total coliforms, fecal coliforms, fecal streptococci or aerobic plate counts in clams.