Safety in special groups
No events of anaphylactic reactions or eosinophilic esophagitis (EoE) were reported. A subgroup analysis did not show any major differences in the risk of experiencing first moderate to severe IMP-related AEs across subgroups including age, asthma history, sensitisation, IgE level and PFS status (Figure 4). Across all subgroups, hazard ratios were less than 1, i.e. there was an increased risk of IMP-related AEs in the active treatment group compared with placebo as expected. The subgroup analysis did not show any major differences in the risk of experiencing a moderate or severe IMP-related AE across subgroups, including age (adolescents versus adults, p=0.487), sensitisation status (mono- versus poly-sensitisation, p=0.571), birch IgE class (class 2-3 versus 4-6, p=0.573), asthma status (asthma versus no-asthma, p=0.077) and PFS status (PFS versus no-PFS, p=0.589).
PFS: At baseline, 296 (63%) and 296 (65%) of subjects treated with 12 SQ-Bet and placebo respectively reported to have PFS. After treatment, 9 subjects reported AEs of PFS: 7 subjects treated with 12 SQ-Bet (including 4 AEs of worsening of PFS) and 2 subjects treated with placebo (including 1 AE of worsening of PFS). All AEs were assessed as IMP-related when treated with 12 SQ-Bet and 1 was assessed as IMP-related with placebo. A larger proportion of subjects with PFS reported AEs compared with those without PFS. This was observed for both treatments: 89% of subjects with PFS and 80% without PFS experienced AEs with 12 SQ-Bet and 67% versus 56% experienced AEs with placebo. Likewise, of those treated with 12 SQ-Bet, oral pruritus was reported by 45% of subjects with PFS and by 29% of subject with no PFS. No major differences between subjects with and without PFS were seen for severity of AEs. A greater proportion of subjects had IMP interruptions in the PFS subgroup (19%) compared with subjects without PFS (7%).
Asthma : The 12 SQ-Bet treatment did not seem to induce an increased risk of asthma events. In total, 18 AEs of asthma were reported (7 in 7 subjects treated with 12 SQ-Bet and 11 AEs in 10 subjects treated with placebo). These included 6 AEs of asthma exacerbation: 2 in 2 subjects treated with 12 SQ-Bet and 4 in 3 subjects on placebo. The majority of asthma AEs were mild or moderate in severity and assessed as unlikely related to IMP.
For subjects treated with 12 SQ-Bet, the proportion of subjects with asthma who reported any severe IMP-related AEs was 7% compared with 3% for subjects without asthma (Figure 3B).
Slightly more adolescents with asthma tended to experience AEs than adolescents without asthma (85% versus 79%), and these AEs were mild in severity. However, these data should be interpreted with caution as only 13 adolescent subjects with asthma participated in the clinical phase-II/III trial programme.
Eczema : Only one subject reported eczema. This was worsening of a pre-existing eczema (atopic dermatitis) in a subject treated with 12 SQ Bet.
Urticaria related to the IMP was reported by 6 subjects treated with 12 SQ Bet and 4 treated with placebo. The 6 subjects treated with 12 SQ Bet experienced contact urticaria at the administration site (2 subjects reported lip urticaria and 1 subject reported local urticaria), urticaria at the hand (1 subject), urticaria in several places of the body (1 subject reported urticaria on the neck after 3 days and on the chest and upper arm after 212 days) and for 1 subject no details were specified. 6 subjects in the placebo group also reported urticaria. In 4 of the subjects the events (5 events) were assessed as possibly related to the treatment despite the subject never being treated with the tree SLIT-tablet. The events included 4 local reactions and 1 with unspecified location. In the remaining 2 subjects, urticaria was assessed as unlikely related to the tree SLIT-tablet.
This suggests either a systemic urticaria or a local urticaria resulting from touching the SLIT-tablet. None of the urticaria events were severe or lead to discontinuation.