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CompletedNCT01483560REMOVALUpdated Jun 19, 2019Results posted

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

A Phase 3 interventional study of Metformin and Placebo in Diabetes Mellitus, Type 1, sponsored by University of Glasgow. Completed at 24 sites in 5 countries. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2019-06-19.

Sponsored by University of Glasgow · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
493
Allocation
Randomized
Ages
40 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Diabetes Mellitus, Type 1

Keywords

  • REMOVAL
  • metformin
  • carotid IMT
  • LDL Cholesterol
  • endothelial function
  • retinopathy
  • HbA1c
03

In context

Diabetes Mellitus

10,925 studies on the registry are indexed under Diabetes Mellitus; 1,319 are open to participants now.

This study's enrollment of 493 is above the median of 80 across 8,367 interventional studies indexed under Diabetes Mellitus.

Browse Diabetes Mellitus studies →

Lead sponsor

University of Glasgow is the lead sponsor of 141 studies on the registry; 20 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
40 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Triple (Participant, Care provider, Investigator)
Enrollment
493 participants (actual)

Study arms

  • Experimental
    Metformin

    Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily

    Drug: Metformin

  • Placebo comparator
    Placebo

    Drug: Placebo

Interventions

  • DrugMetformin

    3 years treatment duration

    Also known as: Glucophage

  • DrugPlacebo

    3 years duration

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: 0, 12 months, 24 months, 36 months

Secondary outcomes

  1. Change in HbA1c

    Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.

    Time frame: Baseline, Year 3

  2. Change in LDL Cholesterol

    mmol/L Centrally assayed at the University of Glasgow

    Time frame: Baseline, Year 3

  3. 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

    Time frame: Baseline, Year 1, Year 2, Year 3

  4. 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.

    Time frame: Baseline, Year 3

  5. Change in Weight

    Measured at sites using calibrated weighing scales

    Time frame: Baseline, Year 1, Year 2, Year 3

  6. 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

    Time frame: Baseline, Year 1, Year 2, Year 3

  7. Change in Endothelial Function

    In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)

    Time frame: Baseline, Year 1, Year 3

07

Results

Posted Jun 3, 2019

Participant flow

Participant flow — Overall Study
MilestoneMetforminPlacebo
Started219209
Completed193194
Not completed2615

Outcome measures

PrimaryChange 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.

Time frame:
0, 12 months, 24 months, 36 months
Reported as:
Mean · mm
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
mmMetforminPlacebo
Baseline0.773 ± 0.140.791 ± 0.183
12 Months0.782 ± 0.1470.788 ± 0.174
24 Months0.792 ± 0.1450.823 ± 0.187
36 Months0.793 ± 0.1340.820 ± 0.177
SecondaryChange in HbA1c

Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.

Time frame:
Baseline, Year 3
Reported as:
Mean · %units
Change in HbA1c
%unitsMetforminPlacebo
Baseline8.1 ± 0.98.0 ± 0.8
36 Months8.1 ± 0.98.1 ± 0.8
SecondaryChange in LDL Cholesterol

mmol/L Centrally assayed at the University of Glasgow

Time frame:
Baseline, Year 3
Reported as:
Mean · mmol/L
Change in LDL Cholesterol
mmol/LMetforminPlacebo
Baseline2.23 ± 0.72.25 ± 0.72
36 Months2.07 ± 0.832.21 ± 0.71
SecondaryChange 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

Time frame:
Baseline, Year 1, Year 2, Year 3
Reported as:
Mean · ml/min/1.73m2
Change in Estimated Glomerular Filtration Rate
ml/min/1.73m2MetforminPlacebo
Baseline92.9 ± 20.991.1 ± 21.6
36 Months92.1 ± 20.887.2 ± 19.6
SecondaryNumber 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.

Time frame:
Baseline, Year 3
Reported as:
Count of participants · Participants
Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
ParticipantsMetforminPlacebo
Baseline191190
36 Months810
SecondaryChange in Weight

Measured at sites using calibrated weighing scales

Time frame:
Baseline, Year 1, Year 2, Year 3
Reported as:
Mean · kg
Change in Weight
kgMetforminPlacebo
Baseline83.9 ± 15.483.5 ± 13.7
36 Months82.0 ± 15.483.2 ± 13.8
SecondaryChange in Insulin Dose

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
Reported as:
Mean · units/kg
Change in Insulin Dose
units/kgMetforminPlacebo
Baseline0.36 ± 0.260.68 ± 0.30
36 Months0.62 ± 0.260.67 ± 0.30
SecondaryChange in Endothelial Function

In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)

Time frame:
Baseline, Year 1, Year 3
Reported as:
Mean · RHI (Arbitrary units)
Change in Endothelial Function
RHI (Arbitrary units)MetforminPlacebo
Baseline2.28 ± 0.742.24 ± 0.75
36 Months2.17 ± 0.692.24 ± 0.73

Adverse events

Collected over Adverse event data collected from the date of consent until 30 days post last IMP dose, an average of 3 years.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Metformin5/219 (2.3%)34/219 (15.5%)112/219 (51.1%)
Placebo2/209 (1%)31/209 (14.8%)52/209 (24.9%)
Most frequent serious events
Showing 10 of 30
Most frequent serious events
EventMetforminPlacebo
Metabolic and nutritionMetabolism and nutrition disorders8/2195/209
Infections and InfestationsInfections and infestations7/2195/209
CardiacCardiac disorders3/2196/209
NeoplasmsNeoplasms benign, malignant and unspecified (incl cysts and polyps)6/2193/209
GastrointestinalGastrointestinal disorders4/2195/209
RespiratoryRespiratory, thoracic and mediastinal disorders1/2195/209
InjuryInjury, poisoning and procedural complications3/2193/209
MusculoskeletalMusculoskeletal and connective tissue disorders1/2192/209
Cerebrovascular accidentNervous system disorders1/2192/209
Transient Ischaemic AttackNervous system disorders2/2191/209
Most frequent other events
Most frequent other events
EventMetforminPlacebo
GastrointestinalGastrointestinal disorders88/21918/209
Opthalmic adverse eventsEye disorders18/21932/209
Hypersensitivity to MetforminProduct Issues5/2191/209
CardiovascularCardiac disorders1/2191/209
NeurologicalNervous system disorders0/2190/209

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)MetforminPlaceboTotal
<=18 years000
Between 18 and 65 years219209428
>=65 years000
Age, Continuous
Age, Continuous(years)MetforminPlaceboTotal
Mean55.2 ± 8.555.8 ± 8.855.5 ± 8.7
Sex: Female, Male
Sex: Female, Male(Participants)MetforminPlaceboTotal
Female9085175
Male129124253
Race and Ethnicity Not Collected
Race and Ethnicity Not Collected(Participants)MetforminPlaceboTotal
Count of participants——0
Region of Enrollment
Region of Enrollment(participants)MetforminPlaceboTotal
Canada5555110
Netherlands161531
Denmark448
United Kingdom112105217
Australia323062
Diabetes Diagnosis Duration
Diabetes Diagnosis Duration(years)MetforminPlaceboTotal
Mean33.4 ± 1134.3 ± 10.533.85 ± 10.75
Existing Cardiovascular Disease
Existing Cardiovascular Disease(participants)MetforminPlaceboTotal
Number302252
Baseline HbA1c
Baseline HbA1c(mmol/mol)MetforminPlaceboTotal
Number64.864.764.75

6 further baseline measures are reported on the registry.

08

Study locations

24 sites
  • Royal Melbourne Hospital
    Melbourne, Australia
  • St Vincent's Hospital
    Melbourne, Australia
  • Royal Prince Albert Hospital
    Sydney, Australia
  • St Joseph's Health Care
    London, Ontario, Canada
  • Ottawa Hospital Riverside Campus
    Ottawa, Canada
  • Steno Diabetes Centre
    Gentofte, Denmark
  • Maastricht University Medical Centre
    Maastricht, Netherlands
  • Aberdeen Royal Infirmary
    Aberdeen, United Kingdom
  • Ayr Hospital
    Ayr, KA6 6DX, United Kingdom
  • University Hospitals Bristol
    Bristol, BS2 8HW, 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, GL1 3NN, 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, United Kingdom
09

References and documents

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. doi: 10.1016/S2213-8587(17)30229-2. Lancet Diabetes Endocrinol. 2017 Nov;5(11):e7. doi: 10.1016/S2213-8587(17)30340-6. PubMed 28615149 ↗

Study documents

  • Study protocol · Nov 9, 2015
  • Statistical analysis plan · Apr 7, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Site specific participant data will be made available to the site PIs later in 2017, after the main publications.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 19, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT01483560
Lead 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
Responsible party
Prof John Petrie (Clinical Professor in Diabetic Medicine, University of Glasgow) — Principal investigator
First posted
Dec 1, 2011
Start date
Dec 2011
Primary completion
Mar 19, 2017
Completion
Apr 18, 2017
Results posted
Jun 3, 2019
Last update
Jun 19, 2019

Study contacts

John Petrie, Prof
principal investigator · University of Glasgow
Helen Colhoun, Prof
study director · University of Dundee

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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