title: Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.
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.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com
authors.forename: Didier
authors.initials: D
authors.lastname: Renard
authors.forename: Michael
authors.initials: M
authors.lastname: Looby
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kramer
authors.forename: David
authors.initials: D
authors.lastname: Lawrence
authors.forename: David
authors.initials: D
authors.lastname: Morris
authors.forename: Donald R
authors.initials: DR
authors.lastname: Stanski
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D018849:Controlled Clinical Trials as Topic; D003661:Decision Support Techniques; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D005541:Forced Expiratory Volume; D006801:Humans; D007189:Indans / Q000008:administration & dosage*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D017711:Nonlinear Dynamics; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D015363:Quinolones / Q000008:administration & dosage*; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D007189:Indans; D015363:Quinolones; C510790:indacaterol