Introduction

The efficacy of inhaled corticosteroid (ICS)-formoterol reliever monotherapy has been demonstrated in adults with mild asthma. This combination has been associated with reduction in asthma attacks as compared to a short-acting β2-agonist (SABA) reliever monotherapy. However, its efficacy in adolescents is restricted to a subgroup analysis of 3306 adolescents aged between 12-17 years from SYGMA 1. The ICS-formoterol reliever monotherapy lowered the risk of severe asthma attacks by 77% as compared to SABA reliever monotherapy. There are no comparative studies done in children aged below 12 years. The scarcity of evidence raises concerns as morbidity and mortality risk in these children with mild asthma is quite substantial despite SABA monotherapy alone.

Aim

To compare the safety and efficacy of as-needed budesonide-formoterol with as-needed salbutamol in asthmatic children aged 5-15 years using SABA monotherapy alone.

Method

Study Design

Patient Inclusion Criteria 

• Children aged between 5-15 years diagnosed with asthma
• Currently using a SABA inhaler only
• Met atleast one of the below sub-criteria       
  1. SABA use on >3 consecutive days during the past 12 months
  2. SABA use >2 days per month in the past 12 months
  3. Urgent medical review for worsening of asthma in the past 12 months

Treatment Strategy 

• Patients were randomised into salbutamol group and budesonide-formoterol groups in this Children’s Anti-Inflammatory Reliever (CARE) study
• Salbutamol group received 100 µg salbutamol; 2 inhalations as needed
• The budesonide–formoterol group received budesonide 50 μg–formoterol 3 μg, two inhalations as needed
• Visits were scheduled at weeks 0, 13, 26, 39 and 52

Endpoints

Primary Endpoint

Secondary Endpoints

• Annualised rate of severe asthma attacks
• Proportion of participants with atleast 1 severe asthma attack
• Time to first severe asthma attack
• Proportion of participants with atleast 1 asthma attack
• Time to first asthma attack
• Proportion of participants on each treatment step
• Days in hospital because of asthma
• Fractional exhaled nitric oxide (FeNO)
• On-treatment forced expiratory volume in 1 sec (FEV₁) % predicted
• Asthma symptom control measured using Asthma Control Questionnaire-5 (ACQ-5) score
• Number of days lost from school due to asthma
• Number of days lost from work because of childcare for asthma
• Total systemic corticosteroid use
• Growth velocity

Safety Endpoint

• Adverse events (AEs)
• Serious AEs

Results

• Of the 382 participants evaluated, 360 were eligible for the study 
• The participants were assigned to the budesonide–formoterol group (n=179) and the salbutamol group (n=181)
• The baseline characteristics of the cohort were as follows
  1. Mean age 10 years
  2. Mean ACQ-5 score of 1.05
• The budesonide-formoterol group had a lower annualized rate of asthma attacks as compared to the salbutamol group; cluster-adjusted rates 0.23 vs 0.41 per participant per year (relative rate 0.55; p=0.012) as seen in Table 1.
• The time to first asthma attack was longer in the budesonide-formoterol group; HR 0.48
• Atleast 1 asthma attack was reported by a lower proportion of patients in the budesonide-formoterol group; 17% vs 32%; OR 0.43
• Lesser patients in the budesonide-formoterol group reported at least 1 severe asthma attack; 9% vs 16%; OR 0.54
• All the outcomes are compared in Table 1.
• There were no significant differences in the rates of at least one AE and at least 1 serious AE between the groups; 91% vs 92% and 3% vs 4% respectively

Table 1. Comparison of outcomes

	Budesonide-Formoterol group	Salbutamol group
Annualized rate of asthma attacks	0.23	0.41
	RR 0.55; p=0.012
Time to first asthma attack, days	329 (103)	295 (122)
	HR 0.48; p=0.0010
Annualised rate of severe asthma attacks	0.11	0.18
	RR 0.60; p=0.11
Time to first severe asthma attack, days	343 (89)	325 (101)
	HR 0.55; p=0.062
FeNO, ppb	35.2	42.3
FEV1 % predicted	99.3	100.2
Days lost from school	1.62 (3.83)	2.11 (3.54)
	RR 0.68; p=0.075

Conclusion

Lancet. 2015 Oct;406(10511):1473-83. Doi: 10.1016/ S0140-6736(25)00861-x.