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Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes (IMPACT-1D)

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ClinicalTrials.gov Identifier: NCT04583462
Recruitment Status : Not yet recruiting
First Posted : October 12, 2020
Last Update Posted : October 12, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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. We 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 consiting 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


Condition or disease Intervention/treatment Phase
Peripheral Arterial Calcification in Type 1 Diabetes Drug: Metformin Drug: Placebo Phase 3

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 consiting 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/orcardiovascular 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 230 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Impact of Metformin on Peripheral Arterial Calcification in Type 1 Diabetes: a Double Blind Randomized Controlled Trial
Estimated Study Start Date : December 1, 2020
Estimated Primary Completion Date : July 1, 2024
Estimated Study Completion Date : January 1, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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)
Drug: 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)
Other Name: METFORMINE ARROW LAB 1000 mg

Placebo Comparator: 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)
Drug: Placebo
Control group : 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)
Other Name: Control group




Primary Outcome Measures :
  1. 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. [ Time Frame: Difference 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


Secondary Outcome Measures :
  1. Difference between below-knee arterial ultrasonographic occlusion score at T0 and T2years in type 1 diabetic patients treated or not with metformin. [ Time Frame: Difference between T0 baseline visit and T2 years ]
    Detailed colour duplex ultrasonography will be performed, from the abdominal tree down to the foot arteries, to all the patients, by one physician by center. Occlusive disease will be defined as the presence of either >70% stenosis or an occlusion in any artery being studied (aorto-ilio-femoral segment, popliteal artery, tibio-peroneal trunk, anterior tibial, posterior tibial, peroneal, and dorsalis pedis arteries). The results will be scored according to an adapted version of an angiographic score based on the severity of the stenosis in the lower limb arteries: 0 if stenosis is <70%, 2 if stenosis is >70%, and 3 in case of occlusion. Consequently, duplex scores range from 0 to 39. Mediacalcosis will be also graded for each infrapopliteal artery (popliteal arteries included): 0 if not visible, 1 if mild and discontinuous, 2 if continuous, and 3 if severe with lumen obstruction. Therefore, mediacalcosis scores range from 0 to 36.

  2. Difference between ankle and toe brachial indexes at T0 and T2years in type 1 diabetic patients supplemented or not with metformin. [ Time Frame: Difference between T0 baseline visit and T2 years ]

    Dorsalis pedis, posterior tibial and brachial arterial systolic blood pressures were measured with a Doppler probe (Parks Medical Electronics, Aloha, OR, USA). Measurements will be taken after participants have rested for 10 min in the supine position. Brachial blood pressure will be measured in the dominant arm with an appropriately sized cuff after 10 min rest in the supine position. Two measurements will be obtained and averaged.

    Toe systolic pressure measurements will be taken with the Systoe Automated Toe Pressure System (Atys Medical, Soucieu-en-Jarrest, France)


  3. Difference between pulse wave velocity at T0 and T2years in type 1 diabetic patients supplemented or not with metformin. [ Time Frame: Difference between T0 baseline visit and T2 years ]
    PWV and pulse wave analysis were measured with applanation tonometry, using SphygmoCor system version 7.1 (Atcor Medical). Central arterial pressure (CAP) and central systolic pressure were derived and central augmentation index (AIx) was calculated. As AIx is influenced by heart rate, an index normalized for a heart rate of 75 beats/min was used. To determine pulse wave velocity, pulse wave forms were recorded at the right carotid artery and left femoral artery sequentially. Wave-transit time was calculated using the R-wave of a simultaneously recorded electrocardiogram as a reference frame.

  4. Difference between coronary calcification score evaluated by CT-scan at T0 and T2years in type 1 diabetic patients treated or not with metformin. [ Time Frame: Difference between T0 baseline visit and T2 years ]
    Agatston score is a semi-automated tool to calculate a score based on the extent of coronary artery calcification detected by an unenhanced low-dose CT scan, which is routinely performed in patients undergoing cardiac CT. Coronary artery calcification scores will be obtained after scanning with a 128-slice multidetector CT scanner without contrast, in a craniocaudal direction. Analysis was performed by radiologists kept blind about the results of laboratory tests and clinical examinations, using a commercially available software package (Heartbeat CaScore; Philips Healthcare). On cross-sectional images, areas of calcification along coronary 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 coronary arteries and added up to obtain the total coronary

  5. Difference between below- knee arterial calcification score progression between T0 and T2years with initial below-knee arterial calcification score ≤ and >400 (subgroup analysis) [ Time Frame: Difference between T0 baseline visit and T2 years ]
    Detailed colour duplex ultrasonography will be performed, from the abdominal tree down to the foot arteries, to all the patients, by one physician by center. Occlusive disease will be defined as the presence of either >70% stenosis or an occlusion in any artery being studied (aorto-ilio-femoral segment, popliteal artery, tibio-peroneal trunk, anterior tibial, posterior tibial, peroneal, and dorsalis pedis arteries). The results will be scored according to an adapted version of an angiographic score based on the severity of the stenosis in the lower limb arteries: 0 if stenosis is <70%, 2 if stenosis is >70%, and 3 in case of occlusion. Consequently, duplex scores range from 0 to 39. Mediacalcosis will be also graded for each infrapopliteal artery (popliteal arteries included): 0 if not visible, 1 if mild and discontinuous, 2 if continuous, and 3 if severe with lumen obstruction. Therefore, mediacalcosis scores range from 0 to 36.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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-HCG test) or breastfeeding woman
  10. Patient under legal protection measure (tutorship or curatorship) or deprived of freedom
  11. Unable to consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04583462


Contacts
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Contact: Olivier OB Bourron, Doctor (33)1-42-17-81-18 olivier.bourron@aphp.fr
Contact: Anne AR Radenne, Project Manager (33)1-42-16-16-99 anne.radenne@aphp.fr

Locations
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France
Pitié Salpêtrière Hospital, AP-HP, Diabetology department
Paris, France, 75013
Contact: Olivier OB Bourron, Doctor    (33)1-42-17-81-18    olivier.bourron@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04583462    
Other Study ID Numbers: D20180102
2018-003121-29 ( EudraCT Number )
First Posted: October 12, 2020    Key Record Dates
Last Update Posted: October 12, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Data are available upon reasonable request The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
Access Criteria: Researchers who provide a methodologically sound proposal.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Metformin, Peripheral arterial calcification, type 1 diabete, Placebo
Additional relevant MeSH terms:
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Arteriosclerosis
Diabetes Mellitus
Diabetes Mellitus, Type 1
Calcinosis
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Calcium Metabolism Disorders
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs