Global Amendment 1: The following main changes were introduced by this amendment: Timing (days) was corrected for Visit 1, flare confirmation, and re-induction. Vital status collection timelines and timing of the assessments were clarified. Details for end of study (EOS) visit were clarified. Further endpoints were added to align with the TSAP. Steroid tapering instructions for budesonide MMX and beclomethasone dipropionate were added since they were previously missing. Criterion for withdrawal from trial treatment of patients not achieving clinical remission within the first 48 weeks of maintenance treatment was modified to consider the investigator’s decision, based on individual patient history and available alternative treatment options. Instructions for s.c. trial drug administration were updated based on the results of trial 1368-0003.

Global Amendment 1 (continued): Detailed instructions for monitoring and handling of systemic hypersensitivity reactions were added since they were previously missing. Instructions for permitted use of corticosteroids were clarified for clinical practice. Storage timelines for pharmacokinetics (PK) and anti-drug antibody (ADA) samples were corrected. Collected medical and surgical history was simplified since not all of this information was required for a roll-over trial. Timing of end of trial (EOT) and end of study (EOS) visits for prematurely discontinued patients was modified since a clarification was required. Baseline definitions for efficacy and safety were aligned. Exposure analysis plan for safety across projects with spesolimab given as rescue medication was aligned for harmonisation across projects. The expected number of patients was corrected.

Global Amendment 2: The following main changes were introduced by this amendment: Further endpoint regarding faecal lactoferrin (FLF) was added since it had been missed in the previous version. Use of birth control for men able to father a child was removed from Inclusion Criterion #3 and from contraception requirements, to reflect changes in the IB. Restriction of sperm donation for male patients was removed to reflect changes in the IB. Adverse event (AE) monitoring instructions and definitions of adverse events of special interest (AESIs) were modified to remove cytokine release syndrome to reflect changes in the IB. Pre-treatment with steroids before next trial medication administration was permitted as secondary prophylaxis in patients who had experienced mild-to-moderate infusion reactions or anaphylactic reactions in the past to provide more clarity for use of steroids as secondary prophylaxis.

Global Amendment 3: This amendment introduced a correction to Flow Chart 3.

Global Amendment 4: The following main changes were introduced by this amendment: Tuberculosis tests were introduced. The benefit-risk assessment section was re-phrased to reflect latest IB wording and BI project standard wording. Blood sampling frequency for PK, ADAs, and biomarkers was modified for reconciliation with planned data analysis. Clarification that patients not eligible to take part in trial 1368-0017 were to complete the follow-up visit 16 weeks after last dose in trial 1368-0004 or 1368-0005 Part 1 was added. Exceptions were added for application of exclusion criteria from the original induction trial (Exclusion Criterion #2) regarding: - Disease limitation to the rectum (since it could have been met by patients with reduced colonic extension of their initial mucosal inflammation who responded to the induction treatment) and - Latent tuberculosis (since it was considered that these patients could benefit from the maintenance treatment in trial 1368-0017)

Global Amendment 4 (continued): The definition of disease flare was updated to align with expert experiences with other ulcerative colitis programmes. The dosing frequency for maintenance treatment was increased from a q12w interval to a q4w interval and the dose for intensified maintenance treatment after disease flare was increased from 300 mg to 600 mg spesolimab. This decision was taken since over 50% of the first 24 patients who rolled over into this trial experienced a relapse/flare during the first 6 months after switching from the induction to the maintenance treatment. This rate was higher than the rate observed with approved drugs for the same condition, which was considered to be related to a decrease in drug exposure below the threshold required to maintain maximum target engagement. It was considered that q4w dosing could maintain drug exposure in the therapeutic range. Since the s.c. injection interval in the intensified maintenance treatment could not be changed to q4w for trial-logistic reasons, it was decided to apply a higher dose of 600 mg to double the exposure compared to the original regimen. The proposed dose change was considered safe for the patients, since it was lower than the doses previously tested in healthy volunteers and ulcerative colitis patients

Global Amendment 5: The following main changes were introduced by this amendment: The benefit-risk assessment was updated based on the results of induction trial 1368-0005. The criterion for patient withdrawal from trial treatment in case of >2 confirmed disease flares within a 12-month time period was changed to >1 confirmed flare during the trial, to allow discontinuation of patients with >1 confirmed flare. The criterion for patient withdrawal from trial treatment if continuation was not in the patient’s best interest in the opinion of the investigator was added for clarification. The timing of electrocardiograms was corrected. The restriction period during which any biologic approved for ulcerative colitis was not allowed was clarified to provide a clear instruction about the end of restriction period. Timing of thyroid-stimulating hormone and haemoglobin A1c assessments was modified in the flow chart footnote to provide a specification.

Global Amendment 6: The following main changes were introduced by this amendment: The frequency of stool sampling for faecal biomarker assessments until Visit M13 was reduced from every 12 to every 24 weeks for patients under maintenance treatment, to simplify the procedures of the trial and reduce the long-term burden for patients. The requirement of vital status collection for patients who discontinued trial medication before EOT was removed since it was not considered necessary for this long-term trial and the change was considered to reduce the burden of visits for these patients. The potential impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection was included in the benefit-risk assessment.

Global Amendment 7: The following main changes were introduced by this amendment: The following main changes were introduced by this amendment: Peripheral neuropathy was included in the benefit-risk assessment and as an AESI, and a stopping rule for peripheral neuropathy was added, to reflect updates at project level. Tables specifying 2 obsolete product formulations were removed, to align with the current investigational medicinal product dossier.