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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

Tracking Information
First Submitted Date  ICMJE November 23, 2011
First Posted Date  ICMJE December 1, 2011
Results First Submitted Date  ICMJE September 20, 2018
Results First Posted Date  ICMJE June 3, 2019
Last Update Posted Date June 19, 2019
Study Start Date  ICMJE December 2011
Actual Primary Completion Date March 19, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 30, 2011)
Change in averaged mean far wall common carotid artery IMT [ Time Frame: 0, 12 months, 24 months, 36 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • Change in HbA1c [ Time Frame: Baseline, Year 3 ]
    Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
  • Change in LDL Cholesterol [ Time Frame: Baseline, Year 3 ]
    mmol/L Centrally assayed at the University of Glasgow
  • 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
  • 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.
  • Change in Weight [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Measured at sites using calibrated weighing scales
  • 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
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2011)
  • Change in HbA1c [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
  • Change in LDL Cholesterol [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
  • Change in albuminuria & estimated glomerular filtration rate [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
    Number of participants developing new microalbuminuria; change in absolute concentration
  • Change in Retinopathy Stage [ Time Frame: Baseline, Year 3 ]
    ETDRS grade
  • Change in Weight [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
  • Change in Insulin Dose [ Time Frame: Baseline, Year 1, Year 2, Year 3 ]
  • Change in Endothelial Function [ Time Frame: Baseline, Year 1, Year 3 ]
    RHI units
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
Official Title  ICMJE Phase 3 Study of Metformin in Adults With Type 1 Diabetes
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE
  • Drug: Metformin
    3 years treatment duration
    Other Name: Glucophage
  • Drug: Placebo
    3 years duration
Study Arms  ICMJE
  • Experimental: Metformin
    Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
    Intervention: Drug: Metformin
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications * Petrie JR, Chaturvedi N, Ford I, Brouwers MCGJ, Greenlaw N, Tillin T, Hramiak I, Hughes AD, Jenkins AJ, Klein BEK, Klein R, Ooi TC, Rossing P, Stehouwer CDA, Sattar N, Colhoun HM; REMOVAL Study Group. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):597-609. doi: 10.1016/S2213-8587(17)30194-8. Epub 2017 Jun 11. Erratum in: Lancet Diabetes Endocrinol. 2017 Aug;5(8):e5. Lancet Diabetes Endocrinol. 2017 Nov;5(11):e7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 18, 2019)
493
Original Estimated Enrollment  ICMJE
 (submitted: November 30, 2011)
500
Actual Study Completion Date  ICMJE April 18, 2017
Actual Primary Completion Date March 19, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Denmark,   Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01483560
Other Study ID Numbers  ICMJE GN10DI406
2011-000300-18 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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.
Responsible Party Prof John Petrie, University of Glasgow
Study Sponsor  ICMJE University of Glasgow
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: John Petrie, Prof University of Glasgow
Study Director: Helen Colhoun, Prof University of Dundee
PRS Account University of Glasgow
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP