Several changes to the protocol as part of the MHRA approval, to include; • A change to the wording of the main exclusion criteria (section 1 and section 5.2) and precautions required (section 7.7.2) to detail the requirements for participants of child bearing potential to use effective contraception. • A change to the schedule of assessments (section 8) and changes to the glossary were made. • Patient information sheet was amended to reduce the amount of blood sample required.

• General - updated trial start date. • Sections 1 and 5.2 – corrections to the objectives of the trial and confirmation of the number of trial sites. • Exclusion criteria updated to include Multiple Sclerosis and HIV patients. • Section 4.1 – overall design updated to reflect timing of assessments as per standard care practice. • Section 4.3 – secondary end points changes to genital ulcer measure with a reduction of 20% considered to be clinically significant. • Section 6 – Enrolment/baseline update to screening log information. Update to randomisation instructions relating to the online enrolment and randomisation system TARDIS. • Section 6.1- screening assessments to be completed within 35 days prior to the first dose of treatment. HIV added. • Section 6.1- symptom directed assessment removed from baseline assessment and the inclusion of a chest X-ray. Addition of screening for alterations in mood/suicide ideation (as known to be a side effect of Roferon treatment). • Section 7- Study treatment, the standardised use of methotrexate has been removed from the trial for clarity. Concomitant immunosuppressants will now be administered at the clinician discretion on a case by case basis. • Section 8.1 amendments were made to the schedule of assessments. • Section 8.2 Electronic CRF updated relating to assessment of efficacy. • Section 8.4.2.2. Further information detailing the collection of urine samples for metabolomics analyses. • Section 8.7. Trial closure has been amended as being when the last patient has completed their final study visit. • Section 9.2. Updated procedure for generating randomisation code lists. • Section 13. Update to clarify the method of data capture as utilising electronic CRF’s. • Quality control procedures at site for primary and secondary endpoints as a consequence of the use of an eCRF platform at sites. • The removal of minimisation techniques for randomisation. • Section 16. Oversight committee members’ inf

Several changes to the protocol as part of the MHRA approval, to include; • A change to the wording of the overall design (section 4.1) as per the ISDMC recommendation. New wording; This is a randomised, two-arm, parallel, open-label design comparing the efficacies of infliximab vs alpha interferon. The population is patients with refractory disease eligible for the first biologic drug. • Primary outcome wording changed to match section 9 of the protocol. New wording; Primary Outcome: Modified Behçet’s Disease Activity Index (BDAI) after 3 months of treatment (Week 12 visit), with 20% change in means being defined as the zone of equivalence of treatment.

• Change to randomisation directions. • Section 7.2.2 – “Target dose of azathioprine is 2.5 mg/kg” added as per ISDMC recommendation. • Section 7.2.1 – Update to provide sites with more information about the IMP. • Section 7.3.2 – Wording added as per ISDMC recommendation “Immunosuppressant’s will be discontinued in Arm B”. • Section 8.1 – Schedule of assessments – New column added to detail the assessments required at Week 36 for patients who swap treatment arms at 12 weeks. • Section 8.2 – Wording changed to include the mandatory visit (Week 36) for patients who swap treatment at Week 12. • Section 8.4.3.2 – Change to amount of urine to be collected at each visit. • Section 9.2 - Additional details were provided in order to make the randomisation procedure more clearly to the reader. • Section 9.3.2 - Week 26 replaced with Week 24. • Section 9.6.1 - Priors were given explicitly as this was missed in the previous version of the protocol. • Section 9.6.2 - Corrected sample amount and added “at each trial visit” to make the collection clearer • Changes to Remicade SmPC. • Changes to Roferon SmPC for notification purposes only • Update to Staff members. Patient Information Sheet • IRAS number added – to comply with HRA guidance. • New wording to make clear that urine sample is required at visit Week 36 if patients swap treatment at Week 12. Informed Consent Form • IRAS number added – to comply with HRA guidance. • New wording to make clear that urine sample is required at visit Week 36 if patients swap treatment at Week 12. GP Letter • IRAS number added – to comply with HRA guidance

Exclusion Criteria added (section 5.2) • Point 8 Evidence for active Tuberculosis (TB testing using local standard practise) • New Wording Section 6.1 – If in the opinion of the Principle Investigator, the patient requires a biologic drug, whether a prior immunosuppressive agent has been given or not, that the patient will be eligible for a biologic under normal standard of care and SSBEH_D054/01 Bio Behçet’s Final Statistical Analysis Report 20/09/2021 Page 14 of 73 therefore may be included in the trial. (Patients previously receiving a prior biologic agent will, currently, not be eligible for the trial) If, in the opinion of the Principle Investigator, the disease is so severe that the benefit of starting the biologic before receiving all screening test results outweighs the risk of not starting it, that patient will remain eligible for the trial, in line with normal practise. • New Wording Section 4.1 – This is a randomised, two-arm, parallel design comparing the efficacies of the infliximab vs alpha interferon. (Previous Wording – This is a randomised, two-arm, parallel, open label design comparing the efficacies of infliximab vs alpha interferon • New Wording Section 6.1 – Section 6.1 Eligibility assessments for entry into the trial will be performed within 42 days prior to the first dose of treatment.(Previous Wording- Eligibility assessments for entry into the trial will be performed within 35 days prior to the first dose of treatment). • Changes to the wording randomisation procedure – New Wording After a patient has been screened and their details entered onto MACRO 4 database by the trial site the randomisation can be performed on the TARDIS website. The clinician must confirm eligibility by signing a paper eligibility Case Report Form (CRF) which trial site staff will email or fax to LCTU along with a copy of the Informed Consent Form. This will confirm eligibility of the patient along with the stratification factors, which will