Protocol amendment 1: The main changes included: The expected number of sites was increased from 16 to 17. Some corrections were made.

Protocol amendment 2 (continued): The emergency code break procedure (section 9.5.4.5) was adapted from web-based to IWRS based. The first secondary endpoint was amended to include CDAI remission rate (proportion of subjects with below 150 points). The second secondary endpoint was changed from "Proportion of subjects with at least 5- point reduction in PRO2 from baseline (PRO2-CR5 response rate), proportion of subjects with at least 8-point reduction from baseline (PRO2-CR8 response rate), and proportion of subjects with reductions below 8 points (PRO2-resmission rate) at each CDAI remission rate evaluation time." to "Proportion of subjects with at least 5-point reduction in PRO2 from baseline (PRO2-CR5 response rate), proportion of subjects with at least 8-point reduction from baseline (PRO2-CR8 response rate), and proportion of subjects with below 8 points (PRO2-resmission rate) at each evaluation time". The last secondary endpoint was changed from: "Steroid-free remission rate and steroid-free response rate in subjects concomitantly using adrenocorticosteroids is to be tabulated by treatment group and evaluation time. Summary statistics for steroid dosage, change and percent change from baseline are also to be calculated for each treatment group and evaluation time" to "In subjects who were concomitantly taking adrenocorticosteroid, dosage, change and percent change of adrenocorticosteroid from baseline". In section 11.4: Data recording, the following sentence was deleted: "For the CDAI assessment items assessed by the investigator, the data entered by investigators in the site staff part of the electronic patient reported outcomes are to be used for evaluations.

Protocol amendment 2: The study design in the synopsis was amended to specify that the screening test had to be carried out within 42 days prior to the start of the IMP administration after obtaining consent, and before the double-blind period. The expected number of sites was increased from 17 to 18. Exclusion criterion 28 and 34 was amended: to clarify that subject with cervical cancers with no metastasis or recurrence observed for 5 more years at the time of giving consent were not excluded from the study. The highly effective contraception methods were altered from including “Contraceptive ring (IUD) or intrauterine progesterone-releasing system (IUS)” to “Use of intrauterine device (IUD)”. (As the use of an intrauterine progesterone-releasing system (IUS) was allowed in the Japanese protocol, exclusion criteria 34 was not altered in the Japanese protocol.) It was stated in the synopsis that safety was analysed using the safety analysis set. The process of keeping the IMP blinded in section 9.4.1. was amended by adding non-transparent sealing covers and seal stickers, which had to be intact during administration. Section 9.4.3: Method of allocating subjects to treatment groups: Statements about stratified allocation algorithm created by IWRS and randomization manager creating a drug number table of randomized drugs were removed. Section 9.4.6.2: Maintenance of Blinding: A statement that randomization manager is to seal the allocation number table immediately upon creating it, and carefully store it until code break, was removed. Section 9.5.1.2.1: History of Crohn's disease: disease types were changed from "enteritis, enterocolitis, colitis" to "small intestine-type, small and large intestine-type, or large intestine-type". Blood sampled for viral and TB test was reduced from 22 mL to 18 mL. (The blood sample for viral and TB testing was 23 mL throughout the study in the Japanese protocol.)

Protocol amendment 6: Inclusion criterion 5 was changed to amend the number of biologics that the subjects could have taken without response to be eligible to enter the clinical study from one to “one or two”. In addition, “subjects who cannot taper oral adrenocorticosteroids” was changed to “subjects who cannot taper adrenocorticosteroids”. Exclusion criterion 17 was amended to exclude subjects with AST or ALT three times the upper limit (previously: twice the upper limit) and subjects with serum creatinine levels more than 1.5 times the upper normal limit (previously: 1.5 mg/dL). Vedolizumab intake was moved from exclusion criterion 27, where it was not permitted any time in the past to exclusion criterion 24, where it was not permitted within 8 weeks prior to the start of the IMP administration. Chest X-ray tests were removed as standard safety examinations throughout the protocol, and were only to be done during screening. Updates in the study schedule (recruitment planned: September 2018 to April 2021, treatment planned: October 2018 to June 2021, follow-up planned: June 2021 to June 2023, close out: July 2023). Added, that the haematocrit value used to calculate the CDAI score at Week 0 or screening test (screening test value may also be used if this is within 7 days of the date of the CDAI assessment).

Protocol amendment 7: Russia was added as a study country. Inclusion criterion 5 was changed to delete the number of biologics (“one or two”) that the subjects could have taken without response to be eligible to enter the clinical study.

Protocol amendment 8: The anticipated number of Japanese subjects was updated from 12 to 22, the anticipated number of non-Japanese subjects was updated from 28 to 18. Updates in the study schedule (end of recruitment planned: October 2020). The analysis of blood biomarkers was added to the protocol.

Protocol amendment 10: Exclusion criterion 10 was amended to include. “In addition, subjects who tested positive for HCV antibody and who were at least 24 weeks post-treatment may participate in clinical trial as long as negative HCV-RNA is confirmed during screening period.” This was also added to section 9.5.1.2.4: Other items assessed during screening period in this clinical trial or specific to disease area. Exclusion criterion 20 was changed from “Subjects with an infectious disease requiring hospitalisation or intravenous administration of antibiotics (including antiviral drugs) within 4 weeks prior to the start of IMP administration, or oral administration of antibiotics (including antiviral drugs) within 2 weeks prior to start of IMP administration” to “Subjects who required any one of following treatments of infection; "hospitalization within 4 weeks prior to start of IMP administration", "intravenous treatment of antibiotics (including antiviral drugs) within 4 weeks prior to start of IMP administration", or "oral treatment of antibiotics (including antiviral drugs) within 2 weeks prior to start of IMP administration". Furthermore, with regard to novel coronavirus infection (COVID-19), subjects who required any one of following treatments: “hospitalization within 4 weeks prior to start of IMP administration”, “any intravenous treatment within 4 weeks prior to start of IMP administration” or “any oral treatment within 2 weeks prior to start of IMP administration”. Exclusion criterion 25 was amended to include vaccines with toxicity equivalent to that of live vaccine. The same changes were made in section 9.4.7: Prior treatment and concomitant treatment and section 9.4.7.1.1: Prohibited concomitant therapies and concomitant drugs. Section 9.4.7.1.2 Restricted concomitant drugs was amended to include: “The SARS-CoV-2 vaccine may be used concomitantly, but it should not be administered within 7 days before or after IMP administration.”

Protocol Amendment 11: Exclusion criterion 25 was amended. Vaccines with a toxicity equivalent to that of a live vaccine were deleted and “vaccine that is considered to have a risk of infection, such as a virus vector vaccine that uses a virus that retains its ability to proliferate” was added. The same changes were made in section 9.4.7: Prior treatment and concomitant treatment and section 9.4.7.1.1: Prohibited concomitant therapies and concomitant drugs. Updates in the study schedule (end of treatment planned: January 2023, end of follow-up planned: January 2025, close out: February 2025).

Protocol Amendment 12: Updates in the study schedule (end of treatment planned: April 2022 instead of January 2023, end of follow-up planned: April 2024 instead of January 2025, close out: May 2024 instead of February 2025). The target sample size in section 9.7.2 was reduced to 25, which was the number of enrolled subjects at the end of recruitment. However, the analyses were not changed.