Fluticasone Furoate and Vilanterol (Page 10 of 11)

14.2 Asthma

The safety and efficacy of fluticasone furoate/vilanterol ELLIPTA were evaluated in 9,969 subjects with asthma. The development program included 4 confirmatory trials (2 of 12 weeks’ duration, 1 of 24 weeks’ duration, 1 exacerbation trial of 24 to 76 weeks’ duration), one 24-week active comparator trial with fluticasone propionate/salmeterol 250/50 mcg, and dose‑ranging trials of shorter duration. The efficacy of fluticasone furoate/vilanterol ELLIPTA is based primarily on the dose-ranging trials and the 4 confirmatory trials described below.

Dose Selection for Vilanterol

Dose selection for vilanterol in asthma was supported by a 28-day, randomized, double-blind, placebo-controlled, parallel-group trial evaluating 5 doses of vilanterol (3 to 50 mcg) or placebo dosed in the evening in 607 subjects with asthma. Results demonstrated dose-related increases from baseline in FEV1 at Day 1 and Day 28 (Figure 5).

Figure 5. Least Squares (LS) Mean Change from Baseline in Postdose Serial FEV1 (0-24 h) (mL) on Days 1 and 28

Day 1

Figure 5 Day 1
(click image for full-size original)

Day 28

Figure 5 Day 28
(click image for full-size original)

The differences in trough FEV1 on Day 28 from placebo for the 3-, 6.25-, 12.5-, 25-, and 50-mcg doses were 64 mL (95% CI: -36, 164), 69 mL (95% CI: -29, 168), 130 mL (95% CI: 30, 230), 121 mL (95% CI: 23, 220), and 162 mL (95% CI: 62, 261), respectively. These results and results of the secondary endpoints supported the evaluation of vilanterol 25 mcg once daily in the confirmatory trials for asthma.

Dose Selection for Fluticasone Furoate

Eight doses of fluticasone furoate ranging from 25 to 800 mcg once daily were evaluated in 3 randomized, double-blind, placebo-controlled, 8-week trials in subjects with asthma. A dose‑related increase in trough FEV1 at Week 8 was seen for doses from 25 to 200 mcg with no consistent additional benefit for doses above 200 mcg. To evaluate dosing frequency, a separate trial compared fluticasone furoate 200 mcg once daily and fluticasone furoate 100 mcg twice daily. The results supported the selection of the once-daily dosing frequency (Figure 6).

Figure 6
(click image for full-size original)

Figure 6. Fluticasone Furoate Dose-Ranging and Dose-Frequency Trials

Confirmatory Trials

The efficacy of fluticasone furoate/vilanterol ELLIPTA was evaluated in 4 randomized, double‑blind, parallel-group clinical trials in adult and adolescent subjects with asthma. Three (3) trials were designed to evaluate the safety and efficacy of fluticasone furoate/vilanterol ELLIPTA given once daily in subjects who were not controlled on their current treatments of ICS or combination therapy consisting of an ICS plus a LABA (Trials 1, 2, and 3). A 24- to 76‑week exacerbation trial was designed to demonstrate that treatment with fluticasone furoate/vilanterol 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 (Trial 5). This trial enrolled subjects 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 6) are provided in Table 7. While subjects aged 12 to 17 years were included in these trials, fluticasone furoate/vilanterol ELLIPTA is not approved for use in this age group [see Indications (1.2), Adverse Reactions (6.2), Use in Specific Populations (8.4)].

Table 7. Demography of Asthma Trials 1, 2, 3, 5, and 6
N/A = Data not collected.
a Trials did not include current smokers; past smokers had fewer than 10 packs per year history.

Parameter

Trial 1

n = 609

Trial 2

n = 1,039

Trial 3

n = 586

Trial 5

n = 2,019

Trial 6

n = 806

Mean age (years) (range)

40 (12, 84)

46 (12, 82)

46 (12, 76)

42 (12, 82)

43 (12, 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 1, 2, and 3 were 12- or 24-week trials that evaluated the efficacy of fluticasone furoate/vilanterol ELLIPTA on lung function in subjects with asthma. In Trial 1, subjects were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate 100 mcg, or placebo. In Trial 2, subjects were randomized to fluticasone furoate/vilanterol ELLIPTA 100/25 mcg, fluticasone furoate/vilanterol ELLIPTA 200/25 mcg, or fluticasone furoate 100 mcg. In Trial 3, subjects were randomized to fluticasone furoate/vilanterol 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. Subjects 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. Subjects reporting symptoms and/or rescue beta2 ‑agonist medication use during the run‑in period were continued in the trial.

In Trials 1 and 3, 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 2, 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. (See Table 8.) Weighted mean FEV1 (0 to 24 hours) was derived from serial measurements 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 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 8. Change from Baseline in Weighted Mean FEV1 (0-24 h) (mL) and Trough FEV1 (mL) at Study Endpoint (Trials 1, 2, and 3)
ICS = inhaled corticosteroid, LABA = long-acting beta2 -adrenergic agonist.

Study (Duration)

Background Treatment

n

Weighted Mean FEV1 (0-24 h) (mL)

Difference from

Treatment

Placebo

(95% CI)

Fluticasone Furoate 100 mcg

(95% CI)

Fluticasone Furoate 200 mcg

(95% CI)

Trial 1 (12 Weeks)

Low- to mid-dose ICS or low-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg

108

302

(178, 426)

116

(-5, 236)

––

Trial 2 (12 Weeks)

Mid- to high-dose ICS or mid-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg

312

––

108

(45, 171)

––

Trial 3 (24 Weeks)

High-dose ICS or mid-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 200/25 mcg

89

––

––

136

(1, 270)

Study (Duration)

Background Treatment

n

Trough FEV1 (mL)

Difference from

Treatment

Placebo

(95% CI)

Fluticasone Furoate 100 mcg

(95% CI)

Fluticasone Furoate 200 mcg

(95% CI)

Trial 1 (12 Weeks)

Low- to mid-dose ICS or low-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg

200

172

(87, 258)

36

(-48, 120)

––

Trial 2 (12 Weeks)

Mid- to high-dose ICS or mid-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 100/25 mcg

334

––

77

(16, 138)

––

Trial 3 (24 Weeks)

High-dose ICS or mid-dose ICS + LABA

Fluticasone furoate/vilanterol ELLIPTA 200/25 mcg

187

––

––

193

(108, 277)

In Trial 1, weighted mean FEV1 (0 to 24 hours) was assessed in a subset of subjects (n = 309). At Week 12, change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with placebo (302 mL; 95% CI: 178, 426; P <0.001) (Table 8); change from baseline in weighted mean FEV1 (0 to 24 hours) for fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with placebo (172 mL; 95% CI: 87, 258; P <0.001) (Table 8); change from baseline in trough FEV1 for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg was numerically greater than fluticasone furoate 100 mcg, but not statistically significant (36 mL; 95% CI: -48, 120).

In Trial 2, the change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (108 mL; 95% CI: 45, 171; P <0.001) at Week 12 (Table 8). In a descriptive analysis, the change from baseline in weighted mean FEV1 (0 to 24 hours) for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg was numerically greater than fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (24 mL; 95% CI: -37, 86) at Week 12. The change from baseline in trough FEV1 was significantly greater for fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg (77 mL, 95% CI: 16, 138; P = 0.014) at Week 12 (Table 8). In a descriptive analysis, the change from baseline in trough FEV1 for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg was numerically greater than fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (16 mL; 95% CI: -46, 77) at Week 12.

In Trial 3, the change from baseline in weighted mean FEV1 (0 to 24 hours) was significantly greater for fluticasone furoate/vilanterol ELLIPTA 200/25 mcg compared with fluticasone furoate 200 mcg (136 mL; 95% CI: 1, 270; P = 0.048) at Week 24 (Table 8). The change from baseline in trough FEV1 was significantly greater for fluticasone furoate/vilanterol 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 fluticasone furoate/vilanterol ELLIPTA in Trials 2 and 3. 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 2 in Figure 7.

Figure 7
(click image for full-size original)

Figure 7. Least Squares (LS) Mean Change from Baseline in Individual Serial FEV1 (mL) Assessments over 24 Hours after 12 Weeks of Treatment (Trial 2)

Subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg (Trial 2) or fluticasone furoate/vilanterol ELLIPTA 200/25 mcg (Trial 3) 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 subjects receiving fluticasone furoate 100 mcg or fluticasone furoate 200 mcg, respectively. In a descriptive analysis (Trial 2), subjects receiving fluticasone furoate/vilanterol 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 subjects receiving fluticasone furoate/vilanterol ELLIPTA 100/25 mcg.

Trial 5 was a 24- to 76-week event-driven exacerbation trial that evaluated whether fluticasone furoate/vilanterol 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 subjects with asthma. Subjects 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. Subjects 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 fluticasone furoate/vilanterol 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 subjects treated with fluticasone furoate/vilanterol 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 subjects treated with fluticasone furoate/vilanterol ELLIPTA 100/25 mcg compared with fluticasone furoate 100 mcg, respectively, were observed (25% reduction in rate; 95% CI: 5%, 40%).

Comparator Trial

Trial 6 was a 24-week trial that compared the efficacy of fluticasone furoate/vilanterol ELLIPTA 100/25 mcg once daily with fluticasone propionate/salmeterol 250/50 mcg twice daily (N = 806). Subjects receiving mid-dose ICS (fluticasone propionate 250 mcg twice daily or equivalent) entered a 4‑week run-in period during which all subjects 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 fluticasone furoate/vilanterol 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).

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