REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)

Study Overview
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Brief Summary
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The trial is conducted in the United Kingdom (UK), Australia, Canada, Denmark and the Netherlands. The aim is to test whether 3 years treatment with metformin added to titrated insulin therapy (towards target HbA1c 7.0%/53 mmol/mol) reduces atherosclerosis, as measured by progression of carotid intima-media thickness (cIMT), in adults with confirmed type 1 diabetes aged 40 years and over at increased risk for cardiovascular disease.

Official Title
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Phase 3 Study of Metformin in Adults With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 Diabetes for five years or more* Age 40 years or above 7.0 =< HbA1c <10.0% (53 - 86 mmol/mol) AND 3 or more of the following ten CardioVascular Disease (CVD) risk factors: BMI >27 kg/m^2 Current HbA1c >8.0% (64 mmol/mol) Known CVD/peripheral vascular disease Current smoker Estimated glomerular filtration rate (eGFR) <90 ml/min per 1.73 m^3 Confirmed micro- or macroalbuminuria [according to local assays and reference ranges] Hypertension (BP >=140/90 millimeters of mercury (mmHg) or established on antihypertensive treatment) Dyslipidaemia [total cholesterol >=5.0 mmol/L (200 mg/dL);OR HDL cholesterol <1.20 mmol/L (46mg/dL) [MEN]; OR <1.30 mmol/L (50 mg/dL) [WOMEN]; or triglycerides >=1.7 mmol/L (150mg/dL); or established on lipid-lowering treatment)] Strong family history of CVD (at least one parent, biological aunt/ uncle, or sibling with myocardial infarction or stroke aged <60 years) Duration of diabetes > 20 years Exclusion Criteria: eGFR < 45 ml/min/1.73m2 woman of childbearing age not on effective contraception Pregnancy and/or lactation Acute coronary syndrome or Stroke/Transient Ischaemic Attack within the last three months NYHA stage 3 or 4 heart failure Significant hypoglycaemia unawareness Impaired cognitive function/ unable to give informed consent Previous carotid surgery/ inability to capture adequate carotid images Estimated glomerular filtration < 45ml/min/1.73m^2 (MDRD) Gastroparesis History of lactic acidosis Other contraindications to metformin (hepatic impairment, known hypersensitivity to metformin, acute illness such as dehydration, severe infection, shock, acute cardiac failure or suspected tissue hypoxia) Any coexistent life threatening condition including prior diagnosis of cancer within two years History of alcohol problem or drug abuse

Ages Eligible for Study
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Minimum Age: 40 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 |
| --- | --- |
| Experimental: Metformin<br>Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily | Drug: Metformin<br>* 3 years treatment duration<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 3 years duration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) | Progression of averaged mean far wall common carotid artery intima media thickness IMT (mean cIMT) measured using B mode ultrasonography with a 7.0 MHz or higher broadband linear array transducer and concurrent recording of 3-lead electrocardiogram (ECG). Longitudinal images of the common carotid artery will be obtained at anterior, lateral and posterior angles at baseline, 12, 24 and 36 months using Meijer's arc to standardize the transducer angle. | 0, 12 months, 24 months, 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c | Measured in accredited local laboratories participating in DCCT-aligned quality control programmes. | Baseline, Year 3 | 
| Change in LDL Cholesterol | mmol/L Centrally assayed at the University of Glasgow | Baseline, Year 3 | 
| Change in Estimated Glomerular Filtration Rate | Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories | Baseline, Year 1, Year 2, Year 3 | 
| Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months | Two color 45° field retinal photographs (fields 1 and 2) from each eye at 0 and 36 months graded at the University of Wisconsin Ocular Epidemiology Reading Center (OERC) using the modified Airlie House classification scheme and the Early Treatment Diabetic Retinopathy Severity scale. | Baseline, Year 3 | 
| Change in Weight | Measured at sites using calibrated weighing scales | Baseline, Year 1, Year 2, Year 3 | 
| Change in Insulin Dose | Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields | Baseline, Year 1, Year 2, Year 3 | 
| Change in Endothelial Function | In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel) | Baseline, Year 1, Year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c