Atherosclerosis of Extremities, Inflammation, Peripheral Arterial Disease
Conditions
Keywords
Acute limb ischemia, Myocardial Infarction, Stroke, Cardiovascular death, Mortality
Brief summary
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.
Detailed description
The LEADER-PAD trial is a randomized, double blind, multicenter trial with an active run-in period, comparing low dose colchicine 0.5 mg daily with placebo in patients with symptomatic peripheral artery disease (PAD) to prevent vascular events (myocardial infarction, stroke, cardiovascular deaths, acute limb ischemia and vascular amputation). The sample size for the trial is 6,150 participants. The primary outcome for the trial is major adverse cardiovascular and limb events (MACE and MALE). This composite outcome consists of cardiovascular death, myocardial infarction, stroke and severe limb ischemia that requires a vascular intervention (i.e., pharmacological reperfusion, endovascular or surgical revascularization) or a major vascular amputation (defined as ankle/transtibial amputation or higher).
Interventions
Colchicine 0.5 mg tablet daily Active drug and placebo are of the same appearance and are indistinguishable. All investigators, study personnel and patients will be blinded to drug treatment assignment. Trial treatment supplies must be stored in a secure, limited-access location under the storage conditions specified on the IP supply label.
Colchicine-Placebo tablet
Sponsors
Population Health Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind and use of similarly active and placebo tablets.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 or verbal informed consent from the patient
Exclusion criteria
1. Contraindication to colchicine 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major adverse cardiovascular and limb events (MACE or MALE) | 3-5 years | This composite outcome consists of cardiovascular deaths, myocardial infarction, stroke, and severe limb ischemia that requires a vascular intervention (i.e., pharmacological reperfusion, endovascular or surgical revascularization) or a major vascular amputation (defined as ankle/transtibial amputation or higher) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Extended MALE | 3-5 years | This composite outcome includes major adverse limb events (MALE) as well as revascularization for new or worsening claudication of new stenosis or occlusion detected on screening after a previous intervention |
| Cardiovascular death | 3-5 years | Death will be classified as cardiovascular or non-cardiovascular. All deaths with a clear cardiovascular or unknown cause will be classified as cardiovascular. Only deaths due to a documented non-cardiovascular cause (e.g., cancer) will be classified as non-cardiovascular. |
| Myocardial infarction | 3-5 years | Acute myocardial infarction (AMI) requires evidence of acute myocardial injury with clinical evidence of acute myocardial ischemia |
| Stroke | 3-5 years | Stroke requires the presence of acute focal or global\* neurological dysfunction caused by brain or retinal vascular injury due to primary hemorrhage or infarction. |
| Hospitalization | 3-5 years | Admission to hospital for any reason |
| Acute or chronic limb-threatening ischemia | 3-5 years | This is defined as an episode severe limb ischemia that requires an acute vascular intervention (i.e., pharmacological reperfusion, endovascular or surgical revascularization) or a major vascular amputation (defined as at ankle or transtibial amputation or higher). |
| All revascularization (coronary or cerebrovascular or lower limb or other peripheral revascularization) | 3-5 years | Defined as coronary or cerebrovascular or lower limb or other peripheral revascularization |
| Total vascular amputation | 3-5 years | All vascular amputations |
| Overall mortality | 3-5 years | All cause (CV and non CV) deaths |
| Any thrombosis or thromboembolism (arterial and venous) | 3-5 years | All arterial and venous thromboembolism |
| Fontaine Stage | 3-5 years | This classification system grades the clinical presentation of patients to four stages of PAD |
| Standard Assessment of Global Everyday Activities (SAGEA) | 3-5 years | The Standard Assessment of Global Everyday Activities (SAGEA) is a 15 item tool to assess activities of daily living including higher executive function used in social situations, everyday activities and basic activities of daily living. Scores range from 0 to 24 with higher scores indicating poorer function.It is a 15 items questionnaire and the scores will range from 0, describing a very independent participant over a broad spectrum of activities, to 48 describing a very dependent participant |
| Vascular Quality of Life Questionnaire-6 (VascQOL-6) | 3-5 years | Six item vascular quality of life instrument: The total score is achieved by summarizing the score on each question, resulting in a score between 6 and 24. Higher value indicates better health status. |
| EuroQol 5 Dimension 5 Level (EQ-5D-5L) | 3-5 years | A survey that measures quality of life across 5 domains. Each domain is scored on a 5-level severity ranking that ranges from "no problems" to "extreme problems". |
Countries
Australia, Belgium, Brazil, Canada, Ecuador, Netherlands, Switzerland, United Kingdom, United States
Contacts
CONTACTNoel C Chan, MD
CONTACTJessica Tyrwhitt
PRINCIPAL_INVESTIGATORNoel C Chan, MD
Population Health Research Institute, Hamilton, Ontario, Canada
Outcome results
None listed