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

June 4, 2019 updated by: Prof John Petrie, University of Glasgow

Phase 3 Study of Metformin in Adults With Type 1 Diabetes

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

493

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Drug: Placebo
3 years duration
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 Names:
  • Glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
0, 12 months, 24 months, 36 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in HbA1c
Time Frame: Baseline, Year 3
Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Baseline, Year 3
Change in LDL Cholesterol
Time Frame: Baseline, Year 3
mmol/L Centrally assayed at the University of Glasgow
Baseline, Year 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
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
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.
Baseline, Year 3
Change in Weight
Time Frame: Baseline, Year 1, Year 2, Year 3
Measured at sites using calibrated weighing scales
Baseline, Year 1, Year 2, Year 3
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
Baseline, Year 1, Year 2, Year 3
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)
Baseline, Year 1, Year 3

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Glasgow

Collaborators

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

Investigators

  • Principal Investigator: John Petrie, Prof, University of Glasgow
  • Study Director: Helen Colhoun, Prof, University of Dundee

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2011

Primary Completion (Actual)

March 19, 2017

Study Completion (Actual)

April 18, 2017

Study Registration Dates

First Submitted

November 23, 2011

First Submitted That Met QC Criteria

November 30, 2011

First Posted (Estimate)

December 1, 2011

Study Record Updates

Last Update Posted (Actual)

June 19, 2019

Last Update Submitted That Met QC Criteria

June 4, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GN10DI406
  • 2011-000300-18 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Site specific participant data will be made available to the site PIs later in 2017, after the main publications.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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