Clinical trial NCT01483560: REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
Official title: Phase 3 Study of Metformin in Adults With Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 1
Keywords: REMOVAL
metformin
carotid IMT
LDL Cholesterol
endothelial function
retinopathy
HbA1c
Lead sponsor: University of Glasgow
Sponsor class: OTHER
Collaborators: name: NHS Greater Glasgow and Clyde
name: Juvenile Diabetes Research Foundation
name: Imperial College London
name: University of Wisconsin, Madison
name: University of Dundee
name: Merck Serono S.A., Geneva
name: Itamar-Medical, Israel
name: University of Western Ontario, Canada
name: University of Melbourne
name: Steno Diabetes Center Copenhagen
name: Maastricht University Medical Center
First posted: 2011-12-01
Enrollment: 493
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
timeFrame: 0, 12 months, 24 months, 36 months
Secondary outcomes:
measure: Change in HbA1c
timeFrame: Baseline, Year 3
measure: Change in LDL Cholesterol
timeFrame: Baseline, Year 3
measure: Change in Estimated Glomerular Filtration Rate
timeFrame: Baseline, Year 1, Year 2, Year 3
measure: Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
timeFrame: Baseline, Year 3
measure: Change in Weight
timeFrame: Baseline, Year 1, Year 2, Year 3
measure: Change in Insulin Dose
timeFrame: Baseline, Year 1, Year 2, Year 3
measure: Change in Endothelial Function
timeFrame: Baseline, Year 1, Year 3
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
city: Melbourne
country: Australia
facility: St Vincent's Hospital
city: Sydney
country: Australia
facility: Royal Prince Albert Hospital
city: London
country: Canada
facility: St Joseph's Health Care
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Riverside Campus
city: Gentofte
country: Denmark
facility: Steno Diabetes Centre
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Ayr
country: United Kingdom
facility: Ayr Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol
city: Dundee
country: United Kingdom
facility: Diabetes Support Unit, Ninewells Hospital and Medical School
city: Durham
country: United Kingdom
facility: University Hospital North Durham
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary
city: Edinburgh
country: United Kingdom
facility: Edinburgh Western Infirmary
city: Exeter
country: United Kingdom
facility: Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Stobhill Hospital, Diabetes Clinic
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Hull
country: United Kingdom
facility: Michael White Diabetes Centre, Hull Royal Infirmary
city: Liverpool
country: United Kingdom
facility: Clinical Sciences Centre, University Hospital
city: London
country: United Kingdom
facility: Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary
city: Newcastle
country: United Kingdom
facility: Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital
city: Plymouth
country: United Kingdom
facility: Diabetes Clinical Research Centre, Plymouth
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust
Study officials:
affiliation: University of Glasgow
name: John Petrie, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Dundee
name: Helen Colhoun, Prof
role: STUDY_DIRECTOR
References:
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.