Dose optimizing study of a depigmented polymerized allergen extract of phleum pollen by means of conjunctival provocation test (CPT)

Background Clinical efficacy of a depigmented polymerized Phleum pollen extract has been shown in one large phase III studies with 1000 DPP/ml. To date dose-response studies are required to show optimal efficacy of an allergen dose. The conjunctival provocation test (CPT) is an outcome parameter accepted from the regulatory authorities (EMA).

Method 308 (ITT) 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, Spain and Czech Republic. A 1-day build-up phase applying 0.1 ml and 2 times 0.2 ml extract was followed by a maintenance period applying 0.5 ml in 3-4 weeks intervals. Before treatment a CPT was performed with increasing doses up to 3 HEP/ml of native Phleum extract, after treatment the CPT was repeated with doses up to 30 HEP/ml. The primary endpoint parameter was the percentage of patients with an increase of allergen extract to provoke a positive CPT after Allergen Immunotherapy (AIT). Secondary parameters were specific IgE, IgG1 and IgG4, Vitamin D baseline level as well as safety.

The primary endpoint 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 The responder rates in the 100 DPP/mL and the 1,000 DPP/mL groups were 72.9% and 72.3%, respectively (ITT), in the 5,000 DPP/mL (75.3%) and the 10,000 DPP/mL groups (77.4%). The respective differences to the 100 DPP/mL group were -4.5% for the 10,000 DPP/mL group, -2.5% for the 5,000 DPP/mL group, and 0.6% for the 1,000 DPP/mL group (ITT). No statistically significant difference was found. For the PP set, similar results were observed. Vitamin D baseline results were low in all groups, but had no influence on the results. Specific IgEs remained stable in all groups whereas specific IgG1 and IgG4 showed dose-dependent increases. Systemic reactions occurred in 12.9% (100 DPP/ml), 10.8% (1000 DPP/ml), 26.4% (5000 DPP/ml) and 33.3% (10.000 DPP/ml) of patients. 79.4% of SR were Grade 1, 8.7% grade 2 and 1 grade 3 reaction occurred in the 100 DPP/ml group.

Conclusion We determined increased allergen amounts to obtain a positive CPT after AIT from 1000 -10.000 DPP/ml depigmented polymerized Phleum pollen extract. Since the CPT results did not discriminate the different doses the dose-finding study will be repeated with a different assessment method.