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

Phase 3 Study of Metformin in Adults With Type 1 Diabetes

Sponsors

Lead Sponsor: University of Glasgow

Collaborator: NHS Greater Glasgow and Clyde
Juvenile Diabetes Research Foundation
Imperial College London
University of Wisconsin, Madison
University of Dundee
Merck Serono S.A., Geneva
Itamar-Medical, Israel
University of Western Ontario, Canada
University of Melbourne
Steno Diabetes Center Copenhagen
Maastricht University Medical Center

Source University of Glasgow
Brief Summary

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.

Overall Status Completed
Start Date December 2011
Completion Date April 18, 2017
Primary Completion Date March 19, 2017
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) 0, 12 months, 24 months, 36 months
Secondary Outcome
Measure Time Frame
Change in HbA1c Baseline, Year 3
Change in LDL Cholesterol Baseline, Year 3
Change in Estimated Glomerular Filtration Rate 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 Baseline, Year 3
Change in Weight Baseline, Year 1, Year 2, Year 3
Change in Insulin Dose Baseline, Year 1, Year 2, Year 3
Change in Endothelial Function Baseline, Year 1, Year 3
Enrollment 493
Condition
Intervention

Intervention Type: Drug

Intervention Name: Metformin

Description: 3 years treatment duration

Arm Group Label: Metformin

Other Name: Glucophage

Intervention Type: Drug

Intervention Name: Placebo

Description: 3 years duration

Arm Group Label: Placebo

Eligibility

Criteria:

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

Gender: All

Minimum Age: 40 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Location
Facility:
Royal Melbourne Hospital | Melbourne, Australia
St Vincent's Hospital | Melbourne, Australia
Royal Prince Albert Hospital | Sydney, Australia
St Joseph's Health Care | London, Ontario, Canada
Ottawa Hospital Riverside Campus | Ottawa, Canada
Steno Diabetes Centre | Gentofte, Denmark
Maastricht University Medical Centre | Maastricht, Netherlands
Aberdeen Royal Infirmary | Aberdeen, United Kingdom
Ayr Hospital | Ayr, KA6 6DX, United Kingdom
University Hospitals Bristol | Bristol, BS2 8HW, United Kingdom
Diabetes Support Unit, Ninewells Hospital and Medical School | Dundee, United Kingdom
University Hospital North Durham | Durham, United Kingdom
Edinburgh Royal Infirmary | Edinburgh, United Kingdom
Edinburgh Western Infirmary | Edinburgh, United Kingdom
Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust | Exeter, United Kingdom
Stobhill Hospital, Diabetes Clinic | Glasgow, United Kingdom
Gloucestershire Royal Hospital | Gloucester, GL1 3NN, United Kingdom
Michael White Diabetes Centre, Hull Royal Infirmary | Hull, United Kingdom
Clinical Sciences Centre, University Hospital | Liverpool, United Kingdom
Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust | London, United Kingdom
Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary | Manchester, United Kingdom
Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital | Newcastle, United Kingdom
Diabetes Clinical Research Centre, Plymouth | Plymouth, United Kingdom
Salford Royal NHS Foundation Trust | Salford, United Kingdom
Location Countries

Australia

Canada

Denmark

Netherlands

United Kingdom

Verification Date

June 2019

Responsible Party

Type: Principal Investigator

Investigator Affiliation: University of Glasgow

Investigator Full Name: Prof John Petrie

Investigator Title: Clinical Professor in Diabetic Medicine

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Metformin

Type: Experimental

Description: Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily

Label: Placebo

Type: Placebo Comparator

Acronym REMOVAL
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov