TABLE 4.

Prospective data on exacerbations and exacerbation-related outcomes in mild asthma from placebo arms of RCTs of ≥24 weeks' duration

Study (year) [ref.]	Age range years	Placebo n	Other asthma medication in placebo arm	Treatment duration	Exacerbation parameter	Placebo arm
Studies not excluding patients with exacerbation history+
Bisgaard et al. (2005) [27]	2–5	271	Rescue OCS or ICS or β2-agonist	48 wks	Pts with exacerbation§	56%
					Exacerbation rate/year (n=257)ƒ	2.34
					Median time to first exacerbation	147 days
					Pts with ≥1 unscheduled visit to physician for asthmaƒ	42.4%
					Pts hospitalised for asthmaƒ	5.8%
					Rate of OCS courses/yearƒ	0.64
Chuchalin et al. (2008) [32]	12–79	315	Rescue ALB	52 wks	Mean exacerbation rate per pt per year (mild, moderate, severe)	2.88
					Moderate (OCS) or severe exacerbation (hospitalisation) rate/year	0.33
					No. unscheduled asthma-related healthcare contacts	7
					Pt withdrawal/discontinued due to exacerbation, n	8
Martinez et al. (2011) [36]	5–18	74	Rescue ALB	44 wks	Probability (95% CI) of first exacerbation by end of trial requiring prednisone course	49 (37–61)%
					Proportion with treatment failure (all defined by requirement for a second course of prednisone)	23%
O'Byrne et al. (2001) [39]	≥12	239	Yes - only after first exacerbation (n=104)¶¶	1 yr	Pts with severe exacerbation	33.3%
					No. of pts with severe exacerbation, pts treated with OCSs	70.9%
					Pts receiving systemic corticosteroids	23.6%
					Severe exacerbation rate per pt per year	0.77
O’Byrne et al. (2018) [38]	≥12	1277	TERB 0.5 mg as needed	1 yr	Pts with ≥1 moderate or severe exacerbation	21.5%
					Pts with ≥1 severe exacerbation	11.9%
					Annualised severe exacerbation rate	0.20
Papi et al. (2007) [40]	18–65	118	ALB as-needed	6 months	Pts with severe exacerbation	3.4%
					Pts with ≥1 exacerbation	17.80%
					Mean no. of exacerbations/pt/year	1.63
Pauwels et al. (2003) [41]	5–66	3568	Usual asthma treatment (SABA 64.6% of placebo pts) plus ICS or systemic corticosteroid if needed	3 yrs	Pts with life-threatening exacerbation over 3 years, n	24 (0.67%)
					Pts with ≥1 SARE over 3 years, n	198
					Pts with ≥2 SAREs over 3 years, n	49
					Mean no. of courses of systemic corticosteroids per year	0.21
					Pts using systemic corticosteroids	3 months: 4.1%
						12 months: 3.1%
						24 months: 3.3%
						36 months: 2.0%
					Pts with ≥1 systemic corticosteroid course	23%
Studies excluding patients with exacerbation history+
Reddel et al. (2008) [42]	18–80	21	ALB as-needed	11 months	Pts with ≥1 mild exacerbation, n	13
					Pts with severe exacerbation, n	3
Studies requiring patients to have a history of frequent exacerbations#
Robertson et al. (2007) [21]	2–14	113	Inhaled β2-agonist or OCS for acute asthma episode	12 months	Proportion of children with ≥1 episode treated with short course of randomised therapy, n (%)	105 (92.9%)
					Total number of treated episodes of asthma	336
					Proportion of treated asthma episodes utilising ≥1 health resource, n (%)	134 (39.9%)
					Proportion of treated asthma episodes requiring ED visit, n (%)	46 (13.7%)
					Proportion of treated asthma episodes requiring hospitalisation, n (%)	13 (3.9%)
					Proportion of treated asthma episodes with OCS use, n/N pts with diary data (%)	78 of 321 (24.3%)

RCT: randomised controlled trial; ED: emergency department; wks: weeks; pt: patient; OCS: oral corticosteroid; ICS: inhaled corticosteroid; CI: confidence interval; SABA: short-acting β2-agonist; SARE: severe asthma-related event; ALB: albuterol; TERB: terbutaline; GP: general practitioner; LABA: long-acting β2-agonist. ^# Study included only patients with a history of 3–6 exacerbations (hospitalisation or ED visit or GP visits) within 12 months prior to enrolment/screening); ^¶ Unscheduled visits to GP, specialist paediatrician, ED or admission to hospital; ⁺: Exacerbation history defined as an exacerbation, hospitalisation or ED visit or OCS use occurring ≥3 months prior to enrolment/screening; ^§: data appear to relate to 48-week double-blind period only (total study duration 1 year including screening and single-blind, placebo run-in period); ^ƒ: source publication refers to “yearly” data, but double-blind treatment period only 48 weeks (total study duration 1 year including screening and single-blind, placebo run-in period); ^##: defined as the requirement for a second dose of prednisone within any 6-month period; ¶¶: most common extra medication in placebo group was systemic corticosteroids (n=56), ICS (n=15) and LABAs (n=11).