Low-dose Colchicine in Patients With Type 2 Diabetes Mellitus and Microalbuminuria

Study Overview
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Brief Summary
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The primary objective of this study was： in patients with type 2 diabetes and microalbuminuria who have been receiving stable treatment of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) for at least 3 months, whether low-dose colchicine slows the progression of microvascular complications. The secondary objective of this study was： (1) whether low-dose colchicine could reduce Urinary Albumin To Creatinine Ratio (UACR), or improve eGFR in patients with type 2 diabetes and microalbuminuria; (2) whether low-dose colchicine decreases carotid intima-media thickness(IMT) in patients with type 2 diabetes and microalbuminuria; (3) whether low-dose colchicine reduces the risk of cardiovascular events or mortality in patients with type 2 diabetes and microalbuminuria.

Detailed Description
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BACKGROUND-Previous study reported that colchicine 0.5 mg/day, in addition to statins and other standard secondary prevention therapies, was effective for the prevention of cardiovascular events in patients with stable coronary disease. An experiment conducted by Li et al. showed that twenty-four-hour urinary albumin excretion was reduced after 6 months colchicine treatment in rats with diabetic nephropathy.As both micro and macrovascular complications of diabetes are closely associated with inflammation,with the anti-inflammation property,colchicine might reduce risk for micro and macrovascular complications of diabetes. STUDY DESIGN-Patients with type 2 diabetes and microalbuminuria(30mg/g Cr≤UACR≤300mg/g Cr) who have received stable dosage of ACEI/ARB for at least 3 months will be randomized to receive colchicine 0.5 mg/day or placebo. This trial includes four phases: Phases 1: A prospective, randomized，double-blind, control study, aims at evaluating microvascular events from date of randomization until the third year. Other parameters included evaluating changes of UACR, eGFR, CIMT from baseline to the follow-up. Phases 2: A prospective observational study, aims at evaluating macrovascular and microvascular events from date of randomization until the 6th year. SAFETY AND DATA MANAGEMENT-Independent Safety and Data Monitoring Committee has been set up to monitor the safety and tolerability of the subjects; this committee will analyze data independent of investigators at the end of any one phase.

Official Title
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Low-dose Colchicine Intervention in Patients With Type 2 Diabetes Mellitus and Microalbuminuria: Chongqing Study

Conditions
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Diabetic Nephropathy

Intervention / Treatment
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* Drug: colchicine 0.5mg/d
* Drug: placebo 0.5mg/d


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Well informed of the procedures of this trial and informed consent is obtained Voluntarily accept standardized treatment 30-70 years old, gender is not limited Diagnosed as type 2 diabetes and have received standardized hypoglycemic therapy Have been receiving stable doses of ACEI or ARBs for at least 3 months Two of three examinations of UACR at random urine are 30-300 mg/g Cr (infection or other factors were ruled out) in 3 months Well compliance Capable of self blood Glucose monitoring Exclusion Criteria: Pregnant or lactating Type 1 diabetes Poor blood glucose control（HbA1c>11%） A history of malignant tumor Abnormal liver or renal function (defined as alanine aminotransferase(ALT)>2.5 times higher than normal range,or eGFR<30 mL/min per 1•73 m²) Poor blood pressure control [systolic blood pressure(SBP)>180mmHg,or diastolic blood pressure(DBP)>110mmHg] With severe heart disease,cardiac function worse than grade II,anemia(Hb<9.0g/d1) Continuous use of colchicine or non-steroidal anti-inflammatory drugs (except aspirin) more than one week in recent 3 months History of gout Blood routine test indicates that the white blood cell count(WBC) <3*109/l Body Mass Index(BMI)<18.5 or ≥35kg/m2 Drug or alcohol abuse Accompanying mental disorder who can't collaborate Abnormal digestion and absorption function Other endocrine diseases Other chronic diseases needed long-term glucocorticoid treatment With severe infection, immune dysfunction A history of colchicine allergies or allergic constitution

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: colchicine<br>0.5mg/d colchicine | Drug: colchicine 0.5mg/d<br>* on the basis of standard therapy to manage hyperglycemia, hypertension,dislipidemia etc.<br>|
| Placebo Comparator: placebo<br>appearance is same as colchicine | Drug: placebo 0.5mg/d<br>* on the basis of standard therapy to manage hyperglycemia, hypertension,dislipidemia etc.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of overt nephropathy | overt nephropathy is defined as any one of the events described below: （1） UACR greater than 300 mg/g Cr; (2) 24 h urinary albumin greater than 300 mg; (3)doubling of the serum creatinine level to at least 200 μmol per liter; (4)the need for renal-replacement therapy;(5) death due to renal disease. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients achieving at least a 15% reduction in UACR | Renal outcome | 3 years | 
| Changes in estimated Glomerular Filtration Rate (eGFR) | Renal outcome | 3 years | 
| The number of patients who have new or worsening diabetic neuropathy | diabetic neuropathy was assessed based on biothesiometer. | 3 years | 
| The number of patients who have new or worsening diabetic retinopathy | Diabetic retinopathy was diagnosed according to the six-level grading scale of the European Community- funded Concerted Action Programme into the Epidemiology and Prevention of Diabetes (EURODIAB) | 3 years | 
| changes in CIMT from baseline to the 3rd year | cardiovascular outcome | 18 months and 3 year | 
| The number of patients who have new cardiovascular events | cardiovascular events include death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction, coronary-artery bypass grafting, percutaneous coronary intervention or revascularization for peripheral atherosclerotic arterial disease, and amputation because of ischemia | 6 years | 
| changes of UACR | evaluated at 6, 12, 18, 24, 36, 48, 60, 72 months | 6 years | 
| changes of eGFR | evaluated at 6, 12, 18, 24, 36, 48, 60, 72 months | 6 years | 
| Death from any cause | All-cause mortality | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colchicine, urinary albumin-to-creatinine ratio, carotid Intima-Media Thickness, overt nephropathy, Type 2 diabetes