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: 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.