Amendment 1 introduced the following changes as requested from the health authority: clarified the period of time following dosing during which women of child-bearing potential were to use highly effective contraception; and introduced a requirement for males to use contraception to minimize potential risk of exposure to the fetus.

Amendment 2 introduced the following changes: revised the blood volumes to reflect accurate volumes for the central laboratory. The overall blood volume taken during the study was reduced from 559.4 mL to 523.4 mL; and revised inclusion criterion 6 to require a peripheral blood eosinophil count > 140/μL combined with serum IgE > 100 IU/mL.

Amendment 3 introduced the following changes: included a blood sample for Serum IgE to be taken at Screening in order for patients to be eligible as per Inclusion Criterion 6 (introduced at Amendment 2 but requirement for sample to be taken was missed); added a requirement for women of child bearing potential to have a negative pregnancy test result up to 14 days prior to the methacholine challenge (as per the package insert for methacholine); and revised inclusion criterion 7 to note that patients taking antihistamine therapy should withhold their medication prior to skin prick testing.

Amendment 4 introduced the following changes: revised inclusion criterion 6 to require peripheral blood eosinophil count ≥ 140/μL and serum IgE ≥ 100 IU/mL at Screening, or IgE ≥ 400 IU/mL at Screening regardless of eosinophil count (change made to enrich the study population with individuals whose asthma was more likely to be characterized by Th2-type inflammation and therefore were more likely to respond to therapy targeting IL-4 and IL-13); clarified ACQ measurements were to be performed at Visit 3 and added a spirometry measurement (integral to measurement of ACQ) at Visit 3; added body weight measurement to Visit 4 (prior to dosing); revised the first Baseline visit from Days -14 to -4 to Days -14 to -3, to allow all Baseline assessments to be performed on Day -3, where logistically possible; revised dispensing of the eDiary to allow the eDiary to be dispensed at the Screening visit while screening results were obtained; revised exclusion criterion 17 to clarify that travel was restricted not to all of Southeast and Southwest Asia, South America, and Africa, but only to those parts that were endemic for schistosomiasis; revised the study stopping rules for clarification that “study-related SAE” referred to a study drug-related or study procedure-related SAE; added windows for early collection of PK assessment and performance of other study procedures; added more details for the withholding of asthma medications prior to spirometry, FeNOand the methacholine challenge; clarified that local spirometers, as opposed to central spirometry, may have been used for safety monitoring of lung function during induced sputum procedures; and added restriction of nitrate-rich foods and allowed for the consumption of water prior to measurements of FeNO.

Amendment 5 introduced the following changes: removed the requirement for the methacholine challenge, sputum collection for biomarker assessments, and Elispot PBMC biomarker collection; shortened the Screening period and Run-in period to minimize study durations; clarified the definition of positive stool sample for ova and parasites; revised exclusion criterion 14 to include a more specific value of ≤ 12mg/dL; clarified the early withdrawal assessments and procedures for individual patient withdrawal; and revised the analysis of placebo treated patients in the additional explorative analysis onthe impact of the Q576R SNP on the QBX258 treatment. Placebo treated patients were not to be pooled but analyzed by their Q576R SNP status.

Amendment 6 introduced the following changes as requested by the Paul- Ehrlich Institute: included a specific futility analysis in the planned interim analysis, and the definition of change from baseline was updated to the current reporting standard; and added Germany-specific requirements for contraception, to recommend against the use of spermicidals and condoms in this country.