Low-Dose Colchicine for Peripheral Artery Disease

(LEADER-PAD Trial)

Recruiting at 3 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

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. ^{1 2 3 4 5}

Is 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. ^{1 2 3 4 6}

How 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. ^{7 8 9 10 11}

Research Team

Noel C Chan, MD

Principal Investigator

Population Health Research Institute, Hamilton, Ontario, Canada

Eligibility 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.

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2023]

2. Japan pubmed.ncbi.nlm.nih.gov

Low-Dose Colchicine in Coronary Artery Disease - Systematic Review and Meta-Analysis. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians. [2022]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Drivers of mortality in patients with chronic coronary disease in the low-dose colchicine 2 trial. [2023]

5. Australia pubmed.ncbi.nlm.nih.gov

Colchicine for Secondary Prevention of Coronary Artery Disease: A Meta-Analysis of Randomised Controlled Trials. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Colchicine: serious interactions. [2013]

7. New Zealand pubmed.ncbi.nlm.nih.gov

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Loss of Kidney Function after Endovascular Treatment of Peripheral Arterial Disease. [2017]

10. England pubmed.ncbi.nlm.nih.gov

A Randomized Controlled Trial of Allopurinol in Patients With Peripheral Arterial Disease. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Peripheral arterial disease. [2013]