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

Prior to Novel START trial, asthma guidelines recommend ICS for maintenance therapy in patients with more than intermittent asthma (SABA therapy >2 days per week). Unfortunately many patients find it difficult to use corticosteroids daily.[1] The 2018 SYGMA 1[2] and SYGMA 2 trials[3] compared various combinations of ICS, LABA, and SABA agents in double-blinded fashion. SYGMA 1 compared SABA PRN (terbutaline) versus ICS+LABA PRN (budesonide+formoterol) versus ICS BID+SABA PRN (budesonide, terbutaline). It found similar rates of severe asthma exacerbation between the ICS+LABA PRN and ICS BID+SABA PRN groups, both of which were lower than the SABA PRN group. SYGMA 2 compared ICS+LABA PRN (budesonide+formoterol) versus ICS BID+SABA PRN (budesonide, terbutaline) among adults with mild asthma eligible for ICS. ICS+LABA PRN was noninferior in controlling severe asthma exacerbations but came with worse overall symptom control.

The 2019 Novel START trial randomized 675 adults with mild asthma to 1 of 3 arms in an open-label fashion: 1. Budesonide+formoterol PRN (ICS+LABA PRN), 2. Albuterol PRN (SABA PRN), or 3. Budesonide BID+albuterol PRN (ICS BID+SABA PRN). There was a similar number of asthma exacerbations per patient per year between the ICS+LABA PRN and ICS BID+SABA PRN arms. The SABA PRN arm had the greatest number of annual asthma exacerbations. Counter to the findings of the SYGMA trials, the ICS BID+SABA PRN arm had fewer severe exacerbations than the ICS+LABA PRN and SABA PRN arms.

Based on the results of this study, ICS+LABA PRN can reduce number of asthma exacerbations, but might not reduce the risk of severe exacerbations when compared to a scheduled ICS regimen. For a subgroup of individuals with mild asthma, ICS+LABA PRN might be reasonable as it is associated with less corticosteroid exposure. Of note, formoterol is a rapid onset LABA so other ICS-LABA combinations with longer onset LABA medications may be less effective as a PRN agent.

Guidelines

GINA Asthma Management and Prevention Guidelines 2020, Adapted[4]

  • Step 1&2: Low-dose ICS-formoterol PRN (evidence B)
  • Alternative Step 1: Take ICS PRN along with SABA PRN
  • Alternative Step 2: Low-dose maintenance ICS + SABA PRN
  • SABA-only only treatment is not recommended.

Design

  • Multicenter, open-label, parallel-group, randomized, controlled trial
  • N=668
    • Albuterol (n=223)
    • Budesonide BID+albuterol PRN (n=225)
    • Budesonide+formoterol PRN (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+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 budesonide+formoterol PRN vs. albuterol PRN vs. budesonide BID+albuterol 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).
0.195 vs. 0.400 vs. 0.175
Budesonide+formoterol PRN vs. Albuterol PRN (ref): RR 0.49 (95% CI 0.33-0.72; P<0.001)
Budesonide+formoterol PRN vs. Budesonide BID+albuterol PRN (ref): RR 1.12 (95% CI 0.70-1.79; P=0.65)

Secondary Outcomes

Number of exacerbations
37 vs. 74 vs. 32 total (see table S5a&b in the supplemental appendix[5] 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.
9 vs. 23 vs. 21
Budesonide+formoterol PRN vs. Albuterol PRN (ref): RR 0.40 (95% CI 0.18-0.86)
Budesonide+formoterol PRN vs. Budesonide BID+albuterol PRN (ref): RR 0.44 (95% CI 0.20-0.96)
ACQ-5 score
(mean difference)
Budesonide+formoterol PRN vs. Albuterol PRN (ref):
Budesonide BID+albuterol PRN vs. budesonide+formoterol PRN (ref):
On-treatment FEV1
Budesonide+formoterol PRN vs. Albuterol PRN (ref): 0.03 liters (95% CI, -0.006 to 0.07)
Budesonide BID+albuterol PRN vs. budesonide+formoterol PRN (ref): 0.004 liters (95% CI -0.03 to 0.04)
Fraction of exhaled nitric oxide at 12 months (ratio of geometric means)
See Figure 1D on pg 2025 for additional details.
Budesonide+formoterol PRN vs. Albuterol PRN (ref): 0.83 (95% CI 0.75-0.91)
Budesonide+formoterol PRN vs Budesonide BID+albuterol PRN (ref): 1.13 (95% CI 1.02-1.25)
Mean daily dose of budesonide
107±109 ug vs. NA vs. 222±113 ug
Prednisone mg use
8±40 mg vs. 17±60 mg vs. 14±51 mg
Median number (Interquartile range) of β2-agonist actuations per day
0.37 (0.15-0.73) vs. 0.50 (IQR 0.18-1.18) vs. 0.18 (0.06-0.46)
Any adverse event
See Table 3 on Pg 2028 for complete list, the most common events were URIs, nasopharyngitis, and asthma events.
78% vs. 82% vs. 84%

Subgroup Analysis

There was no significant treatment effect interaction in subgroup analyses by gender, smoking status, age, history of exacerbations, baseline SABA use, baseline ACQ-5 score, predicted FEV1, eosinophil count, or FENO.

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. Kaplan A et al. Effective Asthma Management: Is It Time to Let the AIR out of SABA?. J Clin Med 2020. 9:.
  2. O'Byrne PM et al. Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma. N Engl J Med 2018. 378:1865-1876.
  3. Bateman ED et al. As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. N Engl J Med 2018. 378:1877-1887.
  4. Global Initiative for Asthma (adapted). Global Strategy for Asthma Management and Prevention, 2020
  5. Supplemental Appendix