Diabetes Mellitus, Type 1Phase 3REMOVALNCT01483560
REducing With MetfOrmin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL)
A Phase 3 study testing Metformin in people with Diabetes Mellitus, Type 1, run by University of Glasgow at 24 sites in 5 countries.
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… Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Diabetes Mellitus, Type 1
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 493 participants
- Where
- 24 sitesin 5 countries
- Study dates
- Dec 2011to 18 Apr 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
24 sites in 5 countries.
24 sites in 5 countries
United Kingdom17 sites
Aberdeen Royal Infirmary
Aberdeen
Ayr Hospital
Ayr, KA6 6DX
University Hospitals Bristol
Bristol, BS2 8HW
Diabetes Support Unit, Ninewells Hospital and Medical School
Dundee
University Hospital North Durham
Durham
Edinburgh Royal Infirmary
Edinburgh
Edinburgh Western Infirmary
Edinburgh
Peninsula NIHR Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust
Exeter
Stobhill Hospital, Diabetes Clinic
Glasgow
Gloucestershire Royal Hospital
Gloucester, GL1 3NN
Michael White Diabetes Centre, Hull Royal Infirmary
Hull
Clinical Sciences Centre, University Hospital
Liverpool
Clinical Investigation Unit, International Centre for Circulatory Health, Imperial College Healthcare NHS Trust
London
Wellcome Trust Clinical Research Facility, Manchester Royal Infirmary
Manchester
Newcastle NIHR Clinical Research Facility, Royal Victoria Hospital
Newcastle
Diabetes Clinical Research Centre, Plymouth
Plymouth
Salford Royal NHS Foundation Trust
Salford
Australia3 sites
Royal Melbourne Hospital
Melbourne
St Vincent's Hospital
Melbourne
Royal Prince Albert Hospital
Sydney
Canada2 sites
St Joseph's Health Care
London, Ontario
Ottawa Hospital Riverside Campus
Ottawa
About this study
Official title: Phase 3 Study of Metformin in Adults With Type 1 Diabetes
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.
- Conditions
- Diabetes Mellitus, Type 1
- Being tested
- Metformin, Placebo
- Keywords
- REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c
- Medical subject headings
- Diabetes Mellitus, Type 1, Retinal Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage
3 years treatment duration
PlaceboDrug
3 years duration
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily Receives: Drug: Metformin |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 0, 12 months, 24 months, 36 months
Secondary outcomes (7)
Change in HbA1c
Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Measured: Baseline, Year 3
Change in LDL Cholesterol
mmol/L Centrally assayed at the University of Glasgow
Measured: Baseline, Year 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
Measured: Baseline, Year 1, Year 2, Year 3
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.
Measured: Baseline, Year 3
Change in Weight
Measured at sites using calibrated weighing scales
Measured: Baseline, Year 1, Year 2, Year 3
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
Measured: Baseline, Year 1, Year 2, Year 3
Change in Endothelial Function
In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Measured: Baseline, Year 1, Year 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2011 (estimated)
- Study startDec 2011
- Primary completion19 Mar 2017
- Study completion18 Apr 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 1Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 493 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Glasgow
- Sponsor type
- University, hospital or other
- 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
- Principal investigator, Prof John Petrie, University of Glasgow
- Investigators
- John Petrie, Prof, Principal investigator, University of GlasgowHelen Colhoun, Prof, Study director, University of Dundee
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01483560
- Sponsor's protocol ID
- GN10DI406
- Other IDs
- 2011-000300-18
- Acronym
- REMOVAL
- Status last verified
- Jun 2019
- First submitted
- 23 Nov 2011
- Last updated
- 19 Jun 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: Site specific participant data will be made available to the site PIs later in 2017, after the main publications.
Publications
El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.
PubMed 38837240Petrie 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.
PubMed 28615149
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 3 Study of Metformin in Adults With Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT01483560
- Acronym / sponsor ID
- REMOVAL / GN10DI406
- Conditions
- Diabetes Mellitus, Type 1
- Keywords
- REMOVAL, metformin, carotid IMT, LDL Cholesterol, endothelial function, retinopathy, HbA1c
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 493 participants (actual)
- Lead sponsor
- University of GlasgowUniversity, hospital or other
- 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
- Study start
- Dec 2011
- Primary completion
- 19 Mar 2017 (actual)
- Study completion
- 18 Apr 2017 (actual)
- First posted
- 1 Dec 2011 (estimated)
- Results
- Posted 3 Jun 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: MetforminOral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Type 1 Diabetes for five years or more*
- Age 40 years or above
- 7.0 =< HbA1c <10.0% (53 - 86 mmol/mol)
- BMI >27 kg/m^2
- Current HbA1c >8.0% (64 mmol/mol)
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: Glucophage3 years treatment duration | Drug | Metformin |
| Placebo3 years duration | Drug | Placebo |
Primary outcome
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.
7 secondary outcomes
Change in HbA1c
Time frame: Baseline, Year 3
Change in LDL Cholesterol
Time frame: Baseline, Year 3
Change in Estimated Glomerular Filtration Rate
Time frame: Baseline, Year 1, Year 2, Year 3
Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
Time frame: Baseline, Year 3
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38837240El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.
- Derived from this study: PubMed 28615149Petrie 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.
- Individual participant dataSharing planned: Yes. Site specific participant data will be made available to the site PIs later in 2017, after the main publications.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John Petrie, Prof principal investigator
University of Glasgow
Helen Colhoun, Prof study director
University of Dundee
24 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Metformin in people with Diabetes Mellitus, Type 1, run by University of Glasgow at 24 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 24 sites in United Kingdom, Australia, Canada, Denmark, Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Jun 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT) (time frame: 0, 12 months, 24 months, 36 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01483560, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2019.