Conditions: Diabetic Retinopathy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1151
Healthy volunteers: no

Brief summary:
LENS is a streamlined multicentre randomised placebo-controlled parallel-group trial investigating the effect of fenofibrate treatment on the progression of diabetic retinopathy/maculopathy.

Detailed description:
LENS is a phase 4 randomised placebo-controlled clinical trial of fenofibrate in participants with diabetes and observable retinopathy or maculopathy. The trial aims to recruit approximately 1,060 participants and to treat them for a median duration of at least 4 years. The main aim of LENS is to investigate the effect of fenofibrate therapy on progression to referable diabetic retinopathy/maculopathy. The trial will be conducted using a pragmatic streamlined trial design with the only planned face-to-face visits being an initial screening visit, followed by a randomisation visit eight weeks later. Contact with participants thereafter will be by means of regular telephone or computer questionnaire, and outcome and safety data will also be sought by means of linkage to NHS Scotland registries. Prior to randomisation, eligible participants will enter an active run-in phase of 6 to 10 weeks.

Arms:
arm 1: Name: Fenofibrate; Form: tablet; Dosage: 145 mg; Frequency: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease) arm 2: Name: Placebo; Form: tablet; Dosage: not applicable; Frequency: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)

Interventions: intervention 1: Fenofibrate 145 mg intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease) intervention 2: One tablet (taken daily with normal renal function, taken every second day with chronic kidney disease)

Protocol document:
Prot_000.pdf: 
 
 
Version 7.0_2022-07-29 
 
EDMS #5230  
 
 
 
 
 
Lowering Events in Non-proliferative retinopathy in Scotland 
(LENS) 
 
 
 
A randomised placebo-controlled trial of fenofibrate to prevent 
progression of non-proliferative retinopathy in diabetes 
 
 
 
 
 
 


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RESEARCH REFERENCE NUMBERS 
 
IRAS Number: 
209579 
EudraCT Number: 
2016-002656-24 
Clinical trials.gov Number: 
NCT03439345 
ISRCTN Number 
ISRCTN15073006 
REC Number: 
16/WS/0149 
Sponsor’s number: 
CTSULENS1 
NIHR Number: 
14/49/84 
 
 


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KEY TRIAL CONTACTS 
Chief Investigator 
Associate Prof David Preiss  
MRC Population Health Research Unit 
Clinical Trial Service Unit, University of Oxford 
Telephone: +44 (0)1865 743527 
Email: david.preiss@ndph.ox.ac.uk  
Co-investigators 
Dr Jennifer Logue (University of Lancaster, UK) 
Prof Jane Armitage (University of Oxford, UK) 
Dr John Olson (NHS Grampian, UK) 
Dr Graham Scotland (University of Aberdeen, UK) 
Prof Naveed Sattar (University of Glasgow, UK) 
Dr Graham Leese (University of Dundee, UK) 
Prof Helen Colhoun (University of Edinburgh, UK) 
Dr Robert Lindsay (University of Glasgow, UK) 
Dr Emily Sammons (University of Oxford, UK) 
Dr Gemma Currie (University of Glasgow, UK) 
Trial Managers 
Clinical Trial Service Unit, University of Oxford: 
Sarah Howard 
Telephone: +44 (0)1865 743825 
Email: sarah.howard@ndph.ox.ac.uk  
NHS Greater Glasgow and Clyde: 
Diann Taggart 
Telephone: +44 (0)141 314 4407 
Email: diann.taggart@ggc.scot.nhs.uk  
Sponsor 
University of Oxford 
Funder(s) 
National Institute for Health Research 
Clinical Trials Unit 
Clinical Trial Service Unit and Epidemiological Studies 
Unit (CTSU), University of Oxford, Richard Doll Building, 
Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF 
Telephone: +44 (0)1865 743743; Fax: +44 (0)1865 
743985 
Email: lens@ndph.ox.ac.uk  
Statistician 
Dr Jonathan Emberson 
Email: jonathan.emberson@ndph.ox.ac.uk 
Trials pharmacy contact 
Kevin Murphy 
Email: kevin.murphy@ndph.ox.ac.uk  
 
 
 


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TRIAL SUMMARY 
 
Trial Title 
A phase 4 randomised placebo-controlled clinical trial of fenofibrate 
to prevent progression of non-proliferative retinopathy in diabetes  
Internal ref. no. (or short 
title) 
LENS: Lowering Events in Non-proliferative retinopathy in Scotland 
Clinical Phase  
4 
Trial Design 
Randomised double-blind placebo-controlled trial 
Trial Participants 
Adult participants with diabetes and observable retinopathy 
Planned Sample Size 
At least 1,060 participants (approximately 530 on fenofibrate tablets 
and 530 on placebo tablets) 
Follow-up duration 
At least 4-years after randomization of the median patient and at 
least 222 primary outcome events  
Planned Trial Period 
6 years  
Primary research objective 
 
 
To estimate the effect of allocation to fenofibrate versus placebo on 
progression to the composite primary outcome of referable diabetic 
retinopathy (DR) or any of the following treatments for DR: retinal 
laser therapy, vitrectomy or intra-vitreal injection  
Secondary research 
objectives 
 
To estimate the effect of allocation to fenofibrate versus placebo 
on: 
 
The composite primary outcome in various subgroups 
 
Individual components of the composite primary outcome 
 
Any progression of DR across the Scottish Diabetic Eye 
Screening (DES) grading scale 
 
Visual acuity 
 
Hard exudates or blot haemorrhages by the macula 
 
Macular oedema 
 
Visual function and quality of life 
To evaluate the: 
 
Total cost to the health service (in terms of additional drug 
treatment and monitoring costs, and health care resource 
use over follow-up) 
 
Cost-effectiveness (in terms of incremental cost per QALY 
gained with fenofibrate versus placebo) 
Investigational Medicinal 
Product 
Fenofibrate  
Formulation, Dose, Route 
of Administration 
One 145mg nanoparticle fenofibrate tablet or matching placebo 
tablet daily (or one tablet every second day in the context of chronic 
kidney disease) taken orally 


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FUNDING AND SUPPORT IN KIND 
 
FUNDERS 
 
FINANCIAL AND NON-FINANCIAL SUPPORT GIVEN 
National Institute for Health 
Research 
Financial support 
Mylan  
Fenofibrate and placebo bulk supplies (free of charge) 
CTSU 
Cost of packaging, storage of study drug 
 
 
 
 


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STUDY SPONSOR AND FUNDER 
The LENS trial is sponsored by the University of Oxford. The trial is funded by the National Institute 
for Health Research. The funder has no influence over trial design, conduct, data analysis and 
interpretation, manuscript writing, and dissemination of results. The research team will send reports 
regarding the progress of the trial to the funder at agreed intervals. 
CO-ORDINATION OF THE TRIAL  
The Central Co-ordinating Office (CCO) for the conduct of the LENS trial is the Clinical Trial Service 
Unit and Epidemiological Studies Unit (CTSU), University of Oxford. The Regional Co-ordinating 
Centre (RCC) for the conduct of the trial is based in Glasgow (BHF Glasgow Cardiovascular 
Research Centre, University of Glasgow together with NHS Greater Glasgow and Clyde). There will 
be up to 11 NHS Scotland mainland health boards taking part with one or more Local Collaborating 
Centres (LCC) per health board.  
The CCO will have overall responsibility for the trial administration and co-ordination including:  
 
obtaining Research Ethics Committee (REC), Medicines and Healthcare products 
Regulatory Agency (MHRA) and Public Benefit and Privacy Panel (PBPP) approval 
 
training of CCO, RCC and LCC staff 
 
monitoring of sites and of centrally collected data 
 
producing abbreviated and detailed patient information leaflets 
 
providing questionnaires and newsletters, and administering electronic questionnaires 
 
randomisation service 
 
the provision of a 24-hr Freephone telephone service for participant and clinical queries 
 
providing the electronic case report form (eCRF) and trial management system 
 
producing regulatory reports 
 
performing statistical data analyses 
 
securing agreements with NHS health boards to enable insertion of abbreviated trial 
leaflets into retinal screening results 
 
maintaining the Trial Master File 
 
receiving completed abbreviated patient information leaflets and reply slips 
The RCC will be responsible for: 
 
site set-up 
 
training LCC site staff 
 
day to day management of sites after set-up 
 
regular monitoring of participants’ renal function using routinely collected blood results via 
the Scottish Care Information (SCI) Diabetes system, for safety purposes 
The LCCs will be responsible for: 
 
obtaining local NHS Research and Development (R&D) approval (with the assistance of 
the CCO and RCC) 
 
contacting potential participants based on Scottish Diabetes Research Network (SDRN) 
register and DES mail-out and replies to Health Informatics Centre mail out 
 
determining eligibility during pre-eligibility checks, screening and randomisation visits 
 
arranging analysis of blood and urine samples for any protocol specified analyses in local 
NHS laboratories 


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 
transcription of biochemistry results from screening and randomisation visits into eCRF 
 
randomisation of eligible participants 
 
seeking information regarding outcomes and other health events of interest from electronic 
and/or paper health records where relevant 
 
administering telephone questionnaires 
 
maintaining site files 
The University of Aberdeen will be responsible for health economic analyses. 
 
ROLES AND RESPONSIBILITIES OF TRIAL COMMITEES  
TRIAL MANAGEMENT COMMITTEES 
 
 
Trial Management Group (TMG): the TMG will consist of the LENS investigators, project 
managers, trial statistician(s), and trial programmer(s). Its primary aim is to deliver the trial in 
accordance with the protocol. It will meet approximately every 3-6 months, either in person or 
by teleconference. 
 
 
Local Management Group (LMG): the LMG will consist of three investigators (David Preiss, 
Jennifer Logue and Jane Armitage), the project managers and the trial statistician. This group 
will meet (face-to-face and/or by teleconference) at least monthly and is intended to ensure the 
smooth operation of the trial on a day-to-day basis. Additional members will be included in 
specific meetings depending on issues to be dealt with. 
 
 
Trial Steering Committee (TSC): the TSC will consist of an independent chairperson (a 
statistician with relevant trial experience), independent physicians with relevant clinical 
experience, an independent colleague from the Royal National Institute for the Blind (RNIB), at 
least one patient representative, the Chief Investigator, the trial statistician(s) and other 
members. In accordance with NIHR guidance, at least 75% of TSC voting members will be 
independent. Meetings will also be attended by the LENS project managers. The TSC will 
meet regularly (more often during recruitment), either in person or by teleconference, to 
discuss trial progress. The TSC will be responsible for protecting patients’ interests and 
provide overall supervision regarding the trial’s progress, adherence to the protocol and patient 
safety. The TSC can decide, based on DMC advice, whether to end or modify the trial or to 
seek additional data. Unless this occurs, the TSC, the CCO (except those who supply any 
confidential analyses), the RCC and the LCC will remain ignorant of any interim results until 
the trial is completed. The TSC is also responsible for decisions regarding the addition of any 
LENS sub-studies during the conduct of the trial. 
 
 
Data Monitoring Committee (DMC): This independent committee will consist of three 
members including two clinicians with relevant experience and an experienced statistician. The 
DMC will review unblinded analyses of the composite primary outcome, deaths and 
hospitalisations along with any other analyses requested, according to randomised treatment 
arm. In the light of these analyses and results from any other trials, the DMC will advise the 
TSC if, in their view, the randomised comparisons have provided both (a) proof beyond 
reasonable doubt that for all patients, or for some specific types, fenofibrate therapy is clearly 
indicated or contra-indicated; and (b) evidence that might reasonably be expected to materially 


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influence the patient management of many clinicians. The DMC will meet approximately 
annually with the possibility of additional meetings, and there will be a DMC chairperson’s 
review of the results every 6 months.  
Collaborators and all others associated with the trial may write (preferably via the CCO) to the 
chairman of the DMC at any time to draw attention to any concerns they may have about particular 
side-effects or about particular categories of patients requiring special consideration, or about any 
other matters. 
 
 
 


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LIST OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
RESEARCH REFERENCE NUMBERS 
2 
KEY TRIAL CONTACTS 
3 
TRIAL SUMMARY 
4 
FUNDING AND SUPPORT IN KIND 
5 
STUDY SPONSOR AND FUNDER 
6 
CO-ORDINATION OF THE TRIAL 
6 
ROLES AND RESPONSIBILITIES OF TRIAL COMMITEES 
7 
Trial Management Committees 
7 
LIST OF ABBREVIATIONS 
11 
TRIAL FLOW CHART 
13 
STUDY PROTOCOL 
14 
1 
BACKGROUND 
14 
2 
RATIONALE 
14 
3 
OBJECTIVES AND OUTCOMES 
18 
3.1 
Objectives 
18 
3.2 
Outcomes 
18 
3.3 
Adjudication of pre-specified outcomes and other events 
21 
4 
TRIAL DESIGN 
22 
4.1 
Study Setting 
22 
4.2 
Eligibility Criteria 
22 
4.3 
Trial Procedures 
23 
4.4 
Recruitment 
23 
4.5 
Screening and Randomisation 
25 
4.6 
Post randomisation follow-up 
29 
4.7 
Trial questionnaires 
32 
4.8 
Stopping study treatment, change of consent and withdrawal 
33 
4.9 
Analysis of blood and urine samples 
34 
4.10 
End of trial 
34 
4.11 
Trial Medication 
35 
5 
PHARMACOVIGILANCE 
40 
5.1 
Definitions to be used in lens 
40 
5.2 
Events associated with fenofibrate use 
40 
5.3 
Recording and reporting adverse events 
41 
5.4 
Notification of specific events 
43 
5.5 
Responsibilities 
44 
6 
STATISTICS AND DATA ANALYSIS 
45 
6.1 
Sample size calculation 
45 


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6.2 
Statistical analysis 
47 
7 
DATA HANDLING 
49 
7.1 
Source Data 
49 
7.2 
Access to Data 
49 
7.3 
Data protection and patient confidentiality 
50 
7.4 
Access to the final trial dataset 
50 
7.5 
Archiving 
50 
8 
MONITORING, AUDIT & INSPECTION 
50 
9 
ETHICAL AND REGULATORY REPORTS AND CONSIDERATIONS 
51 
9.1 
Peer review 
51 
9.2 
Public and Patient Involvement 
51 
9.3 
Amendments 
52 
9.4 
compliance 
52 
9.5 
Financial and other competing interests 
52 
9.6 
Indemnity 
52 
10 
DISSEMINATION POLICY 
53 
11 
REFERENCES 
54 
12 
APPENDICES 
56 
12.1 
Appendix 1 - Risk assessment 
56 
12.2 
Appendix 2 – Authorisation of Local collaborating Centres 
57 
12.3 
Appendix 3 – Schedule of Assessments 
58 
12.4 
Appendix 4 – Protocol Amendment History 
59 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS  
 
ACCORD 
Action to Control Cardiovascular Risk in Diabetes 
AE 
Adverse Event 
ALT  
Alanine aminotransferase 
AR 
Adverse Reaction 
AST 
Alanine aminotransferase 
BNF 
British National Formulary 
CCO 
Central Co-ordinating Office 
CHI 
Community Health Index 
CI 
Chief Investigator 
CK 
Creatine kinase 
CTA 
Clinical Trial Authorisation 
CTSU 
Clinical Trial Service Unit and Epidemiological Studies Unit 
DM 
Diabetes Mellitus 
DMC 
Data Monitoring Committee 
DR 
Diabetic Retinopathy 
DES 
Diabetic Eye Screening  
DSUR 
Development Safety Update Report 
eCRF 
Electronic Case Report Form 
eDRIS 
Electronic Data Research and Innovation Service 
eGFR 
Estimated Glomerular Filtration Rate 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FIELD 
Fenofibrate Intervention and Event Lowering in Diabetes 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GP 
General Practitioners 
HIC 
Health Informatics Centre 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ISD 
Information Services Division 
ISF 
Investigator Site File 
LENS 
Lowering Events in Non-proliferative retinopathy in Scotland 
LMG 
Local Management Group  
LFT 
Liver function tests 
LCC 
Local Collaborating Centre 
MHRA 
Medicines and Healthcare products Regulatory Agency 
NHS 
National Health Service 
NIHR 
National Institute for Health Research 
NRS 
National Records of Scotland 
NSAID 
Non-steroidal anti-inflammatory drug 
OCT 
Optical coherence tomography 
OPCS 
Office of Population Censuses and Surveys 
PBPP 
Public Benefit and Privacy Panel 
PI 
Principal Investigator 


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PIL 
Participant Information Leaflet 
QALY 
Quality adjusted life-years 
QP 
Qualified Person 
RCC 
Regional Co-ordinating Centre 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RNIB 
Royal National Institute for the Blind 
SAE 
Serious Adverse Event 
SCI 
Scottish Care Information 
SDRN 
Scottish Diabetes Research Network 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SMR 
Scottish Morbidity Record 
SSAR  
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMG 
Trial Management Group 
TMS 
Trial Management System 
TSC 
Trial Steering Committee 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
VFQ-25 
Visual Function Questionnaire-25 
 
 
 




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STUDY PROTOCOL 
LENS: Lowering Events in Non-proliferative retinopathy in Scotland 
1 BACKGROUND 
Diabetic retinopathy (DR) and diabetic maculopathy are common microvascular complications in 
patients with diabetes mellitus (DM)1. DR is a progressive disease that includes the following 
stages: no apparent DR, non-proliferative DR, and proliferative DR. Non-proliferative DR is 
characterised by the presence of observable changes in the retina (venous dilatation, 
microaneurysms, retinal haemorrhages, retinal oedema, and hard exudates). Proliferative DR is 
characterised by neovascularisation which occurs in response to the hypoxic condition of the retina. 
The development of these abnormal new retinal blood vessels may lead to vitreal haemorrhage, 
retinal detachment or neovascular glaucoma. Diabetic maculopathy is characterised by the 
development of hard exudates or blot haemorrhages close to the fovea. Maculopathy carries the 
risk of retinal thickening at the macula which is a major threat to vision.  
Diabetic retinopathy and maculopathy (referred to in the protocol hereafter only as diabetic 
retinopathy [DR]) remains a leading causes of blindness and poor vision2, one of the most feared 
complications of DM. In Scotland, Diabetic Eye Screening (DES) Collaborative data show that in 
diabetic individuals not already attending specialist eye clinics, more than 30% have DR in one or 
both eyes. More than 5,500 diabetic patients annually develop referable DR in Scotland3. Of those 
with observable DR (defined as R2 or M1 or bilateral R1 on the Scottish DES grading system – see 
Table 1), DES data indicate that 29% develop referable disease within 4 years. DR leads to the 
certification of blindness in about 1,400 patients in the UK each year2,4 making it one of the most 
important causes of blindness in people of working age. In a survey conducted in a randomly 
selected group of 586 patients with DM from Tayside, Scotland, the presence and intensity of fear 
of visual loss was explored5. Fear of visual loss was frequent for 37% and intense for 47%. Notably 
these patients were not selected based on having any DR. Patients with clinically significant DR 
demonstrated even higher levels of concern for loss of vision.  
While blindness is the most obvious concern raised by patients, the potential impact of reduced 
vision on quality of life extends well beyond this. Qualitative studies have been conducted in adults 
with DM and mild, moderate or severe non-proliferative DR or proliferative DR6. Participants 
described a range of problems such as difficulty driving (especially at night) and reading, notably at 
all grades of DR. Those with more severe eye disease forego important life aspects like working 
and activities related to DM treatment can become difficult, e.g. reading food labels, taking insulin 
injections, glucose testing. Loss of independence is a major fear, especially mobility and increased 
fear of accidents. It is in the interests of the National Health Service (NHS) for patients to remain 
independent, and preservation of vision is an important goal in DM. 
2  RATIONALE  
While the risk of cardiovascular events in DM has been substantially reduced by various preventive 
strategies, there are few effective options to slow the progression of microvascular disease. 
Historical studies like the UK Prospective Diabetes Study7 and the Diabetes Control and 
Complications Trial8 showed that moderately good glycaemic control could reduce microvascular 
complications compared with poor control. However, recent trials of intensive glucose-control, in 
which glycaemic levels in the control arms were considerably better than in the historical trials and 


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therefore more relevant to contemporary care, showed no benefit for microvascular outcomes like 
DR and nephropathy9. We are, therefore, left with few effective options apart from screening for 
progressive retinal disease and then using interventions like laser therapy, intravitreal anti-vascular 
endothelial growth factor injection and vitrectomy at a late stage when DR has already progressed 
to a clinically significant grade.  
Clofibrate, the precursor of fenofibrate, was studied in the 1960-1970s. Although the drug was 
discontinued due to the increased risk of gallbladder complications, various small trials showed that 
clofibrate could reduce hard exudates in patients with DM10. Fenofibrate is a lipid-modifying agent 
which activates peroxisome proliferator-activated receptor alpha to lower circulating triglycerides11. 
It has modest HDL-cholesterol raising and LDL-cholesterol lowering effects. Two major 
cardiovascular trials of fenofibrate therapy conducted in type 2 DM patients have included DR as a 
tertiary outcome12,13. Both suggested that fenofibrate may provide microvascular benefit. The 
Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a placebo-controlled 
clinical trial conducted in 9795 participants with type 2 DM who were not on a statin to assess the 
effect of fenofibrate on cardiovascular outcomes12. In FIELD, 1012 participants agreed to take part 
in the DR sub-study with retinal photographs at 0, 2 and 5 years. Allocation to fenofibrate was 
associated with a reduction in the composite DR endpoint comprising the need for retinal laser 
therapy, the development of macular oedema or 2-step Early Treatment Diabetic Retinopathy 
Study (ETDRS) grade progression14. Based on 53 (11.1%) vs. 75 (16.1%) events the reduction was 
34% (95 CI 6-53%; p=0.022) over 5 years of follow-up. In the full FIELD cohort (n=9795), self-
reported laser therapy was also reduced by 31% (16%-44%); p=0.0002 based on 164 (3.4%) vs. 
238 (4.9%) reports. The placebo-controlled Action to Control Cardiovascular Risk in Diabetes 
(ACCORD)-Lipid study was designed to test the effect of fenofibrate on cardiovascular outcomes in 
5518 participants with type 2 DM who were all on open-label simvastatin therapy 13. In ACCORD-
Lipid, 1593 participants took part in the Eye sub-study which included two standardised eye 
examinations with fundal photography at 0 and 4 years. The composite outcome of laser treatment, 
vitrectomy or 3-step progression on the ETDRS scale was reduced by 40% (13-58%; p=0.006; 52 
[6.5%] vs. 80 [10.2%] events)15. Various other DR outcomes were not improved by fenofibrate 
therapy however. Recent work in an animal model of DR suggests that fenofibrate may be acting 
directly within the eye and that any effect on circulating lipids may therefore not be relevant to its 
potential effects on microvascular disease16. 
Criticisms of these cardiovascular trials' retinal findings are:  
i) the majority of participants had no DR at baseline, a group unlikely to be treated routinely 
with fenofibrate 
ii) the use of composite or self-reported outcomes which may be less robust than objectively 
reported results 
iii) that eye outcomes were tertiary outcomes rather than the primary outcome of the trial 
iv) that the trials were conducted in participants with lipids and HbA1c within certain pre-
specified limits and may therefore not be generally applicable to other patients with DM, 
including those with type 1 DM 
Notably a recent Primary Care Diabetes Society survey indicated that 76% of general practitioners 
(GPs) who are aware of the DR findings from FIELD and ACCORD were unlikely to use fenofibrate 
to treat DR without further trial evidence. Guidelines are also unclear regarding the use of 
fenofibrate for DR. The Royal College of Ophthalmologists suggests its ‘consideration’ in non-
proliferative DR (grade B evidence)17. DM guidelines from the National Institute for Health and 
Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network do not mention 


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fenofibrate18,19. Australia recently approved fenofibrate for DR. Trial registries confirm that only one 
fenofibrate trial is currently being considered or conducted, namely FAME-1-EYE20. However, this 
is a trial restricted to patients with type 1 DM and established macular thickening. 
There is a pressing need for better evidence for the effect of fenofibrate on the progression of DR 
from a dedicated large randomised controlled trial (RCT). Given the nature of DR, a slowly 
progressive condition, it is necessary to recruit individuals at relatively high risk of the condition 
progressing, and to treat and follow them for a number of years for a RCT to have sufficient power 
to detect plausible effects. We have designed a double-blinded randomised placebo-controlled trial, 
LENS. LENS is designed to achieve these objectives at low cost, making use of existing sources of 
relevant healthcare data to both recruit and follow participants. Scotland is a leader in terms of such 
healthcare repositories, central to which is the use of each person’s Community Health Index (CHI) 
number. This provides the excellent environment to conduct such a trial. 
LENS will recruit and randomise at least 1,060 patients with diabetes and retinopathy to receive 
either fenofibrate or placebo tablets, to be taken orally, for at least a median of 4 years (counted as 
4 years from randomization of the median participant). Prior to randomisation, all participants who 
are eligible at screening will enter an active run-in phase in which they will be treated with open-
label fenofibrate tablets for approximately 8 weeks. The purposes of the active run-in are to: 
i) maximise adherence during the trial, thereby providing robust results, and  
ii) allow the research team to establish the best dosing regimen for each participant during the 
trial.  
The dose of fenofibrate tablets to be used in LENS is 145mg. Each participant’s dosing regimen will 
be determined by their renal function. Those with normal renal function will take one fenofibrate 
tablet daily during the active run-in and one study tablet (fenofibrate or placebo) daily after 
randomisation, whereas participants with chronic kidney disease will take one fenofibrate every 
second day during the active run-in and one study tablet every second day after randomisation. 
 
 
 


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Table 1. Scottish DES Collaborative grading system for DR 
Grading 
Description 
Outcome 
RETINOPATHY (excluding the macula) 
R0  
No DR anywhere 
Rescreen in 12-24 months 
R1* 
 
Background DR – mild  
The presence of at least one of any of the following 
features anywhere 
 
dot haemorrhages 
 
microaneurysms 
 
hard exudates 
 
cotton wool spots 
 
blot haemorrhages§ 
 
superficial/ flame shaped haemorrhages 
Rescreen in 12 months 
R2* 
 
Background DR – observable  
Four or more blot haemorrhages§ in one hemi-field only 
(Inferior and superior hemi-fields delineated by a line 
passing through the centre of the fovea and optic disc) 
Rescreen in 6 months 
 
R3 
 
Background DR – referable 
Any of the following features: 
 
Four or more blot haemorrhages§ in both inferior 
and superior hemi-fields 
 
Venous beading  
 
IRMA 
Refer to 
ophthalmology 
 
R4 
 
Proliferative DR 
Any of the following features: 
 
Active new vessels 
 
Vitreous haemorrhage 
Refer to 
ophthalmology 
 
R6 
 
Not adequately visualised 
Retina not sufficiently visible for assessment 
Technical failure 
MACULOPATHY 
M0  
No maculopathy 
No features ≤2 disc diameters from the centre of the fovea 
sufficient to qualify for M1 or M2  
Rescreen in 12-24 months 
M1* 
Observable maculopathy 
Lesions as specified below within a radius of >1 but ≤2 disc 
diameters the centre of the fovea: 
 
Any hard exudates 
Rescreen in 6-12 months 
M2†  
Referable maculopathy 
Lesions as specified below within a radius of ≤1 disc 
diameter of the centre of the fovea: 
 
Any blot haemorrhages§ 
 
Any hard exudates 
May require referral to 
ophthalmology  
* Definition of observable DR in LENS: R1 in both eyes and/or R2 in at least one eye at the most recent retinal 
screening visit; and/or M1 in at least one eye at any retinal screening in the last 3 years (and R3, R4 or M2 [i.e. referable 
DR] not present in either eye) 
§ blot haemorrhage has same or greater diameter as retinal vein crossing the optic disc  
† At the start of LENS in 2018 and until end-2021, all M2 led to specialist ophthalmology referral. During 2022, DES 
started to introduce a phased change to the management pathway of patients with M2 disease. In the new pathway, M2 
in the context of poor visual acuity (e.g. 6/9.5 or worse) leads to optical coherence tomography (OCT) imaging. If OCT 
shows macular oedema, the patient is referred to an ophthalmologist. Patients who do not require OCT, or in whom there 
is no evidence of macular oedema on OCT, are not automatically referred. Given that M2 (or equivalent disease) requires 
specialist referral/review in many countries, the LENS protocol will continue to categorise M2 as referable disease.      


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3 OBJECTIVES AND OUTCOMES 
The main hypothesis is that fenofibrate therapy will slow the progression of observable DR to 
referable DR or DR requiring laser or surgical treatment when compared with placebo. Objectives 
and outcomes are summarised in Table 2.  
3.1 OBJECTIVES 
3.1.1 Primary objective 
The primary objective is to compare the effect of allocation to fenofibrate versus placebo on the 
composite of progression of observable DR to referable DR, or any of retinal laser therapy, 
vitrectomy or intra-vitreal injection of medication due to DR. 
3.1.2 Secondary objectives 
Secondary objectives are to compare the effect of allocation to fenofibrate versus placebo on:  
(i) 
the occurrence of the composite primary outcome in various subgroups 
(ii) 
the individual components of the composite primary outcome (namely progression of 
DR to referable DR; and retinal laser therapy, vitrectomy or intra-vitreal injection for 
DR) 
(iii) 
any progression of DR across the DES grading scale 
(iv) 
visual acuity 
(v) 
the presence of hard exudates or blot haemorrhages (M2) within 1 disc diameter of the 
macula  
(vi) 
macular oedema 
(vii) 
visual function 
(viii) quality of life 
(ix) 
total cost to the health service 
(x) 
cost-effectiveness 
3.2 OUTCOMES 
3.2.1 Primary outcome 
The primary outcome is the composite of progression from observable DR to referable DR, or any 
of retinal laser therapy, vitrectomy or intra-vitreal injection of medication due to DR. Referable DR is 
defined according to the Scottish DES grading as R3 or R4 or M2 in at least one eye on the DES 
grading scheme (see Table 1).  
For those participants in whom the composite primary outcome is reported (whether via data 
linkage or questionnaire), LCC research nurses will review their electronic health records 
periodically to determine any therapy, i.e. retinal laser, vitrectomy or intra-vitreal injection, which 
was provided. While most primary outcomes are expected to come from routine retinal imaging, 
any findings of referable DR recorded during clinical examination (e.g. by an ophthalmologist) will 
also be included as an outcome. 
3.2.2 Secondary outcomes 
The following are pre-specified secondary outcomes: 
 
The individual components of the composite primary outcome, i.e.: 
o Progression of DR to referable DR 
o Retinal laser therapy for DR 
o Vitrectomy for DR 


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o Intra-vitreal injection for DR  
 
 
Composite of retinal laser, vitrectomy or intra-vitreal injection for DR  
 
Any progression of DR across the DES grading scale 
 
Visual acuity (according to LogMAR or Snellen chart measurement conducted at DES visits) 
 
The development of hard exudates or blot haemorrhages within 1 disc diameter of the 
macula (defined as M2 in the DES grading scheme; see Table 1)  
 
The development of macular oedema* 
 
Visual function (according to the Visual Function Questionnaire [VFQ]-25 questionnaire) 
 
Quality of life (according to the EQ-5D questionnaire) 
 
Total cost to the health service (in terms of additional drug treatment and monitoring costs, 
and health care resource use over follow-up) 
 
Cost-effectiveness (in terms of incremental cost per quality adjusted life-years [QALY] 
gained with fenofibrate versus placebo)  
*During 2022, Scotland started to introduce optical coherence tomography (OCT) imaging for 
certain patients who reach M2 grading (based on visual acuity). The availability of data from 
OCT imaging is yet to be established. The presence of macular oedema (i.e. intra-retinal fluid) 
has therefore been included as an additional secondary outcome. 
3.2.3 Tertiary outcomes  
Tertiary outcomes include: urine albumin:creatinine ratio, the occurrence of major cardiovascular 
events (myocardial infarction, stroke, coronary and peripheral revascularisation), and minor and 
major non-traumatic lower limb amputation (minor [defined as distal to the ankle] or major [defined 
as through or proximal to the ankle]).  
3.2.4 Longer term follow up 
Consent will be sought from participants at baseline to facilitate investigation of the longer term 
effects of ~4 years’ fenofibrate treatment after the main study ends. Long-term outcomes may 
include the development of significantly impaired vision or blindness, DR related eye procedures, 
cardiovascular outcomes, progression to end-stage renal failure and other outcomes. Any long term 
follow-up will be described in a further protocol and new ethical and Public Benefit and Privacy 
Panel (PBPP) approvals will be required before such work is undertaken (see section 4.6.5). 
Where possible, we will seek to meta-analyse LENS results with results from FIELD and ACCORD 
and other trials of fenofibrate therapy. 
 
 
 


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Table 2. Summary of LENS objectives and outcomes 
Objectives 
Outcome Measures  
Time-point(s) of 
evaluation  
Primary 
Objective: 
to compare the 
effect of allocation 
to fenofibrate 
versus placebo on 
the primary 
outcome  
Primary outcome: the composite of progression 
from observable DR to referable DR (defined 
according to the Scottish DES grading as R3 or R4 
or M2 in at least one eye*), or any of retinal laser 
therapy, vitrectomy or intra-vitreal injection of 
medication due to DR, whichever occurs first. 
* from retinal imaging or clinical examination 
 
 
6-12 monthly retinal 
screening;  
 
6 monthly trial-
specific 
questionnaires 
Secondary 
Objectives: 
to compare the 
effect of allocation 
to fenofibrate 
versus placebo on 
the secondary 
outcomes 
Secondary outcomes: 
 
the occurrence of the composite primary outcome 
in various subgroups 
 
the individual components of the composite 
primary outcome (namely progression of DR to 
referable DR; and retinal laser therapy, vitrectomy 
or intra-vitreal injection for DR);  
 
Any progression of DR across the DES grading 
scale;  
 
Visual acuity on LogMAR or Snellen scale    
                                  
 
the presence of hard exudates or blot 
haemorrhages (M2) within 1 disc diameter of the 
macula 
 
the presence of macular oedema 
 
Visual function 
 
 
 
Quality of life 
 
 
 
Total cost to the health service and cost-
effectiveness. 
 
 
As for the primary 
outcome 
 
As for the primary 
outcome 
 
 
 
6-12 monthly retinal 
screening  
 
6-12 monthly retinal 
screening 
 
6-12 monthly retinal 
screening 
 
 
OCT analysis 
 
VFQ-25 questionnaire 
at 2 years and trial 
end 
 
EQ-5D questionnaire 
at 2 years and trial 
end 
 
Combination of data 
sources 
Tertiary 
Objectives:  
to compare the 
effect of allocation 
to fenofibrate 
versus placebo on 
the tertiary 
outcomes 
Tertiary outcomes:  
 
urine albumin:creatinine ratio 
 
 
the occurrence of major cardiovascular events 
(myocardial infarction, stroke, coronary and 
peripheral revascularisation) 
 
minor and major non-traumatic lower limb 
amputation (minor [defined as distal to the ankle] 
or major [defined as through or proximal to the 
ankle]) 
 
 
Routinely collected 
biochemistry via SCI-
Diabetes 
 
Linkage to SMR01 
records 
 
 
Linkage to SMR01 
records and 6 
monthly 
questionnaires 
 


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Where retinopathy and maculopathy gradings of retinal images contribute to pre-specified 
outcomes, the grading results generated by the NHS Scotland Diabetic Eye Screening program will 
be used for the pre-specified analyses. However, it is also intended for University of Oxford 
investigators to use image analysis software for exploratory analyses of the effect of fenofibrate on 
DR (after the main trial is completed) and for observational analyses to better understand drivers of 
DR progression. 
3.3 ADJUDICATION OF PRE-SPECIFIED OUTCOMES AND OTHER EVENTS 
Primary, secondary and tertiary outcomes will not be adjudicated with the exception of any medical 
eye procedures, any report of vitreous haemorrhage and the development of macular oedema. Any 
such adjudication will be conducted by experienced doctors at the CCO who are blinded to 
treatment allocation. To inform adjudication LCCs will collect supporting documentation e.g. 
hospital discharge or surgical operation report or OCT report and submit to the CCO for review. 
Documentation of SSARs will be sought to confirm or refute the reported diagnosis. 
LCCs will be required to verify any cardiovascular events, lower limb amputations and deaths which 
are reported to the CCO by questionnaire or other communication from any participant or clinician. 
Hospitalisations for non-cardiovascular reasons will be tabulated but not verified by LCCs.  
Events which are reported and are unrefuted will be assumed to have occurred regardless of the 
source of information (e.g. health records or participant or GP). Where possible, comparison will be 
made between different registry sources of the same data for verification purposes.  


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4 TRIAL DESIGN 
LENS is a multicentre phase 4 randomised placebo-controlled clinical trial. 
4.1 STUDY SETTING 
The national DES service provides regular retinal imaging and grading for all 250,000 with DM in 
Scotland. Retinal screening appointments are organised by each health board. Patients receive a 
summary of their results by post a few weeks after their visit. The trial will be conducted in this real-
life setting. 
LENS is a multicentre trial to be conducted in up to 11 mainland Scottish NHS Health boards. Each 
Health board will have at least one LCC and it is anticipated that the majority of Health boards will 
have one LCC. The trial will be conducted using a pragmatic streamlined trial design with the only 
planned face-to-face visits at the LCC being an initial screening visit, followed by a randomisation 
visit eight weeks later. The 24-hour Freephone service (0808 164 5090) established by the Clinical 
Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, will allow study 
participants and clinical staff involved in their care to discuss any aspects of the trial with 
experienced clinical staff, thereby helping to ensure good compliance and the early identification of 
any major problems.  
Participants will be recruited either via direct contact (if the person has previously given permission 
to do so by agreeing to join a research registry) or via postal invitation (under which circumstances 
the research team will have no knowledge of identifiable data for any individual until that individual 
returns a reply slip) which will either  be included with their NHS DES screening results or mailed to 
potential participants by the Health Informatics Centre (University of Dundee) Safe Haven. The 
majority of participants are likely to be recruited via postal invitation. Participants will be recruited 
regardless of whether their DM is treated in primary or secondary care. LCCs will typically, though 
not necessarily, be at major hospitals.  
The pathway of standard care will not be altered for LENS participants. They will continue to be 
followed up according to standard NHS practice. The DES grading system, which operates to NHS 
Quality Improvement Scotland standards and applies strict external quality control procedures, will 
have no knowledge of which retinal images belong to LENS participants. If a participant’s DR 
grading deteriorates to a level where specialist review and intervention is required, this will occur as 
normal. 
 
4.2 ELIGIBILITY CRITERIA 
4.2.1 Inclusion criteria 
 
Subjects capable of giving informed consent  
 
DM (any type except gestational diabetes)  
 
Age ≥18 years 
 
Observable DR (defined as R1 in both eyes or R2 in one/both eyes at the most recent 
retinal screening assessment; or M1 in one/both eyes at any retinal screening assessment 
in the 3 years prior to screening)  
 
Willing to either complete electronic questionnaires or conduct telephone interviews for 
collection of questionnaire data once every 6 months  
4.2.2 Exclusion criteria 
 
Referable DR (defined as R3 or R4 or M2 in one or both eyes)  


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 
History of gallbladder disease (cholecystitis, symptomatic gallstones, cholecystectomy) 
 
History of acute or chronic pancreatitis  
 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2X the upper limit of 
normal (ULN) according to local NHS laboratory reference range at screening visit 
 
ALT or AST >2.5X ULN according to local NHS laboratory reference range at 
randomisation visit 
 
Creatine kinase (CK) >3X ULN according to local NHS laboratory reference range at 
screening visit 
 
CK >3X ULN according to local NHS laboratory reference range at randomisation visit 
 
Estimated glomerular filtration rate (eGFR) <40mL/min/1.73m2 at screening visit  
 
eGFR <30mL/min/1.73m2 at randomisation visit 
 
Cirrhosis of any aetiology or any other serious hepatic disease (investigator opinion) 
 
Female who is pregnant, breastfeeding, currently trying to become pregnant, or of child-
bearing potential and not practising birth control (as defined in section 4.11.12) 
 
Ongoing vitamin K antagonist (warfarin, phenindione, acenocoumarol), cyclosporine, 
colchicine, ketoprofen, daptomycin, fibrate therapy, or treatment with rosuvastatin 40mg 
daily 
 
Previous myositis, myopathy or rhabdomyolysis of any cause, or diagnosed hereditary 
muscle disorder 
 
Ongoing renal replacement therapy 
 
Any previous organ transplant 
 
Previous reported intolerance to any fibrate 
 
Medical history that might limit the individual’s ability to take trial treatments for the duration 
of the study (e.g. severe respiratory disease, history of cancer within last 5 years other than 
non-melanoma skin cancer; or recent history of alcohol or substance misuse) 
 
Any other significant disease or disorder which, in the opinion of the Investigator, may either 
put the participant at risk because of participation in the trial, or may influence the result of 
the trial, or the participant’s ability to participate in the trial 
 
LENS participants can participate in other research studies, including clinical trials. The only 
exclusions related to co-enrolment will be: if any other study or trial excludes co-enrolment 
or if the intervention being investigated in another trial has the potential to interact with 
fenofibrate therapy. 
 
Not adherent to active run-in treatment 
 
Any queries regarding eligibility due to participation in other trials will be addressed by experienced 
study doctors at the CCO. 
4.3 TRIAL PROCEDURES 
The Schedule of Assessments is provided in Appendix 3. 
4.4 RECRUITMENT 
4.4.1 Patient identification 
The experience of the CCO and Regional Co-ordinating Centre based on large trials like 
ASCEND21 and similar smaller mail-out studies like CAMERA22, suggests that such approaches 
typically lead to the enrolment of 4-5% of recipients. This necessitates mailing information to a large 
number of potential participants. Potential participants will be approached using the following 
methods: 


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 
via the patient research register of the Scottish Diabetes Research Network (SDRN)23 
 
via mail-out with DES results 
 
via mail-out by the Health Informatics Centre (HIC; University of Dundee) Safe Haven’s 
patient recruitment service (https://www.dundee.ac.uk/hic/patientrecruitment/) 
 
via the SHARE register24 
GPs responsible for the care of consenting and eligible patients will be informed by letter from the 
CCO that their patient wishes to take part. GPs will be able to discuss this with the research team 
and withdraw the patient if they consider there is any reason not to randomise that patient. Repeat 
pre-screening (i.e. assessment of eligibility prior to the screening visit) will be permitted for 
interested patients who are initially found to be ineligible. There will be a trial website 
(https://www.ctsu.ox.ac.uk/lens) to provide information about the study for individuals who may be 
interested in participating as well as those who are active participants, for example; the participant 
information sheet and participant bulletins and newsletters. 
4.4.2 Recruitment via the SDRN register 
SDRN holds a national register of patients with DM in Scotland who have given consent to be 
approached regarding research studies23. SDRN will provide lists of potentially eligible participants 
to LCCs in each health board who have agreed to be contacted by phone. The LCC research nurse 
will phone each patient on the list and (i) ask if they would be interested in receiving further 
information regarding the LENS trial and (ii) seek verbal consent to check key eligibility criteria in 
their health records (specifically their most recent eGFR result and most recent retinal screening 
result). If they agree, they will then be mailed a detailed patient information leaflet (PIL), followed by 
a further telephone call from the LCC research nurse to discuss the trial, review contact details and 
arrange a Screening visit if the trial is of interest. Due to the nature of the SDRN register, patients 
are not uniformly distributed across Scotland. Consequently, this is likely to be an efficient method 
of recruitment in some health boards but not in others. In July 2014, the total number of patients on 
the SDRN register likely to be suitable for LENS (based on DES grading) was approximately 2,000.  
4.4.3 Recruitment via DES mail-out 
Based on DES data, it is estimated that at least 25,000 patients with DM have the appropriate DR 
grading to be suitable for LENS. Of these, at least 20,000 regularly attend retinal screening via 
DES. DES will assist with recruitment in LENS. A few weeks after a patient’s retinal screening visit, 
it is standard NHS practice for patients to receive a letter (sent from their NHS health board) with a 
description of their DR results. The research team will liaise with relevant contacts in each health 
board to ensure that an abbreviated PIL (with FREEPOST reply slip) regarding LENS is enclosed 
with the results of their routine retinal screening visit. The content of the results letter enables this to 
be done relatively selectively, so those patients with grades of DR who may be eligible for LENS 
will receive the abbreviated trial leaflet. Interested patients can complete the reply slip with their 
contact details and return it via FREEPOST. It will be specified that, by completing and returning 
the reply slip, a patient is giving permission for the LCC research nurse or LCC study doctor to 
check their eligibility for the trial.  
The research team will use the returned reply slips to populate a list of potential participants with 
the information provided. This will allow LCC research nurses to perform preliminary eligibility 
checks and follow-up with a telephone call to discuss the trial, and check and update contact 
information, complete the preliminary eligibility checks and arrange local appointments for 
screening visits. The LCC research nurse will also mail a copy of the detailed PIL to patients for 
whom screening visits are arranged. As eligible patients have retinal screening performed every 6-


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12 months it enables the research team to contact large numbers of potential participants at the 
time that they receive their retinal screening results. Where it is clear that an individual who has 
returned a reply slip will not be eligible, a letter of appreciation will be mailed to the relevant patient. 
It is possible that during recruitment for LENS, DES will change its procedures for sending 
appointments and results from the current mail-based system to a web-based electronic system for 
a subgroup of individuals who agree to such a change. Should this occur, the process of invitation 
will be amended in conjunction with DES to allow sending of electronic versions of the abbreviated 
trial leaflet to such patients, or downloading of the leaflet, requesting that participants reply to the 
CCO by email. 
4.4.4 Recruitment via HIC mail-out 
On behalf of each health board, SCI Diabetes will create lists of potential participants using the 
LENS Trial inclusion criteria, i.e. age, DES retinopathy grading and renal function. Lists generated 
will be securely transferred to the relevant health board for review and onward secure transfer to 
the HIC’s recruitment service. (For some boards such as NHS Tayside, HIC already holds SCI-
diabetes data locally on their NHS servers, negating the need a file transfer between SCI-diabetes, 
the boards and HIC). HIC’s recruitment service will mail information regarding LENS (in batches) to 
potentially eligible participants across mainland Scotland. These mail-outs will include a named 
invitation letter (signed by the lead DES clinician for that patient’s health board), a reply slip, a 
FREEPOST envelope and a detailed PIL. The return of a reply slip by a potential participant will 
allow LCC research nurses to perform preliminary eligibility checks and follow-up with a telephone 
call to discuss the trial. The LCC research nurse will then check and update contact information, 
complete the preliminary eligibility checks and arrange local appointments for screening visits. 
Where it is clear that an individual who has returned a reply slip will not be eligible, a letter of 
appreciation will be mailed to the relevant patient. HIC will send reminder invitation letters to 
individuals who don’t respond to the initial mailing. 
 
As with recruitment via DES mail-out, the research team will have no knowledge of any potential 
participant’s details unless that individual gives permission to contact them by returning a reply slip 
by FREEPOST. This method of recruitment has been supported by the DES lead clinicians in 
whose name HIC will mail out the invitations (see letters of support), and it will require national 
PBPP approval. This national strategy for recruitment of patients with diabetes across Scotland has 
recently been approved for the adAPT trial (http://adaptdiabetes.org/in-brief-2/). 
4.4.5 Recruitment via the SHARE register 
SHARE is a recently introduced program in Scotland to which individuals give permission to be 
contacted regarding studies for which they may be eligible24. It is unclear how many of the patients 
in the SHARE database might be suitable for the trial, and how much overlap there may be with the 
SDRN register. Never-the-less the option to use the register as a source for recruitment will be kept 
open. The same process will be followed as is planned for the SDRN register. 
4.5 SCREENING AND RANDOMISATION 
4.5.1 Screening visit 
Potential participants will be asked to attend an appointment at the LCC where they will be 
assessed by a research nurse. By the time of the screening visit, these individuals will already have 
had time to consider participation based on information from a detailed telephone discussion with 
the local research nurse and information in the detailed PIL. At the visit, the research nurse and 


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potential participant will discuss the trial in detail. Data will be entered directly into the eCRF with 
limited use of paper wherever possible. After welcoming the patient, relevant details (name, contact 
details, details of patient’s GP and GP practice, date of birth, sex, CHI number) will be entered (if 
not yet recorded) or checked (if already recorded) in the Trial Management System (TMS). 
Eligibility criteria and other relevant clinical information (history of eye disease or procedures, 
previous cardiovascular events, date of DM diagnosis and contraindicated medications, smoking 
history, other medical history) will be recorded using available clinical data (using the NHS board’s 
clinical portal and SCI Diabetes25) and from a clinical history. Patients will be asked, if willing, to 
provide details of a friend or relative living at a different address who may be contacted in the event 
of loss of contact.  
Informed consent will be obtained before any research procedures are conducted (see below). 
After informed consent has been obtained, blood and urine samples will be taken to check 
biochemistry: 
 
renal function 
 
liver function tests – LFT (specific tests in a LFT profile will differ between health boards, 
which is acceptable as long as at least one of ALT or AST is measured)  
 
CK 
 
HbA1c 
 
random lipid profile, including at least total cholesterol, HDL-cholesterol and triglycerides 
 
urine biochemistry (urine albumin/creatinine ratio) 
These samples will be analysed in the LCC’s local NHS laboratory.  
Two questionnaires, namely Quality of Life (EQ-5D) and visual function (VFQ-25), will be 
completed on paper. Participants will be given an appointment to return to the LCC in 
approximately 8 weeks’ time and definitely within 6-11 weeks. Any patients found to be ineligible at 
the time of the screening visit will be informed of this by the LCC research nurse and the CCO will 
mail a letter to the relevant GP to provide this information. 
4.5.2 Consent  
The LCC’s local principal investigator (PI) carries overall responsibility for ensuring informed 
consent is obtained before any protocol specific procedures are carried out; however, responsibility 
will be delegated to the LCC research nurse and it is anticipated that the LCC research nurse will 
obtain consent from most, if not all, screened patients. The decision of a participant to participate in 
clinical research is voluntary and should be based on a clear understanding of what is involved. 
The trial will be described in detail to the potential participant and will cover all the elements 
specified in the abbreviated PIL (only for participants recruited via DES results mail-out), the 
detailed PIL and the Informed Consent Form (ICF). The participant will be given every opportunity 
to clarify any points they do not understand and, if necessary, ask for more information. The 
participant will be informed that their medical records may be inspected by Regulatory Authorities 
and the Sponsor. The potential participant will have had days to decide about taking part in the trial 
after receiving the detailed PIL and discussing the trial with the research nurse on the telephone. 
The research nurse or doctor obtaining consent and the participant will sign and date the ICF to 
confirm that consent has been obtained. The participant will receive a copy of this document, the 
original copy of the ICF will be stored in the Investigator Site File and a copy of the completed ICF 
will be provided to the CCO. A scanned electronic copy will be uploaded to the health board’s 
electronic health record in those health boards which are using electronic health records. In any 


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health boards not using electronic records, a paper copy will be filed in the hospital case notes. The 
participant will be provided with a Treatment Information Leaflet. 
No biological (tissue) specimens are being retained in the trial. However, participants will be asked 
to give permission for their digital retinal images to be stored as part of an imaging biobank to allow 
subsequent research. In addition, participants will be asked for their permission to use electronic 
health records (both those described in the protocol and other currently unspecified NHS datasets) 
to follow them up during the active treatment phase of the trial (i.e. the main study described in this 
protocol) and after its completion (i.e. post-trial long term follow-up). Long term follow-up is not 
covered by this protocol and it will require the development of a further protocol along with further 
ethical and PBPP approval. However, given that some microvascular outcomes such as blindness 
and amputation may take decades to occur, provision of consent will allow us to address these 
outcomes at a later stage. 
4.5.3 Activities after the screening visit including local PI sign-off of eligibility 
Along with the signed ICF, the LCC research nurse will upload a copy of the detailed PIL to the 
health board’s clinical portal (i.e. electronic health record) to enable clinicians involved in the 
patient’s care to be aware of, and gain further information about, the trial. In health boards which 
use paper records, the detailed PIL will be filed in the patient’s case notes. 
When the results of blood biochemistry (renal function, liver function tests [LFT], CK), HbA1c, 
random lipid profile [including at least total cholesterol, HDL-cholesterol and triglycerides]) are 
available these will be transcribed into the TMS and a further assessment made of the patient’s 
eligibility. Urine biochemistry results will be obtained subsequently as part of SCI Diabetes data 
linkage. Local laboratory ULNs will be used for LFTs and CK and these will be entered into the 
eCRF. Local lab ULNs are not required for renal function, lipids, HbA1c. Validation queries will 
highlight clear errors and data will be obtained from SCI Diabetes at regular intervals (every 6-12 
months) to retrospectively verify the accuracy of the transcribed data.  
Based on the details collected at the screening visit and following receipt of the screening 
biochemistry results, eligibility for participating in LENS will be determined according to the eligibility 
criteria. This will be recorded electronically on the eCRF. Both patients and their GPs will be written 
to if their screening blood test results indicate that they are not eligible to enter the trial to explain 
this. For those patients who remain eligible, the local PI or a doctor to whom responsibility has been 
delegated will be required to sign off their eligibility. This sign-off will approve the participant to 
enter the run-in phase and to be randomised after the run-in if their biochemistry results at the 
Randomisation visit are within pre-specified limits (see below) (also termed an ‘order-to-supply’). 
This approval will be in the form of an electronic signature on the trial eCRF. The local PI or 
delegated doctor’s electronic sign-off will remain valid for the entire trial unless the clinical condition 
of the patient requires a reduction in dose or cessation of the study drug after randomisation. The 
‘order-to-supply’ will be an inbuilt part of the eCRF.  
Eligible patients will receive a letter/email from the CCO informing them that they have been 
entered into the run-in period, that a supply of open-label fenofibrate will be mailed to them shortly, 
informing them how often to take the study medication and requesting that all unused run-in study 
medication be returned to the LCC at the randomisation assessment. A letter will also be sent to 
the patient’s GP by the CCO informing them of their patient’s interest and likely participation in the 
trial, and providing the GP with an opportunity to exclude their patient if they feel that the patient’s 
participation is inappropriate and a deadline for notification to the CCO. An automated text or email 
(depending on participant preference) will be sent to the participant informing them that study 


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medication is about to be sent to them and informing them of action to take if the study medication 
does not arrive shortly. Medication will then be mailed to the patient by routine post.  
The LCC research nurse will contact the participant approximately 1-2 weeks after run-in study 
medication has been mailed to verify that it has been safely received, to obtain and record the 
study medication verification code from the participant (which will be entered into the eCRF) and to 
verify appointment details for the planned randomisation assessment.  
4.5.4 Screen failures 
Individuals who are screen failures (i.e. who attend screening visits and are found to be ineligible) 
will not be allowed to be re-screened.  
Participants will receive reasonable travel expenses, including return taxi journeys where needed, 
but no additional funds. 
4.5.5 Active run-in treatment 
Participants who have been confirmed as eligible will be sent a 10-week supply of open-label 
fenofibrate tablets to be taken as one 145mg tablet daily if screening eGFR ≥60mL/min/1.73m2 or 
one 145mg tablet every 2nd day if baseline eGFR 40-59mL/min/1.73m2. The drug will be sent by 
routine post with instructions on how to take the tablets. GPs of any patients who drop out during 
the run-in phase or who ultimately fail to attend a randomisation visit will be informed of this by 
letter. It is thought highly unlikely that an active run-in with fenofibrate will impact upon retinal 
imaging in any material and sustained way.  
4.5.6 Randomisation visit 
Participants who enter the run-in will be seen approximately eight weeks (limits 6-11 weeks) after 
the initial screening visit. At this visit, all concomitant medications, compliance with the run-in 
treatment, and adverse events (including all serious adverse events; and any non-serious adverse 
events leading to the discontinuation of study treatment), will be recorded. Height, weight and vital 
signs (pulse rate and blood pressure) [average of 2 measurements for BP] will be measured and 
recorded. A blood sample for blood biochemistry will be taken and sent to the local laboratory to 
measure renal function, LFTs (including at least one of ALT or AST) and CK. Patients will be asked 
about any treatment-related side-effects that would prevent them from wanting to take part; to verify 
that they remain willing to take part in the trial; and that they have taken approximately 75% of the 
study medication or more to date. The LCC research nurse will have discretion to evaluate 
compliance if there are reasonable extenuating circumstances. Patients will be asked to stop taking 
the open-label fenofibrate. The LCC will dispose of any unused run-in fenofibrate which is returned. 
For any patients who do not wish to proceed to randomisation at this stage, their GP will be 
informed by letter from the CCO. Randomisation will only be possible when results of the blood 
tests from the visit become available, so will not occur immediately. Eligible patients will be given a 
Patient Participation Card. 
It is possible that some participants having been recruited into the trial via HIC mail-out or the 
SDRN research register will receive a further invitation to participate via mail-out with their DES 
results. To avoid confusion, it will be explained at the Randomisation visit that these abbreviated 
PILs should be ignored. 
4.5.7 Random allocation to fenofibrate or placebo 
LENS will be a double-blind trial. Therefore, trial participants, investigators, and trial staff will be 
blinded to intervention group. Matching fenofibrate and placebo tablets will be used.  Patients who 
remain eligible based on their Randomisation visit blood results and on-going consent will then be 


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randomised by the research nurse or local PI at the LCC via the CCO’s TMS. Eligible participants 
will be randomised 1:1 to double-blind:  
 
Fenofibrate 145mg, or  
 
matching placebo 
After the visit, participants will be mailed their first pack of medication containing a 26 week supply 
of study drug along with relevant information about the medication and the CTSU Freephone 
number for any trial-related queries from them or professionals responsible for their care. 
Participants with eGFR ≥60mL/min/1.73m2 at the Randomisation visit will be asked to take one 
tablet daily, while participants with eGFR 30-59mL/min/1.73m2 at the Randomisation visit will be 
informed to take one tablet of study drug every second day. Participants will be asked to take the 
study drug in the morning but they will be allowed to take the study drug at another time of the day 
if they prefer.  
4.5.8 The randomisation scheme 
A minimisation schedule of randomisation will be employed. Minimisation criteria will include: age, 
type of DM (type 1, type 2, other), sex, baseline DES grading, HbA1c, renal function and statin use. 
The randomisation algorithm will also contain a stochastic element. 
4.5.9 Method of implementing the allocation sequence 
A web-based randomisation system will be used for the trial and the server will be based at the 
CCO in the UK. The TMS will provide an immediate allocation to the relevant research nurse or 
doctor.  
4.5.10 After the Randomisation visit 
Patients whose Randomisation visit eGFR is <30mL/min/1.73m2, CK is >3X ULN and/or ALT or 
AST >2.5X ULN will not be eligible to continue. Results will be transcribed into the eCRF when 
available to the LCC (preferably within one week), thereby allowing eligibility to be definitively 
determined according to the TMS. For patients who are now ineligible based on blood results, a 
letter of appreciation will be mailed to them from the CCO and their GP will also be informed by 
letter from the CCO. Likewise, those who remain eligible will be written to by the CCO to confirm 
this. A letter will also be sent from the CCO to the participant’s GP advising that the individual is 
participating in LENS, providing details of the trial and also providing results for the randomisation 
visit blood tests.  
 
4.6 POST RANDOMISATION FOLLOW-UP 
4.6.1 Mailed medication and questionnaires 
Participants will be mailed regular 26 week supplies of study drug starting immediately after 
randomisation (see Section 4.11.4). As with the run-in study medication, texts or emails (according 
to the preference of each participant) will be sent at the time of mailing out study medication 
informing participants that it should be received shortly and providing information on what action to 
take if not received. Participants will also have access to the CCO’s 24 hour Freephone number 
and will be able to contact the CCO at any time with any concerns. Trial-specific questionnaires will 
be administered by telephone (with the option of follow up based on review of medical records 
where a participant cannot be contacted) while EQ-5D and VFQ-25 questionnaires will be 
administered on paper at set intervals as detailed in section 4.7. The LENS trial website 


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(https://www.ctsu.ox.ac.uk/lens) will provide information regarding the progress of the trial and 
newsletters will be sent to participants updating them about the progress of the trial. 
4.6.2 Unplanned follow-up visits 
No face-to-face visits are planned after randomisation. However, participants will be able to attend 
the LCC for a blood test to confirm their renal function status if there is any clinical concern over 
their continuation on allocated study drug. 
4.6.3 Modifying study treatment 
It is well established that fenofibrate leads to an increase in serum creatinine, typically by 10-20%26. 
Lower doses of fenofibrate are recommended in those with chronic kidney disease27. It is therefore 
expected that some trial participants initially taking one tablet daily will need to reduce their dose of 
study drug based on renal function in routinely collected blood tests.  
During follow-up, renal function (based on routinely collected blood tests done at the discretion of 
each participant’s GP and/or hospital doctor) will be monitored for safety in almost ‘real time’ using 
a bespoke SCI Diabetes domain created by SCI Diabetes. This will enable an experienced study 
doctor at the RCC to identify any LENS participants who cross pre-specified eGFR thresholds 
(namely 30 and 60mL/min/1.73m2 respectively) within days of this occurring. To achieve this, the 
study doctor will perform an automated search of SCI Diabetes for any renal function blood results 
for all LENS participants approximately every 2 weeks. Participants whose Randomisation visit 
eGFR was ≥60mL/min/1.73m2 (and who are therefore initially prescribed one study tablet daily) but 
whose on-treatment eGFR subsequently falls to 30-59mL/min/1.73m2 in routinely collected blood 
tests will be asked to reduce study drug to one tablet every second day and no increase in dose 
frequency (i.e. back to one tablet daily) will be permitted thereafter. The LCC’s local PI or LCC 
doctor with delegated responsibility or experienced CCO doctor will be required to electronically 
sign an updated ‘order to supply’ to record any such change. Participants whose on-treatment 
eGFR falls below 30mL/min/1.73m2 will be asked to discontinue study drug therapy. Participants 
who experience a transient worsening in renal function due to a self-limiting illness (e.g. gastro-
enteritis) during which study treatment has been stopped will be able to restart study medication 
subsequently in accordance with their renal function.  
LFTs cannot be monitored in ‘real time’ in the same way via SCI Diabetes though ALT will be 
sought via regular SCI Diabetes data linkage. However, based on ACCORD-Lipid data (provided by 
Dr Henry Ginsberg and Dr Laura Lovato) we would only expect to have one additional participant 
on fenofibrate vs. placebo with ALT >5X ULN over 5 years’ post-randomisation follow-up in LENS. 
This also assumes that fenofibrate treatment can cause deteriorations in LFTs in some patients, an 
assumption which remains unproven. 
Temporary breaks from taking study treatment, whereby a participant indicates that they wish to 
stop taking study tablets for a period of time, are allowed. Changes of consent in the trial, including 
withdrawal, are discussed in section 4.8. 
4.6.4 Follow-up of outcomes by electronic linkage, questionnaire and health records 
Data will be sought by electronic linkage, by questionnaire and by checking health records as 
described in Table 3. Linkage data will either be obtained from Scotland’s electronic Data Research 
and Innovation Service (eDRIS) at agreed intervals or from the relevant registries (in accordance 
with Research Ethics Committee [REC] and Public Benefit and PBPP approvals). Data linkage may 
be considered via other NHS registries for any participants who relocate elsewhere in the UK. 
 
 


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Table 3. Sources of pre-specified outcome and other data 
Primary and Secondary Outcomes 
Progression of DR 
or DR-related 
interventions 
DES, SCI Diabetes system (these datasets are updated at least 
weekly); data will be sought every 6-12 months 
DR-related 
interventions 
SCI Diabetes system; trial-specific questionnaire (with uploading of 
supporting data from local NHS health records to TMS by LCC to 
allow adjudication); data will be sought every 6-12 months from SCI 
Diabetes and trial-specific questionnaires will be sent every 6 
months 
Visual acuity 
DES, SCI Diabetes system; data will be sought every 6-12 months 
Hard exudates 
within 1 disc 
diameter (M2) 
DES, SCI Diabetes system; data will be sought every 6-12 months 
Macular oedema 
OCT analyses 
Questionnaires 
EQ5D, VFQ-25 and trial-specific questionnaires (administered by 
telephone); EQ-5D and VFQ-25 to be administered after 2 years and 
trial end; and trial-specific questionnaire every 6 months and trial 
end 
Total cost to the 
health Service 
Data on health service resource use from study case report forms, 
patient questionnaires, routine datasets (SCI Diabetes system, 
Scottish Morbidity Record (SMR) 01, SMR00) combined with 
national unit cost data.  
Incremental cost-
effectiveness  
Based on total costs to the health service and QALYs estimated 
from participant responses to the EQ-5D 
Tertiary Outcomes 
Cardiovascular 
events 
SMR01, trial-specific questionnaire*, report to Freephone service 
(*for verification by LCC using manual search of NHS health 
records); data linkage to SMR01 to be conducted 2-3X during the 
trial, trial-specific questionnaires to be sent every 6 months  
Lower limb non-
traumatic  
amputation 
Office of Population Censuses and Surveys (OPCS) codes within 
SMR01, trial-specific questionnaire*, report to Freephone service 
(*for verification by LCC using manual search of NHS health 
records); data linkage to SMR01 to be conducted 3X during the trial, 
trial-specific questionnaires to be sent every 6 months 
Urine albumin 
creatinine ratio 
SCI Diabetes system; data will be sought every 6-12 months 
Safety, other events of interest, and prescribing 
Mortality 
National Records of Scotland (NRS) Death Records, reports to 
CCO; patients will be flagged with NRS to ensure prompt recognition 
of any death 


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Hospitalisations 
SMR01, questionnaire, report to Freephone service; data linkage to 
SMR01 to be conducted 2-3X during the trial, trial-specific 
questionnaires to be sent every 6 months 
Biochemistry 
SCI Diabetes system; data will be sought every 6-12 months 
Prescription data 
Prescribing Information System (PIS); data will be sought 2-3X 
during the trial 
 
4.6.5 Long term follow-up assessments 
Consent will be sought from participants to allow extended follow-up after the main study 
(described in this protocol) is concluded, thereby providing valuable information on the longer-term 
safety and efficacy of the study treatment. This can be particularly informative for assessing effects 
on outcomes that may only become evident many years after initiation of treatment, and for deriving 
appropriate cost-effectiveness analyses. However, a further protocol will be developed and further 
ethical approval and PBPP approval will be required before such work is undertaken. Any long term 
follow-up is likely to be achieved using the same electronic registry sources detailed in this protocol 
and potentially other NHS registry sources also. Outcomes of interest are likely to include (but may 
not be limited to) the current trial primary, secondary and exploratory outcomes.  
4.6.6 Unblinding 
Unblinding of treatment allocation (fenofibrate or placebo) for an individual participant is warranted 
when knowledge of the treatment allocation could materially influence the immediate medical 
management. Urgent unblinding is available via a 24-hour Freephone service at CTSU. Requests 
for unblinding will be reviewed urgently and authorised by the CCO on-call clinician. For the 
avoidance of doubt, where an investigator or treating physician requires that a participant under 
their care is unblinded, the CCO will unblind the participant and provide this information. 
4.6.7 Post-trial care 
When study treatment stops at the end of the trial, it will no longer be available to participants 
unless it is prescribed by their usual doctor.  
 
4.7 TRIAL QUESTIONNAIRES 
During LENS, participants will be asked to complete regular questionnaires including the EQ-5D, 
VFQ-25 and a trial-specific follow-up questionnaire. The EQ-5D and VFQ-25 will first be completed 
by the participant during the Screening visit on paper; and then after 2 years and at the final 
assessment. The trial-specific questionnaire will first be completed by telephone 6 months after the 
randomisation visit and then every 6 months by telephone thereafter and at the end of the study as 
described below. Follow up by medical records will be available when participants cannot be 
contacted. EQ-5D and VFQ-25 will be completed by participants on paper. The RCC and CCO will 
support the LCC with the conduct of telephone interviews for questionnaires where necessary.  
4.7.1 EQ-5D  
This is a standardised and validated instrument for use as a measure of health outcome in which 
the respondent is asked to indicate his/her health state by selecting the most appropriate statement 
in each of five dimensions28.  


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4.7.2 VFQ-25  
This is a standardised and validated questionnaire which measures the dimensions of self-reported 
vision-targeted health status that are most important for persons who have chronic eye diseases29. 
4.7.3 Trial-specific follow-up questionnaire 
This questionnaire will require participants to verify their contact details and GP details; to provide 
information regarding their compliance with study treatment and their willingness to continue taking 
the study treatment; to provide information about any contra-indicated medications; and to report on 
specific health events of interest (eye procedures related to DR; lower limb amputation; 
cardiovascular events); and any other serious illnesses or hospital admissions. In addition, 
information will be collected regarding receipt of trial medication by post and study medication pack 
information (pack numbers, verification codes) for received study treatment packs will be recorded 
wherever possible. 
4.8 STOPPING STUDY TREATMENT, CHANGE OF CONSENT AND WITHDRAWAL 
4.8.1 Stopping Study Treatment and Change of Consent 
Study drug will be discontinued if a clear contra-indication to its continued use is reported by a 
participant, by their doctor, or if such information becomes available from linkage to electronic 
health records. Circumstances under which discontinuation of study treatment will occur include 
(but may not be limited to) the following: 
 
a Suspected Serious Adverse Reaction (SSAR) (as defined in section 5.1) or Suspected 
Unexpected Serious Adverse Reaction (SUSAR) (as defined in section 5.1) is reported 
 
eGFR <30mL/min/1.73m2 (Section 4.6.3) 
 
Reporting of the following adverse events (pancreatitis, gallbladder disease [cholecystitis, 
cholecystectomy], severe liver disease, rhabdomyolysis or myopathy, commencement of 
renal replacement therapy) 
 
Commencement of a contraindicated medication (Section 4.11.10) 
 
Overdose of study treatment (Section 5.4.3) 
 
Pregnancy (Section 5.4.2) 
 
Discontinuation of adequate contraception by a female participant of child-bearing potential 
(Section 4.11.12)  
In addition, patients may stop their allocated study treatment at any time and for any duration 
without necessarily giving a reason but reasons for discontinuation will be sought and recorded 
directly in the database; in such cases, these participants will be able to recommence study 
treatment any time at their own request if there is no contra-indication to fenofibrate therapy. Unless 
a participant specifically withdraws permission for all forms of follow-up, he/she will continue to be 
followed up via their electronic records irrespective of whether he/she continues to complete 
questionnaires.  
4.8.2 Withdrawal 
A participant can withdraw from the trial at any time. Withdrawal indicates that the participant no 
longer wishes to take the study drug and that he/she does not agree to ongoing follow up of any 
kind (including telephone follow-up, emailed questionnaire and electronic linkage). There is no 
obligation for a participant to provide signed confirmation of his/her withdrawal. Information 
collected about the participant up to the date of withdrawal will still be retained and analysed but no 
further data will be sought or stored from that date forwards. 


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4.9 ANALYSIS OF BLOOD AND URINE SAMPLES 
No biological samples will be retained or stored during the trial for research purposes. All blood and 
urine samples for assessing eligibility and for research purposes taken at the screening visit and 
randomisation visit will be sent to the LCC’s local NHS hospital biochemistry laboratory for analysis. 
These samples will be discarded or destroyed by these laboratories according to their standard 
operating procedures. LCCs will be responsible for deciding how many blood samples need to be 
sent to their local laboratory for the required analyses in accordance with their laboratory policy. 
Typically, this will be two whole blood samples (one gel tube for renal function, LFTs, CK, and lipid 
profile [hours since last meal will be recorded; there is no requirement to fast]; one EDTA tube for 
HbA1c analysis) and one spot urine sample (in plain tube) at the screening visit; and this will be 
followed by one blood sample (one gel tube for renal function, LFTs, CK) at the randomisation visit 
which again does not require fasting. All relevant NHS laboratories have Clinical Pathology 
Accreditation according to International Standard for Organisation 15189 and currently perform 
regular quality control procedures for the routine assays in question. Biochemistry results taken at 
the screening and randomisation visits will be transferred to the TMS via two routes: either by LCC 
staff manually entering the data directly into the eCRF or by linkage to the SCI Diabetes registry 
and uploading the data. 
Unplanned visits to local sites by participants after randomisation can be arranged by the CCO, 
RCC or LCC for the purposes of biochemistry safety testing if this is felt necessary to determine the 
safety of ongoing treatment with the study drug. 
4.10 END OF TRIAL 
The trial will continue until at least 222 primary events have occurred and until median follow-up is 
at least 4 years, whichever is the later. The ‘end of study’ is defined as the date on which the trial 
database is locked for the primary analysis. The Trial Steering Committee (TSC) has the right to 
terminate the study for clinical or administrative reasons at any time.  
The end of the study will be reported to the REC and Regulatory Authority within 90 days, or 15 
days if the study is terminated prematurely. Investigators will notify participants and inform them of 
appropriate procedures to follow. A summary report of the study will be provided to the REC and 
Regulatory Authority within one year of the end of the study. 
 
 


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4.11 TRIAL MEDICATION 
4.11.1 Name and description of investigational medicinal product(s)  
(IMP) 
 
IMP name:  
Lipantil Supra 145 mg film coated tablet [fenofibrate 
(nanoparticles) 145 mg]. 
Marketing Authorisation Holder: 
Mylan IRE Healthcare Limited, Unit 35/36, Grange Parade, 
Baldoyle Industrial Estate, Dublin 13, Ireland 
Marketing Authorisation Number: 
PA 2010/015/003 
 
The IMP to be used in LENS is fenofibrate in the form of 145mg film-coated tablets with a 
nanoparticle formulation. The control will be a matching placebo tablet. The marketing authorisation 
for this formulation of fenofibrate is held by Mylan in the Republic of Ireland and other member 
states of the European Economic Area (EEA) though not in the UK. Study IMP and matching 
placebo tablets will be supplied in bulk form by Mylan free of charge. 
4.11.2 Legal status of the drug  
Fenofibrate is a licensed drug in the UK to treat “mixed hyperlipidaemia if statin contra-indicated or 
not tolerated, or in severe hypertriglyceridaemia; or as an adjunct to statin in mixed hyperlipidaemia 
if triglycerides and HDL-cholesterol inadequately controlled in patients at high cardiovascular 
risk”27. In LENS the drug will be used outside these indications, and we will use a formulation 
currently in use elsewhere in the EU which is bio-equivalent to doses used in the UK. Notably, 
Australia and Singapore have licensed fenofibrate for participants with DR, the same group to be 
studied in LENS.  
4.11.3 Summary of Product Characteristics (SmPC) 
The relevant section of the SmPC for fenofibrate will be used as the Reference Safety Information 
during the trial for pharmacovigilance reporting purposes. The sponsor will periodically check (at 
least once a year) for any changes to the licensing status of fenofibrate.  
4.11.4 IMP preparation, storage, labelling and supply  
IMP will not be issued to study participants at face-to-face study clinic visits, instead all study 
treatment will be issued from a central location and sent to study participants, on instruction from 
the CCO, via a mailing service.  
Two different types of packaged study IMP will be used (see Table 4 below).  
 
Run-in Treatment will be issued and sent to consenting participants after the initial 
Screening visit (once confirmed eligible by their blood results) to be taken during the pre-
randomisation Run-in phase of the trial. 
 
 
Randomised Treatment will be sent to participants following their Randomisation visit, new 
supplies sent at approximately week 22 post randomisation and at 26-weekly intervals 
thereafter. Participants will be sent a Randomised Treatment pack (Type A or Type B; see 
Table 4) corresponding to their most recently recorded renal function. 
 
 
 


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Table 4. Run-in treatment and randomised treatment to be used in LENS 
Treatment Dose 
Run-in treatment 
Randomised treatment 
fenofibrate 145mg 
(open label) 
One pack containing 
70 tablets 
n/a 
fenofibrate 145mg  
OR  
placebo (double blind) 
n/a 
Type A pack containing 180 tablets 
(for participants with most recent 
recorded eGFR of ≥60/mL/1.73m2  
fenofibrate 145mg  
OR  
placebo (double blind) 
 
n/a 
Type B pack containing 90 tablets 
(for participants with most recent 
recorded eGFR 30-
59mL/min/1.73m2) 
 
Mylan will provide tablets of fenofibrate and matching placebo in bulk form. Batches of tablets will 
be delivered according to an agreed schedule and in agreed quantities to the trial’s contract 
packager (details below): 
Contract packaging company:  
AndersonBrecon (UK) Limited 
Address: 
Pharos House, Wye Valley Business Park, Brecon Park, 
Brecon Road, Hay-on-Wye, Hereford, HR3 5PG, UK 
Authorisation number: 
MIA(IMP) 11724 
 
Under the direction of the CCO the contract packager will be responsible for: 
 
packaging, labelling and QP release of uniquely identifiable packs of finished study IMP in 
accordance with EU Good Manufacturing Practice (GMP) standards 
 
storage of released packaged IMP 
 
selection and preparation for despatch of specified bottles of packaged IMP assigned to 
specified study participants 
Royal Mail (along with other third party mailing/courier service provider(s) if required) will be 
responsible for delivering packs containing specified bottles of packaged IMP assigned to specified 
study participants. All packs of study IMP sent to study participants will be sent by routine post.  At 
the time of mailing out IMP (including both run-in packs and post randomisation packs), participants 
will receive an automated text or email informing them that their study treatment is en route and to 
contact the CCO if the study treatment does not arrive safely. 
Design and formatting of IMP labels required for the two types of Treatment Bottle will be the 
primary responsibility of the contract packager in collaboration with the CCO. All IMP labels will be 
designed in accordance with Annex 13 of the EU GMP Guide. 
The CCO will maintain an inventory and audit trail of all bottles of study IMP on the TMS that have 
been requested, packaged, assigned and sent to participants, returned by participants and 
destroyed. In addition, the TMS will record any bottles of study IMP that have expired or been 
damaged prior to being assigned to study participants as well as a record of their subsequent 
destruction. 
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All bottled study IMP will be labelled with an expiry date beyond which it should not be used, and 
will only be issued to participants with due allowance for the remaining shelf life. 
Participants will be asked to return unused Run-in drug to the LCC at the time of the Randomisation 
visit and the LCC will be responsible for its handling and destruction. When required, study 
participants will be advised to take any expired or unused study IMP to a local pharmacy for safe 
disposal. This goes against normal practice for return and accountability of IMP in standard clinical 
trial settings. However, due to the streamlined design of the LENS trial, where participants will not 
attend routine clinics during the follow-up phase of the trial, it has been deemed to be too 
problematic and prone to unacceptable risk to expect study participants to securely return study 
IMP via the postal system or other courier service. 
The CCO will be responsible for handling and destruction of any returned, expired or unused IMP 
and packaging materials which it may receive back from study participants or that is returned as 
undelivered. Likewise, LCCs will be responsible for handling and destruction of any returned, 
expired or unused IMP and packaging materials which are handed in to them.  
4.11.5 Dosage schedules 
The dose of fenofibrate tablets is 145mg in nanoparticle formulation. After randomisation, study 
drug will be taken orally as one tablet daily (in the context of normal renal function i.e. eGFR 
≥60mL/min/1.73m2) or one tablet every second day (in the context of chronic kidney disease with 
eGFR 30-59mL/min/1.73m2). Study drug can be taken with or without food30.  
Doses of fenofibrate used in earlier trials were 200mg daily (micronised) in FIELD and 160mg daily 
in ACCORD-Lipid. The selected formulation and dose for LENS is bio-equivalent to the doses used 
in FIELD and ACCORD-Lipid. Intermittent dosing is frequently used in clinical practice for other 
clinical conditions (e.g. vitamin D in chronic kidney disease). Give the lack of availability of lower 
dose fenofibrate tablets for LENS and, in the context of data suggesting that fenofibrate treatment 
may in fact be beneficial for patients with chronic kidney disease31, intermittent dosing for those 
with chronic kidney disease represents a suitable option. No further study drug will be provided 
after the completion of the trial. 
4.11.6 Fenofibrate and renal function 
It is well established that fenofibrate therapy increases creatinine, that this effect is exerted quickly 
and that it is fully reversible26,32. British National Formulary (BNF) advice is to use a lower dose at 
eGFR 20-59mL/min/1.73m2 (namely 134mg/d), a further reduced dose at eGFR 15-
19mL/min/1.73m2 (67mg/d) and to stop treatment below eGFR 15mL/min/1.73m2 27. Notably, there 
is no evidence that those with the greatest increase in creatinine on fenofibrate experience any 
clinical disadvantage, the reduction in urine albumin on the drug suggests the possibility of renal 
benefit, and fenofibrate treatment actually slows the rate of the fall in eGFR over time33,34. In 
addition, there is evidence of potential cardiovascular benefit in patients with chronic kidney 
disease who are treated with fenofibrate31. Renal function will be checked at screening and after 
approximately eight weeks’ open-label run-in treatment, providing information on safety. Thereafter, 
monitoring of renal function in LENS will be based on results from blood samples taken as part of 
routine clinical practice. Scottish Diabetes Survey data indicate that 94% with DM have renal 
function checked every 15 months35. Both the eGFR thresholds and doses used in the trial are also 
more conservative than what is recommended in the BNF. In addition, participants can attend the 
LCC for a blood test to confirm their renal function status if there is any clinical concern over their 
continuation on allocated study drug. All biochemistry laboratories in NHS Scotland report both 
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4.11.7 Dosage modifications  
Participants whose Randomisation visit eGFR (i.e. after open-label treatment with fenofibrate) is 
≥60mL/min/1.73m2 and whose eGFR falls to 30-59mL/min/1.73m2 thereafter while on randomised 
study treatment will be required to reduce study drug to one tablet every second day (see section 
4.6.3). The local PI or clinician with delegated responsibility or experienced CCO clinician will be 
required to electronically sign an updated ‘order to supply’ to verify this. Participants whose eGFR 
falls below 30mL/min/1.73m2 will be asked to discontinue study drug therapy (see section 4.6.3). 
Dosage will not be reduced based on patient request alone. Participants who experience a 
transient worsening in renal function due to a self-limiting illness (e.g. gastro-enteritis) during which 
study treatment has been stopped will be able to restart study medication in accordance with their 
renal function. 
4.11.8 Plan for study treatment after the occurrence of a pre-specified outcome 
Participants should keep taking allocated study treatment if a primary, secondary or tertiary 
outcome occurs unless any contra-indication has developed or if a doctor responsible for their care 
wishes to prescribe a fibrate. 
4.11.9 Contra-indications 
Exclusion criteria of the trial are in accordance with the SmPC which lists the following conditions 
as contra-indications − hepatic insufficiency (including biliary cirrhosis), renal insufficiency, children, 
hypersensitivity to fenofibrate or any component of this medication, known photo-allergy or 
phototoxic reaction during treatment with fibrates or ketoprofen, gallbladder disease, chronic or 
acute pancreatitis; no suitable data regarding use in pregnancy and/or lactation exist.  
4.11.10 
Concomitant medications and potential interaction with other therapies 
If a participant commences any fibrate, vitamin K antagonist therapy (warfarin, acenocoumarol or 
phenindione), cyclosporin (an immunosuppressant), colchicine (gout medication), ketoprofen 
(NSAID), daptomycin (antibiotic) or rosuvastatin (only 40mg daily) therapy during LENS, they will 
need to discontinue fenofibrate but they will remain under active follow-up. Participants will be 
asked about such therapies during post-baseline questionnaires. If such a treatment is 
subsequently discontinued at any later point in the trial, the participant will be asked by the 
research team for their permission to recommence study treatment. A post hoc analysis of the 
ACCORD-Lipid trial found that a greater number of participants allocated to fenofibrate developed a 
low HDL-cholesterol level compared to placebo recipients (5% absolute excess) and that this was 
limited to participants receiving a glitazone36. It has not been demonstrated that this biochemical 
finding increases clinical risk. It is anticipated that only approximately 8% (n=80) of LENS 
participants are likely to be treated with a glitazone indicating that this effect, if true, should only 
occur in fewer than five participants on fenofibrate. The numbers of participants who have 
developed a HDL-cholesterol level ≤0.60mmol/L will be reported to the DMC at approximately one 
year after the completion of randomisation.      
4.11.11 
Concomitant statin therapy 
Many adult patients with DM in Scotland are already on statin therapy. Combination therapy 
consisting of gemfibrozil and statins is contraindicated based on an increased risk of 
rhabdomyolysis37,38. This led to previous concerns about a fenofibrate-statin combination however 
there is nowadays widespread clinical use of the combination of statins and fenofibrate. The 
ACCORD-Lipid trial, a double-blinded RCT comparing fenofibrate plus simvastatin to simvastatin 
plus placebo in 5,518 patients with type 2 DM, found no increased rates of any serious side-effects 
including muscle-related side-effects, whether defined in terms of reports of muscle pain, recorded 


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SAEs (myopathy or myositis) or increases in CK levels to >5X or >10X normal among those on 
statin plus fibrate versus statin alone13. In ACCORD-Lipid, the number of participants developing 
elevated ALT was: ALT >3X ULN 52 (1.9%) vs. 40 (1.5%) cases (non-significant) and for ALT >5X 
ULN 16 (0.6%) vs. 6 (0.2%) cases (borderline significant; ALT >3X ULN includes these 22 cases 
with ALT >5X ULN). Systematic reviews of the effects of fenofibrate on a variety of possible side-
effects show no increased rate of side-effects on the combination of statin and fenofibrate39. 
Fenofibrate also does not affect the pharmacokinetics of simvastatin or atorvastatin37,40. The safety 
of combination therapy with a statin is underlined by the UK’s licensing which allows the use of 
fenofibrate as an adjunct to statin therapy in certain groups of patients, as well as by the availability 
of preparations containing both fenofibrate and simvastatin. However, based on regulatory 
feedback, patients taking rosuvastatin 40mg daily will be excluded from the trial and any participant 
who commences rosuvastatin 40mg daily during follow up will be required to discontinue study 
treatment. 
4.11.12 
Trial restrictions  
There are no dietary or lifestyle restrictions during the trial.  
Female participants of child-bearing potential must be using adequate contraception for the 
duration of the trial and for at least 7 days after discontinuing the study drug, whether due to the 
end of the trial or withdrawal. Adequate contraception includes: 
 
Intrauterine Device  
 
Hormonal based contraception (pill, contraceptive injection etc.) 
 
Double Barrier contraception (condom and occlusive cap e.g. diaphragm or cervical cap 
with spermicide) 
 
True abstinence: when this is in line with the preferred and usual lifestyle of the subject 
4.11.13 
Assessment of compliance 
Compliance with open-label active run-in fenofibrate will be assessed at the randomisation visit. 
Thereafter, randomised participants will be asked about their compliance to treatment in six 
monthly trial-specific questionnaires. 
4.11.14 
Drug mail-out  
As noted above, LENS study medication will be sent to participants by routine post, namely by 
Royal Mail which is the only provider obliged to provide coverage to the whole of mainland 
Scotland. Other ongoing or recently completed randomised trials in cardiovascular disease in the 
UK such as ASCEND (https://ascend.medsci.ox.ac.uk; n=15,000 randomised to aspirin or placebo; 
run by CTSU)21, FAST (http://www.fast-study.co.uk; n=5,700 to assess the cardiovascular safety of 
feboxustat) and GLINT (https://www.dtu.ox.ac.uk/GLINT/; n=250 randomised to metformin or 
placebo; jointly run by the Diabetes Trials Unit, University of Oxford) have also sent study 
medication by routine post. Various steps will be taken to ensure the reliability of this method of 
delivery and these are described in the relevant parts of the protocol. These steps include: (i) 
phone calls by LCC nurses during run-in to verify receipt of study medication and to collect and 
record the study medication verification code (ii) automated texts/emails in parallel with study 
medication mail-out to inform participants that their study medication is en route and requesting that 
they contact the CCO if it is not received (iii) asking about receipt of study medication plus, where 
possible, study medication verification codes as part of six monthly trial-specific follow-up 
questionnaires. In addition, LENS participants will have access to an experienced CCO clinician via 
the CTSU Freephone number at any time.   


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5 PHARMACOVIGILANCE 
5.1 DEFINITIONS TO BE USED IN LENS 
 
Table 5. AE definitions to be used in LENS 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction (AR) 
An untoward and unintended response in a participant to an 
investigational medicinal product (IMP) which is related to any dose 
administered to that participant 
Serious Adverse Event 
(SAE) 
A SAE is any untoward medical occurrence that: 
 
results in death 
 
is life-threatening 
 
requires unplanned inpatient hospitalisation (excluding A&E 
attendances without admission to a hospital ward) or 
prolongation of existing hospitalisation 
 
results in persistent or significant disability/incapacity 
 
consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the participant or require an intervention to prevent one of 
the above consequences. 
Suspected Serious 
Adverse Reaction 
(SSAR) 
An AE that is both serious and, in the opinion of the reporting 
Investigator or clinician, believed with reasonable probability to be 
caused by the trial treatment, based on the information provided. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious AR, the nature and severity of which is not consistent with the 
information about the medicinal product in question set out in the 
SmPC. 
Overdose 
Any occasion in which a member of the research team learns that a 
participant has taken at least 6 study tablets within a 24 hour period 
 
5.2 EVENTS ASSOCIATED WITH FENOFIBRATE USE 
 
The most commonly reported AEs during fenofibrate therapy are digestive, gastric or intestinal 
disorders. The SmPC provides a list of the undesirable effects that have been observed during 
placebo-controlled clinical trials and post-marketing studies. The SmPC will be reviewed at least 
annually for changes. 
 


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5.3 RECORDING AND REPORTING ADVERSE EVENTS 
 
Fenofibrate is a well profiled medicine which has been studied intensively in major cardiovascular 
trials of over 15,000 participants and it is also licensed to treat patients with dyslipidaemia. In 2016, 
NHS Scotland data show that 18,600 NHS prescriptions were issued for fenofibrate (and 27,000 
prescriptions for the closely related bezafibrate).  
5.3.1 NSAEs and SAEs 
Participants in LENS are not considered to be at higher risk of ARs than these groups. Information 
regarding the occurrence of non-serious AEs in this streamlined mail-based trial will therefore not 
be systematically collected unless they are medical eye procedures or they lead to the cessation of 
study treatment. Other reasons for cessation of study treatment will also be collected. Information 
on all SAEs will be collected and reported.  The information that will be collected for AEs is: 
 
description of event 
 
seriousness 
 
date of onset 
 
end date (if resolved) 
 
an assessment of the relationship between study treatment and the AE (i.e. relatedness) 
With the exception of AEs identified by registry linkage, where no assessment of relatedness is 
possible, relatedness will be determined by the LCC doctor and/or CCO doctor.  
Information regarding AEs will be collected from the following sources:  
 
six monthly trial-specific questionnaires (by telephone or, where necessary, medical 
records) 
 
electronic linkage to health registry data and death records 
 
24hr Freephone service  
 
manual searches of electronic health records  
 
LCC staff 
Participants will have a card with details of the trial, CCO contact information and the Freephone 
number to facilitate reporting of any events. Data for AEs will be collected from the point of 
screening an individual up until the final registry linkages and questionnaires are completed. 
SAEs brought to the attention of the LCC, whether during phone questionnaires or by ad hoc 
reports, will be reported to the Sponsor immediately (within 24 hours) of trial staff becoming aware 
of them. Such SAEs, and any SAEs reported via Freephone to the CCO, will be recorded in the 
trial’s web-based CRF immediately. Reporting of SSARs is discussed in the next section. 
Verification of all SAEs will not be sought from health records with the following important 
exceptions:  
 
possible cardiovascular events  
 
possible lower limb amputations 
 
SSARs (including  SUSARs) 
Information regarding SAEs provided in trial-specific questionnaires will be assumed to be correct 
unless refuted by information from the participant’s health records or health registry linkage. The 
CCO may request further information where information regarding a SAE is considered incomplete. 


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Procedures for verification and adjudication of potential study endpoints are described in section 
3.3.  
Experienced doctors within the CCO will review the blinded listing of all AEs on a regular basis 
(approximately daily). Tabulations of all SAEs and reasons for stopping study treatment will be 
provided to the DMC (unblinded) and the TSC (blinded) in the relevant reports. Information 
regarding AEs will be reported to Mylan in accordance with the legal agreement between the 
University of Oxford and Mylan. 
 
5.3.2 SSARs 
Any SAE that is considered, with a reasonable probability, to be due to study treatment is 
potentially a SSAR.1 In making this assessment there should be consideration, based on: 
 
the available information,  
 
the probability of an alternative cause 
 
the timing of the reaction with respect to study treatment 
 
the response to withdrawal of the study treatment 
 
the response to subsequent re-challenge (where appropriate)   
Any potential SSAR which comes to the attention of LCC staff must be reported to the CCO 
immediately (at least with 24 hours) of becoming aware of it. The following standard information will 
be obtained and recorded:  
 
Participant study number 
 
Identity of reporting person 
 
Event description 
 
Reason for attribution to study treatment 
 
All such SSAR reports will be reviewed urgently by the Chief Investigator (or delegated deputy) at 
the CCO, who will assess the evidence for seriousness and relatedness, seek any additional 
information required (including relevant information relating to medical history and treatment both 
prior to and following randomisation), and assess expectedness based on the SmPC.  
Any SSAR that is considered to be “unexpected” (i.e. a Suspected Unexpected Serious Adverse 
Reaction [SUSAR]) will lead to the relevant participant being unblinded. All SUSARs for participants 
randomized to active fenofibrate will be reported by the CCO to the MHRA and REC in an 
expedited fashion. For SUSARs that are fatal or life-threatening, an initial report will be submitted 
within 7 days (7 day report) of the date received, with a follow-up report provided within 8 days of 
the initial report, if required. For all other SUSARs, a 15 day report will be required. The following 
minimum information will be required for any SUSAR report: 
 
EudraCT number for the trial (2016-002656-24) 
 
Name of the suspected study medication (fenofibrate) 
 
Participant study number 
 
Identity of reporting person 
                                               
1 As recommended by regulatory authorities, a Suspected Serious Adverse reaction (SSAR) should be 
considered an unanticipated problem requiring expedited reporting only if it is either an event that is 
uncommon and strongly associated with drug exposure (such as angioedema, agranulocytosis, hepatic 
injury, or Stevens-Johnson syndrome), or an event that is not commonly associated with drug exposure, but 
uncommon in the study population (e.g. tendon rupture, progressive multifocal leukoencephalopathy). 


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 
Event description 
 
Reason for attribution to study treatment 
 
Treatment assignment after unblinding  
 
Confirmed reports of SSARs and SUSARs will be promptly forwarded to the chairman of the Data 
Monitoring Committee (DMC) and will be included in the Development Safety Update Report 
(DSUR) sent to the REC and MHRA. Study treatment will be discontinued in the event of a 
confirmed SSAR or SUSAR. Local PIs will be informed of any SUSARs which occur during LENS. 
5.3.3 Reporting urgent safety measures 
If the Protocol needs to be amended urgently because of a safety concern the CI/Sponsor will 
immediately, and in any event no later than 3 days from the date the measures are taken, give 
notice to the MHRA (initially by telephone followed by written notification) and the relevant REC of 
the measures taken and the circumstances giving rise to those measures. 
 
5.3.4 The type and duration of the follow-up of subjects after AEs 
Any participant experiencing a SSAR or SUSAR will be followed up for the remainder of the trial 
period and until the event has resolved (whichever is the longer). 
 
5.3.5 Development Safety Update Reports 
The CCO will submit DSURs once a year throughout the clinical trial or, on request, to the MHRA, 
the REC and the Sponsor. 
 
5.4 NOTIFICATION OF SPECIFIC EVENTS 
5.4.1 Deaths  
If a death is reported by LCC staff or via the Freephone service, as much information as possible 
will be collected, a provisional cause of death assigned and it will be entered into the study 
database. SSARs or SUSARs will be reported as detailed in section 5.3.2. 
5.4.2 Pregnancy  
If a trial participant becomes pregnant, she will be required to discontinue study drug and 
information regarding her participation in LENS (including study treatment allocation) will be 
provided to her caring obstetrician. The outcome of the pregnancy will be followed up by the LCC. 
Information regarding pregnancy will not be collected for male participants whose partners fall 
pregnant during the trial. 
5.4.3 Overdose  
Any overdose of study medication (as defined in Table 5) should be reported to the CCO and 
sponsor according to the same timelines as SSAR notification. The participant will be required to 
discontinue study drug but will continue to be followed up in the trial. 
 


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5.5 RESPONSIBILITIES 
5.5.1 LCC PI and LCC research nurse:  
 
Ensuring that details of SAEs and NSAEs that lead to the cessation of study treatment 
that are reported to the LCC are recorded in the TMS  
 
Ensuring that all SSARs (including any suspected SUSARs) that are reported to the 
LCC are recorded and reported to the CCO within 24 hours of becoming aware of the 
event and provide further follow-up information as soon as available.  
5.5.2 Chief Investigator (CI): 
 
Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
 
Assessment of seriousness, relatedness and expectedness of potential SSARs and 
SUSARs. 
 
Immediate review of all SUSARs (this role will be fulfilled by a nominated deputy when 
the CI is unavailable). 
 
Review of SSARs in accordance with the trial risk assessment and protocol 
 
Assigning Medical Dictionary for Regulatory Activities (MedDRA) coding to all SAEs 
and SSARs. 
 
Preparing the clinical sections, reviewing the SmPC for any updates and final sign off of 
the DSUR. 
 
Unblinding of a participant for the purpose of expedited SUSAR reporting. 
[Note: these responsibilities may be delegated to one or more suitably qualified deputies, 
but the CI always retains overall responsibility.]  
5.5.3 CCO: 
 
Central data collection and verification of SAEs according to the trial protocol.  
 
Reporting safety information to the CI for the ongoing assessment of the trial’s risk / 
benefit. 
 
Reporting safety information to the independent oversight committees identified for the 
trial (DMC and/or TSC) according to the Trial Monitoring Plan. 
 
Expedited reporting of SUSARs to the Competent Authority (MHRA in UK), and 
Sponsor and REC within required timelines. 
 
Notifying local PIs of any SUSARs that occur within the trial. 
 
Checking for and notifying local PIs of updates to the Reference Safety Information for 
the trial. 
 
Preparing standard tables and other relevant information for the DSUR in collaboration 
with the CI and ensuring timely submission to the MHRA and REC. 
5.5.4 Trial Steering Committee:  
The TSC will review safety data and liaise with the DMC regarding safety issues on a regular basis, 
with frequent meetings during recruitment, and with the option of unplanned meetings if required. 
5.5.5 Data Monitoring Committee:  
The DMC will annually review unblinded overall safety data to determine patterns and trends of 
events, or to identify safety issues, which would not be apparent on an individual case basis, with 
the option of more frequent meetings. There will also be a chairperson’s review every 6 months. 


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6 STATISTICS AND DATA ANALYSIS 
6.1 SAMPLE SIZE CALCULATION 
Availability of prospective NHS Scotland DES data allowed progression rates for DR to be 
calculated directly from the target population in which LENS will be conducted. Data in Table 6 
indicate DR progression rates (limited to patients with at least 3 years’ follow-up and a baseline 
result prior to 2009). If it is assumed that participants will be recruited from among the various 
grades with observable DR in proportion to their prevalence, the progression rate from observable 
to ‘referable’ DR would be approximately 29% over 4 years. On that basis, 1060 participants would 
yield approximately 222 events over an average follow-up of 4 years, providing 85% power to 
detect a 33% reduction in progression (allowing for 15% drop-out) at alpha = 0.05. We aim to 
randomise at least 1060 participants.  
As described in LENS’ inclusion criteria, patients with R1 DR will need to have bilateral rather than 
unilateral R1 given that progression rates to referable DR are 2.4X and 3.7X higher in type 1 DM 
and type 2 DM respectively with bilateral R1 compared with unilateral R1. Inclusion of patients with 
unilateral R1 would substantially reduce event rates. 
The LENS composite primary outcome consists of progression of observable DR to referable DR, 
or any of retinal laser therapy, vitrectomy or intra-vitreal injection of medication due to DR. While 
DR progression is likely to dominate in terms of numbers of events, this composite outcome has 
been selected to avoid missing any unexpected rapid progression of DR which requires intervention 
before the next DES screening visit. 
 
 


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Table 6. Progression rates of DR in Scotland (baseline data pre-2009) 
*data available for those screened prior to 2009 and with at least 3 years of follow-up; therefore, these numbers do not 
accurately reflect numbers available for recruitment (45% greater at last count) 
**patient groups to be recruited in LENS; proportional recruitment from each of these groups provides 29% progression 
over 4 years 
6.1.1 Planned recruitment rate 
It is estimated that there are >20,000 patients in Scotland meeting the DR eligibility criteria for 
LENS. It will be necessary to recruit approximately 5% of these individuals. Due to the opportunity 
to perform preliminary screening before meeting potential participants, it is anticipated that face to 
face screening will be highly efficient. The use of an active run-in phase is designed to include 
individuals who are likely to remain adherent to trial procedures, thereby maximising the trial’s 
ability to detect a true effect of the study treatment. We anticipate 25% loss of patients during the 
screening and active run-in phases combined. Approximate total recruitment targets for randomised 
participants in each health board site are listed below, and these are determined by population.  
 
Progression to referable retinopathy or maculopathy over 3 years* 
Baseline grading 
M2 
R3 
R4 
M2 or R3 or R4 
Type 1 DM (n=14,354) 
R0 M0  
(n=7,202) 
131 (1.8%) 
204 (2.8%) 
12 (0.2%) 
347 (4.8%) 
R1 (one eye) 
M0  
(n=2,480) 
170 (6.9%) 
21 (0.9%) 
24 (1.0%) 
215 (8.7%) 
R1 (both eyes) 
M0** 
(n=4,016) 
622 (15.5%) 
121 (3.0%) 
102 (2.5)% 
845 (21.0%) 
R2 or M1**  
(n=656) 
237 (36.1%) 
64 (9.8%) 
48 (7.3%) 
349 (53.2%) 
Type 2 DM (126,639) 
R0 M0  
(n=92,543) 
942 (1.0%) 
73 (0.1%) 
82 (0.1%) 
1,097 (1.2%) 
R1 (one eye) 
M0 (n=20,147) 
822 (4.1%) 
62 (0.3%) 
45 (0.2%) 
929 (4.6%) 
R1 (both eyes) 
M0** 
(n=11,978) 
1,663 
(13.9%) 
264 (2.2%) 
128 (1.1%) 
2,055 (17.2%) 
R2 or M1**  
(n=1,971) 
530 (26.9%) 
184 (9.3%) 
60 (3.0%) 
774 (39.3%) 


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NHS Greater Glasgow and Clyde 
245 
NHS Forth Valley 
62 
NHS Lothian 
170 
NHS Grampian 
115 
NHS Lanarkshire 
114 
NHS Tayside 
84 
NHS Fife 
75 
NHS Ayrshire and Arran 
75 
NHS Highland 
64 
NHS Dumfries and Galloway 
32 
NHS Borders 
24 
TOTAL 
1060 
 
Using the opening of the first site for screening visits as Month 0, we aim to recruit approximately 
the following numbers: 69 participants at 6 months, 368 at 12 months, 729 at 18 months and 1060 
at 24 months from the start of recruitment. These estimates are based on opening all sites over a 
seven month period and aiming to open sites in the largest health boards first, with modest 
recruitment for the first two months followed by stable recruitment until the end of the recruitment 
period. 
6.2 STATISTICAL ANALYSIS  
The trial data will be held in a secure database in the CCO with controlled access in line with 
departmental security policies. Analyses will be performed in accordance with a pre-specified 
Statistical Analysis Plan (SAP), which will be written by the trial statisticians and approved by the 
TSC prior to any unblinding of study results, and which will describe in detail the methods used to 
analyse each outcome and the approaches used to handle any missing data. All analyses will be 
done according to the “intention-to-treat” principle (i.e. participants will be analysed in the group to 
which they were randomised, no matter what treatment they received, and regardless of whether 
they deviated from the protocol in any way). The primary analysis of the primary outcome will be 
considered statistically significant at the 5% significance level. For secondary and, particularly, 
tertiary outcomes, and also for secondary analyses of the primary outcome, allowance in their 
interpretation will be made for multiple hypothesis testing, taking into account the nature of events 
(including timing, duration and severity) and evidence from other studies. In addition to the pre-
specified comparisons, other analyses may be performed with due allowance for their exploratory 
and, perhaps, data-dependent nature. 
6.2.1 Interim analysis and criteria for the premature termination of the trial 
Unblinded interim analyses will be reviewed annually by the DMC, and will be conducted and 
presented by a statistician not involved in the day-to-day management of the trial. Upon review of 
such data, the DMC will advise the Steering Committee if, in their view, the randomised 
comparisons have provided both (a) proof beyond reasonable doubt that for all patients, or for 
some specific types, fenofibrate therapy is clearly indicated or contra-indicated; and (b) evidence 
that might reasonably be expected to influence materially the patient management of many 
clinicians. The TSC can then decide whether to end or modify the trial or to seek additional data, 
and this decision will be communicated in writing to the CI after each TSC meeting. Only members 
of the DMC will have access to unblinded results during the conduct of the trial. Any decision by the 
DMC which is deemed relevant to the safety of participants will be reported in an expedited fashion 
to the MHRA. 


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Appropriate criteria of proof beyond reasonable doubt cannot be specified precisely, but the DMC 
will work on the principle that a difference of at least 3 standard errors in an interim analysis of a 
major outcome event may be needed to justify halting, or modifying, a study before the planned 
completed recruitment. This criterion has the practical advantage that the exact number of interim 
analyses would be of little importance, and so no fixed schedule is proposed41. 
6.2.2 Economic evaluation 
An economic evaluation will be carried out alongside the trial, adopting a health service perspective 
on costs and a patient perspective on health benefits. The cost of providing the study drug over and 
above standard care will be estimated based on drug prescription and administration costs. Any 
increase in primary care monitoring (e.g. blood and urine testing) will be captured from the SCI 
Diabetes system. All secondary care health service resource use will be captured by electronic 
linkage to routine datasets: SMR01 for all inpatient and day case activity; SMR00 for all outpatient 
contacts (http://www.ndc.scot.nhs.uk/National-Datasets/index.asp). DR specific referrals and 
procedures will be captured using a combination of cross checked sources: the SCI diabetes 
system; relevant OPCS codes from SMR01 (SMR00 for ophthalmology outpatient referral and 
monitoring visits); and the trial specific questionnaire (with verification of reported events by a 
research nurse cross checking against NHS records). All resource use events will be valued using 
appropriate national unit prices. The study drug will be costed at list price (by dose and quantity) as 
reported in most up to data version of the BNF (2015). DR related procedures will be costed where 
possible using the Scottish national tariff for the relevant health care resource grouping 
(http://www.isdscotland.org/Health-Topics/Finance/Scottish-National-Tariff/), whilst other inpatient 
and outpatient care will be costed using Scottish specialty unit cost data (ISD 2015). Primary care 
contacts will be costed using Personal Social Services Research Unit cost data (2015), and 
resultant biochemistry tests will costed based on ISD reported unit costs for relevant laboratory 
services (ISD 2015). Following compilation of the cost dataset, the total health service cost will be 
estimated for each participant from baseline through to 4 years post randomisation.  
Analysis of the economic data will be performed by intention to treat in accordance with a pre-
specified economic analysis plan (to be completed before unblinding of the data). The mean 
difference in total service costs between treatment allocation groups will be estimated using 
generalised linear regression adjusted for minimisation and baseline covariates (e.g. baseline 
health status) as appropriate. Costs will be assessed against the primary outcome, and the 
incremental cost per progression of DR (or DR related intervention) averted will be estimated for 
fenofibrate versus placebo. In addition, participant responses to the EQ-5D, at baseline and follow-
up, will be used to estimate QALYs for each participant. The mean difference in QALYs between 
the groups will be estimated using generalised linear regression, allowing the incremental cost-per 
QALY to be estimated for fenofibrate versus placebo based on data collected to 4 years.  
If the use of fenofibrate is found to result in an increased cost to the health service at four years, for 
a modest reduction in progression and a QALY gain of insufficient size to justify the extra cost, 
modelling will be used to extrapolate costs and QALYs beyond the follow-up period of the trial. This 
will rely on the fitting of parametric survival curves to the observed progression data, to predict 
progression beyond four years. Further downstream treatment/monitoring costs (associated with 
progression), and visual acuity and quality of life outcomes of referable disease, will then be 
modelled using a combination of data collected within the trial and published data on expected 
outcomes of treatment. This will allow longer-term cost-effectiveness, in terms of the incremental 
cost per QALY gained, to be estimated for fenofibrate versus placebo. The robustness of any 


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model based estimates of cost-effectiveness will be assessed using deterministic and probabilistic 
sensitivity analysis. 
7 DATA HANDLING 
A web-based eCRF and dedicated TMS will be used to collect study data from the screening and 
randomisation visits as well as for recording subsequent follow-up assessments of participants 
every six months.  The follow-up assessments (questionnaires) will be conducted as a telephone 
interview by the LCC nurse, or by review of medical records where necessary. All data in the study 
will be processed electronically using a set of custom-written applications. CCO staff will use a suite 
of administration applications to manage sites and study participants, including clinical supervision 
(review of reported SAEs and routinely collected blood results), management of follow-up and 
compliance, collection of supporting documentation for relevant events and event adjudication 
(where relevant). All data will be stored securely. All data accesses will require a unique username 
and password, and any changes to data will require the user to enter their username and password 
as an electronic signature. Staff will have access restricted to only the functionality and data that 
are appropriate to their role in the study. Possible errors or omissions in the completion of eCRFs 
by research staff will result either in immediate queries (e.g. if pre-set boundaries are exceeded) or 
subsequent data queries. Errors or omissions in the completion of forms by participants will result, if 
appropriate, in requests to participants for clarification. Procedures for determining if changes to 
recorded data are appropriate will be developed and implemented prior to unblinding of the study 
results. All changes to the data will result in an audit trail. The CCO is also responsible for seeking 
information regarding pre-specified outcomes, deaths and hospitalisations via linkage to data 
registries.  
7.1 SOURCE DATA 
Data recorded in the eCRF from face-to-face visits with participants, lists of potentially eligible 
patients provided by SDRN and known through responses to DES mail-out and HIC mail-out 
invitations (to be stored within respective LCCs and/or the CCO), electronically completed 
questionnaire data, information obtained from telephone calls to the Freephone number regarding 
the study, information obtained via electronic linkage to central registries regarding pre-specified 
outcomes and other events, and biochemistry results, pharmacy records (from the commercial 
partner who will package, store, select and send out study drug by routine post) and documents 
collected regarding medical events of interest (including copies of information regarding eye 
procedures) will constitute the ‘source documents’ for the trial. The CCO will retain these data and 
records for at least 25 years (identifiable data for 10 years) after the end of the trial except in the 
case of any documentation which is legally required to be retained in Scotland in which case such 
documents will be stored at the University of Glasgow under the same conditions. Regulatory 
Authorities will have the right, in accordance with Good Clinical Practice (GCP) guidelines, to 
commission a confidential audit of such records while the trial is in progress or thereafter.  
7.2 ACCESS TO DATA 
Records will be kept in a secure storage area with limited access. CTSU is a secure building with 
access limited to employees and authorised visitors. The study servers are located in a climate 
controlled secure enclosure to which only system support staff have access. Direct access will be 
granted to authorised representatives from the Sponsor, host institution and the regulatory 
authorities to permit trial-related monitoring, audits and inspections. 


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7.3 DATA PROTECTION AND PATIENT CONFIDENTIALITY  
All investigators and trial site staff will comply with the requirements of the United Kingdom General 
Data Protection Regulation (UK-GDPR) and Data Protection Act 2018 with regards to the 
collection, storage, processing and disclosure of personal information. At baseline, identifiable data 
will be recorded as detailed in section 4.5.1 by the LCCs. This will include the CHI number which is 
crucial for performing electronic linkages with relevant registries. Identifiable details will be stored in 
a Contact Database in encrypted format with controlled access for research staff in line with 
departmental security policies. Participants will be identified throughout by means of a unique 
participant ID number made up of an unrelated sequence of numbers. Local sites will securely store 
source data including ICFs, biochemistry results, and information regarding any events of interest 
and these documents will have identifiable data on them. Questionnaire data will be collected 
electronically, processed and securely stored at the CCO. 
Linkage to health registries is entirely dependent on use of each participant’s CHI number and data 
will be collected using pseudonymisation. For the purposes of data linkage, named colleagues in 
each registry (e.g. eDRIS, SCI Diabetes, DES) will be sent a list of CHI numbers and other 
identifiable data that they require for participants along with a unique trial identifier by the CCO. 
Data returned to the CCO will include the relevant results and/or outcomes along with the unique 
trial identifiers but no identifiable characteristics. The data will be incorporated into the TMS. Data 
transmitted for any regulatory purposes will contain no identifiable data. PBPP approval is required 
for linkage to Scottish health registries and this will be required prior to any linkage. 
7.4 ACCESS TO THE FINAL TRIAL DATASET 
The CCO Investigators and statisticians will have full access to the study data-set. Data generated 
by LENS will be available to bona fide researchers via the Richard Doll Centenary Archive (see 
https://www.ndph.ox.ac.uk/about/richard-doll-centenary-archive) which has a Data Access and 
Sharing Policy. 
7.5 ARCHIVING 
The CCO will retain trial data and records for at least 25 years (identifiable data for 10 years) after 
the end of the trial except in the case of any documentation which is legally required to be retained 
in Scotland in which case such documents will be stored at the University of Glasgow under the 
required conditions. Regulatory Authorities will have the right, in accordance with GCP guidelines, 
to commission a confidential audit of such records while the trial is in progress or thereafter. 
8 MONITORING, AUDIT & INSPECTION 
The trial will be conducted in accordance with the principles of the International Conference on 
Harmonisation Guidelines for GCP, and relevant local, national and international regulations 
(including the EU Clinical Trials Directive). 
Monitoring will be based on the study’s risk assessment and will be detailed in the study Monitoring 
Plan. The Monitoring Plan will be agreed by the Trial Management Group (TMG) and TSC. The 
Monitoring Plan will consist of both central monitoring and on site monitoring, both of which will be 
conducted and overseen by the CCO.  
Prior to the initiation of the study at any site, it will be verified that the LCC has adequate facilities 
and resources to carry out the study (and, if considered necessary, a site visit will be undertaken). 
Local PIs and Research Nurses will be provided with materials detailing relevant study procedures, 
and the LCC will be trained in study methods. 


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Monitoring visits at LCCs are intended at the following stages: around site set-up, by the end of 
month 12, by the end of month 30, and around month 48 in preparation for site closure. If, an on-
site visit cannot be accommodated at approximately these time points, the site will be asked to 
complete a review of their Investigator Site File and confirm completeness. During on-site visits, the 
LCC staff are expected to be present. Where an on-site visit coincides with a participant study visit, 
the monitor may be present during the interview (subject to the participant’s verbal agreement) to 
provide ongoing training in study procedures such as consent taking and the use of the study 
eCRF. The purpose of site visits is to help LCC staff to resolve any local problems with the study, to 
ensure that the study is conducted according to the protocol, and to review study records and data 
quality and provide any additional training that may be required. A report of each visit will be 
prepared by the study monitor and reviewed by CCO staff. 
Central monitoring of the study data will be performed to confirm data completeness, timely entry 
and to identify any outliers in relation to study matrix e.g. recruitment rates, reporting of events. This 
central monitoring will be used to direct any non-routine site visits.  
If any party becomes aware of an upcoming audit or inspection, the monitoring team at the CCO 
should be informed. The CCO will advise what preparation may be required and will suggest 
appropriate personnel to support the audit/inspection. 
9 ETHICAL AND REGULATORY reports and CONSIDERATIONS 
Before the start of the trial, approval will be sought from a REC for the trial protocol, ICFs and other 
relevant documents. Substantial amendments that require review by REC will not be implemented 
until the REC grants a favourable opinion (unless failure to do so would introduce risk to 
participant/s in the opinion of the investigator). Correspondence with the REC will be retained in the 
Trial Master File and Investigator Site Files (ISF). Annual progress reports will be submitted to the 
REC within 30 days of the anniversary date on which the favourable opinion was given, and 
annually until the trial is declared ended. It is the CI’s responsibility to produce the annual reports 
as required and to notify the REC of the end of the study. Within one year after the end of the 
study, the CI will submit a final report with the results to the REC. 
9.1 PEER REVIEW 
Prior to submission for funding, the trial proposal was internally reviewed by one expert (Professor 
John Petrie, University of Glasgow). The full trial application to NIHR underwent peer review by 
seven independent experts, and the trial’s design was modified based on their comments and 
suggestions. 
9.2 PUBLIC AND PATIENT INVOLVEMENT 
On 18th March 2015, two LENS investigators met with 15 members of the Glasgow South Diabetes 
UK Group to present and discuss LENS. The members advised on patient perceptions of the 
research question and practicalities of delivering the trial. They indicated that they understood the 
need for a control group. Two patients with diabetes have volunteered to join the TSC as patient 
representatives and these individuals will be involved with preparing and reviewing study 
information and providing patient perspectives on the trial's conduct. The Royal National Institute 
for the Blind (RNIB), Scotland, is also supporting the trial in terms of dissemination of information 
and results of the trial, review of materials, lay summaries and newsletters, and representation on 
the TSC. Feedback regarding the various PILs to be used in the trial and the content of 


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questionnaires will be sought from the Glasgow South Diabetes UK Group and/or other patient 
support groups.  
9.3 AMENDMENTS  
The sponsor may make a non-substantial amendment at any time during a trial. If the sponsor 
wishes to make a substantial amendment to the CTA or the documents that supported the original 
application for the CTA, the sponsor will submit a valid notice of amendment to the MHRA. If the 
sponsor wishes to make a substantial amendment to the REC application or the supporting 
documents, the sponsor must submit a valid notice of amendment to the REC for consideration. It 
is the sponsor’s responsibility to decide whether an amendment is substantial or non-substantial. 
Amendments will be notified to NHS Research & Development departments of participating sites to 
assess whether the amendment affects the NHS permission for that site. The CI will be responsible 
for the decision to amend the protocol. 
9.4 COMPLIANCE 
9.4.1 Protocol compliance  
Protocol deviations, violations, or breaches are departures from the approved protocol. 
Prospective, planned deviations or waivers to the protocol are not allowed under the UK regulations 
on Clinical Trials and must not be used. Accidental protocol deviations must be documented and 
reported to the CI.  
9.4.2 Regulatory Compliance  
The trial will not commence until a Clinical Trial Authorisation (CTA) is obtained from the MHRA. 
Before any site can enrol patients into the trial, the local PI or designee will apply for and obtain 
permission from the site’s NHS Research & Development (R&D) department.  
9.4.3 Notification of Serious Breaches to GCP and/or the protocol  
A “serious breach” is a breach which is likely to affect to a significant degree the safety or physical 
or mental integrity of the subjects of the trial; or the scientific value of the trial.  
In the event that a serious breach is suspected, the CCO and CI must be contacted within 1 
working day. It is the CI’s responsibility to contact the Sponsor without delay. In collaboration with 
the CI, the serious breach will be reviewed by the Sponsor and, if appropriate, the Sponsor will 
report it to the REC committee, Regulatory authority and the NHS host organisation within seven 
calendar days. 
9.5 FINANCIAL AND OTHER COMPETING INTERESTS  
The trial investigators and research team have no conflicts of interest regarding the conduct of the 
trial. 
9.6 INDEMNITY 
The University of Oxford has a specialist insurance policy in place which would operate in the event 
of any participant suffering harm as a result of their involvement in the research (Newline 
Underwriting Management Ltd, at Lloyd’s of London). NHS indemnity operates in respect of the 
clinical treatment that is provided. 
 


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10 DISSEMINATION POLICY 
On completion of the trial, the data will be analysed and tabulated and a Final Study Report 
prepared. Funding organisations will be acknowledged in all resultant publications. Participants will 
be informed of the main results of the trial with a newsletter or letter. The protocol will be made 
publically available on the NIHR website during the conduct of the trial and will also be included as 
a supplementary file at the time of publishing the main trial results.  
Draft copies of manuscripts will be circulated to all co-investigators and local PI for their review prior 
to submission for publication. Results from the trial will be published in the name of the LENS 
collaboration.  
The design paper, primary LENS results publication and subsequent publications will be submitted 
for publication in medical journals in an open access format. RNIB will cover the trial results on their 
webpage and via other strategies. The results will be submitted for presentation at appropriate 
conferences. 
 
 
 


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11 REFERENCES 
1. 
Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: 
pathophysiology, screening, and novel therapies. Diabetes Care 2003; 26(9): 2653-64. 
2. 
Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in 
England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open 2014; 
4(2): e004015. 
3. 
Looker HC, Nyangoma SO, Cromie DT, et al. Rates of referable eye disease in the Scottish 
National Diabetic Retinopathy Screening Programme. Br J Ophthalmol 2014; 98(6): 790-5. 
4. 
Watkins PJ. Retinopathy. BMJ 2003; 326(7395): 924-6. 
5. 
Luckie R, Leese G, McAlpine R, et al. Fear of visual loss in patients with diabetes: results of the 
prevalence of diabetic eye disease in Tayside, Scotland (P-DETS) study. Diabet Med 2007; 24(10): 
1086-92. 
6. 
Coyne KS, Margolis MK, Kennedy-Martin T, et al. The impact of diabetic retinopathy: 
perspectives from patient focus groups. Fam Pract 2004; 21(4): 447-53. 
7. 
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in patients 
with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837-53. 
8. 
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 
Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four 
years after a trial of intensive therapy. N Engl J Med 2000; 342(6): 381-9. 
9. 
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose 
lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 
diabetes: meta-analysis of randomised controlled trials. BMJ 2011; 343: d4169. 
10. 
Duncan LJ, Cullen JF, Ireland JT, Nolan J, Clarke BF, Oliver MF. A three-year trial of atromid 
therapy in exudative diabetic retinopathy. Diabetes 1968; 17(7): 458-67. 
11. 
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of 
action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98(19): 2088-93. 
12. 
Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular 
events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. 
Lancet 2005; 366(9500): 1849-61. 
13. 
The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N 
Engl J Med 2010; 362(17): 1563-74. 
14. 
Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser 
treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 
370(9600): 1687-97. 
15. 
The ACCORD Study Group and ACCORD Eye Study Group. Effects of medical therapies on 
retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363(3): 233-44. 
16. 
Chen Y, Hu Y, Lin M, et al. Therapeutic effects of PPARalpha agonists on diabetic retinopathy 
in type 1 diabetes models. Diabetes 2013; 62(1): 261-72. 
17. 
Royal College of Ophthalmologists. Diabetic Retinopathy Guidelines. 2012. 
https://www.rcophth.ac.uk/wp-content/uploads/2021/08/2012-SCI-267-Diabetic-Retinopathy-
Guidelines-December-2012.pdf. (last accessed 9 June 2022) 
18. 
National Institute for Health and Care Excellence. Type 2 diabetes. 2008. 
http://www.nice.org.uk/guidance/cg66. (last accessed 9 June 2022) 
19. 
Scottish Intercollegiate Guidelines Network. Management of Diabetes. 2010. 
https://www.sign.ac.uk/assets/sign116.pdf. (last accessed 9 June 2022) 
20. 
FAME 1 EYE. 2011. http://clinicaltrials.gov/show/NCT01320345. (last accessed 9 June 2022) 
21. 
Aung T, Haynes R, Barton J, et al. Cost-effective recruitment methods for a large randomised 
trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND). Trials 2016; 
17(1): 286. 
22. 
Preiss D, Lloyd SM, Ford I, et al. Metformin for non-diabetic patients with coronary heart 
disease (the CAMERA study): a randomised controlled trial. Lancet Diabetes Endocrinol 2014; 2(2): 
116-24. 
23. 
Scottish Diabetes Research Network. 2015. http://www.sdrn.org.uk/. (last accessed 9 June 
2022) 
24. 
NHS Research Scotland. SHARE. 2015. 
25. 
Scottish Care Information - Diabetes Collaboration. 2015. 
26. 
Kostapanos MS, Florentin M, Elisaf MS. Fenofibrate and the kidney: an overview. Eur J Clin 
Invest 2013; 43(5): 522-31. 


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Version 7.0, 29 July 2022 
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27. 
British National Formulary. Fenofibrate. 2015. 
https://www.medicinescomplete.com/mc/bnf/current/PHP1686-fenofibrate.htm. (last accessed 9 June 
2022) 
28. 
EuroQol. EQ-5D. 2016. 
29. 
National Eye Institute. National Eye Institute Visual Function Questionnaire. 2016. 
30. 
Sauron R, Wilkins M, Jessent V, Dubois A, Maillot C, Weil A. Absence of a food effect with a 
145 mg nanoparticle fenofibrate tablet formulation. Int J Clin Pharmacol Ther 2006; 44(2): 64-70. 
31. 
Jun M, Zhu B, Tonelli M, et al. Effects of fibrates in kidney disease: a systematic review and 
meta-analysis. J Am Coll Cardiol 2012; 60(20): 2061-71. 
32. 
Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal 
function impairment in ACCORD type 2 diabetic participants. Diabetes Care 2012; 35(5): 1008-14. 
33. 
Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 
diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. 
Diabetologia 2011; 54(2): 280-90. 
34. 
Bonds DE, Craven TE, Buse J, et al. Fenofibrate-associated changes in renal function and 
relationship to clinical outcomes among individuals with type 2 diabetes: the Action to Control 
Cardiovascular Risk in Diabetes (ACCORD) experience. Diabetologia 2012; 55(6): 1641-50. 
35. 
Scottish Diabetes Survey Monitoring Group. Scottish Diabetes Survey 2014. 2014. 
https://www.diabetesinscotland.org.uk/wp-content/uploads/2019/12/Diabetes-in-Scotland-website-
Scottish-Diabetes-Survey-2014.pdf. (last accessed 9 June 2022) 
36. 
Linz PE, Lovato LC, Byington RP, et al. Paradoxical reduction in HDL-C with fenofibrate and 
thiazolidinedione therapy in type 2 diabetes: the ACCORD Lipid Trial. Diabetes Care 2014; 37(3): 686-
93. 
37. 
Whitfield LR, Porcari AR, Alvey C, Abel R, Bullen W, Hartman D. Effect of gemfibrozil and 
fenofibrate on the pharmacokinetics of atorvastatin. J Clin Pharmacol 2011; 51(3): 378-88. 
38. 
Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97(8A): 52C-60C. 
39. 
Guo J, Meng F, Ma N, et al. Meta-analysis of safety of the coadministration of statin with 
fenofibrate in patients with combined hyperlipidemia. Am J Cardiol 2012; 110(9): 1296-301. 
40. 
Bergman AJ, Murphy G, Burke J, et al. Simvastatin does not have a clinically significant 
pharmacokinetic interaction with fenofibrate in humans. J Clin Pharmacol 2004; 44(9): 1054-62. 
41. 
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976; 34(6): 585-612. 
 
 


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12 APPENDICES 
12.1 
APPENDIX 1 - RISK ASSESSMENT 
A risk assessment of the trial was performed prior to final sign-off of the contract with the funder. 
This risk assessment is a controlled version working document which is subject to change. It is 
stored in EDMS, the document management system of CTSU. The risk assessment will form the 
basis of the Trial Monitoring Plan. 


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12.2 
APPENDIX 2 – AUTHORISATION OF LOCAL COLLABORATING CENTRES  
12.2.1 Required documentation  
Prior to opening a LCC, the following essential documentation will be provided to the sponsor: 
 
Evidence of local R&D approval 
 
An original signed Investigator Declaration (signed by the local PI as part of Clinical Trial 
Agreement documentation) 
 
A signed and dated recent CV for the local PI and research nurse 
 
Copies of GCP certificates for the local PI and research nurse 
12.2.2 Procedure for initiating/opening a new site  
Trial staff from the RCC (or from the CCO where this is not possible) will perform training for the 
local PI, research nurse and any other staff involved in the trial at the LCC.  
12.2.3 PI responsibilities  
The local PI at each site is responsible for the overall conduct of the study at their site and for 
compliance with the protocol and any protocol amendments. Responsibilities may, however, be 
delegated to an appropriate member of study site staff. Delegated tasks will be documented on a 
Delegation Log and signed by all those named on the list. The local PI must be familiar with the 
IMP, protocol and the study requirements.  
 
 


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12.3 
APPENDIX 3 – SCHEDULE OF ASSESSMENTS 
 
PROCEDURE 
Screening 
Visit 
Randomisation 
visit 
Subsequent telephone 
/ email follow-up 
(every 6 months for at 
least 3 years unless 
stated otherwise) 
Informed consent  
X 
 
 
Inclusion / exclusion criteria 
X 
X 
 
Record demographics 
X 
X 
 
Medical History 
X 
X 
 
Lifestyle factors 
X 
 
 
Concomitant medications 
X 
X 
 
Height 
 
X 
 
Weight 
 
X 
 
Vital signs 
 
X 
 
Blood eligibility biochemistry 
Xa 
Xa 
 
Blood HbA1c 
X 
 
 
Blood lipids (random) 
X 
 
 
Urine albumin creatinine ratio 
X 
 
 
Trial-specific Questionnaire  
(by telephone or medical 
records)  
 
 
X 
EQ-5D questionnaire  
(on paper) 
X 
 
Xd 
VFQ-25 questionnaire  
(on paper) 
X 
 
Xd 
Open-label fenofibrate mail-out  
(10 week supply) 
Xb 
 
 
Blinded drug mail-out  
(26 week supply) 
 
X 
X 
Compliance with study treatment 
 
X 
X 
Randomisation 
 
Xc 
 
Willingness to start and/or 
continue study treatment 
X 
X 
X 
a U&E, LFTs (including at least one of ALT and AST), CK 
b run-in drug mail-out will not be immediate as it will first be necessary to verify biochemistry; the initial mail-
out of open-label fenofibrate will be followed by a phone call 2-3 weeks later to verify receipt by the 
participant 
c randomisation will not occur at the time of the visit as it depends on visit biochemistry; starting dose 
frequency will depend on renal function 
d for completion after 24 months and then at the final assessment  
 
 


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12.4 
APPENDIX 4 – PROTOCOL AMENDMENT HISTORY 
 
Substantial / 
non-
substantial 
amendment 
Protocol 
version 
no. 
Date 
issued 
Author(s) of 
changes 
Details of changes made 
Approved by 
REC 
2.0 
21-09-2016 
D. Preiss 
S. Howard 
 
Section 4.8: removal of need to provide 
written confirmation of withdrawal 
 
Section 3.2.3: expansion of potential 
exploratory endpoints for OCT 
 
Minor clarifications or corrections to text 
on pages 27, 29, 32, 35, 47, 56 
Substantial 
amendment 
1 
 
3.0 
26-04-2017 
D. Preiss 
S.Howard 
 
Additional method of recruitment – via 
HIC 
 
Revision of section 5 –Safety reporting 
 
Change from registered to routine 
postal delivery of study treatment 
 
Clarifications or corrections to text 
throughout the document 
Substantial 
amendment 
2 
4.0 
07-07-2017 
D.Preiss 
S. Howard 
 
Revised wording in section 4.4.4 to 
clarify procedural steps for recruitment 
using HIC services. 
Substantial 
amendment 
3 
5.0 
05-10-2017 
D. Preiss 
C. Knott 
S. Howard 
 
P.3 Key Trial Contacts – addition of Dr 
R Lindsay 
 
Section 3.2 – movement of text 
 
Section 4.4.2 – addition of a telephone 
call to potential participants to ask if 
they would be interested in receiving 
information about LENS and seek 
verbal consent to check key eligibility 
criteria in their health records 
(specifically their most recent eGFR 
result and retinal screening results). 
 
Section 4.5.1 – correction of 6-10 to 6-
11 weeks 
 
Section 4.11 – updating Manufacturer’s 
Authorisation; inclusion of plan to 
provide low HDL-c data to DMC 
 
Section 5.3 – clarification regarding AE 
reporting 
Substantial 
amendment 
4 
6.0 
10-01-2018 
D. Preiss 
S.Howard 
Changes added based on MHRA review: 
 
Section 4.11.12 – Clarification 
regarding true abstinence  


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 
Sections 4.2.2, 4.11.10, 4.11.11 – 
Exclusion criterion added: rosuvastatin 
40mg daily 
 
Section 4.5.10 – Refinement of creatine 
kinase assessment prior to 
randomisation 
 
Section 4.6.6 – Clarification regarding 
unblinding  
 
Section 4.8.1 – Addition of list of 
circumstances which will lead to 
cessation of study treatment 
 
Section 5.3.3 – Clarification regarding 
reporting urgent safety measures 
Non-
substantial 
amendment 
2 
6.1 
12-02-2019 
D. Preiss 
S. Howard 
Minor edits: 
Addition of collaborators (p4) 
Exclusion criteria clarified to make distinct 
the biochemical eligibility for each face-to-
face assessment visit and for lack of 
adherence to run-in treatment (4.2.2)  
Clarification regarding timing of call to 
check receipt of run-in drug (4.5.3) 
Non-
substantial 
amendment 
4 
6.2 
29-05-2020 
D. Preiss 
Remove treatment duration (summary) 
Clarify minimum trial duration (summary; 
section 2) 
Allow for DRS grading to not change 
(footnote to Table 1) 
Clarify that evidence of clinically significant 
DR may come from retinal imaging or 
clinical examination (3.2.1, Table 2) 
Adjudicate vitreous haemorrhage (3.3) 
Remove comment on discrepancy between 
data sources (3.3) 
Non-
substantial 
amendment 
5 
6.3 
06-01-2021 
D. Preiss 
Participants will not complete follow up 
questionnaires on their own devices; follow 
up by medical records to be used where 
necessary (4.6.1, 4.7, 5.3.1, 7, 12.3) 
EQ-5D and VFQ-25 will only be completed 
on paper (4.5.1, 4.7, Table 3, 12.3) 
Source data to be retained for 25 years, but 
identifiable data for 10 years after trial (7.1, 
7.5) 


LENS Trial 
Version 7.0, 29 July 2022 
EudraCT: 2016-002656-24 
 
 
Page 61 
 
Clarify description of introduction of OCT 
by NHS Scotland (Table 1 and footnote) 
Update site monitoring plan in context of 
COVID pandemic 
Substantial 
amendment 
5 
7.0 
29-07-2022 
D. Preiss 
Remove signature page (protocol is signed 
off in the EDMS system) 
Change Jen Logue details (page 3) 
Remove Enti Spata (page 3) 
Include details of change in NHS Scotland 
management pathway for M2 maculopathy: 
Section 1, Table 1  
Use consistent wording to describe M2, R3 
and R4 as ‘referable’ disease (rather than 
‘clinically significant’ or ‘significant’ 
disease): Trial summary, Sections 3, 4.2 
and 6.1; Table 2 
Diabetic Retinal Screening (DRS) update to 
Diabetic Eye Screening (DES) after NHS 
Scotland change to program name: various 
Sections 
DES definition for blot (vs. dot) 
haemorrhage added: Table 1 
Clarification that M2 includes blot 
haemorrhages (which has always been the 
case): Trial summary, Sections 3.1.2, 3.2.2; 
Table 2 
Include plans for use of image analysis 
software at a later stage: Section 3.2 
Allow for future meta-analyses of all 
fenofibrate trials: Section 3.2.4 
Minor grammatical correction 4.11.13 
Shorten heading Section 5.3 
Correct reference to UK GDPR and Data 
Protection Act 2018: Section 7.3 
It was not possible to offer the option for 
participants to complete follow up forms on 
their own devices, line removed: Section 
4.5.1. 
Show details of amendment numbers in 
Appendix 4 
 

SAP_001.pdf: 
 
 A randomised placebo-controlled trial of fenofibrate to 
prevent progression of non-proliferative retinopathy in 
diabetes  
 
(Lowering Events in Non-proliferative retinopathy in 
Scotland [LENS]) 
 
Statistical Analysis Plan 
 
 
 
EDMS #7695 
Version 1.3 
 
 
 
 
 


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Table of Contents 
 
1 VERSION HISTORY ........................................................................................................................ 3 
2 TRIAL REGISTRATION DETAILS .................................................................................................. 4 
3 INTRODUCTION .............................................................................................................................. 5 
3.1 STUDY DESIGN ........................................................................................................................... 5 
3.2 STUDY OBJECTIVES .................................................................................................................... 5 
4 DEFINITIONS FOR EFFICACY AND SAFETY ENDPOINTS ......................................................... 6 
4.1 ESTIMANDS ................................................................................................................................ 6 
4.2 HYPOTHESES ............................................................................................................................. 6 
4.3 PRIMARY EFFICACY ASSESSMENT ................................................................................................ 6 
4.4 SECONDARY EFFICACY ASSESSMENTS ......................................................................................... 6 
4.4.1 
Secondary assessments based on clinical events ........................................................................ 6 
4.4.2 
Secondary assessments based on questionnaires and visual acuity ............................................ 7 
4.4.3 
Health economic assessments ...................................................................................................... 7 
4.5 TERTIARY EFFICACY ASSESSMENTS ............................................................................................. 7 
4.5.1 
Tertiary assessments based on clinical events ............................................................................. 7 
4.5.2 
Tertiary assessments based on biochemistry ................................................................................ 7 
4.6 CLINICAL SAFETY ASSESSMENTS ................................................................................................. 7 
4.7 OTHER LABORATORY ASSESSMENTS ........................................................................................... 8 
5 ANALYSIS SETS FOR EFFICACY AND SAFETY ANALYSES .................................................... 8 
6 ASCERTAINMENT AND ADJUDICATION OF STUDY ENDPOINTS ............................................ 8 
6.1 ASCERTAINMENT OF INFORMATION .............................................................................................. 8 
6.2 ADJUDICATION ........................................................................................................................... 9 
7 STATISTICAL METHODOLOGY FOR EFFICACY AND SAFETY ANALYSES ............................ 9 
7.1 METHODS OF ANALYSIS .............................................................................................................. 9 
7.2 MULTIPLICITY ADJUSTMENTS ..................................................................................................... 10 
7.3 SUBGROUP ANALYSES AND TESTS FOR HETEROGENEITY ............................................................ 10 
7.4 HANDLING OF MISSING AND INCOMPLETE DATA ........................................................................... 10 
7.5 CENSORING SCHEMA FOR TIME-TO-EVENT ENDPOINTS................................................................ 11 
8 GUIDELINES FOR EARLY STOPPING OR MODIFICATION OF THE TRIAL ............................ 11 
9 REFERENCES ............................................................................................................................... 12 
10 APPENDIX A: DETAILS OF RANDOMISATION ALGORITHM ................................................... 13 
 
 
 
 
 


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1 Version History 
 
0.1 
Draft version 
29 November 2021 
0.2 
Updated after SC comments 
20 April 2022 
1.0 
First released version 
29 June 2022 
1.1 
Minor clarifications to Section 5 
10 January 2023 
1.2 
Exact subgroup categories now defined and description of 
MMRM models for continuous measures measured at multiple 
follow-up time points. Report frequency of NHS retinal screening. 
Add exploratory primary outcome analysis excluding first 12 
months. Clarify visual acuity to be analysed as LogMAR (with 
conversion from Snellen where required). 
12 June 2023 
1.3 
Appendix A: smoking was never included as minimisation 
variable, SAP error corrected 
07 February 2024 
 
 
 


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2 Trial registration details 
 
IRAS Number: 
209579 
EudraCT Number: 
2016-002656-24 
Clinical trials.gov Number: 
NCT03439345 
ISRCTN Number 
ISRCTN15073006 
REC Number: 
16/WS/0149 
Sponsor’s number: 
CTSULENS1 
NIHR Number: 
14/49/84 


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3 Introduction 
 
This Statistical Analysis Plan describes the strategy, rationale and statistical methods that will guide 
assessment of the clinical efficacy and safety of fenofibrate in the LENS trial.  
 
3.1 Study design 
 
LENS is a randomised placebo-controlled trial investigating the effects of prolonged treatment with 
the PPAR alpha agonist, fenofibrate on the progression of diabetic eye disease. At least 1,060 
participants with observable diabetic retinopathy or maculopathy will be randomised (using a 
minimisation algorithm, see Appendix A: Details of randomisation algorithm) between oral fenofibrate 
145mg or placebo tablets. Study treatment is taken once daily in the context of normal renal function, 
or as one tablet every second day in the context of reduced renal function. Follow up is scheduled 
to continue until at least 222 primary outcome events have occurred and median follow up (counting 
from the date of randomisation of the median participant) is at least 4 years.  
 
The trial is designed to be streamlined. Most data for pre-specified efficacy outcomes is obtained by 
linkage to NHS Scotland records. Only the Screening and Randomisation assessments occur in 
person, and all subsequent assessments occur by telephone or by reference to medical records. 
Study treatment is mailed to participants’ homes. After the initial Screening visit is conducted and 
safety blood tests are performed, eligible individuals (who are approved to enter the run-in by the 
local investigator) are provided with active fenofibrate 145mg tablets to be taken (daily with normal 
renal function, one tablet every second day with reduced renal function) for approximately 8 weeks. 
They are then asked to return to the study clinic for a Randomisation assessment. If they remain 
eligible based on information collected at this assessment and further safety blood tests, and are 
willing to continue, participants are randomly allocated to fenofibrate 145mg tablets or placebo. 
 
No research blood or urine samples are taken from randomised participants. Linkage to NHS 
Scotland data-sets is performed to obtain results for HbA1c, renal function (serum creatinine, eGFR, 
urine albumin, urine albumin creatinine ratio) and other assays (e.g. lipids) that have been collected 
as part of routine care. 
 
 
3.2 Study objectives 
 
The primary objective of the LENS trial is to assess the effect of allocation to fenofibrate versus 
placebo on progression to the composite primary outcome of referable diabetic retinopathy (DR) or 
any of the following treatments for diabetic retinopathy: retinal laser therapy, vitrectomy or intra-
vitreal injections (see Section 4.3).  
 
Other objectives include assessments of the effects of fenofibrate on secondary outcomes (see 
Section 4.4), tertiary outcomes (see Sections 4.5) and longer term follow up outcomes (to be covered 
in a separate analysis plan at a later date). 
 
 
 


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4 Definitions for efficacy and safety endpoints  
 
4.1 Estimands 
 
For the efficacy and safety endpoints based on clinical events, the estimand of interest will be the 
rate of first occurrence of the endpoint in the target population allocated fenofibrate relative to the 
rate of first occurrence of the endpoint in the target population allocated placebo, conditional on the 
baseline covariates used in minimised randomisation, ignoring any non-fatal intercurrent events, and 
in the hypothetical absence of death from any cause not included in the efficacy or safety endpoint 
being assessed.  
 
4.2 Hypotheses 
 
For all statistical tests, the null hypothesis will be that the effect of allocation to fenofibrate on the 
endpoint of interest in the target population is the same as the effect of allocation to placebo. 
 
4.3 Primary efficacy assessment 
 
The primary assessment will involve an intention-to-treat comparison, among all randomised 
participants, of the effect of allocation to fenofibrate versus placebo on time to the first occurrence 
during the scheduled treatment period on the following composite primary outcome: the development 
of referable diabetic retinopathya or any of the following treatments for diabetic retinopathy: retinal 
laser therapy, vitrectomy or intra-vitreal injection of medication due to diabetic retinopathy  
 
4.4 Secondary efficacy assessments 
4.4.1 Secondary assessments based on clinical events 
This will involve intention-to-treat comparisons among all randomised participants of the effects of 
allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first 
occurrence of:  
 
4.4.1.1 The composite primary outcome in various subgroups: 
 
Sex (male vs. female) 
 
Age at randomisation (< 60 years vs. ≥ 60 years) 
 
Type of diabetes (Type 1 diabetes vs. Type 2 diabetes and other types) 
 
Renal function (randomisation assessment eGFRb < 60 vs. ≥ 60 mL/min/1.73m2) 
 
HbA1c (screening assessment HbA1c < 70 mmol/mol vs. HbA1c ≥ 70 mmol/mol) 
 
First primary outcome in the first year vs subsequent years of follow-up (because of 
the known reduced impact of lipid modification on cardiovascular events, and 
potentially reduced impact of fenofibrate on laser treatment for diabetic retinopathy, 
in the first year of treatment1,2) 
 
4.4.1.2 The individual components of the composite primary outcome, namely:  
 
The development of referable diabetic retinopathya;  
 
Treatment for diabetic retinopathy: any of retinal laser therapy, vitrectomy or 
intra-vitreal injection of medication due to diabetic retinopathy  
 
                                               
a referable diabetic retinopathy is defined according to NHS Scotland’s DES grading as R3 or R4 [excluding R4i as it 
represents inactive disease] or M2 in at least one eye in the DES grading scheme; such evidence may come from NHS 
retinal screening or clinical examination 
b as entered into the eCRF by research staff using whichever formula is employed by that NHS health board 


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4.4.1.3 Any progression of diabetic retinopathy across the NHS Scotland retinopathy grading 
scalec 
 
4.4.1.4 The presence of hard exudates or blot haemorrhages within 1 disc diameter of the 
maculad  
 
4.4.1.5 Macular oedema 
4.4.2 Secondary assessments based on questionnaires and visual acuity 
This will involve intention-to-treat comparisons among all randomised participants of the effects of 
allocation to fenofibrate versus placebo during the scheduled treatment period on: 
 
4.4.2.1 Visual function (based on the Visual Function Questionnaire [VFQ]-25 questionnaire) 
 
4.4.2.2 Quality of life (based on the EuroQol- 5 Dimension [EQ-5D] questionnaire) 
 
4.4.2.3 Visual acuity (based on visual acuity on LogMar or Snellen chart score collected during 
NHS retinal screening) 
4.4.3 Health economic assessments 
Health economic assessments will be conducted to help guide the appropriate use of fenofibrate by 
health care providers. The detailed analysis plan for health economic assessments will be described 
in a separate document. 
 
4.5 Tertiary efficacy assessments 
 
4.5.1 Tertiary assessments based on clinical events 
This will involve intention-to-treat analyses among all randomised participants of the effects of 
allocation to fenofibrate versus placebo during the scheduled treatment period on time to the first 
occurrence of:  
 
4.5.1.1 The composite of any major cardiovascular event (defined as myocardial infarction, 
stroke, coronary or peripheral revascularisation). 
 
4.5.1.2 The composite of any non-traumatic lower limb amputation (defined as minor amputation 
[distal to the ankle] or major amputation [through or proximal to the ankle]). 
4.5.2 Tertiary assessments based on biochemistry 
Intention-to-treat analyses of the effects of allocation to fenofibrate versus placebo will be 
conducted on the following measures: 
 
4.5.2.1 Urine albumin: creatinine ratio 
 
 
4.6 Clinical safety assessments 
 
SAEs and reasons for stopping study treatment will be captured in the study database to be used 
for safety assessments. The safety assessments will include intention-to-treat analyses among all 
randomised participants of the effects of allocation to fenofibrate versus placebo during the 
scheduled treatment period (with due allowance in their interpretation for multiple comparisons) on: 
 
4.6.1.1 Serious adverse events by Medical Dictionary for Regulatory Activities (MedDRA, 
version 14.0) System Organ Class classification;  
 
                                               
c progression from R’X’ (baseline) to >R’X’ or from M’X’ (baseline) to >M’X’ in either eye 
d M2 grading in the NHS Scotland grading scheme  


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4.6.1.2 Discontinuation of study treatment, overall and by various causes 
 
 
4.7 Other laboratory assessments 
 
Intention-to-treat analyses of the effects of allocation to fenofibrate versus placebo will be conducted 
on the following measures:  
 
4.7.1.1 eGFRe 
 
4.7.1.2 Lipids (total cholesterol, non-HDL cholesterol, HDL cholesterol, triglycerides)  
 
4.7.1.3 HbA1c 
 
Invitation to routine NHS retinal screening is determined by the most recent retinal screening 
results (and has also been affected by the COVID-19 pandemic). The mean (standard error) 
number of retinal screening visits per participant will be calculated for each treatment arm.  
 
 
5 Analysis sets for efficacy and safety analyses 
 
For all outcomes, analyses will compare the outcome from randomisation to the end of the scheduled 
treatment period (see Section 7.5) among all those participants who are allocated at randomisation 
to receive fenofibrate versus all those allocated to receive matching placebo (i.e. “intention-to-treat” 
analyses).3,4 Analyses of binary outcomes will be based on the first occurrence of the specified 
outcome. Per protocol analyses will not be conducted because of the potential for bias in such non-
randomised assessments. 
 
In accordance with the protocol, primary, secondary and tertiary outcomes will not be adjudicated 
with the exception of any medical eye procedures, any adverse event reports of vitreous 
haemorrhage and any adverse event reports of macular oedema. Such events will be adjudicated 
by clinicians blinded to the study treatment assignment (see Section 6). For those events that are 
subject to adjudication, analyses will include confirmed and unrefuted events (excluding any events 
adjudged to be related to a cause other than diabetic retinopathy). 
 
For eye outcome events, the number of people experiencing the outcome (in one or both eyes) will 
be compared between the treatment groups (rather than the total number of eyes affected). 
 
6 Ascertainment and adjudication of study endpoints 
 
6.1 Ascertainment of information 
 
Unless consent to follow-up is withdrawn, follow-up information is to be collected from all study 
participants, irrespective of whether or not they continue to receive study treatment. If a participant 
becomes unwilling or unable to complete follow up study assessments by telephone then study clinic 
staff will review the available medical records and complete the necessary Follow-up form on the 
clinic IT system. Information will also be collected from linkage to NHS Scotland healthcare systems 
and registries. Where retinopathy and maculopathy gradings of retinal images contribute to pre-
specified outcomes, the grading results generated by the NHS Scotland Diabetic Eye Screening 
                                               
e Based on calculations using serum creatinine collected by data linkage and the CKD EPI formula:          
eGFR = 141 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if African American] 
where: 
Scr is serum creatinine in µmol/L; κ is 61.9 for females and 79.6 for males; α is -0.329 for females and -0.411 for males; 
min indicates the minimum of Scr/κ or 1; max indicates the maximum of Scr/κ or 1 


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program will be used. However, it is also intended to use image analysis software at a later time to 
repeat these analyses.  
 
6.2 Adjudication 
 
Adjudicators will follow the standardised procedures in accordance with the pre-specified endpoint 
definitions and adjudication procedures as described in the Adjudication Charter (LENS Adjudication 
Charter and Outcome Definitions EDMS #6781). Only one blinded adjudicator will execute the 
adjudication procedure for each event. 
 
7 Statistical methodology for efficacy and safety analyses 
 
7.1 Methods of analysis 
 
All participants randomised to receive fenofibrate will be compared with all participants randomised 
to placebo, irrespective of whether they received all, some or none of their allocated treatment (i.e. 
intention-to-treat [ITT] analyses).3,4  
 
For the time-to-event analyses, survival analytic methods will be used to evaluate the time to the first 
event during the entire study period. Cox proportional hazards regression analyses, adjusted for 
baseline covariates used in minimised randomisation, will be used to estimate the hazard ratios, 
95% confidence intervals and corresponding p-values, comparing all participants allocated active 
fenofibrate with all those allocated placebo.3 The proportional hazards assumption will be assessed 
through examination of the Schoenfeld residuals. The Kaplan-Meier estimate will also be plotted for 
the time to the primary outcome (with its associated log-rank p-value). When separately assessing 
individual elements of composite outcomes, a participant may contribute to more than one 
assessment if they have events of more than one type (e.g. significant retinopathy followed by laser 
treatment). All p-values will be 2-sided. For each of the events listed as additional safety outcomes 
(Section 4.6), the number of randomised participants with at least 1 event will be compared using 
standard tests for differences in proportions. 
 
For continuous measures collected only at the screening visit, or which may plausibly be affected by 
fenofibrate treatment during the active run-in (namely visual function, quality of life, eGFR, lipids 
[total cholesterol, non-HDL cholesterol, HDL cholesterol, triglycerides], HbA1c, urine albumin: 
creatinine ratio), the screening visit value will be considered to represent the ‘baseline’ value to which 
any post-randomisation values are compared. For continuous measures not collected at the 
screening visit but identified in pre-randomisation NHS linkage data (namely visual acuity), the latest 
value within 18 months prior to randomisation will be considered to represent the ‘baseline’ value. 
 
Any continuous outcomes that display substantial positive skew will be analysed on the log scale. 
For quality of life (Section 4.4.2.2), index values will be derived from EQ-5D-5L questionnaire data 
using a UK-based value set. Visual acuity (Section 4.4.2.3) will be recorded using the LogMAR or 
Snellen chart score. The main analysis of visual acuity will be based on the eye with best acuity at 
baseline, and analysis of the eye with worse acuity will be conducted as a sensitivity analysis. Where 
the baseline visual acuity is the same in both eyes, the right eye shall be chosen for the main analysis 
and the left eye for the sensitivity analysis. Analyses of visual function will be based on LogMAR 
values, with conversion of Snellen chart score to LogMAR values where requiredf. 
 
Visual function (Section 4.4.2.1) and quality of life (Section 4.4.2.2) are collected at baseline, at 
approximately 2 years and at the end of the trial as part of scheduled study assessments. By 
contrast, biochemical measurements (Sections 4.5.2.1 and 4.7) and visual acuity (Section 4.4.2.3) 
are collected at baseline and then collected at multiple times during follow-up as part of routine NHS 
clinical care. For all of these outcomes with baseline and repeated follow-up values, linear mixed 
                                               
f LogMAR value = log10(Snellen denominator / Snellen numerator); it is recognised that conversion from Snellen chart 
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model repeated measures (MMRM) analyses will be conducted to estimate the mean values by 
treatment allocation at each follow-up time point, as well as a trial-averaged difference in mean 
follow-up levels between the randomised treatment groups. For visual function and quality of life, the 
relevant follow-up time points will be 2 years and the end of the trial but, for biochemical 
measurements and visual acuity, the follow-up time points will be the midpoint of each year of follow-
up (any individuals with >1 value in a given 1-year post-randomisation window of time will have those 
values averaged prior to the MMRM analysis). These MMRM models will adjust for the baseline 
value of the measure of interest as well as the baseline minimisation criteria and will assume an 
unstructured covariance matrix.   
 
7.2 Multiplicity adjustments 
 
Assuming that the trial runs to its planned completion, the primary assessment at the final analysis 
will be made first and deemed statistically significant if its two-sided p-value is <0.05.  
 
For the secondary and tertiary assessments, multiple testing will not formally be taken into account. 
However, given the number of such analyses, due allowance will be made in their interpretation, 
taking into account the nature of events (including timing, duration and severity) and evidence from 
other studies.3,4 
 
7.3 Subgroup analyses and tests for heterogeneity  
 
The secondary assessments (see Section 4.4.1.1) include intention-to-treat analyses among all 
randomised participants of the effects of allocation to fenofibrate versus placebo during the 
scheduled treatment period on the primary outcome in sub-categories of patient based on categories 
of data collected at baseline. Tests for heterogeneity of the proportional effect observed in subgroups 
will be used to determine whether the proportional effects in specific subcategories are clearly 
different from the overall effect.2,3 (Note that for the subgroups that can be sensibly ordered [age, 
renal function and HbA1c] this test for heterogeneity is equivalent to a test for trend because each 
of the subgroups is to be split into only two categories [see Section 4.4.1.1].)   
 
When many different subgroups are considered, chance alone may lead to there being no apparent 
effect in some subgroups considered in isolation, even when the effect of treatment really is about 
the same as is observed overall. In such circumstances, “lack of direct evidence of benefit” is not 
good “evidence of lack of benefit”, and clearly significant overall results would provide strong indirect 
evidence of benefit in subgroups where the results, considered in isolation, are not conventionally 
significant (or, even, perhaps, slightly adverse).3-5 Hence, unless the proportional effect in some 
specific subcategory is clearly different from that observed overall, the effect in that subcategory is 
likely to be best estimated indirectly by applying the proportional effect observed among all patients 
in the trial to the absolute risk of the event observed among control patients in that category.5 
 
7.4 Handling of missing and incomplete data 
 
The study protocol and procedures have been designed to minimise loss to follow-up.6 For any binary 
outcome event where the precise date of occurrence is unknown, the midpoint of the plausible range 
will be assumed (e.g. the middle of the month if only the month and year are reported). For subgroup 
analyses of the effects of fenofibrate on such events, patients with missing baseline values for that 
subgroup will be excluded from the subgroup-specific results but included in the overall total (with 
the result just among those with missing baseline data for each subgroup explicitly reported if the 
‘missing’ category proves to be a non-trivial subset). Note that for analyses of the continuous 
measurements recorded at multiple follow-up time points, the MMRM models take account of 
missing data by assuming that such data can be predicted from the correlations seen between the 
non-missing values for other individuals, together with the other covariates in the model (i.e., the 
model assumes that data are ‘missing at random’). 
 


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7.5 Censoring schema for time-to-event endpoints 
 
For all intention-to-treat analyses, participants who do not have the outcome under investigation will 
be censored at the end of the scheduled treatment period, which will be defined as the earliest of 
date of the final follow-up visit, death, or full consent withdrawal. For participants for whom 
information on these 3 criteria is missing, the censoring date will be set as the date when reliable 
information on both vital status and the occurrence/absence of the primary outcome was last reliably 
recorded (e.g. by completion of follow-up visit or access to relevant healthcare records).  
 
 
8 Guidelines for early stopping or modification of the trial 
 
Unblinded interim analyses will be reviewed regularly by the DMC, and will be conducted and 
presented by a statistician not involved in the day-to-day management of the trial. Upon review of 
such data, the DMC will advise the Steering Committee if, in their view, the randomised comparisons 
have provided both (a) proof beyond reasonable doubt that for all patients, or for some specific types, 
fenofibrate therapy is clearly indicated or contra-indicated; and (b) evidence that might reasonably 
be expected to influence materially the clinical management of many patients. The Steering 
Committee can then decide whether to end or modify the trial or to seek additional data, and this 
decision will be communicated in writing to the Chief Investigator after each Steering Committee 
meeting.  
 
Appropriate criteria of proof beyond reasonable doubt cannot be specified precisely, but the DMC 
will work on the principle that a difference of at least 3 standard errors in an interim analysis of a 
major outcome event may be needed to justify halting, or modifying, a study before the planned 
completed recruitment. This criterion has the practical advantage that the exact number of interim 
analyses would be of little importance, and so no fixed schedule is proposed3. 
 
 
 
 
 
 


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9 References 
 
1. 
Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive 
lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. 
Lancet 2010; 376(9753): 1670-81. 
2. 
Preiss D, Spata E, Holman RR, et al. Effect of Fenofibrate Therapy on Laser Treatment for Diabetic 
Retinopathy: A Meta-Analysis of Randomized Controlled Trials. Diabetes Care 2022; 45(1): e1-e2. 
3. 
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient. I. Introduction and design. Br J Cancer 1976; 34(6): 585-612. 
4. 
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring 
prolonged observation of each patient. II. analysis and examples. Br J Cancer 1977; 35(1): 1-39. 
5. 
Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major 
morbidity, I: clinical trials. The Lancet 2001; 357(9253): 373-80. 
6. 
Fleming TR. Addressing missing data in clinical trials. Ann Intern Med 2011; 154(2): 113-7. 
 
 
 


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10 Appendix A: Details of randomisation algorithm 
 
The minimised randomisation algorithm allocates participants to the placebo arm or the active arm. 
The participant is allocated to the treatment arm with the lower minimisation score, with a probability 
of 0.9 (i.e. this occurs for 90% of randomisations). For the other 10% of randomisations, or in the 
event of a tie (i.e. minimisation scores are equal), treatment is allocated randomly with a probability 
of 0.5.  
 
The minimisation score is calculated based on the following categories: 
 
 
Sex: male; female  
 
Age at randomisation visit: <30; ≥30 <50; ≥50 <70; ≥70 years 
 
Type of Diabetes: Type 1, Type 2, Other 
 
eGFR from Randomisation assessment: <60; ≥60 mL/min/1.73m2 
 
HbA1c from Randomisation assessment: <64; ≥64mmol/mol; unknown  
 
Statin therapy: Yes; No 
 
Most recent macula result: consider both eyes and use the worst eye’s macula result as the 
category (in the list below, ‘i’ is the best result and ‘iii’ is the worst result) 
i. 
No result available 
ii. No maculopathy 
iii. Observable diabetic maculopathy  
 
Most recent retina results: consider both eyes and use the worst eye’s retina result as the 
category (in the list below, ‘i’ is the best result and ‘iv’ is the worst result) 
i. 
Other retinopathy (this includes ‘not adequately visualised’ and ‘other result provided’) 
ii. No retinopathy 
iii. BDR – Mild 
iv. BDR – Observable