Information for the local researcher
General
Peripheral artery disease (PAD) is a serious manifestation of atherosclerosis, affecting over 230 million patients worldwide. Despite its significant disease burden and mortality, it receives relatively little attention. Developing new therapies to reduce the risk of serious complications, such as amputations, is crucial.
Chronic inflammation plays a key role in the pathogenesis of atherosclerosis, and modulating it can reduce the incidence of major cardiovascular events. Colchicine is an anti-inflammatory agent and offers several advantages over other therapies: it inhibits various inflammatory factors, is safe, inexpensive, orally available, and has proven effectiveness in reducing serious atherosclerotic complications.
Colchicine has long been used for conditions such as gout, and recent research shows that a low-dose colchicine reduces the risk of major cardiovascular events (MI, stroke, and death) in coronary artery disease (CAD). Since CAD and PAD share a common pathogenesis, it is plausible that colchicine could have a similar beneficial effect on PAD.
Research method
LEADER-PAD is an international multicenter, double-blind, randomized study comparing the effect of low-dose colchicine (0.5mg/day) with a placebo.
To assess the tolerability of the drug, we will begin with a run-in phase of an average of two weeks, during which each participant will be treated with colchicine for two weeks. If no significant adverse events occur, randomization to colchicine or placebo will occur, and the actual study will begin.
International
Randomization
Placebo
Double-blind
Eligibility criteria
To maximize representativeness, we try to maintain broad and practical inclusion criteria.
Inclusion criteria
1) Age > 18 years
2) Symptomatic atherosclerotic LE PAD fulfilling at least one of the following:
a. Intermittent claudication with ankle/arm blood pressure ratio* (ABI ≤ 0.90) or artery stenosis ≥ 50% plus one of
i. >1 vascular bed affected by atherosclerosis
ii. Diabetes
iii. Heart failure
iv. Chronic kidney disease (eGFR < 60 mL/min/1.73 m2)
b. Rest pain (mostly in foot) OR necrosis of limb OR gangrene of limb (corresponding to either Fontaine stages 3 or 4 OR Rutherford Classification categories 4 to 6). All must have an ankle/arm blood pressure ratio* (ABI ≤ 0.90) OR artery stenosis ≥ 50%.
* In cases of incompressible ankle arteries, the presence of toe pressure ≤ 60 mm Hg or toe-brachial index ≤ 0.70 is acceptable
c. Revascularization defined as limb bypass surgery or endovascular revascularization procedures (irrespective of the specific device used), including percutaneous transluminal angioplasty/stent of iliac or infra-inguinal arteries or extra-anatomical bypass surgery
d. Leg or foot amputation for arterial vascular indications
3) Written informed consent from the patient​
Exclusion criteria
1) Contraindication to colchicine (including hypersensitivity to the active substance or to any of the excipients)
2) Long term requirement for colchicine for another clinical indication
3) Active diarrhoea
4) eGFR < 30 mL/min/1.73 m2​
5) Cirrhosis or severe chronic liver disease
6) Woman who is pregnant, or breast-feeding or of child-bearing potential not protected by reliable contraception or is planning conception during the study *
7) Current or planned long term use of cyclosporine, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (with the exception of azithromycin)
8) Patients who are deemed unlikely to return for follow-up
9) Patients with life expectancy < 1 year
10) Patients with blood dyscrasias
11) Patients with severe heart failure (NYHA class IV)
12) Patients with severe gastrointestinal insufficiency
13) Participation in a clinical trial in which an investigational drug was administered within 30 days of screening, or within the 5 half-lives of the study drug, whichever is longer
LEADER-PAD
Relevant Literature
The publications below are related to colchicine in atherosclerotic cardiovascular disease.
Nidorf SM et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383:1838–1847.
d’Entremont M-A et al. Colchicine for secondary prevention of vascular events: a meta-analysis of trials. Eur Heart J. 2025;00:1–12.
