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

Diabetes Mellitus, Type 1 Clinical Trial

— REMOVAL  

Official title:

Phase 3 Study of Metformin in Adults With Type 1 Diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01483560
• Other study ID #: GN10DI406
• Secondary ID: 2011-000300-18
• Status: Completed
• Phase: Phase 3
• Start date: December 2011
• Est. completion date: April 18, 2017

Study information

• Verified date: June 2019
• Source: University of Glasgow
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 493
• Est. completion date: April 18, 2017
• Est. primary completion date: March 19, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• Metformin
3 years treatment duration
• Placebo
3 years duration

Locations

Country	Name	City	State
Australia	Royal Melbourne Hospital	Melbourne
Australia	St Vincent's Hospital	Melbourne
Australia	Royal Prince Albert Hospital	Sydney
Canada	St Joseph's Health Care	London	Ontario
Canada	Ottawa Hospital Riverside Campus	Ottawa
Denmark	Steno Diabetes Centre	Gentofte
Netherlands	Maastricht University Medical Centre	Maastricht
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Ayr Hospital	Ayr
United Kingdom	University Hospitals Bristol	Bristol
United Kingdom	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	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

Sponsors (12)

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

Countries where clinical trial is conducted

Australia,  Canada,  Denmark,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	0, 12 months, 24 months, 36 months
Secondary	Change in HbA1c	Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.	Baseline, Year 3
Secondary	Change in LDL Cholesterol	mmol/L Centrally assayed at the University of Glasgow	Baseline, Year 3
Secondary	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	Baseline, Year 1, Year 2, Year 3
Secondary	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.	Baseline, Year 3
Secondary	Change in Weight	Measured at sites using calibrated weighing scales	Baseline, Year 1, Year 2, Year 3
Secondary	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	Baseline, Year 1, Year 2, Year 3
Secondary	Change in Endothelial Function	In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)	Baseline, Year 1, Year 3