• Inclusion/exclusion - women of child-bearing potential are now excluded, this has been updated due to the new MHRA guidance on contraception. • Safety Reporting text has been updated to be clearer on reporting to the Sponsor. • Correction of minor administrative errors in relation to schedule of events table and study visit text in protocol section 3. • Correction of subsection heading 4.9. • Clarification of sub-study and sub-analysis

AM03 (Non substantial) Update to the Adverse Event Section reporting in the protocol

AM05 (Non-Substantial) Protocol, Section 3.4.1: the inclusion criteria for the Cardiac Sub-study has been expanded to include patients with LVH on ECH using one of two scales PIS/ICF: Clarification that an ultrasound OR an ECG may be used to determine LVH (i.e. the change reflects the updated inclusion criteria in the protocol)

AM08 (Substantial) • Exclusion criteria updated in light of recent publications. Exclusion criteria now include: o 14. eGFR < 60 and of Korean, Han Chinese or Thai descent

AM09 (Non-Substantial) The Study protocol for this study has been updated from v4.0 to v4.1. The changes were as follows: • Image adjudication committee clarification. • Chief Investigator contact details updated. • Sponsor contact details updated • Pharmacy contact details updated.

AM12 (Substantial) The addition of food frequency questionnaires. The eligibility criteria has been reformatted to give additional clarification to the data centre –the eligibility criteria has not changed. Updated information for relatives, site specific information is to be placed here.

AM13 6th Dec 2016 Clarification of sample size required for carotid sub study Change to cardiac sub study eligibility criteria.

AM20 (Substantial) Addition of the MRI Substudy. Aim is to see whether its possible to detect in blood vessels in people with cerebral small vessel disease and whether other findings such as microinfarcts relate to measures such as cognitive function.

AM22 (Substantial) This relates to an update to the protocol for the addition of new exclusion criteria. "Korean, Han Chinese or Thai descent unless negative HLA-B*5801 status is known." The update to the exclusion criteria is being made due updated SmPC: The HLA-B*5801 allele has been shown to be associated with the risk of developing allopurinol related hypersensitivity syndrome and SJS/TEN. The frequency of the HLA-B*5801 allele varies widely between ethnic populations: up to 20% in Han Chinese population, 8-15% in the Thai, about 12% in the Korean population. Risk may also be increased due to chronic kidney disease. As it is not logistically possible to screen patients for this allele it was decided that it would be safer to exclude patients from these populations from the study, unless they were already known to be negative for this allele.

AM26 (Substantial) The eligibility criteria of the 7T MRI sub study has been clarified. For the main study protocol there have been multiple administrative changes and clarification of image reviewers.

AM27 (Substantial) 1. To remove the secondary endpoint ‘to establish whether allopurinol reduces LVH after ischaemic stroke’ , and terminate the cardiac sub-study. The assessment of Left Ventricular Hypertrophy (LVH) was to be obtained from cardiac MRIs done on a subgroup of participants at week 4 and week 104. The sub-study had a target of 100 participants, however only recruited 26 participants, and recruitment to the main study is now completed. There is therefore not enough data to power this assessment. It was therefore decided, following discussion with the Trial Steering Committee, that it would not be appropriate to ask the 26 participants to undergo another cardiac MRI at week 104. The protocol has been updated to indicate that the sub-study was undertaken but was terminated due to poor recruitment, and that participants in the sub-study are not required to undergo a cardiac MRI at week 104. 2. To add a secondary endpoint to assess white matter volume (WMV) at 2 years. This involves no change to the study from a patient perspective, but rather a further analysis of the 3T scans from the study already taken for other assessments. The expertise to allow this was not available when the study started but can now be undertaken by a team member. Clarification of review of study images The study personnel involved in review of the various study images has been clarified, and Dr David Dickie added as a key collaborator. Non-substantial amendments to the study protocol Additional administrative changes and clarifications have been made as listed in the Summary of Protocol Changes document

AM28 (Substantial) The secondary endpoint ‘to establish whether allopurinol reduces LVH after ischaemic stroke’ has been removed and a secondary endpoint of ‘assess white matter volume (WMV) at 2 years has been added.

AM29 (Substantial) The window for the week 104 visit has been modified, this visit can be carried out up to 3 months prior to scheduled visit or up to 6 months after the scheduled visit. The IMP can also be extended for a maximum of 6 months until the week 104 visit can be conducted. These measures will be implemented due to the restrictions imposed to combat the COVID19 pandemic. A patient letter has also been drafted to make patients aware of what will happen whilst continuing on the study.

AM30 (Non-Substantial) The protocol has been update to clarify the dispensing period during the additional 6 months treatment. Patients will be dispensed a 3 month supply at week 104 and again at week 116.