Trial Design and Oversight

The FLAME trial was a multicenter, randomized, double-blind, double-dummy, parallel-group, noninferiority trial (see Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). From July 2013 through September 2015, patients were enrolled at 356 centers in 43 countries. A 1-week screening period was followed by a 4-week run-in period, during which all patients were treated with inhaled tiotropium at a dose of 18 μg once daily. After the run-in period, tiotropium was discontinued, and the patients were randomly assigned, in a 1:1 ratio, to receive either indacaterol (110 μg) plus glycopyrronium (50 μg) once daily or salmeterol (50 μg) plus fluticasone (500 μg) twice daily for 52 weeks; patients were followed for an additional 30 days after discontinuation of the study regimen. Open-label salbutamol (100 μg) was provided as rescue medication. Additional details are provided in Section 3 in the Supplementary Appendix.

The sponsor (Novartis) developed the protocol, with guidance from the first author and advice from the other academic authors. The first draft of the manuscript was written by the first and second authors. Editorial and technical support in the preparation of the manuscript was provided by a professional medical writer at CircleScience (an Ashfield company, part of UDG Healthcare); the medical writing support was funded by Novartis. All the authors reviewed and edited the manuscript and made the decision to submit the manuscript for publication. All the authors contributed to the interpretation of the data and had access to the full data (nondisclosure agreements were in place). The trial was approved by the ethics committee at each trial center, and all the patients provided written informed consent. All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol (available at NEJM.org). Statistical analyses were performed by a statistician at DataMap. Novartis funded the trial and its analyses, performed trial monitoring and reporting, provided oversight, verified key results provided by DataMap, and had no other role in the trial.

Patients

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 determined23), a post-bronchodilator forced expiratory volume in 1 second (FEV 1 ) of at least 25% to less than 60% of the predicted value, and a post-bronchodilator ratio of FEV 1 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 Supplementary Appendix.

Outcome Measures

The primary objective of this trial was to show whether indacaterol–glycopyrronium would be noninferior to salmeterol–fluticasone in reducing the rate of COPD exacerbations. The primary outcome was the annual rate of all COPD exacerbations (mild, moderate, or severe). An important secondary objective, if noninferiority could be established, was to show whether indacaterol–glycopyrronium would be superior to salmeterol–fluticasone in reducing the annual rate of all COPD exacerbations.

The protocol includes a list of 27 secondary outcome measures; we report data for 19 of these outcomes here and in Sections 4 and 5 in the Supplementary Appendix. The outcomes for which data are not reported herein can be found at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/results/NCT01782326). Secondary outcomes included the times to the first COPD exacerbation of any severity, the first moderate or severe COPD exacerbation, and the first severe COPD exacerbation and the annual rates of moderate or severe exacerbations and of severe exacerbations. We also assessed trough FEV 1 , the standardized area under the curve for FEV 1 from 0 to 12 hours (in a subgroup of patients), health status (measured by the total score on the St. George’s Respiratory Questionnaire for COPD [SGRQ-C], on which scores range from 0 to 100, with higher scores indicating worse health status, and the minimum clinically important difference is 4 points, as compared with the score with placebo24), and the use of rescue medication.

COPD exacerbations, which were defined according to the criteria of Anthonisen et al.,25 were categorized as mild (involving worsening of symptoms for >2 consecutive days but not leading to treatment with systemic glucocorticoids or antibiotics), moderate (leading to treatment with systemic glucocorticoids, antibiotics, or both), or severe (leading to hospital admission or a visit to the emergency department that lasted >24 hours in addition to treatment with systemic glucocorticoids, antibiotics, or both). Patients recorded daily symptoms and the use of rescue medication in an electronic diary (Fig. S2 in the Supplementary Appendix). When worsening of symptoms met the prespecified criteria for exacerbation, alerts were triggered in the electronic diary, and patients were advised to contact their trial site.

The safety of indacaterol–glycopyrronium and salmeterol–fluticasone was also assessed. An independent adjudication committee assessed blinded safety data. Radiographic imaging was required to confirm the presence of pneumonia. Additional details are provided in Section 3 in the Supplementary Appendix.

Statistical Analysis

The noninferiority margin of 15% (corresponding to a rate ratio for exacerbations with indacaterol–glycopyrronium versus salmeterol–fluticasone of 1.15) was based on a previous study,11 in which the rate ratio for moderate or severe exacerbations with salmeterol–fluticasone versus placebo was 0.75. If the FLAME trial could rule out a 15% higher rate of exacerbations with indacaterol–glycopyrronium than with salmeterol–fluticasone, the rate ratio for exacerbations with indacaterol–glycopyrronium versus placebo would be 0.8625, thus leading to a meaningfully lower rate of exacerbations with indacaterol–glycopyrronium than with placebo of more than 13.75%.

We calculated that a sample of approximately 3332 patients would be required to give the trial more than 95% power to rule out a 15% higher rate of COPD exacerbations of any severity with indacaterol–glycopyrronium than with salmeterol–fluticasone, at a one-sided error rate of 0.025, assuming a rate of dropouts or major protocol deviations of 30%. The modified intention-to-treat population included all patients who underwent randomization, received at least one dose of a drug during the treatment period, and did not have major violations of compliance with Good Clinical Practice guidelines before unblinding occurred. The per-protocol population included all patients in the modified intention-to-treat population who did not have any major protocol deviations (definitions of major protocol deviations were specified before unblinding occurred). The main analysis of the primary outcome was performed in the per-protocol population; a supportive analysis of that outcome was performed in the modified intention-to-treat population. Analyses of all other efficacy outcomes were performed in the modified intention-to-treat population. All efficacy analyses, unless stated otherwise, were based on on-treatment data (i.e., for participants who discontinued treatment early, only the data obtained while they were receiving treatment were used).

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.

Although the per-protocol analysis was prespecified as the main analysis of the primary outcome and the modified intention-to-treat analysis as the supportive analysis, it was important to achieve consistent results in the two analyses in order to draw convincing conclusions regarding noninferiority and superiority.26,27 No adjustments for multiple testing were performed for the other outcomes.

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 Supplementary Appendix.