Study population
Results in the overall ITT population have been previously published [8]. A total of 10,355 patients were randomized to treatment in the overall ITT population [8]. Of these, 535 were randomized in China (213 to FF/UMEC/VI, 216 to FF/VI, and 106 to UMEC/VI). Patient disposition for each study cohort is shown in Supplementary Figure 1. The percentages of pre-screen or screen failures and reasons for failures were similar across cohorts. The majority of patients completed study treatment and completed the study; of those treated in the China cohort, 463 (87%) completed study treatment and 479 (90%) completed the study (patients who prematurely discontinued study treatment were encouraged to stay in the study to minimize data loss).
Demographics and baseline characteristics were similar across treatment groups. As anticipated, some demographic characteristics in the China cohort differed from the overall ITT population (Table 1). These included body mass index (BMI), % predicted post-bronchodilator FEV1, CAT score and the proportion of current smokers, which were notably lower in patients from China compared with the overall ITT population. In the China cohort, the majority of patients were male (95%–96% compared with 66%–67% in the ITT), with mean age ranging from 65.5 to 66.1 years across the treatment groups (compared with 65.2 to 65.3 in the ITT) and mean BMI ranging from 22.1 to 22.6 kg/m2 (compared with 26.6 to 26.7 kg/m2 in the ITT).
Primary efficacy analysis
In the China cohort, the rate of on-treatment moderate/severe exacerbations among patients randomized to FF/UMEC/VI was 0.81 per year, compared with 0.96 per year among those randomized to FF/VI (rate ratio [RR]: 0.84; 95% confidence interval [CI]: 0.64, 1.11; p=0.227) and 0.80 per year among those randomized to UMEC/VI (RR: 1.02; 95% CI: 0.72, 1.44; p=0.929) (Table 2). These results were similar to those in the overall ITT population, with a point estimate in favor of FF/UMEC/VI versus FF/VI for the reduction in rate of moderate/severe exacerbations. However, unlike in the ITT population, there was no difference between FF/UMEC/VI and UMEC/VI for this endpoint (Table 2).
Secondary efficacy analyses
In the analysis of the time-to-first moderate/severe exacerbation in the China cohort, hazard ratios for FF/UMEC/VI versus FF/VI and UMEC/VI were 0.84 (95% CI: 0.63, 1.11; p=0.218) and 0.89 (95% CI: 0.62, 1.27; p=0.516), respectively (Figure 1 and Table 2).
The proportion of patients experiencing severe exacerbations while on treatment in China was similar across FF/UMEC/VI, FF/VI, and UMEC/VI treatment groups (18%, 17%, and 17%, respectively), and slightly higher to the incidence in the overall ITT population (11%, 11%, and 13%, respectively; Supplementary Table 1).
In the China cohort, FF/UMEC/VI improved trough FEV1 at Week 52 versus FF/VI (treatment difference 137 mL; 95% CI: 86, 188; p<0.001) and versus UMEC/VI (treatment difference 63 mL; 95% CI: 0, 125; p=0.050) (Figure 2). These improvements were similar to those in the overall population, although the point estimates for the between-treatment difference were in each case slightly higher in China than in the ITT (Figure 2).
Other efficacy endpoints
In the China cohort, the proportion of SGRQ total score responders at Week 52 was higher with FF/UMEC/VI (49%) compared with FF/VI (41%; odds ratio [OR]: 1.40; 95% CI: 0.95, 2.05; p=0.090) and UMEC/VI (41%; OR: 1.34; 95% CI: 0.83, 2.15; p=0.233) (Figure 3). These differences were in line with those observed in the overall ITT population. At Week 52, the LS mean change from baseline data were consistent with the responder data (Supplementary Figure 2).
In the China cohort, the proportion of CAT score responders at Week 52 was higher in the FF/UMEC/VI group (41%) than in the FF/VI group (34%; OR: 1.31; 95% CI: 0.88, 1.96; p=0.180), and similar between FF/UMEC/VI and UMEC/VI (42%; OR: 0.90; 95% CI: 0.56, 1.46; p=0.665) (Figure 4). At Week 52, the LS mean change from baseline data were similar to the results in the overall ITT population (Supplementary Figure 3).
In the China cohort, the rates of mild/moderate/severe COPD exacerbations and COPD exacerbations requiring systemic/oral corticosteroids were lowest in the FF/UMEC/VI group, compared with the FF/VI and UMEC/VI groups (Supplementary Table 2).
Safety endpoints
The incidence of AEs within the China cohort was similar across the three treatment groups, ranging from 75% to 79% (Table 3). The most common AESI in the China cohort were cardiovascular effects (15%) and pneumonia (4%–13%). These were also among the most frequent AESI in the overall ITT population (10%–11% and 5%–8%, respectively) (Table 3). There was a higher incidence of pneumonia AESIs in the FF/UMEC/VI and FF/VI groups in the China cohort (13%) compared with the ITT population (8% and 7%), while incidence of pneumonia AESIs in the UMEC/VI group was similar in China and the ITT (4% and 5%, respectively). There were no differences across the cohorts for the incidence of adjudicated pneumonia SAEs (Table 3). The incidence of COPD exacerbation with evidence of pneumonia adjudicated SAEs in the FF/UMEC/VI, FF/VI, and UMEC/VI groups was 6%, 5%, and 5% in China and 3%, 3%, and 3% in the ITT, respectively. The incidence of pneumonia/RTI without COPD exacerbation adjudicated SAEs in the FF/UMEC/VI, FF/VI, and UMEC/VI groups was 2%, <1%, and 0% in China and 2%, 2%, and 1% in the ITT, respectively (Table 3).
SAEs occurred in 25%–29% of patients in the China cohort, compared with 21%–23% in the overall ITT population (Table 3). In total, there were seven fatal SAEs in the China cohort (two [<1%] in the FF/UMEC/VI group, three [1%] in the FF/VI group, and two [2%] in the UMEC/VI group); these proportions were similar to those seen in the overall ITT population (2% across treatment groups) (Table 3).