Amendment-1 • Added visit (weeks 2-4) to Double-blind Maintenance Phase for drug dispensing purposes; revised subsequent visit numbers. • Corrected terminology for subject disease state in the primary and secondary objectives for the Double-blind Maintenance Phase from “with mild to moderate UC” to “who are in remission.” • Removed normal mucosal appearance criterion from “general” exclusion criteria; added to the individual exclusion criteria of the Double-blind Acute Phase. Created individual exclusion criterion for the Double-blind Maintenance Phase. • Specified in re-randomization criteria that subjects may be re-randomized into the Double-blind Maintenance Phase if they turned 18 during participation in either Acute Phase of the study. • Removed text regarding sensitivity analysis of the primary endpoint from “Double Blind Maintenance Phase” section of the protocol in Section 9.8. Also removed text from Synopsis regarding sensitivity analysis of the primary endpoint. Replaced with the newly created Sensitivity Analyses of the Primary Endpoint section. • Changed Double-blind Maintenance Phase primary efficacy endpoint test from chi-squared test to Mantel-Haenszel test with stratification by responder details. • Included Physician’s Global Assessment at week 2 and week 4 of the Double-blind Acute Phase. • Corrected ages for questions and responses for rectal bleeding and stool frequency in e-diary for both versions: children and adolescents (ages 11- 17 years) and caregivers of children (children aged 5-10 years). Specified version of e-diary to be utilized in the case of a change in subject age during the study. Also updated age groups for Global Change in Health questionnaire. • Full Analysis sets have been changed to the Safety Analysis sets. • Removed double-blind Acute Phase Full Analysis Set and Double-blind Maintenance Phase Full Analysis Set.

Amendment-2 • Corrected definition of Clinical Response by removing “Week 8”. • “Continuity-corrected” chi-squared test was added to the method to test the primary/secondary endpoints. • Revised number of active study sites from 35 to 43 • Added comment to footnotes to clarify that final visit of Double-blind Acute Phase and of the Open-label Acute Phase will be used as Week 0 for the subject’s next phase of participation. • Text amended to allow for data from an endoscopy performed within 7 days prior to the screening visit (visit 1) to be used in place of an endoscopy performed during the screening visit (Visit 1) or baseline visit (visit 2) for subjects entering the double-blind acute phase. • Added weight assessment to the end of the Double-blind Maintenance Phase. • Added clarification that an additional endoscopy is not required for subjects enrolling into the Double-blind Maintenance Phase from the Double-blind Acute Phase or the Open-label Acute Phase. • Clarified naming of laboratory assessments. • Detail added to clarify the baseline timepoint for each study phase.

Amendment-3 • Added Shire and CRO contact information for SAE reporting. • Increased maximum duration of screening period from 10 to 14 days. • Updated approximate number of study sites from 43 to 48. • Added pharmacokinetic blood sampling. • Updated approximate number of countries participating in the study from 9 to 8. • Added exploratory endpoint for pharmacokinetic assessment. • Clarification of additional care of subjects added. • Added text to allow for a stool sample obtained per standard of care within 24 hours prior to the Screening Visit (Visit 1), to be used for screening stool assessments.

Amendment-4 • Updated approximate number of subjects to be screened. • Added text indicating that enrollment in the Double-blind Maintenance Phase will be considered complete once 80 subjects have been randomized into this phase. • Increased maximum duration of screening period from 14 to 21 days. • Clarified eligibility criteria for Double-blind Acute Phase and Double-blind Maintenance Phase to indicate that all 3 components of the UC-DAI score are required as well as assessment of the mucosal appearance (endoscopy score). • Generated new study design flow chart to increase clarity on determination of eligibility for entry into each of the 3 treatment phases. • Updated Exclusion criteria. • Added a column and a row to the Schedule of Assessments to increase clarity and awareness for sites that it is recommended that site staff telephone subjects within 4 to 7 days prior to the Baseline Visit and prior to each site visit to remind subject or the subject’s caregiver to enter their UC-DAI symptoms (rectal bleeding and stool frequency) into their e-diaries every night. This was previously only mentioned in Sections 7.1 and 7.2. • Added a footnote indicating that subjects may bring in a standard of care stool sample (if collected within 24 hours) for screening assessments and evaluations. • Updated assessment time points in schedule of assessments for Double-blind Acute Phase, Open-label Acute Phase, and Double-blind Maintenance Phase.

Amendment-5 • Modified to indicate that “at least” 80 subjects will be enrolled in the Double-blind Maintenance Phase of the study. • After agreement with US FDA in September 2018, the sample size for the DBA phase was reduced to 53 subjects due to difficulties with recruitment. • Subgroup analyses for the primary endpoint were added to explore efficacy by weight group and Week 8 responder status. • Added text to indicate that, for the DBM phase, secondary endpoints of the proportion of subjects who had maintained a clinical and endoscopic response at Week 26 using central reading, and using local reading endoscopies, the CMH test was not performed if the number of subjects with central reading endoscopy data was insufficient. The number and percentage of subjects with clinical and endoscopic response were presented by treatment arm. • Added text to indicate that more data were required to perform the psychometric analysis of the DUCS for children and caregivers; therefore, the need to perform these analyses will be considered in the future. • Removed planned duration of enrollment period as this is not accurate for individual subject participation. • Removed text describing sample size calculations as this study is not powered to detect differences between treatment groups. • Added AE assessment during scheduled telephone calls and on Visit 5 • Expanded the window for acceptance of historical endoscopy results from 7 days to 21 days prior to the Screening Visit.