Conditions: Diabetes Mellitus, Type 1
Keywords: REMOVAL metformin carotid IMT LDL Cholesterol endothelial function retinopathy HbA1c
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 493
Healthy volunteers: no

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.

Detailed description:

Arms:
arm 1: Oral Metformin (as Glucophage 500mg x 2 bd) titrated from initial 500mg to target 2000mg daily arm 2: None

Interventions: intervention 1: Metformin intervention 2: Placebo
Intervention descriptions: intervention 1: 3 years treatment duration intervention 2: 3 years duration

Protocol document:
Prot_000.pdf: 
 
REducing with MetfOrmin Vascular Adverse Lesions 
in type 1 diabetes 
(REMOVAL) 
 
 
REMOVAL Investigators   
Version 3.0 (9th November 2015) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
2
Document STUDY PROTOCOL 
 
Title, version number & date 
 
REMOVAL study 
Version 3.0; 09/11/2015 
Compound Metformin (Glucophage 500mg) 
 
Full Title REducing with MetfOrmin Vascular 
Adverse Lesions in T1DM 
 
(REMOVAL) 
Study Numbers EudraCT nr :                         2011-000300-18 
Clinical Trials.gov identifier : NCT01483560 
Sponsor’s protocol code nr:  GN10DI406 
REC reference nr:                 11/WS/0012 
 
Funding Awarded by Juvenile Diabetes Research Foundation 
 
Trial Investigators Contact Details Professor John Petrie 
BHF Cardiovascular Research Centre 
University of Glasgow 
126 University Place 
Glasgow 
G12 8TA 
Email: john.petrie@glasgow.ac.uk 
Tel: 0141 330 3325 
www.removalstudy.org 
Trial Monitor    According to national arrangements 
   (see Section 11, page 33) 
 
Sponsor 
 NHS Greater Glasgow and Clyde Board 
   Dr Maureen Travers, 
   R&D Management Office, 
   Tennent Institute, 38 Church St, 
   Glasgow G11 6NT 
   Email: Maureen.Travers@ggc.scot.nhs.uk 
   Tel: 0141 211 6389 
 University of Glasgow 
   Mr Paul Ellis 
   Research & Enterprise, 
   10 The Square, University of Glasgow, 
   Glasgow G12 8QQ 
   Email: p.ellis@enterprise.gla.ac.uk  
   Tel: 0141 330 3875 
 Australia, Canada, Denmark, Netherlands;  
    delegated responsibilities by contract  
 
Sponsor Pharmacovigilance Officer Dr Eleanor Dinnett, 
Robertson Centre for Biostatistics, 
University of Glasgow 
Chief Investigator Signature 
 


 
 
3
 
Contents 
3 
REMOVAL study contacts and chief investigators 
4 
Abbreviations used in protocol 
7 
1. Study synopsis 
8 
2. Schedule of assessments 
10 
3. Introduction 
11 
4. Study rationale – hypothesis 
12 
5. Objectives 
13 
6. Study design 
14 
7. Study population 
20 
8. Medications 
26 
9, Timeline for participant in study 
31 
10. Clinical measurements and examinations at each visit 
31 
11. Monitoring and evaluations 
33 
12. Assessment and reporting of adverse events / serious adverse 
events 
 
34 
13. Recording and reporting AEs/ SAEs 
34 
14. CRF reporting and data collection 
37 
15. Statistical analysis 
38 
16. Publication and archiving 
39 
17. Changes to Protocol 
39 
18. Management and committee structure 
40 
References 
41 
Appendix 1.  REMOVAL study national Principal Investigators 
 
45 
Appendix 2.  Planned study timelines 
46 
Appendix 3.  Steno Hypoglycaemia Questionnaire 
47 
Appendix 4.  Contraception (women of childbearing age) 
 
48 
Appendix 5.  Definitions of microalbuminuria  
 
Appendix 6.  Abbreviated follow up (for final 50 participants)  
49 
 
50 
 
 


 
 
4
REMOVAL Study Contacts and Chief Investigators  
 
Sponsor : NHS Greater Glasgow and Clyde Board / University of Glasgow, DD1  
Chief Investigator: 
 
John Petrie, Professor of Diabetic Medicine, University of Glasgow; 
Honorary Consultant in Diabetes NHS Greater Glasgow and Clyde, UK 
Deputy Chief Investigator:  
 
Helen Colhoun, Professor of Public Health, University of Dundee, UK Honorary 
Consultant in Public Health Medicine, NHS Fife, UK  
Co-Principal Investigators:  
 
Professor Nish Chaturvedi, University College, London, UK 
 
Professor Ian Ford,  Robertson Centre for Biostatistics, University of Glasgow, UK 
 
Professor Irene Hramiak, London Ontario, Canada 
 
Professor Alun Hughes, University College, London, UK 
 
Professor Alicia Jenkins, Melbourne, Australia 
 
Dr Barbara Klein, University of Wisconsin School of Medicine and Public Health, 
Madison, Wisconsin, USA 
 
Professor Ronald Klein, University of Wisconsin School of Medicine and Public Health, 
Madison, Wisconsin, USA 
 
Professor Peter Rossing, Steno Diabetes Centre, Denmark 
 
Professor Naveed Sattar, BHF Glasgow Cardiovascular Research Centre, University 
of Glasgow, UK 
 
Professor Coen Stehouwer, University of Maastricht, Netherlands  
Collaborators: 
 
Dr Kamal Abouglia,  University Hospital of North Durham, UK 
 
Dr Mathangi Balasubramani, Gloucestershire Royal Hospital, Gloucester, UK 
 
Professor Michiel Bots, Julius Centre for Health Sciences and Primary Care, Utrecht, 
Netherlands 
 
Dr Martijn Brouwers, Maastricht University Medical Centre, Maastricht 
 
Dr Patrick Chong (UK Lead Site), Derriford Hospital, Plymouth, UK 
 
Professor Andrew Collier, Consultant Physician and Honorary Senior Lecturer, Ayr 
Hospital, UK 
 
Professor Peter Colman, Dept. of Endocrinology, Royal Melbourne Hospital, 
Melbourne, Australia 
 
Dr Christian Delles, University of Glasgow, UK 
 
Professor Martin Gibson, Clinical Lead Northwest UKDRN Local Research Network, 
UK 
 
Dr Tine Willum Hansen, Steno Diabetes Centre, Denmark 


 
 
5
 
Professor Anthony Keech, NHMRC Clinical Trials Centre, University of Sydney, 
Australia 
 
Dr Faisel Khan, University of Dundee, UK  
 
Dr Robert Lindsay, University of Glasgow, UK 
 
Professor Graham Leese, NHS Tayside, UK 
 
Dr Soren Lund, Boehringer Ingelheim, Germany 
 
Prof Gerald McKay, NHS Greater Glasgow and Clyde, UK 
 
Professor John McKnight, Western General Hospital, Edinburgh, UK 
 
Professor Sally Marshall, University of Newcastle 
 
Dr Ann Millward (UK Lead Site), Peninsula Medical School, UK 
 
Dr Mike Neider, University of Wisconsin School of Medicine and Public Health, 
Madison, Wisconsin, USA 
 
Dr. David O’Neal, Dept. of Medicine (St. Vincent’s Hospital), Melbourne, Australia 
 
Dr Nick Oliver, Imperial College London, UK 
 
Dr TC Ooi, Ottawa Hospital, Canada 
 
Dr Sam Philip, University of Aberdeen, UK 
 
Dr David Preiss, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK 
 
Dr Martin Rutter, Manchester Diabetes Centre, UK 
 
Dr Thozhukat Sathyapalan, Michael White Centre for Diabetes, Hull, UK 
 
Professor Angela Shore, Associate Director of Experimental Medicine for UKDRN, 
Peninsula Medical School, UK 
 
Dr Mark Strachan, Royal Infirmary of Edinburgh, UK  
 
Professor Simon Thom, Imperial College London, UK 
 
Dr Natasha Thorogood, Consultant in Diabetes, Bristol Royal Infirmary, UK 
 
Associate Professor Stephen Twigg, University of Sydney (Royal Prince Alfred 
Hospital), Sydney, Australia 
 
Professor Mark Walker, Newcastle, Institute of Cellular Medicine, Newcastle 
University, UK 
 
Dr Michael Weingert, London, Ontario, Canada 
 
Professor Matthew Walters, University of Glasgow, UK 
 
Professor John Wilding, University Hospital, Aintree, Liverpool, UK 
 
Dr. Andrew Wilson, Dept. of Medicine (St. Vincent’s Hospital), Melbourne, Australia 
 
Dr Roderick Warren, Royal Devon and Exeter NHS Foundation Trust, Exeter 


 
 
6
Location:   
 
Australia, Canada, Denmark, Netherlands, UK 
 


 
 
7
Abbreviations used in protocol 
 
AE adverse event 
bd twice daily 
β-HCG β -human chorionic gonadotrophin 
BHF GCRC British Heart Foundation, Glasgow Cardiovascular Research Centre 
CCA common carotid artery 
CCA cIMT intima-media thickness of the distal common carotid artery 
CI chief investigator 
cIMT carotid intima-media thickness 
CHD coronary heart disease 
CRF case report form 
CRP C-reactive protein 
CTA clinical trials authorisation 
CV coefficient of variation 
DCCT Diabetes Control and Complications Trial 
DICOM document imaging and storage service provider 
DM diabetes mellitus 
DSMB data and safety monitoring board 
ECG electrocardiogram 
eGFR estimated glomerular filtration rate 
ETDRS early treatment diabetic retinopathy study 
FBC full blood count 
FDA Food and Drug Administration (United States) 
FPG fasting plasma glucose 
GCTU Glasgow Clinical Trials Unit 
GMP good manufacturing practice 
HbA1c glycated haemoglobin A1c 
HBGM home blood glucose monitoring 
IL-6 interleukin 6 
IRB Institutional Review Board 
IMP investigational medicinal product 
IVRS Interactive Voice Response System 
IWS Interactive Web System 
LFT liver function tests 
MDRD modification of diet in renal disease 
MedDRA Medical Dictionary for Regulatory Activities 
MI myocardial infarction 
MHRA Medicines and Healthcare products Regulatory Agency 
NYHA New York Heart Association 
OGTT oral glucose tolerance test 
PI principal investigator 
PV pharmacovigilance 
QP qualified person 
RCB Robertson Centre for Biostatistics, University of Glasgow 
SAE serious adverse event 
sICAM-1 soluble intercellular adhesion molecule-1 
SmPC summary of product characteristics 
SDRN Scottish Diabetes Research Network 
SUSAR suspected unexpected serious adverse reaction 
T1DM type 1 diabetes 
t-PA tissue plaminogen activator 
U&E urea and electrolytes 
ULN upper limit of normal 
UKPDS United Kingdom Prospective Diabetes Study 


 
 
8
1. STUDY SYNOPSIS 
 
 
Title of Study: 
REducing with MetfOrmin Vascular Adverse Lesions in 
T1DM (REMOVAL) 
Brief Title: 
REMOVAL 
National Coordinating 
Centres 
 
British Heart Foundation: Glasgow Cardiovascular Research 
Centre, Glasgow; Steno Diabetes Center, Gentofte; University 
of Western Ontario, London,  Ontario;  NHMRC Clinical Trials 
Centre, Sydney Medical School, Australia; University of 
Maastricht, Netherlands 
Duration of Study: 
Three month run-in period (third month with single-blind 
placebo); 3 years double-blind randomized treatment. 
Primary Objective: 
To assess in a randomized controlled trial the effects of three 
years metformin added to titrated insulin therapy (towards 
target HbA1c 7.0%/ 53 mmol/mol) on progression of atheroma 
as measured by progression of averaged mean far wall 
common carotid artery intima-media thickness (cIMT) in adults 
with type 1 diabetes at risk of cardiovascular disease. 
Secondary Objectives: 
Change in: (i) HbA1c; (ii) LDL cholesterol; (iii) albuminuria and 
estimated glomerular filtration rate; (iv) retinopathy stage (two-
field photographs); (v) weight; (vi) insulin dose; (vii) endothelial 
function  
Tertiary Objectives: 
Change in: (i) frequency of hypoglycaemia; 
(ii) treatment satisfaction; (iii) markers of endothelial function (t-
PA, sE-selectin, sICAM-1); (iv) progression of mean maximal 
distal common carotid artery cIMT; (v) vitamin B12 status. 
Rationale: 
Intensive glucose control reduces long term rates of 
cardiovascular disease (CVD) in people type 1 diabetes 
(T1DM) but the majority of individuals affected by the 
condition do not currently achieve glucose targets with 
standard insulin therapy.  Upward insulin dose titration may 
lead to weight gain, hypoglycaemia and dyslipidaemia. 
Metformin has potential for addressing these issues as it 
may: (i) reduce insulin dose for a given achieved HbA1c; (ii) 
promote weight stabilization; (iii) be associated with low rates 
of hypoglycaemia; and (iv) reduce LDL cholesterol - even on 
a background of statin therapy.  It may also have direct and 
potentially beneficial cardiovascular effects.   
      Progression of carotid artery intima-media thickness 
(cIMT) is the primary endpoint as this is accelerated in type 1 
diabetes. cIMT reliably predicted cardiovascular events in 
DCCT and has been successfully targeted by metformin in a 
number of small studies in conditions other than type 1 
diabetes.  The secondary endpoint is a composite of 
clinically-relevant 
markers 
of 
microvascular 
and 
macrovascular prognosis. 
 
Product, Dose, Modes 
of Administration: 
 
Single-blind placebo Run-In: One tablet once daily with the 
evening meal. 
Double-blind treatment period: Oral metformin (as 
Glucophage 500 mg x 2 twice daily) titrated from initial 500 mg 
to target 2000 mg daily/ matching placebo.  
Sample Size: 
500 enrolled participants. 
Randomisation: 
By telephone call to the study Interactive Voice Response 
System (IVRS) or electronically via the portal providing the 
study electronic Case Report Form (as provided by the 
Robertson Centre for Biostatistics, University of Glasgow).   
 


 
 
9
Inclusion Criteria 
(abbreviated) 
Type 1 diabetes (defined in Section 7.1) for five years or 
more; age ≥ 40 years;  7.0 ≤ HbA1c < 10.0% (53-86 
mmol/mol)  
 
AND three or more of the following ten CVD risk factors: 
(i) BMI ≥ 27 kg/m2 
(ii) current HbA1c > 8.0% (64 mmol/mol) 
(iii) known CVD/ peripheral vascular disease 
(iv) current smoker 
(v) eGFR < 90 ml/ min/ 1.73 m2 
(vi) confirmed micro- (or macro-) albuminuria [according to 
local assays and reference ranges] 
(vii) hypertension (BP≥140/ 90 mmHg; or established on 
antihypertensive treatment) 
(viii) dyslipidaemia [total cholesterol ≥ 5.0 mmol/L (200 
mg/dL); or HDL cholesterol < 1.20 mmol/L (46 mg/dL) [men] 
HDL cholesterol < 1.30 mmol/L (50 mg/dL) [women]; or 
fasting 
triglycerides 
≥ 
1.7 mmol/L 
(150 mg/dL); 
or 
established on lipid-lowering treatment  
(ix) strong family history of CVD (at least one parent, 
biological aunt/ uncle, or sibling with myocardial infarction or 
stroke aged < 60 years) 
(x) duration of diabetes > 20 years. 
Exclusion Criteria 
(abbreviated) 
(i) eGFR <  45 ml/ min/ 1.73m2 
(ii) woman of childbearing age not on effective contraception – 
see Appendix 4 
(iii) pregnancy and/or lactation  
(iv) Acute Coronary Syndrome or Stroke/ TIA within the last 3 
months 
(v) NYHA stage 3 or 4 heart failure  
(vi) uncontrolled angina 
(vi) significant hypoglycaemia unawareness 
(vii) impaired cognitive function/ unable to give informed 
consent 
(viii) previous carotid surgery/ inability to capture adequate 
carotid images 
(ix) gastroparesis  
(x) history of lactic acidosis 
(xi) other contraindications to metformin 
- 
hepatic impairment 
- 
known hypersensitivity to metformin 
- 
acute illness (dehydration, severe infection, shock, 
          acute cardiac failure) 
- 
suspected tissue hypoxia 
(xii) Any coexistent life threatening condition including prior 
diagnosis of cancer within two years  
(xii) history of alcohol problem or drug abuse 
Duration of Treatment: 
Three years per participant (plus one month placebo single-
blind in third month of three month Run-In period) 
Statistical Analysis Primary: 
Mixed effects regression model estimates of between-group 
cIMT differences over time, with 95% confidence intervals and 
p-values.  Primary outcome regression model extended to 
assess whether metabolic effects could explain differences in 
progression of cIMT. 


2. SCHEDULE OF ASSESSMENTS  
Protocol: REMOVAL 
 
Pre-
screening 
Run-in  Period 
Treatment 
*telephone visit only 
Rroutine clinic visit 
Ffasting visit 
 
Visit  
0 R 
Visit 
R1 
 
Visit 
R2* 
Visit 
R3* 
Visit 
R4* 
Visit 
1F 
 
 
Visit 
2* 
Visit 
3* 
Visit 
4* 
Visit 
5
  R 
Visit 
6 R 
Visit 
7* 
Visit 
8F 
Yr 1 
Visit 
9* 
Visit 
10 R 
Visit 
11* 
Visit 
12 F 
Yr 2 
Visit 
13* 
Visit  
14 R 1 
Visit 
15* 1 
 
Visit 
16
 F 
Yr 3 
 
Visit 
17 2 
Close 
out 
Treatment month (±2 weeks; or see Appendix 6) 
 
-3 
 
-2 
-1 
0 
 
 
1 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
38 
Treatment week (±3 days) 
 
 
-10 
-8 
-4 
 
1 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Provide information 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Informed consent 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/ Disease History 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications  
 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
WeightR 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Waist circumference 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
HeightR 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP and heart rateR 
 
x 
 
 
 
x 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Dispense study medication 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Collect/ count unused medication 
 
 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Titrate study medication 
 
 
 
 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Give out new diary 
 
x 
 
 
 
x 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
 
Adjust insulin to HbA1c (review glucose diary) R 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Record insulin dose 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Steno hypoglycaemia questionnaire  
 
x 
 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Treatment satisfaction  questionnaire 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Other adverse events (including cardiovascular) 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Full blood count, vitamin B12R 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
U+E, local lab HbA1c, LFT, routine lipidsR 
 
x 
 
 
 
x 
 
 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
Pregnancy test 
 
x 
 
 
 
x 
Only in women of childbearing age – repeated if clinically indicated in prompted discussion with participant 
C-peptide 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Carotid IMT (±4 weeks except Visit 1: see below**) 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Retinal images (±4 weeks except Visit 1: see below**) 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Endothelial function (ENDOPAT) 
(±4 weeks except Visit 1: see below**) 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
LDL sample for central analysis 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Microalbumunuria
 R 
 
x 
 
 
 
(x) 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Lactate 
 
 
 
 
 
x 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Plasma biomarker samples 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
Urine aliquot 
 
x 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
x 
 
 
 
x 
 
 
** N.B. All Visit 1 assessments [including carotid IMT, retinal imaging and ENDOPAT]  MUST be completed within 4 weeks PRIOR TO randomization** 
1 VISIT 14 and VISIT 15 time windows altered or omitted for participants randomized after the end of March 2014 – see Appendix 6       
2 VISIT 17 must be at least one week after Visit 16 


 
 
11
3. INTRODUCTION 
 
Cardiovascular disease (CVD) is the commonest cause of premature death in type 1 
diabetes (T1DM).1-4 Population-based data from 19,248 individuals with the condition in 
Scotland indicate ten year absolute CVD event rates of 16.7% and 12.7% respectively in 
men and women aged 40-60 years (Colhoun, unpublished data presented at JDRF 
Complications Prevention Workshop, Washington, April 2010), rising to 49% and 39% in 
those aged over 60 years.  These rates are 3-5 fold higher than in the general population.  
While relative risk is even higher in younger individuals, 95% of actual CVD events occur 
in those above 40 years of age. The major risk factors are male gender, hypertension, 
dyslipidaemia, cigarette smoking, hyperglycaemia and nephropathy.   
Few randomized controlled trials (RCTs) have directly addressed myocardial 
infarction (MI) and stroke prevention in T1DM.  It is acknowledged in the 2010 American 
Diabetes Association “Standards of Medical Care”5 that recommendations for people 
with the condition to be prescribed statin therapy to prevent CVD are based on 
extrapolation from type 2 diabetes,6 and on meta-analysis of trials involving a total of 651 
people with T1DM in whom CVD event reduction was not statistically significant.7    A 
period of intensive glycaemic control in the Diabetes Control and Complications Trial 
(DCCT) was associated in later post-randomisation follow up in the Epidemiology of 
Diabetes and Its Complications (EDIC) study with a reduction in CVD events.8,9   
Achievement of target glycaemic control is essential for preventing the complications of 
T1DM, but many years after the DCCT achieving tight glycaemic control remains a 
challenge for many people living with T1DM.  The figures are stark: in the UK, no more 
than 20% of people with the condition achieve HbA1c < 7.5% and about a third typically 
have an HbA1c >9% (Scottish Diabetes Survey 2009).10 With intensified insulin therapy, 
insulin up-titration aimed at achieving target glycaemia can result in more frequent 
hypoglycaemia, and - in a significant subpopulation - weight gain, hypertension and 
dyslipidaemia.11,12   
Metformin has many of the properties desirable for an adjunct oral agent to be 
added in with insulin therapy to improve metabolic control.13,14 Data from ourselves and 
others show that it may: (i) reduce insulin dose (by 6 units) for a given achieved HbA1c; 
(ii) promote weight stabilization; (iii) be associated with low rates of hypoglycaemia; and 
(iv) reduce LDL cholesterol – by 0.5 mmol/L (20 mg/dL) - even on a background of statin 
therapy.15-18  There is considerable evidence that it may also provide direct and 
potentially beneficial cardiovascular effects at least in type 2 diabetes - particularly as 
demonstrated in the UK Prospective Diabetes Study (UKPDS).19,20  
 
Metformin undergoes active transport into cells via the OCT-1 transporter21 and 
activates the AMP-activated protein kinase (AMPK), resulting in decreased hepatic 
glucose production, increased muscle fatty acid oxidation and improved whole-body 
insulin sensitivity.22-24  A meta-analysis of its effects in non-diabetic individuals indicates 
reductions in weight (5%), insulin resistance (23%), LDL cholesterol (6%), and 
triglycerides (5%).25 In some countries, metformin is relatively frequently co-prescribed 
with insulin for people with T1DM, particularly those who are overweight.  For example, 
in Tayside, Scotland (2008 data), 9.7% of people with T1DM and BMI>27 kg/m2  were 
currently prescribed metformin, rising to 15.9% for those with BMI>30 kg/m2 
(unpublished data), even although this is not mentioned or advocated in local or national 
guidelines.    
 
 
 


 
 
12
3.1 Work leading up to this proposal 
The investigators have long-standing interests in the cardiovascular effects of metformin.  
NS and JP previously conducted an RCT in non-diabetic women with chest pain and 
normal coronary arteries which demonstrated a pronounced effect of metformin on 
vascular endothelial function and parameters of exercise tolerance/ sub-maximal 
cardiopulmonary exercise testing.26  On the basis of these results, NS initiated the 
ongoing CAMERA trial to test the effect of 18 months’ metformin treatment on carotid 
intima media thickness (IMT) in 200 non-diabetic adults with stable coronary heart 
disease.27  Recently, in a collaborative epidemiological study between JP (Chief 
Investigator) and cardiology colleagues, positive effects of metformin were observed on 
mortality in people with type 2 diabetes and heart failure (in comparison with 
sulphonylureas).28   
In 2008, colleagues at the Steno Diabetes Center (SL and PR) reported the largest 
and longest RCT to date of adjunct metformin in T1DM in 100 participants over one year 
of follow-up.18  This trial, conducted at the Steno Diabetes Center, demonstrated the 
safety of metformin in this context and contributed important data on metabolic 
endpoints: for example, sustained and statistically significant reductions in mean weight 
(1.74 kg) and total cholesterol (0.37 mmol/L) were reported despite stable HbA1c - which 
may have been a feature of the study design.  The mean reduction in total cholesterol 
associated with randomisation to metformin tended to be larger in patients on stable 
statin therapy (mean 0.50 mmol/L).29 This trial was a major contributor to the recent 
systematic review of the RCT evidence base for metformin therapy in T1DM conducted 
by JP and HC,15 although, like the other previous studies, did not examine 
cardiovascular endpoints or surrogates. In formal meta-analysis of all appropriate 
published RCT data, consisting of only eight smaller studies and fewer than 200 patient 
years of follow-up, we concluded that metformin was associated with a reduction in 
insulin dose by 6.6 units/ day.  There were insufficient data to be confident regarding 
pooled effects on HbA1c, weight and cholesterol.15  It was clear: (i) that there are 
insufficient cardiovascular data, and (ii) that few studies have titrated insulin doses back 
up towards an HbA1c target after metformin therapy has been initiated.  
Finally, CS published in 2009 a major metformin RCT in people with type 2 
diabetes (n=390) treated with insulin therapy (the HOME trial).17 This study 
demonstrated a reduction in cardiovascular disease (prespecified as a secondary 
endpoint) over 4.3 years follow-up (hazard ratio, 0.61 (95% CI, 0.40-0.94; P=.02).  
HbA1c fell significantly (mean 0.4%) in participants randomized to metformin even 
although the protocol did not specify measures aiming to achieve intensive glycaemic 
control.  Like the UKPDS, which involved randomisation of 342 participants to metformin 
therapy, these data cannot be directly extrapolated to T1DM.  However, they contribute 
to the literature recently reviewed by Anfossi et al,14 which suggests that metformin may 
have direct and potentially beneficial cardiovascular effects in a variety of conditions, 
including non-diabetic individuals, which may be independent of (or additional to) effects 
mediated via glycaemia.30-31 
 
 
4. STUDY RATIONALE – HYPOTHESIS 
 
Hypothesis:  Does metformin added to titrated insulin therapy [towards target HbA1c 
7.0% (53 mmol/mol)] reduce progression of atheroma as measured by carotid artery 
intima-media thickness (cIMT) in adults with T1DM at risk of cardiovascular disease? 
 


 
 
13
Secondary and tertiary objectives: to examine the effect of metformin on other 
markers of diabetic micro- and macrovascular complications and intermediate disease- 
related biomarkers.  
 
The primary endpoint - progression of carotid IMT - is widely used as a surrogate of CVD 
morbidity and mortality in studies evaluating the efficacy of interventions targeting 
atherosclerosis.32,33  Thickness of the blood-intima and media-adventitia interfaces (IMT) 
is highly correlated between the carotid and coronary arteries whether measured using 
ultrasound or quantitative angiography.34 In people with T1DM aged 40 years, mean 
common carotid artery (CCA) IMT is similar to in controls 20 years older.35,36   In DCCT-
EDIC, a reduction in carotid IMT was reported36 six years before CVD outcome benefit 
was demonstrated.9  A recent consensus statement including a pooled analysis of more 
than 30 RCTs which used carotid IMT as a primary outcome supported its use in 
intervention trials and its treatment as a linear variable in studies of populations across a 
wide range of CVD risk.37  In small clinical trials, metformin has been reported to reduce 
carotid IMT progression in both metabolic syndrome and T2DM.38-40 
 
We acknowledge the ultimate importance of demonstrating effects of metformin 
on hard clinical endpoints but such a study would necessarily be very expensive and 
lengthy.  A study establishing the effectiveness of metformin on a meaningful surrogate 
endpoint of carotid IMT study is timely and feasible now, will bring results much sooner, 
and will establish whether an endpoint study is fully justified.  If adding metformin to 
insulin therapy in T1DM has favourable cardiovascular, metabolic, and/ or microvascular 
effects - whether via glucose-lowering or other mechanisms - many more people with 
T1DM could benefit from more widespread use given that it is a safe and already-
marketed oral agent.  At the recent JDRF Complications Prevention workshop (April 
2010), there was a near consensus that its potential to reduce macrovascular and 
microvascular complications in T1DM should be tested further. 
 
Current practice.  People with T1DM aged over 40 years should be treated with insulin 
and lifestyle recommendations to achieve and maintain target glycaemic control (HbA1c 
< 7.0%/ 53 mmol/mol).6   Blood pressure lowering therapy is usually commenced 
according to international guidelines where BP is > 140/ 90 mmHg with a target systolic 
BP < 130 mmHg (lower where there is microalbuminuria/ proteinuria).6  HMG-CoA 
reductase inhibitor (statin) therapy is recommended for those with known cardiovascular 
disease (CVD) but as there is no hard clinical trial evidence to guide cholesterol-lowering 
in primary CVD prevention there is considerable geographical variation in practice.  For 
example, T1DM is excluded from some guidelines (e.g. in the Netherlands) but in others 
(e.g. UK) statins are suggested independent of cholesterol levels for some aged over 40 
years, including those with CVD risk factors or long duration of disease.   
 
 
5. OBJECTIVES  
 
Primary objective: to test for the first time in a double-blind randomized, placebo 
controlled trial whether three years treatment with metformin 1000 mg bd added to 
titrated insulin therapy (towards target HbA1c 7.0%/ 53 mmol/mol) reduces 
atherosclerosis, as measured by progression of carotid IMT, in adults with confirmed 
T1DM aged 40 years and over and at increased risk for CVD.  
 


 
 
14
Secondary and tertiary objective: to examine over this period the effect of metformin 
on other markers of diabetic micro- and macrovascular complications and intermediate 
disease- related biomarkers.  The composite secondary endpoint will provide clinically 
meaningful information on the potential of metformin to influence clinical practice in this 
condition. The REMOVAL study will be five times larger and three times longer than any 
previously-conducted trial of metformin in T1DM.   
 
In REMOVAL, participants will be provided with the best care possible throughout the 
five-year follow-up period.    They will be encouraged and supported to work towards 
and maintain target glycaemic control (HbA1c < 7.0%/ 53 mmol/mol) independent of the 
randomization (i.e. metformin or placebo).  This will be achieved by: (i) increased 
attention to lifestyle measures; (ii) careful supported adjustment of insulin doses; and (iii) 
intensifying insulin regimens and doses where necessary.   
 
The primary, secondary and tertiary endpoints are defined below.  
 
Primary endpoint:  progression of averaged mean far wall common carotid artery IMT 
(CCA cIMT, measured in mm, at baseline, 12, 24 and 36 months).   
               
Secondary endpoints:   
(i) HbA1c;  
(ii) LDL cholesterol;  
(iii) albuminuria & estimated glomerular filtration rate  
(iv) retinopathy stage (ETDRS stage = Early Treatment Diabetic Retinopathy Study);  
(v) weight 
(vi) insulin dose;  
(vii) endothelial function (in some centres).  
 
N.B. We will consider a statistically significant improvement in two or more of these 
secondary endpoints to be a clinically meaningful result with the potential to influence 
clinical practice. 
 
Tertiary endpoints: To compare between treatment groups, as above, change in: 
(i) frequency of hypoglycaemia;  
(ii) treatment satisfaction;  
(iii) markers of endothelial function (t-PA, sE-selectin, sICAM-1);  
(iv) progression of averaged maximal distal common carotid artery IMT (CCA cIMT, 
measured in mm, at baseline, 12, 24 and 36 months).   
(v) vitamin B12 status  
 
 
6. STUDY DESIGN 
 
a) Type of study 
Randomized, double-blind, placebo controlled trial  
 
b) Assessments 
Carotid IMT measurements and analysis will be led and coordinated by Professor Nish 
Chaturvedi and Professor Alun Hughes at University College, London, UK where there is 
extensive experience in running large clinical vascular research studies.  Data will be 


 
 
15
acquired using a standard ultrasound scanning protocol.41 Both sonographer and 
participant will be positioned to facilitate high quality, reproducible images.  The same 
ultrasound system and preset image parameter settings (e.g. depth, gain, persistence, 
dynamic range, post processing) will be used throughout the study. Ultrasound 
equipment will be calibrated before commencement and every six months subsequently 
using an ultrasound phantom or as part of each site’s local annual service/ calibration. 
 
Right and left carotid arteries will be interrogated in B mode with a 7.0 MHz or higher 
broadband linear array transducer with concurrent recording of 3-lead ECG.  A plaque 
screen (defined as focal thickening ≥1.5 mm or 50% greater than surrounding IMT) of 
the near and far walls of the common carotid artery (CCA), bulb and internal carotid 
artery segments will be performed.  Then longitudinal images of the common carotid 
artery will be obtained at anterior, lateral and posterior angles, using Meijer’s arc to 
standardize the transducer angle.   
 
If a participant is found to have asymptomatic high grade carotid stenosis (i.e. >50%) on 
scanning, cardiovascular risk factor management will be reviewed and arrangements 
made by their site Principal Investigator (with verbal consent) to facilitate further 
investigation and treatment as appropriate - usually via the participant’s primary care 
physician.  However, our experience, including in older populations with established 
angiographic coronary disease, suggests that significant stenosis affected <1% of the 
study population.42  Participants will be eligible to enter and remain in the trial unless 
cIMT measurements of adequate quality cannot be obtained e.g following carotid artery 
surgery.  Incidental findings, such as tumours or dissection of the carotid artery, will also 
be reported to the site PI.  
 
Cineloops and images from at least five cardiac cycles will be saved in DICOM format.  
They will be uploaded on to the study web-based management system for digital 
archiving; as such they will be accessible to the reading centre at Imperial College 
London for evaluation and analysis.  cIMT measurements will be taken from the distal 1 
cm of the CCA (i.e. immediately proximal to the bulb).  Measurements will be performed 
in triplicate, and the mean of three readings used in analysis.  The primary assessment 
will be the within-person change in the averaged mean far wall common carotid artery 
(CCA) IMT as this is the most reproducible measure.  All measurements will be 
performed by one trained assessor at Imperial College London under the supervision of 
Professor Nish Chaturvedi and Professor Alun Hughes (AH) using a validated semi-
automated program (Wendelhag et al., 1997).43 The assessor will also undergo repeated 
‘masked’ QC cycles to assess repeatability within scans at a given timepoint, and within 
scans over time.   
 
The group has the necessary experience and expertise to carry out the required high 
level of training and standardization with the technical staff at the study sites – e.g. NC 
with the SABRE study (NC; www.sabrestudy.org) and JP with the RISC study 
(www.egir.org).44  NC and AH will be responsible for running the core-lab for blinded 
analysis of the cIMT study data and directing ongoing quality control of the ultrasound 
data acquisition at all study sites. The numbers of sonographers at each field site will be 
kept to a minimum (≤2) and all sonographers will undergo initial training and certification 
at the core laboratory to ensure standardization and high quality of imaging prior to 
commencement of the study.   
 


 
 
16
Carotid IMT QC:  (i) Accreditation – after training by the Carotid IMT reading centre at 
Imperial College London, each sonographer will be asked to submit five accreditation 
scans to demonstrate understanding and adherence to the carotid IMT protocol (these 
can be performed on healthy volunteers); (ii) Reproducibility – sonographers will also be 
asked to perform a repeat baseline carotid IMT measurement on six of the first willing 
study participants on a second occasion.  This can be performed at visit 1 or within a 
week of visit 1.  Sonographers will be expected to demonstrate an intra-operator 
coefficient variation (CV) of <10% in these 6 individuals; (iii) On-going QC – 
sonographers will invite the same study participants to continue to undergo repeat 
carotid IMT measurements at visits 8, 12 and 16 in order to assess for any measurement 
drift.  Results of Quality Control (QC) will be fed back to centres on a regular basis with 
follow up re-training/ certification as necessary.   
 
HbA1c will be measured in accredited local laboratories participating in DCCT-aligned 
quality control programmes.   
 
Lipids: samples of 7 ml EDTA plasma will be collected at Baseline, 0, 12, 24 and 36 
months for centralised total cholesterol, HDL-cholesterol, direct LDL-cholesterol and 
triglycerides assay – participants will be asked to fast from midnight for all of these 
samples except Baseline (Visit R1).  Aliquots will be stored at - 80ºC for transport to the 
laboratory in Glasgow for central assay.  Total and HDL cholesterol and triglycerides will 
also be measured as per routine care in local routine laboratories to guide the 
requirement for and optimisation of statin therapy: the most recent values (within three 
months) will be recorded on Case Report Forms at the time of annual visits. 
 
Microalbuminuria: status (positive or negative - see Appendix 5) as per routine care 
screening systems in local centres will be recorded annually in CRFs.  At the same 
visits, aliquots of urine will be frozen and stored at -80ºC (for later shipment to Glasgow) 
in case later centralised analysis is indicated. 
 
eGFR:  serum creatinine concentrations measured in local laboratories will be reviewed 
at least annually and checked against safety criteria.  Values from annual review (within 
three months) will be recorded on CRFs and used to calculate estimated glomerular 
filtration rate using the MDRD equation [eGFR ml/min/ 1.73m2 = 186 x serum creatinine-
1.154 x age-0.203 x (1.210 if Black) x (0.742 if female)].  In addition, we will retain aliquots of 
plasma in order to have the possibility later to measure cystatin C using laser 
immunonephelometry (Dade Behring).  
 
Retinopathy stage: two color 45° field retinal photographs (fields 1 and 2) will be taken 
in each eye at 0 and 36 months and 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.45 This is an 
ordinal scale based on the presence and severity of a combination of retinal lesions 
determined by comparison with standard photographs. Component retinal lesions are 
evaluated individually and then are used in assigning the diabetic retinopathy severity 
level.   
 
Images captured in each eye at the study site will be uploaded on to the study web-
based management system for digital archiving; as such they will be accessible to the 
OERC in Wisconsin for evaluation.  These images will consist of a 45 degree image 
centered on the optic disc (field 1) and a 45 degree image centred on the macula (field 


 
 
17
2).   Each set of images will be graded using custom designed computer software with 
built in completeness and consistency checks.  The grading system includes a 
preliminary and detailed grading followed by an edit and adjudication if necessary.  (Two 
different graders must agree on the retinopathy severity for the grading to be considered 
“final”.)  The preliminary grading will assess photo quality and will provide an overview of 
the retinopathy status as well as provide an opportunity to evaluate any imminent 
pathology that needs immediate attention.  If significant retinal pathology (e.g. retinal 
vein branch occlusion) exists, notification will be made to the site Principal Investigator 
with a copy sent to the coordinating centre.   
 
After preliminary grading, images will be sent to a second masked grader for a detailed 
evaluation of all diabetic lesions and other common conditions.  A comparison will then 
be made between the preliminary grading and the detailed grading for agreement on 
absence and/or presence and severity of diabetic retinopathy.  If there is a disagreement 
in the retinopathy severity level assigned, the eye will be sent to a third masked grader 
for an edit grade.  A similar comparison between the edit grade and the preliminary 
grade and detail grade will then be done.  If the edited grade still does not agree with 
either the preliminary or detailed retinopathy severity score, the eye will be sent to the 
consulting ophthalmologist for adjudication.  Additionally, since each study participant 
will have a baseline and closeout visit a longitudinal review will also be done towards the 
end of the study to ensure that any change in retinopathy status across visits represents 
real change and not an artifact of photo quality or grader error. 
 
If a participant is found by the Reading Center to have a previously-undetected retinal  
abnormality (at baseline) or an as-yet-undetected significant progression of retinopathy 
(at follow-up), this will be fed back to the site Principal Investigator in order that the 
participant (with verbal consent) can be referred locally for appropriate assessment and 
treatment - if necessary via the participant’s primary care physician.   
 
Blood pressure: will be measured in triplicate with at least 3 minutes between 
recordings and according to Standard Operating Procedures developed by the Scottish 
Diabetes Research Network 
http://www.sdrn.org.uk/sites/default/files/sop08_physicalmeasuresbloodpressure.pdf 
(using a validated  semi-automatic device). 
 
Weight:  will be measured using calibrated weighing scales (kg). 
 
Insulin dosage and frequency of hypoglycaemia:  Insulin dose and home blood 
glucose monitoring (HBGM) will be extracted by study nurses from the Study Diary and 
reported on the study CRF using dedicated fields including the Steno Hypoglycaemia 
Questionnaire (Appendix 3). 
 
Treatment satisfaction:  the Diabetes Treatment Satisfaction Questionnaire [status and 
change (DTSQs/ DTSQc)] will be administered at baseline and annual assessments.46 
 
Biomarker plasma samples: samples of plasma and serum will be stored at baseline, 0, 
12, 24 and 36 months according to the study Sample Handling Protocol.  In total, we will 
withdraw 7 mls serum at each of these time-points (stored in five aliquots of around 0.5 
mls each), and will repeat this procedure for 7 mls EDTA plasma; thus, in total, we will 
retain 10 aliquots (5 serum, 5 plasma) of samples for biomarker tests.  All will stored at -
80ºC for later transport to the central laboratory in Glasgow.  Lipids, hsCRP, t-PA, sE-


 
 
18
selectin, sICAM-1 and apoproteins will initially be measured on two such aliquots. 
hsCRP and apoproteins will be measured on automated platforms in NHS Glasgow 
laboratories.  Other assays will be run using established ELISAs with all samples run at 
the same time to minimise variability. Eight aliquots at each timepoint will be retained for 
future assays of interest as prioritised by the Steering Committee. Transport on to other 
laboratories will be covered by separate Material Transfer Agreements.   These will 
include markers of endothelial function (t-PA, sE-selectin, sICAM-1), vitamin B12 status 
(homocysteine, 
holotranscobolamin-II, 
S-adenosylmethionine), 
and 
Advanced 
Glycosylation  End-products.  As novel genes are currently being identified determining 
therapeutic response to metformin, we will also retain buffy coat for later DNA extraction. 
 
Endothelial function:  will be measured using ENDOPAT (Itamar ®) as Reactive 
Hyperaemia Peripheral Arterial Tonometry (RH-PAT), a non-invasive measurement of 
peripheral microvascular endothelial function using changes in digital pulse volume 
during reactive hyperaemia, at 0, 12 and 36 months (in approximately 400 of the 500 
patients i.e. in 80% of the study centres).  This method has been validated in children 
with T1DM in whom it has been shown to detect endothelial dysfunction.47  As 
Raynaud's phenomenon and treatment with α-blockers are contraindications to 
ENDOPAT, any affected individuals will be excluded from these assessments. 
 
Other assessments:  Serum C-peptide will be measured in local laboratories at the 
screening visit: participants will be withdrawn before randomisation in cases where this 
is > 200 pmol/L (= 0.2 nmol/L or 0.6 ng/ml).  Although the risk of lactic acidosis is almost 
negligible,48 plasma lactate  will be monitored according to the Schedule of Assessment 
in local laboratories; participants with values > 3.0 mmol/L (>27 mg/dL) will be recalled 
for clinical assessment within one week and treatment discontinued if this level is 
sustained: where possible, blood samples for lactate will be performed without a 
tourniquet (“uncuffed)” and following minimal exertion (this approach will be adopted for 
all repeat lactate measurements).   Full blood count and serum vitamin B12 (cobolamin) 
concentrations will also be monitored during the study in view of the small risk of 
metformin induced B12 deficiency identified in recent papers by the applicants (CS/ SL): 
concentrations fell by 80 pmol/L with prolonged therapy, although rarely outwith the 
reference range (150-550 pmol/L).18,49 Any individuals whose levels do fall below the 
reference range (<150 pmol/L) and who do not wish to discontinue therapy will be 
referred to their primary care physician for consideration of replacement therapy.  
 
Long-term follow-up:  The primary and secondary outcomes of the study are robust, 
but they are surrogates for long-term CVD risk. Where national competent authorities 
permit, we will seek informed consent from all participants to “flag” them in national 
systems using national health numbers to permit outcome assessment and to receive 
notifications of deaths.  This will be led by applicant IF who has particular expertise in 
this area. 
 
c) Sample handling storage and shipping  
Following pre-processing and aliquoting, blood and urine samples will be stored locally 
at –70ºC or –80ºC according to the study Sample Handling Plan prior to shipping to the 
central laboratory in Glasgow (Applicant NS). All study samples will be sent on dry ice 
using contracted couriers at annual intervals. All samples will be stored on arrival at –
80ºC. 
 
 


 
 
19
 
d) Statistical considerations/ number of subjects to be included in the study 
Primary endpoint cIMT:  For the primary endpoint of cIMT there will be a baseline 
measurement and repeat measurements at year 1, 2 and 3 (visits 8, 12 and 16). All 
those with a baseline and at least one follow up measurement will be included in 
analysis.   
 
We intend to analyse IMT data using repeated measures regression analysis assuming 
a linear progression in IMT measurements. We expect a mean progression of 0.044mm 
over 3 years (in the control arm) and a standard deviation (SD) for progression of 0.05 
mm; therefore a final sample size of 200 per treatment arm will provide 90% power (at 
5% significance level) to detect a difference of at least one third of an SD (0.0167mm) in 
3 year progression of averaged mean cIMT between treatment arms - an effect size 
more conservative than reported for acarbose, statins, and TZDs on cIMT.    
 
We therefore aim to recruit 500 patients (allowing for around 20-25% treatment 
discontinuation/ drop-out) and making the very conservative assumption that all those 
discontinuing treatment/ and withdrawing consent would not even have one follow up 
measurement  (in reality this may occur after one or more follow up cIMT measurements 
so power will be more than this estimate).    
 
Rates of progression and variation of common carotid artery IMT vary widely between 
different studies and data from T1DM patients, other than the patients in DCCT/EDIC 
who are younger than this trial participants, are sparse.  Our estimate of progression rate 
over three years (0.044 mm) is  at the lower boundary of that reported by Bots in a meta-
analysis  of  cIMT progression rates of control groups (almost all non-diabetic) from 
published RCTs.50  In that analysis the annual rate of change in mean cIMT was 0.0176 
mm (95% CI, 0.0149 to 0.0203).  Whilst many of the control group participants in this 
pooled analysis were not on statins (in contrast to many REMOVAL participants with 
T1DM) almost all were non-diabetic so that their progression rate would be expected to 
be lower than in diabetes. 
 
Other endpoints: The sample size for the study is based on the primary endpoint as 
described above.  This sample size also  yields 90% power at 5% significance level to 
detect differences of approximately  0.3 SD in  continuous outcomes i.e. lipid, metabolic 
and endothelial function parameter changes from baseline  at follow up. To put this into 
context, in the largest trial of metformin in T1DM to date the reported effects on LDL-C 
were considerably larger than this at (0.46 SD) so that we have ample power to replicate 
and refine the precision of this treatment effect.  For other endpoints we acknowledge 
that power is lower but emphasize that the sample size is appropriately based on the 
primary endpoint, and that we are stating a priori that we will consider a change in two of 
the seven secondary endpoints to be clinically meaningful.  Thus, for retinopathy 
progression, based on recent data from the Wisconsin Epidemiologic Study of Diabetic 
Retinopathy (Co-applicant Klein) we expect three year two-step progression in 
categorical ETDRS retinopathy stage to be 13.7%. Assuming follow-up retinal 
photographs in 400 participants, treatment with metformin would have to be associated 
with a hazard ratio of 0.40 to have 80% power to declare significance for this specific 
secondary endpoint (at p<0.05).   Given the relatively low marginal cost of acquiring the 
retinal photographs, many of which will be captured from routine screening, we believe 
incorporation of this endpoint in the study is an opportunity to acquire at least a useful 
point estimate for likely effect size (albeit with wide confidence intervals).  This may be 


 
 
20
useful in assessing the statistical power of any future retinopathy intervention trials with 
metformin. 
 
e) Feasibility of achieving required sample size  
Based on an analysis of the current living population of people with T1DM in Scotland 
with available risk factor data (n=22,891), we estimate that approximately 52% are aged 
40 years and upwards and meet our HbA1c entry criteria.  Of these 25% have at least 
three additional risk factors as per our criteria, such that an overall 13% of all adult clinic 
(≥16 years) attendees meet our entry criteria.   Assuming a response rate of 25% (as 
was achieved in the largest metformin trial in T1DM) to date,18 we therefore need to 
recruit from sites that have a total adult attendee list of about 19,000. It is on this basis 
that we have approached the participating sites which together have the appropriate 
base population.  We will retain the opportunity to extend recruitment rapidly to satellite 
sites in case rates of accrual are lower than expected.  
 
f) Duration of study and timelines 
Following the three month Run-In Period (taking placebo in the third month), participants 
will remain on therapy as randomized for three years (see Appendix 6).  All of the 22 
study visits on the Schedule of Assessments (page 10), are timed to coincide with three-
monthly appointments in routine care except nine which are “telephone-only” 
assessments. Recruitment will be completed within 12 months.  Data analysis will be 
conducted at the end of the trial.  
 
g) Number of sites 
18 sites with the capabilities to deliver all the assessments required are signed up to 
recruit into REMOVAL following regulatory and ethical approval.  This follows a detailed 
feasibility exercise in the five countries involved: Australia, Denmark, Canada, 
Netherlands and the UK.  Five “reserve” sites in the UK have also been identified by way 
of contingency planning. 
 
 
7. STUDY POPULATION  
7.1 Inclusion Criteria:  
 
1. 
Type 1 diabetes for five years or more* 
 
2.  
age ≥ 40 years  
3. 
7.0 ≤ HbA1c < 10.0% (53-86 mmol/mol) 
 
*defined as diagnosis below age 40 years AND insulin use within 1 year of diagnosis 
 
AND three or more of the following ten CVD risk factors: 
 
(i) BMI > 27 kg/m2 
 
(ii) current HbA1c > 8.0% (64 mmol/mol) 
 
(iii) known CVD/ peripheral vascular disease 


 
 
21
 
(iv) current smoker 
 
(v) estimated glomerular filtration rate < 90 ml/min per 1.73 m2 (MDRD equation) 
 
(vi) confirmed micro- or macroalbuminuria  [according to local assays and reference 
ranges - see Appendix 5] 
 
(vii) hypertension (BP ≥ 140/ 90 mmHg or established on antihypertensive treatment) 
 
(viii) dyslipidaemia:  
- total cholesterol ≥ 5.0 mmol/L (200 mg/dL); 
- OR HDL cholesterol < 1.2 mmol/L (46 mg/dL) [men] or < 1.3 mmol/L (50 mg/dL) [women]; 
- OR triglycerides ≥ 1.7 mmol/L (150 mg/dL); or established on lipid-lowering treatment 
 
(ix) strong family history of CVD (at least one parent, biological aunt/ uncle, or sibling 
with myocardial infarction, coronary artery bypass graft or stroke aged < 60 years) 
 
(x) duration of diabetes > 20 years. 
 
7.2 Exclusion Criteria: 
 
(i) Women of childbearing age (i.e. continuing menstrual cycle) not using effective 
contraception – see Appendix 4.  
 
(ii) Pregnancy and/or lactation; planning to get pregnant or not using effective 
contraception  
 
(iii) Patients with Acute Coronary Syndrome or Stroke/ Transient Ischaemic Attack within 
the last three months 
 
(iv) Symptomatic angina on mild or moderate exertion 
 
(v) Stage 3 or 4 heart failure defined according to the NYHA criteria 
 
(vi) Estimated glomerular filtration rate <  45 ml/min/1.73m2 (MDRD) 
 
(vi) Contraindications to metformin  
- hepatic impairment (ALT > 3.0 times ULN) 
- known hypersensitivity to metformin 
- acute illness [dehydration, severe infection, shock, acute cardiac failure] 
- suspected tissue hypoxia 
 
(vii) Metformin treatment for more than three months within last two years  
 
(viii) Anaemia (haemoglobin < 10.0 g/dL) 
 
(ix) Ongoing treatment with oral steroids, pramlintide or GLP-1 agonist therapy 
 


 
 
22
(x) Hypoglycaemia unawareness confirmed as significant by site Principal Investigator 
 
(xi) Impaired cognitive function/ unable to give informed consent 
 
(xii) Previous carotid surgery or inability to capture adequate carotid images 
 
(xiii) Gastroparesis (on gastric emptying studies) confirmed as significant by site 
Principal Investigator OR more than two hospital admissions with unexplained vomiting 
in last year 
 
(xiv) history of biochemically-confirmed acidosis (with lactate > 5.0 mmol/L) 
 
(xv) Any coexistent life-threatening condition including diagnosis of cancer within prior 
two years  
 
(xvi) history of alcohol problem or drug abuse 
 
(xvii) diabetes other than type 1 diabetes (e.g. secondary to pancreatitis, 
pancreatectomy or primary pancreatic disease) 
 
(xviii) Involvement in a clinical trial involving an investigational medicinal product within 
the last six months 
 
7.3 Identification of participants and Informed Consent.   
 
a) Pre-screening: Procedures may vary between sites, but all have systems in place for 
identifying potentially eligible participants in secondary and tertiary care.  In many sites, 
participating investigators will systematically review their clinical record systems for 
potentially eligible patients and invite them to specific screening visits.  In other sites, 
clinical visit lists will be pre-reviewed in order that potentially eligible individuals can be 
sent an information sheet by post one week before their routine scheduled review visit.  
Eligibility criteria of those indicating agreement to be approached will then be checked at 
the routine visit, and the information sheet and study procedures explained.  Potential 
participants will be given a Patient Information Sheet and an Expression of Interest Form 
(with prepaid envelope) at this time and will be asked for permission to contact again to 
discuss further and (if appropriate) arrange a screening visit 
 
b) Screening: A separate non-fasting visit will then be arranged within two weeks at 
which potential participants will have further time to discuss with the study nurse and 
doctor.  Eligibility criteria will be checked by the study doctor and a research nurse. 
Risks and side-effects of the active trial medication will be explained. Metformin is long 
established in clinical practice and has a good safety profile. The main side effects are 
gastrointestinal disturbances that are dose dependent see below.   The procedures for 
management 
of 
hypoglycaemia 
will 
be 
discussed: 
(http://www.sdrn.org.uk/sites/default/files/sop27_managementofhypoglycaemia.pdf). 
 
c) Pregnancy: Women of childbearing age will be asked about pregnancy status and 
contraceptive usage and a urine pregnancy test will be conducted (following informed 
consent – see below – and prior to entering the Run-In Period).  There have been 


 
 
23
several recent trials of metformin use in pregnancy, especially for treatment of 
gestational diabetes mellitus. Systematic review of these trials concludes no adverse 
effects of metformin as compared with insulin therapy.51,52  Nonetheless in this trial we 
will not recruit those wanting to become pregnant and will discontinue study drug in 
women who become pregnant.  All such pregnancies will be notified to the 
pharmacovigilance sponsor using the standard pregnancy notification form of the 
sponsor and the pregnancy followed to outcome. 
 
d) Run-in Period: Those who choose to participate will be invited to give informed 
consent as per Good Clinical Practice standards and will be invited to enter the three 
month Run-In Period.  They will be given a unique identifying number based on the 
country of origin, specific site and sequence of recruitment; this will be used for all 
subsequent correspondence, transfer of samples and data input.  They will be 
encouraged to conduct frequent home blood glucose monitoring (HBGM) and record the 
results in a standardised Study Diary designed to record (and permit easy extraction) of 
changes in insulin dosages and episodes of hypoglycaemia (severe or symptomatic).   
Technique will be reinforced by study nurses.  “Sick day rules” as in usual clinical care 
will be reinforced and supplemented using information printed in the Study Diary.  
 
Individuals with higher glucose/ HbA1c concentrations at the time of enrolment will be 
carefully reviewed.  Where possible any major changes to insulin regimen thought to be 
necessary at this time or during study follow-up (e.g. switch from multiple daily injections 
to pump therapy) will be discussed and implemented in the Run-in Period.  BP control 
will also be reviewed in detail for each participant and any additional assessments 
necessary scheduled (e.g. 24 hour ambulatory BP monitoring).  If these confirm that new 
therapy is indicated according to the above criteria, this will be discussed and explained.  
Where there is agreement, such therapy will be initiated (with any additional monitoring 
required) during the Run-in Period.   Cardiovascular risk factors and cholesterol levels 
will be reviewed with the aim of identifying participants for whom statin therapy may be 
indicated at present (or in the near future).  As in clinical practice, a final decision will be 
reached in discussion with individual participants.  
 
It is recognised that during the years followed up in the trial many participants will require 
further changes to be made in their regimens in order to achieve glucose (and other) 
targets: such changes will be encouraged, supported  and implemented. 
 
During the third month of the Run-in Period, participants will be asked to take one tablet 
of run-in medication (i.e. placebo matching metformin 500 mg) once daily with their 
evening meal. 
 
e) Baseline assessments: see Schedule of Assessments (page 10).  At the beginning 
of the Run-in Period, relevant items from past medical history, concomitant medications 
(including duration, type and dose of any previous statin therapy) will be extracted from 
routine health records and validated with the participant. HbA1c, liver function tests, 
albuminuria and renal function results will also be captured into the electronic Case 
Report Form from the recent clinic visit.   Where liver function tests and FBC were not 
performed in routine care within the previous 90 days, or where there are missing data, 
these will be requested  from local laboratories as additional tests.   
 
Height, body weight, ethnicity, and smoking status will be extracted where possible from 
routine clinic data and validated with patient. The Investigator/ study nurse will be 


 
 
24
responsible for extracting validation information from clinical records.   Adherence will be 
assessed by tablet counts 3-6 monthly (which will be documented on the electronic Case 
Report Form).  
 
f) Randomisation visit: At the end of the three-month Run-In Period, participants will 
attend after avoiding strenuous exercise and having fasted from 10 pm the previous 
evening including avoidance of smoking and caffeine (free water intake permitted).  This 
visit will include: (i) check of adherence to study medication over the third month (tablet 
counts); (ii) measurement of the primary endpoint (carotid IMT); and (iii) repeat 
anthropometric and metabolic assessments (see Schedule of Assessments – Section 2).  
Pregnancy testing will be conducted if indicated.   
Participants with: (i) less than 70% adherence on tablet counts who are non-
adherent in the view of site staff; or (ii) inadequate quality carotid images in the view of 
the local sonographer will be withdrawn at this stage i.e. before randomization.  Those 
who met HbA1c criteria at the screening visit (R1) but who now have HbA1c < 7.0% (53 
mmol/mol) will not be excluded at this visit. 
Participants remaining eligible, who satisfy the study inclusion/ exclusion criteria 
and have provided written informed consent can then be randomized to metformin or 
placebo by telephone via a call to the study Interactive Voice Response System (IVRS) 
or electronically via the study portal for the study electronic CRF, see section 14.1.   
 
g) Follow up: see Schedule of Assessments (page 10) and Section 10 (page 31).  
Participants will then have visits at one month, three months and 3-6 monthly thereafter 
until study cessation. As almost all patients will be attending for routine clinic care, we 
envisage that most visits will be conducted by study nurses in the same location and 
time as usual care and include: 
- 
assessment of adherence 
- 
capture of data on prespecified clinical events (see Section 13) 
- 
safety questionnaire  
- 
Diabetes Treatment Satisfaction Questionnaire  
- 
routine clinic bloods and additional trial specific bloods  
- 
capture of data on prespecified concurrent medications  
- 
capture of data held in Study Diary to be used  by patient to record hypoglycaemic 
episodes and insulin dose 
 
h) Insulin dose titration:  At the beginning of the Run-in Period, insulin regimen will be 
reviewed by the Investigator and optimized against standard of care [target HbA1c < 
7.0% (53 mmol/L)] according to local practice under national guidelines.  For example, 
participants may be referred into existing structured education programmes and insulin 
regimens may be changed e.g. from twice daily biphasic injections to multiple dose 
injections (MDI), or from MDI to insulin pump therapy.   
Study nurses will arrange to telephone participants at 2, 4 and 8 weeks to reinforce 
frequent HBGM recording and monitoring, encourage hypoglycaemia reporting, discuss 
ongoing titration of insulin and reinforce concordance with any additional therapies 
prescribed.  Email may be used to facilitate communication and exchange of data as an 
adjunct to telephone communication when convenient for participants and permitted by 
the relevant IRBs and Ethics Committees; however, in the UK communications of 
recommended changes of insulin doses will be by telephone only.  Telephone visits will 
continue in the first four weeks following randomization with calls at 1, 2, 4 and 8 weeks 
between study nurse and participant during which HBGM results will be discussed.  


 
 
25
The need to optimize glycaemic control in all participants will be emphasized at the 
initial Investigator Meeting and subsequent regular Investigator Teleconferences.  To 
this end, HbA1c data, blinded to randomized therapy, will be reviewed by study centre at 
the University of Glasgow and fed back to Investigators three monthly with their own site 
performance plotted against the other sites (anonymised).  Therapeutic strategies will be 
discussed at a teleconferences three and six months after “first-patient, first visit” and six 
monthly thereafter (or more frequently if required).   In those centres in which average 
glucose control is higher than in other centres, a Steering Committee member (Dr Irene 
Hamriak) with particular expertise in achievement of glucose targets within trials 
(including DCCT and ACCORD) will lead on supporting local investigators and 
participants to achieve targets with every available means.  
i) Hypoglycaemia management plan: Symptoms of hypoglycaemia include paleness, 
shaking, perspiration, a feeling of weakness, increased heart rate, hunger, agitation, 
difficulty in concentrating, irritability, fatigue, blurred vision, temporary loss of 
consciousness, 
confusion, 
convulsions 
and 
coma 
(see 
http://www.sdrn.org.uk/sites/default/files/sop27_managementofhypoglycaemia.pdf). 
 
Participants will be asked to record all hypoglycaemic episodes on the relevant page 
in their Study Diary. Throughout the trial they will be encouraged to check their blood 
sugar if they feel hypoglycaemic and record the result. However, they should not delay 
treating symptoms if their blood sugar meter is not readily available. All major (severe) 
hypoglycaemia should be reported to the Investigator/ nurse team within 24 hours during 
the metformin dose titration phase of the study (see page 27 below).  Contact should be 
maintained with the participant so that insulin dose can be adjusted appropriately. A 
hypoglycaemic event will be defined as “an event which causes the symptoms of 
hypoglycaemia at any level of blood glucose measurement or a blood glucose 
measurement of less than 2.8.mmols/l  with or without symptoms.” 
 
Hypoglycaemic events will be categorised into minor, major episodes and any 
involving unconsciousness as follows:  
 
Minor episodes are treated by the participant and will be resolved by eating 
some short acting glucose source, followed by a longer acting carbohydrate.  
 
Major (or severe) episodes require assistance from one or more other 
persons to resolve the event e.g. another family member or paramedic.   
 
Major (or severe) episodes involving unconsciousness (self-reported) 
All episodes of severe hypoglycaemia should be reported to study nurses as soon as 
possible in order that the hypoglycaemia management plan can be followed. 
As in the study by Lund et al,18 we will also record information on self-reported 
blood/ plasma glucose levels during hypoglycaemic events as captured from the Study 
Diary.   
Following an episode of severe hypoglycaemia, standard causes of hypoglycaemia 
will be reviewed in order to identify an obvious precipitating factor (insulin dosing error, 
accidental intravascular injection or other injection site problem, excessive unplanned 
exercise, missed meal, alcohol consumption, renal impairment, loss of warning signs).  
HbA1c will be repeated where the most recent available value is more than six weeks 
previously.  Where no obvious reversible precipitant is identified, participants will be 
advised to reduce insulin dose by 10% over the following month and perform more 
intensive HBGM.  At review, after one month, the aim will be to uptitrate insulin dose 
once again, unless glycaemic target HbA1c < 7.0%/ 53 mmol/mol continues to be met on 
the reduced dose or there have been further episodes of major or unacceptable minor 
hypoglycaemia. 


 
 
26
If the participant has a major hypoglycaemic event and is brought into the 
Emergency Department, this will only be considered an SAE if the hospital stay is longer 
than 12 hours.  Minor hypoglycaemic episodes (i.e those not requiring assistance from 
another individual) will not be recorded as an AE.  
 
j) Participant discontinuation: Participants will be free to discontinue study medication 
at any point during the study.  Where possible, follow up in the trial will be continued with 
continuing titration of insulin doses to target.  If informed consent for follow-up is 
withdrawn, data collected up to self-withdrawal will be included in the study unless the 
participant wishes otherwise.  Clinical samples will be destroyed at their request. 
 
k) Source documents:  Participants will be asked to provide informed consent for 
investigators to obtain copies of official documentation (discharge letter or clinic letter) of 
any cardiovascular events which will be made available at the request of study monitors. 
This will also apply for Severe Adverse Event reporting (Section 13, page 34 for which we 
will obtain copies of official documentation (discharge letter or clinic letter).  
 
l) Long term follow-up:  Informed consent will be sought from participants for later long-
term follow-up for events occurring following completion of the trial via linkage to national 
databases (e.g. cardiovascular events/ mortality). Where permitted by ethics/ IRB 
committees in the various national territories, consent will also be sought for up to 20 
years for: (i) contacting the participant’s primary care practitioner; (ii) contacting by 
telephone to complete questionnaire(s); (iii) sending out questionnaire(s); and/or (iv) 
inviting to follow-up visit(s). 
 
 
8. MEDICATIONS 
 
Formulation, source and labelling of study medication. The Investigational Medicinal 
Product (IMP) in the study is metformin 500mg or matching placebo tablets. The 
metformin tablet is identical in chemical composition to Glucophage 500mg licensed in 
the UK.  See the Summary of Product Characteristics for further details.53 The matched 
placebo will be formulated as film-coated tablets matching Glucophage 500 mg tablets 
(tablet core - cellactose, calcium hydrogenphosphate, magnesium stearate; film coating 
– hypromellose). Metformin 500mg and placebo tablets will be manufactured in 
accordance with Good Manufacturing Practice.   Both active and placebo medication will 
be packaged and distributed by Merck-Serono® and supplied to study sites free-of-
charge. 
 
The single-blind run-in packs will contain sufficient supplies for 28 days treatment.  For 
the double-blind treatment period, metformin 500 mg and matching placebo tablets, will 
be packed in matching packs so as to maintain the blind.  Each pack contains sufficient 
supplies for 90 days’ treatment with a small overage (excess).  Packs will be labelled 
with a unique pack number that will be used to assign treatment to the patient via the 
IVRS/IWS system whilst maintaining the blind. Packs will be labeled in accordance with 
Good Manufacturing Practice and local regulatory requirements.  Labelling text will 
include protocol identification reference, storage caution statements, dosing instructions, 
batch number and expiry date. A tear-off label will be attached for dispensing purposes.   
 


 
 
27
Drug storage and stability. All study drug must be stored in the original container 
below 30ºC in a secure location.  Although the investigator is ultimately responsible for 
ensuring that all study drug received at the site is inventoried and accounted for 
throughout the study this should be delegated to an appropriately trained pharmacist at 
the site who will be responsible for the accountability of all used and unused trial 
supplies.  The study drug must be stored in accordance with the study medication label. 
The study medication provided for use in the study will be used only as directed in the 
study protocol and only for trial participants.   
 
Drug ordering. Study drug will only be released to the study site once all the 
appropriate regulatory and governance approvals are in place.  The IVRS/IWS will track 
drug supplies at individual study sites and trigger additional drug supply shipments when 
required.    
 
Drug accountability. A record of study drug movements will be maintained for 
accountability purposes.  Delegated pharmacy staff will be required to receipt the drug 
via the IVRS/IWS system and record the dispensing of the study drug to participants on 
appropriate drug accountability forms.  Study drug should not be dispensed or supplied 
to patients without the appropriate IVRS/IWS notifications being completed.  Drug 
accountability records will include the use by each patient, disposal of patient returned 
medicines and any unused study medication.  Accountability records will include dates, 
quantities, batch numbers, expiration dates and the unique code numbers assigned to 
the investigational medicinal product and study participants.   
Only those supplies intended for use in the study will be dispensed to study 
participants.  Unused study drug will be disposed of in accordance with the guidance in 
the “Disposal” section below. Study drug will not be used for any purpose other than the 
present study.  Study participants must be instructed to return all original containers 
including empty, partially filled or unused medication at the end of each treatment period 
in order that an assessment of medication adherence can be performed.   
Accountability logs will be made available for inspection by the study sponsor or 
their designee and regulatory inspectors.  Sites may be required to send anonymised 
accountability log information to permit remote site monitoring.  Study sites will be 
provided with appropriate drug accountability logs and further detailed written 
information on study drug management.   
 
Maintaining blinding. Study medication will be assigned electronically or by IVRS 
(Interactive Voice Response System) supplied by the Robertson Institute for Biostatistics, 
see section 14.1.  
 
Unblinding. Ceasing treatment, rather than unblinding, will be carried out as far as 
possible. In any case of hospitalisation with acute illness participants will be advised to 
discontinue the study medication and inform the relevant clinician. However, where 
knowledge of treatment may assist emergency treatment, unblinding will be supported.  
Study participants will be provided with a Patient Alert Card indicating the name of the 
investigational study drug, the study number, the investigator’s name, a 24-hour contact 
number and information on how to unblind in an emergency: a freephone number will be 
provided which permits this via a telephone menu system.  Several prompts in the 
system warn the user that they require to be a health professional and to record their 
name and other pertinent information.  For each unblinding an email alert is generated to 
the Study Coordinator and Chief Investigator.  Requests are set at a maximum of 2-3 per 
24 hours in case of malicious unblinding. The most likely scenarios for unblinding will be: 


 
 
28
confirmed pregnancy, overdose/ accidental ingestion, development of acute renal failure.  
The Patient Alert Card will be collected from patients at the end of their involvement in 
the study. 
 
Route of administration. Tablets should be taken orally and swallowed with a glass of 
water and food (at mealtime). 
 
Double-blind treatment periods dose and dose titration. Metformin as Glucophage 
500mg two tablets twice daily (= 1000mg twice daily) or matching placebo tablets. 
Participants will be asked to titrate up the medication according to usual practice with 
metformin i.e. they will take one tablet with the evening meal for one week; this will then 
be increased to additional tablets at weekly intervals with the morning meal, evening 
meal and then morning meal until a dose of 1000 mg twice daily is achieved.  This dose 
titration, and any insulin adjustment required, will be supported by the weekly telephone 
calls and guidance printed in the Study Diary.  Participants will also be able to call study 
nurses.  If it is found that a participant is only able to tolerate a lower daily dose of study 
medication, in particular due to gastrointestinal side-effects (see below), this will be 
permissible and will be documented accordingly.  
 
Risks of treatment. Please refer also to the SmPC.53 
o Lactic acidosis (blood pH <7.35 with plasma lactate >5.0 mmol/L): This condition 
has been associated with metformin, usually in cases of acute renal failure, but 
there remains no evidence that metformin causes lactic acidosis in stable 
individuals with adequate renal function.23,24 The reported incidence of lactic 
acidosis in patients receiving metformin hydrochloride is very low (approximately 
0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 
patient-years) and in 8.4 vs 9.0 cases per 100,000 patient years MF vs other 
diabetes medications of placebo (www.ahrq.gov – Johns Hopkins). In more than 
20,000 patient-years exposure to metformin in clinical trials, there were no 
reports of lactic acidosis. Risk factors are significant renal insufficiency,  liver 
dysfunction,  severe acute congestive heart failure and  any state where  there  is 
risk of hypoperfusion and hypoxaemia. 
o Hypoglycaemia: metformin without concomitant diabetes medications has not 
been shown to cause hypoglycaemia. However, in combination with insulin 
therapy, there may be a small additional risk, although neither minor or major 
overall hypoglycaemia risk was statistically elevated in the largest previous trial.18  
Participants will be informed of the symptoms of hypoglycaemia, namely skin 
pallor, trembling, perspiration, a feeling of weakness and/or hunger, blurred 
vision and advised to take appropriate corrective measures e.g. sugar-containing 
drink or food.  
o Pregnancy and lactation: metformin is increasingly considered safe in 
pregnancy25 but will be an exclusion criterion in this study [see Section 7.3(c)].  
o Renal dysfunction: Metformin is excreted renally and may therefore accumulate 
during significant renal dysfunction. Therefore renal function will be assessed by 
regular U&E analyses during the trial. Intravascular administration of iodinated 
contrast agents in particular (e.g. coronary or peripheral angiograms, contrast 
imaging such as CT scans) may precipitate renal failure with resultant 
accumulation of metformin. Therefore standard procedures will be followed in 
such circumstances: the study drug will be discontinued prior to the test and not 
reinstated until >48 hours later only after it has been verified that renal function 
has returned to pretest levels. 


 
 
29
Choice of eGFR threshold (45mL/min/1.73m2) in study: Metformin is commonly used 
safely in patients with moderate chronic renal impairment. In one example in Tayside,54 
4.8% of patients on metformin in Tayside had a serum creatinine >150umol/L with one 
case of lactic acidosis in 4600 patient years; that case was related to acute myocardial 
infarction with secondary acute renal failure and not due to metformin therapy. In 
another study from Edinburgh,55 researchers concluded that an eGFR threshold 
between 36 – 40mL/min/1.73m2  would be useful and safe. The UK National Institute for 
Clinical Excellence published criteria for use of metformin in chronic renal impairment in 
2008.56 This guidance states that metformin is contraindicated with a serum creatinine 
>150 micromol/L or eGFR <30 ml/minute/1.73 m2. Furthermore the guideline 
recommends that the dose of metformin be reviewed if the serum creatinine exceeds 
130 micromol/L or the eGFR is below 45 ml/minute/1.73 m2. 
Accordingly, we have selected a baseline eGFR threshold of 45mL/min/1.73m2 in this 
study below which participants will not be recruited. If during participation a subject’s 
eGFR falls to <45mL/min/1.73 m2 consideration will be given to IMP dose reduction. If 
during participation a subject’s eGFR falls to <30mL/min/1.73 m2 IMP will be 
discontinued. 
 
Side effects. Please refer also to the SmPC.53 
- Very rare (<1/10 000): Chest discomfort, palpitation.  These should only be recorded as 
AEs  if associated with an SAE, or if they result in discontinuation of study medication or 
dose reduction.  
- Common (>1/100): taste disturbance, abnormal stools, hypoglycaemia (see below), 
myalgia, lightheadedness, dyspnoea, nail disorder, rash, sweating increased, chills, flu 
syndrome, flushing, skin reactions.  These should only be recorded as AEs if they result 
in discontinuation of study medication or dose reduction. 
- Common (> 1/100): Decreased vitamin B12 absorption has been reported in long term 
use, however although plasma levels fell significantly in the HOME trial over 4.3 years,17 
actual levels usually remained within standard reference ranges.  Vitamin B12 Serum 
levels falling below the local assay reference range (150 pmol/L or equivalent) should be 
recorded as AEs. 
- Very common (>1/10): Gastrointestinal effects are most common and may include 
nausea, vomiting, diarrhoea, abdominal discomfort, headache and loss of appetite. It is 
well recognised that these side-effects usually resolve spontaneously following initiation 
of therapy and are minimised if the dose is titrated upwards (as will be done in the study).  
These events should only be recorded as AEs if they result in discontinuation of study 
medication or treatment dose reduction. 
 
Serious Adverse Reactions that are expected (<0.5%)  
- Lactic acidosis may occur extremely rarely (see page 28 above).  It will usually be 
associated with hospitalisation and reported as an SAE.   
 
Abnormal Laboratory Findings 
The following will be specifically recorded as AEs on CRF pages: 
- LFTs: any abnormal results of >2.5 times upper limit of normal  
- Reduction in eGFR to < 45 ml/min/1.73 m2 and < 30 ml/min/1.73 m2 
- Hb < 10.0 g/dL AND fall of >1.5 g/dL from baseline 
- MCV > 105 fL  
 
Other. Participants will be advised to avoid alcohol excess during the study though this 
is not an exclusion criteria. Their primary care physician (where applicable) will be 


 
 
30
advised that if commencing a medication which may lead to a deterioration in renal 
function, such as NSAIDs, they should monitor renal function and advise the study 
doctor of any deterioration. 
 
Interruption of treatment: in preference to permanent treatment withdrawal or 
withdrawal from the study, investigators will permit treatment interruption of any duration 
(which will be documented) in any participant who develops any of the following: 
-  Acute illness: severe infection, shock, acute or clinically unstable cardiac failure 
-  Acute myocardial infarction or other acute coronary syndrome 
-  Surgery: treatment will be discontinued 48 hours prior to elective surgery with general 
anaesthesia and will be recommenced no earlier than 48 hours following surgery and 
only when it has been confirmed that renal function has returned to pre-operative levels. 
-  Requirement for investigation involving intravascular iodine-containing contrast agent 
(as per national guidelines): treatment will be discontinued 48 hours prior to investigation 
and recommenced no earlier than 48 hours afterwards. 
-  Anaemia (Hb<10.0 g/dL AND fall of >1.5 g/dL from baseline) considered by the local 
investigator to be potentially related to study medication. 
 
In these cases, treatment will be restarted where possible in accordance with the 
Investigator’s clinical judgement, local practice, standard-of-care, and national guidelines 
(renewed titration from a lower starting dose is not usually required unless interruption 
has been prolonged e.g. more than four weeks).  Where treatment interruption has 
persisted for four weeks or more it will be documented as permanent. 
 
Withdrawal of treatment:  Investigators will withdraw from treatment any participant 
who develops any of the following: 
-  Pregnancy: discontinue if participant becomes, or intends to become, pregnant 
-  Development of new contraindications to metformin  
o hepatic impairment (ALT > 3.0 ULN) 
o renal impairment with eGFR <30 mL/min/1.73m2 during study – see page 28 
-  Biochemically-confirmed severe lactic acidosis (>5.0 mmol/L with acidosis) 
-  Hypersensitivity to metformin 
 
Dose reduction of treatment:  Where eGFR falls below 45 ml/min/ 1.73m2 on any 
measurement Investigators should permanently reduce metformin dose to 500 mg twice 
daily. 
 
Withdrawal from study: Investigators will withdraw from the study any randomized 
participants with: 
- 
confirmed pregnancy 
- 
withdrawal of consent for follow-up 
- 
any other reason  agreed between the participant and the site Principal Investigator  
 
At the end of the study:  No further study medication will be provided.  
 
Assessment of adherence: Tablet counts will be carried out by study nurses following 
at relevant study visits, including the final clinic visit, to assess adherence. This will be 
documented in the eCRF.  Site medical and nursing staff will also discuss and reinforce 
adherence to study medication with participants. 
 
Concomitant medication. No concomitant medication is specifically excluded.  


 
 
31
9.  TIMELINE FOR PARTICIPANT IN STUDY 
Males and females with T1DM, aged > 40 years, HbA1c>7.0%;
not on metformin, three or more CVD risk factors.
Eligibility/ informed consent: metabolic, anthropometric assessments
Carotid IMT, retinal images, metabolic/ anthropometric assessments
Metformin 500mg daily, 
titrating to 1 g bd over 4 weeks 
with supported insulin dose 
titration to target HbA1c 7.0%
Matching placebo, 
titrating over 4 weeks 
with supported insulin dose 
titration to target HbA1c 7.0%
3-6 monthly dispensing, tablet checks, insulin dose and hypoglycaemia recording 
Three annual repeat visits for carotid IMT, metabolic/ anthropometric 
assessments; repeat retinal images at final visit.
Study close-out after three complete years for each participant
3-month run-in: optimise insulin and CV risk factor management (placebo in third month)
RANDOMIZATION
 
 
10. CLINICAL MEASUREMENTS AND EXAMINATIONS 
AT EACH VISIT 
 
Prescreening visit.  Provision of Patient Information Sheet and Expression of Interest 
form.  Request for permission to contact. 
 
Screening Visit (R1 start of Run-in Period) – non-fasting:  Informed consent 
requested: if provided, full medical history, vital signs, weight, waist circumference, 
height measurements. Dispense study medication (which will be commenced following 
telephone prompting at visit R4). Give out diary. Treatment satisfaction questionnaire. 
Hypoglycaemia questionnaire. Titrate insulin. Blood samples (U&E, LFT, HbA1C, local 
laboratory total cholesterol, HDL and triglycerides, FBC, vitamin B12, C-peptide. 
microalbuminuria status.  Samples for LDL, plasma biomarkers.  Urine aliquot. 
Pregnancy testing if appropriate. Concomitant medications recorded.  Review 
requirement for statin or ACE inhibitor against local practice, national guidelines and 
standard-of-care. 
 
Telephone visits (R2-R4): insulin dose titration.  Questions on adverse events.  Visit R4 
only: commence study medication.   
 
Study Visit 1 (randomization): Vital signs, weight, waist circumference.  Carotid IMT 
(can be done during last four weeks of Run-In).  Retinal imaging.  Endothelial function.  
Collect/ count unused medication.  Dispense study medication with advice on dose 
titration.  Give out diary. Hypoglycaemia questionnaire. Treatment satisfaction 


 
 
32
questionnaire. Insulin dose titration/ record insulin dose.  Blood samples (U&E, LFT, 
HbA1C, local laboratory total cholesterol, HDL and triglycerides, FBC, vitamin B12, 
microalbuminuria status if not available from Screening visit R1).  Samples for LDL, 
plasma biomarkers.  Lactate. Urine aliquot.  Pregnancy testing if appropriate. 
Concomitant medications recorded.  Questions on adverse events.  Randomisation. 
 
Telephone Visits 2-4 (0–1 month). Insulin dose titration/ record insulin dose, study 
medication dose titration (except at telephone visit 4). Questions on adverse events.  
Concomitant medications and Hypoglycaemia questionnaire (visit 4 only). 
 
Study Visit 5 (3 months).  Weight, waist circumference; U&E, LFTs, HbA1c as per 
routine care.  Lactate. Insulin dose titration/ record insulin dose. Hypoglycaemia 
questionnaire. Dispense study medication.  Collect unused medication. In some subjects 
it will be clear by this stage whether they will only tolerate a single daily dose of study 
medication. This will be documented and subsequent prescriptions will be reduced 
accordingly. Remaining study medication will be sent to pharmacy for tablet count. Any 
change in concomitant medications will be recorded. Questions on adverse events.  
 
Study Visit 6 (6 months).  Vital signs, weight, waist circumference; U&E, LFTs, HbA1c 
as per routine care.  Hypoglycaemia questionnaire. Insulin dose titration/ record insulin 
dose. Give out diary. Dispense study medication.  Collect unused medication. Any 
change in concomitant medications will be recorded. Questions on adverse events.  
 
Telephone Visit 7 (9 months).  Insulin dose titration/ record insulin dose. 
Hypoglycaemia questionnaire. Any change in concomitant medications will be recorded. 
Questions on adverse events. 
 
Study Visit 8 (12 months).  Vital signs, weight, waist circumference.  Carotid IMT.  
Endothelial function. Dispense study medication. Collect unused medication.  
Hypoglycaemia questionnaire. Treatment satisfaction questionnaire. Insulin dose 
titration/ record insulin dose.  Blood samples (U&E, LFT, HbA1c, local laboratory total 
cholesterol, HDL and triglycerides, FBC, Vitamin B12, lactate), microalbuminuria status.  
Samples for LDL, plasma biomarkers.  Urine aliquot.  Pregnancy testing if appropriate. 
Concomitant medications recorded.  Questions on adverse events. 
 
Telephone Visit 9 (15 months).  Insulin dose titration/ record insulin dose. 
Hypoglycaemia questionnaire. Questions on adverse events. 
 
Study Visit 10 (18 months).  Vital signs, weight, waist circumference; U&E, LFTs, 
HbA1c as per routine care.  Insulin dose titration/ record insulin dose. Give out diary. 
Hypoglycaemia questionnaire. Dispense study medication.  Collect unused medication. 
Any change in concomitant medications will be recorded. Questions on adverse events.  
 
Telephone Visit 11 (21 months).  Insulin dose titration/ record insulin dose. 
Hypoglycaemia questionnaire. Questions on adverse events. 
 
Study Visit 12 (24 months).  Vital signs, weight, waist circumference.  Carotid IMT.  
Dispense study medication. Collect unused medication.  Hypoglycaemia questionnaire. 
Treatment satisfaction questionnaire. Insulin dose titration/ record insulin dose.  Blood 
samples (U&E, LFT, HbA1C, local laboratory total cholesterol, HDL and triglycerides, 
FBC, vitamin B12, lactate), microalbuminuria status.  Samples for LDL, plasma 


 
 
33
biomarkers.  Urine aliquot.  Pregnancy testing if appropriate. Concomitant medications 
recorded.  Questions on adverse events. 
 
Telephone Visit 13 (27 months).  Insulin dose titration/ record insulin dose. 
Hypoglycaemia questionnaire. Questions on adverse events. 
 
Study Visit 14 (30 months – omitted for participants randomized after September 
2014 as per Appendix 6).  Vital signs, weight, waist circumference; U&E, LFTs, HbA1c 
as per routine care.  Insulin dose titration/ record insulin dose. Give out diary. 
Hypoglycaemia questionnaire. Dispense study medication.  Collect unused medication. 
Any change in concomitant medications will be recorded. Questions on adverse events.  
 
Telephone Visit 15 (33 months – omitted for participants randomized after June 
2014 as per Appendix 6).  Insulin dose titration/ record insulin dose. Hypoglycaemia 
questionnaire. Questions on adverse events. 
 
Study Visit 16 (36 months - earlier for participants randomized after March 2014 as 
per Appendix 6).  Vital signs, weight, waist circumference.  Carotid IMT.  Retinal 
imaging.  Endothelial function. Hypoglycaemia questionnaire. Treatment satisfaction 
questionnaire. Insulin dose titration/ record insulin dose.  Blood samples (U&E, LFT, 
HbA1C, local laboratory total cholesterol, HDL and triglycerides, FBC, vitamin B12, 
lactate), microalbuminuria status.  Samples for LDL, plasma biomarkers.  Urine aliquot.  
Pregnancy testing if appropriate. Collect all unused medication. Concomitant 
medications recorded.  Questions on adverse events.   
 
Close out Visit 17 (at least one week after Visit 16 but within two weeks).  Insulin 
dose titration following withdrawal of randomized medication.  Provide information. 
Remaining study medication will be sent to pharmacy for tablet count.  Questions on 
adverse events. 
 
Unscheduled visit (at any time): Adverse event reporting; treatment dose reduction or 
discontinuation; lost medication. 
 
 
11. MONITORING & EVALUATIONS 
 
Monitoring will be carried out by the study Co-sponsor and out with the UK by delegated 
organizations with sponsorship equivalent and study insurance responsibilities in 
Australia, Canada, Denmark and Holland.  Remote monitoring will be used as 
appropriate.  The level of monitoring will be based on the outcome of the completed risk 
assessment; however the minimum requirement per site will be: (i) an initiation visit 
following the issue of all approvals and prior to the start of recruitment; (ii) a full 
monitoring visit when the first few patients have been randomized; and (iii) a close-out 
visit at each site after the last patient has completed the last visit. All Informed Consent 
Forms will be reviewed; a minimum of 10% of subjects will be reviewed for Source Data 
Verification (SDV). These will be chosen at random and will consist of both subjects with 
reported SAEs and those without any reported SAEs. Greater Glasgow and Clyde R&D 
Governance will agree a Monitoring Plan which will form the template for delegated 
organizations. The sponsor will obtain and review the monitoring tools and processes of 
delegated organizations to ensure they satisfy the minimum requirements of the sponsor.   


 
 
34
12. ASSESSMENT AND REPORTING OF ADVERSE 
EVENTS / SERIOUS ADVERSE EVENTS 
12.1 Definitions  
These are in accordance with the Medicines for Human Use (Clinical Trials) Regulations 
2004(as amended):  
 
Adverse Event (AE)  
Any untoward medical occurrence in a subject to whom a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to 
that product.  
 
Adverse Reaction (AR)  
Any untoward and unintended response in a subject to an investigational medicinal 
product which is related to any dose administered to that subject.  
 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
Any adverse event or adverse reaction that  
 
a. results in death  
 
b. is life threatening  
 
c. requires hospitalisation or prolongation of existing hospitalisation  
 
d. results in persistent or significant disability or incapacity  
 
e. consists of a congenital anomaly or birth defect 
 
f. is otherwise considered medically significant by the investigator.  
 
i.e. important adverse events/ reactions that are not immediately life-threatening 
or do not result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above 
 
Suspected Serious Adverse Reaction (SSAR)  
Any adverse reaction that is classed in nature as serious and which is consistent with 
the information about the medicinal product in question set out in the summary of 
product characteristics (SmPC).53 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
Any adverse reaction that is classed in nature as serious and which is not consistent 
with the information about the medicinal product in question set out in the SmPC.53 
 
 
13. RECORDING and REPORTING AEs/SAEs 
 
Adverse events (AEs) will be recorded, notified, assessed, reported, analysed and 
managed in accordance with the Medicines for Human Use (Clinical Trials) Regulations 
2004 (as amended) and as defined within this protocol. (See flow chart) 
 
Metformin is widely available and has been used in the treatment of type 2 diabetes in 
the UK for more than 50 years, and in the US for more than 10 years.  We will therefore 
collect specific Adverse Events of Medical Interest (see list below): (i) of specific 
relevance to its potential use in T1DM; (ii) related to the complications of T1DM; and (iii) 


 
 
35
related to the study endpoints.  All Serious Adverse Events with exception of planned 
routine hospitalisations and outpatient hospital visits will be collected within the eCRF.  
 
 Adverse Events of Medical Interest 
 
Hypoglycaemia: as per the Steno Hypoglycaemia Questionnaire (Appendix 3) 
administered at study visits as per the Schedule of Assessments  
 
Gastrointestinal: Diarrhoea, abdominal pain, nausea and vomiting, constipation, 
loss of appetite resulting in discontinuation of study medication or dose reduction. 
 
Cardiovascular: chest discomfort, palpitations resulting in discontinuation of 
study medication or dose reduction 
 
Any revascularisation:  coronary (angioplasty/ stent/ CABG); carotid 
(endarterectomy); peripheral (angioplasty/ stent/ surgical) 
 
Foot:  ulceration; lower limb surgical procedure: amputation (digit/ below knee/ 
above knee); ulcer debridement. 
 
Eye:   laser treatment; vitrectomy; cataract surgery; vitreous haemorrhage; 
retinal vein or artery occusion; loss of vision in one eye. 
 
Neurological: headache resulting in discontinuation of study medication or dose 
reduction 
 
Metabolic: biochemically-confirmed unexplained acidosis with lactate > 5.0 
mmol/L, abnormal LFTS results >2.5 times upper limit of normal, or reduction in 
eGFR of > 25% 
 
Other: hypersensitivity reaction to metformin, overdose" 
 
As outlined above, the following symptoms should only be reported as AEs if leading 
to an SAE or treatment dose reduction/ discontinuation: 
- 
diarrhoea, abdominal pain, nausea and vomiting, constipation, loss of appetite 
- 
taste disturbance, abnormal stools, nail disorder, rash  
- 
increased sweating, chills, flu syndrome, flushing, skin reactions 
- 
chest pain, palpitations 
- 
headache, myalgia, light-headedness 
 
At all study visits patients will be questioned about any illnesses, hospitalisations and the 
expected adverse reactions/ events listed above.   Completion of patient diaries will aid 
the research team to elicit adverse events.  In addition to adverse event data, at annual 
visits we will measure liver function tests (AST, ALT and γGT) and a Full Blood Count. 
 
Full details of AEs of medical interest and SAEs including the nature of the event, start 
and stop dates, severity, relationship to study drug and outcome will be recorded in the 
subject's medical records and in the eCRF. AEs will be monitored and followed up until 
satisfactory resolution or stabilization.  
 
All Serious Adverse Events must be assessed for seriousness, causality, severity (which 
will be undertaken by Principal Investigators at each site) and expectedness (which is 
the responsibility of the Chief Investigator).  


 
 
36
 
Severity. This should be assessed and described using the following categories: 
 
Mild 
 
awareness of event but easily tolerated 
Moderate 
discomfort enough to cause some interference with usual activity   
Severe  
inability to carry out usual activity. 
 
All SAEs arising during the clinical trial will be reported by entering the details into the 
eCRF as soon as reasonably practicable and in any event within 24 hours of first 
becoming aware of the event. Any follow up information should also be reported.  
 
Serious adverse events recorded in the eCRF will be transferred to the Glasgow 
Pharmacovigilance database.  
 
SAEs that occur at any time after the inclusion of the subject in the study (defined as the 
time when the participant signs the informed consent) up to 30 days after the subject 
completed or discontinued the study will be reported.  
 
The participant is considered to have completed the study after the completion of the last 
visit when any remaining medication will be collected. The date of discontinuation is 
when a subject and/or investigator determines that the subject can no longer comply 
with the requirements for any further study visits or evaluations.   
 
All SUSARS will be reported an expedited fashion to the MHRA and other relevant 
regulatory authorities as well as to the relevant IRBs and Ethics Committees.  
 
Fatal or life threatening SUSARs. Not later than 7 days after the CI had information 
that the case fulfilled the criteria for a fatal or life threatening SUSAR, and any follow up 
information within a further 8 days.  
 
All other SUSARs. Not later than 15 days after the CI had information that the case 
fulfilled the criteria for a SUSAR. The Glasgow Clinical Trials Unit Pharmacovigilance 
(PV) Office will report SUSARs on behalf of the CI to the MHRA and other relevant 
regulatory authorities via the eSUSAR reporting system and to the Ethics committee in 
paper format. 
 
A copy of the SUSAR report will be forwarded by the PV Office to the sponsor’s 
representative in other host countries for submission as appropriate to the national 
ethical and regulatory authorities. 
 
The Principal Investigator at each site will be informed about any SUSARs which have 
occurred during the study by the Pharmacovigilance Office in liaison with the Project 
Manager. A report will also be placed on the study web portal. 
 
Unblinding. In the event of a SUSAR, participant treatment will be unblinded by the 
sponsor before reporting to the MHRA and REC. SUSAR reporting to the participating 
investigators will be blinded. 
 
Pregnancy is not considered an AE or SAE. However, Principal Investigators will report 
pregnancy information on any female participant or female partner of a male participant 
who becomes pregnant while participating in the Trial to the sponsor within two weeks of 


 
 
37
first becoming aware of the pregnancy. This report should be provided to the PV office 
on the Pregnancy Notification Form provide by the sponsor (on www.glasgowctu.org) 
The subject will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded by the PI to the PV 
Office. 
Annual Safety Report 
As required by the Medicines for Human Use (Clinical Trials) Regulations 2004 (as 
amended), an annual safety report will be prepared by the CI in liaison with the PV 
Office. 
 
This report will be submitted to the UK ethical and regulatory authorities within 60 days 
of the anniversary of the issue of the Clinical Trials Authorisation (CTA) by the PV Office 
on behalf of the CI. A copy of the report will be forwarded by the PV Office to the 
sponsor’s representative in other host countries for submission as appropriate to the 
national ethical and regulatory authorities. 
 
 
14. CRF REPORTING AND DATA COLLECTION 
14.1 Randomisation 
A central randomisation facility based at the Robertson Centre for Biostatistics, 
University of Glasgow will be contacted either by telephone or by a web-based service 
and randomised therapy will be assigned. Randomisation will be stratified by study site 
and based on randomly permuted blocks allocated within each trial centre. 
14.2 Emergency Unblinding Procedures 
Breaking of the study blind will be performed only: (i) for SUSARs; and, (ii) where 
knowledge of the treatment is considered by local health personnel absolutely necessary 
for further management of the patient. A central unblinding facility based at the 
Robertson Centre for Biostatistics, University of Glasgow, will be available by telephone 
(see Section 8, page 26).  Notification of all unblinding will be sent to the Chief 
Investigator. 
14.3 Case Report Forms / Electronic Data Record 
An electronic case report form (e-CRF) will be used to collect study data at each site.  
The e-CRF will be developed by the study Data Centre at the Robertson Centre for 
Biostatistics, University of Glasgow.  Access to the e-CRF will be restricted, with only 
authorised site-specific personnel able to make entries or amendments to their patients’ 
data. It is the investigator's responsibility to ensure completion and to review and 
approve all data captured in the e-CRF.  
 
Data will be validated at the point of entry into the e-CRF and at regular intervals during 
the study.  Data discrepancies will be flagged to the study site coordinator and any data 
changes will be recorded in order to maintain a complete audit trail (reason for change, 
date change made, who made change).  


 
 
38
14.4 Data Handling 
The Robertson Centre for Biostatistics at the University of Glasgow will be responsible 
for collating, cleaning and analysing the data for the study. The Robertson Centre will 
also be responsible for data back-up and security. This centre will also manage the 
electronic reporting of SUSARS on behalf of the sponsor. 
14.5 Data Transfers 
Data for IMT and retinal image data analysis will be transferred at agreed intervals 
during the study via the study web portal.  A data transfer protocol will be developed and 
approved by the study team involved in the generation of these data/images and the 
Robertson Centre for Biostatistics.  
14.6 Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigators agree 
to keep records, including the identity of all participating subjects (sufficient information 
to link records, all original signed informed consent forms serious adverse event forms, 
source documents, and detailed records of treatment disposition.  The records should be 
retained by the study country coordinators and investigator according to ICH GCP, local 
regulations, or as specified in the Clinical Study Agreement, whichever is longer. 
 
 
 
15. STATISTICAL ANALYSIS  
 
Prof Ian Ford and Prof H Colhoun will draft the Statistical Analysis Plan (with the study 
statistician).  Primary analysis will be done at the Robertson Centre/ University of  
Glasgow  CTU with University of Dundee receiving copy of stable dataset on study 
database lock.  University of Dundee will maintain a copy of the endpoint and safety 
datasets and will write data analysis code that mirrors the CTU analyses as validation. 
Professor Ian Ford, Director of the Robertson Centre for Biostatistics (RCB) at the 
University of Glasgow, a co-investigator on the study, has calculated that we need to 
recruit 500 participants (see Section 6; statistical considerations, page 18). Data 
management, statistical analysis and other aspects of clinical trial support will be 
supervised by Professor Ford. 
The data for the CCA cIMT (cIMT) will be analysed using repeated measures 
regression analysis using all data available for each subject. The hypothesis is that all 
participants have individual regression lines defining their own disease progression over 
time and that, on average, the slopes of these regression lines will be reduced by 
metformin (Glucophage 500 mg bd) treatment. The analysis will be adjusted for 
cardiovascular risk factors which are strong predictors of IMT progression over and 
above the baseline measurement to minimise the residual standard deviation and 
thereby maximise the power of the study. Regression model effect estimates with 95% 
confidence intervals and associated p-values will be calculated to compare patterns of 
CCA cIMT progression (primary end-point). 
The primary analysis will be extended to determine if the metabolic effects of 
metformin could potentially explain differential effects on progression of cIMT.  
We will report baseline characteristics by treatment group to determine whether 
randomization was successfully achieved.  We will tabulate SARs and SUSARS and the 
adverse reactions, including hypoglycaemic episodes listed above.  The effect of 


 
 
39
metformin on the primary endpoint and secondary endpoints will be evaluated using 
standard mixed linear and survival analysis methods.   
Premature withdrawal, treatment non-adherence and other protocol deviations will be 
summarised by treatment group without formal statistical comparison. The primary 
analysis will be repeated for the subgroup of patients that completed the study according 
to the protocol. Adverse events will be summarised by treatment group, as a whole and 
by MedDRA system organ class and preferred term, without formal statistical 
comparison. For the purposes of analysis, visit attendance out with three weeks of the 
intended study visit date will constitute a protocol deviation. 
A full Statistical Analysis Plan covering all study outcomes will be created and signed 
off before study close-out and unblinding. 
The RCB and the Glasgow Clinical Trials Unit (GCTU) within which it sits, have 
significant experience of coordinating and analysing clinical trials. All aspects of the 
study will be conducted to satisfy GCTU standard operating procedures that are 
compliant with existing guidelines and regulations for the conduct of clinical trials. GCTU 
has UKCRN registration and all aspects of data management and statistical analysis will 
be conducted in accordance with ISO 9001:2008 for quality systems and TickIT for 
software development. 
 
 
16. PUBLICATION & ARCHIVING 
 
Results from this study will be submitted for publication in a peer reviewed journal at a 
maximum of 6 months post database lock. Given the importance of the subject we 
anticipate publication in high ranking journals. The work will also be presented at major 
international and national meetings. Data from the study will be stored by the Chief 
Investigator for a minimum of 10 years. A final report of the study will be provided to the 
MHRA and CSO as per requirements. 
 
 
17. CHANGES TO PROTOCOL 
 
Any changes to the protocol will be submitted to the Sponsor and, if considered 
substantial, will be submitted thereafter to the MHRA and to the relevant Ethics 
Committee. 


 
 
40
18. MANAGEMENT AND COMMITTEE STRUCTURE 
 
A Steering Committee will oversee the progress of the trial.  It will consist of key 
investigators, key nominated collaborators, a patient representative, and a (non-voting) 
funding body representative. Its functions will be to provide oversight of the protocol, 
study progress, study analysis and dissemination of results.  It will meet at least annually 
and will take any final decision on study termination based on DSMB recommendation.  
The Study Coordinator will be in attendance at Steering Committee meetings. 
.                                                                                                                                         .  
 
.                                                                                                                                         .  
A Study Management Group will consist of the Chief Investigator and representatives of 
the Project Management Unit, the Sponsor, the Robertson Centre for Biostatistics, 
research pharmacy, the Pharmacovigilance Office, the Study Monitoring Team and other 
relevant personnel as appropriate.  Its functions are to manage the trial day-to-day, 
oversee recruitment, and progress towards analysis and dissemination of trial results.  
Minutes will be disseminated to non-UK National Coordinators. 
A Data and Safety Monitoring Board (DSMB) will be established by the University of 
Dundee with an independent statistician who will be provided with a cleaned but blinded 
dataset every six months. The study statistician will write the code for running DSMB 
analyses but the unblinding and running of analyses will be done by DSMB statistician. 
The DSMB will make recommendations to the Steering Committee on any safety issues.  
 
All study committees will have formal Charters describing the roles and responsibilities 
of the members.   


 
 
41
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45
Appendix 1  
 
REMOVAL study national Principal Investigators 
 
 
Country (City) 
National PI 
Address 
 
 
 
 
Australia 
 
Alicia Jenkins 
NHMRC Clinical Trials 
Centre, Sydney Medical 
School, Levels 4-6 
Parramatta Road, 
Camperdown, NSW 2050, 
Australia 
Canada 
 
Irene Hramiak 
St. Joseph’s Health Care, 
268 Grosvenor Street, 
London, Ontario  N6A 4V2, 
Canada 
 
Denmark 
 
Peter Rossing 
Steno Diabetes Center A/S, 
Niels Steensens Vej 2, 
DK-2820, Gentofte, 
Denmark 
 
Netherlands 
 
Coen Stehouwer 
Maastricht University 
Medical Centre,  
PO Box 5800, 
6202 AZ Maastricht, 
The Netherlands  
 
UK 
 
John Petrie 
BHF Cardiovascular 
Research Centre, 
University of Glasgow 
126 University Place 
Glasgow G12 8TA, UK 
 
 


 
 
46
Appendix 2 
 
Planned study timelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
47
Appendix 3: Steno Hypoglycaemia Questionnaire 
 
 
          
 
 
 
 
HYPOGLYCAEMIA 
 
Minor events 
|___||___| no. of events 
 
 
(since last contact) 
               
 
 
Major events (without coma*)     |___||___| no. of events  
BG: |___||___|,|___| mmol/l 
 
                 (since last contact) 
               (average) 
- Potential cause:  
 
Too little food Physical activity 
 Alcohol  
Betablocker  
Insulin 
Unknown 
 
 1 
 2 
 3 
 4 
 5 
 6 
- Treatment: 
Carbohydrate 
Glucagon 
Glucose iv                Other ………………. 
 
 1 
 2 
  3 
  4  
 
 
Major events (with coma*)          |___||___| no. of events 
BG: |___||___|,|___| mmol/l 
 
                 (since last contact) 
               (average) 
- Potential cause:  
 
Too little food Physical activity 
 Alcohol  
Betablocker  
Insulin 
Unknown 
 
 1 
 2 
 3 
 4 
 5 
 6 
- Treatment: 
Carbohydrate 
Glucagon 
Glucose iv                Other ………………. 
 
 1 
 2 
  3 
  4  
 
                                                 
* Coma is defined as unconsciousness during a hypoglycaemic event. 
  
      Major event is one requiring assistance for recovery 


 
 
48
Appendix 4:  Contraception 
 
For women of childbearing potential in REMOVAL, acceptable forms of effective 
contraception include:*  
 
 
1. Established use of oral, injected or implanted hormonal methods of contraception 
(note oestrogens may decrease glucose-lowering effect of oral glucose-lowering 
medications including metformin)  
 
 
2. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
[Consideration should be given to the type of device or system being used, as 
there are higher failure rates quoted for certain types, e.g. steel or copper wire]  
 
 
3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) – must be combined with spermicidal 
foam/gel/film/cream/suppository.  
 
 
4. Sole male partner has been sterilised with appropriate post-vasectomy 
documentation of the absence of sperm in ejaculate.  
 
 
5. True abstinence: When this is in line with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*See MHRA “Clarification of contraceptive wording in clinical trials conducted in the 
UK - Version 2 amended 21st May 2010”  


 
 
49
Appendix 5:  Microalbuminuria definitions 
 
 
 
For the presence or absence of microalbuminuria to be judged in relation to the 
inclusion criteria, the results of local assays conducted on at least two separate 
urine specimens must be available.  The final decision will lie with the site 
Principal Investigator according to local protocols, guided by the following criteria. 
 
 
  
Units 
Definition 
 
Male 
Female 
 
First morning sample 
mg/ mmol1  
≥ 2.5 
≥ 3.5 
mg/g1 
≥ 25 
≥ 35 
g/ mg1 
≥ 25 
≥ 35 
mg/L* 
≥30 
 
 
 
Timed 
g/ min 
>20 
mg/ 24 hours 
>30 
 
 
 
1ACR = albumin: creatinine ratio;  
*simple concentration (not preferred method) 
 
 
 
Occurrence of new microalbuminuria during the trial will be judged according to local 
assays, the results of which will be recorded in the eCRF.  
 
Central assays may later be performed on stored urine aliquots to support the 
microabuminuria secondary endpoint analysis.  


 
 
50
Appendix 6: Abbreviated follow up (final 50 participants) 
 
 
Calendar month 
randomized 
 
 
 
Number of 
participants 
affected 
 
Visit window  
adjustment 
 
 
Abbreviation 
of follow-up 
(months) 
 
Up to end March 
2014 
 
 
(379) 
 
Visit 15 – Visit 16 window 
3 months (per protocol) 
 
0 
(per protocol) 
 
April 2014 
 
 
8 
 
Visit 15 – Visit 16 window reduced 
to 2 months 
 
 
1 
 
May 2014 
 
8 
 
 
Visit 15 – Visit 16 window reduced 
to 1 months 
 
 
2 
 
 
June 2014 
 
12 
 
Visit 15 omitted 
(i.e. Visit 14 – Visit 16 window  
reduced to 3 months) 
 
3 
 
 
July 2014 
 
7 
 
Visit 14 – Visit 16 window reduced 
to 2 months 
 
 
4 
 
 
August 2014 
 
6 
 
Visit 14 – Visit 16 window reduced 
to 1 month 
 
 
5 
 
 
September  2014 
 
7 
 
Visit 14 and 15 omitted 
(i.e. Visit 13 – Visit 16 window  
reduced to 3 months) 
 
6 
 
 
October 2014 
 
1 
 
Visit 13 – Visit 16 window reduced 
to 2 months 
 
 
7 
 
 
November 2014 
 
1 
 
Visit 13 – Visit 16 window reduced 
to 1 month 
 
 
8 
 
 
 
50 
 
 
 
 
Please refer to Schedule of Assessments (page 10) for visit windows “per protocol” 
 
These arrangements affect a total of 50 participants at the following sites (site number):  
Canada: Ottawa (12) 
Australia: Royal Melbourne (16), Prince Alfred, Sydney (17) 
Denmark: Steno Diabetes Center (13) 
Netherlands: Maastricht (14) 
UK: Aberdeen (21), Aintree (7), Ayr (24), Royal Infirmary Edinburgh (19), Hull (6), London(UK)(8) 
 
 

SAP_001.pdf: 
Robertson Centre for Biostatistics, University of Glasgow  
REMOVAL STATISTICAL ANALYSIS PLAN FOR FINAL ANALYSIS  
Version 1.1 7th April 2017 
Page 1   
 
REDUCING WITH METFORMIN VASCULAR ADVERSE 
LESIONS IN TYPE 1 DIABETES 
(REMOVAL) 
 
 FINAL ANALYSIS 
 STATISTICAL ANALYSIS PLAN
Study Title: 
Reducing with Metformin vascular adverse lesions in type 1 diabetes 
Short Title: 
REMOVAL 
IDs: 
EudraCT nr:  2011-000300-18 
 
MHRA reference:  24712/0022/001-0001 
 
MREC reference:  11/WS/0012 
 
Clinicaltrials.gov identifier:  NCT01483560 
 
Sponsor’s reference:  GN10DI406 
 
 
Funded by: 
Juvenile Diabetes Research Foundation 
Protocol Version: 
Version 3.0, 9th November 2015 
 
 
SAP Version: 
V1.1 
Date: 
7th April 2017 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 
 
 
Prepared by: 
Ms Nicola Greenlaw 
 
 
 
 
Statistician  
Robertson Centre for Biostatistics 
University of Glasgow 
 
 
 
 
 
 
 
 
Approved by: 
Ms Michele Robertson 
 
 
 
 
Assistant Director Commercial 
Biostatistics 
Robertson Centre for Biostatistics 
University of Glasgow 
 
 
 
 
 
 
 
 
Approved by: 
Professor Ian Ford 
 
 
 
 
Senior Research Fellow 
Robertson Centre for Biostatistics 
University of Glasgow 
 
 
 
 
 
 
 
 
Chief Investigator 
Professor John Petrie 
 
 
 
 
Professor of Diabetic Medicine 
Institute of Cardiovascular and 
Medical Sciences 
University of Glasgow 
 
 
 
 
 
 
 
 
Deputy Chief Investigator 
Professor Helen Colhoun 
AXA Chair of Medical Informatics 
and Life Course Epidemiology 
University of Edinburgh 
 
 
 
 
 
 
 
 


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CONTENTS 
1. Introduction ........................................................................................................................... 3 
1.1. Study Background .......................................................................................................... 3 
1.2. Study Objectives ............................................................................................................ 3 
1.3. Study Design .................................................................................................................. 3 
1.4. Sample Size and Power .................................................................................................. 3 
1.5. Study Population .......................................................................................................... 44 
1.5.1. Inclusion Criteria................................................................................................... 44 
1.5.2. Exclusion Criteria ................................................................................................. 44 
1.6. Statistical Analysis Plan (SAP) .................................................................................... 44 
1.6.1. SAP Objectives ..................................................................................................... 44 
1.6.2. General Principles ................................................................................................. 44 
1.6.3. Current Protocol .................................................................................................... 55 
1.6.4. Deviations to those specified in the Protocol ........................................................ 55 
1.6.5. Additional analyses to those specified in the Protocol ......................................... 55 
1.6.6. Software ................................................................................................................ 55 
2. Analysis ............................................................................................................................... 55 
2.1. Study Populations and Analysis Sets ........................................................................... 55 
2.2. Subject Disposition ...................................................................................................... 66 
2.3. Baseline Characteristics ............................................................................................... 66 
2.4. Study Outcomes ........................................................................................................... 77 
2.4.1. Primary  Outcome ................................................................................................. 77 
2.4.2. Secondary  & Tertiary Outcomes .......................................................................... 77 
2.4.3. Imputation/Sensitivity Analysis .............................................................................. 9 
2.4.4. Subgroup Analysis ............................................................................................ 1010 
2.4.5. Other Safety Outcomes ..................................................................................... 1010 
2.4.5.1. Study Treatment ............................................................................................. 1010 
2.4.5.2. Adverse Events of medical interest ................................................................ 1011 
2.4.5.3. Serious Adverse Events ..................................................................................... 11 
2.4.5.4. Events of Particular interest ........................................................................... 1112 
2.4.5.5. Vital Signs .......................................................................................................... 12 
2.4.5.6. Blood Tests ........................................................................................................ 12 
3. Document History ........................................................................................................... 1213 
4. Tables, Figures and Listings ............................................................................................... 13 
 
Field Code Ch
Field Code Ch


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1. INTRODUCTION 
1.1. STUDY BACKGROUND 
Intensive glucose control reduces long term rates of cardiovascular disease (CVD) in people 
with type 1 diabetes (T1DM) but the majority of individuals affected by the condition do not 
currently achieve glucose targets with standard insulin therapy.  Upward insulin dose 
titration may lead to weight gain, hypoglycaemia and dyslipidaemia.  Metformin has the 
potential for addressing these issues as it may (i) reduce insulin dose for a given achieved 
HbA1c; (ii) promote weight stabilization; (iii) be associated with low rates of 
hypoglycaemia; and (iv) reduce LDL cholesterol – even on a background of statin therapy.  
It may also have direct and potentially beneficial cardiovascular effects. 
Common carotid artery intima-media thickness (cIMT) is increased in type 1 diabetes.  cIMT 
reliably predicted cardiovascular events in DCCT and has been successfully targeted by 
metformin in a number of small studies in conditions other than type 1 diabetes.   
1.2. STUDY OBJECTIVES 
The primary objective of the study is to assess whether three years treatment with metformin 
1000mg bd added to titrated insulin therapy (towards target HbA1c 7.0% / 53 mmol/mol) 
reduces atherosclerosis, as measured by progression of cIMT, in adults with confirmed type 
1 diabetes aged 40 years and over and at increased risk for CVD. 
Secondary and tertiary objectives are to examine over the same period the effect of 
metformin on other markers of diabetic micro- and macrovascular complications and 
intermediate disease-related biomarkers.   
1.3. STUDY DESIGN 
The study is a randomised, double-blind, placebo controlled trial.  Subjects will be 
randomised to either oral metformin or matching placebo.  After recruitment each subject 
will remain in the study for three years during which they will be followed up by telephone 
and during clinics (telephone follow-up at weeks 1 and 2 and months 15, 21, 27 and 33 and 
clinic visits at months 3, 4, 6, 9, 12, 18, 24, 30 and 36).  The primary outcome will be 
measured at baseline and at months 12, 24 and 36.   
1.4. SAMPLE SIZE AND POWER 
Assuming a mean linear progression of 0.044mm over three years (in the control arm) and a 
standard deviation (SD) for progression of 0.05mm and to have 90% power at a 5% 
significance level to detect a difference of at least one third of a SD (0.0167 MM) in three 
year progression of averaged mean far wall cIMT between treatment arms we will require 
200 subjects per treatment group.  Allowing for 20-25% drop-outs/discontinuations, 500 
subjects, in total, will be recruited.   


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1.5. STUDY POPULATION 
1.5.1. INCLUSION CRITERIA 
Subjects with a confirmed diagnosis of type 1 diabetes (i.e. diagnosis below age of 40 years 
and insulin use within one year of diagnosis) for five years or more, aged 40 or over, with 
7.0 ≤ HbA1c < 10.0% (53 – 86 mmol/mol) and at risk of CVD [i.e. three or more of the 
following CVD risk factors: BMI ≥ 27 kg/m2; current HbA1c > 8.0% (64 mmol/mol); known 
CVD / peripheral vascular disease; current smoker; eGFR < 90 ml/min/1.73m2; confirmed 
micro- (or macro-) albuminuria (according to local assays and reference ranges); 
hypertension (BP ≥ 140/90mmHg, or established hypertensive treatment); dyslipidaemia; 
strong family history of CVD; and duration of diabetes > 20 years]. 
1.5.2. EXCLUSION CRITERIA 
eGFR < 45 ml/min/1.73m2; women of childbearing age not on effective contraception; 
pregnancy and/or lactation; Acute Coronary Syndrome or Stroke/TIA within the last three 
months; NYHA stage 3 or 4 heart failure; uncontrolled angina; significant hypoglycaemia 
unawareness; impaired cognitive function / unable to five informed consent; previous carotid 
surgery or inability to capture adequate carotid images; gastroparesis; history of lactic 
acidosis; other contraindications to metformin (hepatic impairment, known sensitivity to 
metformin, acute illness – dehydration, severe infection, shock, acute cardiac failure, 
suspected tissue hypoxia; any coexistent life threatening condition including prior diagnosis 
of cancer within two years; history of alcohol problem or drug abuse; diabetes other than 
type 1 diabetes; and involvement in a clinical trial involving an investigational medicinal 
product within the last six months. 
1.6. STATISTICAL ANALYSIS PLAN (SAP) 
1.6.1. SAP OBJECTIVES 
The objective of this SAP is to describe the statistical analyses to be carried out for the final 
analysis of the REMOVAL study. 
1.6.2. GENERAL PRINCIPLES 
All study data will be summarised as a whole and by treatment group at each study 
assessment point.  Continuous variables will be summarised by the number of observations, 
number of missing values, mean, standard deviation (SD), median, quartiles and range.  
Categorical variables will be summarised by the number of observations, number of missing 
values and the number and percentage of individuals in each category. 
Baseline data will be extracted from the Treatment Visit 1 electronic case report form 
(eCRF) page where possible; if values are missing, then data from the first screening visit 
(Run-in Visit 1) will be used. 
The primary analysis, and all secondary analyses, will be carried out using all randomised 
individuals who provide sufficient data to conduct the particular analysis, regardless of their 
adherence to study protocol.  For the primary outcome, a sensitivity analysis will be carried 
out using a Per-Protocol dataset, consisting of those individuals that completed the study 
according to protocol.   


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Graphical presentations will be specified and provided according to the results of the final 
analysis. 
1.6.3. CURRENT PROTOCOL  
The current version of the protocol at the time of writing is version 3.0, dated 9th November 
2015 and the accompanying NHS GG&C R&D protocol filenote.  Future amendments to the 
protocol will be reviewed for their impact on this SAP, which will be updated only if 
necessary.  If no changes are required to this SAP following future amendments to the 
protocol, this will be documented as part of the Robertson Centre Change Impact 
Assessment processes. 
1.6.4. DEVIATIONS TO THOSE SPECIFIED IN THE PROTOCOL 
The biomarker sample assays will be received after the database lock and therefore are not 
covered by this SAP, but will be detailed in a future SAP. 
1.6.5. ADDITIONAL ANALYSES TO THOSE SPECIFIED IN THE PROTOCOL 
There are no planned additional analyses to those specified within the Protocol. 
1.6.6. SOFTWARE 
Analyses will be conducted using SAS for Windows v9.3 or higher, SPlus for Windows v8.1 
and/or R for Windows v2.7.0 or higher. 
2. ANALYSIS 
2.1. STUDY POPULATIONS AND ANALYSIS SETS 
The Screened population will consist of all subjects screened for inclusion into the study. 
The Intention To Treat (ITT) population will consist of all subjects randomised, regardless of 
subsequent participation in the study. 
The modified-ITT (mITT) analysis set will include all subjects from the ITT population with 
data as available (without imputation) for analysis for each individual outcome. 
The Per Protocol (PP) population will consist of all members of the ITT population with no 
major protocol deviations (met inclusion and exclusion criteria and no prohibited 
medications at randomisation), and who have cIMT available at treatment visits 1, 8, 12 and 
16. All identified protocol deviations will be reviewed prior to unblinding the dataset, and 
classified as major or minor.   
The Safety population will consist of all members of the ITT population who received at 
least one dose of study medication. 
For any analyses to be carried out in multiple populations, if the populations are identical 
(e.g. if all members of the ITT population take at least one dose of study medication, then the 
ITT and Safety population are the same), then the analysis will only be reported once. 
 


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2.2. SUBJECT DISPOSITION 
The number of patients in the Screened populations will be reported, as well as the number 
and percentage in the ITT Population.  The reasons for screening exclusion will also be 
reported. 
For those in the ITT population, the number and percentage in each treatment group will be 
reported. 
For those in the ITT population, as a whole and by treatment group, the numbers and 
percentages in the Safety and PP populations will be reported. 
Reasons for exclusion for populations will be summarised overall and by treatment group. 
The number of subjects in the ITT population who completed or withdrew will be 
summarised, overall and by treatment group, along with the reasons for and time to 
withdrawal. 
A by subject listing of all withdrawals from study after randomisation, and the reasons for 
withdrawal, will be provided. 
Eligibility criteria and protocol deviations will also be summarised for the ITT population, 
overall and by treatment group. 
A by subject listing of all protocol deviators will be provided. 
2.3. BASELINE CHARACTERISTICS 
In the ITT population, as a whole and by treatment group, summaries will be provided of the 
following baseline characteristics as included in the eCRF: 
 
 Age and sex; 
 ethnicity; 
 smoking and alcohol habits; 
 SBP, DBP and heart rate; 
 height, weight, BMI and waist circumference; 
 time since diabetes diagnosis; 
 medical history – macrovascular, microvascular and other; 
 family medical history (CV disease and diabetes); 
 insulin regimen, including pump therapy; 
 concomitant medications – statins, ACE-inhibitors, ARBs, antiplatelet and beta-
blockers; 
 treatment satisfaction questionnaire; 
 hypoglycaemic events – minor and major; 
 blood tests – creatinine, eGFR, capillary glucose (3-day average of each of: before 
breakfast, before mid-day meal, before evening meal and before bed) and C-peptide;  
 average mean far wall cIMT (mm) of the common carotid artery; 
 Lipid Assays – LDL cholesterol, HDL cholesterol, Total cholesterol and 
Trigylcerides. 


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2.4. STUDY OUTCOMES 
2.4.1. PRIMARY  OUTCOME 
The primary outcome will be the rate of progression of average mean far wall cIMT of the 
common carotid artery over the course of the study (36 months).  In the mITT analysis set, as 
a whole and by treatment group, summary statistics for cIMT and change from baseline will 
be provided at baseline, 12, 24 and 36 months.  The treatment effect estimate, 95% 
confidence interval (CI) and p-value will be estimated from a repeated measures regression 
model, with random intercept and random slopes, with cIMT as the outcome, and predictor 
variables of treatment, baseline cIMT and time.  Time will be measured in years from 
baseline.  A time by treatment interaction term will be included in the model, allowing 
different slopes for the two treatment groups.  Adjustments for baseline covariates age, sex, 
smoking status, systolic blood pressure, BMI, HbA1c and LDL cholesterol will also be 
included as fixed effects. 
A sensitivity analysis will also be carried out extending the model noted above to further 
adjust for the ultrasound probe frequency used. 
Initial analyses will only include the measurements recorded with values < 1.5mm, in line 
with the Mannheim consensus, but the analyses will be duplicated to include all 
measurements regardless of value as a sensitivity analysis (see section 2.4.3). 
Average mean far wall cIMT of the common carotid artery will be calculated as the average 
of the left and right mean measurements at each time point, using the following hierarchy: 
1. Use all available data for the mean far wall IMT regardless of data availability at 
other time points. 
2. In instances where any duplicate angles are included (resulting in more than six 
angles per time point), average these duplicate angles first to result in one single 
measurement per angle. 
3. Average next the angles within each side to result in one single measurement for each 
of the left and right sides 
4. Average the remaining left and right measurements to obtain one result per time point 
No imputation of the primary outcome will be performed for the main analysis (the model 
described above will make use of all analysable data available for a subject).  However, if 
any baseline covariates included as adjustments in the model (systolic blood pressure, BMI, 
HbA1c and LDL cholesterol) have neither treatment visit 1 data, nor run-in visit 1 data 
available, multiple imputation will be used, using the other baseline covariates included as 
adjustments with complete data at baseline (including age, sex and smoking status). 
The analysis will be repeated for the PP population. 
2.4.2. SECONDARY  & TERTIARY OUTCOMES 
The secondary outcome measures include: 
 DCCT-aligned HbA1c (local assays); 
 LDL cholesterol (central assay); 
 Albuminuria (as per Protocol Appendix 5.0) 
 Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2 by MDRD equation); 
 Retinopathy stage (ETDRS) (two or more step progression, concatenated score from 
baseline); 


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 Weight (kg); 
 Insulin dose per 24 hours per kg (units/kg); 
 Endothelial function (Reactive Hyperaemia Index by peripheral arterial tonometry).* 
 
*This measurement is only collected in a subset of centres with available equipment. 
Each of the above secondary outcome measures will be analysed separately and the 
individual results will be reported.  The protocol has a pre-defined composite interpretation 
of all secondary outcomes, where results will be considered as clinically meaningful with the 
potential to influence clinical practice only in the event that a statistically significant 
improvement in two or more of the individual secondary outcomes is observed on 
metformin. 
Tertiary outcomes include: 
 Frequency of major hypoglycaemia (per patient-year) (Steno Questionnaire); 
 Frequency of minor hypoglycaemia (per patient-year) (Steno Questionnaire) 
 Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire); 
 Progression of averaged maximal distal IMT of the common carotid artery at 12, 24 
and 36 months; 
 Occurrence of biochemical Vitamin B12 deficiency, defined as values of vitamin B12 
< 150pmol/L reported in the lab data in the eCRF. 
All secondary and tertiary outcomes will be analysed using the relevant mITT analysis set. 
All continuous secondary and tertiary outcomes will be summarised, overall and by 
treatment group at each time point; change from baseline will also be summarised.  Non-
Normally distributed variables will be transformed first. Repeated measures models will be 
applied to all continuous secondary and tertiary outcomes (except for the tertiary outcome 
“Progression of averaged maximal distal common carotid artery IMT” which will be 
analysed as per the primary outcome, using the maximal far wall IMT measurements as the 
main analysis, calculated as detailed below), assuming a general residual covariance 
structure, with the change from baseline as the outcome, and predictor variables of treatment, 
visit number (included as a class variable) and the outcome baseline level where available.  
The main analyses will test the significance of and provide an estimate of the main effect of 
treatment in this model.  The treatment effect estimate, corresponding 95% confidence 
interval and p-value will be reported. 
As an exploratory analysis to investigate whether the treatment effect varies over time, a visit 
by treatment interaction term will be added to each model and tested for significance.  The p-
value for the interaction term will be reported.  In addition, the treatment effect, 95% 
confidence interval and p-value will be reported for each visit. 
The main analysis of the averaged maximal distal IMT of the common carotid artery will use 
solely the maximum far wall cIMT measurements, and unlike the main analysis of the 
primary outcome, will not restrict to values < 1.5mm.  A sensitivity analysis will also be 
performed using both the maximum near wall and the maximum far wall measurements as 
detailed in section 2.4.3. 
The calculation of the averaged maximal distal IMT at each time point will use the following 
hierarchy: 
1. Use all available data for the maximum far wall IMT regardless of data availability at 
other time points. 


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2. In instances where any duplicate angles are included (resulting in more than six 
angles per time point), average these duplicate angles first to result in one single 
measurement per angle. 
3. Average next the angles within each side to result in one single measurement for each 
of the left and right sides 
4. Average the remaining left and right measurements to obtain one result per time point 
The frequency of hypoglycaemia will be analysed using a Negative-Binomial regression 
model, accounting for over-dispersion using the scale option, with the logarithm of time as 
an offset variable.  The frequency of the minor hypoglycaemia will be further adjusted for 
the method of collection, with results provided for all collection methods combined.  Each 
method of collection will then be analysed and reported separately.  In instances where there 
has been a change in the method of collection, the method that was most commonly used for 
each subject will be adjusted for. 
New onset microalbuminuria will be analysed in a time to event analysis using a Cox 
Proportional Hazards Model.  The results will be summarised graphically using the Kaplan-
Meier method.  Similar methods will be used to analyse the first occurrence of biochemical 
vitamin B12 deficiency. 
For the retinopathy outcome, logistic regression analysis will be performed.  If the numbers 
of patients with retinopathy are too small to allow logistic regression analysis to be 
performed, Fisher’s exact test will be used instead. 
The regression model for the primary outcome will be extended to determine if glucose- 
and/or lipid-lowering effects of metformin could potentially explain differential effects on 
the progression of cIMT.  This will be accomplished by including baseline and on-treatment 
HbA1c and LDL-cholesterol values as time-dependent covariates in the model described 
above for the primary outcome. 
2.4.3. IMPUTATION/SENSITIVITY ANALYSIS 
 
The following sensitivity analyses involving imputation of missing data will be carried out: 
 A multiple imputation will be used to analyse the primary outcome, with imputation 
of cIMT measurements that are missing other than because the patient had died, 
withdrawn consent or was censored due to end of follow-up.  The multiple 
imputation approach will use the baseline covariates included in the adjusted primary 
outcome model (age, sex, smoking status, systolic blood pressure, BMI, HbA1c and 
LDL cholesterol) after imputation of any missing values.   
 A similar approach will be used to impute missing retinopathy and endothelial 
function data. 
 
The following sensitivity analyses will also be included: 
 Inclusion of all mean far wall cIMT measurements of the common carotid artery for 
the calculation of the averaged mean for the primary outcome, regardless of whether 
the individual measurements are < 1.5mm or not, using the same hierarchy as 
detailed above in section 2.4.1. 
 Inclusion of both the maximum near wall and the maximum far wall IMT 
measurements in the calculation of the averaged maximal distal IMT of the common 
carotid artery at 12, 24 and 36 months for the tertiary outcome. 


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The calculation of the averaged maximal distal IMT at each time point for the sensitivity 
analysis will use the following hierarchy: 
1. Use all available data for the maximum near wall and the maximum far wall IMT 
regardless of data availability at other time points. 
2. Take the single absolute maximum value across both the near wall and the far wall 
for all available angles and sides, resulting in one maximum value at each time point. 
2.4.4. SUBGROUP ANALYSIS 
The following subgroup analyses for the main analysis of the primary outcome (ie. the 
analysis using the measurements available, with values < 1.5mm on the mITT population) 
will be provided: 
 Age (≤ / > median) 
 Sex (Males/Females) 
 Baseline cIMT tertile 
 Existing CV Disease (Yes/No) 
 Duration of diabetes (≤ / > median) 
 Baseline HbA1c (≤ / > median) 
 Baseline BMI (≤ / > median) 
 Smoker status (Never / Ever) 
 LDL cholesterol (≤ / > median) 
 SBP (≤ / > median) 
 Pump User (Yes/No) 
 
2.4.5. OTHER SAFETY OUTCOMES 
2.4.5.1. STUDY TREATMENT 
The number of doses of study medication that were taken throughout the entire study (ie. 
from the date of randomisation to the last treatment visit attended) will be calculated as the 
total number of doses supplied – the total number of doses returned and will be summarised 
as a whole and by treatment group.   
The number of subjects down-titrating and permanently discontinuing study medication 
during the study will be summarised overall and by treatment group, along with the reasons 
for down-titration and discontinuations.  Time to permanent discontinuation will also be 
summarised. 
Differences between the two treatment groups in terms of permanent withdrawals of study 
medication will be tested using Chi-squared tests.  No other formal statistical testing will be 
applied. 
2.4.5.2. ADVERSE EVENTS OF MEDICAL INTEREST 
Adverse events of medical interest have been defined as: 
 Gastrointestinal 
o diarrhoea 
o abdominal pain 
o nausea and vomiting 
o constipation 
o loss of appetite 


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 Any revascularisation: 
o coronary (angioplasty/stent/CABG) 
o carotid (endarterectomy) 
o peripheral (angioplasty/stent/surgical) 
 Foot (left/right) 
o Ulceration 
o amputation – digit, below knee, above knee 
o ulcer debridement 
 Eye (left/right) 
o laser treatment 
o vitrectomy 
o cataract surgery 
o vitreous haemorrhage 
o retinal vein or artery occlusion 
o loss of vision in one eye 
 Neurological 
o Headache 
 Metabolic 
o reduction in eGFR of > 25% 
 Other 
o Hypersensitivity reaction to metformin 
o Overdose 
The total number (and subjects experiencing at least one) adverse events of medical interest 
will be summarised.  The type, duration, outcome, relationship to study drug and seriousness 
will also be summarised for all adverse events of medical interest.   
A by subject listing of adverse events of medical interest will also be provided. 
No formal statistical testing will be applied. 
2.4.5.3. SERIOUS ADVERSE EVENTS 
The number of serious adverse events will be reported overall and by treatment group for 
any event, and by classifications of expectedness, relationship to study medication, severity 
and outcome. 
The number and percentage of patients experiencing at least one adverse event will be 
reported overall and by treatment group for all events, and for events classified by MedDRA 
System Organ Class and Preferred Term.  
A by subject listing of serious adverse events will also be provided. 
Listings of all deaths will also be provided. 
2.4.5.4. EVENTS OF PARTICULAR INTEREST 
Events of particular interest have been defined as: 
 Lactic acidosis 
 ALT > 3 times upper limit of normal 
 eGFR < 30 ml/min/1.73m2 
 Major hypoglycaemic events 


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 Renal dysfunction (eGFR < 45 ml/min/17.3m2 or reduction in eGFR > 25%) 
 LFTs > 2.5 times upper limit of normal 
 Hb < 10.0 g/dL and fall > 1.5 g/dL from baseline 
 Occurrence of clinically relevant Vitamin B12 deficiency, defined  as values < 
110pmol/L reported in the lab data recorded in the eCRF 
 Acute coronary syndrome 
 
These events will be grouped according to whether they warrant discontinuation of study 
medication or not.  The first three events above (lactic acidosis, ALT and eGFR < 30 
ml/min/1.73m2) all warrant discontinuation of study medication. 
The number and percentage of events of particular interest will be reported.  For the events 
warranting discontinuation of study medication, the number of events occurring whilst taking 
study medication will be summarised along with these number of events that resulted in 
discontinuation.   
The number and percentage of subjects experiencing at least one event for any and each 
specific event will also be summarised. 
No formal statistical testing will be applied. 
2.4.5.5. VITAL SIGNS 
SBP, DBP and heart rate will be summarised as a whole, by treatment and by visit.  Changes 
from baseline will also be summarised.  Formal statistical comparisons of the changes will 
be made between the treatment groups using a baseline adjusted ANCOVA. 
2.4.5.6. BLOOD TESTS 
To identify any potential safety signal, blood tests not included as secondary or tertiary 
outcomes will be summarised as overall, by treatment group and by visit.  Changes from 
baseline will also be summarised.  Formal statistical comparisons of the changes shall be 
made between the treatment groups using a baseline adjusted ANCOVA. Any laboratory 
results with evidence of non-Normality of their distribution will be transformed 
appropriately prior to analysis. 
 
The number of subjects with values of clinical significance will be summarised at each visit 
for each blood test as appropriate. 
3. DOCUMENT HISTORY 
This is version 1.1 of the Statistical Analysis Plan (SAP) for the REMOVAL study. The 
following updates were made to version 1.0: 
1. Include pre-specified subgroup analysis for the main primary outcome analysis in 
section 2.4.4. 
2. Slight clarification to the wording of the primary outcome model. 


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4. TABLES, FIGURES AND LISTINGS 
A dummy report will be provided for external review prior to study lock.