2 Dose Optimizing Study of a Depigmented Polymerized Allergen Extract of Birch Pollen by Means of Conjunctival Provocation Test

BACKGROUND: Clinical efficacy of a depigmented polymerized birch pollen extract has been shown in 2 large phase III studies with 1000 DPP/mL. To date dose-response studies are required to show optimal efficacy at a defined allergen dose. The conjunctival provocation test (CPT) is a possible outcome parameter and from the regulatory authorities accepted test procedure. METHODS: 301 (PP) patients with confirmed rhinitis and/or rhinoconjunctivitis were treated in a double-blind study with 4 doses of 100 DPP/mL, 1000 DPP/mL, 5000 DPP/mL and 10.000 DPP/mL allergen extract over 22 weeks in Germany, Poland, and Lithuania. A 1-day build-up phase applying 0.1 mL and 2 times 0.2 mL allergen extract was followed by a maintenance period applying 0.5 mL in 3 to 4 weeks intervals. Before treatment a CPT was performed with semi-logarithmically increasing doses up to 10,000 SQ-U/mL of native birch extract, after treatment the CPT was repeated with doses up to 100,000 SQ-U/mL. The main parameter was the percentage of patients with an increase of allergen extract to provoke a positive CPT after SIT. Secondary parameters were specific IgE, IgG1 and IgG4 as well as safety. The main parameter was investigated using a hierarchic test procedure comparing the highest dose against the lowest, if statistically significant testing the next lower dose against the lowest until the difference was no longer significant. RESULTS: An increase in allergen amount to provoke a positive CPT after SIT was reached in 37.5% of the 100 DPP/mL, 50.7% of the 1000 DPP/mL, 54.9% of the 5000 DPP/mL and 55.8% of the 10,000 DPP/mL group. Results compared to the lowest dose were statistically significant for the 5000 DPP/mL (P = 0.0236) and 10,000 DPP/mL group (P = 0.0159). Specific IgEs remained stable in all groups whereas specific IgG1 and IgG4 showed dose-dependent increases. Grade 1 systemic reactions occurred in 18% (100 DPP/mL), 14.8% (1000 DPP/mL), 17.4% (5000 DPP/mL) and 25.3% (10,000 DPP/mL) of patients. CONCLUSIONS: We determined increased allergen amounts to obtain a positive CPT after SIT from 1000 to 10,000 DPP/mL depigmented polymerized birch pollen extract. The 5000 DPP/mL dose extract suggest a good benefit/risk ratio with the potential for further development.