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Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.

Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR - Respir. Res. (2011)

Bottom Line: We 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com

ABSTRACT

Background: Indacaterol 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.

Methods: We 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.

Results: The 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.

Conclusions: Comprehensive 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.

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Improvement in trough FEV1 (mL) with indacaterol 150 μg observed at different days in six of the studies in the study-level analysis ranked by median value.
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Figure 2: Improvement in trough FEV1 (mL) with indacaterol 150 μg observed at different days in six of the studies in the study-level analysis ranked by median value.

Mentions: The potential of indacaterol as a bronchodilator is best appreciated when the responses across all the tested dose levels are expressed together in a dose-response relationship. However, given the inherent variability in measurements of lung function relative to the drug-induced change achieved by bronchodilators, accurate characterization of the dose response relationship is difficult. Figure 1 shows individual-patient trough FEV1 data over a range of indacaterol doses (using data from the studies included in the patient-level analysis discussed below) and includes a locally weighted scatterplot smoothing (LOESS) curve to highlight the main trend. While the overall FEV1 in the population varied from about 0.5 to 3 L, the maximum drug response vs placebo is under 200 mL as depicted in the figure inset. This is indicative of the low signal-to-noise ratio of the bronchodilatory response in COPD. The impact of this issue on the interpretation of study results is best illustrated by considering the variability of a single dose level within and between trials. Figure 2 depicts the variability in trough FEV1 response to indacaterol 150 μg across six different studies. Each panel represents the results from one trial. The data points are the least square means (LSM) for each study visit. The grey area within each panel provides a visual representation of the range of responses observed within each trial. The panels are ranked by the median response observed in each trial. This figure shows that the intra- and inter-study variability in mean trough FEV1 may be as high as 50 mL, whereas the inter-study variability in median response may be about 60 mL. The implications of this observation is that relying on single LSM values does not provide adequate precision to easily differentiate between dose levels.


Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.

Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR - Respir. Res. (2011)

Improvement in trough FEV1 (mL) with indacaterol 150 μg observed at different days in six of the studies in the study-level analysis ranked by median value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102616&req=5

Figure 2: Improvement in trough FEV1 (mL) with indacaterol 150 μg observed at different days in six of the studies in the study-level analysis ranked by median value.
Mentions: The potential of indacaterol as a bronchodilator is best appreciated when the responses across all the tested dose levels are expressed together in a dose-response relationship. However, given the inherent variability in measurements of lung function relative to the drug-induced change achieved by bronchodilators, accurate characterization of the dose response relationship is difficult. Figure 1 shows individual-patient trough FEV1 data over a range of indacaterol doses (using data from the studies included in the patient-level analysis discussed below) and includes a locally weighted scatterplot smoothing (LOESS) curve to highlight the main trend. While the overall FEV1 in the population varied from about 0.5 to 3 L, the maximum drug response vs placebo is under 200 mL as depicted in the figure inset. This is indicative of the low signal-to-noise ratio of the bronchodilatory response in COPD. The impact of this issue on the interpretation of study results is best illustrated by considering the variability of a single dose level within and between trials. Figure 2 depicts the variability in trough FEV1 response to indacaterol 150 μg across six different studies. Each panel represents the results from one trial. The data points are the least square means (LSM) for each study visit. The grey area within each panel provides a visual representation of the range of responses observed within each trial. The panels are ranked by the median response observed in each trial. This figure shows that the intra- and inter-study variability in mean trough FEV1 may be as high as 50 mL, whereas the inter-study variability in median response may be about 60 mL. The implications of this observation is that relying on single LSM values does not provide adequate precision to easily differentiate between dose levels.

Bottom Line: We 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com

ABSTRACT

Background: Indacaterol 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.

Methods: We 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.

Results: The 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.

Conclusions: Comprehensive 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.

Show MeSH
Related in: MedlinePlus