Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease

The investigators will recruit 50 patients with peripheral arterial disease for a randomised, double-blind, placebo-controlled parallel group study to see if allopurinol prolongs time to leg pain and maximum walking distance as assessed by treadmill testing and the six minute walk test. Recruitment will take place in Dundee, i.e. a single-centre trial. Treatment will last for 24 weeks.

Participants will be recruited from current and past attendees at the vascular laboratory and both the intermittent claudication clinic and other outpatient clinics at Ninewells.

Participants will be allowed to continue all their usual medication throughout. After two baseline treadmill tests, they will be randomised to either allopurinol or placebo in a parallel group study and in a double blind fashion. Each participant will be on-study for 24 weeks (which is the standard time for all PAD medical intervention trials). The ultimate dose of allopurinol will be 300 mg BD, which is the dose known to work in angina. However, for safety purposes, the initial dose will be 100 mg/day for two weeks, rising to 300 mg/day for four weeks, followed by 600 mg/day for the next 18 weeks. Participants and their bloods (UE, LFT, FBC) will be monitored at weeks 0, 6, 18 and 24 weeks and medication stopped or reduced in dose if concerns arise. If study drug dose is reduced, they will stay in study. If study drug needs to be stopped, they will stay in study in order to do an "intention to treat" analysis.

Double blind medication (allopurinol or placebo) will be prepared and packaged by Tayside Pharmaceuticals. The medication will come labelled as "Participant 1", "Participant 2", etc. and will be distributed to the participant by the research fellow according to their sequence number. The blinded treatment code will be kept by the Clinical Trials Pharmacy Department, Ninewells, who operate a 24 hour emergency unblinding facility (as necessary) and in a sealed envelope in a locked fireproof cabinet accessible by a responsible member of University of Dundee staff not directly involved in the study.

The following is the programme of visits involved in this study (list taken from the participant information sheet) -

• Visit 1 (week 0) - screening visit 1

• Consent - answer any outstanding questions you may have and complete the consent form.
• Measurement of blood pressure in arms and legs
• Treadmill test
• Blood samples
• Visit 2 (week 0) - screening visit 2

• Treadmill test - if this is stable and similar to the previous test then you are able to continue in the study
• Six minute walk test
• Measurement of blood vessel 'stiffness'
• Supply of initial study medication along with instructions.
• Two questionnaires - Walking Impairment and Quality of Life
• Visit 3 (week 6) - progress visit

• Check how you are doing on the medications
• Blood samples
• Supply of study medication for the remainder of the study
• Visit 4 (week 12) - progress visit

• Treadmill test
• Six minute walk test
• Check how you are doing on the medications
• Two questionnaires - Walking Impairment and Quality of Life
• Visit 5 (week 18) - progress visit

• Measurement of blood vessel 'stiffness'
• Check how you are doing on the medications
• Blood samples
• Visit 6 (week 24) - final visit

• Measurement of blood vessel 'stiffness'
• Treadmill test
• Six minute walk test
• Measurement of blood pressure in arms and legs
• Check how you are doing on the medications
• Blood samples
• Two questionnaires - Walking Impairment and Quality of Life

Inclusion criteria

• stable peripheral arterial disease (demonstrated by having a reproducible pain free walking distance on 2 consecutive treadmill tests, i.e. less than 25% variance with the reason for termination of the treadmill test must be claudication pain only)

Exclusion criteria

• rest pain
• childbearing potential
• heart failure
• any other exercise limiting cardiac disease
• BP > 180/100 mHg
• eGFR < 60 ml/min
• liver disease
• malignancy
• already on allopurinol or had an adverse reaction to it
• recent marked change in symptoms or recent (in the last six months) intervention for PAD
• receiving treatment with either 6-mercaptopurine, azathioprine, warfarin, or theophylline