Abstract
BackgroundIndacaterol is a once-daily long-acting inhaled β2-agonist indicated for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). The large inter-patient and inter-study variability in forced expiratory volume in 1 second (FEV1) with bronchodilators makes determination of optimal doses difficult in conventional dose-ranging studies. We considered alternative methods of analysis.MethodsWe utilized a novel modelling approach to provide a robust analysis of the bronchodilatory dose response to indacaterol. This involved pooled analysis of study-level data to characterize the bronchodilatory dose response, and nonlinear mixed-effects analysis of patient-level data to characterize the impact of baseline covariates.ResultsThe study-level analysis pooled summary statistics for each steady-state visit in 11 placebo-controlled studies. These study-level summaries encompassed data from 7476 patients at indacaterol doses of 18.75-600 μg once daily, and showed that doses of 75 μg and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 μg achieved 74% of the maximum effect on trough FEV1, and exceeded the midpoint of the 100-140 mL range that represents the minimal clinically important difference (MCID; ≥120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 μg achieved 85% of the model-predicted maximum effect on trough FEV1 and was numerically superior to all comparators (99.9% probability of exceeding MCID). Indacaterol 300 μg was the lowest dose that achieved the model-predicted maximum trough response.The patient-level analysis included data from 1835 patients from two dose-ranging studies of indacaterol 18.75-600 μg once daily. This analysis provided a characterization of dose response consistent with the study-level analysis, and demonstrated that disease severity, as captured by baseline FEV1, significantly affects the dose response, indicating that patients with more severe COPD require higher doses to achieve optimal bronchodilation.ConclusionsComprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 μg is the minimum effective dose, and that 150 and 300 μg are expected to provide optimal bronchodilation, particularly in patients with severe disease.
Highlights
Indacaterol is the first long-acting inhaled b2-agonist indicated for once-daily maintenance treatment in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), and has been approved in more than 40 countries
In an analysis of data from 801 patients with moderate-to-severe COPD after 2 weeks of treatment (Stage 1 of a Phase II/III study employing an adaptive seamless design), indacaterol 150 μg once daily was identified as the lowest dose that was numerically superior to the active comparators and, along with the highest dose (300 μg), was selected for further evaluation [5]
The key metrics of interest were: the minimum effective dose (MED), defined as the lowest dose that achieved a median trough forced expiratory volume in 1 second (FEV1) that exceeded the midpoint of the 100-140 mL range considered to represent the minimum clinically important difference (MCID) for FEV1 in COPD [15]; the optimal dose, defined as the lowest dose that achieved or exceeded the criteria for the MED and was superior to all active comparators; and the maximum dose defined as the lowest dose with a 95% confidence interval (CI) for the predicted response that includes the expected maximum response
Summary
Indacaterol is the first long-acting inhaled b2-agonist indicated for once-daily maintenance treatment in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD), and has been approved in more than 40 countries (including throughout the European Union) for use at doses of 150 and 300 μg once daily. In an analysis of data from 801 patients with moderate-to-severe COPD after 2 weeks of treatment (Stage 1 of a Phase II/III study employing an adaptive seamless design), indacaterol 150 μg once daily was identified as the lowest dose that was numerically superior to the active comparators (formoterol twice daily and open label tiotropium once daily) and, along with the highest dose (300 μg), was selected for further evaluation [5] This additional evaluation (Stage 2 of the adaptive seamless design study) showed that indacaterol 150 and 300 μg provided statistically significant and clinically relevant improvements in trough forced expiratory volume in 1 second (FEV1) vs placebo up to 26 weeks [2].
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