Amendment 2 (Substantial) was for the addition of new sites, and change of PI at 1 site. Approved 30Sep15 by ethics: N12 – Imperial, PI Mr Nandi N14 – James Cook, PI Prof Kane N34 – Sheffield, PI Mr Al-Tamimi N29 – Liverpool, PI Miss McMahon N48 – Leeds, PI Mr Timothy N08 – Brighton, PI Mr Critchley N46 – Stoke, PI Mr Tzerakis N18 – Aberdeen, PI Mr Bhatt N24 – Edinburgh, PI Mr Kandasamy N25 – Glasgow, PI Mr Suttner N30 – Salford, PI changed from Mr Holsgrove to Mr D’Urso

Amendment 3 (Substantial) was for the addition of 5 new sites. Approved 17Feb16 by ethics: N36 – St George’s, PI Mr Papadopoulos N13 – Royal London, PI Mr Paraskevopoulos N03 – Cardiff, PI Mr Nannapaneni N23 –Dundee, PI Mr Hossain-Ibrahim N26 – Hull, PI Mr M Hussain

Amendment 5 (Substantial) was for the change in PI at site N18 – Aberdeen, from Mr Bhatt to Mr Bodkin. Approved 09May16 by ethics.

Amendment 4 (Substantial) was to update the protocol (to v2.0 dated 01Mar16). This was approved by ethics on 23Jun16, and the MHRA on 15Jun16. The study was also submitted for HRA approval (under the HRA “Lite” submission process for studies with pre-existing IRAS approval) and approval for the study was granted by the HRA on 21Oct16.

Amendment 6 (Substantial) was for the change in PI at site N48 – Leeds, from Mr Timothy to Mr Thomson. Approved 08Jul16 by ethics.

Amendment 9 (Substantial) to MHRA – Updated IMPD as 2nd manufacturing run was outsourced to Tio Pharma. Approved 02Dec16 by MHRA. This Amendment was also notified to the HRA and was categorised on 12Dec16.

Amendment 8 (Substantial), was to add Queen’s Hospital, Romford as an additional participating site, and change the PI at the N13 Royal London Hospital from Mr Paraskevopoulos to Mr Ganesalingam Narenthiran. Approved 05Dec16 by ethics and the HRA confirmed on 09Jan17 that HRA assessment was not needed.

Amendment 10 (Substantial), was to change the PI at the N13 Royal London Hospital from Mr Ganesalingam Narenthiran to Mr Dimitrios Paraskevopoulos. Approved and categorised on 12Apr17 by ethics and the REC confirmed on 12Apr17 that HRA assessment was not needed.

Amendment 11 (Substantial) was to update the Protocol to v3.0 dated 27Apr17. Key protocol changes were as follows: 1. CHANGE TO ELIGIBILITY CRITERIA - only exclude patients on previous PO/IV GLUCOCORTICOID (other types of adrenocortcosteroids such as fludrocortisone are allowed). See list of steroids in protocol v3.0 page 23. 2. CHANGE TO CATAGORISATION OF AESI - now includes hyperglycaemia necessitating stopping of IMP (not necessarily requiring treatment). Please only report adverse events that fall specifically into one of these categories - see page 37 of protocol v3.0 3. CLARIFICATION ON REPORTING MEDICATION NON-COMPLIANCE - please report non-compliances for doses of medication that are given incorrectly or missed by ward staff or that you feel are clinically significant (if patient chooses not to take doses then this is not a non-compliance). This was submitted to ethics on 26May17 and classified as a Category A amendment, impacting all participating NHS organisations. The amendment was approved by ethics on 20Jun2017, and by the MHRA on 21Jun17. The study was also approved by the HRA on 27Jul17.

Amendment 12 (Substantial), was to change the PI at the N03 Queen’s Medical Centre, Nottingham, from Mr Stuart Smith to Mr Simon Howarth and to add the John Radcliffe Hospital, Oxford, as an additional site (PI Mr Patel). This was a Category B amendment, and was approved on 03Nov17 by ethics and the HRA.

Amendment 13 (Substantial) to MHRA - This was to register updated RSI (Reference Safety Information) from the SmPC for Aspen dexamethasone (Date of revision of text 23Jan18, Updated in Electronic Medicines Compendium 26Jan18) – Approved by MHRA on 19Apr18. This Amendment was also notified to the REC for information only and was categorised (Category C) on 03Apr18. No REC validation or HRA approval was required, as this was an MHRA only approval.

Amendment 14 (Non-Substantial) to HRA only - This was to register an extension in recruitment period from 28Feb18 to 28Feb19, following approval by the funder to extend the funding and duration of recruitment. Submitted 19Jul18 and approved by HRA on 23Jul18. However, the initial approval notification was not received, so was re-sent on 23Aug18.

**Amendment 15 – This application was voided, and was not applicable due to a change in circumstances. Please see details below** This Substantial amendment (to REC and MHRA) was initially planned and submitted to the REC and MHRA on 26Sep18, as a substantial amendment, to increase the number of participants to up to 1000 patients, in-case this was mandated by our interim analysis results. This would have updated the Protocol to v4.0 dated 17Sep18. REC approval was granted on 15Oct18, but there was a delay in receiving MHRA approval. When the MHRA approval was chased, it was found that the application was in-valid and would need to be resubmitted. Initially we were going to re-submit the Amendment 15 but in the meantime, our Interim Analysis result had since confirmed (on 12Oct18) that we did not need to recruit above 750 patients. As the MHRA submission had never been granted, we notified REC on 11Dec18 that we would not be proceeding with implementation of Amendment 15. Therefore, the Protocol in use remains unchanged as the Protocol v3.0 dated 27Apr17.

Amendment 16 (Substantial) to ethics only – This amendment approved a thank you card for patients or their surviving next of kin, and a GP treatment unblinding notification letter, advising which treatment the patient received during the trial, which will also be enclosed for patients when the thank you cards are issued. A patient friendly summary of the trial results will also be included in the card pack when sent out. In this amendment, changes to the methods of dissemination of trial information were also made, and a patient permission letter to request specific permission from 4 patients to use their questionnaire data were approved also. (In this submission, ethics were also notified for information only, of the GDPR letter that had been sent to ongoing patients in the trial, which was deemed a non-notifiable document). Approved by HRA 02Jan20. (Approval date listed as EOT date above as true date not accepted)