Repurposing Colchicine for Reduction of Residual Inflammatory Risk in Type 1 Diabetes: A Randomized, Double-blind, Placebo-controlled, Investigator-initiated Trial
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 102
- 试验地点
- 1
- 主要终点
- Change in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L)
研究概览
简要总结
The aim of this clinical trial is to evaluate if colchicine in addition to standard of care improves markers of inflammation and cardiovascular disease in persons with type 1 diabetes. Participants will be assigned to either 0,5 mg colchicine daily or placebo in a 1:1 ratio for 26 weeks with the possibility of an additional 26 week extension of the intervention period. After the treatment period, there will a 5-year follow-up on all available outcome measures via electronic patient records for those who took part in the extension.
详细描述
The current study aims to evaluate the efficacy of 0.5 mg colchicine once-daily added to existing standard of care in persons with established type 1 diabetes, existing arteriosclerotic cardiovascular disease (CVD) or at high risk thereof and C-reactive protein (CRP) ≥ 2 mg/L. Specifically, the primary objective is to determine the effect of colchicine (0.5 mg/daily) on levels of CRP (as assessed by high-sensitivity assays) as compared with placebo following 26-52 weeks of treatment. Additionally, the study will investigate the short and long-term effects of colchicine treatment on other markers of CVD and inflammation, markers of metabolism and markers of glycemic control in type 1 diabetes, including glycated hemoglobin (HbA1c), time spent in hypoglycemia (level 1 glucose readings 3.0-3.8 mmol/L and level 2 glucose readings < 3.0 mmol/L), target glycemia (glucose readings 3.9-10 mmol/L) and hyperglycemia (level 1 glucose readings 10.1-13.9 mmol/L and level 2 glucose readings > 13.9 mmol/L) together with measures of glycemic variability evaluated by continuous glucose monitoring (CGM), insulin dosage, risk of hypoglycemia, risk of diabetic ketoacidosis and body weight. During the 5-year follow-up, we will collect all available outcome measures via electronic patient records.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Type 1 diabetes for more than five years according to World Health Organization criteria
- •Age 18-80 years
- •Hemoglobin A1c < 80 mmol/mol
- •Stable insulin therapy (defined as no change in insulin brand and no newly initiated continous subcutaneus insulin infusion (CSII) or multiple-daily injection (MDI) therapy) and, if applicable, stable usage of glucose monitoring technology (e.g., continous glucose monitor (CGM) or intermittently scanned CGM) ≥ 3 months with either MDI or CSII
- •CRP ≥ 2 mg/L (measured by high-sensitivity assay)
- •eGFR > 50 mL/min/L/1.73 m^2
- •Either stable arteriosclerotic cardiovascular disease (ASCVD) (as defined by ischemic heart disease including previous acute myocardial infarction, acute coronary syndrome and coronary revascularization; other arterial revascularization procedures; stroke and transient ischemic attack; aortic aneurysm; peripheral arterial disease, including carotid atherosclerosis)
- •and/or risk of cardiovascular (CV) death > 5 % within 10 years (i.e., high or very high CV risk) as defined by the European Society of Cardiology or 10-year CV risk ≥ 20 % (i.e., high CV risk) as according to 'Steno Type 1 Diabetes Risk Engine' (https://steno.shinyapps.io/T1RiskEngine/)
排除标准
- •Hypoglycemia unawareness (inability to register low blood glucose) am modum Pedersen-Bjergaard, unless usage of CGM with alarm function
- •Liver disease with elevated plasma alanine aminotransferase (ALT) > three times the upper limit of normal (measured at screening with the possibility of one repeat analysis within seven days, and the last measured value as being conclusive)
- •History of cirrhosis, chronic active hepatitis or severe hepatic disease
- •Inflammatory bowel disease or chronic diarrhea
- •Pre-existing progressive neuromuscular disease or persons with creatinine kinase levels > three times the upper limit of normal (measured at screening with the possibility of one repeat analysis within a week, and the last measured value as being conclusive)
- •Cancer or lymphoproliferative disease unless in complete remission for > 5 years
- •Immunosuppressive therapy or state of chronic immunodeficiency, including infection with human immunodeficiency virus (HIV)
- •Blood dyscrasias (e.g., myelodysplastic syndromes or related hematological disorders)
- •Leukocyte cell count < 3.0 X 10^9/L
- •Thrombocyte count < 110 X 10^9/L
- •Systemic (oral or intravenous), long-term steroid therapy (topical or inhaled steroids are allowed)
- •Hemodialysis or peritoneal dialysis therapy (since colchicine cannot be removed by dialysis or exchange transfusion)
- •Renal or hepatic impairment treated with a P-gp inhibitor or a strong CYP3A4 inhibitor
- •Intake of grapefruit juice during trial participation
- •Other concomitant disease or treatment that according to the investigator's assessment makes the person unsuitable for study participation
- •Alcohol/drug abuse
- •Fertile women not using hormonal (tablet/pill, depot injection of progesterone, subdermal gestagen implantation, hormone intrauterine devices (IUD), hormonal vaginal ring or transdermal hormonal patch), chemical (copper IUD) or mechanical (condom, femidom, sterilization) contraceptives
- •Pregnant or nursing women
- •On permanent treatment with colchicine that is not discontinued within 30 days of screening visit
- •Known or suspected hypersensitivity to colchicine
- •Receipt of any investigational drug within 30 days prior to screening visit
- •Simultaneous participation in any other clinical intervention trial
研究组 & 干预措施
Colchicine
Colchicine tablet 0.5 mg once-daily
干预措施: Colchicine 0.5 MG Oral Tablet (Drug)
Placebo
Placebo tablet once-daily
干预措施: Placebo (Drug)
结局指标
主要结局
Change in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L)
时间窗: From week 0 (baseline) to week 26 (end of treatment)
%-point
次要结局
- Change in fasting serum/plasma concentrations of C-reactive protein (CRP) measured by a high-sensitivity assay (hsCRP) (mg/L)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in fasting serum/plasma concentrations of hemoglobin A1c (mmol/mol)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Time spent in target blood glucose range (3.9 - 10 mmol/L) evaluated by a continous glucose monitor (CGM)(From week 0 (baseline) to week 26 (end of treatment) or to 52 weeks (extension))
- Time spent in hyperglycemia level 1 (10-13.9 mmol/L) evaluated by a continous glucose monitor (CGM)(From week 0 (baseline) to week 26 (end of treatment) or to 52 weeks (extension))
- Time spent in hyperglycemia level 2 (> 13.9 mmol/L) evaluated by a continous glucose monitor (CGM)(From week 0 (baseline) to week 26 (end of treatment) or to 52 weeks (extension))
- Time spent in hypoglycemia level 1 (3.0-3.8 mmol/L) evaluated by a continous glucose monitor (CGM)(From week 0 (baseline) to week 26 (end of treatment) or to 52 weeks (extension))
- Time spent in hypoglycemia level 2 (< 3.0 mmol/L)evaluated by a continous glucose monitor (CGM)(From week 0 (baseline) to week 26 (end of treatment) or to 52 weeks (extension))
- Insulin dosage(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in body weight (kg)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in waist:hip ratio(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in fasting serum/plasma concentrations of low-density lipoprotein cholesterol (LDL) (mmol/L)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in fasting serum/plasma concentrations of interleukin (IL)-6 (pg/mL)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Change in fasting serum/plasma concentrations of tumor necrosis factor alpha (pg/mL)(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
- Safety-related events(From week 0 (baseline) to week 30 (safety follow-up) or to 56 weeks (extension))
研究者
Asger Lund, MD
Ass. Professor, MD, PhD
University Hospital, Gentofte, Copenhagen