Substantial amendment 1 - Changes made in relation to conditions specified by the REC in the REC approval letter dated 16th September 2010. - Additional site at Chelsea & Westminster Hospital added - The definition of severe sepsis as an exclusion criterion and as a treatment suspension criterion has been modified. - Changes have been made to the randomisation procedure and emergency unblinding in the protocol - Additional study assessments have been included:  Monocyte-platelet aggregates  Bacterial metagenomic analysis from a buccal (mouth) swab sample

Substantial amendment 2 19 January 2011 - Minor changes made to the simplified IMPD to remove reference to the study protocol. This is to avoid having to amend the sIMPD every time we amend the study protocol and consequently change its version number. - Randomisation amended in protocol to blocks of 4 for C&W and blocks of 6 for SGUL - Pharmacovigilance section amended regarding wording and reporting requirements

Substantial amendment 3 22 August 2011 Substantial Amendment 3 first submitted to REC and MHRA on 22 August 2011 with the following major changes: 1. Inclusion/exclusion criteria amended: 1.1. Inclusion criterion 4 (able to enter the study within 48 hours of admission) has been amended as the study team have found this criterion quite restrictive, precluding study entry for a significant proportion of patients screened. 1.2. The definition of exclusion criterion 4 (acute coronary syndrome), has been updated to accomodate the introduction of fondaparinux in place of dalteparin in the treatment of this condition. 2. The ‘monocyte-platelet aggregates’ assessment has been removed as it was not possible to establish the necessary laboratory assay. 3. The upper limit for the acceptable plasma lactate concentration has been increased from 2.7 to 3.0 mmol/L. 4. The requirement that study therapy be stopped pre-emptively in patients requiring a radiological examination with the administration of intravenous contrast has been removed 5. Addition of 4 new sites – Conquest Hospital, Hastings, Freeman Hospital, Notting ham, North Tees and New Castle 6. We would like to extend the study end date to 31st December 2012. 7. Change of PI at St George’s from Dr Andrew Hitchings to Professor Emma Baker MHRA rejected first submission on 26/09/2011 with GNA. Resubmitted to MHRA on 04th October 2011 & REC on 06th October 2011 with further change in protocol to include the foll: “Retention of a requirement to suspend metformin before administration of intravascular iodinated contrast agent and that it not be reinstituted until 48 hours afterwards and only after renal functions has been re-evaluated and found to be normal’ as per SmPC.”

Substantial amendment 4 29th June 2012 1. The active: placebo allocation ratio will increase from 1:1 to 2:1. Accordingly, the target sample size will increase from 46 to 69 participants.. 2. To accommodate 2:1 allocation, the randomisation block size will be fixed at 6. 3. The intention to explore feasibility, safety and tolerability of the investigational treatment will be made explicit. 4. The secondary exploratory endpoints based on collection of a buccal swab and performance of the McKenzie skin blanch test will be removed, as it has not proved feasible to perform these tests with sufficient reliability. 5. The number of missed capillary glucose concentration measurements (≥3 out of 7 in a calendar day), or the maximum interval between consecutive measurements (>12 h), that will constitute a protocol deviation shall be defined. 6. Recurrence of COPD exacerbation will be added as a Protocol Defined Event, as it is a common event in the population under study, and contributes to the secondary analysis. 7. Change of sponsor contact from Ira Jakupovic (Clinical R&D Manager) to Nicki Collins (Sponsor representative). The Participant Information Leaflet, Informed Consent Form and GP Letter have been updated due to the changes in the protocol and also submitted for your review in tracked and clean versions.

Substantial amendment 5 03rd April 2013 • 1. Adding new sites in uk · 2. Extending the recruitment period 3. A typographical error has been correct in the introductory section 4. Definitions for ‘expectedness’ have been updated to align with standard regulatory framework 5. The interpretation of Protocol Defined Events has been clarified 6. Fructosamine concentration has been added as a secondary endpoint 7. The terms used for sampling time-points have been standardised within the protocol 8. Reference to a Trial Management Group has been removed, as in practice, its membership and function has become the same as that of the Trial Steering Committee · 9. Updating GP letter in light of these changes · 10. Change of sponsor representative to Lucy Parker