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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01483560
Recruitment Status : Completed
First Posted : December 1, 2011
Results First Posted : June 3, 2019
Last Update Posted : June 19, 2019
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
Information provided by (Responsible Party):
Prof John Petrie, 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.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 1 Drug: Metformin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 493 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Phase 3 Study of Metformin in Adults With Type 1 Diabetes
Study Start Date : December 2011
Actual Primary Completion Date : March 19, 2017
Actual Study Completion Date : April 18, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: Metformin
Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
Drug: Metformin
3 years treatment duration
Other Name: Glucophage

Placebo Comparator: Placebo Drug: Placebo
3 years duration

Primary Outcome Measures :
  1. Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) [ Time Frame: 0, 12 months, 24 months, 36 months ]
    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.

Secondary Outcome Measures :
  1. Change in HbA1c [ Time Frame: Baseline, Year 3 ]
    Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.

  2. Change in LDL Cholesterol [ Time Frame: Baseline, Year 3 ]
    mmol/L Centrally assayed at the University of Glasgow

  3. Change in Estimated Glomerular Filtration Rate [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories

  4. Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months [ Time Frame: Baseline, Year 3 ]
    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.

  5. Change in Weight [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Measured at sites using calibrated weighing scales

  6. Change in Insulin Dose [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields

  7. Change in Endothelial Function [ Time Frame: Baseline, Year 1, Year 3 ]
    In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT01483560

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Royal Melbourne Hospital
Melbourne, Australia
St Vincent's Hospital
Melbourne, Australia
Royal Prince Albert Hospital
Sydney, Australia
Canada, Ontario
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
United Kingdom
Aberdeen Royal Infirmary
Aberdeen, United Kingdom
Ayr Hospital
Ayr, United Kingdom, KA6 6DX
University Hospitals Bristol
Bristol, United Kingdom, BS2 8HW
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, United Kingdom, GL1 3NN
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
Sponsors and Collaborators
University of Glasgow
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
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Principal Investigator: John Petrie, Prof University of Glasgow
Study Director: Helen Colhoun, Prof University of Dundee
  Study Documents (Full-Text)

Documents provided by Prof John Petrie, University of Glasgow:
Study Protocol  [PDF] November 9, 2015
Statistical Analysis Plan  [PDF] April 7, 2017

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Prof John Petrie, Clinical Professor in Diabetic Medicine, University of Glasgow Identifier: NCT01483560     History of Changes
Other Study ID Numbers: GN10DI406
2011-000300-18 ( EudraCT Number )
First Posted: December 1, 2011    Key Record Dates
Results First Posted: June 3, 2019
Last Update Posted: June 19, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Site specific participant data will be made available to the site PIs later in 2017, after the main publications.
Keywords provided by Prof John Petrie, University of Glasgow:
carotid IMT
LDL Cholesterol
endothelial function
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Hypoglycemic Agents
Physiological Effects of Drugs