As-needed Budesonide-Formoterol in Mild Asthma: Pooled Analysis of SYGMA Studies

6 Jul, 21

Introduction

The SYGMA studies assessed the efficacy and safety of as-needed budesonide-formoterol (BUD-FORM) in two pre-specified subpopulations.

Subgroup 1 included patients whose asthma was uncontrolled on as-needed inhaled short-acting bronchodilators.
Subgroup 2 comprised patients whose asthma was controlled on inhaled corticosteroid (ICS) or leukotriene receptor antagonist (LTRA).

Aim

This post-hoc analysis evaluated the influence of pre-study treatment on the clinical outcomes in the SYGMA studies.

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

A total of 6,735 mild asthma patients were randomized to as-needed budesonide-formoterol (BUD-FORM), low-dose budesonide + as-needed terbutaline (BUD maintenance), or as-needed terbutaline (SYGMA 1 only).
The subgroups were analyzed for exacerbation rates and changes in symptom control and pulmonary function.

End Points

Annualized severe exacerbation rates
Time to first severe exacerbation
Change from baseline in pre-bronchodilator FEV1
Asthma symptom control using Asthma Control Questionnaire (ACQ-5,minimal clinically important difference 0.5).

Results

Out of the total of 3836 and 4176 patients in SYGMA 1 and 2 respectively, 1706 (44%) and 1934 (46%) patients had previously been taking short-acting ?-agonists (SABA) alone (Subgroup 1).
Subgroup 2 included 2130 (56%) and 2242 (54%) patients from SYGMA 1 and SYGMA 2 respectively who had previously been treated with low-dose ICS or LTRA.
The pooled population comprised 6735 patients – 46% and 54% from subgroups 1 and 2 respectively.
The annual severe exacerbation rate was significantly lower in Subgroup 1 with as-needed BUD-FORM vs BUD maintenance (rate ratio [RR] 0.74, p=0.03), and was similar in Subgroup 2 with BUD-FORM and BUD maintenance (RR 1.10, p=0.44) as seen in Figure 1.

Figure 1. Annual severe exacerbation rate

In SYGMA 1, the annual severe exacerbation rate was significantly lower in both subgroups with as-needed BUD-FORM vs as-needed terbutaline (Subgroup 1: RR 0.34, p<0.001; Subgroup 2: RR 0.37, p<0.001).
There were no significant differences in the time to first severe exacerbation between BUD-FORM and BUD maintenance in the overall cohort (HR 0.94; p=0.46) and subgroup 2 (HR 1.13; p=0.30)
The time to first exacerbation was delayed with BUD-FORM treatment in subgroup 1 (HR 0.74; p=0.02)
The differences in the improvements with respect to symptom control from baseline between as-needed BUD-FORM and BUD maintenance in overall cohort as well as in both the subgroups (p<0.001 for all) were very small, with a significant effect of pre-study treatment.
Both the subgroups in SYGMA 1 demonstrated small differences in improvements in mean percentage of symptom-free days from baseline between as-needed BUD-FORM and BUD maintenance
BUD-FORM resulted in 9.7 and 10.6 additional symptom-free days in subgroups 1 and 2 respectively as compared to as-needed terbutaline.
There were no clinically significant differences in symptom control and lung function between BUD-FORM and BUD maintenance across subgroups.
NNT defined as number of patients needed to treat to have an additional patient free from severe exacerbation over 1 year, with as-needed BUD-FORM and BUD maintenance vs as-needed terbutaline was 20 and 34 in Subgroup 1 and 13 and 12 in Subgroup 2, respectively.
BUD-FORM treatment was associated with a lower median ICS load in both the subgroups.

Conclusions

Patients with mild asthma previously treated with short-acting ?-agonists (SABA) alone and randomized to as-needed budesonide-formoterol had fewer severe exacerbations than those on twice daily budesonide.
As-needed inhaled corticosteroid (ICS)-formoterol should be preferred to as-needed SABA alone in patients whose asthma is controlled on maintenance low-dose ICS.
Both these low dose ICS therapies are associated with significant reduction in exacerbations and hence are safer than switching to SABA-only treatment.

Ann Am Thorac Soc. 2021 May 12. Doi: 10.1513/AnnalsATS.202011-1386OC.