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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01483560
Recruitment Status : Completed
First Posted : December 1, 2011
Results First Posted : June 3, 2019
Last Update Posted : June 19, 2019
Sponsor:
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
Information provided by (Responsible Party):
Prof John Petrie, University of Glasgow

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 1
Interventions Drug: Metformin
Drug: Placebo
Enrollment 493
Recruitment Details  
Pre-assignment Details 493 participants where enrolled and consented. All participants entered a 3 month Run In phase with placebo. Participants who remained eligible were randomly assigned to receive metformin or placebo for 3 years. 65 participants where ineligible to be randomized.
Arm/Group Title Metformin Placebo
Hide Arm/Group Description

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Period Title: Overall Study
Started 219 209
Completed 193 194
Not Completed 26 15
Arm/Group Title Metformin Placebo Total
Hide Arm/Group Description

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo Total of all reporting groups
Overall Number of Baseline Participants 219 209 428
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 219 participants 209 participants 428 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
219
 100.0%
209
 100.0%
428
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 219 participants 209 participants 428 participants
55.2  (8.5) 55.8  (8.8) 55.5  (8.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 219 participants 209 participants 428 participants
Female
90
  41.1%
85
  40.7%
175
  40.9%
Male
129
  58.9%
124
  59.3%
253
  59.1%
Race and Ethnicity Not Collected   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 0 participants 0 participants
0
[1]
Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Canada Number Analyzed 219 participants 209 participants 428 participants
55 55 110
Netherlands Number Analyzed 219 participants 209 participants 428 participants
16 15 31
Denmark Number Analyzed 219 participants 209 participants 428 participants
4 4 8
United Kingdom Number Analyzed 219 participants 209 participants 428 participants
112 105 217
Australia Number Analyzed 219 participants 209 participants 428 participants
32 30 62
Diabetes Diagnosis Duration  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 219 participants 209 participants 428 participants
33.4  (11) 34.3  (10.5) 33.85  (10.75)
Existing Cardiovascular Disease  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 219 participants 209 participants 428 participants
30 22 52
Baseline HbA1c  
Measure Type: Number
Unit of measure:  Mmol/mol
Number Analyzed 219 participants 209 participants 428 participants
64.8 64.7 64.75
Daily Insulin Dose  
Measure Type: Number
Unit of measure:  Units/kg
Number Analyzed 219 participants 209 participants 428 participants
0.63 0.68 0.66
BMI  
Mean (Standard Deviation)
Unit of measure:  Kg/m2
Number Analyzed 219 participants 209 participants 428 participants
28.4  (4.5) 28.5  (4.1) 28.5  (4.3)
Blood Pressure  
Mean (Standard Deviation)
Unit of measure:  Systolic BP (mmHg)
Number Analyzed 219 participants 209 participants 428 participants
130.5  (15) 128.5  (14.6) 129.5  (14.8)
Total Cholesterol  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 219 participants 209 participants 428 participants
4  (0.88) 4  (0.93) 4  (0.91)
eGFR  
Mean (Standard Deviation)
Unit of measure:  Ml/min/1.73m2
Number Analyzed 219 participants 209 participants 428 participants
92.9  (20.9) 91.1  (21.6) 92  (21.3)
Diabetic Retinopathy  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 219 participants 209 participants 428 participants
51 58 109
1.Primary Outcome
Title Change in Averaged Mean Far Wall Common Carotid Artery Intima-media Thickness (cIMT)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: mm
Baseline 0.773  (0.14) 0.791  (0.183)
12 Months 0.782  (0.147) 0.788  (0.174)
24 Months 0.792  (0.145) 0.823  (0.187)
36 Months 0.793  (0.134) 0.820  (0.177)
2.Secondary Outcome
Title Change in HbA1c
Hide Description Measured in accredited local laboratories participating in DCCT-aligned quality control programmes.
Time Frame Baseline, Year 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: %units
Baseline 8.1  (0.9) 8.0  (0.8)
36 Months 8.1  (0.9) 8.1  (0.8)
3.Secondary Outcome
Title Change in LDL Cholesterol
Hide Description mmol/L Centrally assayed at the University of Glasgow
Time Frame Baseline, Year 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: mmol/L
Baseline 2.23  (0.7) 2.25  (0.72)
36 Months 2.07  (0.83) 2.21  (0.71)
4.Secondary Outcome
Title Change in Estimated Glomerular Filtration Rate
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: ml/min/1.73m2
Baseline 92.9  (20.9) 91.1  (21.6)
36 Months 92.1  (20.8) 87.2  (19.6)
5.Secondary Outcome
Title Number of Participants With Retinopathy and at Least a 2 Stage Progression in Retinopathy From Baseline to 36 Months
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 219 209
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline
191
  87.2%
190
  90.9%
36 Months
8
   3.7%
10
   4.8%
6.Secondary Outcome
Title Change in Weight
Hide Description Measured at sites using calibrated weighing scales
Time Frame Baseline, Year 1, Year 2, Year 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: kg
Baseline 83.9  (15.4) 83.5  (13.7)
36 Months 82.0  (15.4) 83.2  (13.8)
7.Secondary Outcome
Title Change in Insulin Dose
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: units/kg
Baseline 0.36  (0.26) 0.68  (0.30)
36 Months 0.62  (0.26) 0.67  (0.30)
8.Secondary Outcome
Title Change in Endothelial Function
Hide Description In some centres (Arbitrary units) Reactive Hyperaemia Index using the ENDOPAT device (Itamar, Israel)
Time Frame Baseline, Year 1, Year 3
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Metformin Placebo
Hide Arm/Group Description:

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
Overall Number of Participants Analyzed 193 194
Mean (Standard Deviation)
Unit of Measure: RHI (Arbitrary units)
Baseline 2.28  (0.74) 2.24  (0.75)
36 Months 2.17  (0.69) 2.24  (0.73)
Time Frame Adverse event data collected from the date of consent until 30 days post last IMP dose, an average of 3 years.
Adverse Event Reporting Description Definition used same as clinical trials.gov
 
Arm/Group Title Metformin Placebo
Hide Arm/Group Description

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

Metformin: 3 years treatment duration 219 of 428 randomised were assigned to Metformin Group

Placebo: 3 years duration 209 of the 428 randomised were assigned to Placebo
All-Cause Mortality
Metformin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   5/219 (2.28%)      2/209 (0.96%)    
Hide Serious Adverse Events
Metformin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   34/219 (15.53%)      31/209 (14.83%)    
Blood and lymphatic system disorders     
Blood and Lymphatic   1/219 (0.46%)  1 0/209 (0.00%)  0
Cardiac disorders     
Cardiac   3/219 (1.37%)  3 6/209 (2.87%)  6
Gastrointestinal disorders     
Gastrointestinal   4/219 (1.83%)  4 5/209 (2.39%)  5
General disorders     
Sudden Death   1/219 (0.46%)  1 0/209 (0.00%)  0
Chest Pain   1/219 (0.46%)  1 1/209 (0.48%)  1
Immune system disorders     
Immune System Disorder   1/219 (0.46%)  1 0/209 (0.00%)  0
Infections and infestations     
Infections and Infestations   7/219 (3.20%)  7 5/209 (2.39%)  5
Injury, poisoning and procedural complications     
Injury   3/219 (1.37%)  3 3/209 (1.44%)  3
Investigations     
Angiogram   1/219 (0.46%)  1 0/209 (0.00%)  0
Blood Glucose Fluctuation   0/219 (0.00%)  0 1/209 (0.48%)  1
Metabolism and nutrition disorders     
Metabolic and nutrition   8/219 (3.65%)  8 5/209 (2.39%)  5
Musculoskeletal and connective tissue disorders     
Musculoskeletal   1/219 (0.46%)  1 2/209 (0.96%)  2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasms   6/219 (2.74%)  6 3/209 (1.44%)  3
Nervous system disorders     
Cerebral haemorrhage   1/219 (0.46%)  1 0/209 (0.00%)  0
Cerebrovascular accident   1/219 (0.46%)  1 2/209 (0.96%)  2
hypoglycaemic coma   1/219 (0.46%)  1 1/209 (0.48%)  1
Transient Ischaemic Attack   2/219 (0.91%)  2 1/209 (0.48%)  1
Headache   0/219 (0.00%)  0 1/209 (0.48%)  1
Respiratory, thoracic and mediastinal disorders     
Respiratory   1/219 (0.46%)  1 5/209 (2.39%)  5
Surgical and medical procedures     
Coronary artery bypass graft   1/219 (0.46%)  1 0/209 (0.00%)  0
lung lobectomy   1/219 (0.46%)  1 1/209 (0.48%)  1
coronary stent insertion   1/219 (0.46%)  1 1/209 (0.48%)  1
Amputation revision   0/219 (0.00%)  0 1/209 (0.48%)  1
Surgery (unspecified)   0/219 (0.00%)  0 1/209 (0.48%)  1
Coronary angioplasty   0/219 (0.00%)  0 1/209 (0.48%)  1
Spinal fusion Surgery   0/219 (0.00%)  0 1/209 (0.48%)  1
Aortic valve repair   0/219 (0.00%)  0 1/209 (0.48%)  1
Vascular disorders     
Circulatory collapse   1/219 (0.46%)  1 0/209 (0.00%)  0
Ischaemic Necrosis   0/219 (0.00%)  0 1/209 (0.48%)  1
Peripheral Ischaemia   0/219 (0.00%)  0 1/209 (0.48%)  1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Metformin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   112/219 (51.14%)      52/209 (24.88%)    
Cardiac disorders     
Cardiovascular   1/219 (0.46%)  1 1/209 (0.48%)  1
Eye disorders     
Opthalmic adverse events   18/219 (8.22%)  18 32/209 (15.31%)  32
Gastrointestinal disorders     
Gastrointestinal   88/219 (40.18%)  88 18/209 (8.61%)  18
Nervous system disorders     
Neurological   0/219 (0.00%)  0 0/209 (0.00%)  0
Product Issues     
Hypersensitivity to Metformin   5/219 (2.28%)  5 1/209 (0.48%)  5
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Prof John Petrie
Organization: University of Glasgow
Phone: +44 141 330 ext 3325
EMail: John.Petrie@glasgow.ac.uk
Layout table for additonal information
Responsible Party: Prof John Petrie, University of Glasgow
ClinicalTrials.gov Identifier: NCT01483560    
Other Study ID Numbers: GN10DI406
2011-000300-18 ( EudraCT Number )
First Submitted: November 23, 2011
First Posted: December 1, 2011
Results First Submitted: September 20, 2018
Results First Posted: June 3, 2019
Last Update Posted: June 19, 2019