Albuterol-Budesonide Pressurized Metered Dose Inhaler in Patients With Mild-to-Moderate Asthma: Results of the DENALI Double-Blind Randomized Controlled Trial

Abstract

Background: In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy.

Research question: Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma?

Study design and methods: This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 μg or 180/80 μg, albuterol 180 μg, budesonide 160 μg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV₁ area under the curve from 0 to 6 h (FEV₁ AUC_0-6h) over 12 weeks (assessing albuterol effect) and trough FEV₁ at week 12 (assessing budesonide effect).

Results: Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV₁ AUC_0-6h over 12 weeks was greater with albuterol-budesonide 180/160 μg vs budesonide 160 μg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV₁ at week 12 was greater with albuterol-budesonide 180/160 and 180/80 μg vs albuterol 180 μg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents.

Interpretation: Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy.

Clinical trial registration: ClinicalTrials.gov; No.: NCT03847896; URL: www.

Clinicaltrials: gov.

Keywords: albuterol-ICS; albuterol-budesonide; asthma; bronchodilators; inflammation; inhaled corticosteroid; rescue therapy; short-acting β(2)-agonist.

Graphical abstract

Figure 1

Sequential testing of dual-primary end points. For FEV₁ AUC_0-6h over 12 weeks (which evaluated the contribution of albuterol 180 μg), albuterol-budesonide 180/80 μg was not selected for testing in the statistical hierarchy, as the albuterol dose is the same in both albuterol-budesonide 180/160 μg and 180/80 μg. FEV₁ AUC_0-6h = FEV₁ area under the curve from 0 to 6 h; NS = nonsignificant.

Figure 2

Patient disposition. The efficacy analysis included patients aged ≥ 12 y, and the safety analysis included patients of all ages. AE = adverse event.

Figure 3

A and B, Change from baseline in FEV₁ on day 1 (A) and week 12 (B) (serial spirometry profile).

Figure 4

ACQ-7 response at week 12. Response defined as a decrease of ≥ 0.5 units from baseline at week 12 among patients with a baseline score ≥ 1.5. OR (95% CI) albuterol vs placebo: 0.7 (0.4, 1.1); P = .12. OR (95% CI) budesonide vs placebo: 1.4 (0.9, 2.2); P = .16. ∗P < .05 vs placebo; ∗∗P < .001 vs albuterol. ACQ-7 = Asthma Control Questionnaire-7.