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 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. That 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. Based on the results of this study, ICS-formorterol can reduce the risk of severe exacerbations, while not exposing patients to as much ICS as daily regimens. Notably formoterol is long-acting but has quick onset, which is why it was chosen as part of a relief inhaler. This may not apply to other ICS-LABA combinations.

Guidelines

GINA Guidelines 2020 [1]

Step 1: Low-dose ICS-formoterol as needed

Step 2: Daily low-dose ICS or as needed low-dose ICS-formoterol for controller; low-dose ICS formoterol prn for reliever

Low-dose ICS formoterol prn for reliever inhaler vs SABA across steps.

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 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[2] 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. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2020.
  2. Supplemental Appendix