Trial Population

Table 1. Table 1. Baseline Characteristics of the Patients (Intention-to-Treat Population).

The intention-to-treat population included 10,355 patients who underwent randomization and received investigational medication (4151 received triple therapy, 4134 received fluticasone furoate–vilanterol, and 2070 received umeclidinium–vilanterol). Overall, 9087 patients (88%) completed the trial, and 7991 (77%) completed the trial while receiving investigational medication (Fig. S1 in the Supplementary Appendix). In the intention-to-treat population, there were no clinically significant differences among the three treatment groups with regard to baseline demographic characteristics, COPD exacerbations, lung function, and CAT score (Table 1). The majority of patients (66%) were male, and the mean age was 65.3 years. A total of 18% of the patients had bronchodilator reversibility (defined as an increase in FEV 1 of ≥12% and ≥200 ml after administration of albuterol). A total of 43% had a baseline blood eosinophil level of less than 150 cells per microliter.

On trial entry, 38% of the patients were receiving triple therapy including an inhaled glucocorticoid, a LABA, and a LAMA; 29% were receiving an inhaled glucocorticoid and a LABA; and 8% were receiving a LAMA and a LABA. Details on medications at trial entry are provided in Table S4 in the Supplementary Appendix. After the initiation of investigational medication, the rate of premature discontinuation of treatment was lower in the triple-therapy group than in the dual-therapy groups; 758 patients (18%) withdrew from triple therapy, 1040 (25%) from fluticasone furoate–vilanterol, and 566 (27%) from umeclidinium–vilanterol.

Primary Efficacy Analysis

Figure 1. Figure 1. Moderate or Severe COPD Exacerbations (Intention-to-Treat Population). 𝙸 bars indicate 95% confidence intervals. COPD denotes chronic obstructive pulmonary disease, FF fluticasone furoate, UMEC umeclidinium, and VI vilanterol.

The rate of moderate or severe exacerbations during treatment among patients assigned to triple therapy was 0.91 per year, as compared with 1.07 per year among those assigned to fluticasone furoate–vilanterol (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year among those assigned to umeclidinium–vilanterol (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). Thus, the rate of moderate or severe exacerbations was significantly lower with the combination of fluticasone furoate, umeclidinium, and vilanterol than with fluticasone furoate–vilanterol or umeclidinium–vilanterol (Figure 1A).

Secondary Efficacy Analyses

Triple therapy was associated with a lower risk of moderate or severe exacerbations during treatment than dual therapy, as assessed in a time-to-first-event analysis. The hazard ratio for triple therapy versus fluticasone furoate–vilanterol was 0.85 (95% CI, 0.80 to 0.91; 15% difference; P<0.001), and the hazard ratio for triple therapy versus umeclidinium–vilanterol was 0.84 (95% CI, 0.78 to 0.91; 16% difference; P<0.001) (Figure 1B).

The annual rate of moderate or severe exacerbations was lower with triple therapy than with either dual-therapy combination, regardless of eosinophil level, although a greater reduction in the exacerbation rate was observed in patients with eosinophil levels of at least 150 cells per microliter. Among patients with eosinophil levels of less than 150 cells per microliter, the annual rate of moderate or severe exacerbations was 0.85 (95% CI, 0.80 to 0.91) with triple therapy, 1.06 (95% CI, 0.99 to 1.14) with fluticasone furoate–vilanterol, and 0.97 (95% CI, 0.88 to 1.07) with umeclidinium–vilanterol. Among patients with eosinophil levels of at least 150 cells per microliter, the annual rate was 0.95 (95% CI, 0.90 to 1.01) with triple therapy, 1.08 (95% CI, 1.02 to 1.14) with fluticasone furoate–vilanterol, and 1.39 (95% CI, 1.29 to 1.51) with umeclidinium–vilanterol.

The annual rate of severe exacerbations during treatment was 0.13 among patients assigned to triple therapy, 0.15 among those assigned to fluticasone furoate–vilanterol (rate ratio with triple therapy, 0.87; 95% CI, 0.76 to 1.01; 13% difference; P=0.06), and 0.19 among those assigned to umeclidinium–vilanterol (rate ratio with triple therapy, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). Thus, the rate was not significantly lower with triple therapy than with fluticasone furoate–vilanterol but was significantly lower with triple therapy than with umeclidinium–vilanterol.

Table 2. Table 2. Trough FEV 1 and St. George’s Respiratory Questionnaire (SGRQ) Total Score (Intention-to-Treat Population).

For the spirometric outcome of the mean change from baseline in trough FEV 1 , the difference between the triple-therapy and fluticasone furoate–vilanterol groups was 97 ml (95% CI, 85 to 109; P<0.001), and the difference between the triple-therapy and umeclidinium–vilanterol groups was 54 ml (95% CI, 39 to 69; P<0.001). There were significant differences between the triple-therapy group and the fluticasone furoate–vilanterol and umeclidinium–vilanterol groups in the mean change from baseline in the SGRQ total score and in the percentage of patients who had a response as defined by a decrease in the SGRQ total score of at least 4 points (P<0.001 for both comparisons on both outcomes) (Table 2).

Analyses of Other Outcomes

All tests within the predefined statistical testing hierarchy achieved statistical significance, with P<0.001. No adjustments for multiplicity were made for the other comparisons, and P values of less than 0.05 were considered to indicate statistical significance. Beyond the prespecified primary and secondary outcomes, there were multiple prespecified protocol-defined other outcomes, among which were death from any cause during treatment, all exacerbations (mild, moderate, or severe), and dyspnea according to the TDI. Results for these other outcomes provided support for the primary findings, although treatment comparisons were not corrected for multiplicity.

Death during treatment occurred in 50 patients (1%) in the triple-therapy group, 49 patients (1%) in the fluticasone furoate–vilanterol group, and 39 patients (2%) in the umeclidinium–vilanterol group. All-cause mortality was significantly lower with the regimens that included the inhaled glucocorticoid fluticasone furoate (triple therapy and fluticasone furoate–vilanterol) than with umeclidinium–vilanterol. The hazard ratio for triple therapy versus umeclidinium–vilanterol was 0.58 (95% CI, 0.38 to 0.88; 42% difference; unadjusted P=0.01), and the hazard ratio for fluticasone furoate–vilanterol versus umeclidinium–vilanterol was 0.61 (95% CI, 0.40 to 0.93; 39% difference; unadjusted P=0.02). The results of a prespecified analysis of the time to death from any cause including data from patients during treatment and not during treatment provided support for the findings during treatment. Further details are provided in the Supplementary Appendix.

An analysis of adjudicated cause–specific death during treatment showed a lower rate of deaths from both cardiovascular and respiratory causes in the inhaled-glucocorticoid groups than in the umeclidinium–vilanterol group. There were 16 adjudicated cardiovascular deaths during treatment in the triple-therapy group, 21 in the fluticasone furoate–vilanterol group, and 15 in the umeclidinium–vilanterol group (rate per 1000 patient-years, 4.2, 6.0, and 8.7, respectively). There were 15 adjudicated deaths from respiratory causes during treatment in the triple-therapy group, 12 in the fluticasone furoate–vilanterol group, and 9 in the umeclidinium–vilanterol group (rate per 1000 patient-years, 4.0, 3.4, and 5.2, respectively). The rate of deaths that were associated with the patients’ underlying COPD according to the independent adjudicators was lower in the inhaled-glucocorticoid groups than in the umeclidinium–vilanterol group. There were 18 deaths during treatment that were determined to be associated with the patient’s COPD in the triple-therapy group, 14 in the fluticasone furoate–vilanterol group, and 15 in the umeclidinium–vilanterol group (rate per 1000 patient-years, 4.8, 4.0, and 8.7, respectively). Similar results were observed in an analysis that included deaths that occurred in patients no longer receiving treatment. For a summary of adjudicated causes of death, see Tables S9 and S10 in the Supplementary Appendix.

Findings similar to those of the primary efficacy analysis were observed when mild exacerbations (those determined to require only increased albuterol) were included. The annual rate of mild, moderate, or severe exacerbations was 1.05 with triple therapy, 1.25 with fluticasone furoate–vilanterol, and 1.40 with umeclidinium–vilanterol. The rate was 16% lower with triple therapy than with fluticasone furoate–vilanterol (rate ratio, 0.84; 95% CI, 0.79 to 0.89; P<0.001) and 25% lower with triple therapy than with umeclidinium–vilanterol (rate ratio, 0.75; 95% CI, 0.70 to 0.81; P<0.001).

In a subset of 5058 patients, the percentage of patients who had a response as defined by an increase in the TDI of at least 1 unit was higher with triple therapy than with either dual therapy. The rate of response was 36% in the triple-therapy group, 29% in the fluticasone furoate–vilanterol group, and 30% in the umeclidinium–vilanterol group. The odds ratio for response was 1.36 for triple therapy versus fluticasone furoate–vilanterol (95% CI, 1.19 to 1.55; P<0.001) and 1.33 for triple therapy versus umeclidinium–vilanterol (95% CI, 1.13 to 1.57; P<0.001).

Safety and Adverse-Event Profile

Table 3. Table 3. Adverse Events of Special Interest in the Intention-to-Treat Population.

Overall, the adverse-event profile of triple therapy was similar to that of the dual-therapy comparators, and there were no new safety findings associated with the use of an inhaled glucocorticoid, a LAMA, or a LABA in combination (Table 3). There were no clinically relevant differences in ECG measurements, vital signs, or clinical laboratory values among the treatment groups.

The incidence of adverse events during treatment that led to discontinuation of trial treatment or withdrawal from the trial was 6% for triple therapy, 8% for fluticasone furoate–vilanterol, and 9% for umeclidinium–vilanterol; the incidence of discontinuation or withdrawal due to an adverse event of COPD was 2%, 2%, and 3%, respectively. Serious adverse events during treatment occurred in 895 patients (22%) receiving triple therapy, 850 (21%) receiving fluticasone furoate–vilanterol, and 470 (23%) receiving umeclidinium–vilanterol. A total of 14 patients (<1%) receiving triple therapy, 25 (<1%) receiving fluticasone furoate–vilanterol, and 14 (<1%) receiving umeclidinium–vilanterol were reported to have had a nonserious adverse event of COPD worsening. A serious adverse event of pneumonia occurred in 184 patients (4%), 152 patients (4%), and 54 patients (3%), respectively. Further details are provided in Table S12 in the Supplementary Appendix.

There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium–vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium–vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). There was no significant difference in the risk of pneumonia between triple therapy and fluticasone furoate–vilanterol (hazard ratio, 1.02; 95% CI, 0.87 to 1.19; P=0.85).