Changes to the protocol exclusion criteria. Changes to the acceptable forms of effective contraception. Changes to withdrawal procedures of participants from study treatment due to pregnancy. Changes to safety profile of procedures section. Changes to the SAE reporting section. Additional information added to the Patient Information Sheet.

Addition of tertiary objective: Enrich the detailed phenotyping of the COPD Cohort. Information to Withdrawal of Participants from Study Treatment section added. Due to the design of the database, data already entered onto it cannot be deleted, but will be excluded from analysis. Clarification regarding adverse event followup of patients following withdrawal from the trial. Addition of safety reporting procedure for unexpected adverse events which the PI deems are possibly related to the trial medication or trial procedures. Clarification that SAEs must be reported to the sponsor (CTRG) and not ORTU (Oxford Respiratory Trials Unit) within 24 hours of knowledge of the event. Explanation of why full dataset will be collected from screen failures at the screening visit. The patient information sheet has been altered to explain to the patient why the researcher's wish to complete the full set of screening assessments even if the patient is not eligible to take part in the study. The consent form now has an additional question (question 7) so that patients can give their consent for this. Minimisation to be carried out using the sofware program Sealed Envelope.

New primary endpoint: oxygen status in response to intravenous iron. This has led to the following changes in the text of the protocol as detailed below: 2. Rationale 3. New endpoints 4. Inclusion exclusion criteria 5. Simplification of study visits 6. Revised sample size Corresponding changes have also been made in the patient information sheet and GP letter. The final change is that not all patients will already be carrying out daily diary cards as part of their participation in the COPD Cohort (this protocol was simplified), and therefore this test was described as if it is new to the patient. Patients had to be free of an exacerbation as documented on the daily diary card for at least four weeks prior to the baseline study.

Change of CI from Dr Annabel Nickol to Dr Mona Bafadhel.

Minor admin updates. Addition of blood tests and lung function testing at screening visit for patients who did not have a recent result in either of these tests. The study team felt that the patients should not be asked to keep a diary card beyond the end of the study as no provision of diary follow-up had been made and the study had ends at 8 weeks post baseline for each patient. Clarification of who will carry out the study assessments. The protocol and the Patient Information Sheet were updated to reflect this. Simplification for recording AEs and a time limit on when to stop recording AEs. The CI and the sponsor felt that this section of the protocol was not clear and needed clarification. Clarification of safety reporting to confirm which SAEs must be reported immediately and a time frame for the end of reporting. The CI and sponsor felt it was unnecessary to report all SAEs and that there needed to be a time limit on when to stop reporting SAEs. The Patient Information Sheet has been updated to inform patients that a blood test and spirometry may be performed at the screening visit if a recent test is not available. The Patient Information Sheet has been updated to inform patients that diary cards only need to be kept for the duration of the study and no longer. The Patient Information Sheet has been updated to inform patients that the Baseline visit is more likely going to take 4 hours rather than 3 hours.

As requested by the MHRA in order to comply with UK Statutory Instrument 2004 No 1031 Part, the protocol was updated to clarify that all Serious Adverse Events, regardless of the causality, must be reported within 24 hours of knowledge of the event to the sponsor.

This study stopped recruiting from the COPD cohort. Patients first to be identified in the Oxford Centre for Respiratory Medicine or in a Primary Care by a member of their clinical care team who asked them if they wished to be contacted about the study. The following additional tests were added which were originally carried out in the COPD Cohort: - Patient’s weight, height and neck circumference measurements - A 12 lead electrocardiogram (ECG) GP letter and Consent form removal of references to COPD cohort.

To ensure the study recruitment target was met, the study staff were looking at a number of ways of encouraging recruitment including the use of recruitment posters and fliers for patients to take away. The study team to send out a study appointment letter for the remaining study visits once the patient has had their screening visit and to thank them for taking part in the study. Letter from patient's clinician or GP inviting patient to take part in the study and to accompany Patient Information Sheet. New document: PULSOX instruction sheet. Patient Information Sheet updated. Recruitment section of the protocol updated to reflect the additional sources where patients will be recruited from and how they will be recruited.

Removal of a need to collect sputum samples and conduct an exacerbation visit post baseline in the event of infective exacerbation (removal of observation of change in sputum microbiology as a secondary outcome) (protocol and PIS updated). Introduction of a "Consent to Contact Form" to maximise recruitment opportunities. Addition of a new poster (to enable the poster to be displayed electronically).