The safety and efficacy of TRELEGY ELLIPTA were evaluated in 2,436 subjects in a randomized, double-blind, parallel-group, active-controlled confirmatory trial of 24 to 52 weeks’ duration in adult subjects with asthma inadequately controlled on their current treatments of combination therapy (ICS plus a LABA) (Trial 4, NCT02924688).
Subjects with an Asthma Control Questionnaire (ACQ-6) score ≥1.5 on their current asthma treatment of ICS (greater than fluticasone propionate 250 mcg/day or equivalent) plus LABA entered a 3-week run-in period of treatment with fluticasone propionate/salmeterol 250/50 mcg twice daily. Subjects who remained inadequately controlled (ACQ-6 ≥1.5) after the run-in period were transferred to fluticasone furoate/vilanterol 100/25 mcg once daily for a 2-week stabilization period. After the 5-week run-in/stabilization period, eligible subjects were randomized to receive once-daily inhalations of TRELEGY ELLIPTA 100/62.5/25 mcg (n = 406), TRELEGY ELLIPTA 200/62.5/25 mcg (n = 408), fluticasone furoate/umeclidinium/vilanterol 100/31.25 mcg/25 mcg (n = 405), fluticasone furoate/umeclidinium/vilanterol 200/31.25 mcg/25 mcg (n = 404), fluticasone furoate/vilanterol 100/25 mcg (n = 407), or fluticasone furoate/vilanterol 200/25 mcg (n = 406).
Across all treatment groups, baseline demographics were similar. The majority of subjects were female (62%), White (80%), and had never smoked (81%), with a mean age of 53 years and mean asthma duration of 21 years (range: 1 to 70). The trial excluded current smokers; past smokers had an average smoking history of 4.3 pack-years. In the prior 12 months, 85% of subjects reported having any exacerbation; approximately 63% of subjects reported having an exacerbation that required oral/systemic corticosteroids and/or hospitalization.
At screening, the mean prebronchodilator percent predicted FEV1 was 58.5% (SD: 12.8%); the mean percent reversibility was 29.9% (SD: 18.1%), with a mean absolute reversibility of 484 mL (SD: 274 mL), and the mean ACQ-6 score was 2.5 (SD: 0.6). During the 5-week run‑in/stabilization period, subjects had improvements in both lung function (trough FEV1 improvement of 287 mL) and asthma control (mean ACQ-6 score decreased by 0.6). At randomization, the majority (93%) remained not well controlled (mean ACQ-6 score of 1.9) and the mean prebronchodilator percent predicted FEV1 was 68.2% (SD: 14.8%).
Lung Function: The primary efficacy endpoint was change from baseline in trough FEV1 at Week 24. Both TRELEGY ELLIPTA 100/62.5/25 mcg and TRELEGY ELLIPTA 200/62.5/25 mcg showed statistically significant improvements in lung function compared with fluticasone furoate/vilanterol 100/25 mcg and fluticasone furoate/vilanterol 200/25 mcg, respectively (Table 6, Figures 8 and 9).
|FEV1 = Forced Expiratory Volume in 1 Second, FF/VI = Fluticasone Furoate/Vilanterol.|
Trough FEV1 (mL)
(n = 407)
(n = 406)
(n = 406)
(n = 408)
Least squares mean
Least squares mean change (SE)
TRELEGY ELLIPTA 100/62.5/25 mcg vs. FF/VI 100/25 mcg
TRELEGY ELLIPTA 200/62.5/25 mcg vs. FF/VI 200/25 mcg
Figure 8. Least Squares Mean Change from Baseline in Trough FEV1 (mL) with TRELEGY ELLIPTA 100/62.5/25 mcg over 24 Weeks of Treatment
Figure 9. Least Squares Mean Change from Baseline in Trough FEV1 (mL) with TRELEGY ELLIPTA 200/62.5/25 mcg over 24 Weeks of Treatment
The difference in change from baseline in trough FEV1 at Week 24 for TRELEGY ELLIPTA 100/62.5/25 mcg compared with fluticasone furoate/vilanterol 200/25 mcg was 59 mL (95% CI: 15, 102).
The change from baseline in FEV1 at 3 hours post-dose was supportive of the primary endpoint with improvements for TRELEGY ELLIPTA 100/62.5/25 mcg compared with fluticasone furoate/vilanterol 100/25 mcg (111 mL, 95% CI: 67, 155) and TRELEGY ELLIPTA 200/62.5/25 mcg compared with fluticasone furoate/vilanterol 200/25 mcg (118 mL, 95% CI: 74, 162).
Onset of action was determined in a separate trial conducted with fluticasone furoate/vilanterol; the median time to onset (defined as a 100-mL increase from baseline in mean FEV1 ) was approximately 15 minutes.
Additional bronchodilator effects of umeclidinium in TRELEGY ELLIPTA compared with fluticasone furoate/vilanterol were present over the 24-hour dosing period as shown by 3 hours post-dose FEV1 , PM FEV1 , and trough FEV1 endpoints. The bronchodilator effects of TRELEGY ELLIPTA were consistently observed from Week 1 through Week 24.
Exacerbations: Asthma exacerbations were assessed over the 52-week treatment period. Asthma exacerbations were defined as deterioration of asthma requiring the use of systemic corticosteroid (or at least a doubling of maintenance dose) for at least 3 days or an inpatient hospitalization or emergency department visit due to asthma that required systemic corticosteroid.
In a descriptive pooled analysis, the mean annualized rate of exacerbations was 0.31 for TRELEGY ELLIPTA [100/62.5/25 and 200/62.5/25 mcg, 127 of 814 (16%) patients reported exacerbations] and 0.31 for fluticasone furoate/vilanterol [100/25 and 200/25 mcg, 132 of 813 (16%) patients reported exacerbations] (2.6% reduction in rate; 95% CI: -26.2, 24.9).
In descriptive unpooled analyses, the mean annualized rates of exacerbations were 0.41 and 0.23 for TRELEGY ELLIPTA 100/62.5/25 mcg and TRELEGY ELLIPTA 200/62.5/25 mcg, respectively. The mean annualized rates of exacerbations were 0.38 and 0.26 for fluticasone furoate/vilanterol 100/25 mcg and fluticasone furoate/vilanterol 200/25 mcg, respectively.
Health-Related Quality of Life: Additional efficacy measures included Asthma Control Questionnaire (ACQ). The ACQ-7 incorporates 5 questions on symptoms, FEV1 , and rescue bronchodilator use and was assessed at Week 24. ACQ-7 (7-items) responder was defined as a decrease in score of ≥0.5.
In a descriptive pooled analysis, the ACQ-7 responder rate was 63% for TRELEGY ELLIPTA (100/62.5/25 and 200/62.5/25 mcg) compared with 55% for fluticasone furoate/vilanterol (100/25 and 200/25 mcg) at Week 24, favoring TRELEGY ELLIPTA (OR: 1.43; 95% CI: 1.16, 1.76).
In an unpooled descriptive analysis, the ACQ-7 responder rate was 62% for TRELEGY ELLIPTA 100/62.5/25 mcg compared with 52% for fluticasone furoate/vilanterol 100/25 mcg (OR: 1.59; 95% CI: 1.18, 2.13) at Week 24, favoring TRELEGY ELLIPTA. The ACQ-7 responder rate was 64% for TRELEGY ELLIPTA 200/62.5/25 mcg compared with 58% for fluticasone furoate/vilanterol 200/25 mcg (OR: 1.28; 95% CI: 0.95, 1.72) at Week 24, favoring TRELEGY ELLIPTA.
The ACQ-5 (comprising the 5 questions on symptoms from ACQ-7) responder rates at Week 24 for pooled and unpooled analyses were similar to the ACQ-7 results.
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