Novel START

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Beasley R, et al. "Controlled trial of budesonide-formoterol as needed for mild asthma". The New England Journal of Medicine. 2019. 380(21):2020-2030.
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Clinical Question

In patients with mild asthma treated only with as-needed asthma, does budesonide-formoterol reliever therapy used as-needed reduce the risk of asthma exacerbations compared to albuterol as-needed?

Bottom Line

As-needed budesonide-formoterol was found to reduce the risk of asthma exacerbations compared to albuterol as needed.

Major Points

Current asthma guidelines recommend inhaled corticosteroids for maintenance therapy in patients with more than intermittent asthma (short-acting beta-2 agonist therapy >2 days per week). Unfortunately many patients find it difficult to use corticosteroids daily. The SYGMA trial randomized patients requiring maintenance low-dose corticosteroids in a double-blind fashion to either twice daily placebo with budesonide-formoterol as needed or twice daily budesonide with terbutaline as needed. The trial found that budesonide-formoterol as needed was non inferior to budesonide maintenance therapy in terms of severe exacerbations, but inferior in controlling symptoms.

The Novel START trial aimed to apply the findings of the highly controlled SYGMA trial to reflect real-world practice using an open-label regimen. In the Novel START trial, patients with mild asthma were treated with as-needed budesonide-formoterol compared to as-needed albuterol with or without budesonide maintenance therapy. As-needed budesonide-formoterol was found to be superior to both therapies in terms of the risk of severe exacerbations. Maintenance therapy with budesonide plus as needed albuterol was found to be superior in terms of control of asthma symptoms.

Guidelines

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=668
    • Albuterol (n=223)
    • Budesonide maintenance (n=225)
    • Budesonide-formoterol (n=220)
  • Setting: 16 centers in New Zealand, United Kingdom, Italy, and Australia
  • Enrollment: 2016-2017
  • Follow-up: 52 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: Asthma exacerbations per patient per year

Population

Inclusion Criteria

  • Aged 18-75 years
  • Asthma diagnosis, with one of the following:
    • If no severe exacerbations in the prior year, SABA use on ≥2 occasions in the prior 4 weeks and ≤2 occasions per day (average) in prior 4 weeks
    • If a severe exacerbation in the prior year (not requiring hospitalization), SABA use ≤2 occasions per day in the previous 4 weeks

Exclusion Criteria

  • Hospitalization for asthma in the previous 12 months, or any admissions to an ICU for asthma
  • Smoking with >20 PYH
  • Self-reported onset of respiratory symptoms after the ago of 40 years in current or previous smokers with at least a 10 pack-year smoking history
  • Maintenance therapy with ICS, LABA, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone in prior 3 months
  • Treatment with oral prednisone in the prior 6 weeks, or a home supply of prednisone for use in worsening asthma
  • COPD, bronchiectasis, ILD, HF, unstable CAD, AF, other significant cardiac disease
  • Pregnancy
  • Unwilling to switch asthma treatment
  • FEV1 ≤50% predicted at visit 1

Baseline Characteristics

  • Mean ACQ-5 score 1.1

Interventions

  • Randomized 1:1:1 to a group:
    • Albuterol PRN - Albuterol dose 100 ug
    • Budesonide BID maintenance + albuterol PRN - Budesonide dose 200 ug, albuterol dose 100 ug
    • Budesonide-formoterol PRN - Budesonide-formoterol dose 200-6 ug
  • Electronic monitors recorded inhaler use
  • Withdrawal from trial after a severe exacerbation (worsening asthma leading to prescription of systemic glucocorticoid treatment for at ≥3 days or hospitalization/ED visit leading to systemic glucocorticoid treatment), 3 exacerbations separated by ≥7 days, or unstable disease requiring change in medication from what they were assigned

Outcomes

Presented as albuterol PRN vs. budesonide BID+albuterol PRN vs. budesonide-formoterol PRN

Primary Outcomes

Annual rate of asthma exacerbations
Exacerbations was defined as worsening asthma that leading to an urgent outpatient, ED, or inpatient medical care consultation, prescription of systemic glucocorticoids for any duration, or an episode of high β2-agonist use (>16 actuations of albuterol or >8 actuations of budesonide-formoterol in 24 hours).
0.400 vs. 0.175 vs. 0.195
Albuterol PRN vs. budesonide-formoterol PRN (ref): RR 0.49 (95% CI 0.33-0.72; P<0.001)
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref): RR 1.12 (95% CI 0.70-1.79; P=0.65)

Secondary Outcomes

Number of exacerbations
74 vs. 32 vs. 37 total (see table S5a&b in the supplemental appendix[1] for additional details)
Number of severe exacerbations
Severe exacerbations was defined as worsening asthma that required prescription of systemic glucocorticoid treatment for ≥3 days or ED visit/hospitalization resulting in systemic glucocorticoid treatment; participants were excluded after their first severe exacerbation so there were no repeat severe exacerbations.
23 vs. 21 vs. 9
Albuterol PRN vs. budesonide-formoterol PRN (ref): RR 0.40 (95% CI 0.18-0.86)
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref): RR 0.44 (95% CI 0.20-0.96)
ACQ-5 score
(mean difference)
Albuterol PRN vs. budesonide-formoterol PRN (ref):
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref):
On-treatment FEV1
See Figures S9&10 in the supplemental appendix[1] for details. These values were similar between groups during the follow-up.
Fraction of exhaled nitric oxide at 12 months (ratio of geometric means)
See Figure 1D on pg 2025 for additional details.
Albuterol PRN vs. budesonide-formoterol PRN (ref): 0.83 (95% CI 0.75-0.91)
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref): 1.13 (95% CI 1.02-1.25)
Mean daily dose of budesonide
NA vs. 222±113 ug vs. 107±109 ug
Albuterol PRN vs. budesonide-formoterol PRN (ref):
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref):
Prednisone mg use
17±60 mg vs. 14±51 mg vs. 8±40 mg
Median number of β2-agonist actuations per day
0.50 (IQR 0.18-1.18) vs. 0.18 (0.06-0.46) vs. 0.37 (0.15-0.73)
Any adverse event
See Table 3 on Pg 2028 for complete list, the most common events were URIs, nasopharyngitis, and asthma events.
82% vs. 84% vs. 78%
Albuterol PRN vs. budesonide-formoterol PRN (ref):
Budesonide BID+albuterol PRN vs. budesonide-formoterol PRN (ref):

Subgroup Analysis

Criticisms

  • Insufficiently powered (225 participants per study arm required to achieve sufficient power as per reported calculation)
  • Lack of smoking pack-year history (SPYH) stratification
  • Mean age of 35.6 limits external validity for older patient populations

Funding

  • AstraZeneca
  • Health Research Council of New Zealand

Further Reading

  1. 1.0 1.1 Supplemental Appendix