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

Chest. 2023 Sep;164(3):585-595. doi: 10.1016/j.chest.2023.03.035. Epub 2023 Mar 30.

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 AUC0-6h) 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 AUC0-6h 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.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Albuterol
  • Asthma* / chemically induced
  • Asthma* / drug therapy
  • Bronchodilator Agents
  • Budesonide*
  • Child
  • Double-Blind Method
  • Formoterol Fumarate
  • Humans
  • Metered Dose Inhalers
  • Treatment Outcome

Substances

  • Budesonide
  • Formoterol Fumarate
  • Albuterol
  • Bronchodilator Agents

Associated data

  • ClinicalTrials.gov/NCT03847896