The following changes were requested: 1) Incorporation into the protocol that should a patient lose capacity throughout the trial, they will be given the opportunity to remain the trial. 2) Reformatting of some sections within the protocol 3) Addition of Section 1.5 (Disease Progression) – incorporation of allowing participants to stay in the study should they lose capacity after consenting 4) More detailed description of LAEP and EQ-5D-5L (Section 2.5) 5) Addition of PHQ9 questionnaire which is used as a screening tool for depressive symptoms. This was a recommendation from the MHRA following their protocol review (Section 2.5). The protocol has also been updated to remove patients with severe depression as defined by a PHQ-9 score of 20+ 6) Addition of Cognitive/capacity monitoring section (Section 2.6) 7) Addition of Treatment Breaks section (Section 4.4)

This amendment encompasses the following: Addition of sites and PIs: 1) Poole Hospital NHS Foundation Trust – PI - Dr Maxine Flubacher 2) Portsmouth Hospitals NHS Trust – PI - Dr Yogeshkumar Nishchal 3) The Clatterbridge Cancer Centre NHS Foundation Trust - PI - Dr Shaveta Mehta 4) South Tees Hospitals NHS Trust – PI - Dr KS Manjunath Prasad Change of PI: 5) The Leeds Teaching Hospitals NHS Trust - Mr Ryan Mathew Furthermore, there have been some minor updates to the protocol including: 1) KEY CONTACTS - Removal of Kirsten Murray as Senior Trial Coordinator 2) Section 5.3 – Modified Safety Reporting section has been updated to provide further clarification 3) Section 7.3.5 – (2 - 2) Assessment of utility associated with seizures) has been updated to clarify the analysis that will be performed 4) Appendix 3 – References have been updated where appropriate

Addition of new sites: Pietro D'Urso Salford Royal Hospital, Stott Lane, Salford, M6 8HD Isaac Phang Royal Preston Hospital, Sharoe Green Lane, Preston, PR2 9HT Puneet Plaha John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU Patrick Mitchell Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP

Summary of changes 1. SmPC 14 March 2019 - Section 4.8 Undesirable Effects: A new adverse reaction of gait disturbance has been added to the list of Nervous System Disorders, affecting between 1 in 1000 and 1 in 10000 people. 2. SmPC 01 April 2019 - Section 4.8 Undesirable Effects: A new adverse reaction of delirium has been added to the list of Psychiatric Disorders, affecting between 1 in 1000 and 1 in 10000 people. 3. SmPC 01 April 2019 - Section 4.8 Undesirable Effects: A new adverse reaction of encephalopathy has been added to the list of Nervous System Disorders, affecting between 1 in 1000 and 1 in 10000 people. 4. SmPC 04 October 2019 - Section 4.4 Special warnings and precautions for use of Keppra has been updated to include abnormal thoughts, feeling irritable or reacting more aggressively than usual or if patient or family or friends notice important changes in mood or behaviour. The protocol and PIS have been updated to reflect these changes to the SmPC. Amendments to section 4.8 of the SmPC has resulted in amendments to the protocol and the PIS. (

Sponsorship of the SRING trial has transferred from the Common Services Agency to Public Health Scotland on 01 April 2020. This is due to the formal transfer of the staff and functions responsible for overseeing sponsorship and research governance of clinical trials managed by the Scottish Clinical Trials Research Unit, transferring to Public Health Scotland.

This substantial amendment has been created in order to:1. Bring all documentation in line with the change to Sponsor in substantial amendment 062. Remove pregnancy testing for IMP patients at follow up, justification for this is covered within the covering letter3. Enable a 2 step consent process to allow patients additional time for consideration and to minimise requirement for hospital visits4. Allow nominated patient Carers to collect IMP, in the event that patients may be shielding or are too unwell to collect their IMP. 5. Add collection of data for the COVID-19 pandemic, in order to capture any COVID-19 related effect on the analysis. 6. Amend PHQ-9 withdrawal and exclusion criteria from 20+ to ≥20 in order to improve clarity

Addition of a new site: Principal Investigator: Mr Andrew McEvoy Site Name: National Centre for Neurology and Neurosurgery Address: National Hospital for Neurology & Neurosurgery, Queen SquareLondon, WC1N 3BG

Updated SmPC documents are included for the IMP.The protocol has been updated in line with changes to the Reference Safety Information; QT prolongation and aggravated seizures have been added to the rare side effects. As such post randomisation ECG has been introduced for patients on the IMP arm. Patients that have QT prolongation will not start IMP. In addition the protocol has other changes:1.Introduction of Standard Gamble exercise within Health Economics2.Electronic patient reported outcomes to help reduce the burden for patients3.Other minor changes to improve clarity for sites. The Patient Information sheet has been redesigned based on patient feedback and to help simplify information. Patient documentation updated in line with the changes above.

This amendment is to update the reference safety information (RSI), section 4.8 of the SmPC, to add wording regarding predisposition of Neuroleptic Malignant syndrome in the the Japanese population. This is not a contraindication but rather, something clinicians are to be aware of.

This amendment is to update the Carer information sheet and consent form. Carers will be given the option to provide their email address in order to complete Quality of Life questionnaires online. This was omitted in error in the submission of substantial amendment 09.

This amendment is to notify of the change of Chief Investigator from Dr Robert Grant to Professor Michael Jenkinson, as Dr Grant is retiring.

This amendment is to notify of the early closure of the SPRING trial due to the early withdrawal of funding.