Protocol Amendment 1, dated 16 August 2013, was applicable to all sites that were open at the time (United Kingdom, Germany, Finland, France) and made a number of changes. Hydrocortisone cream was added to the list of rescue medications provided, as hydrocortisone acetate was not available in all countries, so an equivalent medication was required as an alternative. This amendment also stated that the prescribed creams for each subject should not change during the course of the study. Subjects with a known allergy to hydrocortisone or hydrocortisone acetate were added to the exclusion criterion on allergies to hydrocortisone preparations. For serology, hepatitis B surface antigen was measured instead of hepatitis B antibodies. Important/significant medical events were also defined. In addition, minor corrections and clarifications were made. At the request of the French competent authority, glycated haemoglobin testing was added to the protocol and subjects with diabetes mellitus were excluded from the study; therefore, a country-specific amendment was issued to include these additional changes for sites in France only.

Protocol Amendment 2, dated 24 October 2013, was applicable to all sites open at the time, and was a non-substantial amendment. This amendment added a new country, Austria, along with additional sites in the United Kingdom and Germany. This was because projections indicated that there were insufficient sites recruiting subjects into the study to complete recruitment in the required timelines. The number of planned sites was increased from approximately 20 to up to 40. The estimated number of subjects to be screened was changed from approximately 250 to at least 250.

Protocol Amendment 3, dated 30 January 2014 (08 February 2014 in France), was applicable to all sites open at that time. The changes were designed to improve recruitment and to reduce the number of subjects needed. Data from a study with dupilumab reported a significant effect on EASI score after 4 weeks of treatment. Dupilumab, an interleukin-4 receptor alpha subunit inhibitor which attenuates Th2-mediated inflammation, represented a relevant comparison for OC000459 and indicated that a significant effect on EASI could be achieved with fewer patients within a shorter treatment period than the 26 weeks defined in the protocol. The treatment period was thus reduced from 26 to 16 weeks. The estimated number of subjects to be screened was decreased from at least 250 to approximately 200, and the number of subjects in each treatment arm was reduced from approximately 100 (90 evaluable) to at least 70 (64 evaluable). The upper age limit was increased from 40 to 48 years. An inclusion criterion on AD and co-morbid conditions was removed (subjects must meet at least one of: diagnosed with AD below 2 years of age; co-existing asthma and/or allergic rhinoconjunctivitis; or a history of these conditions). Recruitment criteria for blood eosinophil results, systemic corticosteroid use and use of NSAIDs were relaxed. Short-term use of NSAIDs was added to the list of permitted medications. The following secondary objectives (and corresponding endpoints) were also added: EASI at 4, 8 and 12 weeks; subject withdrawal due to treatment failure. The number of flares was added to the list of secondary endpoints. Unnecessary pregnancy tests were reduced and the number of blood draws for plasma drug levels was decreased. Minor clarifications were also made.

Protocol Amendment 4, dated 09 October 2014, applied to all sites open at that time. This amendment extended the recruitment timeline, added sites in three new countries (Poland, Czech Republic and Slovakia) and included new sites in Germany, increasing the total number of sites defined in the protocol to 60. On review of screening failures and discussions with some of the investigators a relaxation of some of the permitted medications was permitted, to allow concomitant use of anti-hypertensives, antidepressants, anti-migraine, anti-epileptics, oral contraceptives, hormone replacement therapies and thyroid medications. As some investigators treat AD with high-dose vitamin D, a washout period for high-dose vitamin D treatment was defined. This amendment also clarified the definition and procedures for flares, and defined visit windows more clearly. Amendment 4 was subsequently withdrawn in Germany.