Shortened up-dosing with sublingual immunotherapy drops containing tree allergens is well tolerated and elicits dose-dependent clinical effects during the first pollen season

Ralph Mösges, Nils Y Breitrück, Silke Allekotte, Kija Shah-Hosseini, Van-Anh Dao, Petra Zieglmayer, Katrin Birkholz, Mark Hess, Maximilian Bastl, Katharina Bastl, Uwe Berger, Matthias F Kramer, Sonja Guethoff, Ralph Mösges, Nils Y Breitrück, Silke Allekotte, Kija Shah-Hosseini, Van-Anh Dao, Petra Zieglmayer, Katrin Birkholz, Mark Hess, Maximilian Bastl, Katharina Bastl, Uwe Berger, Matthias F Kramer, Sonja Guethoff

Abstract

Background: This study compared a rapid home-based up-dosing schedule for sublingual immunotherapy (SLIT) drops containing tree pollen allergens with two previously established schedules. Furthermore, the clinical effect of the SLIT was investigated with respect to patients' first pollen season under treatment.

Methods: In this open-label, prospective, patient-preference, non-interventional study, local and systemic reactions were compared between three up-dosing groups using a SLIT formulation containing birch, alder, and hazel pollen extracts (ORALVAC® Compact Bäume). Clinical improvement after patients' first season under treatment was analysed using symptom scores, ARIA classification, symptom control, and the use of symptomatic medication and was compared with data from the previous, pre-treatment pollen season. As the real-life study design allowed no placebo group, the late-treated patients (co-seasonal) served as a control, and crowd-sourced symptom data from persons with hay fever were used from a free web-based online diary.

Results: In 33 study centres in Germany and Austria, 164 patients were included. The treatment was well tolerated, without difference between the groups during the up-dosing phase. At the end of the assessment, 96.1% rated the tolerability of the treatment as good or very good. Local reactions were mostly mild in severity and no serious adverse events occurred. Symptom scores decreased from the 2016 pollen season to the 2017 pollen season. As for the ARIA classification, 79.0% of patients had persistent, moderate-to-severe rhinitis before treatment, but only 18.6% had the same classification after treatment. In all, 62.4% of patients achieved symptom control, and 34.3% of patients required no symptomatic medication after treatment. The rhinoconjunctivitis score was 34.4% lower for pre-seasonal treatment initiation than for the control group. Crowd-sourced symptom load indices showed that the 2016 season caused slightly more symptoms; however, it is assumed that this difference of 0.3-0.5 (score range 0-10) was of less clinical relevance.

Conclusion: The treatment administered using the rapid home-based up-dosing schedule was safe and well tolerated. Symptom relief and reduction in medication use were observed during the first pollen season with SLIT.

Trial registration number: NCT03097432 (clinicaltrials.gov).

Keywords: AE, adverse event; ARIA, Allergic Rhinitis and its Impact on Asthma; Adherence; Asthma; Conjunctivitis; IgE, immunoglobulin E; Immunotherapy; N, number; PHD, Patient's Hay Fever Diary; Pollen allergy; Pre-seasonal; RCAT, Rhinitis Control Assessment Test; Rhinitis; SD, standard deviation; SLI, symptom load index; SLIT; SLIT, sublingual immunotherapy; SmPC, Summary of Product Characteristics; Sublingual immunotherapy; TU, therapeutic units; V, visit; sIgE, specific immunoglobulin E.

Figures

Fig. 1
Fig. 1
Up-dosing schedules investigated. (a) The conventional schedule lasts 10–12 days and uses three different bottles with three increasing allergen concentrations to reach the maintenance dose. This schedule permits complete home administration. (b) The ultra-rush office-based schedule consists of two or four administrations. It lasts up to 2 h and must be administered under medical observation. This schedule requires only the highest allergen concentration. (c) The rapid home-based schedule uses the same up-dosing doses as the ultra-rush schedule but are scheduled for 2 to 4 consecutive days. Only the first administration requires medical observation; three subsequent daily administrations are taken at home. Regardless of the up-dosing schedule, the SLIT used in this study can be continued as a short-term treatment with a higher dose (usually seven pumps daily over a period of 3 months per year) or as a long-term treatment with a lower dose (usually three pumps daily over a period of 8 months per year). The investigated up-dosing schedules correspond to the SmPCs for use in Germany and Austria. The SLIT treatment should only be used according to SmPC and in adherence with local legislation and or guidelines.
Fig. 2
Fig. 2
Study flowchart.
Fig. 3
Fig. 3
Patients' assessment of treatment tolerability. Percentage of patients who assessed (a) the tolerability of up-dosing administrations as “good” or “very good” at visit 2 comparing three up-dosing schedules (conventional vs. ultra-rush office-based vs. rapid home-based) and (b) the overall tolerability of the entire treatment as “good” or “very good” at V5 comparing treatment initiation (pre-seasonal vs. co-seasonal) and maintenance dose (three pumps vs. seven pumps).
Fig. 4
Fig. 4
Tolerability of the up-dosing administrations. Analysis of the percentage of patients who experienced (a) local or (b) systemic reactions during the up-dosing phase comparing the tolerability of the three up-dosing schedules (conventional vs. ultra-rush office-based vs. rapid home-based). Reactions were assessed as mild, moderate or severe by the patients. P values between groups were obtained using the chi-square test, but clinical significance was not shown.
Fig. 5
Fig. 5
Reductions in symptom scores. (a) The rhinoconjunctivitis score (0–6 points) and (b) the rhinitis, conjunctivitis, and asthma scores (1–7 points) were assessed retrospectively at visit 1 for the 2016 pollen season and after SLIT initiation at V5 for the 2017 pollen season. The difference between both seasons is shown as mean ± SD. P values between 2016 and 2017 were obtained using the Wilcoxon-Mann-Whitney test: *** indicates P < 0.001.
Fig. 6
Fig. 6
Reduction in symptomatic medication use. The frequency of the use of different symptomatic medications was assessed retrospectively at V1 for the 2016 pollen season and after SLIT initiation at V5 for the 2017 pollen season.
Fig. 7
Fig. 7
Improved ARIA (Allergic Rhinitis and its Impact on Asthma) classification of rhinitis. Rhinitis symptoms were assessed and classified as persistent or intermittent as well as mild or moderate-to-severe based on a questionnaire at V1 for the 2016 pollen season and after SLIT initiation at V5 for the 2017 pollen season, retrospectively. The status in 2017 was also assessed and compared to 2016 and rated as improved, equal, or worsened. Data is shown as the number of patients and their respective shift in ARIA classification from 2016 to 2017.
Fig. 8
Fig. 8
Comparison of average symptom load index (SLI) values for Germany and Vienna, respectively, from January to May in the years 2016 and 2017, including the total tree season.
Fig. 9
Fig. 9
Impact of treatment start on clinical parameters. Subgroup analysis comparing (a) the rhinitis symptom control during the peak of the 2017 pollen season (assessed prospectively at V4), (b) the rhinoconjunctivitis score during the peak of the 2017 pollen season (assessed prospectively at V4), (c) the reduction in the rhinoconjunctivitis score comparing the 2016 and 2017 pollen seasons (assessed retrospectively at V1 vs V5), and (d) the reduction in mean rhinitis, conjunctivitis, and asthma symptom scores comparing the 2016 and 2017 pollen season (assessed retrospectively at V1 vs V5), with respect to treatment start (pre-seasonal vs. co-seasonal) respectively. In (b), the pre-seasonal and the co-seasonal treatments were compared, while in (c) and (d) the respective treatment was compared to the previous season (2016 vs 2017). P values were obtained using the Wilcoxon-Mann-Whitney test: *** indicates P < 0.001, n. s. = not significant.

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