Low-Dose Colchicine for Peripheral Artery Disease

(LEADER-PAD Trial)

Recruiting at 16 trial locations

Overseen By Jessica Tyrwhitt

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Population Health Research Institute

Must not be taking: Cyclosporine, Verapamil, HIV protease, others

Disqualifiers: Cirrhosis, Severe liver disease, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3-5 years

6150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a low dose of colchicine, a medicine that reduces inflammation, can help people with peripheral artery disease (PAD) by decreasing the risk of future vascular events, such as heart attacks or strokes. Participants will receive either colchicine or a placebo (a pill that looks like the medicine but contains no active ingredients). The trial seeks individuals with PAD symptoms, such as pain while walking or sores on their legs or feet, and who may also have diabetes, heart failure, or have undergone certain vascular procedures. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that colchicine is generally safe for people with peripheral artery disease (PAD). Studies have found that colchicine reduces the risk of major heart and limb issues in these patients, indicating good tolerance.

Colchicine reduces inflammation, which can protect the arteries. In studies involving people with heart conditions, it lowered the risk of major heart problems. This finding is encouraging for its use in PAD as well.

Overall, colchicine has been studied extensively, and results are mostly positive. It appears to be a safe option for addressing artery issues. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for peripheral artery disease?

Colchicine is unique because it targets inflammation directly, offering a potentially new approach for treating Peripheral Artery Disease (PAD). Unlike standard treatments like antiplatelet therapy or statins, which primarily focus on improving blood flow and reducing cholesterol levels, colchicine works by reducing inflammation in the arteries. Researchers are excited because this anti-inflammatory effect could improve outcomes for PAD patients by addressing a different aspect of the disease process that current treatments don't directly target.

What evidence suggests that colchicine might be an effective treatment for peripheral artery disease?

Research has shown that colchicine, which participants in this trial may receive, might help reduce complications for people with peripheral artery disease (PAD). In people with PAD, colchicine has been linked to lower risks of serious limb problems and heart-related deaths. By blocking certain processes that cause inflammation, colchicine reduces inflammation in the body. One study showed it reduced major heart problems by 31% in people with stable atherosclerosis, a condition where arteries become narrowed. These findings suggest that colchicine could help reduce blood vessel issues in PAD patients. ^{1 2 4 5 6}

Who Is on the Research Team?

Noel C Chan, MD

Principal Investigator

Population Health Research Institute, Hamilton, Ontario, Canada

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Colchicine
• Colchicine-Placebo

Trial Overview 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.

How Is the Trial Designed?

Group I: Colchicine Active Control 1 Intervention

Colchicine 0.5mg daily for the duration of the trial

Group II: Colchicine-Placebo Placebo Group 1 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

Who Is Running the Clinical Trial?

Population Health Research Institute

Lead Sponsor

Trials

165

Recruited

717,000+

Published Research Related to This Trial

Low-dose colchicine significantly reduces the rate of major adverse cardiovascular events and acute coronary syndrome in patients with coronary artery disease, based on a review of 11,955 patients across multiple randomized controlled trials.

While colchicine is generally safe, it is associated with an increased risk of gastrointestinal events, highlighting the need for monitoring in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Dose Colchicine in Coronary Artery Disease - Systematic Review and Meta-Analysis. Abrantes, AM., Nogueira-Garcia, B., Alves, M., et al.[2021]

In a study involving 50 participants with peripheral arterial disease (PAD), allopurinol did not improve walking distance or exercise capacity over 6 months, despite significantly reducing uric acid levels by 52%.

The trial found no evidence that allopurinol provided any benefit in alleviating leg pain or enhancing overall health and walking ability in PAD patients, indicating it may not be an effective treatment for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Controlled Trial of Allopurinol in Patients With Peripheral Arterial Disease. Robertson, AJ., Struthers, AD.[2018]

The LoDoCo2 trial is investigating the efficacy and safety of low-dose colchicine (0.5 mg daily) in 5522 patients with stable coronary artery disease, aiming to confirm its potential for secondary prevention of cardiovascular events.

This study is designed to detect a 30% reduction in major cardiovascular events, such as heart attacks and strokes, while also monitoring for any adverse effects related to colchicine, indicating a thorough approach to evaluating its safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. Nidorf, SM., Fiolet, ATL., Eikelboom, JW., et al.[2023]

In the LoDoCo2 trial involving 5522 patients with chronic coronary disease, low-dose colchicine (0.5 mg daily) significantly reduced cardiovascular deaths without adversely affecting specific causes of death, indicating its safety in this context.

Most deaths during the study were due to non-cardiovascular causes, with age over 65 being a strong predictor of non-cardiovascular mortality, highlighting the role of comorbidities in overall mortality for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial. Opstal, TSJ., Nidorf, SM., Fiolet, ATL., et al.[2023]

Low-dose colchicine (0.5 mg daily) has been shown to improve cardiovascular outcomes in patients with stable coronary artery disease (CAD) and those who have had recent myocardial infarctions, based on multiple large-scale randomized controlled trials.

Colchicine is generally safe with few mild side effects and can be used alongside high-intensity statin therapy without serious adverse effects, but it should be avoided in patients with severe renal or hepatic disease due to toxicity risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians. Marquis-Gravel, G., Goodman, SG., Anderson, TJ., et al.[2022]

Endovascular interventions for peripheral arterial disease (PAD) resulted in a significant reduction in estimated glomerular filtration rate (eGFR) by 8.6 mL/min after one year, indicating a clinically relevant long-term loss of kidney function.

In contrast, supervised exercise therapy led to a much smaller reduction in eGFR of only 1.7 mL/min, suggesting that exercise therapy may be a safer option for preserving renal function in PAD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loss of Kidney Function after Endovascular Treatment of Peripheral Arterial Disease. Sigterman, TA., Bolt, LJJ., Krasznai, AG., et al.[2017]

Patients with renal failure or those taking nephrotoxic drugs are at a higher risk for adverse effects when using colchicine, necessitating careful monitoring and dose adjustments.

Colchicine should only be used in gout patients after other treatments have failed, and if prescribed, it should be at the minimum effective dose to minimize the risk of serious side effects, particularly in vulnerable populations like the elderly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colchicine: serious interactions. [2013]

Peripheral arterial disease (PAD) in the elderly can lead to serious health risks, including increased mortality from cardiovascular diseases, making early treatment of associated conditions like hypertension and diabetes crucial.

Statins and antiplatelet drugs are effective in managing PAD, as they can reduce symptoms like intermittent claudication and improve exercise capacity, while exercise rehabilitation and cilostazol can further enhance leg function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peripheral arterial disease. Aronow, WS.[2013]

In a study involving 167 cases of peripheral artery disease (PAD) and 250 matched controls, higher baseline levels of plasma amino acids like tryptophan, serine, and threonine were found to be inversely associated with the risk of developing PAD, suggesting they could serve as early biomarkers for the disease.

The Mediterranean diet supplemented with extra-virgin olive oil (EVOO) was shown to provide a protective effect against PAD, regardless of baseline threonine levels, highlighting the potential of dietary interventions in reducing PAD risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial. Razquin, C., Ruiz-Canela, M., Toledo, E., et al.[2023]

Colchicine significantly reduces the incidence of major adverse cardiovascular events (MACEs) in patients with coronary artery disease (CAD), with a risk ratio of 0.64 based on a meta-analysis of 12,071 patients from seven randomized controlled trials.

The drug specifically lowers the risk of myocardial ischaemia, coronary revascularisation, and stroke, while showing no significant impact on cardiovascular death or other serious adverse events, indicating it is both effective and safe for secondary prevention in CAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colchicine for Secondary Prevention of Coronary Artery Disease: A Meta-Analysis of Randomised Controlled Trials. Xu, H., Mao, L., Liu, H., et al.[2022]

Effective management of peripheral arterial disease (PAD) includes stopping smoking and treating conditions like hypertension and diabetes, which can significantly reduce the risk of mortality associated with PAD.

Medications such as statins and cilostazol improve exercise capacity in PAD patients, potentially reducing the need for invasive procedures like angioplasty or bypass surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug treatment of peripheral arterial disease in the elderly. Aronow, WS.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39115507/

Effects of Colchicine on Major Adverse Limb and ... In patients diagnosed with PAD, the use of colchicine is associated with lower risks of MALE and cardiovascular death.

2. sciencedirect.com sciencedirect.com/science/article/pii/S1078588425003818

Low Dose Colchicine in Patients with Peripheral Artery ... Colchicine is inexpensive and has a broad anti-inflammatory effect, inhibiting NLRP3 inflammasome assembly, thereby inhibiting interleukin 1β pathway activation ...

3. mayoclinicproceedings.org mayoclinicproceedings.org/article/S0025-6196(24)00368-9/fulltext

Colchicine, a Novel Treatment of Peripheral Artery Disease Effects of Colchicine on Major Adverse Limb and Cardiovascular Events in Patients With Peripheral Artery Disease

4. ahajournals.org ahajournals.org/doi/10.1161/circ.148.suppl_1.14449

Abstract 14449: Long-Term Colchicine for Cardiovascular ... Evidence from randomized trials suggests colchicine may reduce major adverse cardiovascular events (MACE) in patients with coronary artery disease.

5. jacc.org jacc.org/doi/10.1016/j.jacc.2023.05.055

Low-Dose Colchicine for Secondary Prevention of ... Low-dose colchicine (0.5 mg/d orally) has been shown to safely lower major adverse cardiovascular events by 31% among those with stable atherosclerosis and by ...

6. atherosclerosis-journal.com atherosclerosis-journal.com/article/S0021-9150(24)01135-3/fulltext

Association of colchicine use with cardiovascular and limb ... We demonstrated that colchicine was associated with reduced risks of major adverse cardiovascular and limb events in peripheral artery disease.