Low-dose Colchicine Inhibit Abdominal Aortic Aneurysm Growth Trial (COIN)

COIN trial is a a prospective, randomized, placebo-controlled, double-blind, multicenter clinical study. Approximately 230 patients with small abdominal aortic aneurysms (AAA) will be randomly allocated to low-dose colchicine group or placebo group. All study patients will be followed up in the outpatient clinic every 3 months and undergo CTA scans after 24 months from randomization. The primary objective is to test the hypothesis that low dose colchicine can inhibit the progression of AAA diameter. The secondary objective is to test the hypothesis that low dose colchicine can inhibit the progression of AAA volume, reduce the incidence of clinical outcomes associated with AAA, reduce the incidence of major adverse cardiovascular events and all-cause mortality.

Study Overview

• Status: Not yet recruiting
• Conditions: Progression; Abdominal Aortic Aneurysm; Colchicine
• Intervention / Treatment: Drug: colchicine; Drug: Placebo

Detailed Description

This study is a prospective, randomized, placebo-controlled, double-blind, multicenter clinical study to test the research hypothesis that low-dose colchicine (0.5 mg/d) can delay the progression of AAA.

The study will enroll patients with infrarenal abdominal aortic aneurysms with a maximum diameter of 30-50 mm and no indication for surgical or endovascular treatment. All patients will receive the best standard medical treatment. Before randomization, all patients will undergo a 1-month lead-in period, during which open-label colchicine 0.5 mg/d will be administered. If there is colchicine intolerance, they will not be randomized.

The study center performed computer-generated block randomization (block size 8). Randomization method and block size will not unblinded until all data analyses are completed. Enrolled patients will randomly assigned to each hospital in a 1:1 ratio by the randomization center through sequentially coded, sealed, light-tight envelopes, to colchicine and placebo groups.

After randomization, patients will receive low-dose colchicine (0.5 mg/d) or placebo, respectively, and will be followed up for 24 months. We will evulate whether low-dose colchicine can delay the progression of AAA by assessing the change in maximum aneurysm diameter by CTA. At the same time, its effects on abdominal aortic aneurysm-related and cardiovascular-related clinical events will be observed.

• Study Type: Interventional
• Enrollment (Anticipated): 230
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Songyuan Luo, MD; Phone Number: +86-13570337597; Email: 656781257@qq.com
• Study Contact Backup: Name: Guokui Zhang, MM; Phone Number: +86-13622266656; Email: 772379801@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Aged over 55 and under 85; 2. Diagnosis of infrarenal abdominal aortic aneurysm within 3 months by CTA; 3. No indication for endovascular repair or surgery of abdominal aortic aneurysm

Exclusion Criteria:

• 1. Currently using colchicine; 2. Allergic to colchicine; 3. History of abdominal aortic aneurysm repair or surgery; 4. Combined with aortic dissection, thoracic aortic aneurysm, penetrating aortic ulcer (ulcer width>2cm and depth>1cm) and other aortic diseases requiring intervention; 5. Abdominal aortic aneurysm involving the renal artery or suprarenal abdominal aortic aneurysm; 6.Diameter of iliac aneurysm >29mm; 7. Renal artery stenosis or iliac artery stenosis planned for immediate intervention; 8. AAA caused by connective tissue disease (eg, collagen vascular disease), hereditary or genetic syndrome (eg, Marfan syndrome, Ehlers-Danlos syndrome); 9. Severe renal dysfunction (serum creatinine >176.8umol/L or eGFR <30ml/min) in the last 3 months 10. Severe liver dysfunction (ALT>2 ULN or TBIL>2 ULN)in the last 3 months; 11.Abnormal blood routine (hemoglobin <115g/L, white blood cell count<3.0×10^9/L, or platelet count <110×10^9/L) in the last 3 months; 12. Presence of inflammatory bowel disease or chronic diarrhea; 13. Current or planned usage of systemic immunosuppressants (eg, prednisone, azathioprine, methotrexate, cyclosporine for autoimmune disease or after bone marrow, heart, liver, lung, or other solid organ transplantation) ; 14.Patients with malignant tumors and autoimmune diseases; 15. Unable to take care of themselves, frail or expected survival time < 2 years; 16. Peripheral neuritis, myositis, or statin-related elevation of muscle enzymes; 17. Premenopausal, pregnant or lactating female patients; 18. Participated in other clinical studies of interventional therapy or drug therapy, which may interfere with the research results; 19. Refused or unable to sign informed consent to enter clinical research or to follow the research protocol and follow up.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: low-dose colchicine group; colchicine 0.5mg per day for 24 months	Drug: colchicine; colchicine 0.5mg per day for 24 months
Placebo Comparator: placebo group; placebo 0.5mg per day for 24 months	Drug: Placebo; placebo 0.5mg per day for 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes of the maximum diameter of abdominal aortic aneurysm	the changes of the maximum diameter of abdominal aortic aneurysm on CTA in 24 months	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
changes of the maximum volume of abdominal aortic aneurysm	the changes of the maximum volume of abdominal aortic aneurysm on CTA in 24 months	24 months
aorta-related adverse events	rupture of abdominal aortic aneurysm, endovascular repair or surgery repair of abdominal aortic aneurysm,aortic-related death	24 months
major adverse cardiovascular events	cardiovascular death, acute coronary syndrome, interventon for coronary artery disease, ischemic stroke or transient ischemic attack	24 months
all-cause mortality	all-cause mortality	24 months
aortic-related mortality	aortic-related mortality	24 months
cardiovascular -related mortality	cardiovascular -related mortality	24 months
change of inflammatory biomarkers	change of CRP，D-dimer，MMP-9, IL-1β, IL-18	24 months
change of living quality	SF - 36 questionnaires	24 months

Collaborators and Investigators

• Sponsor: Guangdong Provincial People's Hospital
• Collaborators: Peking Union Medical College Hospital; Peking University Shougang Hospital; The First Affiliated Hospital of Guangzhou Medical University; Shenzhen People's Hospital; Zhongshan People's Hospital, Guangdong, China; The Second Xianya Hospital of Central South University; Shenzhen Bao an People's Hospital

Publications and helpful links

General Publications

• Sakalihasan N, Michel JB, Katsargyris A, Kuivaniemi H, Defraigne JO, Nchimi A, Powell JT, Yoshimura K, Hultgren R. Abdominal aortic aneurysms. Nat Rev Dis Primers. 2018 Oct 18;4(1):34. doi: 10.1038/s41572-018-0030-7.
• Li W, Luo S, Luo J, Liu Y, Ning B, Huang W, Xue L, Chen J. Predictors Associated With Increased Prevalence of Abdominal Aortic Aneurysm in Chinese Patients with Atherosclerotic Risk Factors. Eur J Vasc Endovasc Surg. 2017 Jul;54(1):43-49. doi: 10.1016/j.ejvs.2017.04.004. Epub 2017 May 17.
• Guirguis-Blake JM, Beil TL, Senger CA, Coppola EL. Primary Care Screening for Abdominal Aortic Aneurysm: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2019 Dec 10;322(22):2219-2238. doi: 10.1001/jama.2019.17021.
• Kuivaniemi H, Elmore JR. Opportunities in abdominal aortic aneurysm research: epidemiology, genetics, and pathophysiology. Ann Vasc Surg. 2012 Aug;26(6):862-70. doi: 10.1016/j.avsg.2012.02.005.
• Umebayashi R, Uchida HA, Wada J. Abdominal aortic aneurysm in aged population. Aging (Albany NY). 2018 Dec 6;10(12):3650-3651. doi: 10.18632/aging.101702. No abstract available.
• Liu CL, Ren J, Wang Y, Zhang X, Sukhova GK, Liao M, Santos M, Luo S, Yang D, Xia M, Inouye K, Hotamisligil GS, Lu G, Upchurch GR, Libby P, Guo J, Zhang J, Shi GP. Adipocytes promote interleukin-18 binding to its receptors during abdominal aortic aneurysm formation in mice. Eur Heart J. 2020 Jul 7;41(26):2456-2468. doi: 10.1093/eurheartj/ehz856.
• Golledge J. Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol. 2019 Apr;16(4):225-242. doi: 10.1038/s41569-018-0114-9.
• Oliver-Williams C, Sweeting MJ, Jacomelli J, Summers L, Stevenson A, Lees T, Earnshaw JJ. Safety of Men With Small and Medium Abdominal Aortic Aneurysms Under Surveillance in the NAAASP. Circulation. 2019 Mar 12;139(11):1371-1380. doi: 10.1161/CIRCULATIONAHA.118.036966.
• Freiberg MS, Arnold AM, Newman AB, Edwards MS, Kraemer KL, Kuller LH. Abdominal aortic aneurysms, increasing infrarenal aortic diameter, and risk of total mortality and incident cardiovascular disease events: 10-year follow-up data from the Cardiovascular Health Study. Circulation. 2008 Feb 26;117(8):1010-7. doi: 10.1161/CIRCULATIONAHA.107.720219. Epub 2008 Feb 11.
• Forsythe RO, Dweck MR, McBride OMB, Vesey AT, Semple SI, Shah ASV, Adamson PD, Wallace WA, Kaczynski J, Ho W, van Beek EJR, Gray CD, Fletcher A, Lucatelli C, Marin A, Burns P, Tambyraja A, Chalmers RTA, Weir G, Mitchard N, Tavares A, Robson JMJ, Newby DE. 18F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study. J Am Coll Cardiol. 2018 Feb 6;71(5):513-523. doi: 10.1016/j.jacc.2017.11.053.
• MA3RS Study Investigators. Aortic Wall Inflammation Predicts Abdominal Aortic Aneurysm Expansion, Rupture, and Need for Surgical Repair. Circulation. 2017 Aug 29;136(9):787-797. doi: 10.1161/CIRCULATIONAHA.117.028433. Epub 2017 Jul 18.
• Vainas T, Lubbers T, Stassen FR, Herngreen SB, van Dieijen-Visser MP, Bruggeman CA, Kitslaar PJ, Schurink GW. Serum C-reactive protein level is associated with abdominal aortic aneurysm size and may be produced by aneurysmal tissue. Circulation. 2003 Mar 4;107(8):1103-5. doi: 10.1161/01.cir.0000059938.95404.92.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2022
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): December 31, 2025

Study Registration Dates

• First Submitted: April 30, 2022
• First Submitted That Met QC Criteria: April 30, 2022
• First Posted (Actual): May 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 5, 2022
• Last Update Submitted That Met QC Criteria: April 30, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Aortic Diseases; Aneurysm; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: KY-N-2022-027-03

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