Subcutaneous Allergen Immunotherapy in Adults Allergic to House Dust Mites: A Phase 3 Randomized Controlled Trial.

BACKGROUND Subcutaneous allergen immunotherapy (SCIT) has a longstanding history as a safe and effective treatment. Nevertheless, to meet the European Medicines Agency's regulatory requirements for continued market authorization, its efficacy and safety must be confirmed in a pivotal Phase III trial. OBJECTIVE Based on a successful Phase II dose-finding study, the aim was to confirm the safety and efficacy of a subcutaneous house dust mites (HDM) preparation in a randomized controlled trial using an optimal higher dose than the current maintenance dose. METHOD Seven hundred sixty-seven subjects were randomized in a 1:1 ratio to 1-year treatment with SCIT-product at a dose of 50,000 AUeq/mL or placebo. Out of these, 682 subjects completed the study. The primary endpoint was assessed using the combined symptom and medication score (CSMS(n)), which focuses on nasal symptoms, as specified by the European Academy of Allergy and Clinical Immunology (EAACI). RESULTS The primary endpoint showed a trend (p = 0.0767) with a mean treatment effect of -0.12 (95% CI, -0.3 to 0) toward a favorable change in mean CSMS(n) for active compared to placebo treatment. This treatment effect of 0.12 points did however not meet the prespecified minimal clinically relevant difference of 0.25 points. Among the 767 randomized patients, 539 had mild symptoms and 228 patients had moderate to severe HDM allergic symptoms, defined by a mean baseline daily symptom score (dSS(n)) of at least 2. Post hoc analysis of the clinical data, focusing on this subgroup of patients with moderate to severe symptoms, revealed a significant treatment effect for the primary endpoint, with a clinically meaningful reduction of -0.39 points (95% CI, -0.64 to -0.13; p = 0.0031) thereby surpassing the minimal prespecified difference of 0.25 points. No additional safety concerns were observed in the moderate to severe symptom group compared with the minor symptom group. CONCLUSION Treatment with the tested SCIT-product at a dose of 50,000 AUeq/mL was safe and well tolerated. The primary outcome was not met, with no significant difference observed between the active and placebo groups. A likely explanation might be the inclusion of mainly patients with mild symptoms of rhino conjunctivitis (539 of in total 767 randomized subjects). Post hoc analysis, however, indicated that SCIT was effective in the subgroup of patients with moderate to severe disease, suggesting that the overall study outcome may have been influenced by the inclusion of a large proportion of patients with only mild symptoms of HDM-induced rhino-conjunctivitis. As a consequence, reconfirming efficacy requires adequate baseline symptom severity, especially in HDM allergic patients.