3.2 Safety
AEs were frequent, but mostly local and mild (Tables 2 and 3 ). In total 970 AEs were reported in 271 (65.3%) patients. 836 AEs were possibly related to the study drug (86.2%) and described in Tables 2 and 3. Data on relatedness were missing for 3.3% of AEs. Overall, 65.3% of patients experienced at least one AE over the study period, most frequently oral allergy reactions (oral paresthesia (11.0%), throat irritation (10.2%) and oral pruritus (8.1%), see also Table E1).
Of all AEs reported 563 (67.3%) were mild, 196 (23.4%) moderate and 64 (7.7%) severe. 81 (9.7%) AEs resulted in treatment discontinuation, 29 (3.5%) in temporary discontinuation and the majority of AEs 724 (86.6%) had no effect on treatment. The most prevalent severe AEs leading to discontinuation were swollen tongue (0.7%), mouth swelling (0.6%), nausea (0.5%). Most patients fully recovered (81.1%), in 10 (1.2%) cases the patient recovered with some symptoms remaining at end of study, in 36 (4.3%) cases the patient did not recover during the study and in 112 (13.4%) cases this was unknown (Table 3 )
24 SAEs were reported. Only 1 SAE (angioedema) was related to the study drug. It occurred at the 3-month visit. The patient recovered fully after discontinuation of treatment.
The percentage of patients reporting AEs decreased from 51.8% at day 1 to 5.8% after 1 year in those remaining on treatment. The odds that a patient had any AE compared to having any AE(s) directly after first intake, decreased after 1 week (Odds Ratio (OR) = 0.33, P<0.0001), 3 months (OR = 0.13, P <0.0001), and 1 year (OR = 0.04, p<0.0001). These results did not change after correction for potential confounders.
3.3 Treatment adherence: persistence and compliance
In total 138 patients discontinued the treatment (60 because of AEs, 76 due to motivation/other reasons). Treatment persistence was, therefore, 66.7% overall (Figure 1 ). Subsequently, 248 (59.8%) patients intended to continue treatment for another 2 years in line with the guidelines. A high treatment compliance, i.e., at least 80% of medication taken daily, was observed for those that persisted with treatment. High compliance was reported for 96.7%, 91.5% and 86.6% of patients at week 1, 3 months and 1 year, respectively.