Rationale Over-use and reliance on short-acting β2-agonists and poor adherence to inhaled corticosteroid (ICS) controller therapy can increase the risk of exacerbations in patients with mild asthma. The SYGMA 1 and 2 studies in patients with mild asthma demonstrated a reduction in risk of severe exacerbations with as-needed budesonide/formoterol (BUD/FORM) compared with as-needed terbutaline and similar to BUD maintenance plus as-needed terbutaline. In this pre-specified analysis of pooled data from the SYGMA studies, the efficacy of as-needed BUD/FORM for reducing severe exacerbations in the subgroup of adolescent patients is reported. Methods SYGMA 1 and 2 were 52-week, double-blind, randomized, multinational, parallel-group studies (NCT022149199; NCT02224157) in patients aged ≥12 years with mild asthma. In SYGMA 1, patients were randomized to placebo twice-daily (bid) plus as-needed terbutaline 0.5 mg, placebo bid plus as-needed BUD/FORM 200/6 µg, or BUD 200 µg bid plus as-needed terbutaline (BUD maintenance). In SYGMA 2, patients were randomized to placebo bid plus as-needed BUD/FORM 200/6 µg, or BUD 200 µg bid maintenance. The adolescent population (12−<18 years) from the two studies was pooled (n=889). Assessments included the effect of as-needed BUD/FORM versus as-needed terbutaline and BUD maintenance on annual severe exacerbation rates, treatment adherence (SYGMA 1 included twice-daily automatic e-diary reminders, unlike SYGMA 2), and adverse events. A negative binomial model was used including pre-study asthma treatment, region, number of severe exacerbations in the last 12 months (0, ≥1), and study as factors, with follow-up time as offset variable. Results The annual rate of severe exacerbations in adolescents was significantly lower with as-needed BUD/FORM versus as-needed terbutaline (p=0.014) and was comparable to BUD maintenance (p=0.66) (Table), consistent with findings across the entire study population in SYGMA 1 and 2. Adolescents had lower adherence to blinded maintenance medication (mean adherence 67−70% and 52−53% in SYGMA 1 and 2, respectively) compared with the adult population (80−81% and 64−65%, respectively). The proportion of adolescents with any adverse event was similar between as-needed BUD/FORM (n=124/366, 33.9%) and BUD maintenance (n=126/379, 33.2%) but higher with as-needed terbutaline (n=59/144, 41.0%). Conclusions In adolescents with mild asthma, as-needed BUD/FORM was superior to as-needed terbutaline for severe exacerbation reduction, with comparable efficacy to BUD maintenance; it was also well tolerated. Adherence to study medications in adolescents was lower than the adult population. As-needed BUD/FORM provides an alternative treatment option for adolescents with mild asthma.