Protocol Amendment 1, dated 26 Aug 2011, was implemented prior to the start of enrollment and submitted to Food and Drug Administration (FDA). The primary purpose of this substantial protocol amendment was to revise the protocol in line with change requests from health authorities following discussions on the CZP pediatric arthritis development program. In addition, a list of anticipated SAEs for CZP in the juvenile idiopathic arthritis (JIA) population was added based on the FDA Final Rule on safety reporting for investigational new drug studies. Further key revisions included updates of eligibility criteria, updates of the protocol to current terminology used in the rheumatology community and to current company standards, and clarification of assessments and concomitant medications.

Protocol Amendment 3 was dated 06 May 2013, and a total of 54 study participants had entered the study at the time of this amendment. The primary purpose of this substantial amendment was to update the exclusion criteria and guidelines related to tuberculosis (TB) detection and monitoring in order to comply with the revised UCB TB Task Force policy applied to all UCB-sponsored studies that include study participants with immunological diseases who are at risk of developing or reactivation of TB infection, which might be associated with the class of tumor necrosis factor inhibitor (TNFi), including the investigational medicinal product (IMP). These instructions are evidence-based and reflect the updated recommendations of various national guidelines (eg, diagnosis of latent TB infection [LTBI] [Centers for Disease Control and Prevention]). This guideline includes the preference of use of tuberculin purified protein derivative skin test (TST) over interferon-gamma release assay (IGRA) in children below the age of 5 years. With the implementation of Protocol Amendment 3, TST was mandatory for study participants from 2 to 4 years of age in this study, unless the study participant had received a Bacille Calmette-Guérin (BCG) vaccination, and IGRA testing was required for study participants from 5 to 17 years of age. An independent Data and Safety Monitoring Board (DSMB) was implemented to conform to the standards for pediatric clinical studies. The DSMB reviewed emerging safety, PK, and efficacy data from the study. Activities were defined in the DSMB charter. Furthermore, this substantial amendment introduced a full interim analysis at Week 24 (Visit 10) involving a complete data analysis for the inclusion in the marketing application for the JIA indication.

Continuation of Protocol Amendment 3: At the same time, the planned analysis at Week 16 (Visit 8) was reduced to an analysis of the American College of Rheumatology Pediatric 30% (PedACR30) response rate required to confirm adequate response of the study population to CZP treatment and to confirm continuation of RA0043. Key revisions also included modifications and clarifications of eligibility criteria related to the diagnosis of JIA, use of disease-modifying antirheumatic drug (DMARDs) and methotrexate (MTX), TB, hepatitis screening panel, Follow-up Period for pregnancy and contraception, and infections. Further revisions were made to clarify study-related procedures (eg, the process of analyzing CZP plasma concentrations in the first cohort of study participants and the completion of parent-reported questionnaires), to clarify the CZP assay methodology, and to correct errors in the previous protocol version (eg, in relation to the core set measures of the American College of Rheumatology Pediatric (PedACR). In addition, the definition of the Physician’s Global Assessment criterion for Clinically Inactive Disease (CID) and clinical remission (CRM) previously defined as "clinical remission on medication") was changed to conform to the most current standard as defined by Wallace et al, 2011.

Protocol Amendment 4, dated 01 Aug 2013, was implemented after a total of 78 study participants had entered the study. The primary purpose of this substantial amendment was to implement a change in the dosing algorithm for children and adolescents who were participating currently in RA0043 at the time. Based on the results of the interim population pharmacokinetic (PopPK) analysis conducted in Jun 2013 (report Aug 2013) that included data from 34 pediatric study participants, new enrollment into RA0043 was suspended, effective 17 Jul 2013, and the maintenance dose for study participants already in RA0043 was reduced with Protocol Amendment 4. An overall dose reduction for pediatric study participants of 50% of the dose used in RA0043 at that time was proposed to provide a pragmatic dose that would yield a closer match to the plasma concentration range achieved in adults with the approved dose for RA (CZP 400mg at Weeks 0, 2, and 4 [Visits 2, 4, and 5, respectively] followed by CZP 200mg Q2W thereafter). Additional Unscheduled Visits were implemented, as required, in order to closely monitor the study participants over a period of 12 weeks after the dose change.

Protocol Amendment 5, dated 20 Jan 2014, was implemented after a total of 78 study participants had entered the study. The primary purpose of this substantial amendment was to reopen enrollment under the new Reduced CZP Dose, as defined in Protocol Amendment 4 and to update the statistical analyses to account for the changes in the CZP dose. Two CZP dose subgroups were defined as follows: • Original CZP Dose: included all study participants in the Safety Set (SS) who began treatment in accordance with the Original CZP Dose defined for the study (including study participants who underwent a dose reduction under Amendment 4). • Reduced CZP Dose: included all study participants in the SS who began treatment under Protocol Amendment 5 in accordance with the Reduced CZP Dose defined for the study. At the time of Protocol Amendment 4, a total of 78 study participants had entered the study and started treatment on the Original CZP Dose. To allow for a comparison of the group of 78 study participants on the Original CZP Dose with a comparable group of study participants on the revised CZP dose, a further 78 study participants were planned for the Reduced CZP Dose. Thus, the overall number of study participants was increased from 125 to at least 156. Study participants who fulfilled the eligibility criteria but could not enter the study due to the suspended enrollment as of 17 Jul 2013 were allowed to be rescreened. Key changes included the clarification that only study participants who entered the study under Protocol Amendment 5 and began treatment on the Reduced CZP Dose were taken into account for the study stopping rule based on the Week 16 (Visit 8) PedACR30 interim analysis and that a minimum number of 10 study participants in each weight category needed to enter the study for the Reduced CZP Dose.

Continuation of Protocol Amendment 5: In addition, the requirement that a study participant’s dosing category may only be changed if the 20 kg and 40 kg weight boundaries are crossed due to weight changes of >2.5 kg and >5 kg, respectively, was removed from the protocol. Applying this requirement at the time of dose reduction would have led to potential underdosing of study participants who just crossed the weight boundary, as they would have had their doses reduced by 50% even though, based on their actual weight, they already fell into the next higher weight category. Furthermore, additional changes were made to the exclusion criteria and guidelines related to TB detection and monitoring to adapt the protocol to the current UCB standard, and descriptions of clinically inactive disease (CID) and clinical remission on medication (CRM) were modified for clarity.

Protocol Amendment 7: The primary purpose of this substantial amendment, dated 22 Sep 2016, was to update the protocol in accordance with current UCB TB detection procedures, including the introduction of yearly TB testing and the extension of the prophylactic TB treatment duration from 4 to 8 weeks. Furthermore, it was clarified that long-term efficacy data from study participants who withdrew from the study after Week 56 or initiated any rescue medication use after Week 56 would be analyzed “as observed” and would no longer be imputed as nonresponse or missing. Moreover, a section on “Suspected transmission of an infectious agent via a medicinal product” was added in accordance with current company standards.

Protocol Amendment 8: The primary purpose of this substantial amendment, dated 24 Jun 2019, was to reduce the study participants’ burden by limiting the frequency of on-site visits, safety sampling, and efficacy assessments. The frequency of on-site visits was reduced from every 8 weeks to every 16 weeks in this long-term study. At the time of implementing Protocol Amendment 8, all ongoing study participants had at least completed the visit for Week 180. As before, on-site CZP administration between scheduled visits was offered as needed. The frequency of safety sampling (blood sampling and urinalysis) was extended from every 8 weeks to every 16 weeks to reduce the study participants’ burden in line with the updated on-site CZP administration schedule. Safety data collected previously during the study and close evaluation by the DSMB supported the extension of sampling frequency. This longer interval was also implemented for efficacy assessments to further reduce study participants’ burden and was appropriate to describe the long-term efficacy of CZP. UCB also determined there was limited value in collecting ADAb and CZP plasma concentration data after >4 years of CZP exposure. UCB determined that collection of additional samples to determine CZP plasma concentrations and ADAb samples would be of limited utility and an undue burden on the study participants. Discontinuation of blood sample collection for further characterization of CZP PK and immunogenicity was supported by the DSMB as the PK and immunogenicity data available to date were considered sufficient from a safety perspective and for PK characterization.

Protocol Amendment 9, dated 27 Apr 2020, was undertaken following an interaction with FDA in Jan 2020 in context of the pJIA Pediatric Research Equity Act (PREA) requirement for CZP. The primary purpose of this substantial amendment was to enroll an additional 30 study participants on the Original CZP Dose in order to adequately assess the exposure levels and clinical experience of CZP in pcJIA at both the Reduced CZP Dose and Original CZP Dose, and also adequately support the safety assessment of the Original CZP Dose. The ECLIA methods, for which selectivity had previously been assessed in the rheumatoid arthritis (RA) matrix, were validated to meet the standards set in the regulatory guidance for analytical procedures and methods validations for drugs and biologics (FDA, Guidance for Industry – Bioanalytical Method Validation, 2018). Sampling for CZP plasma concentration and ADAb was reinitiated for study participants enrolled following Protocol Amendment 9. All study participants enrolled following Protocol Amendment 9 had plasma concentrations of CZP and ADAb analyzed using the ECLIA methods. In addition, PK and ADAb samples (for which sufficient volume and stability data for PK analysis were available) collected in this study prior to Protocol Amendment 9 were reanalyzed with the ECLIA methods. The collective ECLIA-based PK data for this study form the basis of any future CZP modeling and simulation work. In addition, exclusion criteria related to TB, hepatis B, hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) were updated to align with current clinical guidelines in Protocol Amendment 9. After Protocol Amendment 9, study participants on the Reduced CZP Dose were able to switch to the Original CZP Dose at the discretion of the Investigator.