The Novel START trial found that among patients with mild asthma, using budesonide-formoterol as needed significantly reduced the risk of asthma exacerbations compared to using albuterol as needed. It also showed a lower exacerbation rate than the budesonide maintenance group, though the difference was not statistically significant. Based on these results, the 2022 GINA guidelines were updated to recommend using budesonide-formoterol as needed as the preferred treatment approach for mild asthma. Budesonide-formoterol is currently available as a hydrofluoroalkane inhaler in two strengths.

1. BACKGROUND

2. ASTHMA
Journal of Allergy and Clinical Immunology. 2007;120(5):S94-S138.

3. LEARNING
OBJECTIVES
Outline the major change in the
2019 Global Initiative for Asthma
(GINA) guidelines
Discuss budesonide-formoterol’s
place in therapy for mild asthma
based on recent literature
Recognize the dose and dosage
form that budesonide-formoterol is
supplied as

4. MEASUREMENTS
OF ASTHMA
CONTROL
Severity
Intrinsic
intensity of
the disease
process
Control
Degree to
which they
are
minimized
Responsivene
ss
The ease with
which control is
achieved by
therapy
Journal of Allergy and Clinical Immunology. 2007;120(5):S94-S138.

5. CONSEQUENCES OF UNCONTROLLED
ASTHMA
Airway remodeling
Scarring of the lungs
Permanent decline in respiratory function
Journal of Allergy and Clinical Immunology. 2007;120(5):S94-S138.

6. Beasley RD et al. NEJM. 2019; 380(21):2020-2030.
NOVEL START TRIAL:
CONTROLLED TRIAL OF BUDESONIDE-
FORMOTEROL AS NEEDED FOR MILD
ASTHMA

7. PURPOSE
ICS use is low as maintenance therapy for mild asthma
An ICS + LABA takes advantage of a patient’s natural
response to use therapy when symptomatic
Two previous clinical trials have been done showing
efficacy and safety in using budesonide-formoterol as
needed
These two trials had high internal validity, but low external
validity
Novel START trial was designed to overcome limitations
of previous 2 trials
Beasley RD et al. NEJM. 2019; 380(21):2020-2030.

8. PREVIOUS TRIALS
SYGMA-1
• Conclusion: inhaled
budesonide-formoterol
when used as needed
was superior to
terbutaline, but was
inferior to budesonide
maintenance therapy
SYGMA-2
• Conclusion: inhaled
budesonide-formoterol
was non-inferior to the
budesonide
maintenance therapy
for severe
exacerbation
• Bateman E et al. NEJM. 2018;378(20):1877-1887.

9. 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?

10. TRIAL 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

11. 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

12. • 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

14. 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

15. OUTCOMES
• Presented as budesonide+formoterol PRN vs. albuterol PRN vs.
budesonide BID+albuterol PRN
Primary Outcomes
• Annual rate of asthma exacerbationsExacerbations 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).

17. RESULTS: PRIMARY OUTCOME
0.4
0.175
0.195
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
Albuterol Group Budesonide Maintenance
Group
Budesonide-Formoterol Group
Annualized Exacerbation Rate
*
Beasley RD et al. NEJM. 2019; 380(21):2020-2030.
* P < 0.05

18. Secondary outcomes
• The risk of exacerbation in the budesonide–formoterol group was
lower than that in the albuterol group, as assessed in a time-to-
first-event analysis and did not differ significantly from that in the
budesonide maintenance group.
• Across all time points, the score on the ACQ-5 was lower in the
budesonide–formoterol group than in the albuterol group, but
was higher in the budesonide–formoterol group than in the
budesonide maintenance group.

19. STRENGHTS
• Good trial design
• Good monitoring and follow up.
• 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
WEAKNESSES
CRITICISM

20. IMPLICATIONS
• If available and not costly a very budesonide-formoterol will be
practice changing in our setting

21. MOVING FORWARD
FDA approval
for
budesonide-
formoterol
Turbuhaler
Changes in
labeling of
budesonide-
formoterol
Further trials
with variety
of doses and
long-term
effects
Guideline
update

22. Low dose ICS whenever
SABA taken, or daily LTRA,
or add HDM SLIT
Medium dose ICS, or
add LTRA, or add
HDM SLIT
Add LAMA or LTRA or
HDM SLIT, or switch to
high dose ICS
Add azithromycin (adults) or
LTRA. As last resort consider
adding low dose OCS but
consider side-effects
RELIEVER: As-needed short-acting beta2-agonist
STEP 1
Take ICS whenever
SABA taken
STEP 2
Low dose
maintenance ICS
STEP 3
Low dose
maintenance
ICS-LABA
STEP 4
Medium/high
dose maintenance
ICS-LABA
STEP 5
Add-on LAMA
Refer for assessment
of phenotype. Consider
high dose maintenance
ICS-LABA, ± anti-IgE,
anti-IL5/5R, anti-IL4R,
anti-TSLP
RELIEVER: As-needed low-dose ICS-formoterol
STEPS 1 – 2
As-needed low dose ICS-formoterol
STEP 3
Low dose
maintenance
ICS-formoterol
STEP 4
Medium dose
maintenance
ICS-formoterol
STEP 5
Add-on LAMA
Refer for assessment
of phenotype. Consider
high dose maintenance
ICS-formoterol,
± anti-IgE, anti-IL5/5R,
anti-IL4R, anti-TSLP
Treatment of modifiable risk factors
and comorbidities
Non-pharmacological strategies
Asthma medications (adjust down/up/between tracks)
Education & skills training
Adults & adolescents
12+ years
Personalized asthma management
Assess, Adjust, Review
for individual patient needs
Symptoms
Exacerbations
Side-effects
Lung function
Patient satisfaction
Confirmation of diagnosis if necessary
Symptom control & modifiable
risk factors (see Box 2-2B)
Comorbidities
Inhaler technique & adherence
Patient preferences and goals
CONTROLLER and
PREFERRED RELIEVER
(Track 1). Using ICS-formoterol
as reliever reduces the risk of
exacerbations compared with
using a SABA reliever
Other controller options for either
track (limited indications, or less
evidence for efficacy or safety)
CONTROLLER and
ALTERNATIVE RELIEVER
(Track 2). Before considering a
regimen with SABA reliever,
check if the patient is likely to be
adherent with daily controller
See GINA
severe
asthma guide
© Global Initiative for Asthma, www.ginasthma.org
GINA 2022, Box 3-5A

23. AUTHOR’S
CONCLUSIONS
• Among patients with mild
asthma, the risk of asthma
exacerbations was lower with
budesonide-formoterol used as
needed than with albuterol used
as needed
Beasley RD et al. NEJM. 2019; 380(21):2020-
2030.

24. FURTHER
DISCUSSION

25. CURRENT BUDESONIDE-
FORMOTEROL FORMULATION
HFA inhaler available in the US
Label: NOT for use during acute bronchospasm
Asthma approved dose: 80 mcg/4.5 mcg or 160 mcg/4.5 mcg
Formoterol onset of action: 15 minutes
Albuterol onset of action: 25 minutes
Budesonide- Formoterol. Lexi-Drugs. Lexicomp

26. BUDESONIDE 80 MCG &
FORMOTEROL 4.5 MCG
BUDESONIDE 160 MCG &
FORMOTEROL 4.5 MCG
BUDESONIDE-FORMOTEROL
Dose = 2 inhalations twice daily

27. SUMMARY
Budesonide-formoterol as-needed
lowers exacerbation rates
2022 GINA guidelines have been
updated to include using
budesonide-formoterol as-needed
first line for mild asthma
Budesonide-formoterol is an HFA
inhaler available as 2 strengths

28. THANK YOU