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Aspirin versus placebo for the treatment of venous leg ulcers-a phase II, pilot, randomised trial (AVURT).

ABSTRACT: BACKGROUND:Venous leg ulcers (VLUs) can take many months to heal and 25% fail to heal. The main treatment for venous leg ulcers is compression therapy and few additional therapies exist. Two previous trials indicated that low-dose aspirin may improve healing time, but these trials were insufficiently robust. METHODS:A multi-centred, pilot, phase II, randomised, double blind, parallel-group, placebo-controlled, efficacy trial (RCT) was conducted to determine: if aspirin improves VLU healing time; the safety of aspirin in this population; treatment compliance; and the feasibility of recruitment to a phase III trial. We recruited patients from secondary care who were aged ??18?years, had a chronic VLU and not regularly taking aspirin. Participants were randomly assigned (1:1) to receive 300?mg of daily aspirin or placebo in addition to standard care, which consisted of multi component compression therapy aiming to deliver 40?mmHg at the ankle where possible. The randomisation list was stratified by ulcer size (??5?cm2 or?>?5?cm2). The primary endpoint was time to ulcer healing, which was defined as 'complete epithelial healing in the absence of scab (eschar) with no dressing required'. Safety outcomes were assessed in all participants who received at least one dose of the study drug. RESULTS:Twenty-seven patients were recruited from eight sites (target 100 patients). A short time-frame to recruit and a large number of patients failing to meet the eligibility criteria were the main barriers to recruitment. There was no evidence of a difference in time to healing of the reference ulcer following adjustment for log ulcer area and duration (hazard ratio 0.58, 95% confidence interval 0.18 to 1.85; p?=?0.357). One expected serious adverse event related to aspirin was recorded. A number of options to improve recruitment were explored. CONCLUSIONS:There was no evidence that aspirin was effective in expediting the healing of chronic VLUs. However, the analysis was underpowered due to the low number of participants recruited. The trial design would require substantial amendment in order to progress to a phase III (effectiveness) trial. TRIAL REGISTRATION:Clinicaltrials.gov, NCT02333123. Registered on 5 November 2014.

SUBMITTER: Helen T

PROVIDER: S-EPMC6660698 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Aspirin versus placebo for the treatment of venous leg ulcers-a phase II, pilot, randomised trial (AVURT).

Helen Tilbrook T Liz Cook C Laura Clark C Illary Sbizzera S Martin Bland B Hannah Buckley B Ian Chetter C Jo Dumville D Chris Fenner F Rachael Forsythe F Rhian Gabe G Keith Harding H Alison Layton L Ellie Lindsay L Catriona Mc Daid MD Christine Moffatt M Debbie Rolfe R Gerard Stansby S David Torgerson T Peter Vowden V Laurie Williams W Robert Hinchliffe H

Trials 20190726 1

<h4>Background</h4>Venous leg ulcers (VLUs) can take many months to heal and 25% fail to heal. The main treatment for venous leg ulcers is compression therapy and few additional therapies exist. Two previous trials indicated that low-dose aspirin may improve healing time, but these trials were insufficiently robust.<h4>Methods</h4>A multi-centred, pilot, phase II, randomised, double blind, parallel-group, placebo-controlled, efficacy trial (RCT) was conducted to determine: if aspirin improves VL ...[more]

PMID: 31349862

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Project description:BACKGROUND:Venous leg ulcers (VLUs) are the commonest cause of leg ulceration, affecting 1 in 100 adults. There is a significant health burden associated with VLUs - it is estimated that the cost of treatment for 1 ulcer is up to £1300 per year in the NHS. The mainstay of treatment is with graduated compression bandaging; however, treatment is often prolonged and up to one quarter of venous leg ulcers do not heal despite standard care. Two previous trials have suggested that low-dose aspirin, as an adjunct to standard care, may hasten healing, but these trials were small and of poor quality. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established. METHODS/DESIGN:AVURT is a phase II randomised double blind, parallel-group, placebo-controlled efficacy trial. The primary objective is to examine whether aspirin, in addition to standard care, is effective in patients with chronic VLUs (i.e. over 6 weeks in duration or a history of VLU). Secondary objectives include feasibility and safety of aspirin in this population. A target of 100 participants, identified from community leg ulcer clinics and hospital clinics, will be randomised to receive either 300 mg of aspirin once daily or placebo. All participants will receive standard care with compression therapy. The primary outcome will be time to healing of the reference ulcer. Follow-up will occur for a maximum of 27 weeks. The primary analysis will use a Cox proportional hazards model to compare time to healing using the principles of intention-to-treat. Secondary outcomes will include ulcer size, pain evaluation, compliance and adverse events. DISCUSSION:The AVURT trial will investigate the efficacy and safety of aspirin as a treatment for VLU and will inform on the feasibility of proceeding to a larger phase III study. This study will address the paucity of information currently available regarding aspirin therapy to treat VLU. TRIAL REGISTRATION:The study is registered on a public database with clinicaltrials.gov ( NCT02333123 ; registered on 5 November 2014).

Project description:IntroductionLow-frequency, low-intensity ultrasound has been previously shown to promote healing of chronic wounds in humans, but mechanisms behind these effects are poorly understood. The purpose of this study was to evaluate gene expression differences in debrided human venous ulcer tissue from patients treated with low-frequency (20 kHz), low-intensity (100 mW/cm2) ultrasound compared to a sham treatment in an effort to better understand the potential biological mechanisms.MethodsDebrided venous ulcer tissue was collected from 32 subjects one week after sham treatment or low-frequency, low-intensity ultrasound treatment. Of these samples, 7 samples (3 ultrasound treated and 4 sham treated) yielded sufficient quality total RNA for analysis by ultra-high multiplexed PCR (Ampliseq) and expression of more than 24,000 genes was analyzed. 477 genes were found to be significantly differentially expressed between the ultrasound and sham groups using cut-off values of p < 0.05 and fold change of 2.Results and discussionThe top differentially expressed genes included those involved in regulation of cell metabolism, proliferation, and immune cell signaling. Gene set enrichment analysis identified 20 significantly enriched gene sets from upregulated genes and 4 significantly enriched gene sets from downregulated genes. Most of the enriched gene sets from upregulated genes were related to cell-cell signaling pathways. The most significantly enriched gene set from downregulated genes was the inflammatory response gene set. These findings show that therapeutic ultrasound influences cellular behavior in chronic wounds as early as 1 week after application. Considering the well-known role of chronic inflammation in impairing wound healing in chronic wounds, these results suggest that a downregulation of inflammatory genes is a possible biological mechanism of ultrasound-mediated venous chronic wound healing. Such increased understanding may ultimately lead to the enhancement of ultrasound devices to accelerate chronic wound healing and increase patient quality of life.

Dataset Information

Aspirin versus placebo for the treatment of venous leg ulcers-a phase II, pilot, randomised trial (AVURT).

Publications

Aspirin versus placebo for the treatment of venous leg ulcers-a phase II, pilot, randomised trial (AVURT).

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