Does Pre-operative D-chart Score Predict Improvement in VFQ-25 Score Following Surgery for Epiretinal Membrane?
Conditions: Epiretinal Membrane, Distortion, Quality of Life
Sponsor: NHS Greater Glasgow and Clyde

Tennent Institute of Ophthalmology, Glasgow 
NHS Greater Glasgow and Clyde 
 
 
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Full title of trial 
 
Does pre-operative D-chart score predict 
improvement in VFQ-25 score following surgery 
for epiretinal membrane? 
Short title 
 
‘Distortion as a predictor of ERM surgery 
outcome’ 
Version and date of protocol 
Version 7.8 01.10.2019 
 
Sponsor: 
NHS GGC 
Sponsor protocol number 
IRAS Project ID 
GN18OP439 
246530 
Funder (s) : 
Royal College of Surgeons of Edinburgh 
(Ophthalmology Small Research Grant awarded 
March 2019) 
 
Sites(s) 
Gartnavel General Hospital Glasgow G12 0YN UK 
Note: Idea is to collaborate with hospitals in 
England and Madrid in the future, after Glasgow 
study has been set up 
Chief investigator& co-investigators: 
Dr David Yorston (chief investigator) 
Email: David.Yorston@ggc.scot.nhs.uk; 
Tel: +447740945843 
Principal investigators 
Dr Lona Jawaheer, Tennent Institute of 
Ophthalmology 
Email: lonajawaheer@doctors.org.uk; 
Tel+447783520779 
Sponsor Representative: 
Emma McDonough 
Email: Emma.Mcdonough@ggc.scot.nhs.uk 
Tel 0141 201 9329 
 

Tennent Institute of Ophthalmology, Glasgow 
NHS Greater Glasgow and Clyde 
 
 
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Dr Gerard McGowan, Tennent Institute of 
Ophthalmology 
Email: gerry_emod@yahoo.co.uk; 
Tel +447544938836 
 
 
 
 

Tennent Institute of Ophthalmology, Glasgow 
NHS Greater Glasgow and Clyde 
 
 
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Signatures 
The Chief Investigator and the R&D have discussed this protocol. The investigators agree to 
perform the investigations and to abide by this protocol. 
Chief investigator 
Dr Yorston 
 
 
TIO 
Signature 
Date 
Sponsor Representative 
 
 
 
 
Signature 
Date 
 
 
 
 
This Protocol template is intended for use with Glasgow site only (other UK 
sites, and Spanish site, might be recruited at later stage) 
 
 
 

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Contents 
Signatures .......................................................................................................................... 3 
Contents............................................................................................................................. 4 
List of abbreviations .......................................................................................................... 7 
1 
Trial personnel ........................................................................................................ 8 
2 
Summary ................................................................................................................. 9 
3 
Introduction .......................................................................................................... 11 
3.1 
Background and literature review ................................................................. 11 
3.2 
Clinical data ................................................................................................... 13 
3.3 
Rationale and risks/benefits .......................................................................... 14 
3.4 
Assessment and management of risk ............................................................ 14 
4 
Objectives ............................................................................................................. 15 
5 
Trial design ........................................................................................................... 15 
5.1 
Overall design ............................................................................................... 15 
5.2 
Unit of Analysis ............................................................................................ 16 
6 
Selection of Subjects ............................................................................................ 16 
6.1 
Inclusion criteria ............................................................................................ 16 
6.2 
Exclusion criteria ........................................................................................... 16 
7 
Recruitment .......................................................................................................... 17 
8 
Study procedures and schedule of assessments .................................................... 17 
8.1 
Informed consent procedure .......................................................................... 17 
8.2 
Baseline visit ................................................................................................. 18 
8.3 
Assessment timeline ...................................................................................... 19 
8.4 
Definition of end of trial ................................................................................ 20 
8.5 
Discontinuation/withdrawal of participants and ‘stopping rules’ ................. 20 
9 
Treatment of subjects ............................................................................................ 21 
10 
Recording and reporting of adverse events and reactions .................................... 21 
10.1 
Definitions ..................................................................................................... 21 
10.2 
Recording adverse events .............................................................................. 23 
10.3 
Assessments of Adverse Events .................................................................... 24 

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10.3.1 
Severity .................................................................................................... 24 
10.3.2 
Causality ................................................................................................... 24 
10.3.3 
Expectedness ............................................................................................. 25 
10.3.4 
Seriousness ............................................................................................... 25 
10.4 
Procedures for recording and reporting Serious Adverse Events ................. 25 
10.4.1 
Notification of deaths ................................................................................. 26 
10.4.2 
Reporting SUSARs .................................................................................... 26 
10.4.3 
Development Safety Update Reports ............................................................ 27 
10.4.4 
Annual progress reports .............................................................................. 27 
10.4.5 
Reporting Urgent Safety Measures ............................................................... 27 
10.4.6 
Notification of Serious Breaches to GCP and/or the protocol ........................... 27 
11 
Data management and quality assurance .............................................................. 27 
11.1 
Confidentiality ............................................................................................... 27 
11.2 
Data collection tools and source document identification ............................ 28 
11.3 
Data handling and analysis ............................................................................ 28 
12 
Record keeping and archiving .............................................................................. 29 
13 
Statistical Considerations ..................................................................................... 29 
13.1 
Outcomes ....................................................................................................... 29 
13.1.1 
Primary outcome ........................................................................................ 29 
13.1.2 
Secondary outcomes ................................................................................... 29 
13.1.3 
Exploratory outcomes ................................................................................. 29 
13.2 
Sample size and recruitment ......................................................................... 30 
13.2.1 
Sample size calculation ............................................................................... 30 
13.2.2 
Planned recruitment rate ............................................................................. 30 
13.3 
Statistical analysis plan ................................................................................. 30 
13.3.1 
Summary of baseline data and flow of patients .............................................. 30 
13.3.2 
Primary outcome analysis............................................................................ 30 
13.3.3 
Secondary outcome analysis ........................................................................ 30 
13.3.4 
Exploratory outcome analysis ...................................................................... 31 
13.4 
Interim analysis ............................................................................................. 31 

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13.5 
Other statistical considerations ...................................................................... 31 
14 
Name of Committees involved in trial ................................................................. 31 
15 
Direct Access to Source Data/Documents ............................................................ 32 
16 
Ethics and regulatory requirements ...................................................................... 32 
17 
Monitoring requirement for the trial ..................................................................... 32 
18 
Finance.................................................................................................................. 32 
19 
Insurance ............................................................................................................... 32 
20 
Publication policy ................................................................................................. 33 
21 
Statement of compliance ...................................................................................... 33 
22 
References ............................................................................................................ 33 
 
 

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List of abbreviations 
AE 
Adverse Event 
AR 
Adverse Reaction 
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
Main REC 
Main Research Ethics Committee 
NHS R&D 
National Health Service Research & Development   
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TSC 
Trial Steering Committee 

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1 
Trial personnel 
Chief Investigator (CI) and co-investigators: 
 
Dr David Yorston, Tennent Institute of Ophthalmology. 
Email: David.Yorston@ggc.scot.nhs.uk; tel: 
+447740945843. 
 
 
Dr Gerard McGowan, Tennent Institute of 
Ophthalmology. Email: gerry_emod@yahoo.co.uk, tel 
+447544938836 
 
 
Dr Lona Jawaheer, Tennent Institute of 
Ophthalmology, 1053 Great Western Road, Glasgow 
G12 0YN 
 
 Email: lonajawaheer@doctors.org.uk;  tel:  
07783520779, +44 1412113223 
 
 
 
 
 
 
Sponsor’s Representative 
TBC 
 
Clinical Trial Coordinator 
TBC (Research Nurse) 
 
Statistician 
Dr David Young, University of Strathclyde, Glasgow 
 

Tennent Institute of Ophthalmology, Glasgow 
NHS Greater Glasgow and Clyde 
 
 
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2 
Summary 
Research question 
Does pre-operative D-chart score predict improvement in 
VFQ-25 score following surgery for epiretinal membrane? 
Title: 
Predictive value of pre-operative distortion score for 
improvement in vision-related quality of life following 
epiretinal membrane surgery  
Short title: 
Change in VFQ-25 following ERM surgery 
Trial medication: 
No medications.  Trial of surgery. 
Objectives: 
Primary:  
To assess how pre-op D chart score correlates with VFQ-25 
scores 26 and 52 weeks after surgery.  
 
Secondary: 
To summarise the changes over time (i.e. from pre op, to 26 
then 52 weeks after the surgery) of the following variables: 
i. D-chart score 
ii. BCVA (ETDRS) 
iii. VFQ-25 
iv. Central retinal thickness obtained from 
OCT scans 
 
Type of trial: 
Prospective case series consisting of patients with 
symptomatic epiretinal membranes presenting to 
vitreoretinal department in a tertiary referral centre. 
Trial 
design 
and 
methods: 
The study group will include patients who choose to undergo 
surgery for epiretinal membrane peel +/- cataract surgery.  
The following data will be collected pre-operatively: 
demographics (age, gender), laterality, duration of symptoms, 
lens status (clear lens/ cataract/ PCIOL), past ophthalmic 
history, BCVA, central retinal thickness, degree of distortion, 
vision-related quality of life.  The patients are typically seen 
at Day 1 and Week 1/2 after the surgery.  They will be seen at 
26 weeks and 52 weeks after surgery for the assessment of: 

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i) 
their retinal function (visual acuity and assessment 
of distortion) and retinal imaging (OCT), and 
ii) 
their vision-related quality of life 
Symptoms of distortion will be quantified and characterised 
using a novel methodology used previously in patients with 
retinal detachments and macular holes (D Chart). 
NEI VFQ-25 quality of life questionnaire will be used to 
measure the vision-related quality of life. 
Trial 
duration 
per 
participant: 
12 months 
Estimated total trial 
duration: 
24-36 months 
Planned trial sites: 
Tennent Institute of Ophthalmology, Gartnavel Hospital, 
Glasgow UK 
Total 
number 
of 
participants planned: 
60-70 (2/3 of 80-100) 
Main 
inclusion/exclusion 
criteria: 
Principal Inclusion Criteria: 
• Idiopathic epiretinal membrane 
• Patients undergoing epiretinal membrane surgery, 
under local or general anaesthetic 
• Able to give informed consent 
• 18 years old and over 
Principal Exclusion Criteria: 
• Epiretinal membrane secondary to retinal detachment, 
uveitis or retinal vascular disease 
• Previous vitreoretinal surgery 
• Pre-existing 
ophthalmic 
condition 
other 
than 
epiretinal membrane which limits the patient’s visual 
acuity (documented BCVA 6/36 or worse) 
• Pre-existing 
ophthalmic 
condition 
other 
than 
epiretinal membrane which cause metamorphopsia 
(e.g. exudative ARMD, central serous retinopathy) 
• VA < 6/60 

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Statistical methodology 
and analysis: 
The study statistician will be responsible for statistical 
aspects of the trial from design through to analysis and 
dissemination. 
Regression analysis will be used to determine the 
relationship between D chart scores and VQF-25 scores 26 
and 52 weeks post-surgery while correcting for baseline 
VFQ-25 scores. Changes over time in D chart scores, BCVA 
(ETDRS), VFQ-25 and central retinal thickness will be 
summarised graphically with appropriate descriptive 
statistics. All statistical analyses will be done using Minitab 
(version 18) at a 5% significance level. 
 
 
 
 
3 
Introduction 
3.1 
Background and literature review 
Epiretinal membranes result from an anomaly of the vitreoretinal interface.  They 
consist of a proliferation of avascular fibrocellular tissue along the inner limiting 
membrane of the retina, and are thought to arise from retinal glial cells that have been 
liberated during a precipitating event such as a posterior vitreous detachment or surgery.  
Risk factors for ERM include ageing, intraocular surgery/ cryotherapy, inflammation, 
vascular ischaemic disease trauma and retinal detachment – idiopathic cases make up a 
significant proportion of the patient population.  About 6% of those over the age of 50 
years have an epiretinal membrane [1].  Over time, this membrane can result in anterior-
posterior traction, intraretinal cystic changes and macular detachment [2].  The patient 
may become symptomatic with distorted vision, with straight lines appearing bent or 
wavy, or blurred vision.  
 
Management of epiretinal membrane includes observation (over 75% of patients 
stabilise after diagnosis) or surgery for severely symptomatic membranes.  The surgery 
consists of vitrectomy and epiretinal +/- inner limiting membrane peel. 
 

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Literature review 
60-85% of patients undergoing epiretinal membrane surgery experience a significant 
improvement in quality of life.  Patients with ERM now constitute one of the most 
common referrals to the vitreoretinal service.  Being able to identify the patients who 
are the most likely to experience an improvement from ERM surgery, and to quantify 
this improvement, would be of practical help to both the patient and the surgeon.  For 
the patient, this would help weigh up the benefits and risks of proceeding with an 
elective operation.   
 
Numerous studies have shown that epiretinal membrane surgery leads to an 
improvement in visual acuity [3,4,5].  Dawson et al [3] showed that patients with better 
initial VA achieved better final VA outcome, but that patients with poorer pre-op VA 
showed greater change in VA following surgery. Some studies have advocated patient 
selection based on pre-operative visual acuity.  A retrospective study of 40 cases by 
Thompson [6] concluded that surgery for ERM is beneficial in pseudophakic eyes with 
relatively good preoperative visual acuities (better than 20/60).  Rahman et al [7] 
compared patients with ‘early’ ERM (pre-operative logMAR score < 0.3) and ‘medium’ 
or ‘late’ ERM (logMAR score of 0.4 & 0.5, and score of > 0.6 respectively), and 
showed that the ‘early’ ERM group had better mean postoperative logMAR score, and a 
greater proportion achieved of that group achieved a logMAR visual score of < 0.1. 
 
However, it has also been shown that vision-related quality of life can improve even in 
the absence of improvement in visual acuity [8]. This implies that surgery improves 
aspects of visual function other than acuity, such as metamorphopsia and aniseikonia 
[8]. Therefore some patients who are experiencing these symptoms might still be good 
candidates for surgery in spite of having relatively good visual acuity. 
 
Numerous tests exist to measure the degree of metamorphopsia such as the M-chart and 
the Foresee monitoring programme.  Recently, the D-chart, which aims to overcome 
some of the limitations of the other existing tests, was developed in Glasgow in 
collaboration with Glasgow Caledonian University by some of the authors of this study 

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[1].  This test has been shown to be consistent and practical (taking patients 5-10 
minutes to complete). 
 
A few studies have been published on metamorphopsia and quality of life in patients 
undergoing ERM surgery.  Ghazi-Nouri et al [8] prospectively followed 20 patients 
undergoing epiretinal membrane surgery, looking at the effect on visual acuity, contrast 
sensitivity, metamorphopsia (using an Amsler chart) and health-related quality of life 
(using the VFQ-25 and SF36 questionnaires). Ichikawa et al [9], Kinoshita et al [10], 
and Okamoto et al [11] studied pre- and post-op metamorphopsia using M-charts. 
However, these studies are limited by small numbers (<30 eyes) and short follow-up (< 
4 months) [8,9,11] and retrospective nature [9].  Validated vision-related quality of life 
questionnaires were not always used [9,10] and none of the studies measured 
metamorphopsia using the D-chart, which we believe to be a superior tool.  
 
As our study measures the effects on distortion (using D chart), visual acuity and quality 
of life from ERM surgery, it will allow us to investigate whether the pre-op D chart 
score can predict subsequent improvement in quality of life following surgery.  This 
will provide vitreoretinal surgeons and patients with an evidence base regarding the 
success of this elective procedure and offer realistic expectations regarding surgical 
outcomes. Ultimately, we hope that the results of this study will facilitate the decision 
of whether or not to proceed with ERM surgery. 
 
3.2 
Clinical data 
a. Measurement of Distortion 
The D Chart system [12] will be used to measure distortion.  This method consists of 
24 test plates each of which assess four concentric zones around the point of fixation 
(0.0-1.5, 1.5-3.5, 3.5-7.0, and 7.0-12.0 degrees from fixation).  The severity of 
distortion, in degrees is assessed in each zone at a number of fixed points.  A ‘D-
score’ is then calculated which reflects both the number of locations within that zone 
where distortion is perceived, and the severity of that distortion.  This approach has 
been used in patients with distortion secondary to other retinal pathologies (epiretinal 
membranes, macular holes and retinal detachments) [12] and been found to be 
consistent and practical (taking patients 5-10 minutes to complete). 

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b. Measurement of vision-related quality of life 
The National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) will be 
used as a measure of patient-reported, vision-related functioning.  This questionnaire 
is the product of the longer field test version of the survey called the 51-item National 
Eye Institute Vision Function Questionnaire [13], and was developed to measure the 
range of vision-related functioning experienced by persons with a variety of chronic 
eye diseases. It has been used in a number of studies to measure the health-related 
quality of life related to vision in patients with diabetes [14], dry eyes [15], age-related 
macular degeneration [16] and visual impairment in the elderly [17], as well as for 
patients undergoing ERM surgery [8].  
3.3 
Rationale and risks/benefits 
 
Research Question: 
Does pre-operative D-chart score predict improvement in VFQ-25 score following 
surgery for epiretinal membrane? 
Exploratory aims are to: 
o To investigate the sustained effect of epiretinal membrane surgery on distortion 
and BCVA 
o To determine the relationship between distortion and vision-related quality of life 
 
The decision regarding whether to proceed with surgery will be made by the patient.  
Participation in the study will mean one additional visit .Appointment times will also be 
slightly longer in order to allow measurement of distortion (estimated to take around 5 
minutes per eye) and vision-related quality of life.  However this study is an 
observational one and designed to record the patient experience rather than influencing 
it. 
 
3.4 
Assessment and management of risk 
This study does not expose the patients to a higher risk than standard medical care.   
Once the patient has decided to participate in the study, they will receive the same 
standard of care as any other patient who decides to pursue epiretinal membrane 
surgery, with some additional observational tests (use of D-chart for measurement of 

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distortion and administration of VFQ-25 questionnaire), and therefore are not exposed 
to any other additional risk. 
 
4 
Objectives 
Primary: 
To assess how pre-op D score correlates with VFQ-scores 26 weeks and 52 weeks after 
epiretinal membrane surgery. 
Secondary: 
To summarise the changes over time (i.e. from pre op, to 26 then 52 weeks after the 
surgery) of the following variables: 
v. D-chart score 
vi. BCVA (ETDRS) 
vii. VFQ-25 
viii. Central retinal thickness obtained from OCT scans 
 
 
5 
Trial design 
5.1 
Overall design 
This non-commercial prospective interventional case series aims to determine whether it 
is possible to predict the amount of improvement in vision-related quality of life that a 
patient will experience following ERM surgery, from a pre-operative measurement of 
distortion. 
Around 60-70 patients will be recruited in Glasgow.  The decision regarding whether to 
proceed with surgery will be made by the patient, and following enrolment onto the study 
they will receive standard care. 
Standard 3 port pars plana vitrectomy and epiretinal membrane and ILM peel with gas 
tamponade will be performed. Phakic patients will undergo cataract surgery. Any 
intraoperative or postoperative complications will be recorded. 
Any patient undergoing epiretinal membrane surgery is routinely reviewed at Day 1 and 
Week 1/2. The study visits are at 26 weeks (+/- 8 weeks) and 52 weeks (+/- 8 weeks). A 
full clinical examination will be performed at each visit. At the 26 and 52-week follow 

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ups, bilateral OCT and D-chart assessments will be performed.  VFQ-25 will also be 
assessed at 26 and 52-week follow ups. 
Visual improvement following epiretinal membrane surgery is thought to continue for up 
to 1-2 years after surgery.  At our centres patients having undergone epiretinal membrane 
surgery tend to be discharged around the 6-month post-operative period, with advice to 
the patient regarding likelihood of gradual continued improvement in distortion.  In this 
trial, involvement of individual participants will be for a maximum of 12 months.   
 
5.2 
Unit of Analysis 
There will be one eye recruited per study patient. The operated eye will be the study 
eye, and the eye related outcome measures will be for that eye only. If the patient 
presents with bilateral epiretinal membranes, then, provided both eyes satisfy the 
inclusion criteria, one eye will be randomly selected for the study. 
 
6 
Selection of Subjects 
6.1 
Inclusion criteria 
a) Idiopathic epiretinal membrane 
b) Patients undergoing vitrectomy and gas surgery, under local or general 
anaesthetic 
c) Able to give informed consent 
d) 18 years old and over 
6.2 
Exclusion criteria 
a) Epiretinal membrane secondary to retinal detachment, uveitis or retinal vascular 
disease 
b) Previous vitreoretinal surgery 
c) Pre-existing ophthalmic condition which limits the patient’s visual acuity 
(Documented BCVA 6/36 or worse) 
d) Pre-existing ophthalmic conditions which cause metamorphopsia (exudative 
ARMD, central serous retinopathy) 
e) VA < 6/60 
 

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7 
Recruitment 
Patients will be recruited from the vitreoretinal clinics at the Tennent Institute of 
Ophthalmology in Glasgow, UK.  
The doctors working in these clinics will be informed in advance about the trial.  Posters will 
be placed in the clinic rooms to serve as a reminder.  There will be no advertising directly to 
patients or outside the clinic setting.  
8 
Study procedures and schedule of assessments 
8.1 
Informed consent procedure 
Consent for the trial will be taken by the principal or co-investigator or person delegated 
by the investigator (study doctor or research nurse). These persons will have been GCP 
trained, will be fully informed regarding the trial and be trained in taking informed 
consent.  Persons eligible to take consent will be specified in the delegation log.  Written 
consent will be obtained from each subject prior to participation in the trial, following 
adequate explanation of the aims, methods, anticipated benefits and potential hazards of 
the study. 
Patients will undergo a routine assessment with the clinical care team. During this 
assessment if it becomes apparent that the patient is eligible for the study, the clinical care 
team will inform the research team. Some of the data from this assessment (which will be 
obtained prior to informed consent being taken) will be used to complete baseline 
demographics on the CRF by the study team. 
Patients identified as being eligible for the study in the vitreoretinal clinic will have the 
opportunity to discuss the trial in advance of their surgery. Should they be confirmed as 
being eligible and wish to proceed, a consent form will be signed in advance of their 
surgery and the patient will be given a copy of the consent form.   
At the completion of the epiretinal membrane surgery, the operating surgeon will confirm 
that the patient remains eligible for the trial.  
No clinical trial procedures will be conducted prior to taking consent from the participant. 
Consent will not denote enrolment into trial. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form will be reviewed and updated if necessary. All subjects, including those 
already being treated, will be informed of the new information, giving a copy of the 
revised form and give their consent to continue in the study. 
If a participant who has given informed consent loses capacity to consent during the study, 
they would be withdrawn from the study. Identifiable data or tissue already collected with 

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consent would be retained and used in the study. No further data or tissue would be 
collected or any other research procedures carried out on or in relation to the participant. 
 
Interval between patients being informed about trial and commencement.  Patients with 
possible epiretinal membranes will attend a routine vitreoretinal clinic (screening visit).  
This visit will include only assessments that are part of the standard clinical care of 
patients prior to epiretinal membrane surgery, namely: 
• History of ocular disease 
• Previous vitreoretinal surgery 
• Clinical examination: evidence of epiretinal membrane 
Patients with an epiretinal membrane who choose to proceed with surgery will be 
scheduled for non-urgent surgery (usual waiting time 2 weeks to 3 months).  Consent for 
participation in the study will be taken at this initial clinic visit.  There will therefore be 
adequate time for the patient to consider their involvement and study the patient 
information sheet prior to the operation.   
 
Withdrawal.  The investigator, or designee, will explain to patients that they are under no 
obligation to enter the trial and can withdraw at any time without having to provide an 
explanation. 
 
Documentation of consent.  A copy of the signed consent form will be given to the 
participant.  The original form will be retained at the study site and a copy placed in the 
medical notes. 
 
New developments. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form will be reviewed and updated if necessary. All 
subjects, including those already being treated, will be informed of the new information, 
giving a copy of the revised form and give their consent to continue in the study. 
 
8.2 
Baseline visit 
After having been listed for surgery at the initial clinic visit (screening visit), the patient 
will be seen at the pre-operative assessment clinic (baseline visit).  At this visit, the 
research nurse will obtain informed consent and carry out the protocol assessments as per 
table 8.3. 
Surgery will occur within 28 days of the baseline visit.

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8.3 
Assessment timeline 
 
 
Screening 
Baseline 
Follow-up 
Visit # 
1 
2 
3 
4 
5 
 
Initial Clinic 
Pre-op assessment 
Week 2 post-op 
Week 26 post 
op (+/- 8 weeks) 
Week 52 post 
op (+/- 8weeks) 
Seen by doctor 
X 
 
X 
X 
X 
Eligibility determination 
X 
 
 
 
 
Seen by Research Nurse 
 
X 
 
X 
X 
Informed Consent 
 
X 
 
 
 
Protocol 
Assessments  
BCVA (ETDRS) 
 
X 
X 
X 
X 
OCT 
 
X 
 
X 
X 
D-chart 
 
X 
 
X 
X 
VFQ-25 
 
X 
 
X 
X 
Adverse Events review 
 
 
X 
X 
X 
 
 

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Baseline assessments 
BCVA (ETDRS) and slit lamp/indirect ophthalmic examination (anterior segment assessment, 
lens status, presence and severity of epiretinal membrane).  
 
Subsequent assessments 
Adverse events:  
To be documented in patient casenotes at the 2 and 26-week follow up appointments, 
and transcribed to Case Report Form Appendix 5 (Adverse Event Reporting Form) by 
research nurses. 
 
Follow-up visits:   
o Best-corrected ETDRS visual Acuity.  This assessment is part of standard clinical care 
and non-invasive.  
o Macular OCT imaging.  This assessment is part of standard clinical care and non-
invasive.  
o Assessment of distortion (D-Chart).  This non-invasive test requires patients to view a 
series of charts and describe distortion where seen. 
o Visual function questionnaire 
 
8.4 Definition of end of trial 
The trial will end on the date of the last 52-week follow up visit by the last participant.  
8.5 Discontinuation/withdrawal of participants and ‘stopping rules’ 
Circumstances for patient withdrawal from trial: 
• Patient choice - If at any time the patient decides to withdraw from the study after giving 
informed consent they may do so at any time and without giving reason. The patient 
will be advised that their standard of care will not be affected should they withdraw 
from the study. 
• Development of other conditions that could cause metamorphopsia or loss of vision e.g. 
AMD 
Documentation in event of withdrawal: 
• Reason for withdrawal 

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If patients are withdrawn or discontinue the trial, they will be asked if they are willing to attend 
the 26-week visit, in which they will undergo the planned 26-week assessments.  
It is not intended that withdrawn subjects be replaced, but their permission will be asked for 
their data to be used as part of an intention to treat analysis.  The trial would be stopped 
prematurely in the event of new information that undermined the validity of the research. 
 
9 
Treatment of subjects 
This study will involve following up patients who have chosen to undergo epiretinal 
membrane surgery.  The patients will receive standard surgical treatment.  Furthermore, it 
does not evaluate any medicinal product, medical device, food supplement, radiation, surgery 
or behavioural interventions. 
Post-operative medications - routine topical antibiotic, steroids and mydriatics which are part 
of the standard post-operative care. 
10 
Recording and reporting of adverse events and reactions 
10.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical trial 
subject undergoing the study intervention and which does not 
necessarily have a causal relationship with this intervention. 
 
Adverse Reaction (AR) 
Any untoward and unintended response in a subject to the study 
intervention which is related to any study intervention. 
Term 
Definition 
Serious adverse event 
(SAE), serious adverse 
reaction (SAR) or 
unexpected serious 
adverse reaction  
Any adverse event, adverse reaction or unexpected adverse 
reaction, respectively, that: 
• 
results in death, 
• 
is life-threatening, 
• 
requires hospitalisation or prolongation of existing 
hospitalisation, 

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• 
results in persistent or significant disability or 
incapacity, or 
• 
consists of a congenital anomaly or birth defect 
Important Medical 
Event 
These events may jeopardize the subject or may require an 
intervention 
to 
prevent 
one 
of 
the 
above 
characteristics/consequences. Such events should also be 
considered ‘serious’. 
Unexpected adverse 
reaction 
An adverse reaction the nature and severity of which is not 
consistent with the study intervention. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

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10.2 
Recording adverse events 
Adverse events will be recorded with clinical symptoms and accompanied with a simple, brief 
description of the event, including dates as appropriate.  Adverse events noted up to and during 
the last study visit will be recorded. 
Adverse events will be recorded for study patients up until their final study visit at 12 months.  
Regarding Ocular Adverse Events 
All ocular adverse events (AEs) reported by patients and observed by the study team will be 
recorded in the medical records and CRF following randomisation until the patient has 
completed their final study visit at 12 months. The exception to this will be events which are 
inevitable consequences of the surgical intervention (refer to later in text for examples). These 
events will only be recorded in the medical records. 
Expected Ocular AEs to be recorded in the CRF& Medical Notes: 
1. Elevated intraocular pressure (IOP)(see below) 
2. Hypotony (IOP <6mmHg) 
3. Retinal detachment 
4. Further ocular surgery 
5. Endophthalmitis 
6. Uveitis occurring more than 4 weeks after surgery 
More specifically, the following definition of elevated IOP will be used for this study: 
Mild: >25mmHg – 35mmHg 
Moderate: >35mmHg 
Severe: Any interventional invasive procedure (eg. surgery or laser) required to control 
IOP acutely or long-term, during the study period. 
Expected Ocular AEs to be Recorded in Medical Notes Only: 
These will not be considered adverse events, as they are expected findings in this disease 
population and as such will only be recorded in the medical notes. Reporting these findings as 
AEs are not deemed to add additional safety data to the study.No electronic record of these 
events will be kept. Examples include: 
Subconjunctival haemorrhage, conjunctival chemosis, periorbital oedema, routine 
postoperative pain, cataract formation, corneal epithelial defect secondary to 
intraoperative epithelial debridement, CMO. If any of the above events occur to a 
severity or duration that is unexpected by the PI, they may then be reported as AE's, 
making clear the reason (e.g. 'prolonged post-operative pain' or 'severe subconjunctival 
haemorrhage'). 

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Regarding Non-Ocular Adverse Events 
Expected Non-Ocular AEs, Recorded in CRF & Medical Notes: 
None expected 
 
10.3 
Assessments of Adverse Events 
Each adverse event will be assessed for the following criteria: 
10.3.1 Severity 
 
 
10.3.2 Causality 
The assessment of relationship of adverse events to the study protocols is a clinical decision 
based on all available information at the time of the completion of the case report form.  The 
following categories will be used to define the causality of the adverse event: 
Category 
Definition 
Mild 
The adverse event does not interfere with the volunteer’s daily routine, 
and does not require intervention; it causes slight discomfort 
Moderate 
The adverse event interferes with some aspects of the volunteer’s routine, 
or requires intervention, but is not damaging to health; it causes moderate 
discomfort 
Severe 
The adverse event results in alteration, discomfort or disability which is 
clearly damaging to health 
Category 
Definition 
Definitely: 
There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
Probably: 
There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely 
Possibly 
There is some evidence to suggest a causal relationship (e.g. the 
event occurred within a reasonable time after administration of 

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10.3.3 Expectedness 
 
Category 
Definition 
Expected 
An adverse event that is classed in nature as serious and which is 
clearly defined in this protocol. 
Unexpected 
An adverse event that is classed in nature as serious and which 
has not been anticipated and specified in this protocol.  
 
The protocol will be used as the reference document to assess disease related and/or procedural 
expected events.  
 
10.3.4  
Seriousness 
Seriousness as defined for an SAE in section 10.1. 
10.4 
Procedures for recording and reporting Serious Adverse Events 
Reportable SAEs: 
An SAE occurring to a research participant will be reported both to the sponsor via an SAE 
form at the following email address: pharmacovig@glasgowctu.org, and to the main REC 
within 24 hours of becoming aware where in the opinion of the Chief or Principal Investigator 
the event was: 
• Related – that is, it resulted from administration of any of the research procedures, and 
the trial related procedures). However, the influence of other 
factors may have contributed to the event (e.g. the patient’s 
clinical condition, other concomitant events). 
Unlikely 
There is little evidence to suggest there is a causal relationship 
(e.g. the event did not occur within a reasonable time after 
administration of the trial related procedures). There is another 
reasonable explanation for the event (e.g. the patient’s clinical 
condition, other concomitant treatments). 
Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 

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• Unexpected – that is, the type of event is not listed in the protocol as an expected occurrence. 
(Expected Adverse Events are listed in 10.2.) 
 
Recordable SAEs: 
Ocular events that meet the definition of serious, but are expected (see section 10.2), will be 
recorded in the medical notes and the CRF as an SAE, but not immediately reported as an SAE 
to the sponsor. Examples include further ocular surgery (e.g. cataract surgery). 
Non-ocular events that meet the definition of serious will be recorded in the hospital notes but 
only recorded in the CRF if they are thought to be possibly, probably or definitely related to 
epiretinal membrane surgery. They will only be immediately reported to the sponsor as an SAE 
if they are not expected (see section 10.2). 
The events will be recorded in the study SAE log and submitted to the Sponsor on a monthly 
basis using the following email address: pharmacovig@glasgowctu.org and an SAE form will 
not be completed. However, if any of the above events require unexpected urgent surgery and 
the investigator deems the event to be possibly related to epiretinal membrane surgery, they 
will be considered a reportable SAE and will be immediately reported to the sponsor (within 
24hours). 
 
Examples of recordable& reporting AEs&SAEs: 
Clarification for recording and reporting non-ocular AEs: 
a) Coryzal illness not satisfying criteria for serious – record in medical notes only. 
b) A fall resulting in a fractured wrist, requiring a hospital admission and urgent 
surgery to repair – record in medical notes only. 
c) Further ocular surgery for retinal detachment during the study period – record 
in medical notes AND log in CRF. Record as an SAE, but do not immediately 
report to sponsor. 
10.4.1 Notification of deaths 
All deaths will be reported to the sponsor irrespective of whether the death is related to disease 
progression, trial procedures, or an unrelated event.  This report will be immediate. 
10.4.2 Reporting SUSARs 
The sponsor will notify the main REC of all SUSARs within 15 days after the sponsor has 
learned of them.   

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10.4.3 Development Safety Update Reports 
Not Applicable 
10.4.4 Annual progress reports 
An annual progress report (APR) 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. 
The research coordinator will prepare the APR. 
10.4.5 Reporting Urgent Safety Measures 
If any urgent safety measures are taken the PI/Sponsor shall immediately and in any event no 
later than 3 days from the date the measures are taken, give written notice the relevant REC of 
the measures taken and the circumstances giving rise to those measures. 
 
10.4.6 Notification of Serious Breaches to GCP and/or the protocol 
A “serious breach” is a breach which is likely to effect to a significant degree – 
(a) the safety or physical or mental integrity of the subjects of the trial; or 
(b) the scientific value of the trial. 
The sponsor of a clinical trial shall notify the licensing authority in writing of any 
serious breach of: 
(a) the conditions and principles of GCP in connection with that trial; or (b) the 
protocol relating to that trial, as amended from time to time, within 7 days of becoming 
aware of that breach. 
The sponsor will be notified immediately of any case where the above definition 
applies during the trial conduct phase.  The sponsor’s SOP on the ‘Notification of 
violations, urgent safety measures and serious breaches’ will be followed.  
11 
Data management and quality assurance 
11.1 
Confidentiality 
All data will be handled in accordance with the General Data Protection Regulation.. 
The Case Report Forms (CRFs) will not bear the subject’s name or other personal identifiable 
data.  Trial number will be used for identification on the CRFs. The chief investigator or 
delegated authorised individual will be responsible for keeping a separate log file which links 
the study ID and the patient’s details and will be kept on a protected computer. 

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11.2 
Data collection tools and source document identification 
The investigator will work with the trial team to maintain source documents for each patient in 
the study, consisting of case and visit notes (hospital or clinic medical records) containing 
demographic and medical information, results of OCT scans, D-chart assessments and visual 
function questionnaire. 
A subset of the information in the source documents will be determined by the chief investigator 
and other suitably trained members of the study team to be the trial dataset for the Case Report 
Forms (CRFs). This will be agreed with the study statistician and communicated to the R&D 
IT team. CRFs will be designed and produced by the R&D IT Team according to the sponsor’s 
CRF template. All data will be entered legibly in black ink with a ball-point pen.  If an error is 
made, the error will be crossed through with a single line in such a way that the original entry 
can still be read.  The correct entry will then be clearly inserted, and the alterations will be 
initialed and dated by the person making the alteration.  Overwriting or use of correction fluid 
will not be permitted. The completion of CRFs will be signed off by the Chief Investigator or 
delegated authorized individual (Principal Investigator) as outlined in the delegation log. The 
delegation log will identify all those personnel with responsibilities for data collection and 
handling. It will be the responsibility of the investigator to ensure the accuracy of all data 
recorded on the CRFs.  
 
All information on CRFs must be traceable to the source documents in the patient's file. The 
investigator must also keep the original informed consent form signed by the patient (a signed 
copy is given to the patient). 
 
11.3 
Data handling and analysis 
The completed CRFs will be checked for completion by the research nurse / research 
manager. The delegated authorised individual will then enter data onto the trial database 
created by the R&D IT team. Data entry will be carried out within 1 week of CRF 
completion. When all patients have been recruited, the R & D data officer will double data 
enter 10 CRFs randomly selected by the senior data manager, plus 100% of primary outcome 
data for all patients. The first and second data entries will be compared for completion and 
consistency checks will be performed. The error rate will be calculated and errors will be 
corrected as necessary. Sense checks, logic checks and range checks will be performed. Data 
queries will be corrected and data will be cleaned. When all parties agreed and signed the data 
lock request – sign off form with reference to DM_S04 clinical trial data validation, data 
cleaning and database lock. The database will then be locked and data transferred for analysis 
by trial statisticians using STATA statistical software. Data management process will follow 
the trial data management plan. 
Data handling will be performed adhering to the General Data Protection Regulation.. 

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12 
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report.  
Chief Investigators are responsible for the secure archiving of essential trial documents for each 
site and the trial database as per their trust policy. All essential documents will be archived for 
a minimum of 5 years after completion of trial.  
Destruction of essential documents will require authorisation from the Sponsor.   
13 
Statistical Considerations 
The study statistician who will be responsible for statistical aspects of the trial from design 
through to analysis and dissemination. 
13.1 
Outcomes 
13.1.1 Primary outcome 
VFQ-25 score at final visit (52 weeks after ERM surgery) 
13.1.2 Secondary outcomes 
Descriptive statistics and graphs as appropriate for the following variables, pre-
operatively and at 26 and 52 weeks after ERM surgery: 
i. 
D-chart score 
ii. 
BCVA (ETDRS) 
iii. 
VFQ-25 score 
iv. 
Central retinal thickness obtained from OCT scans 
13.1.3 Exploratory outcomes 
Correlation between pre-operative D-chart score and VFQ-25 score 26 and 52 weeks 
after ERM surgery 
 

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13.2 
Sample size and recruitment 
13.2.1 Sample size calculation 
All available patients over a 12-month period will be targeted. About 80 to 100 patients have 
ERM surgery in a year in Gartnavel General Hospital.  We would except to enrol about two 
thirds of these (i.e. about 60 patients in total).  This should allow us to detect a correlation of 
about 0.345 with 89% power. 
 
13.2.2 Planned recruitment rate 
A total of 60-70 patients will be entered into the study in Gartnavel General Hospital. To recruit 
these patients over 12 months, we would need to recruit 5-6 patients per month, which based 
on the audit data, should be achievable across both sites.  
13.3 
Statistical analysis plan 
Regression analysis will be used to determine the relationship between D chart scores and VQF-
25 scores at 26 and 52 weeks post-surgery while correcting for baseline VFQ-25 scores. 
Changes over time in D chart scores, BCVA (ETDRS), VFQ-25 and central retinal thickness 
will be summarised graphically with appropriate descriptive statistics. All statistical analyses 
will be done using Minitab (version 18) at a 5% significance level. 
 
13.3.1 Summary of baseline data and flow of patients 
Summary statistics will be presented as mean and standard deviation for continuous 
(approximate) normally distributed variables, median and interquartile range for non-normally 
distributed variables and frequency and percentage for categorical variables.   
 
 
13.3.2 Primary outcome analysis 
The primary outcome is the VFQ-25 score 52 weeks after the ERM surgery. 
13.3.3 Secondary outcome analysis 
Summary statistics for all secondary outcomes will be presented.  Where appropriate 
the standard error and two-sided 95 % confidence interval will be presented.  For 
outcome measures which are presented as proportions, a 95 % confidence interval will 
be computed by the exact binomial method. 

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13.3.4 Exploratory outcome analysis 
Regression analysis will be used to determine the relationship between pre-op D chart scores 
and VQF-25 scores 26 and 52 weeks post-surgery while correcting for baseline VFQ-25 scores. 
It is inevitable that some patients will be lost to follow-up, for example due to changes in 
health, social or personal circumstances. In cases of missed appointments, the research nurse 
will contact the participant by phone, and then by post. The reason for missing the 
appointment will be documented, and, where possible, a more convenient follow up will be 
arranged. The chief investigator will be informed by email of any patients lost to follow up.  
If data are missing for any patients, reasons for this may be important and these will be 
investigated using logistic regression of covariates on an indicator of missingness.   If there 
are less than 5 % missing data and data appear to be missing completely at random, we may 
report the available case analysis as our main analysis.  Sensitivity analysis will however be 
conducted allowing a best and worst case scenarios and these results reported alongside the 
available case report. 
 
 
Please note that a more detailed statistical analysis plan should be produced as a separate 
document at some point prior to the final analysis (as recommended by the ICH E9 
guidelines). In this document, a more technical and detailed elaboration of the principal 
features stated in the protocol should be included. The plan may include detailed procedures 
for executing the statistical analysis of the primary and secondary variables and other data. 
The plan should be reviewed and possibly updated as a result of the masked review of the 
data and should be finalized before breaking the mask. Formal records should be kept of when 
the statistical analysis plan was finalized as well as when the mask was subsequently broken. 
 
13.4 
Interim analysis 
No interim statistical analyses are planned. 
13.5 
Other statistical considerations 
Any deviations from the statistical analysis plan will be described and justified in the final 
report, as appropriate. 
14 
Name of Committees involved in trial 
Trial Steering Committee (TSC): consisting of principle and co-investigators, research 
coordinator and statistician. 
 
 

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15 
Direct Access to Source Data/Documents 
The investigator(s)/ institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents.  Study participants 
are informed of this during the informed consent discussion.  Participants will consent to 
provide access to their medical notes. 
16 
Ethics and regulatory requirements 
The sponsor will ensure that the study protocol, patient information sheet, consent form, and 
submitted supporting documents have been approved by a main research ethics committee, 
prior to any patient recruitment. The protocol and all agreed substantial protocol amendments 
will be documented and submitted for ethical approval prior to implementation. 
Before the site can enrol patients into the trial, the Chief Investigator/Principal Investigator or 
designee must apply for NHS permission from their Trust Research & Development (R&D) 
and be granted written permission.  It is the responsibility of the Chief Investigator/ Principal 
Investigator or designee at each site to ensure that all subsequent amendments gain the 
necessary approval.  This does not affect the individual clinician’s responsibility to take 
immediate action if thought necessary to protect the health and interest of individual patients 
(see section 10.4.5 for reporting urgent safety measures). 
Within 90 days after the end of the trial, the CI/Sponsor will ensure that the main REC are 
notified that the trial has finished.  If the trial is terminated prematurely, those reports will be 
made within 15 days after the end of the trial. 
The CI will supply the Sponsor with a summary report of the clinical trial, which will then be 
submitted to the main REC within 1 year after the end of the trial.  
17 
Monitoring requirement for the trial 
18 
This section will be completed by the NHS GG&C Monitoring 
team and research coordinator.Finance 
This is a non-commercial trial funded by the Royal College of Surgeons of Edinburgh 
(Ophthalmology Small Research Grant of £9,828 awarded March 2019). 
19 
Insurance 
NHS GGC participates in the Clinical Negligence and Other Risks Indemnity Scheme 
(CNORIS) which has been in operation since 2000.  CNORIS covers: 
- 
 clinical negligence claims when they arise and are made against members in 
connection with the acts or omissions of their employees 

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- 
non-clinical claims and actions that arise following loss or bodily injury affecting third 
parties or employees or certain other pecuniary risks 
 
 
CNORIS will cover GGC employees, both substantive and honorary, who are working in the 
course of their NHS employment and in respect of conducting research projects which must 
have received NHS Permission.  GGC will not accept liability for any activity that has not 
been properly registered and Trust approved. 
 
20 
Publication policy 
All proposed publications will be discussed with Sponsor prior to publishing other than those 
presented at scientific forums/meetings.  
21 
Statement of compliance 
The trial will be conducted in compliance with the approved protocol, the UK Regulations, 
GCP and anyapplicable regulatory requirement(s). 
 
22 
References 
See attachment