Changes to protocol V2.0: • Section 1 Trial Personnel: Updated investigator team telephone numbers. • Section 8.2. Delete “Minimisation will be used to balance groups according to age and gender. This will reduce the imbalance between the active treatment and placebo groups” This was removed as the investigator and the statistician decided minimisation was not necessary. • Section 8.2: Delete” Brecon Pharmaceuticals” and change “UCLH” to “The Heart Hospital, UCLH Pharmacy”. Brecon Pharmaceuticals were left in the protocol in error as we had originally planned to use them. As per the CTA application form we will be using RFH Pharmacy Production. Changes to all other documents: Updated investigator team telephone numbers.

Changes to protocol V3.0: Section 3.2.1 (Clinical Particulars): Updates made to therapeutic indications, contraindications and side effect table in light of updates to the SmPc Section 2.0 (Summary) and Section 6.1 (Inclusion Criteria): Updates made to the inclusion criteria to include patients with atrial fibrillation and also to clarify that patients who are fitted with a pacemaker are eligible. Expanded the inclusion criteria to include patients with atrial fibrillation as it is considered that this will increase recruitment by 10-20%. These individuals are usually asymptomatic and challenging to treat, so their inclusion is of clinical relevance. We have also clarified that patients with a pacemaker fitted are also eligible for the trial. Section 6.2 (Exclusion Criteria) Added ‘Participant has Parkinson’s disease or Parkinsonism’ as an exclusion in line with the updated SmPc. Annex 1 updated in line with changes to protocol. Non-substantial amendment documents also sent.

Protocol V4.0 Creation of advert and patient invitation letter to increase recruitment rate to the trial. Protocol updated to incorporate use of advert and recruitment plan.

Changes to protocol V5.0: • Addition of 3 PIC sites to enhance the recruitment rate to the trial. Sites will potentially be • The Royal Brompton & Harefield NHS Foundation Trust • Barts Health NHS Trust • Guys and St Thomas’ NHS Foundation Trust

Protocol V6.0 Change to the inclusion criteria: • No significant left ventricular outflow tract obstruction on echocardiography at rest or during exercise (gradient < 50 mmHg) as determined at screening (if not done within previous 2 years).