14 CLINICAL STUDIES

14.1 Chronic Obstructive Pulmonary Disease

Four trials evaluated the efficacy of BREO ELLIPTA on lung function (Trial 1, NCT01053988 and Trial 2, NCT01054885) and exacerbations (Trial 3, NCT01009463 and Trial 4, NCT01017952).

Lung Function: Trials 1 and 2 were 24-week, randomized, double-blind, placebo-controlled trials designed to evaluate the efficacy of BREO ELLIPTA on lung function in patients with COPD. In Trial 1, patients were randomized to BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, and placebo. In Trial 2, patients were randomized to BREO ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, fluticasone furoate 100 mcg, vilanterol 25 mcg, and placebo. All treatments were administered as 1 inhalation once daily.

Of the 2,254 patients, 70% were male and 84% were White. They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), mean postbronchodilator FEV1/FVC ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%).

The co-primary efficacy variables in both trials were weighted mean FEV1 (0 to 4 hours) postdose on Day 168 and change from baseline in trough FEV1 on Day 169 (the mean of the FEV1 values obtained 23 and 24 hours after the final dose on Day 168). The weighted mean comparison of the fluticasone furoate/vilanterol combination with fluticasone furoate was assessed to evaluate the contribution of vilanterol to BREO ELLIPTA. The trough FEV1 comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA.

BREO ELLIPTA 100/25 mcg demonstrated a larger increase in the weighted mean FEV1 (0 to 4 hours) relative to placebo and fluticasone furoate 100 mcg at Day 168 (Table 6).

Table 6. Least Squares Mean Change from Baseline in Weighted Mean FEV1 (0-4 h) and Trough FEV1 at 6 Months
FEV1 = Forced Expiratory Volume in 1 second.
a At Day 168.
b At Day 169.
Treatment	N	Weighted Mean FEV1 (0-4 h)a (mL)			Trough FEV1b (mL)
		Difference from			Difference from
		Placebo (95% CI)	Fluticasone Furoate 100 mcg (95% CI)	Fluticasone Furoate 200 mcg (95% CI)	Placebo (95% CI)	Vilanterol 25 mcg (95% CI)
Trial 1
BREO ELLIPTA 100/25 mcg	204	214 (161, 266)	168 (116, 220)	––	144 (91, 197)	45 (-8, 97)
BREO ELLIPTA 200/25 mcg	205	209 (157, 261)	––	168 (117, 219)	131 (80, 183)	32 (-19, 83)
Trial 2
BREO ELLIPTA 100/25 mcg	206	173 (123, 224)	120 (70, 170)	––	115 (60, 169)	48 (-6, 102)

Serial spirometric evaluations were performed predose and up to 4 hours after dosing. Results from Trial 1 at Day 1 and Day 168 are shown in Figure 3. Similar results were seen in Trial 2 (not shown).

Figure 3. Raw Mean Change from Baseline in Postdose Serial FEV1 (0-4 h) (mL) on Days 1 and 168

Day 1

Day 168

The second co-primary variable was change from baseline in trough FEV1 following the final treatment day. At Day 169, both Trials 1 and 2 demonstrated significant increases in trough FEV1 for all strengths of the fluticasone furoate/vilanterol combination compared with placebo (Table 7). The comparison of BREO ELLIPTA 100/25 mcg with vilanterol did not achieve statistical significance (Table 7).

Trials 1 and 2 evaluated FEV1 as a secondary endpoint. Peak FEV1 was defined as the maximum postdose FEV1 recorded within 4 hours after the first dose of trial medicine on Day 1 (measurements recorded at 5, 15, and 30 minutes and 1, 2, and 4 hours). In both trials, differences in mean change from baseline in peak FEV1 were observed for the groups receiving BREO ELLIPTA 100/25 mcg compared with placebo (152 and 139 mL, respectively). The median time to onset, defined as a 100-mL increase from baseline in FEV1, was 16 minutes in patients receiving BREO ELLIPTA 100/25 mcg.

Exacerbations: Trials 3 and 4 were randomized, double-blind, 52-week trials designed to evaluate the effect of BREO ELLIPTA on the rate of moderate and severe COPD exacerbations. All patients were treated with fluticasone propionate/salmeterol 250/50 mcg twice daily during a 4-week run-in period prior to being randomly assigned to 1 of the following treatment groups: BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, fluticasone furoate/vilanterol 50/25 mcg, or vilanterol 25 mcg.

The primary efficacy variable in both trials was the annual rate of moderate/severe exacerbations. The comparison of the fluticasone furoate/vilanterol combination with vilanterol was assessed to evaluate the contribution of fluticasone furoate to BREO ELLIPTA. In these 2 trials, exacerbations were defined as worsening of 2 or more major symptoms (dyspnea, sputum volume, and sputum purulence) or worsening of any 1 major symptom together with any 1 of the following minor symptoms: sore throat, colds (nasal discharge and/or nasal congestion), fever without other cause, and increased cough or wheeze for at least 2 consecutive days. COPD exacerbations were considered to be of moderate severity if treatment with systemic corticosteroids and/or antibiotics was required and were considered to be severe if hospitalization was required.

Trials 3 and 4 included 3,255 patients, of which 57% were male and 85% were White. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the patient population had moderate to very severely impaired airflow obstruction. The mean percent reversibility was 15% (range: -65% to 313%).

Patients treated with BREO ELLIPTA 100/25 mcg had a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol in both trials (Table 7).

Table 7. Moderate and Severe Chronic Obstructive Pulmonary Disease Exacerbations
Treatment	n	Mean Annual Rate (exacerbations/year)	Ratio vs. Vilanterol	95% CI
Trial 3
BREO ELLIPTA 100/25 mcg	403	0.90	0.79	0.64, 0.97
BREO ELLIPTA 200/25 mcg	409	0.79	0.69	0.56, 0.85
Fluticasone furoate/vilanterol 50/25 mcg	412	0.92	0.81	0.66, 0.99
Vilanterol 25 mcg	409	1.14	––	––
Trial 4
BREO ELLIPTA 100/25 mcg	403	0.70	0.66	0.54, 0.81
BREO ELLIPTA 200/25 mcg	402	0.90	0.85	0.70, 1.04
Fluticasone furoate/vilanterol 50/25 mcg	408	0.92	0.87	0.72, 1.06
Vilanterol 25 mcg	409	1.05	––	––

Comparator Trials

Three 12-week, randomized, double-blind, double-dummy trials were conducted with BREO ELLIPTA 100/25 mcg once daily versus fluticasone propionate/salmeterol 250/50 mcg twice daily to evaluate the efficacy of serial lung function of BREO ELLIPTA in patients with COPD. The primary endpoint of each trial was change from baseline in weighted mean FEV1 (0 to 24 hours) on Day 84. Of the 519 patients in Trial 5 (NCT01323634), 64% were male and 97% were White; mean age was 61 years; average smoking history was 40 pack years, with 55% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV1 was 48% (range: 19% to 70%), the mean (SD) FEV1/FVC ratio was 0.51 (0.11), and the mean percent reversibility was 11% (range: -12% to 83%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV1 was 47% (range: 14% to 71%), the mean (SD) FEV1/FVC ratio was 0.49 (0.10), and the mean percent reversibility was 11% (range: -13% to 50%).

Of the 511 patients in Trial 6 (NCT01323621), 68% were male and 94% were White; mean age was 62 years; average smoking history was 35 pack years, with 52% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV1 was 48% (range: 18% to 70%), the mean (SD) FEV1/FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -56% to 77%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV1 was 49% (range: 15% to 70%), the mean (SD) FEV1/FVC ratio was 0.50 (0.10), and the mean percent reversibility was 12% (range: -66% to 72%).

Of the 828 patients in Trial 7 (NCT01706328), 72% were male and 98% were White; mean age was 61 years; average smoking history was 38 pack years, with 60% identified as current smokers. At screening in the treatment group using BREO ELLIPTA 100/25 mcg, the mean postbronchodilator percent predicted FEV1 was 48% (range: 18% to 70%), the mean (SD) FEV1/FVC ratio was 0.52 (0.10), and the mean percent reversibility was 12% (range: -26% to 84%). At screening in the treatment group using fluticasone propionate/salmeterol 250/50 mcg, the mean postbronchodilator percent predicted FEV1 was 48% (range: 16% to 70%), the mean (SD) FEV1/FVC ratio was 0.51 (0.10), and the mean percent reversibility was 12% (range: -15% to 67%).

In Trial 5, the mean (SE) change from baseline in weighted mean FEV1 (0 to 24 hours) with BREO ELLIPTA 100/25 mcg was 174 (15) mL compared with 94 (16) mL with fluticasone propionate/salmeterol 250/50 mcg (treatment difference 80 mL; 95% CI: 37, 124; P<0.001). In Trials 6 and 7, the mean (SE) change from baseline in weighted mean FEV1 (0 to 24 hours) with BREO ELLIPTA 100/25 mcg was 142 (18) mL and 168 (12) mL, respectively, compared with 114 (18) mL and 142 (12) mL, respectively, for fluticasone propionate/salmeterol 250/50 mcg (Trial 6 treatment difference 29 mL; 95% CI: -22, 80; P = 0.267; Trial 7 treatment difference 25 mL; 95% CI: -8, 59; P = 0.137).

Mortality Trial

A randomized, double-blind, multicenter, multinational trial (NCT01313676) prospectively evaluated the efficacy of BREO ELLIPTA 100/25 mcg compared with placebo on survival. The trial was event-driven, and patients were followed until a sufficient number of deaths occurred. In this trial, 16,568 patients aged 40 to 80 years received BREO ELLIPTA 100/25 mcg (n = 4,140), fluticasone furoate 100 mcg (n = 4,157), vilanterol 25 mcg (n = 4,140), or placebo (n = 4,131). Patients were treated for up to 4 years, with a median treatment duration of 1.5 years. Median duration of follow-up for the endpoint of survival was 1.8 years for all treatment groups. All patients had COPD with moderate airflow limitation (≥50% and ≤70% predicted FEV1) and either had a history of, or were at risk of, cardiovascular disease. The primary endpoint was all-cause mortality. Secondary efficacy endpoints included the rate of decline in FEV1, annual rate of moderate/severe COPD exacerbations, and health-related quality of life as measured by the St. George’s Respiratory Questionnaire for COPD patients (SGRQ-C).

Survival: Survival with BREO ELLIPTA 100/25 mcg was not significantly improved compared with placebo (hazard ratio 0.88; 95% CI: 0.74, 1.04). Mortality per 100 patient-years was 3.1 for BREO ELLIPTA 100/25 mcg, 3.5 for placebo, 3.2 for fluticasone furoate, and 3.4 for vilanterol.

Lung Function: A reduction of 8 mL/year was estimated on-treatment for BREO ELLIPTA 100/25 mcg compared with placebo in the rate of lung function decline as measured by FEV1 (95% CI: 1, 15).

Exacerbations: Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of moderate/severe exacerbations by 29% compared with placebo (95% CI: 22, 35). Treatment with BREO ELLIPTA 100/25 mcg reduced the annual rate of moderate/severe exacerbations by 19% compared with fluticasone furoate (95% CI: 12, 26) and by 21% compared with vilanterol (95% CI: 14, 28). The on-treatment annual rate of moderate/severe exacerbations was 0.25 for BREO ELLIPTA 100/25 mcg, 0.35 for placebo, 0.31 for fluticasone furoate, and 0.31 for vilanterol.

Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of severe exacerbations (i.e., requiring hospitalization) by 27% compared with placebo (95% CI: 13, 39). Treatment with BREO ELLIPTA 100/25 mcg reduced the on-treatment annual rate of exacerbations requiring hospitalization by 11% compared with fluticasone furoate (95% CI: -6, 25) and by 9% compared with vilanterol (95% CI: -8, 24).

Health-Related Quality of Life: The St. George’s Respiratory Questionnaire (SGRQ) is a disease-specific patient-reported instrument that measures symptoms, activities, and impact on daily life. The SGRQ-C, a shorter version derived from the original SGRQ, was used in this trial. Results were transformed to the SGRQ for reporting purposes. In a subset of 4,443 patients, the on-treatment SGRQ responder rates at 1 year (defined as a change in score of 4 or more as threshold) were 49% for BREO ELLIPTA 100/25 mcg, 47% for placebo, 48% for fluticasone furoate, and 48% for vilanterol (odds ratio 1.18; 95% CI: 0.97, 1.44 for BREO ELLIPTA 100/25 mcg compared with placebo).

14.2 Asthma

Adult Patients

The efficacy of BREO ELLIPTA for the maintenance treatment of asthma was based on data from 4 randomized, double-blind, parallel-group clinical trials (Trial 8 [NCT01165138], Trial 9 [NCT01686633], Trial 10 [NCT01134042] and Trial 12 [NCT01086384]). While these 4 trials enrolled pediatric patients 12 to 17 years of age, these trials only support efficacy in adults [see Use in Specific Populations (8.4)]. In addition, patients in these trials were treated with BREO ELLIPTA 200/25 mcg once daily by oral inhalation, which is not the approved recommended dosage for pediatric patients 12 years of age and older [see Dosage and Administration (2.2)]. Trials 8, 9, and 10 were designed to evaluate the safety and efficacy of BREO ELLIPTA given once daily in patients who were not controlled on their current treatments of ICS or combination therapy consisting of an ICS plus a LABA. Trial 12 (24- to 76-week exacerbation trial) was designed to demonstrate that treatment with BREO ELLIPTA 100/25 mcg significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg. This trial enrolled patients who had 1 or more asthma exacerbations in the year prior to trial entry. The demographics of these 4 trials and the comparator trial (Trial 13, NCT01147848) are provided in Table 8.

Table 8. Demography of Asthma Trials 8, 9, 10, 12, and 13
N/A = Data not collected.
a Trials did not include current smokers; past smokers had fewer than 10 packs per year history.
Parameter	Trial 8 n = 609	Trial 9 n = 1,039	Trial 10 n = 586	Trial 12 n = 2,019	Trial 13 n = 806
Mean age (years) (range) for all patients	40 (12, 84)	46 (12, 82)	46 (12, 76)	42 (12, 82)	43 (12, 80)
Mean age (years) (range) for adult patients	44 (18, 84)	48 (18, 82)	47 (18, 76)	46 (18, 82)	46 (18, 80)
Female (%)	58	60	59	67	61
White (%)	84	88	84	73	59
Duration of asthma (years)	12	18	16	16	21
Never smokeda (%)	N/A	84	N/A	86	81
Predose FEV1 (L) at baseline	2.32	1.97	2.15	2.20	2.03
Mean percent predicted FEV1 at baseline (%)	70	62	67	72	68
% Reversibility	29	30	29	24	28
Absolute reversibility (mL)	614	563	571	500	512

Trials 8, 9, and 10 were 12- or 24-week trials that evaluated the efficacy of BREO ELLIPTA on lung function in patients with asthma. In Trial 8, patients were randomized to BREO ELLIPTA 100/25 mcg, fluticasone furoate 100 mcg, or placebo. In Trial 9, patients were randomized to BREO ELLIPTA 100/25 mcg, BREO ELLIPTA 200/25 mcg, or fluticasone furoate 100 mcg. In Trial 10, patients were randomized to BREO ELLIPTA 200/25 mcg, fluticasone furoate 200 mcg, or fluticasone propionate 500 mcg. All inhalations were administered once daily, with the exception of fluticasone propionate, which was administered twice daily. Patients receiving an ICS or an ICS plus a LABA (doses of ICS varied by trial and asthma severity) entered a 4-week run-in period during which LABA treatment was stopped. Patients reporting symptoms and/or rescue beta2-agonist medication use during the run-in period were continued in the trial.

In Trials 8 and 10, change from baseline in weighted mean FEV1 (0 to 24 hours) and change from baseline in trough FEV1 at approximately 24 hours after the last dose at study endpoint (12 and 24 weeks, respectively) were co-primary efficacy endpoints. In Trial 9, change from baseline in weighted mean FEV1 (0 to 24 hours) at Week 12 was the primary efficacy endpoint; change from baseline in trough FEV1 at approximately 24 hours after the last dose at Week 12 was a secondary endpoint. Table 9 provides the change from baseline in weighted mean FEV1 in mL (0 to 24 hours) and trough FEV1 in mL at study endpoint. Weighted mean FEV1 (0 to 24 hours) was derived from serial measurements taken within 30 minutes prior to dosing and post-dose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours after the final dose. Other secondary endpoints included change from baseline in percentage of rescue-free 24-hour periods and percentage of symptom-free 24-hour periods over the treatment period.

Table 9. Change from Baseline in Weighted Mean FEV1 (0-24 h) (mL) and Trough FEV1 (mL) at Study Endpoint (Trials 8, 9, and 10)a
FEV1 = Forced Expiratory Volume in 1 second, ICS = Inhaled Corticosteroid, LABA = Long-acting Beta2-adrenergic Agonist.
a Although these trials included pediatric patients 12 to 17 years of age, they only support the efficacy in adult patients.
Study (Duration) Background Treatment	n	Weighted Mean FEV1 (0-24 h) (mL)
Study (Duration) Background Treatment		Difference from
Treatment		Placebo (95% CI)	Fluticasone Furoate 100 mcg (95% CI)	Fluticasone Furoate 200 mcg (95% CI)
Trial 8 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA
BREO ELLIPTA 100/25 mcg	108	302 (178, 426)	116 (-5, 236)	––
Trial 9 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA
BREO ELLIPTA 100/25 mcg	312	––	108 (45, 171)	––
Trial 10 (24 Weeks) High-dose ICS or mid-dose ICS + LABA
BREO ELLIPTA 200/25 mcg	89	––	––	136 (1, 270)
Study (Duration) Background Treatment	n	Trough FEV1 (mL)
Study (Duration) Background Treatment		Difference from
Treatment		Placebo (95% CI)	Fluticasone Furoate 100 mcg (95% CI)	Fluticasone Furoate 200 mcg (95% CI)
Trial 8 (12 Weeks) Low- to mid-dose ICS or low-dose ICS + LABA
BREO ELLIPTA 100/25 mcg	200	172 (87, 258)	36 (-48, 120)	––
Trial 9 (12 Weeks) Mid- to high-dose ICS or mid-dose ICS + LABA
BREO ELLIPTA 100/25 mcg	334	––	77 (16, 138)	––
Trial 10 (24 Weeks) High-dose ICS or mid-dose ICS + LABA
BREO ELLIPTA 200/25 mcg	187	––	––	193 (108, 277)

In Trial 8, weighted mean FEV1 (0 to 24 hours) was assessed in a subset of patients (n = 309). At Week 12, change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 mcg compared with placebo (302 mL; 95% CI: 178, 426; P<0.001) (Table 9); change from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (116 mL; 95% CI: -5, 236). At Week 12, change from baseline in trough FEV1 was significantly greater for BREO ELLIPTA 100/25 mcg compared with placebo (172 mL; 95% CI: 87, 258; P<0.001) (Table 9); change from baseline in trough FEV1 for BREO ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 mL; 95% CI: -48, 120).

In Trial 9, the change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P<0.001) at Week 12 (Table 9). In a descriptive analysis, the change from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 200/25 mcg was numerically greater than BREO ELLIPTA 100/25 mcg (24 mL; 95% CI: -37, 86) at Week 12. The change from baseline in trough FEV1 was significantly greater for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 (Table 9). In a descriptive analysis, the change from baseline in trough FEV1 for BREO ELLIPTA 200/25 mcg was numerically greater than BREO ELLIPTA 100/25 mcg (16 mL; 95% CI: -46, 77) at Week 12.

In Trial 10, the change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for BREO ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 (Table 9). The change from baseline in trough FEV1 was significantly greater for BREO ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (193 mL, 95% CI: 108, 277; P<0.001) at Week 24.

Lung function improvements were demonstrated through weighted mean FEV1 (0 to 24 hours) over the 24-hour period following the final dose of BREO ELLIPTA in Trials 9 and 10. Serial FEV1 measurements were taken within 30 minutes prior to dosing and postdose assessments at 5, 15, and 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23, and 24 hours in Trials 1, 2, and 3. A representative figure is shown from Trial 9 in Figure 4.

Figure 4. Least Squares (LS) Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments over 24 Hours after 12 Weeks of Treatment (Trial 9)a

: a Although these trials included pediatric patients 12 to 17 years of age, the data only support the efficacy in adult patients.

Patients receiving BREO ELLIPTA 100/25 mcg (Trial 9) or BREO ELLIPTA 200/25 mcg (Trial 10) had significantly greater improvements from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with patients receiving fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, respectively. In a descriptive analysis (Trial 9), patients receiving BREO ELLIPTA 200/25 mcg had numerical improvements from baseline in percentage of 24-hour periods without need of beta2-agonist rescue medication use and percentage of 24-hour periods without asthma symptoms compared with patients receiving BREO ELLIPTA 100/25 mcg.

Trial 12 was a 24- to 76-week event-driven exacerbation trial that evaluated whether BREO ELLIPTA 100/25 mcg significantly decreased the risk of asthma exacerbations as measured by time to first asthma exacerbation when compared with fluticasone furoate 100 mcg in patients with asthma. Patients receiving low- to high-dose ICS (fluticasone propionate 100 mcg to 500 mcg twice daily or equivalent) or low- to mid-dose ICS plus a LABA (fluticasone propionate/salmeterol 100/50 mcg to 250/50 mcg twice daily or equivalent) and a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroid or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry, entered a 2-week run-in period during which LABA treatment was stopped. Patients reporting symptoms and/or rescue beta2-agonist medication use during the run-in period were continued in the trial.

The primary endpoint was time to first asthma exacerbation. Asthma exacerbation was defined as deterioration of asthma requiring the use of systemic corticosteroid for at least 3 days or an in‑patient hospitalization or emergency department visit due to asthma that required systemic corticosteroid. Rate of asthma exacerbation was a secondary endpoint. The hazard ratio from the Cox Model for the analysis of time to first asthma exacerbation for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg was 0.795 (95% CI: 0.642, 0.985). This represents a 20% reduction in the risk of experiencing an asthma exacerbation for patients treated with BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (P = 0.036). Mean yearly rates of asthma exacerbations of 0.14 and 0.19 in patients treated with BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg, respectively, were observed (25% reduction in rate; 95% CI: 5%, 40%).

Comparator Trial

Trial 13 was a 24-week trial that compared the efficacy of BREO ELLIPTA 100/25 mcg once daily with fluticasone propionate/salmeterol 250/50 mcg twice daily (N = 806). Patients receiving mid-dose ICS (fluticasone propionate 250 mcg twice daily or equivalent) entered a 4-week run-in period during which all patients received fluticasone propionate 250 mcg twice daily. The primary endpoint was change from baseline in weighted mean FEV1 (0 to 24 hours) at Week 24.

The mean change (SE) from baseline in weighted mean FEV1 (0 to 24 hours) for BREO ELLIPTA 100/25 mcg was 341 (18.4) mL compared with 377 (18.5) mL for fluticasone propionate/salmeterol 250/50 mcg (treatment difference -37 mL; 95% CI: -88, 15; P = 0.162).

Pediatric Patients Aged 5 to 17 Years

The efficacy of BREO ELLIPTA for the maintenance treatment of asthma in pediatric patients aged 5 to 17 years of age was based on Trial 14 (NCT03248128), a 24-week, randomized, double-blind, stratified, parallel-group clinical trial. This trial evaluated the efficacy of BREO ELLIPTA compared with fluticasone furoate in 902 pediatric patients with asthma aged 5 to 17 years who were uncontrolled on their current ICS treatment. All inhalations were administered once daily in the morning. At trial entry patients had at least a 6-month history of asthma and had been receiving stable asthma therapy for at least 4 weeks prior to screening. Patients had to have a pre-bronchodilator FEV1 >50% to ≤100% of predicted normal and demonstrate a ≥12% reversibility of FEV1 within 15 to 40 minutes following 2 to 4 inhalations of albuterol inhalation aerosol (or 1 nebulized treatment with albuterol solution). Exclusion criteria included a history of life-threatening asthma or any asthma exacerbation requiring the use of oral corticosteroids, systemic or depot corticosteroids, emergency department visit, or hospitalization within 6 weeks, 3 months, or 6 months of screening, respectively.

Patients entered a 4-week open-label run-in period during which all patients received fluticasone propionate 100 mcg twice daily. Patients reporting symptoms and/or rescue beta2-agonist medication use during the last week of the run-in period were continued in the trial and were stratified by age. Pediatric patients aged 12 to 17 years (n = 229) were randomized 1:1 to BREO ELLIPTA 100/25 mcg once daily (n = 117) or fluticasone furoate 100 mcg once daily (n = 112). Pediatric patients aged 5 to 11 years (n = 673) were randomized 1:1 to BREO ELLIPTA 50/25 mcg once daily (n = 337) or fluticasone furoate 50 mcg once daily (n = 336). The primary endpoint was weighted mean FEV1 (0 to 4 hours) at Week 12. Of the 902 patients, the mean age was 10.0 years, 61% were male, and 73% were White, 8% African American, 6% American Indian or Alaska Native, 6% Asian, and 7% Other. Lung function improvements based on the primary endpoint of weighted mean FEV1 (0 to 4 hours) are presented in Table 10.

Table 10. Weighted Mean FEV1 (0-4 h) (mL) at Week 12 in Patients Aged 5 to 17 Years (Intent to Treat Population)
FEV1 = Forced Expiratory Volume in 1 second, LS = Least Squares, SE = Standard Error.
Primary Endpoint	Fluticasone Furoatea (N = 448)	BREO ELLIPTAb (N = 454)
Weighted Mean FEV1 (0-4 h) (mL)	n = 397	n = 394
LS mean	1999	2081
LS mean change (SE)	323 (16.4)	406 (16.5)
Difference vs fluticasone furoate		83
(95% CI)		(37, 129)

: a The dose of fluticasone furoate was 100 mcg once daily for pediatric patients aged 12 to 17 years and 50 mcg once daily for pediatric patients aged 5 to 11 years.
: b The dose of BREO ELLIPTA was 100/25 mcg once daily for pediatric patients aged 12 to 17 years and 50/25 mcg once daily for pediatric patients aged 5 to 11 years.

Difference in LS mean change from baseline at Week 12 for BREO ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg was 106 mL (95% CI: -8, 220) in pediatric patients 12 to 17 years of age, and difference in LS mean change from baseline at Week 12 for BREO ELLIPTA 50/25 mcg compared with fluticasone furoate 50 mcg was 73 mL (95% CI: 28, 118) in pediatric patients 5 to 11 years of age.