Aim

To compare the safety and efficacy of budesonide/formoterol as needed to (short-acting ?2 –agonists (SABA) as needed to budesonide maintenance therapy plus SABA as needed.

Patient Profile

• N= 3849
• Patients ≥12 years of age

• Documented diagnosis of asthma as per Global Initiative for Asthma [GINA] 2012 criteria for at least 6 months prior

• Patients who need step 2 treatment according to Global Initiative for Asthma guidelines  for at least 30 days before run-in period

Study Design

• Double-blind, randomized, parallel-group, 52-week, phase 3 trial

Treatment

• Terbutaline group: Twice-daily placebo plus terbutaline (0.5 mg, used on an as-needed basis)
• Budesonide-formoterol group: Twice-daily placebo plus budesonide– formoterol (200 ?g of budesonide and 6 ?g of formoterol, used on an as-needed basis)
• Budesonide maintenance group: Twice-daily budesonide (200 ?g) plus terbutaline (0.5 mg, used on an as-needed basis)
• Duration: 52 week

Endpoints

Primary Endpoint 

• To show that budesonide–formoterol used as needed was superior to terbutaline used as needed in terms of asthma symptom control, measured according to the electronically recorded weeks with well-controlled asthma

Secondary Endpoints

• Non inferiority of study treatment ie formoterol-budesonide as-needed vs budesonide maintenance treatment in terms of asthma control
• Time to the first severe exacerbation (defined as worsening asthma leading to the use of systemic glucocorticoids for ≥3 days, inpatient hospitalization, or an emergency department visit leading to the use of systemic glucocorticoids)
• The rates and time to the first moderate-to-severe exacerbation (including worsening asthma requiring the addition of inhaled budesonide at a dose of 200 ?g twice daily to avoid progression to a severe exacerbation) in the budesonide-formoterol group versus the terbutaline group and versus the budesonide maintenance group
• Asthma Control Questionnaire–5 (ACQ-5) scores,
• Lung function variables
• Quality of life (according to the Asthma Quality of Life Questionnaire [AQLQ] score)
• Safety was evaluated according to the type, incidence, and severity of adverse events and by monitoring of vital signs

Results

• The final analysis included  data from 3836 patients

• 3363 patients (87.4%) completed the trial
• Budesonide-formoterol was superior to terbutaline but inferior to budesonide maintenance therapy as assessed by electronically recorded weeks with well-controlled asthma per patient

• Budesonide-formoterol used as needed prolonged the time to the first severe exacerbation, as compared with terbutaline used as needed (hazard ratio, 0.44)

• No significant difference in adherence was observed between groups
  •  Rate of adherence in budesonide maintenance group was (78.9%); terbutaline group (79.0%); budesonide –formoterol group (79.1%)
• Fewer patients in budesonide-formoterol group were prescribed inhaled or systemic glucocorticoids for asthma than in terbutaline or budesonide maintenance group

• The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57?g) was 17% of the dose in the budesonide maintenance group (340?g)

Conclusion

• Budesonide–formoterol used as needed resulted in
  • 64% lower rate of severe exacerbations than terbutaline used as needed
  • 60% lower rate of moderate-to-severe exacerbations than terbutaline used as needed

• Budesonide-formoterol was superior to terbutaline but inferior to budesonide maintenance therapy in terms of in terms of electronically recorded weeks with well-controlled asthma
  • Budesonide-formoterol group (34.4%) 
  • Terbutaline group (31.10%)
  • Budesonide –formoterol Maintenance group (44.4%)

The budesonide /formoterol treatment was as effective as budesonide maintenance group with less than 1/5^th the dose of inhaled corticosteroid used in the budesonide/formoterol group compared to the budesonide maintenance therapy

N Engl J Med 2018; 378:1865-76