Severe exacerbations and inhaled corticosteroid load with as-needed budesonide/formoterol vs maintenance budesonide in mild asthma

Eric D. Bateman1, Helen K. Reddel2, Paul M. O’Byrne3, Peter J. Barnes4, Nanshan Zhong5, Christina Keen6, Carin Jorup6, Rosa Lamarca7, Agnieszka Siwek-Posluszna8, and J. Mark FitzGerald9
1
Division of Pulmonology, Department of Medicine, University of Cape Town, South Africa; 2Woolcock Institute of Medical Research, University of Sydney, Australia; 3Firestone Institute for Respiratory Health, St Joseph’s Healthcare and Department of Medicine, Michael G.
DeGroote School of Medicine, McMaster University, Hamilton, Canada; 4Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 5State Key Laboratory of Respiratory Diseases, First Affiliated Hospital, Guangzhou Medical University, China;
6
AstraZeneca R&D, Gothenburg, Sweden; 7AstraZeneca, Barcelona, Spain; 8AstraZeneca, Warsaw, Poland; 9Institute for Heart and Lung Health, University of British Columbia, Vancouver, Canada

• The primary analysis used a negative binomial model that
Introduction
• Current guidelines recommend that patients with mild
asthma should be prescribed regular low-dose inhaled
• There were fewer participants with high use of as-needed
included terms for treatment, pre-study treatment, and region,
Figure 1. Annualized severe asthma exacerbation rate
(non-inferiority test and superiority test)
Figure 2. Time to first severe exacerbation
Budesonide maintenance (N=2087)
BUD/FORM than as-needed terbutaline: fewer took
and was conducted on the full analysis set population. Non- As-needed BUD/FORM (N=2089) >8 inhalations per day (10.4% vs 15.0%) or >12 inhalations
0.10 Number (%) patients with event:
inferiority could be claimed if the upper bound of the 1-sided As-needed BUD/FORM 177 (8.5) per day (4.1% vs 7.4%) at least once.
Budesonide maintenance 184 (8.8)
95% confidence interval (CI) was less than 1.2.

a severe exacerbation
Probability of having
As-needed Budesonide Rate ratio P value
corticosteroids (ICS) as maintenance medication.1 Test
BUD/FORM maintenance (95% CI)
Hazard ratio (95% CI 2-sided): 0.96 (0.78 to 1.17); p=0.66
Figure 4. Change in ACQ-5 over time
• There was no adjustment for multiplicity testing for
• However, adherence to regular maintenance therapy is
secondary variables. Non-inferiority test 2084 2083 0.97 (NA to 1.16) –
poor,2 and patients tend to rely on and overuse as-needed 0.05 As-needed BUD/FORM (N=2089) Budesonide maintenance (N=2087)
0.2 Change in ACQ-5, from baseline to treatment period average, LS Mean (± 95% CI)
short-acting β2-agonists (SABAs), which do not address
underlying airway inflammation. SABA overuse is associated Results 0.1
As-needed BUD/FORM –0.35
Budesonide maintenance –0.46

Change in ACQ-5 score

Superiority test 2089 2087 0.97 (0.78 to 1.20) 0.75 Treatment difference (95% CI): 0.11 (0.07 to 0.15); p<0.001
with severe exacerbations3 and death.4 0.0
Patients

from baseline
• The SYGMA 2 (SYmbicort Given as needed in Mild Asthma) –0.1
• Of 6634 patients enrolled, 4215 were randomized, and 4176 0.00
study was designed in parallel with SYGMA 1 using a more 0.6 0.8 1.0 1.2 1.4
0 4 8 12 17 20 24 28 34 36 40 44 48 52 –0.2
patients were included in the full analysis set (as-needed Time (weeks)
pragmatic study design, without daily maintenance As-needed BUD/FORM Budesonide maintenance –0.3
BUD/FORM, N=2089; budesonide maintenance, N=2087) (Table 1). better better
medication reminders, to determine whether as-needed Adherence and ICS dose –0.4
budesonide/formoterol (BUD/FORM) is non-inferior to regular Table 1. Baseline demographics and clinical characteristics • Electronically-recorded adherence with blinded maintenance –0.5
budesonide maintenance therapy in preventing severe
As-needed Budesonide • A similar number of patients in both treatment groups had treatment was 63–64% across randomization groups. –0.6
exacerbations in patients with mild asthma. 0 4 8 12 16 20 24 28 32 36 40 44 48 52
BUD/FORM Maintenance Total severe exacerbations requiring emergency department visits or • Median daily ICS dose was 75% lower in the as-needed Time (weeks)
200/6 µg 200 µg BID (N=4176) hospitalizations (Table 2).
(N=2089) (N=2087)
BUD/FORM arm compared with the budesonide maintenance
Methods Age, years, mean (SD) 41.3 (16.8) 40.7 (17.1) 41.0 (17.0) Table 2. Severe asthma exacerbations and exacerbation rate
arm (metered doses 66 µg and 267 µg, respectively). Safety
Lung function and asthma control • One death in each arm, adjudicated as acute asthmatic
• SYGMA 2 was a 52-week, double-blind, randomized, parallel- Female sex, n (%) 1308 (62.6) 1289 (61.8) 2597 (62.2)
As-needed Budesonide exacerbation in the budesonide maintenance arm and
group study (ClinicalTrials.gov identifier: NCT02224157).5 BUD/FORM maintenance • The change in pre-bronchodilator FEV1 from baseline was
200/6 µg 200 µg BID lower with as-needed BUD/FORM compared to budesonide cardiorespiratory arrest in the as-needed BUD/FORM arm.
Time since asthma
• Patients aged ≥12 years with a clinical diagnosis of asthma (N=2089) (N=2087) maintenance (mean difference: -32.6 mL [95% CI -53.7 to
diagnosis, years, 7.9 (0.5 to 62.4) 7.3 (0.4 to 71.2) 7.6 (0.4 to 71.2)
(GINA 2012 criteria6) for ≥6 months, and considered by the
investigator to require GINA Step 2 treatment (regular low-dose
median (range) All severe exacerbations
Patients with at least 177 (8.5) 184 (8.8)
-11.4]) (Figure 3). Conclusions
ICS or LTRA6), were randomized to either twice-daily placebo ACQ-5 score, mean (SD) 1.49 (0.89) 1.53 (0.90) 1.51 (0.90) one exacerbation, n (%) • ACQ-5 score decreased over time for both groups (Figure 4). • In patients with mild asthma, who in this study were
plus as-needed BUD/FORM 200/6 µg (Symbicort® Turbuhaler®, Total number of exacerbations/ 0.11 0.11 moderately adherent with blinded maintenance treatment,
Pre-bronchodilator FEV1, patient-year Figure 3. Change in pre-bronchodilator FEV1 over time as-needed BUD/FORM was associated with a similar
AstraZeneca) or twice-daily budesonide 200 µg (Pulmicort®
% predicted N=2079 N=2075 N=4154 Severe exacerbations requiring
Turbuhaler®, AstraZeneca) plus as-needed terbutaline 0.5 mg Mean (SD) 84.4 (13.9) 84.1 (13.9) 84.3 (13.9)
(non-inferior) rate of severe exacerbations but slightly less
systemic corticosteroid use for symptom control compared to maintenance budesonide.
(budesonide maintenance). at least 3 days
As-needed BUD/FORM (N=2089) Budesonide maintenance (N=2087)
180
Reversibility (%) N=2069 N=2058 N=4127 • This was achieved at 75% less daily ICS dose than

Change in pre-bronchodilator
• Primary objective: to demonstrate non-inferiority of as-needed Patients with at least one 171 (8.2) 173 (8.3)
Mean (SD) 15.1 (12.4) 15.2 (13.0) 15.2 (12.7) 160

FEV1 (mL) from baseline

BUD/FORM to budesonide maintenance for the annualized rate exacerbation, n (%) maintenance budesonide without the need for twice-daily
Total number of exacerbations/ 0.10 0.10 140
of severe exacerbations (worsening asthma leading to systemic Pre-study treatment maintenance dosing.
patient-treatment year 120
corticosteroid treatment for ≥3 days, hospitalization, or subgroup, n (%)
100
emergency department visit leading to systemic Uncontrolled* on BD 959 (45.9) 975 (46.7) 1934 (46.3) Severe exacerbation requiring
Controlled* on ICS 1130 (54.1) 1112 (53.3) 2242 (53.7) emergency department visit and 80 References
corticosteroid treatment). systemic corticosteroids 1. Global Strategy for Asthma Management and Prevention 4. Stanford RH, et al. Ann Allergy Asthma Immunol
or LTRA 60
2018 (http://ginasthma.org/). 2012;109:403-7.
• Secondary objectives included: Patients with at least one 25 (1.2) 36 (1.7) 40
Change in pre-bronchodilator FEV1, from baseline to treatment period average, LS Mean (± 95% CI)
2. Rand C, et al. J Allergy Clin Immunol 2007;119:916-23. 5. O’Byrne PM, et al. Trials 2017;18:12.
As-needed BUD/FORM 104.0 mL
Severe exacerbation in exacerbation, n (%) 20 Budesonide maintenance 136.6 mL
3. Suissa S, et al. J Respir Crit Care Med 1994;149:604-10.

– between-group differences in efficacy assessed as time to first previous 12 months, n (%) Total number of exacerbations/ 0.01 0.02 Treatment difference (95% CI): –32.6 mL (–53.7 to –11.4); p=0.003
0
severe exacerbation; 0 1630 (78.0) 1627 (78.0) 3257 (78.0) patient-treatment year 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Acknowledgments
1 365 (17.5) 362 (17.3) 727 (17.4) Severe exacerbations requiring Time (weeks) We thank the health care providers, research staff, patients, and caregivers who participated in this trial. Sophieanne
– inhaled and systemic corticosteroid use; ≥2 94 (4.5) 98 (4.7) 192 (4.6) hospitalization Wastling of inScience Communications, Springer Healthcare, provided medical writing support, which was funded by
AstraZeneca in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).
– pre-bronchodilator forced expiratory volume in 1 second *Asthma control on pre-study treatment was physician-assessed. Patients with at least one 17 (0.8) 17 (0.8)
(FEV1); exacerbation, n (%) As-needed medication use Disclosure statement
Exacerbations Total number of exacerbations/ 0.01 0.01 • An average of 0.52 (SD 0.55) inhalations/day of as-needed EDB reports non-financial support from AstraZeneca, and personal fees from AstraZeneca during the conduct of the
study; personal fees from Novartis, Cipla, Vectura, Menarini, ALK, ICON, Sanofi Regeneron, and Boehringer Ingelheim;
– Asthma Control Questionnaire (5-item version; ACQ-5). patient-treatment year BUD/FORM were taken, compared with 0.49 (SD 0.70) and grants to institutions from Novartis, Boehringer Ingelheim, Merck, Takeda, GlaxoSmithKline,
• As-needed BUD/FORM was non-inferior to budesonide Hoffmann-La Roche, Actelion, Chiesi, Sanofi-Aventis, Cephalon, and TEVA, outside of the
• Use of all randomized medications (maintenance and as maintenance for annualized severe asthma exacerbation rate inhalations/day of as-needed terbutaline in the budesonide submitted work; and is a Member of the Global Initiative for Asthma Board and Science

needed) was electronically recorded using Turbuhaler® Usage
Monitors (Adherium).
• There was no difference between the two treatment groups in maintenance group. Patients randomized to as-needed Committee. JMF reports grants and personal fees from AstraZeneca during the conduct of the
(0.11 [95% CI 0.10 to 0.13] and 0.12 [0.10 to 0.14], time to first severe asthma exacerbation (Figure 2).
study; grants to UBC from AstraZeneca, Novartis, Boehringer Ingelheim, GlaxoSmithKline,
respectively) (Figure 1). BUD/FORM had fewer days with no as-needed use (69.0% Hoffmann-La Roche, Sanofi-Aventis, and TEVA outside the submitted work; personal fees from
Novartis, Sanofi Regeneron, Merck, and Boehringer Ingelheim; and is a Member of the Global
vs 75.9%). Initiative for Asthma Board and Science Committee.

Presented at the ATS International Conference 2018, May 18–23, San Diego, CA, USA