Randomized immunotherapy trial in dual-allergic patients using “active allergen placebo” as control

Abstract

Background: Placebo control in allergen immunotherapy (AIT) trials presents ethical and blinding concerns. We tested a trial design with an “active allergen placebo,” as proposed by ARIA-GA2LEN, to investigate in a double-blind trial the efficacy and safety of AIT in dual-allergic patients (grass and birch pollen) using active untargeted treatments as controls. Methods: We randomized 95 patients to receive either grass (N = 47) or birch AIT (N = 48). Patients were exposed to both allergens in an allergen challenge chamber (ACC) before and after 9 months of AIT. Targeted (ACC-allergen = AIT-allergen) and untargeted (ACC-allergen ≠ AIT-allergen) treatment effects were assessed. Results: Immunotherapy reduced significantly the mean (95% confidence interval) area under the curve of total nasal symptom score (targeted effects) by −13.55 (−17.56, −9.54; P < 0.001) after grass and −9.81 (−14.13, −5.50; P < 0.001) after birch AIT. Differences in targeted vs untargeted effects between AIT groups (utility of control group) were statistically significant for both grass (P = 0.02) and birch (P = 0.02) allergens. Targeted vs untargeted differences within-treatment groups (specificity of ACC measurement) were significant for grass AIT (P < 0.001) but not significant for birch AIT group (P = 0.24). Specific immunoglobulin G4 to both allergens increased significantly (P < 0.001) after targeted treatment, while remained unchanged for untargeted treatments. Both treatments were well tolerated. Conclusions: Immunotherapies for both grass and birch allergens were efficacious and safe. The study confirms the specificity of AIT. Untargeted treatment groups could serve as controls in future AIT trials.