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

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 mu g or 180/80 mu g, albuterol 180 mu g, budesonide 160 mu g, 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 mu g vs budesonide 160 mu g (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P 1/4 .003). Change in trough FEV1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 mu g vs albuterol 180 mu g (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.