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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.
 
ClinicalTrials.gov Identifier: NCT01483560
Recruitment Status : Completed
First Posted : December 1, 2011
Results First Posted : June 3, 2019
Last Update Posted : June 19, 2019
Sponsor:
Collaborators:
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

Study Description
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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

Study Design
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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

Arms and Interventions
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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


Outcome Measures
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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)


Eligibility Criteria
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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
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
Contacts and Locations
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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): NCT01483560


Locations
Show Show 24 study locations
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
Investigators
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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

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Prof John Petrie, Clinical Professor in Diabetic Medicine, University of Glasgow
ClinicalTrials.gov Identifier: NCT01483560    
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:
REMOVAL
metformin
carotid IMT
LDL Cholesterol
 endothelial function
retinopathy
HbA1c
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
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs