Study Title	Allopurinol and cardiovascular outcomes in patients with ischaemic heart disease (ALL-HEART)
NIHR Portfolio Ref	UKCRN ID 15328; IRAS ID 135900
Sponsor Funder Principle Investigator	University of Dundee / NHS Tayside NIHR HTA Professor Chris Hawkey – University of Nottingham
Study design	Interventional: A multi-centre, controlled, prospective randomised open-label blinded endpoint (PROBE) trial.
Study Aim and Objectives (refer to protocol for full details)	Primary Objective: To determine whether the addition of allopurinol 600mg daily to usual therapy improves cardiovascular outcomes. Secondary Objectives: Cost-effectiveness of adding allopurinol 600mg daily to usual therapy. Assessment of quality of life Safety and tolerability
Practice recruitment & study duration	Practice recruitment: 13 patients; 5215 target overall Average follow-up of 4-5 years Study is endpoint driven - the study will end when 631 adjudicated primary endpoints have occurred
Recruitment period	The study will run from February 2016 to March 2018
Summary of Eligibility Criteria (refer to protocol for full criteria)	Inclusions: Male or female patients aged 60 years and over Ischaemic heart disease (IHD) defined as a diagnosis of angina or myocardial infarction (MI) at any time or other evidence of ischaemic heart disease (investigator opinion) Main exclusions: History of gout, known renal impairment (eGFR <60 ml/min), moderate to severe heart failure (NYHA III-IV), significant hepatic disease, previous allergy to allopurinol, previous serious adverse cutaneous (skin) reaction to any drug, patients already taking urate lowering therapy, patients taking azathioprine, mercaptopurine, ciclosporin or theophylline. Malignancy (except non-metastatic, non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years (investigator opinion).
Study Activities	Primary care practice lists will be searched for suitable patients with IHD who will be invited to participate. At a screening visit, written informed consent will be taken, inclusion and exclusion criteria checked and blood samples taken for baseline full blood count, urea and electrolytes, creatinine, eGFR and urate. Patients will be randomised via a web portal or interactive voice response system (IVRS) to either allopurinol or no drug to be given in addition to their usual medications. Allopurinol will be started at 100mg daily for 2 weeks, then titrated to 300mg daily for 2 weeks, then titrated to 600mg daily if tolerated. In patients randomised to allopurinol, bloods will be taken for full blood count, urea and electrolytes, creatinine, eGFR and urate 6 weeks after starting study medication. Patients will be asked to report any treatment-related adverse events, particularly rash (~1% incidence with allopurinol) and gout flares, and any serious adverse events. Study medications will be prescribed by the GP. An eCRF and dedicated study web portal will be used to collect study data and aid pharmacovigilance reporting and trial management. Patients will receive questionnaires annually to complete, which will be posted out by the study sponsor.
Practice Activities	Nominated practice staff to attend site initiation visit GCP-trained GP to act as Site Study Coordinator (SSC) to lead on the study Practice to search electronic patient records for potentially eligible patients SSC will review list to confirm eligibility for inviting and screening Once list checked by SSC, arrange for the invitation letters to be mailed to patients using Docmail Provision of a room and facilities for research nurse to conduct baseline clinics Prescribe allopurinol to those randomised to this arm GP to report any serious adverse events and treatment-related adverse events (via a web-based portal)
Assurances	Approvals will be obtained for the trial from ethics committees, the Medicines and Healthcare products Regulatory Agency (MHRA) and local research and development departments. Assurance documentation will be provided to the practice who will be asked to return a signed agreement. GP practices should inform their indemnity provider of each study being conducted: additional information on indemnity can be provided.
Practice reimbursement	An estimated NHS service support payment of £400 has been calculated for this study. This figure is based upon the information provided by the study team regarding the likely activities to be performed by your practice; it is an approximation only and may be adjusted in line with the level of practice activity and the amount of CRN support received.
Research Team contact	Jennifer Dumbleton Clinical Trials Manager University Hospital Nottingham NG7 2UH (0)115 8231053 (0)7584 151610 jennifer.dumbleton@nottingham.ac.uk
Local CRN contacts	Rebecca Harrison (r.l.harrison@warwick.ac.uk) Research Facilitator Eleanor Hoverd (e.j.hoverd@warwick.ac.uk) Research Nurse

ALL HEART Allopurinol Study

GP search for eligible patients 60+ years Ischaemic heart disease (IHD) – angina or myocardial infarction Not taking ULT (no history of gout)

CONSENT VISIT (website access required at practice) Inclusion / exclusion criteria checked Blood samples taken ( FBC, urea & electrolytes, creatinine, eGFR & urate) – 1 gold (spun) and 1 purple Questionnaires (all electronic except paper EQ-5D) Randomisation (50:50 allopurinol / no medication)

50% of patients to take: Prescription generated by GP for 2 weeks of 100mg, 2 weeks of 300mg, and 2-3 weeks 600mg. Patients must wait for a call from the nurse to say screening bloods are OK before starting on allopurinol

50% of patients to have no addition to their medication

Any rash / allergy: allopurinol to be stopped straight away. For GI upsets: consider downtitrating allopurinol Nurse to phone for updates (side effects?) 100mg allopurinol daily for 2 weeks

Increased to 300mg daily for 2 weeks

Increased to 600mg daily if tolerated (to be prescribed as 300mg twice daily)

6 WEEK VISIT (+/- 1 week) Bloods are re-taken (FBC, urea & electrolytes, creatinine, eGFR & urate) Repeat 600mg prescription generated by GP

Annually (for 4-5 years) Contact by phone / post / email (questionnaires) – DUNDEE TO PERFORM Record linkage for endpoint identification