As the global burden of peripheral arterial disease (PAD) continues to rise, so too does the need for strategies to reduce an “unacceptably high” vascular risk in patients with the condition. Enter colchicine: a low-cost drug designed to target primary inflammation that has already proven beneficial and safe in coronary artery disease. Chief investigator of the UK arm of a recently initiated international multicentre trial to test the drug in PAD is Robert Hinchliffe (University of Bristol, Bristol, UK), who here speaks to Vascular News about how—if successful—the trial could prove transformative for the management of this disease.
Hinchliffe begins by highlighting a paradox at the heart of PAD. Despite its ubiquity—affecting around 230 million people worldwide, with numbers only set to rise among an ageing and increasingly diabetes-prone population—and making up a growing proportion of vascular cases given the decline of conditions such as aortic aneurysms, the disease receives less attention than other manifestations of atherosclerosis. “Everyone’s aware of heart disease and stroke,” he says, “but PAD has much less of a spotlight on it.”
Another “critical issue” related to PAD, as identified by Hinchliffe, is that patients still have a high risk of premature mortality, limb loss, and other cardiovascular events, regardless of secondary prevention measures. Nowhere is this more evident than in people with the most severe manifestation of the disease: chronic limb-threatening ischaemia (CLTI). “Around one in two patients [with CLTI] will die in the next two to three years,” Hinchliffe stresses, underlining “a real unmet need to try and improve the quality of those people’s lives by preventing limb-related and cardiovascular events and also extending their life.”
Understudied inflammation factor
Regarding opportunities pertaining to PAD treatment, Hinchliffe notes that a long-recognised inflammation element to the disease has yet to be fully explored. “Management of atherosclerosis and PAD has largely been related to trying to reduce and manage lipids and cholesterol, blood pressure, and diabetes,” he notes, “but there hasn’t been much focus on the inflammatory component of atherosclerosis.”
Some research has been conducted on the role of anti-inflammatory medication canakinumab in patients with PAD. “[Canakinumab] was identified to have an impact on atherosclerosis, but also caused significant side effects,” Hinchliffe shares, referring to the CANTOS trial by Ridker and colleagues published in 2017 in the New England Journal of Medicine (NEJM).
While canakinumab proved not to be the answer to the inflammation question, Hinchliffe describes that work as “the first time there was a feeling that inflammation could be modified and might have a beneficial impact for atherosclerosis”. The work paved the way for the exploration of other inflammation-modifying alternatives.
“One of the first drugs that came to everyone’s consciousness was colchicine,” Hinchliffe recalls. He describes the drug as one that has been available for many years and is a frequent treatment for gout, among other conditions, working on similar pathways to canakinumab.
Low-dose colchicine has already been assessed in patients with ischaemic heart disease—notably in the LoDoCo2 and COLCOT trials—showing potential promise in this cohort. Furthermore, the medication is now licensed by the US Food and Drug Administration (FDA) for the treatment of ischaemic heart disease and is within the European Society of Cardiology (ESC) guidelines for the treatment of coronary-related atherosclerosis.
Translation to PAD
At the centre of the LEADER-PAD trial is the question of whether low-dose colchicine, given its beneficial effects in ischaemic heart disease, “might work and may work even better in patients with a really high burden of atherosclerosis, i.e. PAD patients”, says Hinchliffe.
The study is a combined effort between research teams led in Australia by Shirley Jansen (Harry Perkins Institute for Medical Research, Perth, Australia), Canada by Noel Chan (McMaster University, Hamilton, Canada), the Netherlands by Martin Teraa and Gert de Bost (University Medical Centre Utrecht, Utrecht, Netherlands) and the UK by Hinchliffe. The study was supported by the Global Cardiovascular Research Funders Forum [GCRFF] and funding has been achieved through individual participating countries.
The British Heart Foundation was the first cardiovascular research funder to support the UK arm of the trial. Since then, Hinchliffe shares, “there have been trials being funded in other countries, including the Netherlands, Australia, the USA and Canada, Belgium, Brazil, Ecuador and Switzerland. And there is pending activation in Germany, Italy, Mexico, North Macedonia and Turkey”.
“The idea is that patients receive either a low dose of colchicine (a lower dose than you would receive for gout), compared to a placebo medication,” Hinchliffe explains. Patients will then be followed up to evaluate whether the colchicine has any impact on cardiovascular events and limb events compared with the placebo.
As of September 2026, there are 19 sites running in the UK. The plan is to run the study for another two years and achieve a recruitment of around 1,000 patients in the UK. “We anticipate that we will probably need between 5,000 and 6,000 patients internationally,” he says, with the ultimate aim being that researchers “will be able to inform funders, vascular surgeons, and patients about whether colchicine seems to be effective and whether it’s effective in specific subgroups of patients with PAD to prevent cardiovascular events”.
Safe, inexpensive and few contraindications
A large part of the appeal of the LEADER-PAD trial, according to Hinchliffe, is the strong evidence and low-cost base for colchicine. “I think that’s the attractiveness of this in terms of setting up the trial,” he says. “It’s much easier when you are effectively repurposing medications for other indications.”
“It’s easier from the regulatory perspective and for ethics committees to proceed with the trial because the drug is safe in another population of patients,” he continues. In addition, as colchicine has been used for many years already, it is “very, very cheap indeed”.
Furthermore, the trial assesses a lower dose of colchicine than is needed for its presently most common use as a treatment for gout. “That’s another attractive aspect to it,” Hinchliffe says. And, while patients with the most severe forms of chronic kidney disease would not be eligible, there are “very few other contraindications to use” of the drug.
“We’re very keen to engage with centres who are interested in the trial,” says Hinchliffe. “You’ve got a medication that seems to be generally well tolerated, doesn’t seem to cause too many side effects, is cheap and doesn’t interact with any other medications. It ticks quite a few boxes,” he says in summary, alluding to the potential impact of the trial for PAD patients.
More information on the LEADER-PAD trial can be found here.
