Table 1.
Pivotal Trials with Triple Therapy FDCs Approved for Maintenance Treatment of COPD versus Dual Bronchodilation
| Study | Patients | Study Design | Therapy | Key Findings |
|---|---|---|---|---|
| Beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide | ||||
| TRIBUTE52 | Patients with a post-bronchodilator FEV1 <50% of the predicted normal value, ≥1 moderate-to-severe COPD exacerbation in the previous 12 months, CAT total score ≥10 and, who had used LABA/ICS, LAMA/ICS, LAMA/LABA, or LAMA monotherapy, but not triple therapy, for at least 2 months before screening | Multicentre, randomised, parallel-group, double-blind, double-dummy study over 52 weeks | BDP/FF/GB 200/12/25 μg twice daily in 764 patients IND/GB 85/43 μg once daily in 768 patients |
Moderate-to-severe exacerbation rates were 0.50 per patient per year (95% CI 0.45 to 0.57) for BDP/FF/GB and 0.59 per patient per year (95% CI 0.53 to 0.67) for IND/GB BDP/FF/GB significantly reduced the rate of moderate or severe exacerbations compared with IND/GB (0.848 (95% CI 0.723 to 0.995; p = 0.043) The time to first moderate or severe exacerbation and the time to the first severe exacerbation were similar between the two treatment groups (hazard ratio 0.901, 95% CI 0.763 to 1.064, p = 0. 219; and 0.864, 95% CI 0.613 to 1.219, p = 0.405. respectively) Change in FEV1 and improvement in mean SGRQ total score from baseline were significantly better with BDP/FF/GB than with IND/GB Pneumonia occurred in 28 (4%) patients receiving BDP/FF/GB versus 27 (4%) patients receiving IND/GB |
| Fluticasone furoate/vilanterol/umeclidinium | ||||
| IMPACT82 | Patients with FEV1 < 50% of the predicted normal value and CAT ≥ 10 and ≥1 moderate or severe exacerbation in the previous year, or patients with FEV1 ≥50–<80% and CAT ≥10, and ≥2 moderate exacerbations in the past year or ≥1 severe exacerbation in the previous year | Multicentre, randomized, double-blind, parallel-group trial over 52 weeks | FLF/VI/UMEC 100/25/62.5 μg once daily in 4251 patients VI/UMEC 25/62.5 μg once daily in 2070 patients |
Moderate-to-severe exacerbation rates were 0.91 per patient per year for FLF/VI/UMEC, and 1.21 per patient per year for VI/UMEC (rate ratio with triple therapy, 0.75; 95% CI 0.70 to 0.81; 25% difference; p < 0.001) The annual rate of moderate or severe exacerbations was lower with triple therapy, regardless of eosinophil level The annual rate of severe exacerbations was significantly lower with triple therapy than with VI/UMEC Change in FEV1 and improvement in mean SGRQ total score from baseline were significantly better with VI/UMEC The risk of clinician-diagnosed pneumonia was significantly higher with FLF/VI/UMEC than with VI/UMEC, as assessed in a time-to-first event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; p < 0.001) |
| Budesonide/formoterol fumarate/glycopyrronium bromide | ||||
| KRONOS83 | Patients with post-bronchodilator FEV1 ≥25–<80% of the predicted normal value, and CAT ≥10 despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening | Multicentre, randomised, double-blind, parallel-group trial over 24 weeks | BUD/FF/GB 320/9.6/18 μg twice daily in 640 patients FF/GB 9.6/18 μg twice daily in 627 patients |
BUD/FF/GB did not significantly improve morning pre-dose trough FEV1 at week 24 versus FF/GB (13 mL, −9 to 36 mL; p=0·2375) BUD/FF/GB resulted in nominally significant improvements in SGRQ total score but not TDI focal score over 24 weeks versus FF/GB The rates of moderate or severe exacerbations with BUD/FF/GB were lower than with FF/GB for patients in both eosinophil subgroups (<150 cells/mm3 or ≥150 cells/mm3) Pneumonia incidence was low (<2%) and similar across treatments. |
| ETHOS51 | Patients with post-bronchodilator FEV1 ≥25–<65% of the predicted normal value, CAT ≥10 and history of at least one moderate or severe COPD exacerbation (if their FEV1 was <50% of the predicted normal value) or at least two moderate or at least one severe COPD exacerbation (if their FEV1 was ≥50% of the predicted normal value) in the year before screening | Multicentre, randomized, double-blind, parallel-group trial over 52 weeks | BUD/FF/GB 320/9.6/18 μg twice daily in 2157 patients or 160/9.6/18 μg twice daily in 2137 patients, both using co-suspension delivery FF/GB 9.6/18 μg twice daily in 2143 patients using co-suspension delivery |
The annual rates of moderate or severe exacerbations were 1.08 with BUD/FF/GB 320/9.6/18 μg, 1.07 BUD/FF/GB 160/9.6/18 μg, 1.42 with FF/GB Both triple-therapy regimens significantly prolonged the time to the first moderate or severe exacerbation as compared with FF/GB The incidence of confirmed pneumonia was 3.5% with BUD/FF/GB 160/9.6/18 μg, 4.5% with BUD/FF/GB 320/9.6/18 μg and 2.3% with FF/GB |
Abbreviations: BDP, beclomethasone dipropionate; BUD, budesonide; CAT, COPD assessment test; FEV1, forced expiratory volume in 1 second; FF, formoterol fumarate; FLF, fluticasone furoate; GB, glycopyrronium bromide; IND, indacaterol; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnea index; UMEC, umeclidinium; VI, vilanterol.