Nurse-led drug trial for 'orphan disease'

April 2016 Vol 16 (2)

Venous leg ulcers (VLU) are an ‘orphan disease’ in which nurse researcher Dr Andrew Jull has a longstanding interest. He talks to Nursing Review about his team’s latest VLU research project – Asprin4VLU – his first, and one of New Zealand’s first ever nurse-led, randomised, controlled trials of a drug treatment.

 

Andrew JullVenous leg ulcers are unsightly, unhealing painful sores that can rule people’s lives.

“VLU has big impacts but it’s the kind of disease that can be hidden under people’s trousers,” says nurse researcher Dr Andrew Jull. “And folk live with these things for a very long time believing there is no treatment that will help them. Yet we’ve known what works since the 17th century – and that is tight compression – all we are doing now is trying to find out what else we can do.”

Finding ‘what else we can do’ has been a research focus for Jull for coming up two decades (see bio box) but his seventh research project in the area is the first time he has been a lead investigator for a drug trial.

In 2014, on the research team’s fourth attempt, they won a Health Research Council (HRC) grant to see whether taking low-dose aspirin could accelerate healing of VLU when taken alongside standard compression bandaging therapy (at present 30–60 per cent of participants in compression trials remain unhealed after 12 weeks of treatment).

Early in Jull’s research career he found evidence that another adjuvant treatment – pentoxifylline (Trental) – was beneficial, but using it was complex.

Two small trials suggested that the much simpler to use, over-the-counter drug aspirin may also be effective, but more research was needed. Jull and The University of Auckland research team, working with the five wound care nurse experts who are the trial site investigators and the trial’s research nurses, have designed a pragmatic, randomised, controlled trial (RCT) to do just that.

Balancing who to exclude and who to include

It is believed that aspirin may aid VLU healing because firstly VLUs result from chronic venous insufficiency (CVI), which is associated with platelet aggregation, and aspirin is known to inhibit platelet aggregation. Secondly, aspirin may also have an effect on the underlying inflammatory pathway associated with ulcers.
A major part of the trial design was debating the daily dosage of aspirin. Geriatricians advised the team that it wouldn’t be appropriate to give a 300mg dose (two standard aspirin pills) to the elderly. So to replicate the previous trials – which used a high daily dose of aspirin – the trial risked excluding the very old, who make up about a third of people with VLUs.

“Because venous leg ulcers typically happen in older people, you don’t want to exclude the very old from the treatment you are offering,” says Jull. 

But on the other hand, the platelet inhibition effect of aspirin is known to be variable when using low-dose aspirin (75–100mg a day is the dosage prescribed for prevention of heart disease). It was decided to compromise by using a 150mg dose – on the high end of the low-dose range, but low enough that geriatricians were happy for the elderly to take it daily.

Manufacturing own drugs

But deciding on that dose posed another challenge to the research team. No New Zealand manufacturer was registered to make 150mg aspirin tablets so they had to seek a clinical trial exemption under the Medicines Act to manufacture and distribute an unregistered medicine.

The team contracted a New Zealand company to make the aspirin capsules one day and the placebo the next.
The trial statistician generated a randomisation sequence that was given to the manufacturers so that each bottle of aspirin, or placebo, was allocated a unique trial treatment number, which meant all the investigators, research nurses, district nurses and other clinical providers were ‘blind’ to what treatment participants received.

There is no ‘emergency unblinding’ service so if there is a medical event clinicians are advised to assume the venous leg ulcer sufferer is taking aspirin. So ‘blind’ is the study that the data analysis will also be conducted blind and the unique treatment code only broken once the trial steering committee has decided on interpreting the blinded results.

Trial so far

The trial kicked off in March 2015 in district nursing services in five centres around the country: Auckland, South Auckland, Waikato, Christchurch and Dunedin. Each centre has a senior site investigator – a senior nurse who is a wound care specialist – and a part-time research nurse seconded from the district nursing team. Wound care clients who meet the inclusion criteria are given normal compression therapy along with a 24-week course of trial treatment and told to take a capsule a day until their VLU heals. The study’s main aim is to evaluate whether aspirin makes a difference to healing time, but it will also look at health-related quality of life and adherence to the treatment capsule routine.

The trial is aiming to sign up at least 260 people over the two-year trial period. By the end of the first year, the trial had signed 140 people; that, says Jull, is a good response, but of course the team wants more.

“I would dearly love that we could have more people in our trials – that folk turned up at the district nursing services where we are conducting the studies and knocked on the door and said, ‘Hey check out my wound – is it a leg ulcer and can I help by participating in your trial?’ I would love to have more people knock on our door to help us answer these questions for other patients.” ✚

 

Researcher bio: Andrew Jull

Research was on Andrew Jull’s horizon before nursing. He started an undergraduate degree – ‘playing around’ in an eclectic mix of subjects, including psychology, philosophy, economics and English, while also ‘majoring’ in the many movements that made up campus life in the early 1980s. He didn’t emerge with a degree, but did emerge knowing he wanted to do research. By now in his mid-20s, he decided to apply for nursing – he’s still not totally sure why, but thinks maybe a mix of his strong feeling for the underdog and a tendency to not “swim in the same stream as other folk” meant starting nursing training as a man in 1986 felt the non-traditional and right thing to do. “Those things all sort of coalesced into wanting to be of service – and ultimately that’s what I’ve always wanted, is to be of service – it’s just a question of how to be of service.”

He started practising in 1989 in orthopaedics and by the late 1990s was a clinical nurse consultant (including wound care) and an ‘early adopter’ of the Cochrane Collaboration movement, which led him to be involved in developing the first New Zealand VLU guidelines. This work revealed the gap in evidence about the effectiveness of pentoxifylline (Trental) in assisting VLU healing, which he sought to fill through a systematic review of existing trials for his master’s thesis at Victoria University. The review became a paper in The Lancet and set him off on his now well-trodden research path in VLU. He was successful in 2001 in applying to the Health Research Council (HRC) for a Foxley Fellowship, allowing him to take a year’s research sabbatical in 2002.

During that year he carried out the quality of life data analysis for the already completed Auckland Leg Ulcer Study. He also did an investigation into adherence to the national leg ulcer guidelines that sparked a number of ideas for further research, including the effectiveness of honey in healing VLU, which won funding in the 2002 HRC round. This turned into the HALT (Honey as Adjuvant Leg ulcer Therapy) trial, which to his knowledge is still the world’s biggest trial of using honey in wound care, and ultimately his PhD.

The Foxley Fellowship and HALT trial saw him working with The University of Auckland’s Clinical Trials Research Unit –now known as the National Institute for Health Innovation (NIHI), where he has been involved in a variety of VLU trials, and also in other areas including the development of clinical weight management guidelines. 
Since 2009 he has held a joint position as associate professor with the School of Nursing and nurse advisor, quality & safety for the Auckland District Health Board, as well as continuing to do research with NIHI.

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