MANDALA and DENALI pattern success for albuterol-budesonide in asthma

In patients with uncontrolled moderate-to-severe asthma, the risk of asthmatic exacerbation was significantly reduced when patients used a fixed-dose inhaler with a combination of albuterol and budesonide as-needed compared with the use of an inhaler with albuterol alone as-needed, in a dose-dependent manner. A second clinical trial confirmed that both components contributed to albuterol/budesonide efficacy, with the combinations demonstrating superior effects on lung function.

Short-acting β₂-agonists provide quick asthma symptom relief but fail to address underlying inflammation. Combining short-acting β₂-agonist albuterol (180 μg) and corticosteroid budesonide (160 μg) in a single, as-needed, rescue inhaler for asthma could provide rapid bronchodilation while treating airway inflammation. The phase 3, double-blind, randomised, event-driven MANDALA trial (NCT03769090) looked at patients with uncontrolled moderate-to-severe asthma and asked whether this fixed-dose rescue inhaler could lower the risk for severe asthma exacerbations compared with albuterol monotherapy used as a rescue inhaler. Prof. Alberto Papi (University of Ferrara, Italy) presented the results, which were simultaneously published in the New England Journal of Medicine [1,2].

MANDALA enrolled patients with moderate-to-severe asthma of >3 years old who had had ³1 severe exacerbation in the prior 12 months. Despite allowing children, only 183 of 3,132 randomised participants were paediatric patients; the mean age of the intention-to-treat population was 49 years. Participants were allocated to 1 of 3 arms: an arm receiving the combination with a high-dose of budesonide (albuterol 180 µg/budesonide 160 µg), a lower-dose arm (albuterol 180 µg/budesonide 80 µg), or albuterol 180 µg alone. Study medication was administered through blinded, pressurised metered-dose inhalers. All patients continued receiving maintenance inhaled corticosteroids either with or without other medications for their asthma.

The primary endpoint was time to first severe asthma exacerbation, which reported a 27% reduction among participants assigned a fixed-dose combination of the higher dose combination compared with albuterol 180 µg alone (HR 0.73; 95% CI 0.61–0.88; P<0.001). Similarly, a 17% reduction was observed with the lower-dose combination arm (HR 0.83; 95% CI 0.7–0.99; P=0.041), but the data did suggest a dose-response. In an additional intention-to-treat analysis, risk was reduced by 26% with the higher-dose combination (HR 0.74; 95% CI 0.62–0.89; P=0.001) and 16% with the lower-dose combination (HR 0.84; 95% CI 0.71–1.0; P=0.052).

With regard to safety, the incidence of any adverse event was nearly identical across all 3 groups, with 46.2% in the higher-dose combination group, 47.1% in the lower-dose combination group, and 46.4% in the albuterol-only group. Similarly, serious adverse events occurred in 5.2%, 3.8%, and 4.5%, respectively. Adverse events were consistent with the known safety profiles of the individual components; the most common adverse events were nasopharyngitis, headache, and upper respiratory tract infection.

In another session, Dr Bradley Chipps (Capital Allergy & Respiratory Disease Center, CA, USA) presented the results of the phase 3 DENALI trial (NCT03847896) [3]. DENALI was a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial. Similar to MANDALA, it evaluated the efficacy and safety of albuterol/budesonide in a single inhaler but compared it with albuterol and budesonide monotherapy in patients with mild-to-moderate asthma (excluding children aged 4–11 years). Participants (n=1,001) were randomised to 5 treatment groups in a 1:1:1:1:1 ratio: albuterol/budesonide 180/160 μg 4 times daily, albuterol/budesonide 180/80 μg 4 times daily, albuterol alone 180 μg 4 times daily, budesonide 160 µg 4 times daily, or placebo 4 times daily. The trial started with 2–4 weeks of baseline screening, 12 weeks of treatment, and included an additional 2 weeks of follow-up.

The 2 primary efficacy endpoints were designed to gauge the effect of the individual components: (1) the change from baseline in forced expiratory volume in one second (FEV₁) area under the curve 0–6 hours over 12 weeks of albuterol/budesonide treatment compared with budesonide monotherapy to assess the effect of albuterol, and (2) change from baseline in trough FEV₁ at week 12 of albuterol/budesonide compared with albuterol monotherapy to assess the effect of budesonide. Secondary endpoints included the time to onset and duration of response, number of patients who achieved a clinically meaningful benefit in asthma control at week 12, and trough FEV₁ at week 1.

DENALI met its dual primary endpoints. The researchers reported a statistically significant improvement for combined albuterol/budesonide in FEV₁ at week 12 compared with budesonide (least-squares mean [LSM] difference 80.7 mL; 95% CI 28.4–132.9; P=0.003), as well as versus albuterol (LSM difference 132.8 mL; 95% CI 63.6–201.9 and 120.8 mL; 95% CI 51.5–190.1, for 80 and 160 μg budesonide, respectively; both P<0.001). The onset of action and duration of effect were similar on day 1. The safety profiles for both albuterol/budesonide doses were similar to those of each of the individual components.

“Given the efficacy of adding budesonide to albuterol as a rescue medication and the duration of the treatment, we believe that this is going to be a potential change in the paradigm of the use of rescue medication,” Prof. Papi concluded.

1. Papi A, et al. Efficacy and safety of as-needed albuterol/budesonide versus as-needed albuterol in adults, adolescents and children aged ≥4 years with moderate-to-severe asthma: Results of the MANDALA study. Session B12, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.
2. Papi A, et al. N Engl J Med 2022; May 15. DOI: 10.1056/NEJMoa2203163.
3. Chipps BE, et al. Efficacy and safety of albuterol/budesonide (PT027) in mild-to-moderate asthma: Results of the DENALI study. Session B93, ATS International Conference 2022, San Francisco, CA, USA, 13–18 May.

 

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Posted on 18 July 2022