Changes were requested by the MHRA: - Protocol section 8.6 now clarifies that the IMP administration will be done in an in-patient setting with appropriate resuscitation facilities & staff available - Protocol section 8.6 now clearly documents that the study treatment must stop immediately in the event of intolerance or allergic reaction during administration. Section 8.11 also clarifies this - Protocol section 2.0 flowchart time point for follow-up now clarifies that it is post operation - Protocol section 11.4 now states that SAEs will be reported to LSHTM CTU within 24 hours of their knowledge - Protocol section 8.4 now clarifies that the treating clinical physician will have the final decision to unblind, & that the reason & rational will be discussed with the PREVENTT office at UCL

Summary of the main changes: - Physical Examination removed as this data will not be collected or needed and ECG monitoring removed from post baseline assessments as ECG monitoring not required by safety profile of IMP and some sites do not routinely perform this - Clarification to co-primary endpoint relating to risk of blood transfusion or death, and have added that deaths will be adjusted for in the analysis. - POMS: this data also needs to be collected at day 5, due to patients being discharged much sooner nowadays - Health Economics: these sections revised following review and update from the trial Health Economist - TSC & DSMC: membership of both these committees has been added, now they have been approved by the HTA - AE section: revised to reflect the LSHTM CTU AE processes (because the sponsor has delegated this responsibility to the LSHTM CTU) - Restarting treatment: following on from review by the TSC it was agreed that the treatment could be restarted under certain conditions

Summary of main changes: - Changes made in light of updated advice from the MHRA on IV iron: a) added two new exclusion criteria (patients with severe asthma or severe allergy, patients unfit for elective surgery), and b) added the new information that patients should be monitored for at least 30 minutes following treatment - Updated the side effects to reflect changes in the latest version of the SmPC - Changes made to the preoperative visit: this additional visit to hospital has been removed and the preoperative QoL forms will now be completed at home, and the central bloods done on admission to hospital (sites had difficulties fitting in this extra visit) - Changes to the timelines from treatment to surgery: the lower limit of this timeline shortened from 14 to 10 days, as sites found this restrictive when trying to recruit and it also meant cancer patients were excluded (agreed by the TSC that 10 days was sufficient time for the IV iron to take effect) - Further clarified documentation for drug returns and drug destruction to ensure blinding is not compromised by blinded staff at site and the wording relating to destruction of remaining drug has been removed - Included the system which will be used to document the post-operative complications (Clavien) - Included UE tests as a requirement rather than if available in follow-up visits as this is needed to calculate eGFR - Further clarification to haemoglobin measurements, immunosuppressive therapy in exclusion criteria, timing of screening pregnancy test, vital signs assessment, DSUR and APR anniversary dates and non exclusion of those on oral iron supplements’ - Clarified IMP administration masking with iodine so that it allows flexibility of other methods in the event of those patients who are allergic to iodine - Added additional details so sites can call patients prior to consenting (as requested by site R&Ds)

Summary of main changes: - Changed inclusion criteria to increase the upper limit of haemoglobin for men, to match the WHO definition of anaemia, and to help aid recruitment - Amended the definition of major surgery, so sites can now include patients having surgery which doesn’t include the removal of an organ - Changed the exclusion criteria so that is it clear that only untreated B12/folate deficiency would make a patient ineligible - Added in how severe asthma/allergy is defined in the exclusion criteria - Increased the number of sites from 20 to 35, to help aid recruitment - Removed brand names of masking IV bags and giving sets to allow flexibility across sites - Included 200ml vials of Ferinject to allow flexibility in use of hospital stocks across sites - SAE form can be submitted via online AE database - Data monitoring changed to reflect new Monitoring SOP requirements - Administrative changes to update TSC members and observers

Summary of main changes: - Changed exclusion criteria for Liver Function Tests (LFTs) to reflect local hospital practise and pathways - Changed exclusion criteria so that patients who have had a previous blood transfusion within the previous 12 weeks can still be included in the trial - Changed assessment of LFTs at baseline to clarify this is only done if clinically indicated according to local hospital practice and pathways - Updated the risk/benefits section of the protocol to reflect the change to the exclusion criteria for patients who have not had their LFTs checked - Increased the number of sites from 35 to 40 to help with recruitment - Update to reflect the approval by the funder of an additional 2 years of recruitment - Updated summary of product characteristics