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"To my knowledge, this study represents the first time a therapy appears to reverse -- to a greater or lesser degree depending on the stage of disease -- cognitive and motor decline in patients with these neurodegenerative disorders," researcher Fernando Pagan, in a press statement. "But it is critical to conduct larger and more comprehensive studies before determining the drug's true impact."
In October 2007, after a mean of 30 months of treatment exposure and with data on 979 patients with primary adjudicated end points (59.6% of the originally projected primary end points), the data and safety monitoring committee observed a difference between the two treatment groups that exceeded the boundary of the prespecified stopping rule and recommended early termination of the study. For the analysis used by the data and safety monitoring committee, the boundary value for the z-score interim analysis was 2.74, corresponding to a nominal alpha level of approximately 0.0062 and a cumulative level (based on the alpha-spending function) of 0.0074. The z score for the October 2007 interim analysis was 2.92. Accordingly, the executive committee terminated the trial. However, by January 2008, when all patients had been called back for a final visit within 3 months of the data and safety monitoring committee's recommendation, 1231 patients had reached a primary end point, representing 75.0% of the projected number of patients with primary end points.
This clinical trial was powered for a noninferiority analysis to determine whether the combination of a LABA (indacaterol) and a LAMA (glycopyrronium) would be as effective as the combination of a LABA (salmeterol) and an inhaled glucocorticoid (fluticasone) for the prevention of COPD exacerbations. The LABA–LAMA regimen showed not only noninferiority but also, on a subsequent superiority analysis, consistent superiority to the LABA–inhaled glucocorticoid regimen for all outcomes related to exacerbations, lung function, and health status.
An independent data and safety monitoring committee met twice yearly. For each formal interim analysis of efficacy, a spending function was used to determine significance criteria or stopping rules. Interim analyses performed between January 2006 (6 months after study recruitment ended) and October 2007, the results of which prompted the data and safety monitoring committee to recommend termination, were based on 326, 541, 720, 850, and 979 events, and the associated normal-distribution z-value criteria were determined to be 4.90, 3.73, 3.20, 2.95, and 2.74, respectively. (For the last analysis, despite the pending decision to shorten the trial, the boundary value was determined according to the original trial design, since this was a more cautious approach with regard to potential stopping.)
A potential limitation of the study is that some patients who were treated with a LABA–inhaled glucocorticoid regimen before enrollment and were then assigned to the indacaterol–glycopyrronium group may have had withdrawal effects from the long-term use of their previous regimen, which could have resulted in an increase in exacerbations. There was no evidence that patients who had been receiving inhaled glucocorticoids before the trial withdrew from the trial during the run-in period at higher rates than did patients who had not been receiving inhaled glucocorticoids, and exacerbation rates during the run-in period were low. In addition, analyses of exacerbation rates according to previous therapy showed no meaningful interaction between the treatment and the type of maintenance therapy the patient had previously received.
The number of exacerbations that occurred during the treatment period was analyzed with the use of a negative binomial model that included terms for treatment, baseline smoking status, use of inhaled glucocorticoids at the time of screening, severity of airflow limitation, and geographic region as fixed effects and baseline total symptom score (on a scale ranging from 0 to 18, with higher total scores indicating worse symptoms) and 1-year history of COPD exacerbations as covariates. The overall two-sided type I error rate for the noninferiority and subsequent superiority analyses was controlled at 0.05. Noninferiority of indacaterol–glycopyrronium to salmeterol–fluticasone in reducing the annual rate of COPD exacerbations could be claimed if the upper limit of the 95% confidence interval of the rate ratio for exacerbations with indacaterol–glycopyrronium versus salmeterol–fluticasone was less than 1.15; if noninferiority was established, superiority of indacaterol–glycopyrronium to salmeterol–fluticasone in reducing the annual rate of COPD exacerbations could be claimed if the upper limit of the same 95% confidence interval was less than 1.
We enrolled patients 40 years of age or older who had COPD with a grade of 2 or higher on the modified Medical Research Council scale (which ranges from 0 to 4, with higher grades indicating more severe dyspnea; a minimum clinically important difference has not been determined), a post-bronchodilator forced expiratory volume in 1 second (FEV1) of at least 25% to less than 60% of the predicted value, and a post-bronchodilator ratio of FEV1 to forced vital capacity (FVC) of less than 0.70. Patients were required to have a documented history of at least one COPD exacerbation during the previous year for which they received treatment with systemic glucocorticoids, antibiotic agents, or both. Additional details are provided in Section 2 and Table S1 in the .
Long-term use of glucocorticoids is associated with a small but important risk of pneumonia and other adverse effects. An alternative to the combination of a LABA and an inhaled glucocorticoid for the prevention of COPD exacerbations in patients with a history of exacerbation is a dual bronchodilator regimen of a LABA and a LAMA.
Rates of exacerbations were also analyzed in 19 prespecified subgroup analyses, defined according to 15 baseline characteristics, including baseline blood eosinophil count, to assess the consistency of the treatment effect. All exacerbation outcomes were analyzed with the use of the negative binomial model. The outcomes for the time to the first event were analyzed with the use of a Cox regression model, which included the same terms as the negative binomial model. Additional details are provided in Section 3 in the .