Back to resultsREducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) (REMOVAL)
Primary Purpose
Diabetes Mellitus, Type 1
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Metformin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c
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
Sites / Locations
- Royal Melbourne Hospital
- St Vincent's Hospital
- Royal Prince Albert Hospital
- St Joseph's Health Care
- Ottawa Hospital Riverside Campus
- Steno Diabetes Centre
- Maastricht University Medical Centre
- Aberdeen Royal Infirmary
- Ayr Hospital
- University Hospitals Bristol
- Diabetes Support Unit, Ninewells Hospital and Medical School
- University Hospital North Durham
- Edinburgh Royal Infirmary
- Edinburgh Western Infirmary
- Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust
- Stobhill Hospital, Diabetes Clinic
- Gloucestershire Royal Hospital
- Michael White Diabetes Centre, Hull Royal Infirmary
- Clinical Sciences Centre, University Hospital
- Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust
- Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary
- Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital
- Diabetes Clinical Research Centre, Plymouth
- Salford Royal NHS Foundation Trust
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Metformin
Placebo
Arm Description
Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
Outcomes
Primary Outcome Measures
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
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
Change in HbA1c
Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Change in LDL Cholesterol
mmol/L Centrally assayed at the University of Glasgow
Change in Estimated Glomerular Filtration Rate
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
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
Measured at sites using calibrated weighing scales
Change in Insulin Dose
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
In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Full Information
NCT ID
NCT01483560
First Posted
November 23, 2011
Last Updated
June 4, 2019
Sponsor
University of Glasgow
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
1. Study Identification
Unique Protocol Identification Number
NCT01483560
Brief Title
REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
Acronym
REMOVAL
Official Title
Phase 3 Study of Metformin in Adults With Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
June 2019
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
March 19, 2017 (Actual)
Study Completion Date
April 18, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Glasgow
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
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
493 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metformin
Arm Type
Experimental
Arm Description
Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Metformin
Other Intervention Name(s)
Glucophage
Intervention Description
3 years treatment duration
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
3 years duration
Primary Outcome Measure Information:
Title
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
Description
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.
Time Frame
0, 12 months, 24 months, 36 months
Secondary Outcome Measure Information:
Title
Change in HbA1c
Description
Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Time Frame
Baseline, Year 3
Title
Change in LDL Cholesterol
Description
mmol/L Centrally assayed at the University of Glasgow
Time Frame
Baseline, Year 3
Title
Change in Estimated Glomerular Filtration Rate
Description
Number of participants developing new microalbuminuria; change in absolute concentration Calculated using the MDRD equation1 based on creatinine measured in accredited local laboratories
Time Frame
Baseline, Year 1, Year 2, Year 3
Title
Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
Description
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.
Time Frame
Baseline, Year 3
Title
Change in Weight
Description
Measured at sites using calibrated weighing scales
Time Frame
Baseline, Year 1, Year 2, Year 3
Title
Change in Insulin Dose
Description
Units/ kg body weight Extracted by study nurses from the Study Diary and reported on the study CRF using dedicated fields
Time Frame
Baseline, Year 1, Year 2, Year 3
Title
Change in Endothelial Function
Description
In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Time Frame
Baseline, Year 1, Year 3
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Petrie, Prof
Organizational Affiliation
University of Glasgow
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Helen Colhoun, Prof
Organizational Affiliation
University of Dundee
Official's Role
Study Director
Facility Information:
Facility Name
Royal Melbourne Hospital
City
Melbourne
Country
Australia
Facility Name
St Vincent's Hospital
City
Melbourne
Country
Australia
Facility Name
Royal Prince Albert Hospital
City
Sydney
Country
Australia
Facility Name
St Joseph's Health Care
City
London
State/Province
Ontario
Country
Canada
Facility Name
Ottawa Hospital Riverside Campus
City
Ottawa
Country
Canada
Facility Name
Steno Diabetes Centre
City
Gentofte
Country
Denmark
Facility Name
Maastricht University Medical Centre
City
Maastricht
Country
Netherlands
Facility Name
Aberdeen Royal Infirmary
City
Aberdeen
Country
United Kingdom
Facility Name
Ayr Hospital
City
Ayr
ZIP/Postal Code
KA6 6DX
Country
United Kingdom
Facility Name
University Hospitals Bristol
City
Bristol
ZIP/Postal Code
BS2 8HW
Country
United Kingdom
Facility Name
Diabetes Support Unit, Ninewells Hospital and Medical School
City
Dundee
Country
United Kingdom
Facility Name
University Hospital North Durham
City
Durham
Country
United Kingdom
Facility Name
Edinburgh Royal Infirmary
City
Edinburgh
Country
United Kingdom
Facility Name
Edinburgh Western Infirmary
City
Edinburgh
Country
United Kingdom
Facility Name
Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust
City
Exeter
Country
United Kingdom
Facility Name
Stobhill Hospital, Diabetes Clinic
City
Glasgow
Country
United Kingdom
Facility Name
Gloucestershire Royal Hospital
City
Gloucester
ZIP/Postal Code
GL1 3NN
Country
United Kingdom
Facility Name
Michael White Diabetes Centre, Hull Royal Infirmary
City
Hull
Country
United Kingdom
Facility Name
Clinical Sciences Centre, University Hospital
City
Liverpool
Country
United Kingdom
Facility Name
Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust
City
London
Country
United Kingdom
Facility Name
Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary
City
Manchester
Country
United Kingdom
Facility Name
Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital
City
Newcastle
Country
United Kingdom
Facility Name
Diabetes Clinical Research Centre, Plymouth
City
Plymouth
Country
United Kingdom
Facility Name
Salford Royal NHS Foundation Trust
City
Salford
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Site specific participant data will be made available to the site PIs later in 2017, after the main publications.
Citations:
PubMed Identifier
28615149
Citation
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.
Results Reference
derived
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REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
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