Low-Dose Colchicine for Peripheral Artery Disease
(LEADER-PAD Trial)
Recruiting in Palo Alto (17 mi)
+3 other locations
Overseen byNoel C Chan, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Population Health Research Institute
Must not be taking: Cyclosporine, Verapamil, HIV protease, others
Disqualifiers: Cirrhosis, Severe liver disease, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?The Low dose ColchicinE in pAtients with peripheral Artery DiseasE to address residual vascular Risk (LEADER-PAD) trial will evaluate if anti-inflammatory therapy with colchicine will reduce vascular events in patients with symptomatic peripheral artery disease.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently using or plan to use certain medications like cyclosporine, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (except azithromycin) long-term.
What data supports the effectiveness of the drug colchicine for peripheral artery disease?
Research shows that low-dose colchicine is effective in reducing cardiovascular events in patients with coronary artery disease, which is related to peripheral artery disease. It works by reducing inflammation, a common factor in both conditions, suggesting potential benefits for peripheral artery disease as well.
12345Is low-dose colchicine generally safe for humans?
Low-dose colchicine is generally considered safe for humans, but it can cause gastrointestinal issues like stomach upset. It should be used cautiously in people with kidney or liver problems, and it may interact with other medications, so close monitoring is recommended.
12346How does the drug colchicine differ from other treatments for peripheral artery disease?
Colchicine is unique for peripheral artery disease because it is primarily known for its anti-inflammatory effects, which may help reduce inflammation in blood vessels, unlike standard treatments like statins and antiplatelet drugs that focus on cholesterol and blood clot prevention.
7891011Eligibility Criteria
This trial is for adults over 18 with symptomatic lower extremity peripheral artery disease (PAD) and certain high-risk features. It's not for pregnant or breastfeeding women, those without reliable contraception, people unlikely to return for follow-up, individuals with severe kidney or liver issues, active diarrhea, or those taking specific medications like cyclosporine.Inclusion Criteria
I am older than 18 years.
Written or verbal informed consent from the patient
I have had symptoms of poor blood flow in my legs with at least one high-risk feature.
Exclusion Criteria
I am currently experiencing diarrhea.
My kidney function is very low.
I am not pregnant, breastfeeding, and use reliable contraception without planning to conceive.
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Active Run-in
Participants undergo an active run-in period to assess tolerance to the study medication
2-4 weeks
Treatment
Participants receive either low dose colchicine 0.5 mg daily or placebo to prevent vascular events
3-5 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The LEADER-PAD trial is testing if low-dose colchicine can reduce vascular events in PAD patients. Participants will either receive a colchicine tablet or a placebo to assess the effectiveness and feasibility of this anti-inflammatory treatment.
2Treatment groups
Active Control
Placebo Group
Group I: ColchicineActive Control1 Intervention
Colchicine 0.5mg daily for the duration of the trial
Group II: Colchicine-PlaceboPlacebo Group1 Intervention
Colchicine-Placebo daily
Colchicine is already approved in United States for the following indications:
🇺🇸 Approved in United States as Colcrys for:
- Gout
- Familial Mediterranean Fever
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hamilton General HospitalHamilton, Canada
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Who Is Running the Clinical Trial?
Population Health Research InstituteLead Sponsor
References
The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. [2023]Because patients with stable coronary artery disease are at continued risk of major atherosclerotic events despite effective secondary prevention strategies, there is a need to continue to develop additional safe, effective and well-tolerated therapies for secondary prevention of cardiovascular disease. RATIONALE AND DESIGN: The LoDoCo (Low Dose Colchicine) pilot trial showed that the anti-inflammatory drug colchicine 0.5 mg once daily appears safe and effective for secondary prevention of cardiovascular disease. Colchicine's low cost and long-term safety suggest that if its efficacy can be confirmed in a rigorous trial, repurposing it for secondary prevention of cardiovascular disease would have the potential to impact the global burden of cardiovascular disease. LoDoCo2 is an investigator-initiated, international, multicentre, double-blind, event driven trial in which 5522 patients with stable coronary artery disease tolerant to colchicine during a 30-day run-in phase have been randomized to colchicine 0.5 mg daily or matching placebo on a background of optimal medical therapy. The study will have 90% power to detect a 30% reduction in the composite primary endpoint: cardiovascular death, myocardial infarction, ischemic stroke and ischemia-driven coronary revascularization. Adverse events potentially related to the use of colchicine will also be collected, including late gastrointestinal intolerance, neuropathy, myopathy, myositis, and neutropenia. CONCLUSION: The LoDoCo2 Trial will provide information on the efficacy and safety of low-dose colchicine for secondary prevention in patients with stable coronary artery disease.
Low-Dose Colchicine in Coronary Artery Disease - Systematic Review and Meta-Analysis. [2021]Background: Recent studies have revealed the benefits of using colchicine, a drug with anti-inflammatory properties, in coronary artery disease (CAD). This study systematically reviewed the benefits and risks of low-dose colchicine in patients with CAD. Methods and Results: We searched for randomized controlled trials (RCTs) in MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science databases (March 2020). Efficacy and safety outcomes were evaluated. Estimates are expressed as risk ratios (RRs) and 95% confidence intervals (95% CIs). Heterogeneity was assessed with I2 test. Confidence in the pooled evidence was appraised using the GRADE framework. Colchicine reduced the rate of major adverse cardiovascular events (RR 0.65; 95% CI 0.49-0.86; 6 RCTs; I2=50%; 11,718 patients; GRADE, moderate confidence), acute coronary syndrome (RR 0.64; 95% CI 0.46-0.90; I2=47%; 7 RCTs; 11,955 patients; GRADE, very low confidence), stroke (RR 0.49; 95% CI 0.30-0.78; I2=0%; 6 RCTs; 11,896 patients; GRADE, moderate confidence), and cardiovascular interventions (RR 0.61; 95% CI 0.42-0.89; I2=40%; 4 RCTs; 11,284 patients; GRADE, high confidence). Colchicine did not increase the risk of adverse events, except for gastrointestinal events (RR 1.54; 95% CI 1.11-2.13; I2=72%; 9 RCTs; 12,374 patients; GRADE, very low confidence). Conclusions: Low-dose colchicine in patients with CAD is associated with beneficial effects on prognosis, although an increased risk of gastrointestinal events was confirmed.
Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians. [2022]A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.5 mg once daily) should be considered in patients with recent myocardial infarctions-within 30 days and, ideally, within 3 days-or with stable CAD to improve cardiovascular outcomes. Colchicine should not be used in patients with severe renal or hepatic disease because of the risk of severe toxicity. No serious adverse effect was associated with the combined use of colchicine and high-intensity statin therapy in large trials. The impact of colchicine in high-risk populations of patients with peripheral arterial disease and in those with diabetes for the primary prevention of CAD remains to be established.
Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial. [2023]Low-dose colchicine significantly reduces the risk of cardiovascular events in patients with chronic coronary disease. An increase of non-cardiovascular death raised concerns about its safety. This study reports cause-specific mortality and baseline predictors of mortality in the Low-Dose Colchicine 2 (LoDoCo2) trial.
Colchicine for Secondary Prevention of Coronary Artery Disease: A Meta-Analysis of Randomised Controlled Trials. [2022]Colchicine has become prominent as an anti-inflammatory therapy for secondary cardiovascular prevention in patients with coronary artery disease (CAD). This meta-analysis was performed to evaluate the efficacy and safety of colchicine in patients with CAD.
Colchicine: serious interactions. [2013](1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.
Drug treatment of peripheral arterial disease in the elderly. [2018]Peripheral arterial disease (PAD) may be asymptomatic, may be associated with intermittent claudication or may be associated with critical limb ischaemia. Coronary artery disease (CAD) and other atherosclerotic vascular disorders may coexist with PAD. Persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality and mortality from CAD. Smoking should be stopped and hypertension, diabetes mellitus, dyslipidaemia and hypothyroidism treated. HMG-CoA reductase inhibitors (statins) reduce the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolaemia. Antiplatelet drugs such as aspirin or clopidogrel (especially the latter), ACE inhibitors and statins should be given to all persons with PAD. beta-Adrenoceptor antagonists should be given if CAD is present. The phosphodiesterase type 3 inhibitor cilostazol improves exercise time until intermittent claudication. Chelation therapy should be avoided. Correct implementation of medical therapy significantly reduces the excess mortality associated with PAD. In addition, medical therapy may result in significant improvements in walking ability that may obviate the need for lower extremity angioplasty with stenting and bypass surgery.
Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial. [2023]Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61-0.99); 0.67 (0.51-0.86) and 0.75 (0.59-0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14-1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.
Loss of Kidney Function after Endovascular Treatment of Peripheral Arterial Disease. [2017]Administration of radiocontrast during endovascular procedures for peripheral arterial disease (PAD) may cause acute kidney injury, which generally recovers with supportive treatment. Long-term effects of endovascular procedures on renal function remain to be investigated.
A Randomized Controlled Trial of Allopurinol in Patients With Peripheral Arterial Disease. [2018]Patients with peripheral arterial disease (PAD) are limited by intermittent claudication in the distance they can walk. Allopurinol has been shown in coronary arterial disease to prolong exercise before angina occurs, likely by prevention of oxygen wastage in tissues and reduction of harmful oxidative stress.
Peripheral arterial disease. [2013]Peripheral arterial disease (PAD) in the elderly can be: 1) asymptomatic, 2) associated with intermittent claudication, or 3) cause critical limb ischemia. Persons with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from coronary artery disease (CAD). Hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism should be treated, and smoking should be stopped. Statins reduce the incidence of intermittent claudication and increase exercise duration until the onset of intermittent claudication in persons with PAD and hypercholesterolemia. Antiplatelet drugs (eg, aspirin, clopidogrel, angiotensin-converting enzyme [ACE] inhibitors, statins) should be given to all persons with PAD. Beta blockers should be given if CAD is present. Exercise rehabilitation programs and cilostazol lengthen exercise time until leg pain develops. Chelation therapy has no scientific basis and should be avoided. Revascularization or amputation may be indicated in some cases.