The main purpose was to address operational challenges, changes were considered practical, not to carry excess risk to the study subjects, and to have minimal impact on the study outcome. The changes included: •Washout Periods for analgesic and nonbiologic DMARDs were added to clarify subject eligibility. •Upper limit of eligibility for the liver function tests (LFTs) was increased to >1.5 times since many subjects in the targeted population were taking medications that can cause modest elevations in LFTs. RA is also an inflammatory process, whereby subjects may also have modestly elevated LFTs. •The definition of an inadequate response to MTX was revised to align with clinical practice. •Adjustments to MTX doses and oral corticosteroid doses were permitted during the study. •Revisions to the exclusion criterion that listed bacteria/fungal infections, due to false negative rate associated with various serological tests as well as the lack of specificity provided by chest x-rays with respect to granulomatous changes. •Clarification of the definitions of a positive and negative purified protein derivative test, to minimize the risk of missing a subject with possible LTB infection. •Addition of -cotinine level measurement, as a validated marker of exposure to smoking, since smoking exposure is linked to an increase risk of developing RA, and exposure to smoking also impedes the effectiveness of biologic DMARDs. -extra sampling time points for IMP antibody determination and in particular for the genomic analysis were included to allow for early detection of IMP antibodies and genomic biomarkers. •Since prior anti-TNF use was an exclusion criterion, this class of medication was removed as a covariate in the primary efficacy analysis. •Changes were implemented to minimize/eliminate the confounding effect of substance abuse, since recreational drugs frequently can induce expectations or effects that may enhance or mask a disease entity under study such as pain.

The main purpose of this protocol amendment was to update all procedures related to tuberculosis (TB) detection and monitoring in line with the revised UCB policy. The amended changes also included updates of a number of eligibility criteria, specifically: •Clarification of the required clinical parameters to define moderate to severe RA disease at Screening and Baseline and the duration of the Washout Periods for analgesics and nonbiologic DMARDs. •The upper limit of eligibility for the LFTs was increased to >2.0 times since RA is an inflammatory process that may lead to modestly elevated LFTs and many subjects in the targeted population were taking medications, which can also cause modest elevations in LFTs. Study procedure revisions included: •Any safety laboratory parameter could be repeated when the result was considered erroneous in the judgment of the Investigator or if it was known that the sample could have been mishandled. •The number of sampling times for the genomic analysis was reduced. •The definition of an inadequate response to MTX was revised to emphasize that the decision was based on the Investigator’s clinical judgment.

The main purpose was to provide further clarification to support interpretation. The clarifications included: •Dose adjustments of oral corticosteroids during the 28 days prior to Baseline were to be avoided unless clinically necessary. The respective language was updated for clarity. Guidelines for discontinuation/tapering of oral corticosteroids permitted during the study were amended with more details •Guidance to ensure an appropriate washout of prior medication was updated for clarity and also specified information regarding the washout of leflunomide •RA-related exclusion criteria were updated with more specific information regarding subjects with systemic lupus erythematosus, lupus nephritis, and Sjogren’s Syndrome •Duration of exclusionary periods for subjects with a history of chronic/recurrent infections was decreased to 6 months preceding the study for subjects with more than 3 episodes requiring antibiotics/antivirals and increased to 12 months prior to Baseline for subjects with recent serious/life-hreatening infection •Exclusion criterion related to a history/active systemic/respiratory infection was updated with more details regarding radiographic findings •Guidance for the exclusion of subjects with hepatitis B or C infection including assessments of hepatitis-related biomarkers and for subjects with any positive findings in the urine drug screen •Noncompliance with the protocol-defined visit schedule was a reason for withdrawal. This withdrawal criterion was updated to provide additional guidance •Amendment of inclusion criterions to further emphasize that abstinence was not considered an acceptable method •Addition of albumin and creatinine to the list of clinical chemistry parameters •Update of the -list of the most common adverse reactions in clinical studies of ADA to match the latest version of the ADA SmPC -section describing the handling of protocol deviations to reflect process related changes resulting from the Submission Excellence Program

The main purposes were: •To clarify the timing of the primary endpoint analyses •To note how unblinding of individual treatment allocation codes were to be handled at the Week 104/WD visit The analysis of data for the Week 12 and Week 104 primary endpoints was changed to be done only at the completion of the study. The reason for this change was that knowledge of the Week 12 efficacy results could bias the way that the Investigators and/or subjects performed assessments or completed the study, which could compromise the interpretation of the final results and/or conclusions. Once all the efficacy assessments were performed for an individual subject at Week 104/WD, the blinded team had the opportunity to unblind the treatment allocation code for that subject. The reason was to aid the Investigator’s decision regarding RA treatment after the study. To confirm that this by subject-unblinding did not impact the study results, a sensitivity analysis was added in which all subjects who had their TJC/SJC values at Week 104/WD changed post-visit were excluded. Other changes were: •Modification of text relating to storage and handling of study drugs. •Blood sampling for cotinine at withdrawal did not need to be done if the withdrawal was due to the subject being ineligible to continue in the study at Week 24. •Clarification that all chest radiographs had to be both read and reported by a qualified radiologist. •Addition of text regarding the method of documentation of RA treatment after Week 104/WD. •The ISRQ/SIAQ was performed throughout the study as planned. However, statistical analysis of these questionnaires might not be performed for data at later time points in the study, because the available commercial ADA had undergone an alteration of the needle gauge during this study, which could affect the responses of the subjects to these questionnaires. •Addition of analysis sets needed for selected analyses based on subjects that reached Week 12 and continued in the study.