As-needed Budesonide-Formoterol Effective and Safe in Adolescents with Mild Asthma: Pooled Analysis of SYGMA Studies

5 Aug, 21

Introduction

Low-dose inhaled corticosteroids (ICS) brings about effective symptom control and reduces the risk of exacerbations in asthma including mild asthma. However, poor adherence to medications and over-reliance on short acting ?-agonists (SABA) have been the major challenges in the management of asthma, especially for adolescents. The results of SYGMA 1 trial concluded that treatment with as-needed budesonide-formoterol (BUD-FORM) reduces the severe exacerbations as compared to as-needed terbutaline, with similar efficacy to BUD maintenance. The severe exacerbation rates over 12 months were similar between as-needed BUD-FORM and BUD maintenance, as per the findings of SYGMA 2 trial.

Aim

This post hoc pooled analysis of SYGMA 1 and 2 evaluated the efficacy, medication adherence and safety of as-needed BUD-FORM in adolescents with mild asthma.

Patient Profile

Subjects aged >12 years with mild asthma either uncontrolled with as-needed inhaled short-acting bronchodilators or controlled on low-dose ICS or LTRA.

Method

Study Design

Post-hoc analysis of two randomized, double-blind, parallel-group, 52-week phase 3 studies SYGMA 1 and SYGMA 2

Treatment Strategy

Patients were randomized into 3 arms
- Twice-daily placebo + as-needed BUD-FORM 200/6 ?g
- Twice-daily BUD 200 ?g + as-needed terbutaline (BUD maintenance)
- Twice-daily placebo + as-needed terbutaline 0.5 mg (SYGMA 1 only).

End Points

Annualized severe exacerbation rates
Time to first severe exacerbation
Pulmonary function in terms of forced expiratory volume in 1 sec % predicted (%FEV₁)
Asthma symptom control using Asthma Control Questionnaire (ACQ-5).
Adherence to randomized maintenance treatment
Adverse events (AEs)
Severe AEs (SAEs)

Results

The overall cohort comprised of 889 adolescents: 478 from SYGMA 1 and 411 from SYGMA 2.
In SYGMA 1, annualized severe exacerbation rate was 77% lower with as-needed BUD-FORM than as-needed terbutaline (p=0.005) as seen in Figure 1.
The results of pooled analysis revealed no significant difference in the annual rate of severe exacerbations in BUD-FORM group vs BUD maintenance group; 0.08 vs 0.07 per patient per year (p=0.634).

Figure 1. Annual rate of severe exacerbations (SYGMA 1)

Time to first severe exacerbation was significantly longer in BUD-FORM group as compared to as-needed terbutaline; hazard ratio (HR) 0.33; p=0.02.
There was no significant difference in the time to first severe exacerbation in both the groups in pooled analysis; HR 1.23; p=0.47.
The mean ACQ-5 score improved from baseline across all the 3 groups and the difference was not significant.
A significant difference in change in FEV₁ % predicted from baseline was demonstrated with as-needed BUD-FORM versus BUD maintenance in SYGMA 1 (estimated difference, −3.9%; p < .001) and in the pooled analysis (estimated difference, −2.3%; p < .001), but not in SYGMA 2
The overall median adherence to medication was 73% and 51% in SYGMA 1 and SYGMA 2 respectively.
The adolescents aged ≥12 years to <14 years in the BUD-FORM group had significantly greater change in height from baseline as compared to BUD maintenance (4.8 vs 3.9 cm); p < 0.046.
In SYGMA 1, the mean change in height of adolescents was similar between as-needed BUD-FORM and as-needed terbutaline (4.5 cm vs 4.1 cm); p = 0.500.
The incidence of AEs was similar in BUD-FORM and BUD-maintenance groups and higher in as-needed terbutaline group as seen in Figure 2.
SAEs were also slightly higher in as-needed terbutaline group.

Figure 2. Incidence of AEs and SAEs

There were no new or unexpected safety concerns that were identified in this pooled analysis.

Conclusions

Reliever therapy with as-needed budesonide-formoterol (BUD-FORM) was superior to as-needed terbutaline and significantly reduced the rate of severe exacerbations and demonstrated similar efficacy to BUD maintenance in terms of symptom control and lung function in adolescents with mild asthma.
As-needed BUD-FORM can be considered as an ideal alternative in adolescents with mild asthma, which can avoid daily maintenance treatment.

J Allergy Clin Immunol Pract. 2021 Apr 22; S2213-2198(21)00456-6. Doi: 10.1016/j.jaip.2021.04.016.