Clinical Trial Results:
REducing with MetfOrmin Vascular Adverse Lesions in T1DM (The REMOVAL study)
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Summary
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EudraCT number |
2011-000300-18 |
Trial protocol |
GB NL DK |
Global end of trial date |
17 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Jun 2019
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First version publication date |
21 Jun 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
GN10DI406
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01483560 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
NHS Greater Glasgow and Clyde
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Sponsor organisation address |
Dalnair Street, Glasgow, United Kingdom, G3 8SW
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Public contact |
Dr Maureen Travers, NHS Greater Glasgow and Clyde
Research and Development , 0044 01412321813, R&DIMP@ggc.scot.nhs.uk
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Scientific contact |
Dr Maureen Travers, NHS Greater Glasgow and Clyde
Research and Development , 0044 01412321813, john.petrie@glasgow.ac.uk
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Sponsor organisation name |
University of Glasgow
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Sponsor organisation address |
126 University Place, Glasgow, United Kingdom, G12 8TA
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Public contact |
Prof John Petrie, University of Glasgow, 0044 01413303325, john.petrie@glasgow.ac.uk
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Scientific contact |
Prof John Petrie, University of Glasgow, 0044 01413303325, john.petrie@glasgow.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Apr 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Feb 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Feb 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The objective of REMOVAL is to test whether metformin tablets added in with insulin treatment in type 1 diabetes can prevent the early blood vessel complications which lead to heart attacks and strokes.
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Protection of trial subjects |
Participants were provided with the best care possible throughout the follow-up period. They were encouraged and supported to work towards and maintain
target glycaemic control (HbA1c < 7.0%/ 53 mmol/mol) independent of the treatment to which they were randomized (i.e. metformin or placebo). This was achieved by: (i) increased attention to lifestyle measures; (ii) supported adjustment of insulin doses; and (iii) intensifying insulin regimens and doses where necessary.
Before inclusion in the study, all participants were screened by a physician to ensure that the entry criteria were met. During the study, participants were seen in their local diabetes clinic regularly at 3-6 monthly intervals. At these visits, measures related to patient safety were monitored and action taken if clinically relevant as per the Study Protocol. Telephone calls to participants were made and documented by study personnel four times during the initial three months and thereafter half-yearly (alternating with the study visits) in order to monitor and record adverse events and advise on dosing of insulin
and titration of study medication. All participants had a contact number for local clinical personnel on a study card in case of medical needs outside the planned study visits or telephone contacts. All adverse effects were reported using established standard operating procedures meeting international regulatory requirements. A Data and Safety Monitoring Board met six monthly to review unblinded details of adverse events and had the sanction of recommending study termination to the Steering Committee if appropriate. In addition, a Glycaemia Committee met six monthly to review summarized details of glycaemic
control (HbA1c) and rates of major and minor hypoglycaemia. It sent detailed reports (masked to treatment allocation) on participants’ HbA1c and rates of hypoglycaemia to each site every 6 months along with benchmarking data from other sites in their region.
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Background therapy |
During the run-in period CVD risk factor management was optimised in accordance with local guidelines at sites and insulin regimens were reviewed with the aim of optimising glycaemic control (target HbA1c 7·0% [53 mmol/mol]) with additional clinic visits if necessary. Adjustments in insulin doses towards target HbA1c were made at the discretion of site staff rather than being specified by the protocol. Participants continued to have access to usual local arrangements for diet, lifestyle and weight management throughout the trial; ongoing management of glycaemia, blood pressure and lipids was under the care of the site principal investigator and usual care team. Participants with ongoing treatment with oral steroids, pramlintide or GLP-1 agonist therapy were specifically excluded. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Oct 2011
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Scientific research | ||
Long term follow-up duration |
20 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 254
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Country: Number of subjects enrolled |
Australia: 75
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Country: Number of subjects enrolled |
Canada: 113
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Country: Number of subjects enrolled |
Netherlands: 38
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Country: Number of subjects enrolled |
Denmark: 13
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Worldwide total number of subjects |
493
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EEA total number of subjects |
305
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
493
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
501 participants screened 493 participants enrolled 428 participants randomised 36 participants withdrew prior to randomisation 61 participants withdrew post randomisation (35 metformin, 26 placebo) | |||||||||||||||
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Pre-assignment
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Screening details |
4 week Run-In period | |||||||||||||||
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Period 1
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Period 1 title |
Baseline (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator, Monitor | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Metformin | |||||||||||||||
Arm description |
- | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Metformin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
500mg tablets
Either 1 or 2 tablets, once or twice a day.
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Arm title
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Placebo | |||||||||||||||
Arm description |
- | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
1 or 2 tablets, once or twice a day.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 493 subjects were enrolled into the trial. 65 were found to be ineligible during the Run-In period. Reasons such as: Did not meet inclusion/exclusion criteria, withdrew prior to randomisation, unwilling to attend visits etc. This left 428 subjects to be randomised to either arm. |
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Baseline characteristics reporting groups
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Reporting group title |
Metformin
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Mean Carotid
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set 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 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.
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End points reporting groups
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Reporting group title |
Metformin
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Reporting group description |
- | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Subject analysis set title |
Mean Carotid
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Subject analysis set type |
Per protocol | ||
Subject analysis set 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 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.
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End point title |
Mean Carotid IMT | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Baseline, 12, 24 and 36 months
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Statistical analysis title |
Averaged Mean far wall cIMT | ||||||||||||
Comparison groups |
Metformin v Placebo
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Number of subjects included in analysis |
387
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.1664 [1] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Confidence interval |
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| Notes [1] - The primary cIMT endpoint treatment effect was not statistically significant. |
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Adverse events information
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Timeframe for reporting adverse events |
From signing the informed consent form up to 30 days after the subject completed or discontinued the study.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
10.0
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Reporting groups
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Reporting group title |
Metformin
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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20 Sep 2012 |
Protocol Change - principal change in inclusion criteria and adverse event reporting
An update to the Merck Licence and IMP Dossier. |
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09 Sep 2015 |
The main update to the protocol was procedures to allow abbreviated follow up of the last 50 participants recruited. In order to achieve adequate power for the primary endpoint and minimize the need for time extensions from the funder, the Steering Group took the decision when 90% of the target number of participants had been enrolled to continue to recruit but to abbreviate the duration of follow up for the remaining participants (n=50). By this method, exposure to randomized treatment will still be 98.8% of that originally planned.
Point of clarification regarding ongoing carotid IMT Quality Control: Protocol v2.0 stated that each centre would perform six monthly carotid IMT scans on five healthy volunteers from the start of the study and every six months until completion of the study to assess for any measurement drift. Results of Quality Control (QC) would then be fed back to centres on a regular basis with follow up retraining/ certification as necessary. However it is increasingly difficult to retain the same healthy volunteers for repeated measurements. The possibility of repeat scans on patients had been included in version 2.3 of the PIS (in Oct 2012) in case this became a problem, and therefore patients had consented to the option of additional scans at visits 1, 8, 12 qnd 16 (i.e. annual visits) for QC purposes. On a pragmatic basis therefore an alternative Quality Assurance plan has been agreed so that a subgroup of actual study participants are invited to undergo repeat scans at each annual visit to assess reproducibility Protocol v3.0 includes an update to reflect this arrangement. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
