The protocol amendment included. [a] Replaced “Week 26” by “visit E1” when appropriate, removed “Drug screening”, added evaluation of Adverse Event (AE) at visit 1.1 [Flow Chart A (Blinded Intravenous Therapy (Period 1))], added “during period 1” to footnote 1 of Flow Chart A, added assessment of eligibility at visit 2, added fecal samples in the list of other sampling and testing. [b] Replaced “months” by “weeks”. [c] Exclusion criterion number 21 added per Health Authority request. [d] Reference to section 5.1.2 (Assessment of Efficacy) was added to clarify which hematocrit result should be used for calculation of Crohn’s Disease Activity Index (CDAI). [e] Clarification was added to footnote 6 of Flow Chart A. [f] The amendment included “Assessment of AE after subcutaneous injections will also include assessment of local tolerability. The assessment of local tolerability should be done just before the patient leaves the investigator site.” [g] If, in the investigator’s opinion, the patient required additional medical therapy for their Crohn’s Disease due to persistently high disease activity or worsening based on CDAI score (>450, or an increase by 100 points from baseline), the study treatment may be stopped and patients may receive conventional treatment for active disease as per investigator’s judgment. [h] Section 4.1.3 (Selection of doses in the trial) was amended. [i] Replaced “normal saline (0.9% NaCl)” by “5% Dextrose in Water (D5W)”. [j] The detailed procedures for preparing and handling the study drug were provided in Investigator Site File (ISF). [k] Section 5.6 [Biomarker (s)] was amended. [l] Additional unscheduled visits for the purpose of re-testing of laboratory parameters or AE monitoring were included as deemed necessary by the investigator. [m] To remove CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ) and Crohn’s Disease Endoscopic Index of Severity (CDEIS) from the protocol.

The protocol amendment included. a) Contact detail for Nasri Abdallah was updated and Ivona Herichova was added as Trial Clinical Monitor (TCM). b) Reference to ISF added. Intravenous (IV) infusions, as detailed in the Instructions for Preparation and Handling of BI 655066/Placebo in the Investigator Site File. c) Instruction how to proceed in case of Infusion reaction added. In case of infusion reactions emerging during or after infusion of BI 655066 or Placebo, the investigator should consider in accordance with severity of the reaction and local standard of care to 1) Immediately interrupt the infusion 2) Treat with systemic anti-histamines and intravenous steroids. Based on patient`s clinical course and medical judgment, the infusion may be re-initiated in case of mild or moderate reactions (according to RCTC grading in appendix 10.3) at lower speed with gradual increase to complete the infusion as detailed out in the Instructions for Preparation and Handling of BI 655066/Placebo in the Investigator Site File. d) Added recommendations in case of infusion reaction. In case of an infusion reaction monitor the patient per standard of care, grade the intensity of the reaction according to RCTC grading and proceed as described in Section 4.2.1 (Rescue medication, emergency procedures, and additional treatment(s)).

The protocol amendment included. a) Change in TCM, TCM Nasri Abdallah was replaced by Ivona Herichova. b) Endoscopic remission criterion added for patients with initial isolated ileitis. c) Inclusion Criterion for Period 3 more specified. d) To add inclusion criteria for roll-over trial. e) To add CDEIS threshold for patients with initial isolated ileitis. f) Update on start point of oral corticosteroids tapering. g) To specify inclusion criteria (CDEIS score) for patients with isolated ileitis. h) The inclusion criteria for treatment experienced patients was simplified to clarify that stopping of previous anti-TNF treatment for other reason is not exclusionary. i) Editorial change - to add restriction on concomitant medication into the exclusion criteria. j) Editorial change – Deletion of the exclusion criteria #20 since is already added to exclusion criteria #4. k) To specify inclusion criteria (CDEIS score) for patients with isolated ileitis as is stated in rationale for change 7. l) This exclusion criterion #21 is added due to a harmonization across the project. m) To update secondary efficacy endpoints. To update other efficacy endpoint, rationale as for change 14. n) To fecal calprotectin and lactoferrin are collected for the analysis of biomarkers. o) The times of visit clarification. p) To add eligibility criteria and timing for roll-over from trial 1311.6 to 1311.20. q) To exclude assessments obligation. r) Justification of CDEIS scoring for patients with isolated ileitis. s) Reasoning for adding SES-CD and PRO-2. t) To add opioids to restricted medication. u) To add Guidelines on tapering of corticosteroids. v) To add PRO-2 description, which is likely to be the new FDA requested primary endpoint in CD trials. w) To clarify procedure in case of CDEIS/SES-CD discrepancies.

The protocol amendment included. a) Information about roll over trial inserted in Clinical Trial Protocol (CTP) version 3 was deleted considering postponing of roll over study start. b) Emphasize that CDEI assessment is mandatory at visits R0 or E1only at certain circumstances. c) Administrative change: Reformulation of footnotes 6 and 7 wording to make them more clear for the readers. d) Sponsor decision on CDEIS score rounding. e) To cover intra-articular administration. f) Sponsor decision to not apply unblinding rules. g) Administrative change: Inconsistency correction, to be compliant with section 3.1 [Overall trial design and plan]. h) Administrative change: correction of incorrect statement. i) Sponsor decision to allow re-screening for specified patients. j) Administrative change: More appropriate name assignment to differentiate between Clinical and PRO response.

The protocol amendment included. a) Vedolizumab deleted from the list of drugs requiring 6 months of wash-out in exclusion criterion #4. b) Rewording as per request from Korean HA to make the statement more clear: Rectal 5-ASA compounds, parenteral or rectal corticosteroids must have been discontinued at least 4 weeks prior to visit 2. Rectal 5-ASA compounds, parenteral or rectal corticosteroids within 4 weeks prior to visit 2. c) Change in calculation, weekly weighted average instead of daily weighted average. d) Additional other efficacy endpoints added. e) Added: “The trial bioanalyst (TBA) and bioanalytical laboratory will be unblinded and provided with randomization codes in order to support PK/ADA sample bioanalysis.” f) Cannabis added to restricted medication list due to rather common use in the population and the interference with key efficacy endpoints. g) Clarification of alternative treatment added: “1). Re-screening of patients will not be allowed unless they have received and failed alternative treatment after first SF now meet eligibility criteria. “ changed to: “Re-screening of patients will not be allowed unless they have received and failed alternative treatment (not limited to Anti-TNF) and started to meet eligibility criteria.”

The protocol amendment included. a) Administrative change: Sponsor includes the changes implemented in the Investigator’s Brochure (IB), version 6, dated 03 June 2015. b) Administrative change, sponsor decision on efficacy endpoints categorization c) Administrative change: correction of mistake in definition of CDEIS response and the typo correction in the week of endoscopic assessment should be week 52. d) Administrative change: typo correction - mistake in the week of endoscopic assessment, should be week 52. e) Deleted endpoints: Change in SES-CD at week 26. Change in CDEIS at week 26. f) Added information about blinding procedure for the Interim analysis: An interim analysis for planning purposes only will be performed when approximately 90 out of 120 patients will complete week 12 assessment. The Trial Statistical Analysis Plan (TSAP) will be approved before the interim analysis snapshot BI personnel specified in the Interim Analysis Logistic plan will have access to selected unblinded information necessary to perform and interpret the Interim analysis Internal Planning. The results of this interim analysis will be used for planning purposes only. g) Analysis for Internal Planning. An interim analysis for efficacy will be performed for the first approximately 90 patients out of the 120 targeted patients who complete the week 12 visit. This analysis is for internal planning purposes only to facilitate further substance development. No need to account for an alpha penalty since this analysis is for internal planning only, it will not affect the conduct of the current trial and the conclusion of the trial will be based on the primary analysis. Details of this interim analysis are specified in the interim analysis logistic plan which will be finalized before the fast track approval snapshot will be performed. The results will be documented separately, no interim analysis CTR will be written.

The protocol amendment included. a) Patients fulfilling eligibility criteria for long term extension roll-over trial (1311.20) can be entered directly to 1311.20 trial after completion either visit E1 or E5 in 1311.6. b) Boolean remission endpoint added because it is a new way grouping CDAI subscores which was defined in the statistical plan. The analysis by visit was added for CDAI and PRO-2 which means a more detailed look at the data. c) The primary efficacy endpoint is the clinical remission of Crohn’s Disease defined as a CDAI score of below 150 after 12 weeks. Changed to: The primary efficacy endpoint is the clinical remission of Crohn’s Disease after 12 weeks, defined as a CDAI score of below 150. d) Added wording: The Simple Endoscopic Score in Crohn`s Disease (SES-CD) (R14-2969), has also been validated for CD and correlates closely with CDEIS, despite its reduced complexity. e) Follow up period is 15 weeks after the last administration of study medication. Changed to: Follow up period is 15 weeks after the last administration of study medication. Patients rolling over to 1311.20 trial are not requested to complete follow up period and are not counted as premature discontinuations. f) The statistical model for the binary endpoint is a stratified Cochran-Mantel-Haenszel test with randomisation factor of naïve or experienced to TNF antagonists as the stratification variable. There are three treatment arms, A is BI 655066 600 mg IV, B is BI 655066 200 mg IV, while C is the placebo arm. Changed to: The statistical model for the binary endpoint is a stratified Cochran-Mantel-Haenszel test with naïve or experienced to TNF antagonists as the stratification variable. There are three treatment arms, A is BI 655066 600 mg IV, B is BI 655066 200 mg IV, while C is the placebo arm. g) Adding comparison against placebo for clarification. Also, due to anticipated low number of patients in the TNF naïve group, an additional analysis is mentioned.

The protocol amendment included. a) Changed “Boehringer Ingelheim” into “AbbVie/Boehringer Ingelheim”. b) Added ABBV-066 (risankizumab) after BI 655066. c) “The trial is sponsored by Boehringer Ingelheim (BI)” was changed to “The trial is sponsored by AbbVie in the US and Boehringer Ingelheim (BI) ex-US. (d) “Data Management and Statistical Evaluation will be done by BI according to BI SOPs” was changed to “Data Management will be done by BI according to BI SOPs and the Statistical Evaluation will be done by AbbVie according to their SOPs.” e) The sample for DNA banking will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until there is no more material available for tests” was changed to “The sample for DNA banking will be stored at AbbVie or a third party delegate (e.g. Boehringer Ingelheim Pharma GmbH & Co. KG; Birkendorfer Str. 65, 88397 Biberach, Germany).” for 15 years after the end of the clinical trial or until there is no more material available for tests.