Clinical trial NCT04583462: Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes
Official title: Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes: a Double Blind Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Type 1 Diabetes
Peripheral Arterial Calcification
Keywords: Metformin
Peripheral arterial calcification
Type 1 diabetes
Placebo
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-10-12
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Type 1 diabetes
2. 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
3. For women in childbearing age, effective contraception during the whole trial
4. Signed written informed consent
5. Affiliation of a social security regime (AME excluded)

Exclusion Criteria:

1. Creatinine clearance of less than 3 months \<60 mL/mn (MDRD) at the inclusion time
2. 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
3. Know sensitivity to metformin or to any of its excipients or placebo excipients (lactose)
4. Indication or history of lower limb angioplasty (with stenting) and/or bypass
5. Previous treatment with metformin (within 3 months prior to inclusion)
6. HbA1c of less than 3 months \>11%
7. Chronic inflammatory disease or chronic immune-suppressive drugs intake
8. Participation in an another interventional trial (Jardé 1 and 2) or in the exclusion period of any other interventional study
9. Pregnancy woman (confirmed by a sanguine beta-human chorionic gonadotropin test) or breastfeeding woman
10. Patient under legal protection measure (tutorship or curatorship) or deprived of freedom
11. Unable to consent

Primary outcomes:
measure: 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.
timeFrame: Change between T0 baseline visit and T2 years
Secondary outcomes:
measure: Change between below-knee arterial ultrasonographic occlusion score at T0 and T2years in type 1 diabetic patients treated or not with metformin.
timeFrame: Change between T0 baseline visit and T2 years
measure: Change between ankle and toe brachial indexes at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.
timeFrame: Change between T0 baseline visit and T2 years
measure: Change between pulse wave velocity at T0 and T2years in type 1 diabetic patients supplemented or not with metformin.
timeFrame: Change between T0 baseline visit and T2 years
measure: Change between coronary calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin.
timeFrame: Change between T0 baseline visit and T2 years
measure: Change between below- knee arterial calcification score progression between T0 and T2years with initial below-knee arterial calcification score ≤ and >400 (subgroup analysis)
timeFrame: Change between T0 baseline visit and T2 years
Other outcomes:
Locations:
city: Paris
country: France
facility: Pitié Salpêtrière Hospital, AP-HP, Diabetology department
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Olivier OB Bourron, Doctor
role: PRINCIPAL_INVESTIGATOR
References: