Chronic Limb-Threatening Ischemia
Conditions
Keywords
CIRCLE-Asia, Chronic limb-threatening ischemia, Peripheral artery disease, Colchicine, Amputation-free survival
Brief summary
Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease, a condition in which narrowed or blocked arteries reduce blood flow to the legs. People with CLTI may have severe leg pain at rest, non-healing wounds, or gangrene, and face a high risk of leg amputation and death. Even after successful procedures to restore blood flow to the leg (called revascularization), many patients still experience serious complications. Inflammation in the blood vessels is believed to play an important role in these poor outcomes. Colchicine is an anti-inflammatory medication that has been used safely for decades to treat gout and other inflammatory conditions. Recent large clinical trials have shown that a low dose of colchicine (0.5 mg per day) can reduce heart attacks and strokes in patients with coronary artery disease. However, it has not been studied in patients with CLTI. The CIRCLE-Asia trial (Colchicine in Chronic Limb-Threatening Ischemia for Reduction of Complications and Limb Events in Asia) is a pilot study designed to evaluate whether colchicine can improve outcomes in patients with CLTI who have recently undergone a successful procedure to restore blood flow to their leg. Treatment begins within 7 days of the procedure. This is a randomized, double-blind, placebo-controlled, multicenter trial conducted at five hospitals in Taiwan. A total of 200 adult patients with CLTI who have undergone successful revascularization will be randomly assigned in a 1:1 ratio to receive either colchicine 0.5 mg once daily or a matching placebo pill, in addition to their usual medications, for 12 months. Neither the patients nor the study doctors will know which treatment each patient receives. The main outcome of interest is amputation-free survival, defined as the time until major amputation of the affected leg (above the ankle) or death from any cause, over 12 months of follow-up. The study will also assess other important outcomes including major limb complications, heart attacks, strokes, wound healing, changes in blood flow measurements, inflammatory blood markers, quality of life, and medication safety. This pilot trial will provide the first randomized evidence on the potential benefits and safety of colchicine in CLTI patients and will help inform the design of a larger definitive trial.
Interventions
Colchicine 0.5 mg oral tablet (Colchicine Tablets 0.5mg, Synmosa), taken once daily in addition to standard of care, for 12 months. Treatment is initiated within 7 days of successful lower-extremity revascularization. For patients experiencing intolerance such as diarrhea or gastrointestinal discomfort, the dose may be reduced to 0.25 mg daily (half tablet). If the medication is considered harmful, treatment is interrupted and resumed when safe.
DRUGPlacebo
Matching placebo tablet, identical in appearance to the colchicine 0.5 mg tablet (supplied by Synmosa Biopharma Corporation), taken orally once daily in addition to standard of care, for 12 months. Treatment is initiated within 7 days of successful lower-extremity revascularization. The same dose adjustment and discontinuation rules apply as for the active treatment arm.
Sponsors
Shin Kong Wu Ho-Su Memorial Hospital
National Taiwan University Hospital
Chi Mei Medical Hospital
Taipei Veterans General Hospital, Taiwan
Chang Gung Memorial Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years. 2. Documented chronic limb-threatening ischemia, meeting the following: * Presence of ischemic symptoms compatible with CLTI, defined as arterial insufficiency with gangrene, non-healing ischemic ulcer, or rest pain consistent with Rutherford classes 4-5 AND * Imaging evidence within the past 12 months showing atherosclerotic PAD, including CTA, MRA, angiography or duplex ultrasound AND * Ankle-Brachial Index (ABI) ≤0.80 or Toe-Brachial Index (TBI) ≤0.60 for patients without prior revascularization; ABI ≤0.85 or TBI ≤0.65 for those with prior revascularization OR * Ischemic rest pain alone (Rutherford class 4) defined as ankle systolic pressure \<50 mmHg, toe pressure of \<30 mmHg, transcutaneous PO2 of \<30 mmHg, or flat-line transtarsal pulse volume recording OR * Tissue loss with or without ischemic rest pain (Rutherford class 5) defined as ankle systolic pressure \<70 mmHg, toe pressure of \<50 mmHg, transcutaneous PO2 of \<30 mmHg, or flatline transtarsal pulse volume recording 3. Recent successful revascularization: * Underwent technically successful endovascular therapy (EVT) or surgical bypass within the last 7 days prior to randomization * For individuals requiring multiple revascularization attempts on the same index leg, the procedure considered for eligibility (in other words, the qualifying or index procedure) must be the final planned or anticipated revascularization attempt * There must be demonstrated graft or vascular patency after the qualifying revascularization procedure with one in-line blood flow to the foot, either by angiography, duplex ultrasound, CTA or MRA * There must be no immediate plan for reintervention 4. Informed Consent: * Demonstrated ability and willingness to adhere to the study protocol, attend scheduled follow-up visits, complete all required assessments, and provide written informed consent
Exclusion criteria
1. Age \<18 years 2. Asymptomatic or mild disease: Patients who underwent revascularization for disease graded Rutherford classes 0-3 3. Patients with major tissue loss (Rutherford 6) in whom major amputation was planned at the time of screening 4. Failure to establish at least one tibial artery outflow after revascularization 5. Recent acute limb ischemia events within 2 weeks of screening 6. Clinical signs of active, uncontrolled, severe limb infection or septicemia, such as fever exceeding 38.5°C, a white blood cell count above 15,000 cells/µL, or hypotension, at the time of screening (this does not include osteomyelitis confined to the phalanges or metatarsal heads or foot cellulitis treatable with IV antibiotics at the time of revascularization) 7. Unstable hemodynamics after the index revascularization procedure 8. Unable to tolerate any antiplatelet agent or with severe bleeding diathesis 9. Acute coronary syndrome, acute stroke, or hospitalization for heart failure within 30 days of screening 10. Any contraindication or known intolerance to colchicine 11. Requirement for colchicine for another indication 12. Need for use of medications known to have drug-drug interactions with colchicine, particularly drugs known to inhibit CYP3A4 or P-glycoprotein 13. Active hepatitis or severe liver cirrhosis (Child Pugh C) 14. Pregnancy, breastfeeding, or women of childbearing potential who are not using an effective method of contraception 15. Previous (within 30 days) or concomitant participation in another clinical study with investigational medicinal product(s) 16. Life expectancy \<1 year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amputation-free survival | 12 months | Defined as the time to major (above the ankle) amputation of the study limb or death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants with Major (Above the Ankle) Non-Traumatic Amputation of the Study Limb | 12 months | Number of participants who underwent major (above the ankle) non-traumatic amputation of the study limb during the 12-month follow-up period. |
| Major adverse limb event (MALE, including non-traumatic above-ankle amputation and major lower limb artery reintervention) and its components | 12 months | — |
| Major adverse cardiovascular event (MACE, including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) and its components | 12 months | — |
| Wound healing rates at 3, 6, 9 and 12 months for Rutherford 5 patients (or time to wound healing) | 12 months | — |
| Number of Participants with Acute Limb Ischemia | 12 months | Number of participants experiencing acute limb ischemia of the study limb during the 12-month follow-up period, adjudicated by a blinded clinical events committee. |
| Number of Deaths from Any Cause | 12 months | Number of participants who died from any cause during the 12-month follow-up period. |
| Number of Deaths from Cardiovascular Causes | 12 months | Number of participants who died from cardiovascular causes during the 12-month follow-up period, adjudicated by a blinded clinical events committee. |
| Number of Deaths from Limb-Related Causes | 12 months | Number of participants who died from limb-related causes (e.g., fatal limb sepsis, complications of major amputation) during the 12-month follow-up period. |
| Number of Participants with Adverse Gastrointestinal Events | 12 months | Number of participants experiencing adverse gastrointestinal events (including nausea, vomiting, abdominal pain, and diarrhea) during the 12-month treatment period. |
| Number of Participants with Adverse Hematologic Events | 12 months | Number of participants experiencing adverse hematologic events (including leukopenia, thrombocytopenia, and anemia) during the 12-month treatment period. |
| Number of Participants with Serious Infections | 12 months | Number of participants experiencing serious infections (defined as infections requiring hospitalization or intravenous antibiotics) during the 12-month follow-up period. |
| Number of Participants with Diarrhea | 12 months | Number of participants experiencing diarrhea as an adverse event during the 12-month treatment period. Diarrhea is defined as the passage of three or more loose or watery stools within a 24-hour period, and severity is graded by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1 = increase of \<4 stools/day over baseline; Grade 2 = increase of 4-6 stools/day; Grade 3 = increase of ≥7 stools/day or hospitalization indicated; Grade 4 = life-threatening consequences; Grade 5 = death. |
| Number of Participants with Drug Discontinuation Due to Any Adverse Event | 12 months | Number of participants who permanently discontinued the study drug due to any adverse event during the 12-month treatment period. |
| Change in Health-Related Quality of Life as Measured by the EQ-5D-5L Index Score | Baseline and 12 months | Change from baseline in EQ-5D-5L index score at 12 months. The EQ-5D-5L is a generic health status questionnaire. Index scores range from -0.6 to 1.0, where higher scores indicate better health-related quality of life. |
| Change in Disease-Specific Quality of Life as Measured by the VASCUQOL-6 Score | Baseline and 12 months | Change from baseline in Vascular Quality of Life Questionnaire-6 (VASCUQOL-6) summary score at 12 months. VASCUQOL-6 scores range from 6 to 24, where higher scores indicate better vascular disease-specific quality of life. |
| Change in Walking Ability as Measured by the Walking Impairment Questionnaire (WIQ) Score | Baseline and 12 months | Change from baseline in Walking Impairment Questionnaire (WIQ) composite score at 12 months. The WIQ assesses walking distance, walking speed, and stair climbing. Each domain is scored from 0 to 100, where higher scores indicate better walking ability. |
| Change in Ankle-Brachial Index (ABI) | Baseline and 12 months | Change from baseline in ankle-brachial index (ABI) of the study limb at 12 months. ABI is calculated as the ratio of ankle systolic blood pressure to brachial systolic blood pressure (unitless ratio). Higher values indicate better lower-extremity arterial perfusion. |
| Change in Toe-Brachial Index (TBI) | Baseline and 12 months | Change from baseline in toe-brachial index (TBI) of the study limb at 12 months. TBI is calculated as the ratio of toe systolic blood pressure to brachial systolic blood pressure (unitless ratio). Higher values indicate better distal perfusion. |
| Change in Transcutaneous Oxygen Pressure (TcPO2) | Baseline and 12 months | Change from baseline in transcutaneous oxygen pressure (TcPO2) of the study limb at 12 months, measured in mmHg. Higher values indicate better tissue oxygenation. |
Countries
Taiwan
Contacts
CONTACTDonna SH Lin, MD
PRINCIPAL_INVESTIGATORDonna SH Lin, MD
Shin Kong Wu Ho-Su Memorial Hospital
Outcome results
None listed