Laura Day

Background/Objectives: Placebo responses can complicate the interpretation of allergen immunotherapy (AIT) trials because symptom- and medication-based outcomes may be influenced by the trial context in addition to treatment-specific effects. Injection-free comparison cohorts are rarely available in conventional double-blind, placebo-controlled AIT trials. We therefore conducted an exploratory post hoc cross-study comparison of clinical outcomes in two placebo-injection cohorts and an injection-free cohort of birch pollen-allergic participants. Methods: Data from three prospective clinical studies evaluating the mannan-conjugated birch pollen allergoid EP-088-T502—T502-SIT-020, T502-SIT-045, and T502-SIT-068—were assembled for this cross-study comparison. Placebo-injection cohorts from studies T502-SIT-020 and T502-SIT-045 were compared with the injection-free cohort from study T502-SIT-068. Clinical outcomes included the Combined Symptom and Medication Score (CSMS), daily Symptom Score (dSS), and daily Medication Score (dMS). Results: The primary peak-period analysis included 60, 93, and 160 participants from T502-SIT-020, T502-SIT-045, and T502-SIT-068, respectively. During the site-specific 14-day peak birch pollen periods, median CSMS was 2.14 in the injection-free cohort compared with 1.34 and 1.07 in the T502-SIT-020 and T502-SIT-045 placebo-injection cohorts, respectively. These values corresponded descriptively to approximately 37% and 50% lower cohort medians, respectively, relative to the injection-free cohort. Median dSS, which was defined consistently across the three source studies, was 1.22 in the injection-free cohort compared with 0.78 and 0.70 in the two placebo-injection cohorts. Median dMS was 0.93 compared with 0.39 and 0.36, respectively. The same between-cohort pattern was observed in the secondary fixed 1–30 April analysis. Conclusions: Both placebo-injection cohorts showed lower CSMS and dSS values than the injection-free cohort. Because the cohorts were non-concurrent and derived from separate studies, the observed differences do not establish a causal effect of placebo injections.

Background/Objectives: Placebo responses can substantially influence patient-reported outcomes in clinical trials and are particularly relevant in allergen immunotherapy (AIT), where treatment efficacy is commonly assessed using symptom- and medication-based endpoints. We conducted an exploratory post hoc cross-study comparison of birch pollen-allergic participants who received pre-seasonal placebo injections in two randomised, double-blind, placebo-controlled AIT trials with participants from a third trial in whom the planned study injections were not administered before the corresponding birch pollen season. Methods: Data were pooled from three prospective clinical studies evaluating the mannan-conjugated birch pollen allergoid EP-088-T502: T502-SIT-020, T502-SIT-045, and T502-SIT-068. Placebo-injection cohorts from studies T502-SIT-020 and T502-SIT-045 were compared with the injection-free cohort from study T502-SIT-068. Clinical outcomes included the Combined Symptom and Medication Score (CSMS), daily Symptom Score (dSS), and daily Medication Score (dMS). Results: The three comparison cohorts comprised 321 participants: 161 in the injection-free cohort and 160 in the placebo-injection cohorts. Participants in the injection-free cohort had significantly higher symptom and medication scores during the secondary fixed 1–30 April analysis period than participants in the placebo-injection cohorts. Median CSMS was 1.97 in the injection-free cohort compared with 1.32 and 0.86 in the placebo-injection cohorts. Likewise, median dSS (1.08 vs. 0.79 and 0.59) and dMS (0.87 vs. 0.33 and 0.25) were higher in the injection-free cohort. Pairwise comparisons indicated statistically significant between-cohort differences. Conclusions: In this non-randomised, non-concurrent cross-study comparison, symptom and rescue-medication scores were lower in the placebo-injection cohorts than in the injection-free cohort. Because the cohorts were derived from separate studies conducted in different years, these findings are hypothesis-generating and do not establish a causal effect of placebo injections. Trial-related contextual factors and other cross-study differences should be considered when interpreting the results.

Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regimen has not yet been investigated. As climate change is associated with earlier and less predictable onset of birch pollen seasons, planned pre-seasonal allergen immunotherapy may unintentionally overlap with natural pollen exposure. Therefore, evaluation of the safety of treatment administered during the pollen season is of increasing clinical relevance. This study aimed to compare, in a purely descriptive manner, the safety and tolerability of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Methods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.: 2022-004082-20), patients (N = 109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10,000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and, thus, before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N = 20). Those who performed the last treatment visit thereafter were assigned to the pre-/co-seasonal group (N = 83). Due to post hoc subgroup allocation and unequal subgroup sizes, all subgroup analyses were purely descriptive. Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N = 3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions, according to the German AWMF classification, were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm; late-phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm; late-phase reactions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N = 89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs appeared descriptively similar between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment-related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well-tolerated, even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regi-men has not yet been investigated. This study aimed to compare the safety and tolera-bility of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Meth-ods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.:2022-004082-20), patients (N=109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10.000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and thus before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N=20). Those who performed the last treatment visit thereafter were assigned to the pre/co-seasonal group (N=83). Both groups were compared in terms of local and sys-temic immediate and late phase reactions and other EP-088-T502-related adverse events (AEs). Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N=3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions according to the German AWMF classification were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm, late phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm, late-phase reac-tions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N=89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs was comparable between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well tolerated even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Background/Objectives: The guideline on allergen-specific immunotherapy of the European Academy of Allergy and Clinical Immunology recommends subcutaneous allergen-specific immunotherapy for the treatment of allergic rhinitis in children and adults with moderate to severe symptoms. The five years cohort study described below was designed in 2020 to demonstrate non-inferiority in terms of safety, tolerability and efficacy in a paediatric population compared with adult patients treated with microcrystalline tyrosine-adsorbed allergoids for their tree and grass pollen allergy in a perennial setting. Here, we present the preliminary findings from the first year. Methods: The Combined Symptom and Medication Score was chosen as the primary endpoint of this therapy. Secondary endpoints include the Rhinoconjunctivitis Quality of Life Questionnaire, the retrospective Rhinoconjunctivitis score, the Asthma Control Test and the Rhinitis Control Test, as well as an analysis of adverse drug reactions. Results: A total number of 320 patients were enrolled into this study, with 129 of these patients in the age group between 5 and 17 years and 191 patients in the adult age group. Mean Combined Symptom and Medication Score values did not differ significantly between minors and adults in the first pollen season after treatment induction. The retrospective score showed a strong and significant reduction in rhinoconjunctivitis and asthma symptoms. Treatment was well tolerated, with more than 80% of patients reporting no adverse drug reactions. Conclusions: The validity of this study approach of a cohort study has been confirmed by this first interim analysis for the initial course of therapy in the first year.