Low Dose Aspirin for Venous Leg Ulcers (Aspirin4VLU)

Low Dose Aspirin for Venous Leg Ulcers: a Randomised Trial

Venous leg ulcers (VLU) are the most common leg ulcer, can be painful, and limit work, lifestyles and activity, especially in older patients. There are few effective treatments - compression therapy (tight bandaging or stockings) helps healing, but about half the people with a VLU remain unhealed even after 12 weeks of treatment. Research suggests taking aspirin as well as using compression may speed up healing for VLU, but the current evidence is not enough to change clinical practice. We will conduct a randomised controlled trial to test whether using low dose aspirin (150 mg daily or placebo) really does speed up healing.

Study Overview

• Status: Completed
• Conditions: Venous Leg Ulcer
• Intervention / Treatment: Drug: Aspirin; Drug: Placebo

Detailed Description

A pragmatic, community based, double-blind, placebo-controlled, randomised trial to determine whether low dose aspirin accelerates venous leg ulcer healing at 24 weeks when used in addition to compression. Participants in have compression therapy (system of choice guided by patient and/or clinical preference) as delivered through district nursing services at the study centres as a background treatment. Low dose aspirin (150 mg) or placebo will be taken once daily as an oral capsule.

Participants will be district nursing service patients in five study centres in New Zealand with prevalent or incident venous leg ulcers. A venous leg ulcer will be defined as a wound on the lower leg that has remained unhealed for 4 or more weeks, appears to be primarily venous in aetiology with other causative diseases ruled out. If the participant has two or more venous leg ulcers, the largest ulcer will be the reference ulcer.

Participants will receive three visits from the research nurse - visit 1 to screen for eligibility, visit 2 to consent and randomise the participant, visit 3 to collect outcome data. District nurses will continue to visit the participant (about weekly or more frequently if required) to provide routine care between research nurse visits.

Block randomisation will be used, stratified by study centre and prognostic index (ulcer size greater than 5cm2 and ulcer duration greater than 6 months) to ensure a balance of participants within study centres and for participants likely to be slow healers. Research nurses in the study centres will contact a central telephone answering service, provide information on inclusion criteria, exclusion criteria, and relevant clinical history on consented participants. Randomised participants will receive a bottle of 168 capsules of study medication identified only by unique code and will take the capsule until the reference ulcer heals or up to 24 weeks, whichever occurs sooner.

Participants will take the study medication for up to 24 weeks or until the reference ulcer heals. If the participant has a serious adverse event, needs to start taking aspirin, or must stop taking aspirin to use other medications, they will be withdrawn from treatment, although they will still be followed up at 24 weeks.

• Study Type: Interventional
• Enrollment (Actual): 251
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Aged 18 years or older
• Determined to have a venous leg ulcer (clinical indications of venous ulceration, Ankle Brachial Index ≥ 0.8, and other causative aetiologies ruled out)
• Able to tolerate compression therapy
• Able to provide written informed consent
• Confirmation with participant's general practitioner that the participant can take low dose aspirin or placebo.

Exclusion Criteria:

• Pregnant or breast-feeding women
• History of myocardial infarction, stroke, transient ischaemic attack, angina or significant peripheral arterial disease
• History of adverse effects related to aspirin use
• Currently using aspirin, or other anti-platelet or anticoagulant therapy
• Opinion of screening medical practitioner at National Institute of Health Innovation that participant has an existing condition or treatment that is a contraindication to use of aspirin or to participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aspirin; 150 mg capsule once daily for up to 24 weeks	Drug: Aspirin; 150 mg aspirin in capsule form once daily for up to 24 weeks
Placebo Comparator: Inert capsule; Matching capsule once daily for up to 24 weeks	Drug: Placebo; Matching placebo capsule containing inert bulking agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Complete Healing of Reference Ulcer	Time to event (complete healing defined as intact skin with absence of scab)	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Healed Venous Leg Ulcers	Number of participants in each arm with completely healed reference ulcers at 24 weeks	24 weeks
Change in Estimated Ulcer Area	Change in estimated ulcer area from baseline to 24 weeks	Baseline, 24 weeks
Change in Health-related Quality of Life (Short Form 36)	Mean difference in change in Short Form 36 (SF36) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group.	Baseline, 24 weeks
Change in Health-related Quality of Life (EuroQol-5D 3L)	Mean difference in change measured by EuroQol 5D (EQ5D 3L) from baseline to 24 weeks. Crude health state scores for each group are not shown (health state is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on health state for that group.	Baseline, 24 weeks
Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire)	Mean difference in change in Charing Cross Venous Ulcer Questionnaire (CXVUQ)) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group.	24 weeks
Number of Participants With Adherence to Treatment	Adherence to study medication as measured by pill counts (agreement between expected number of tablets remaining after healing and days to healing)	24 weeks
Incidence of Adverse Events at 24 Weeks	Total number of different types of adverse events in participants who reported with any untoward medical event	24 weeks

Collaborators and Investigators

• Sponsor: University of Auckland, New Zealand
• Collaborators: Health Research Council, New Zealand
• Investigators: Principal Investigator: Andrew Jull, RN PhD, School of Nursing, University of Auckland

Publications and helpful links

General Publications

• Jull A, Wadham A, Bullen C, Parag V, Kerse N, Waters J. Low-dose aspirin as an adjuvant treatment for venous leg ulceration: study protocol for a randomized controlled trial (Aspirin4VLU). J Adv Nurs. 2016 Mar;72(3):669-79. doi: 10.1111/jan.12864. Epub 2015 Dec 28.
• Jull A, Wadham A, Bullen C, Parag V, Kerse N, Waters J. Low dose aspirin as adjuvant treatment for venous leg ulceration: pragmatic, randomised, double blind, placebo controlled trial (Aspirin4VLU). BMJ. 2017 Nov 24;359:j5157. doi: 10.1136/bmj.j5157.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 6, 2014
• First Posted (Estimate): June 9, 2014

Study Record Updates

• Last Update Posted (Actual): January 4, 2019
• Last Update Submitted That Met QC Criteria: December 10, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Venous ulcer, varicose ulcer, gravitational ulcer, aspirin
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Skin Ulcer; Varicose Veins; Ulcer; Leg Ulcer; Varicose Ulcer; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: Aspirin4VLU

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: We have a plan to share individual participant data with other aspirin for VLU triallists. All other requests for de-identified individual participant data or study documents will be considered where the proposed use aligns with public good purposes, does not conflict with other requests, or planned use by the Trial Steering Committee, and the requestor is willing to sign a data access agreement.
• IPD Sharing Time Frame: No limitations to timeframe
• IPD Sharing Access Criteria: We have a plan to share individual participant data with other aspirin for VLU triallists. All other requests for de-identified individual participant data or study documents will be considered where the proposed use aligns with public good purposes, does not conflict with other requests, or planned use by the Trial Steering Committee, and the requestor is willing to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)