Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes: a Double Blind Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 230
- 试验地点
- 1
- 主要终点
- Change between below-knee arterial calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.
研究概览
简要总结
Vascular calcification (VC) is a complication frequently observed in elderly, in chronic kidney disease (CKD) and in diabetes (particularly in type 1 diabetes). VC is a dynamic pathophysiological process that causes cardiovascular morbidity and is an independent risk factor of major amputation. In vitro and human observational studies have suggested a role of metformin in preventing VC. The investigators propose to test the effect of metformin treatment during two years on lower limb arterial calcification evaluated by CT-scan in patients with type 1 diabetes and without CKD.
This research is a phase III double blind randomized controlled trial consisting of 2 years double-blind treatment phase (patients randomized to metformin or placebo) in type 1 diabetic patients.
The participants and the investigators will be blinded to the study medications taken during the double-blind treatment period
详细描述
The main objective of this study is to show that metformin, in patients with type 1 diabetes but without chronic kidney disease, is able to slow below- knee arterial calcification evaluated by the difference between below-knee arterial calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin. This research is a phase III double blind randomized controlled trial consisting of 2 years treatment phase (patients randomized to metformin or placebo).The participants and the investigators will be blinded to the study medications taken during the treatment period. The treatment delivered will be metformin vs placebo started at 500 mg per day per os and titrated up to 2000 mg (increase of 500 mg every two weeks). The duration of the treatment will be two years. The main inclusion criteria are: Type 1 diabetes / Women and Men ≥ 18 years old and ≤ 80 years old with complications: diabetic retinopathy and/or nephropathy (with creatinine clearance ≥ 60 mL/mn) and/or neuropathy and/or peripheral arterial occlusive disease and/or cardiopathy and/or stroke and/or cardiovascular risk factors (hypertension and/or dyslipidemia (HDL < 0.35g/L or LDL > 1.9g/L or treated dyslipidemia) and/or tobacco use (old or active smoking greater than 5 pack years))and/or Diabetes duration >20 years.
The secondary objectives and endpoints are: 1. To show that metformin, in patients with type 1 diabetes but without CKD, is able to slow below-knee arterial occlusive disease evaluated by the difference between below-knee arterial ultrasonographic occlusion score at T0 and T2years in type 1 diabetic patients supplemented or not with metformin, 2. To show that metformin, in patients with type 1 diabetes but without CKD, is able to improve ankle and toe brachial indexes evaluated by the difference between ankle and toe brachial indexes at T0 and T2years in type 1 diabetic patients supplemented or not with metformin, 3. To show that metformin, in patients with type 1 diabetes but without CKD, is able to improve pulse wave velocity evaluated by the difference between pulse wave velocity at T0 and T2 years in type 1 diabetic patients supplemented or not with metformin, 4. To show that metformin, in patients with type 1 diabetes but without chronic kidney disease, is able to slow coronary arterial calcification evaluated by the difference between coronary calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin, 5. To conduct a subgroup analysis for the primary outcome to evaluate whether the effect of metformin on the difference of below-knee arterial calcification score evaluated by CT-scan at T0 and T2years varies according to initial below-knee arterial calcification score (≤ versus >400) evaluated by the difference between below-knee arterial calcification score progression between T0 and T2years in type 1 diabetic patients treated or not with metformin and with initial below-knee arterial calcification score ≤ and >400.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Women and Men ≥ 18 years old and ≤ 80 years old with:
- •Complications: diabetic retinopathy and/or nephropathy (with creatinine clearance ≥ 60 mL/mn) and/or neuropathy and/or peripheral arterial occlusive disease and/or cardiopathy and/or stroke and/or
- •cardiovascular risk factors : hypertension and/or dyslipidemia (HDL < 0.35g/L or LDL > 1.9g/L or treated dyslipidemia) and/or tobacco use (old or active smoking greater than 5 pack years) and/or
- •Diabetes duration >20 years
- •For women in childbearing age, effective contraception during the whole trial
- •Signed written informed consent
- •Affiliation of a social security regime (AME excluded)
排除标准
- •Creatinine clearance of less than 3 months <60 mL/mn (MDRD) at the inclusion time
- •Known metformin contra-indication: severe liver insufficiency -CHILD B or C, heart failure (FEVG<45%) or history of pulmonary edema, respiratory insufficiency with history of acute respiratory failure or patients receiving oxygen therapy, chronic ethylism, lactic acidosis
- •Know sensitivity to metformin or to any of its excipients or placebo excipients (lactose)
- •Indication or history of lower limb angioplasty (with stenting) and/or bypass
- •Previous treatment with metformin (within 3 months prior to inclusion)
- •HbA1c of less than 3 months >11%
- •Chronic inflammatory disease or chronic immune-suppressive drugs intake
- •Participation in an another interventional trial (Jardé 1 and 2) or in the exclusion period of any other interventional study
- •Pregnancy woman (confirmed by a sanguine beta-human chorionic gonadotropin test) or breastfeeding woman
- •Patient under legal protection measure (tutorship or curatorship) or deprived of freedom
- •Unable to consent
研究组 & 干预措施
Metformin
Metformin, started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)
干预措施: Metformin (Drug)
Placebo
Placebo (coated tablet similar to metformin tablet titrated following the same schedule as in the experimental arm), started at 500 mg per day per os and titrated up to 2000 mg during 2 years (increase of 500 mg every two weeks)
干预措施: Placebo (Drug)
结局指标
主要结局
Change between below-knee arterial calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.
时间窗: Change between T0 baseline visit and T2 years
Below-knee artery calcification scores will be obtained after scanning with a 128-slice multidetector CT scanner without contrast, in a craniocaudal direction, from the bottom of the patella down to the ankle region. The 3-mm cross-sectional slices were separately analyzed. Analysis was performed by radiologists kept blind about the results of the color duplex ultrasonography, laboratory tests, and clinical examinations, using a commercially available software package (Heartbeat CaScore; Philips Healthcare). On cross-sectional images, areas of calcification along below-knee arteries with a density ≥130 Hounsfield units attenuation and a surface \>1 mm2 were identified automatically. Calcification score, determined according to the method described by Agatston et al, will be obtained separately for each of the main below-knee arteries (distal popliteal, anterior tibial, posterior tibial, and peroneal arteries) and added up to obtain the calc
次要结局
- Change between coronary calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.(Change between T0 baseline visit and T2 years)
- Change between below-knee arterial ultrasonographic occlusion score at T0 and T2years in type 1 diabetic patients treated or not with metformin.(Change between T0 baseline visit and T2 years)
- Change between ankle and toe brachial indexes at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.(Change between T0 baseline visit and T2 years)
- Change between below- knee arterial calcification score progression between T0 and T2years with initial below-knee arterial calcification score ≤ and >400 (subgroup analysis)(Change between T0 baseline visit and T2 years)
- Change between pulse wave velocity at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.(Change between T0 baseline visit and T2 years)