Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approachesReport as inadecuate

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Respiratory Research

, 12:54

First Online: 01 December 2011Received: 03 February 2011Accepted: 26 April 2011


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.

AbbreviationsCI confidence interval

COPD chronic obstructive pulmonary disease

FEV 1 forced expiratory volume in 1 second

LOESS locally weighted scatterplot smoothing

LSM least squares mean

MCID minimal clinically important difference

MED minimum effective dose

NLME nonlinear mixed effects

TDI transition dyspnoea index

Electronic supplementary materialThe online version of this article doi:10.1186-1465-9921-12-54 contains supplementary material, which is available to authorized users.

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Author: Didier Renard - Michael Looby - Benjamin Kramer - David Lawrence - David Morris - Donald R Stanski


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