The rationale for this substantial amendment dated 17-Aug-2015 was to consolidate feedback from Competent Authorities in United Kingdom (UK), France, and Spain, resulting in a new core protocol. The country-specific amendments (France Protocol Amendment 0.1 and 0.2 and UK Protocol Amendment 0.2) were incorporated into Global Protocol Amendment 1. In addition, the Spanish Competent Authority recommended the inclusion of electrocardiogram (ECG) assessments within the study design; this was also implemented within Global Protocol Amendment 1.

The protocol dated 04-Mar-2016 was amended to provide further information regarding prohibited P-glycoprotein substrate (PGP) inhibitors. Rather than specify “strong” inhibitors, all known inhibitors were excluded until further information was obtained regarding UCB5857’s PGP substrate status. To facilitate identification of known PGP inhibitors, a sample, but nonexhaustive, list of PGP inhibitors was added as a table to the protocol. In addition, the definition of the Pharmacokinetic Set (PKS) was amended to correct an error. Previously the PK Set was incorrectly defined as a subset of the Full Analysis Set (FAS) when it should have been a subset of the Safety Set where subjects were assigned to the actual treatment received rather than their randomized treatment.

The protocol dated 24-Jul-2016 was amended as an urgent safety measure to include potential drug-induced liver injury (PDILI)-related 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 subjects receiving UCB5857 in ongoing studies, including 2 subjects in SS0004, and 1 subject in APD001 (open-label study of UCB5857 in subjects with activated phosphoinositide 3 kinase [PI3K] delta syndrome). All available blinded clinical data for these cases were medically assessed and in addition, all available data from other subjects in these 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 study subjects against any possible liver injury caused by UCB5857. Additionally, and unrelated to the main purpose of the amendment, further guidance was provided on suspected transmission of an infectious agent via a medicinal product in alignment with UCB’s updated procedures.

The rationale for this substantial protocol amendment dated 05-Apr-2017 was to modify the restriction regarding PGP inhibitors and remove the table of PGP inhibitors from the protocol based on newly available nonclinical data. In addition, procedures for assessment and management of Tuberculosis (TB) were added in order to comply with the UCB policy applied to all UCB-Sponsored studies (excluding noninterventional studies) that included subjects with immunological diseases, who were at increased risk of TB infection either associated with the investigational drug, underlying disease, concomitant treatments, or other medical or sociological factors. Updates to the interim analysis section were made to include text stating that an interim analysis for futility may be performed.