Colchicine in Chronic Limb-Threatening Ischemia (CIRCLE-Asia)

Colchicine in Chronic Limb-Threatening Ischemia for Reduction of Complications and Limb Events in Asia

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Limb-Threatening Ischemia
• Intervention / Treatment: Drug: Colchicine 0.5 MG Oral Tablet Once Daily; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Donna SH Lin, MD; Phone Number: +886-2-2833-2211; Email: donna.lin24@gmail.com

Study Locations

• Taiwan
  • Tainan, Taiwan, 710
    • Chi Mei Medical Center
    • Contact: Chon-Seng Hong, MD; Phone Number: +886-6-281-2811; Email: Ahsingsing@gmail.com
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
    • Contact: Jen-Kuang Lee, MD, PhD; Phone Number: +886-2-2312-3456; Email: b85401104@gmail.com
  • Taipei, Taiwan, 112
    • Taipei Veterans General Hospital
    • Contact: Tai-Wei Chen, MD; Phone Number: +886-2-2871-2121; Email: radiant107@gmail.com
  • Taoyuan District, Taiwan, 333
    • Linkou Chang Gung Memorial Hospital
    • Contact: Chun-Chi Chen, MD; Phone Number: +886-3-328-1200; Email: mr3228@gmail.com
  • Taipei
    • Taipei, Taipei, Taiwan, 111
      • Shin Kong Wu Ho-Su Memorial Hospital
      • Contact: Donna SH Lin, MD; Phone Number: +886-2-2833-2211; Email: donna.lin24@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Colchicine; Colchicine 0.5 mg per tab, taken 1 tab daily	Drug: Colchicine 0.5 MG Oral Tablet Once Daily; 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.
Placebo Comparator: Placebo; Placebo tablets matching in appearance with study drug, taken 1 tab per day	Drug: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amputation-free survival	Defined as the time to major (above the ankle) amputation of the study limb or death from any cause	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with Major (Above the Ankle) Non-Traumatic Amputation of the Study Limb	Number of participants who underwent major (above the ankle) non-traumatic amputation of the study limb during the 12-month follow-up period.	12 months
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	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.	12 months
Number of Deaths from Any Cause	Number of participants who died from any cause during the 12-month follow-up period.	12 months
Number of Deaths from Cardiovascular Causes	Number of participants who died from cardiovascular causes during the 12-month follow-up period, adjudicated by a blinded clinical events committee.	12 months
Number of Deaths from Limb-Related Causes	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.	12 months
Number of Participants with Adverse Gastrointestinal Events	Number of participants experiencing adverse gastrointestinal events (including nausea, vomiting, abdominal pain, and diarrhea) during the 12-month treatment period.	12 months
Number of Participants with Adverse Hematologic Events	Number of participants experiencing adverse hematologic events (including leukopenia, thrombocytopenia, and anemia) during the 12-month treatment period.	12 months
Number of Participants with Serious Infections	Number of participants experiencing serious infections (defined as infections requiring hospitalization or intravenous antibiotics) during the 12-month follow-up period.	12 months
Number of Participants with Diarrhea	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.	12 months
Number of Participants with Drug Discontinuation Due to Any Adverse Event	Number of participants who permanently discontinued the study drug due to any adverse event during the 12-month treatment period.	12 months
Change in Health-Related Quality of Life as Measured by the EQ-5D-5L Index Score	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.	Baseline and 12 months
Change in Disease-Specific Quality of Life as Measured by the VASCUQOL-6 Score	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.	Baseline and 12 months
Change in Walking Ability as Measured by the Walking Impairment Questionnaire (WIQ) Score	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.	Baseline and 12 months
Change in Ankle-Brachial Index (ABI)	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.	Baseline and 12 months
Change in Toe-Brachial Index (TBI)	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.	Baseline and 12 months
Change in Transcutaneous Oxygen Pressure (TcPO2)	Change from baseline in transcutaneous oxygen pressure (TcPO2) of the study limb at 12 months, measured in mmHg. Higher values indicate better tissue oxygenation.	Baseline and 12 months

Other Outcome Measures

Outcome Measure	Time Frame
Changes in systemic inflammatory markers (e.g., C-reactive protein [CRP], interleukin-6 [IL-6]) from baseline	12 months

Collaborators and Investigators

• Sponsor: Shin Kong Wu Ho-Su Memorial Hospital
• Collaborators: National Taiwan University Hospital; Chang Gung Memorial Hospital; Taipei Veterans General Hospital, Taiwan; Chi Mei Medical Hospital
• Investigators: Principal Investigator: Donna SH Lin, MD, Shin Kong Wu Ho-Su Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): April 1, 2030

Study Registration Dates

• First Submitted: April 5, 2026
• First Submitted That Met QC Criteria: April 11, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 11, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Peripheral artery disease; Colchicine; Chronic limb-threatening ischemia; CIRCLE-Asia; Amputation-free survival
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Chronic Disease; Disease Attributes; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Peripheral Vascular Diseases; Ischemia; Pathological Conditions, Signs and Symptoms; Chronic Limb-Threatening Ischemia; Peripheral Arterial Disease; Heterocyclic Compounds; Alkaloids; Colchicine
• Other Study ID Numbers: 20250310R

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No