Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease (APOSA-PAD)
Primary Purpose
Peripheral Arterial Disease
Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Allopurinol
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring Peripheral arterial disease, Allopurinol
Eligibility Criteria
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
Sites / Locations
- Ninewells Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Allopurinol
Placebo
Arm Description
Participants will be given blinded medication and asked to take one tab/day for the first six weeks (100mg strength for two weeks then 300mg strength for four weeks) followed by two tabs/day for the remaining 18 weeks.
Same number of tablets and appearance as active drug.
Outcomes
Primary Outcome Measures
Onset of claudication pain
Our primary endpoint will be the distance to onset of claudication pain at 24 weeks but we will also measure total exercise distance.
Secondary Outcome Measures
Quality of life
To see if allopurinol improves quality of life in patients with PAD.
Anti-oxidant effects
To investigate the anti-oxidant effects of allopurinol of patients with PAD.
Full Information
NCT ID
NCT01147705
First Posted
June 18, 2010
Last Updated
May 1, 2017
Sponsor
University of Dundee
Collaborators
NHS Tayside, British Heart Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01147705
Brief Title
Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease
Acronym
APOSA-PAD
Official Title
Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease
Study Type
Interventional
2. Study Status
Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
July 2012 (Actual)
Study Completion Date
July 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Dundee
Collaborators
NHS Tayside, British Heart Foundation
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Peripheral arterial disease (PAD) is a common condition that arises due to the build up of atheroma in the arteries supplying blood to the peripheral muscles and other tissues. This imbalance between oxygen supply and demand becomes particularly apparent when patients with the condition are walking. The pain and weakness they experience (mainly in the calf but less commonly in the thigh) is known as intermittent claudication and resolves upon cessation of exercise.
It is an important disease to study as it is (i) common (est. prevalence of symptomatic intermittent claudication in Scotland of 4.5%) and (ii) those with it have a 1.6 times higher relative risk of ischaemic heart disease. These patients also have a significantly higher mortality than age-matched controls at around 12% per year.
There are two main aims of therapy - (i) to reduce the risk of cardiovascular events by way of standard secondary prevention measures (smoking cessation, anti-platelet, anti-hypertensive and cholesterol-lowering therapy, diabetic control) and (ii) to treat symptoms.
Supervised exercise therapy has been shown to be beneficial in improving walking time and distance in selected patients with leg pain from intermittent claudication with an overall increase in walking distance of approximately 150 metres at three months.
There are numerous drug treatments available for consideration in PAD patients (mainly cilostazol in the UK), but many of these have either undesirable side effects or no clear evidence of benefit. The range of increase in walking distance on cilostazol was reported to be a 50-76% increase over three months compared to 20% with placebo with some significant improvements in Quality of Life (QOL) indicators, although with a significant number of adverse effects (16% vs 8% on placebo) limiting therapy. The current cost (March 2010) is £35.31/month.
Other options for therapy include angioplasty and bypass surgery. At present these are only recommended for patients who fail to respond to medical therapy and have severely disabling symptoms (in the absence of significant exercise-limiting comorbidities).
Detailed Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease
Keywords
Peripheral arterial disease, Allopurinol
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Allopurinol
Arm Type
Active Comparator
Arm Description
Participants will be given blinded medication and asked to take one tab/day for the first six weeks (100mg strength for two weeks then 300mg strength for four weeks) followed by two tabs/day for the remaining 18 weeks.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Same number of tablets and appearance as active drug.
Intervention Type
Drug
Intervention Name(s)
Allopurinol
Intervention Description
Participants will be given blinded medication and asked to take one tab/day for the first six weeks (100mg strength for two weeks then 300mg strength for four weeks) followed by two tabs/day for the remaining 18 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Same appearance/dosing as active drug.
Primary Outcome Measure Information:
Title
Onset of claudication pain
Description
Our primary endpoint will be the distance to onset of claudication pain at 24 weeks but we will also measure total exercise distance.
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Quality of life
Description
To see if allopurinol improves quality of life in patients with PAD.
Time Frame
24 weeks
Title
Anti-oxidant effects
Description
To investigate the anti-oxidant effects of allopurinol of patients with PAD.
Time Frame
24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
35 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Allan Struthers, MD FRCP
Organizational Affiliation
University of Dundee
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Alan J Robertson, MBChB MRCP
Organizational Affiliation
University of Dundee
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ninewells Hospital
City
Dundee
ZIP/Postal Code
DD1 9SY
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
26277090
Citation
Robertson AJ, Struthers AD. A Randomized Controlled Trial of Allopurinol in Patients With Peripheral Arterial Disease. Can J Cardiol. 2016 Feb;32(2):190-6. doi: 10.1016/j.cjca.2015.05.010. Epub 2015 May 19.
Results Reference
result
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Allopurinol as a Possible Oxygen Sparing Agent During Exercise in Peripheral Arterial Disease
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