Description of amendments to V2 of the FOCUS trial protocol Substantial amendment 1: Section 10.3 Removal of the second mailing of patient questionnaires at 1, 6 and 12 months and change to telephone. Substantial amendment 2: Section 12.5.2 Removal of neuroleptic malignant syndrome-like events; anaphylactoid reactions; serotonin Syndrome; pancytopenia, thrombocytopenia or haemolytic anaemia from the list of adverse reactions which will be collected systematically on the discharge form and follow ups. Will be considered as AEs and reported according to our pharmacovigilance procedures which are unchanged. Substantial amendment 3: Timelines (page 47) Change to the expected start date from April 2012 to July 2012 due to delays in receiving the IMP. Substantial amendment 4: Section 14.4 Data Monitoring Committee. Clarification of the arrangements for sharing data with other parallel trials which will be based on the discretion of the Chair of our DMC. Substantial Amendment 5 Traditional PIB for Proxies V1 110512 was reworded to reflect that it is being read by the proxy rather than the patients. Substantial amendment 6 Removal of Protocol Appendix 1 which was replaced by a link.

The original CTA was submitted prior to the final supplier of trial IMP being confirmed. Therefore the details of the MA holder which we originally submitted was not the MA holder of the IMP that we are now using (ATC code N06A B03). this amendment provided the correct MA details for the Oxactin 20mg we are using and ensures consistency with the details provided in our annual DSUR reports. Amendments: Change of MA holder and MA number details to reflect the specific IMP used for the trial Change in the response to question D2-2 in the CTA from ‘yes’ to ‘no’ as the same IMP has been used for each patient. Additional clerical amendments made: Section A4: Update to the ISRCTN number (this was not available at the time of the original submission). Section B1: Amendment to sponsor contact Section C1-5: Update to sponsor responsibility for sign off of CTA Section G4: Update to Network name and contact details Section H2-2: Date of ethics submission added as the original CTA was submitted prior to approval given. Section H2-3: Status changed to ‘approved’ and date of ethical approval added as the original CTA was submitted prior to approval given.  Protocol amendments relating to the IMP Section 1.1 Background: Updated the link address to current SmPC Section 9.1 Study Drug: Updated IMP details Section 9.1.1 MA number: Updated MA number Section 9.1.3 MA holder: Updated MA holder details Section 9.4 Storage: Storage temperature updated Section 9.5 Management: Storage temperature updated Notification of change of funder from the 1st October 2014 for the main phase to the NIHR HTA.

Change of Chief Investigator.

This amendment was required following notification to the sponsor of a revision of the summary of Product characteristics for Oxactin 20mg PL 19611/0017 on 24th July 2015. The SmPC was revised as a result of a variation to the marketing authorisation to update the safety information in line with the Core Safety Profile which was issued following conclusion of Periodic Safety Update Report (PSUR) work sharing procedure FR/H/PSUR/0069/001. In addition, the SmPC was updated to align with the layout and headings in the current Quality Review of Documents (QRD) templates, including the standard statements now required to encourage reporting of suspected adverse reactions. Information included in the latest version of the SmPC contra-indicates the combined use of metoprolol for heart failure and fluoxetine. Following discussion with the trial sponsor it was agreed that immediate action could be implemented to ensure that any patients taking metoprolol for heart failure were excluded with immediate effect. Urgent Safety Measures taken to ensure patient safety: A change was made to the database on 16/11/16 to add metoprolol for hear failure to our current list of excluded medications with immediate effect. All contacts at each site were emailed to inform them of the immediate change to the exclusion criteria and a revised paper randomisation form provided for use with immediate effect. A database report was created for patients randomised who were taking metoprolol at the time of randomisation and who would still be taking the trial medication. Only five patients were affected and each one was checked by the Chief Investigator as to the indication for metoprolol and none were found to be taking the drug for heart failure 17th The MHRA were contacted to advise them of action taken on November and 21st it was confirmed as an urgent safety measure on November 2016. The Data Monitoring Committee and Steering Committee informed. .