Adult and Adolescent Patients Aged 12 Years of Age and Older

The safety and efficacy of DULERA were demonstrated in two randomized, double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in duration involving 1509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline FEV1 means of 66% to 73% of predicted normal). These studies included a 2 to 3-week run-in period with mometasone furoate to establish a certain level of asthma control. One clinical trial compared DULERA to placebo and the individual components, mometasone furoate and formoterol (Trial 1) and one clinical trial compared two different strengths of DULERA to mometasone furoate alone (Trial 2).

Trial 1: Clinical Trial with DULERA 100 mcg/5 mcg

This 26-week, placebo-controlled trial (NCT00383240) evaluated 781 patients 12 years of age and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate 100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo (n=196 patients); each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2 inhalations twice daily. This trial included patients ranging from 12 to 76 years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian. Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization. All treatment groups were balanced with regard to baseline characteristics. Mean FEV1 and mean percent predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Eight (4%) patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure.

FEV1 AUC(0-12 hr) was assessed as a co-primary efficacy endpoint to evaluate the contribution of the formoterol component to DULERA. Patients receiving DULERA 100 mcg/5 mcg had significantly higher increases from baseline at Week 12 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 100 mcg (the primary treatment comparison) and vs. placebo (both p<0.001) (Figure 1). These differences were maintained through Week 26. Figure 1 shows the change from baseline post-dose serial FEV1 evaluations in Trial 1.

Clinically judged deteriorations in asthma or reductions in lung function were assessed as another primary endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison DULERA vs. formoterol). Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Fewer patients who received DULERA 100 mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg (p<0.001).

The change in mean trough FEV1 from baseline to Week 12 was assessed as another endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg. A significantly greater increase in mean trough FEV1 was observed for DULERA 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment comparison) as well as to placebo (Table 4).

The effect of DULERA 100 mcg/5 mcg, two inhalations twice daily on selected secondary efficacy endpoints, including proportion of nights with nocturnal awakenings (-60% vs. -15%), change in total rescue medication use (-0.6 vs. +1.1 puffs/day), change in morning peak flow (+18.1 vs. -28.4 L/min) and evening peak flow (+10.8 vs. -32.1 L/min) further supports the efficacy of DULERA 100 mcg/5 mcg compared to placebo.

The subjective impact of asthma on patients' health-related quality of life was evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). A change from baseline ≥0.5 points is considered a clinically meaningful improvement. The mean difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo was 0.5 [95% CI 0.32, 0.68].

Trial 2: Clinical Trial With DULERA 200 mcg/5 mcg

This 12-week double-blind trial (NCT00381485) evaluated 728 patients 12 years of age and older comparing DULERA 200 mcg/5 mcg (n=255 patients) with DULERA 100 mcg/5 mcg (n=233 patients) and mometasone furoate 200 mcg (n=240 patients), each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This trial included a 2 to 3-week run-in period with mometasone furoate 200 mcg, 2 inhalations twice daily. Patients had persistent asthma and were uncontrolled on high dose inhaled corticosteroids prior to study entry. All treatment groups were balanced with regard to baseline characteristics. This trial included patients ranging from 12 to 84 years of age, 44% male and 56% female, and 89% Caucasian and 11% non-Caucasian. Mean FEV1 and mean percent predicted FEV1 values were similar among all treatment groups (2.05 L, 66%). Eleven (5%) patients receiving DULERA 100 mcg/5 mcg, 8 (3%) patients receiving DULERA 200 mcg/5 mcg and 13 (5%) patients receiving mometasone furoate 200 mcg discontinued the trial early due to treatment failure.

The primary efficacy endpoint was the mean change in FEV1 AUC(0-12 hr) from baseline to Week 12. Patients receiving DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg had significantly greater increases from baseline at Day 1 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 200 mcg. The difference was maintained over 12 weeks of therapy.

Mean change in trough FEV1 from baseline to Week 12 was also assessed to evaluate the relative contribution of mometasone furoate to DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg (Table 5). A greater numerical increase in the mean trough FEV1 was observed for DULERA 200 mcg/5 mcg compared to DULERA 100 mcg/5 mcg and mometasone furoate 200 mcg.

Clinically judged deterioration in asthma or reduction in lung function was assessed as an additional endpoint. Fewer patients who received DULERA 200 mcg/5 mcg or DULERA 100/5 mcg compared to mometasone furoate 200 mcg alone reported an event, defined as in Trial 1 by any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol.

Other Studies in Adults

In addition to Trial 1 and Trial 2, the safety and efficacy of the individual components, mometasone furoate MDI 100 mcg and 200 mcg (each administered as 2 inhalations by MDI), in comparison to placebo were demonstrated in two other, 12-week, placebo-controlled trials that evaluated the mean change in FEV1 from baseline as a primary endpoint. The safety and efficacy of formoterol MDI 5 mcg (administered as 2 inhalations twice daily) alone in comparison to placebo was replicated in another 26-week trial (NCT00383552) that also evaluated the same endpoint with a lower dose of mometasone furoate MDI in combination with formoterol.

Pediatric Patients Aged 5 to Less Than 12 Years

The efficacy of DULERA 50 mcg/5 mcg in children aged 5 to less than 12 years was demonstrated in a randomized, active-controlled, multicenter clinical trial (NCT02741271) in which DULERA 50 mcg/5 mcg (administered as two inhalations, twice daily; n=91) was compared with mometasone furoate MDI 50 mcg (administered as two inhalations, twice daily; n=90), in 181 asthma patients aged 5 to less than 12 years. These participants had been adequately controlled on an ICS/LABA for at least 4 weeks and had no symptoms of asthma worsening during a 2-week run-in on mometasone furoate MDI 50 mcg (administered as two inhalations twice daily). Primary endpoint results showed that patients receiving DULERA 50 mcg/5 mcg had a statistically significant change from baseline to Week 12 in 60-min AM post-dose % predicted FEV1 compared to mometasone furoate MDI 50 mcg (5.21, 95% CI: 3.22, 7.20) [Figure 2]. Bronchodilatory improvement with DULERA 50 mcg/5 mcg relative to mometasone furoate MDI 50 mcg was significant from the first assessment at 5 minutes and was sustained through 4 hours post-dose. These improvements were evident as early as the first dose and were maintained through Week 12. 

Figure 2: Change from Baseline AM Post-Dose in % Predicted FEV1 Through Week 12

MF = mometasone furoate; MF/F = mometasone furoate/formoterol fumarate  
Population consists of all subjects who received at least one dose of blinded treatment and completed at least one efficacy evaluation.  
Treatment Effects were estimated using the Primary Analysis Method [i.e., a cLDA model with control-based multiple imputation, including terms for treatment, time, age strata (5-7 yrs., 8-11 yrs.), treatment by time interaction, and region (US, ex-US)].

Postmarketing Safety and Efficacy Trial with DULERA

This 26-week double-blind, randomized control trial evaluated 11,729 patients, 12 years of age and older, who received at least one dose of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg, n=5868) or mometasone furoate monotherapy (100 mcg or 200 mcg, n=5861) each administered as 2 inhalations twice daily by metered dose inhalation aerosols (NCT01471340). The primary safety objective was to evaluate whether the addition of formoterol to mometasone furoate (DULERA) was non-inferior to mometasone furoate in risk of serious asthma-related events (adjudicated hospitalization, intubation, and death). A blinded adjudication committee determined whether events were asthma-related. The study was designed to rule out a pre-defined risk margin of 2.0. Enrolled patients had a diagnosis of persistent asthma, had been receiving a stable dose of asthma maintenance therapy for at least 4 weeks and had a history of one to four asthma exacerbations requiring hospitalization or systemic corticosteroid use in the previous year. The assigned dose level of inhaled corticosteroid was based on the patients' disease severity, considering their prior asthma medication and current level of asthma control. The study included patients ranging in age from 12 to 88 years (median age 47 years), and were 66% female and 77% Caucasian.

DULERA was non-inferior to mometasone furoate in terms of time to first serious asthma-related event based on the pre-specified risk margin with an estimated hazard ratio of 1.22 [95% CI: 0.76, 1.94].

The key efficacy endpoint was time to first asthma exacerbation [defined as a clinical deterioration of asthma associated with systemic corticosteroid use for ≥3 consecutive days (or ≥1 depot injectable), emergency department visits <24 hours requiring systemic corticosteroid, or hospital stays of ≥24 hours]. The estimated hazard ratio for time to first exacerbation for DULERA relative to mometasone furoate was 0.89 [95% CI: 0.8, 0.98]. This outcome was primarily driven by a reduction in those events requiring systemic corticosteroid use, which accounted for 87% of the total number of first asthma exacerbations.