Global Protocol Amendment 1, dated 24 Feb 2016, provided the following key changes: •Prohibited the co-administration of known P-glycoprotein (PGP) inhibitors with UCB5857. Since UCB5857 was likely (although not yet confirmed) to be a substrate of PGP, the possibility existed that UCB5857 might be susceptible to pharmacokinetic (PK) interactions as victim drug when co‑administered with a PGP inhibitor. •The local Protocol Amendment 0.1, for Germany only, was included. The local amendment restricted the maximum number of years in the study to 5 years per study participant, since insurance coverage in Germany was limited to 5 years per participant or 8 years for the duration of the complete APD003 study.

Global Protocol Amendment 2, an urgent safety measure amendment dated 22 Sep 2016, provided the following key changes: •Included updated and new potential drug-induced liver injury (PDILI) exclusion criteria, withdrawal criteria, and guidance for the management of such cases. Cases of elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) had been observed in 3 participants receiving UCB5857 in ongoing studies (2 participants in SS0004 and 1 participant in APD001). All available blinded clinical data for these cases were medically assessed and, in addition, all available data from other participants in the ongoing studies were reviewed to identify any other potential cases of interest but no other clinically relevant elevations in aminotransferases or other hepatobiliary laboratory values were noted. UCB considered that from the currently available information, there was a possible causal association of UCB5857 with increased aminotransferases. Consequently, additional risk minimization and pharmacovigilance measures were implemented in the protocol in order to safeguard participants against any possible liver injury caused by UCB5857. •Provided further guidance on suspected transmission of an infectious agent via a medicinal product in alignment with UCB’s updated procedures.

Global Protocol Amendment 3, a substantial amendment dated 05 Apr 2017, provided the following key changes: •Modified the restriction regarding P-glycoprotein (PGP) inhibitors and removed the table of PGP inhibitors from the protocol based on newly available nonclinical data. •Added procedures for assessment and management of tuberculosis (TB) in order to comply with the UCB policy applied to all UCB-sponsored studies (excluding noninterventional studies) that include participants with immunological diseases, who are at increased risk of TB infection either associated with the investigational drug, underlying disease, concomitant treatments, or other medical or sociological factors. •Aligned local versions of the protocol into a single global version. •Added guidance on adverse events of interest (AEOI), management of AEOIs, and immediate reporting of Adverse Events (AEs).

Global Protocol Amendment 4, a substantial amendment dated 22 Jan 2018, provided the following key changes: •Changed the duration for safety follow up. UCB5857 has a relative short half-life of 18 hours and therefore 30 days was considered long enough to ascertain any potential late safety events and the 90-day follow-up call was removed from the schedule of assessments. •Adjusted the frequency of an imaging technique scan (high-resolution computer tomography [HRCT] only) for the assessment of global lung disease and hepatosplenomegaly, due to the high level of exposure to radiation. Based on the date of the amendment, 4 participants were enrolled at the time of the amendment. This protocol amendment was not submitted in France because at the time of submission, the single participant enrolled in APD001 in France was withdrawn.