Conditions: Macular Oedema Retinitis Pigmentosa
Keywords: Macular Oedema Retinitis Pigmentosa
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the safety and efficacy of intravitreal injections of Aflibercept (Eylea) in treating Cystoid Macula Oedema (CMO) in patients with underlying Retinitis Pigmentosa (RP).

Detailed description:
This is a 17 month phase II therapeutic exploratory trial in Cystoid Macular Oedema (CMO) with underlying Retinitis Pigmentosa (RP). The study design is a prospective, open-label, interventional non-randomised trial. All patients enrolled in the study will receive intravitreal injections of Aflibercept (Eylea).

There will be a 9 month recruitment window and patient participation will be for 12 months; 30 patients aged 16 years or older presenting in the Medical Retina and Genetics clinics at Moorfields Eye Hospital with Cystoid Macula Oedema (CMO) with underlying Retinitis Pigmentosa (RP) will be approached by the study team to discuss participation in the AMOUR study and be given a patient information leaflet. If patients decide to participate in the study they will be invited to the NIHR Moorfields Clinical Research Facility for a baseline screening where written informed consent will be given by the patient and various assessments will be performed to confirm eligibility.

Patients enrolled in the study will receive intravitreal injections of 2mg of 40mg/ml of Aflibercept (Eylea) solution in the study eye. In the first three months, patients will receive a loading dose of Aflibercept (Eylea) with one injection every four weeks. After the first three months, treatment frequency will follow a treat and extend protocol for up to 12 months from date of study enrolment. Extension from 4 weekly to 6,8,10 and 12 week follow up will occur when there is no further reduction in macula fluid compared to the previous visit. Patients will receive a minimum of 5 injections before being deemed as non-responders to treatment.

Imaging and assessments such as optical coherence tomography imaging, microperimetry and visual acuity will be used to assess response to treatment.

Arms:
arm 1: All patients recruited to the study will receive 3 loading intravitreal injections of Aflibercept (Eylea) at monthly intervals followed by a treat and extend protocol up to 12 months. Extension from monthly to 6, 8, 10 and 12 week follow-up will occur when there is evidence of OCT stability in the view of the investigator i.e. there is no further reduction in macular fluid compared to the previous visit. All patients will receive 5 injections before considering them non-responders.

Interventions: intervention 1: Aflibercept
Intervention descriptions: intervention 1: 2mg of 40mg/ml of Eylea Solution administered via intravitreal injection every four weeks for three months (loading dose), followed by a treat and extend protocol up to 12 months. Extension from monthly to 6, 8, 10 and 12 week follow up will occur where there is no reduction in macula oedema compared with the previous visit.

Number of cycles; minimum of 5 injections and maximum of 13 injections per study eye.

Protocol document:
ICF_002.pdf: 
 
 
 
 
 
AMOUR Consent Form Version 1.1, 14th March 2016 
 
 
 
City Road 
London 
EC1V 2PD 
 
Tel: 020 7253 3411 
www.moorfields.nhs.uk 
 
 
 
 
 
 
 
 
 
 
Full title of trial 
 
 
Prospective non-randomised exploratory 
study to assess the safety and efficacy of 
Eylea in cystoid macular oedema 
associated with Retinitis Pigmentosa 
 
Short title 
 
 
 
Aflibercept for Macular Oedema with 
Underlying Retinitis Pigmentosa (AMOUR) 
study 
 
Version and date of consent form: 
 
Version 1.1   14th March 2016 
Sponsor: 
Moorfields Eye Hospital NHS Foundation 
Trust 
Sponsor protocol number 
MICM1014 
Funder (s) : 
Bayer PLC 
EudraCT no 
2015-003723-65  
ACTIVE IMP(s): 
Aflibercept (Eylea) 
PLACEBO IMP(s): 
N/A 
Phase of trial 
Therapeutic exploratory trial (phase II) 
Sites(s) 
Single site – Moorfields Eye Hospital 
 
 
 
 


AMOUR Consent Form Version 1.1, 14th March 2016 
 
2 
 
Chief investigator: 
 
Professor Michel Michaelides 
Moorfields Eye Hospital 
City Road 
London 
EC1V 2PD 
UK 
  
 
Department of Genetics 
UCL Institute of Ophthalmology  
11-43 Bath Street 
London  
EC1V 9EL 
UK   
 
 
 
Sponsor Representative: 
 
Gisela Barreto 
Research Portfolio Manager  
Moorfields Eye Hospital NHS Foundation 
Trust 
162 City Road 
London 
EC1V 2PD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONSENT FORM 
 
Study Title:  Aflibercept for Macular Oedema with Underlying Retinitis Pigmentosa 
(AMOUR) trial 


AMOUR Consent Form Version 1.1, 14th March 2016 
 
3 
 
Patient ID: 
 
Researchers:  Dr. Stacey Strong, Professor Michel Michaelides, and Professor Andrew 
Webster 
 
 
 
 
 
 
           Please initial box 
 
1. I confirm that I have read and understand the information sheet dated  
 
version 2.1 dated 14th March 2016 for the above study and have had  
the opportunity to ask questions. 
 
2. I understand that my participation is voluntary and that I am free to  
     withdraw at any time, without giving any reason and without my 
     medical care or legal rights being affected. 
 
3. I understand that sections of my medical notes may be looked   
          at by responsible individuals from Moorfields Eye Hospital or from  
regulatory authorities where it is relevant to my taking part in research.   
I give permission for these individuals to have access to my records. 
 
4. I understand that my GP will be informed of my participation in this  
     research project and of any findings significant to my general health 
 
5. I understand that I will not benefit financially from participating in the study 
 
 
6. I agree to take part in the above study. 
 
 
 
 
 
 
 
 
 
For women of child bearing potential only 
 
7. I understand that if I am a woman of child bearing potential I will be 
asked to undertake a pregnancy test prior to enrolment. I agree to use 
adequate contraception throughout the duration of the trial (12 months) 
and for at least 3 months after my last injection. I agree to be monitored 
by my GP +/- obstetrics and gynaecology team should I fall pregnant 
during my participation in the study or within 3 months of my last 
injection.  
 
 
 
_________________________  
 _______ 
 
________________ 


AMOUR Consent Form Version 1.1, 14th March 2016 
 
4 
Name of patient  
 
  
Date  
 
Signature 
 
 
 
_________________________  
________ 
 
________________ 
Name of person taking consent Date  
 
Signature 
(if different from researcher)  
 
 
 
 
_________________________  
 _______ 
 
________________ 
Researcher 
 
  
 
Date  
 
Signature 
 
 
When completed: Original for researcher site file; a copy for the participant; a copy for the medical notes. 
 

Prot_000.pdf: 
 
 
 
AMOUR Protocol 2.0    26th November2015        
Page 1 of 93 
 
 
Full title of trial 
 
 
Prospective non-randomised exploratory 
study to assess the safety and efficacy of 
Eylea in cystoid macular oedema 
associated with Retinitis Pigmentosa 
 
Short title 
 
 
 
Aflibercept for Macular Oedema with 
Underlying Retinitis Pigmentosa (AMOUR) 
study 
 
Version and date of protocol 
 
Version 2.0   26th November2015 
Sponsor: 
Moorfields Eye Hospital NHS Foundation 
Trust 
Sponsor protocol number 
MICM1014 
Funder (s) : 
Bayer PLC 
EudraCT no 
2015-003723-65  
ACTIVE IMP(s): 
Aflibercept (Eylea) 
PLACEBO IMP(s): 
N/A 
Phase of trial 
Therapeutic exploratory trial (phase II) 
Sites(s) 
Single site – Moorfields Eye Hospital 
 
 
 
 
 
 


 
 
 
AMOUR Protocol 2.0    26th November2015        
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Chief investigator: 
 
Professor Michel Michaelides 
Moorfields Eye Hospital 
City Road 
London 
EC1V 2PD 
UK 
  
 
Department of Genetics 
UCL Institute of Ophthalmology  
11-43 Bath Street 
London  
EC1V 9EL 
UK   
 
 
Sponsor Representative: 
 
Gisela Barreto 
Research Portfolio Manager  
Moorfields Eye Hospital NHS Foundation 
Trust 
162 City Road 
London 
EC1V 2PD 
 
 


 
 
 
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Signatures 
The Chief Investigator and the R&D (sponsor office) have discussed this protocol.  
 
The investigators agree to perform the investigations and to abide by this protocol.  
 
The investigator agrees to conduct the trial in compliance with the approved  
protocol, EU GCP and UK Regulations for CTIMPs (SI 2004/1031; as amended),  
the UK Data Protection Act (1998), the Trust Information Governance Policy  
(or other local equivalent), the Research Governance Framework (2005’ 2nd  
Edition; as amended), the Sponsor’s SOPs, and other regulatory requirements  
as amended. 
 
Chief investigator 
Michel Michaelides 
 
 
 
Signature 
Date 
Sponsor Representative 
Gisela Barreto 
 
 
Moorfields Eye Hospital 
Signature 
Date 
 
 
 
 
 
 
 


 
 
 
AMOUR Protocol 2.0    26th November2015        
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Contents 
Signatures…………………………………………………………………………..…..3 
Contents……………………………………………………………………………..….4 
List of abbreviations…………………………………………………………………....8 
1       Trial Personnel…………………………………………………….……………10 
2       Summary…………………………………………………………….……….....12 
3        Introduction………………………………………………………….…….……17 
    3.1           Background………………………………………………….………….17 
    3.2           Preclinical data……………………………………………….…………17 
    3.3           Clinical data……………………………………………………………..18 
    3.4           Rationale and risks/benefits…………………………………..………18 
    3.5           Assessment and management of risk………………………………..44 
4        Objectives………………………………………………………………………46 
5        Trial design……………………………………………………………………..48 
     5.1          Overall design…………………………………………………………..48 
6         Selection of subjects………………………………………………………….49   
     6.1           Inclusion criteria………………………………………………………..49 
     6.2           Exclusion criteria……………………………………………………….49 
  7         Recruitment…………………………………………………………………….51 
8         Study procedures and schedule of assessments………………………….52 
      8.1          Informed consent procedure………………………………………….52 
      8.2          Randomisation procedures……………………………………………52 
      8.3          Unmasking…………………………………………………………...….53 
      8.4          Screening Period……………………………………………………….53 
       8.5         Baseline and subsequent assessments……………………………...55 


 
 
 
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      8.6          Treatment procedures………………………………………………….56 
      8.7          Flowchart of study assessments………………………………………56 
      8.8          Methods………………………………………………………………….57 
          8.8.1         Laboratory procedures……………………………………………..57 
      8.9          Definition of end of trial…………………………………………………57 
      8.10        Discontinuation/withdrawal of participants and ‘stopping rules’ …...57 
9    Name and description of all drugs used in the trial……………………………..58 
       9.1         Concomitant medication………………………………………………...62 
10     Investigational Medicinal Product……………………………………………….63 
      10.1         Name and description of investigational medicinal product(s)……..63 
      10.2         Name and description of each Non-IMP (NIMP)…………………….63 
      10.3         Summary of findings from non-clinical studies………………………63 
      10.4         Summary of findings from clinical studies……………………………63 
      10.5         Summary of known and potential risks and benefits………………..63 
      10.6         Description and justification of route of administration and dosage.64 
      10.7         Dosages, dosage and modifications and method of administration.64 
      10.8         Preparation and labelling of Investigational Medicial Product……...65 
      10.9         Drug accountability……………………………………………………...65 
      10.10       Source of IMPs including placebo……………………………………..65 
      10.11       Dose modifications………………………………………………………66 
      10.12       Assessment of compliance……………………………………………..66 
      10.13       Post-trial IMP arrangements……………………………………………66 
11   Recording and reporting of adverse events and reactions…………………….67 
       11.1        Definitions………………………………………………………………..67 
       11.2        Recording adverse events……………………………………………...69 


 
 
 
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        11.3 Procedures for recording and reporting Serious Adverse Events……..71 
             11.3.1  Notification of deaths…………………………………………………72 
             11.3.2 Reporting SUSARs……………………………………………………72 
             11.3.3 Development Safety Update Reports……………………………….73 
             11.3.4 Annual progress reports………………………………………………73 
             11.3.5 Pregnancy (if applicable)……………………………………………..73 
             11.3.6 Overdose……………………………………………………………….74 
             11.3.7 Reporting Urgent Safety Measures………………………………….74 
         11.4 The type and duration of follow-up of subjects after adverse events…74 
              11. 4.1Notification of Serious Breaches to GCP and/or the protocol……75 
12  Data management and quality assurance……………………………….……….76 
         12.1 Confidentiality…………………….……………………………….…………76 
         12.2 Data collection tools and source document identification………………76 
         12.3 Data handling and analysis………………………………………………..77 
13  Record keeping and archiving……………………………………………………..79 
14  Statistical Considerations…………………………………………………………..80 
          14.1  Outcomes…………………………………………………………………..80 
                14.1.1  Primary outcomes…………………………………………………..80 
                14.1.2   Secondary outcomes………………………………………………80 
          14.2  Sample size and recruitment……………………………………………..82 
                14.2.1 Sample size calculation...........……………………………………..82  
                14.2.2 Planned recruitment rate……………………………………………82 
          14.3  Statistical analysis plan…………………………………………………...82 
                 14.3.1 Summary of baseline data and flow of patients………………….82 
                 14.3.2 Primary outcome analysis………………………………………….83 


 
 
 
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                 14.3.3 Secondary outcome analysis………………………………………83 
                 14.3.4 Sensitivity and other planned analyses…………………………...85 
           14.4  Randomisation methods………………………………………………….85 
           14.5  Interim analysis…………………………………………………………….85 
           14.6  Other statistical considerations…………………………………………..85 
15  Name of committees involved in trial………………………………………………86 
16  Direct Access to Source Data/Documents………………………………………..86 
17  Ethics and regulatory requirements………………………………………………..87 
18  Monitoring requirement for the trial………………………………………………...89 
19  Finance………………………………………………………………………………..89 
20  Insurance……………………………………………………………………………...89 
21  Publication policy…………………………………………………………………….89 
22 Statement of compliance…………………………………………………………….90 
23 References……………………………………………………………………….91 - 93 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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List of abbreviations 
 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
CMO 
Cystoid Macular Oedema 
CMT 
Central Macular Thickness 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GAfREC 
Governance Arrangements for NHS  
                                                          Research Ethics 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 


 
 
 
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ISRCTN 
International Standard Randomised   
IVT 
Intravitreal injection 
MA 
Marketing Authorisation 
MEH 
Moorfields Eye Hospital 
MHRA 
Medicines and Healthcare products  
                                                          Regulatory Agency 
MS 
Member State 
Main REC 
Main Research Ethics Committee 
NHS R&D 
National Health Service Research  
                                                          & Development   
OCT 
Optical Coherence Tomography 
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person for release of trial drug 
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
RP 
Retinitis Pigmentosa 
SAR 
Serious Adverse Reaction 
SAE 
Serious Adverse Event 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSA 
Site Specific Assessment 
SUSAR 
Suspected Unexpected Serious  
                                                          Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 


 
 
 
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1 
Trial personnel 
 
Chief Investigator (CI) 
 
Professor Michel Michaelides 
Moorfields Eye Hospital 
City Road 
London 
EC1V 2PD 
UK 
  
Department of Genetics 
UCL Institute of Ophthalmology  
11-43 Bath Street 
London  
EC1V 9EL 
UK   
 
Tel:  0207 608 6864   
Fax:  0207 608 6903 
michel.michaelides@ucl.ac.uk 
 
Sponsor’s representative 
 
Gisela Barreto - Research Portfolio Manager  
Moorfields Eye Hospital NHS Foundation Trust 
162 City Road 
London 
EC1V 2PD 
gisela.barreto@moorfields.nhs.uk 
 


 
 
 
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Statistician 
 
Catey Bunce 
Moorfields Eye Hospital NHS Foundation Trust 
162 City Road 
London 
EC1V 2PD 
Catey.bunce@moorfields.nhs.uk 
0207 253 3411 Ext: 2820 
 
 
NIHR Moorfields Clinical Research Facility Imaging and Nursing Personnel 
2nd Floor, 162 City Road, London, EC1V 2PD 
Moorfields Eye Hospital NHS Foundation Trust 
Tel: 020 7566 2108 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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2 
Summary 
 
Full title                      Prospective non-randomised exploratory study to assess the  
                                    safety and efficacy of Eylea in cystoid macular oedema  
                                    associated with Retinitis Pigmentosa  
 
 
Short title                    Aflibercept for Macular Oedema with Underlying Retinitis  
                                     Pigmentosa (AMOUR)  
 
 
 
Trial medication: 
 
Aflibercept (Eylea) 
 
 
Phase of trial: 
 
 
Therapeutic exploratory trial (phase II) 
Objectives: 
To assess the safety and efficacy of Eylea in cystoid 
macular oedema (CMO) associated with Retinitis 
Pigmentosa (RP)Primary End-point:  
Ø Mean Central Macular Thickness (CMT) on 
Spectral Domain OCT (SDOCT) at  12 months 
 
Secondary End-points: 
Ø Mean Central Macular Thickness (CMT) on 
Spectral Domain OCT (SDOCT) at  6 months 
 
Ø Mean change in CMT on SDOCT from baseline to 


 
 
 
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6 months and baseline to 12 months 
Ø Mean Best Corrected ETDRS Visual Acuity 
(BCVA) at 6 and 12 months 
Ø Mean change in ETDRS BCVA from baseline to 6 
months and baseline to 12 months 
Ø Mean macular volume on SDOCT at 6 and 12 
months 
Ø Mean change in macular volume on SDOCT from 
baseline to 6 months and baseline to 12 months 
Ø Report all AEs and SAEs  
Ø Mean retinal sensitivity using microperimetry at 6 
and 12 months  
Ø Mean change in retinal sensitivity using 
microperimetry from baseline to 6 months and 
baseline to 12 months 
Ø Mean number of intravitreal injections administered  
 
Type of trial: 
Therapeutic exploratory trial (phase II), prospective, non-
randomised, single site exploratory trial in patients with 
Retinitis Pigmentosa associated with cystoid macula 
oedema 
 
Trial 
design 
and 
methods: 
Ø 16 years of age, Prospective, non-randomised, 
Molecularly confirmed patients prioritised (to be 
able to potentially explore any pharmacogenetic 
aspects), Recruited over a 9 month period, with 
each patient having 12 month follow-up. 
Ø All patients receive 3 loading injections of Eylea at 
monthly intervals followed by a treat and extend 


 
 
 
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protocol up to 12 months, Extension from monthly 
to 6, 8, 10 and 12 week follow-up will occur when 
there is evidence of OCT stability in the view of the 
investigator i.e. there is no further reduction in 
macular fluid compared to the previous visit. 
Ø All patients will receive 5 injections before 
considering them non-responders 
Ø BCVA and SDOCT undertaken at every visit 
Ø Microperimetry undertaken at Baseline, 6 months 
and 12 months 
Ø Fundus Autofluorescence (FAF) Imaging Baseline, 
6 and 12 months  
Ø Refracted BCVA at baseline, 6 months and 12 
months 
Ø SDOCTs will be graded by Moorfields Eye Hospital 
Reading Centre 
 
Trial duration per 
participant: 
 
                 12 months 
Estimated total trial 
duration: 
 
                 24 months 
Planned trial sites: 
                 Single-site 
Total 
number 
of 
participants 
planned: 
          30 
 
Main 
 


 
 
 
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inclusion/exclusion 
criteria: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       Inclusion criteria:  
Ø CMO in association with RP 
Ø 16 years of age 
Ø Unilateral or Bilateral CMO (the worse eye only will 
be treated – defined as the eye with a greater 
central macular thickness (CMT) on OCT) 
Ø No previous oral treatment for CMO for last 3 
months 
Ø No previous peribulbar or intravitreal treatment for 
CMO in the study eye for last 3 months 
Ø No previous topical treatment for CMO in the study 
eye for last 1 month  
Ø Central visual impairment that in the view of the 
Principal Investigator is due to CMO 
Ø BCVA better than 3/60 
 
Exclusion criteria:  
Ø  Insufficient patient cooperation or media clarity to 
allow adequate fundus imaging 
Ø Evidence of visually significant vitreo-retinal 
traction or epiretinal membrane on OCT that in the 
Principal Investigator’s opinion is highly likely to 
significantly limit the efficacy of intravitreal therapy  
Ø History of cataract surgery within prior 3 months or 
cataract surgery anticipated within 6 months of 
starting the study 
Ø Any anti-VEGF treatment to study eye within 3 
months 
Ø History of YAG capsulotomy performed within 3 


 
 
 
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Statistical 
methodology and 
analysis: 
months 
Ø Uncontrolled IOP > = 24 mmHg for ocular 
hypertension (on topical IOP lowering medications) 
Ø Advanced glaucoma (in the opinion of a glaucoma 
specialist)  
Ø Patients with active or suspected ocular or 
periocular infections 
Ø Patients with active severe intraocular 
inflammation 
Ø Patients with a new, untreated retinal tear or 
detachment 
Ø Patients with a stage 3 or 4 macular hole 
Ø Thromboembolic event (MI/CVA/Unstable Angina) 
within 6 months 
Ø Pregnancy or family planned within 15 months 
Ø Females who are breast feeding 
Ø Known allergy or hypersensitivity to anti-VEGF 
products 
 
 
A consort flow chart will be constructed to illustrate the 
flow of patients through the study.  The primary analysis 
will be an available case analysis but baseline 
characteristics of those who are lost to follow up will be 
compared with those who are not. If the findings from this 
study are favourable, these data will be used to plan a 
definitive randomised controlled trial.  A third of 
patients showing more than 40% reduction in CMT on 
OCT would be ‘favourable’ and supportive of further study 


 
 
 
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3 
Introduction 
3.1 
Background 
• Inherited retinal disease is the second commonest cause of visual loss in 
childhood and the commonest cause of visual loss in the working age 
population 
• Retinitis Pigmentosa (RP) is the commonest inherited retinal disorder with an 
incidence of 1 in 3,000  
• There are no cures currently for RP  
• Patients with RP experience two complications for which there is potential 
treatment – cataracts and cystoid macular oedema (CMO) 
• Approximately 20% of patients with RP develop CMO which causes 
significant central visual loss and disability 
• Several different treatments for CMO have been employed including laser 
therapy, topical trusopt, oral acetazolamide, peri-ocular and intravitreal 
steroids, and intravitreal anti-VEGF agents 
• The current mainstay of treatment are topical and oral carbonic anhydrase 
inhibitors 
• The vast majority of the published literature is retrospective and thereby 
inherently limited and often involves small numbers of participants and short 
duration of follow-up 
3.2 
Preclinical data 
• In a retrospective review of patients seen at Moorfields Eye Hospital in the 
Retinal Genetics Clinics (Professors Moore, Michaelides and Webster) with 
RP on treatment for CMO (n=93), ascertained over a 12 month period (June 
2012 to June 2013), – approximately 50% were deemed non-responders 
(defined as less than 20% reduction in central macular thickness (CMT) on 
OCT between visits) to topical or systemic carbonic anhydrase inhibitors 


 
 
 
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3.3 
 Clinical data 
• There is some evidence in the literature that anti-VEGF therapy may be 
effective – Artunay et al (2009) observed significant response to a single 
injection of Lucentis in 15 eyes of 15 patients with RP and CMO over a 6 
month follow-up period 
 
3.4 
 Rationale and risks/benefits 
Primary research question: 
1) Is there a reduction in central macular thickness (CMT) in patients with 
Retinitis Pigmentosa associated with cystoid macula oedema after the use of 
Eylea? 
 
 
Treatment currently available and their limitations: 
• Includes: laser therapy, topical trusopt, oral acetazolamide, peri-ocular and 
intravitreal steroids, and intravitreal anti-VEGF agents. The current mainstay 
of treatment are topical and oral carbonic anhydrase inhibitors 
• The vast majority of the published literature is retrospective and thereby 
inherently limited and often involves small numbers of participants and short 
duration of follow-up 
• In a retrospective review of patients seen at Moorfields Eye Hospital in the 
Retinal Genetics Clinics (Professors Moore and Webster, and Mr Michaelides) 
with RP on treatment for CMO (n=93), ascertained over a 12 month period 
(June 2012 to June 2013), – approximately 50% were deemed non-
responders (defined as less than 20% reduction in CMT on OCT between 
visits) to topical or systemic carbonic anhydrase inhibitors 


 
 
 
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• There is some evidence in the literature that anti-VEGF therapy may be 
effective – Artunay et al (2009) observed significant response to a single 
injection of Lucentis in 15 eyes of 15 patients with RP and CMO over a 6 
month follow-up period 
• A case report by Moustafa G.A and Moschos M (2015) observed 
improvement in BCVA and reduction of macula oedema following treatment 
with a single injection of Eylea in a patient with RP associated CMO 
• Professor Michel Michaelides has observed similar responses in two patients 
treated with Eylea who had failed all other treatments 
 
 
Risk/benefit analysis of Eylea 
 
Risks 
Intravitreal injection-related reactions  
Intravitreal injections, including those with Eylea, have been associated with 
endophthalmitis (1 in 2000), intraocular inflammation, rhegmatogenous retinal 
detachment, retinal tear and iatrogenic traumatic cataract. Aseptic injection 
techniques must always be used when administering Eylea. Patients should be 
instructed to report any symptoms suggestive of endophthalmitis or any of the above 
mentioned events without delay. 
 
Increases in intraocular pressure have been seen within 60 minutes of intravitreal 
injection, including those with Eylea. Special precaution is needed in patients with 
poorly controlled glaucoma (Eylea must not be injected if the intraocular pressure is 
≥ 30 mmHg). In all cases, both the intraocular pressure and the perfusion of the optic 
nerve head must be monitored and managed appropriately if it is thought to be 
compromised in any way. 
 
Immunogenicity 


 
 
 
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Being a therapeutic protein, there is a potential for immunogenicity with Eylea. 
Patients should be instructed to report any signs or symptoms of intraocular 
inflammation, e.g. pain, photophobia, or redness, which may be a clinical sign 
attributable to hypersensitivity. 
 
Systemic effects 
Systemic adverse events including non-ocular haemorrhages and arterial 
thromboembolic events have been reported following intravitreal injection of VEGF 
inhibitors and there is a theoretical risk that these may relate to VEGF inhibition. 
There are limited data on safety in the treatment of patients with CRVO, BRVO or 
DMO with a history of stroke or transient ischaemic attacks or myocardial infarction 
within the last 6 months. Caution should be exercised when treating such patients  
 
Other 
As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO and DMO 
the following also applies: 
 
• The safety and efficacy of Eylea therapy administered to both eyes concurrently 
has not been systematically studied. If bilateral treatment is performed at the same 
time this could lead to an increased systemic exposure, which could increase the risk 
of systemic adverse events. 
 
• There is no data available on the concomitant use of Eylea with other anti-VEGF 
medicinal products (systemic or ocular). 
 
• Risk factors associated with the development of a retinal pigment epithelial tear 
after anti-VEGF therapy for wet AMD, include a large and/or high pigment epithelial 
retinal detachment. When initiating Eylea therapy, caution should be used in patients 
with these risk factors for retinal pigment epithelial tears. 
 
• Treatment should be withheld in patients with rhegmatogenous retinal detachment 
or stage 3 or 4 macular holes. 


 
 
 
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• In the event of a retinal break the dose should be withheld and treatment should  
not be resumed until the break is adequately repaired. 
 
• The dose should be withheld and treatment should not be resumed earlier than the 
next scheduled treatment in the event of:  
             • a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared  
with the last assessment of visual acuity;  
 
             • a sub-retinal haemorrhage involving the centre of the fovea, or, if the size  
of the haemorrhage is ≥50%, of the total lesion area.  
 
• The dose should be withheld within the previous or next 28 days in the event of a 
performed or planned intraocular surgery. 
 
• Eylea should not be used in pregnancy unless the potential benefit outweighs the 
potential risk to the foetus. 
 
• Women of childbearing potential have to use effective contraception during 
treatment and for at least 3 months after the last intravitreal injection of aflibercept. 
 
Populations with limited data 
 
Eylea has not been studied in patients with active systemic infections or in patients 
with concurrent eye conditions such as retinal detachment or macular hole. There is 
also no experience of treatment with Eylea in diabetic patients with uncontrolled 
hypertension. This lack of information should be considered by the physician when 
treating such patients. 
 
 
Interaction with other medicinal products and other forms of interaction 


 
 
 
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No interaction studies have been performed. Adjunctive use of verteporfin 
photodynamic therapy (PDT) and Eylea has not been studied, therefore, a safety 
profile is not established. 
 
 
Fertility, pregnancy and lactation 
 
Women of childbearing potential  
Women of childbearing potential have to use effective contraception during treatment 
and for at least 3 months after the last intravitreal injection of aflibercept. 
 
Pregnancy  
There are no data on the use of aflibercept in pregnant women. Studies in animals 
have shown embryo-foetal toxicity. Although the systemic exposure after ocular 
administration is very low, Eylea should not be used during pregnancy unless the 
potential benefit outweighs the potential risk to the foetus. 
 
Breastfeeding  
It is unknown whether aflibercept is excreted in human milk. A risk to the breast-fed 
child cannot be excluded. Eylea is therefore not recommended during breastfeeding. 
A decision must be made whether to discontinue breastfeeding or to abstain from 
Eylea therapy taking into account the benefit of breastfeeding for the child and the 
benefit of therapy for the woman. 
 
Fertility 
Results from animal studies with high systemic exposure indicate that aflibercept can 
impair male and female fertility. Such effects are not expected after ocular 
administration with very low systemic exposure. 
 
4.7 Effects on ability to drive and use machines 
 


 
 
 
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Injection with Eylea has a minor influence on the ability to drive and use machines 
due to possible temporary visual disturbances associated either with the injection or 
the eye examination. Patients should not drive or use machines until their visual 
function has recovered sufficiently. 
 
 
4.8 Undesirable effects 
 
 
Summary of the safety profile 
 
The following information has been taken from the electronic Medicines 
Compendium (eMC): https://www.medicines.org.uk/emc/medicine/27224.  
A total of 2,957 patients constituted the safety population in the seven phase III 
studies. Among those, 2,356 patients were treated with the recommended dose of 2 
mg. 
 
Serious adverse reactions related to the injection procedure have occurred in less 
than 1 in 2,200 intravitreal injections with Eylea and included blindness, 
endophthalmitis, retinal detachment, cataract traumatic, vitreous haemorrhage, 
cataract, vitreous detachment, and intraocular pressure increased (see section 4.4). 
The most frequently observed adverse reactions (in at least 5% of patients treated 
with Eylea) were conjunctival haemorrhage (24.9%), visual acuity reduced (10.7%), 
eye pain (9.9%), intraocular pressure increased (7.1%), vitreous detachment (6.8%), 
vitreous floaters (6.6%) and cataract (6.6%).  
 
Tabulated list of adverse reactions 
 
The safety data described below include all adverse reactions from the seven phase 
III studies in the indications wet AMD, CRVO, BRVO and DMO with a reasonable 
possibility of causality to the injection procedure or medicinal product. 
 


 
 
 
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The adverse reactions are listed by system organ class and frequency using the 
following convention:  Very common (≥1/10), common (≥1/100 to <1/10), uncommon 
(≥1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000). Within each frequency grouping, 
adverse drug reactions are presented in order of decreasing seriousness. 
 
 
Table 1: All treatment-emergent adverse drug reactions reported in patients in phase 
III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, 
BRVO and DME). (Bayer plc., 2015) 
System Organ 
Class 
Very 
common 
Common 
Uncommon 
Rare 
Immune system 
disorders 
  
  
Hypersensitivity***  
  
Eye disorders 
Visual acuity 
reduced,  
Conjunctival 
haemorrhage, 
Retinal pigment epithelial tear*, 
Detachment of the retinal 
pigment epithelium,  
Retinal degeneration,  
Vitreous haemorrhage,  
Cataract,  
Cataract nuclear,  
Cataract subcapsular,  
Cataract cortical,  
Corneal erosion,  
Corneal abrasion,  
Intraocular pressure increased, 
Vision blurred,  
Vitreous floaters,  
Corneal oedema,  
Vitreous detachment,  
Injection site pain,  
Eye pain,  
Foreign body sensation in 
eyes,  
Lacrimation increased,  
Eyelid oedema,  
Injection site haemorrhage,  
Punctate keratitis,  
Conjunctival hyperaemia,  
Ocular hyperaemia  
Blindness,  
Endophthalmitis**,  
Retinal detachment,  
Retinal tear,  
Iritis,  
Uveitis,  
Iridocyclitis,  
Lenticular opacities,  
Corneal epithelium 
defect,  
Injection site irritation,  
Abnormal sensation in 
eye,  
Eyelid irritation,  
Anterior chamber flare  
Cataract 
traumatic,  
Vitritis  
Hypopyon  
 
* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only. 
** Culture positive and culture negative endophthalmitis 
*** including allergic reactions 
 
 
 
 


 
 
 
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Description of selected adverse reactions 
 
In the wet AMD phase III studies, there was an increased incidence of conjunctival 
haemorrhage in patients receiving anti-thrombotic agents. This increased incidence 
was comparable between patients treated with ranibizumab and Eylea.  
 
Arterial thromboembolic events (ATEs) are adverse events potentially related to 
systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic 
events following intravitreal use of VEGF inhibitors. 
 
ATEs, as defined by Antiplatelet Trialists' Collaboration (APTC) criteria, include 
nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of 
unknown cause).  
 
The incidence of ATEs in the phase III wet AMD studies during the 96 weeks study 
duration was 3.3% (60 out of 1,824) in the combined group of patients treated with 
Eylea compared to 3.2% (19 out of 595) in patients treated with ranibizumab (see 
section 5.1). The corresponding numbers in the DME studies during the first 52 
weeks were 3.3% (19 out of 578) (Eylea) and 2.8% (8 out of 287) (control group) 
(see section 5.1). 
 
The incidence of ATEs in the phase III CRVO studies during the 76/100 weeks study 
duration was 0.6% (2 out of 317) in patients treated with at least one dose of Eylea 
compared to 1.4% (2 out of 142) in the group of patients receiving only sham 
treatment (see section 5.1) whilst for the Phase III BRVO study during the 52 weeks 
study duration it was 0% (0 out of 91) in patients treated with Eylea compared with 
2.2% (2 out of 92) in the control group (see section 5.1). One of these patients in the 
control group had received Eylea rescue treatment. 
 
As with all therapeutic proteins, there is a potential for immunogenicity with Eylea. 
 
 


 
 
 
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Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is 
important. It allows continued monitoring of the benefit/risk balance of the medicinal 
product. Healthcare professionals are asked to report any suspected adverse 
reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.  
 
 
Overdose 
 
In clinical trials doses of up to 4 mg in monthly intervals have been used and isolated 
cases of overdoses with 8 mg occurred.  
 
Overdosing with increased injection volume may increase intraocular pressure. 
Therefore, in case of overdose, intraocular pressure should be monitored and if 
deemed necessary by the treating physician, adequate treatment should be initiated. 
 
 
 
Benefits 
 
Eylea has been shown to improve visual acuity and reduce central macular thickness 
in wet AMD, as well as oedema secondary to CRVO, BRVO and DMO. Please see 
below for the literature surrounding this. It is hoped that Eylea will achieve similar 
effects for patients who have oedema associated with RP. 
 
Pharmacodynamic effects 
 
Wet AMD 
 


 
 
 
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Wet AMD is characterised by pathological choroidal neovascularisation (CNV). 
Leakage of blood and fluid from CNV may cause retinal thickening or oedema and/or 
sub-/intra-retinal haemorrhage, resulting in loss of visual acuity. In patients treated 
with Eylea (one injection per month for three consecutive months, followed by one 
injection every 2 months), retinal thickness decreased soon after treatment initiation, 
and the mean CNV lesion size was reduced, consistent with the results seen with 
ranibizumab 0.5 mg every month. 
 
In the VIEW1 study there were mean decreases in retinal thickness on optical 
coherence tomography (OCT) (-130 and -129 microns at week 52 for the Eylea 2 mg 
every two months and ranibizumab 0.5 mg every month study groups, respectively). 
Also at the 52 week time point, in the VIEW2 study there were mean decreases in 
retinal thickness on OCT (-149 and -139 microns for the Eylea 2 mg every two 
months and ranibizumab 0.5 mg every month study groups, respectively). 
The reduction of CNV size and reduction in retinal thickness were generally 
maintained in the second year of the studies. 
 
Macular Oedema secondary to CRVO and BRVO 
 
In CRVO and BRVO retinal ischaemia occurs and signals the release of VEGF which 
in turn destabilises the tight junctions and promotes endothelial cell proliferation. Up-
regulation of VEGF is associated with the breakdown of the blood retina barrier and 
this increased vascular permeability results in retinal oedema, stimulation of 
endothelial cell growth and neovascularisation. 
 
In patients treated with Eylea (one injection every month for six months) there was 
consistent, rapid and robust response in morphology (central retinal thickness [CRT] 
as assessed by OCT). Improvements in mean CRT were maintained through week 
24. 
 
Retinal thickness on OCT at week 24 compared to baseline was a secondary 
efficacy variable in the COPERNICUS and GALILEO studies (CRVO) and the 


 
 
 
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VIBRANT study (BRVO). In all three studies, the mean change in CRT from baseline 
to week 24 was statistically significant, favouring Eylea. 
 
In the COPERNICUS and GALILEO studies the mean decrease from baseline in 
retinal thickness on OCT at week 24 was significantly greater in patients treated with 
Eylea 2 mg every month than in the control group (-457 microns vs. -145 microns in 
COPERNICUS, and -449 microns vs. -169 microns in GALILEO). The decrease from 
baseline in retinal thickness was maintained to the end of study, week 100 in 
COPERNICUS, and to week 76 in GALILEO.  
 
In the VIBRANT study the mean decrease from baseline in retinal thickness on OCT 
at week 24 was significantly greater in patients treated with Eylea 2 mg every month 
than in the control group (-280 microns vs. -128 microns). This decrease from 
baseline was maintained to week 52. 
 
Diabetic macular oedema 
 
Diabetic macular oedema is characterised by increased vasopermeability and 
damage to the retinal capillaries which may result in loss of visual acuity.  
 
In patients treated with Eylea, rapid and robust response in morphology (central 
retinal thickness [CRT]) as assessed by OCT was seen soon after treatment 
initiation. The mean change in CRT from baseline to week 52 was statistically 
significant favoring Eylea. 
 
In the VIVID-DME study there were mean decreases in retinal thickness on optical 
coherence tomography (OCT) (-192.4 and -66.2 microns at week 52 for the Eylea 
2Q8 and laser group, respectively). Also at the 52 week time point, in the VISTA-
DME study there were mean decreases in retinal thickness on OCT (-183.1 and -
73.3 microns for the Eylea 2Q8 and laser group, respectively). 
 
Clinical efficacy and safety 


 
 
 
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Wet AMD 
 
The safety and efficacy of Eylea were assessed in two randomised, multi-centre, 
double-masked, active-controlled studies in patients with wet AMD. A total of 2,412 
patients were treated and evaluable for efficacy (1,817 with Eylea) in the two studies 
(VIEW1 and VIEW2). In each study, patients were randomly assigned in a 1:1:1:1 
ratio to 1 of 4 dosing regimens:  
 
1) Eylea administered at 2 mg every 8 weeks following 3 initial monthly doses (Eylea 
2Q8);  
2) Eylea administered at 2 mg every 4 weeks (Eylea 2Q4); 
3) Eylea administered at 0.5 mg every 4 weeks (Eylea 0.5Q4); and  
4) ranibizumab administered at 0.5 mg every 4 weeks (ranibizumab 0.5Q4).  
 
Patient ages ranged from 49 to 99 years with a mean of 76 years. 
In the second year of the studies, patients continued to receive the dosage strength 
to which they were initially randomised but on a modified dosing schedule guided by 
assessment of visual and anatomic outcomes with a protocol-defined maximum 
dosing interval of 12 weeks. 
 
In both studies, the primary efficacy endpoint was the proportion of patients in the 
Per Protocol Set who maintained vision, defined as losing fewer than 15 letters of 
visual acuity at week 52 compared to baseline.  
 
In the VIEW1 study, at week 52, 95.1% of patients in the Eylea 2Q8 treatment group 
maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. 
Eylea treatment was shown to be non-inferior and clinically equivalent to the 
ranibizumab 0.5Q4 group. 
 
In the VIEW2 study, at week 52, 95.6% of patients in the Eylea 2Q8 treatment group 
maintained vision compared to 94.4% patients in the ranibizumab 0.5Q4 group. 


 
 
 
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Eylea treatment was shown to be non-inferior and clinically equivalent to the 
ranibizumab 0.5Q4 group. 
 
Detailed results from the combined analysis of both studies are shown in the Table 2 
and Figure 1 below. 
 
 
Table 2: Efficacy outcomes at week 52 (primary analysis) and week 96; combined 
data from the VIEW1 and VIEW2 studiesB) (Bayer plc., 2015) 
Efficacy Outcome 
Eylea 2Q8 E) 
(Eylea 2 mg every 8 weeks 
following 3 initial monthly doses)  
(N = 607) 
Ranibizumab 0.5Q4  
(ranibizumab 0.5 mg every 4 weeks)  
(N = 595) 
  
Week 52  
Week 96 G) 
Week 52  
Week 96 G) 
Mean number of 
injections from baseline 
7.6  
11.2  
12.3  
16.5  
Mean number of 
injections during 
second year (Week 52 
to 96)  
  
4.2  
  
4.7  
Proportion of patients 
with maintained visual 
acuity  
(< 15 letters of BCVAA) 
loss) (Per Protocol Set)  
95.33%B) 
92.42%  
94.42% B) 
91.60%  
DifferenceC) 
(95% CI)D) 
0.9% 
(-1.7, 3.5)F) 
0.8% 
(-2.3, 3.8)F) 
  
  
Mean change in BCVA 
as measured by 
ETDRSA) letter score 
from baseline  
8.40  
7.62  
8.74  
7.89  
Difference in LS A) 
mean change (ETDRS 
letters)C) 
(95% CI)D) 
-0.32 
(-1.87, 1.23)  
-0.25 
(-1.98, 1.49)  
  
  
Proportion of patients 
who gained at least 15 
letters of vision from 
baseline  
30.97%  
33.44%  
32.44%  
31.60%  
DifferenceC) 
(95% CI)D) 
-1.5% 
(-6.8, 3.8)  
1.8% 
(-3.5, 7.1)  
  
  
 
A) BCVA: Best Corrected Visual Acuity 
ETDRS: Early Treatment Diabetic Retinopathy Study 
LS: Least square means derived from ANCOVA 


 
 
 
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B) Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) for all analyses except 
proportion of patients with maintained visual acuity at week 52 which is Per Protocol Set (PPS) 
C) The difference is the value of the Eylea group minus the value of the ranibizumab group. A positive 
value favours Eylea. 
D) Confidence interval (CI) calculated by normal approximation 
E) After treatment initiation with three monthly doses 
F) A confidence interval lying entirely above -10% indicates a non-inferiority of Eylea to ranibizumab 
G) Beginning at week 52, all groups were treated using a modified quarterly treatment paradigm where 
patients could be dosed as frequently as every 4 weeks but not less frequently than every 12 weeks 
based upon pre-specified retreatment criteria 
Figure 1. Mean Change in Visual Acuity from Baseline to Week 96 for the Combined Data from the 
View1 and View2 Studies 
 
 
 
*) From Baseline to Week 52, Eylea was dosed every 8 weeks following 3 initial monthly doses. From  
 
 
Baseline to Week 52, ranibizumab 0.5 mg was dosed every 4 weeks. Beginning at 
Week 52, all groups were treated using a modified quarterly treatment paradigm 
where patients could be dosed as frequently as every 4 weeks but not less 
frequently than every 12 weeks based upon pre-specified retreatment criteria. 
 
The proportion of patients at week 96 gaining at least 15 letters from baseline was 
33.44% in the Eylea 2Q8 group, and 31.60% in the ranibizumab 0.5Q4 group.  
 
In combined data analysis of the VIEW1 and VIEW2 studies Eylea demonstrated 
clinically meaningful changes from baseline in pre-specified secondary efficacy 
endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The 
magnitude of these changes was similar to that seen in published studies, which 
corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA). 


 
 
 
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No clinically meaningful differences were found between Eylea and the reference 
product ranibizumab in changes of NEI VFQ-25 total score and subscales (near 
activities, distance activities, and vision-specific dependency) at week 52 from 
baseline. 
 
Decreases in mean CNV area were evident in all dose groups in both studies. 
 
Efficacy results in all evaluable subgroups (e.g. age, gender, race, baseline visual 
acuity, lesion type, lesion size) in each study and in the combined analysis were 
consistent with the results in the overall populations. 
 
In the second year of the studies, efficacy was generally maintained through the last 
assessment at week 96.  
 
In the second year of the studies, 2-4% of patients required all injections on a 
monthly basis, and a third of patients required at least one injection with a treatment 
interval of only one month. 
 
Elderly Population 
In the clinical studies, approximately 89% (1,616/1,817) of the patients randomised 
to treatment with Eylea were 65 years of age or older and approximately 63% 
(1,139/1,817) were 75 years of age or older. 
 
 
Macular Oedema secondary to CRVO 
 
The safety and efficacy of Eylea were assessed in two randomised, multi-centre, 
double-masked, sham-controlled studies in patients with macular oedema secondary 
to CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with 
Eylea) in the two studies COPERNICUS and GALILEO. In both studies, patients 
were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 


 
 
 
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weeks (2Q4) or the control group receiving sham injections every 4 weeks for a total 
of 6 injections. 
 
After 6 monthly injections, patients received treatment only if they met pre-specified 
retreatment criteria, except for patients in the control group in the GALILEO study 
who continued to receive sham (control to control) until week 52. Starting from this 
timepoint all patients were offered treatment if they met pre-specified criteria. 
 
Patient ages ranged from 22 to 89 years with a mean of 64 years. 
 
In both studies, the primary efficacy endpoint was the proportion of patients who 
gained at least 15 letters in BCVA at week 24 compared to baseline. 
 
Change in visual acuity at week 24 compared to baseline was a secondary efficacy 
variable in both COPERNICUS and GALILEO studies. 
 
The difference between treatment groups was statistically significant in favour of 
Eylea in both studies. In both pivotal studies the maximal improvement in visual 
acuity has been achieved at month 3 with subsequent stabilisation of the effect on 
visual acuity and central retinal thickness until month 6. The statistically significant 
difference was maintained through week 52. 
 
Detailed results from the analysis of both studies are shown in the Table 3 and 
Figure 2 below. 
 
Table 3: Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set 
with LOCFC)) in COPERNICUS and GALILEO studies (Bayer plc., 2015) 
Efficacy 
Outcomes 
COPERNICUS 
GALILEO 
24 Weeks 
52 Weeks 
100 Weeks 
24 Weeks 
52 Weeks 
76 Weeks 
Eylea 
2 mg 
Q4 
(N = 
114)  
Cont
rol 
(N= 
73)  
Eylea 
2 mg  
(N = 
114) 
Contr
olE) 
(N 
=73) 
Eylea 
F) 
2 mg  
(N= 
114) 
Contr
ol E,F) 
(N=73) 
Eylea 
2 mg 
Q4 
(N = 
103) 
Contr
ol 
(N = 
68) 
Eylea 
2 mg 
(N = 
103) 
Contr
ol  
(N = 
68) 
Eylea 
G) 
2 mg 
(N = 
103) 
Cont
rol G) 
(N = 
68) 


 
 
 
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Proportion 
of patients 
who 
gained at 
least 15 
letters in 
BCVAC) 
from 
baseline  
56%  
12%  55%  
30%  
49.1%  23.3%  60%  
22%  
60%  
32%  
57.3%  29.4
%  
Weighted 
differenceA,
B,E) 
(95% CI)  
44.8% 
(33.0, 
56.6)  
  
25.9% 
(11.8, 
40.1)  
  
26.7% 
(13.1, 
40.3)  
  
38.3% 
(24.4, 
52.1)  
  
27.9% 
(13.0, 
42.7)  
  
28.0% 
(13.3, 
42.6)  
  
p-value  
p < 
0.0001  
  
p = 
0.0006  
  
p=0.00
03  
  
p < 
0.0001  
  
p = 
0.0004  
  
p=0.00
04  
  
Mean 
change in 
BCVA as 
measured 
by 
ETDRSC) 
letter score 
from 
baseline 
(SD)  
17.3 
(12.8)  
-4.0 
(18.0
)  
16.2 
(17.4)  
3.8 
(17.1)  
13.0 
(17.7)  
1.5 
(17.7)  
18.0 
(12.2)  
3.3 
(14.1)  
16.9 
(14.8)  
3.8 
(18.1)  
13.7 
(17.8)  
6.2 
(17.7
)  
Difference 
in LS 
meanA,C,D,E
) 
(95% CI)  
21.7 
(17.4, 
26.0)  
  
12.7 
(7.7, 
17.7)  
  
11.8 
(6.7, 
17.0)  
  
14.7 
(10.8, 
18.7)  
  
13.2 
(8.2, 
18.2)  
  
7.6 
(2.1, 
13.1)  
  
p-value  
p < 
0.0001  
  
p < 
0.0001  
  
p < 
0.0001 
  
p < 
0.0001  
  
p < 
0.0001  
  
p=0.00
70  
  
 
 
A) Difference is Eylea 2 mg Q4 weeks minus control 
B) Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test 
adjusted for region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for 
GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200) 
C) BCVA: Best Corrected Visual Acuity 
ETDRS: Early Treatment Diabetic Retinopathy Study 
LOCF: Last Observation Carried Forward 
SD: Standard deviation 
LS: Least square means derived from ANCOVA 
D) LS mean difference and confidence interval based on an ANCOVA model with factors treatment 
group, region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for 
GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200) 
E) In COPERNICUS study, control group patients could receive Eylea on an as-needed basis as 
frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks. 
F) In COPERNICUS study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-
needed basis as frequently as every 4 weeks starting from Week 52 to Week 96; patients had 
mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.  
G) In GALILEO study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-
needed basis every 8 weeks starting from Week 52 to Week 68; patients had mandatory visits every 8 
weeks. 
 


 
 
 
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Figure 2: Mean change from baseline to week 76/100 in visual acuity by treatment group for the 
COPERNICUS and GALILEO studies (Full Analysis Set) 
 
 
 
The proportion of perfused patients in the Eylea group was high in the GALILEO 
study at baseline 86.4%; (n = 89). Perfusion at week 24 primary endpoint was 91.8% 
(n = 89). The patients were largely able to maintain their perfusion status until week 
76 84.3%; (n = 75). The number of perfused patients that started on sham was 


 
 
 
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79.4% (n = 54) at baseline. Perfusion at week 24 primary endpoint was 85.5% (n = 
47). Patients in the sham group were switched to Eylea according to pre-specified 
criteria at week 52, 83.7% (n = 41) were perfused at this time. The patients were 
able to maintain their perfusion status until week 76, 84.0% (n = 42).  
 
The proportion of perfused patients in the Eylea group in the COPERNICUS study at 
baseline was 67.5% (n = 77). Perfusion at week 24 primary endpoint was 87.4%; (n 
= 90). After week 24, patients in the Eylea group were treated according to pre-
specified criteria. At week 100 76.8 % (n = 76) of patients were perfused. The 
percentage of perfused patients that started on sham was 68.5% (n = 50) at 
baseline. Perfusion at week 24 primary endpoint was 58.6% (n = 34). Patients in the 
sham arm were eligible to receive Eylea from week 24. The proportion of perfused 
patients increased to 83.9% (n = 47) at week 52 and was largely maintained until 
week 100 78%; (n = 39). The beneficial effect of Eylea treatment on visual function 
was similar in the baseline subgroups of perfused and non-perfused patients. 
 
In combined data analysis of the GALILEO and COPERNICUS studies, Eylea 
demonstrated clinically meaningful changes from baseline in pre-specified secondary 
efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). 
The magnitude of these changes was similar to that seen in published studies, which 
corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA). 
 
Treatment effects in all evaluable subgroups (e.g. age, gender, race, baseline visual 
acuity, retinal perfusion status, CRVO duration) in each study were in general 
consistent with the results in the overall populations. 
 
Elderly population 
 
In the CRVO studies, approximately 52% (112/217) of the patients randomised to 
treatment with Eylea were 65 years of age or older, and approximately 18% (38/217) 
were 75 years of age or older. 
 


 
 
 
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Macular Oedema secondary to BRVO 
 
The safety and efficacy of Eylea were assessed in a randomised, multi-centre, 
double-masked, active-controlled study in patients with macular oedema secondary 
to BRVO which included Hemi-Retinal Vein Occlusion. A total of 181 patients were 
treated and evaluable for efficacy (91 with Eylea) in the VIBRANT study. In the 
study, patients were randomly assigned in a 1:1 ratio to either 2 mg Eylea 
administered every 8 weeks following 6 initial monthly injections or laser 
photocoagulation administered at baseline (laser control group). Patients in the laser 
control group could receive additional laser photocoagulation (called 'rescue laser 
treatment') beginning at week 12, if needed. The minimum interval between laser 
photocoagulation treatments was 12 weeks. Beginning at week 24, patients in the 
laser treatment group could receive rescue treatment with Eylea 2mg, if needed, 
administered every 4 weeks for 3 months followed by intravitreal injections every 8 
weeks, based on pre-specified criteria. 
 
Patient ages ranged from 42 to 94 years with a mean of 65 years.  
 
In the VIBRANT study, the primary efficacy endpoint was the proportion of patients 
who gained at least 15 letters in BCVA at week 24 compared to baseline. At week 
24, the Eylea group was superior to laser control for the primary endpoint.  
 
Change in visual acuity at week 24 compared to baseline was a secondary efficacy 
variable in the VIBRANT study. The difference between treatment groups was 
statistically significant in favour of Eylea. The course of visual improvement was 
rapid and maximal improvement was achieved at month 3 with subsequent 
stabilisation of the effect on visual acuity and central retinal thickness until month 6 
and subsequent maintenance of the effect until month 12. 
 


 
 
 
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In the laser group 67 patients received rescue treatment with Eylea beginning at 
week 24 (Active Control/ Eylea 2mg group). In this treatment group visual acuity 
improved by about 5 letters from week 24 to 52. 
Detailed results from the analysis of the VIBRANT study are shown in the Table 4 
and Figure 3 below. 
 
Table 4: Efficacy outcomes at week 24 and week 52 (Full Analysis Set with LOCF) 
in VIBRANT study (Bayer plc., 2015) 
Efficacy Outcomes VIBRANT 
24 weeks 
52 weeks 
  
Eylea 2mg Q4 
(N = 91) 
Active Control 
(laser) 
(N = 90) 
Eylea 2mg Q8 
(N = 91)D) 
Active Control 
(laser)/Eylea 2mgE) 
(N = 90) 
Proportion of patients 
who gained at least 
15 letters in BCVA 
from Baseline (%)  
52.7%  
26.7%  
57.1%  
41.1%  
Weighted Difference 
A,B (%)  
(95% CI)  
p-value  
26.6%  
(13.0, 40.1)  
p=0.0003  
  
16.2%  
(2.0, 30.5)  
p=0.0296  
  
Mean change in 
BCVA as measured 
by ETDRS letter 
score from Baseline 
(SD)  
17.0  
(11.9)  
6.9  
(12.9)  
17.1  
(13.1)  
12.2 (11.9)  
Difference in LS 
mean A,C 
(95% CI)  
p-value  
10.5  
(7.1, 14.0)  
p<0.0001  
  
5.2  
(1.7, 8.7)  
p=0.0035F) 
  
 
 
A) Difference is Eylea 2 mg Q4 weeks minus Laser Control 
B) Difference and 95% CI are calculated using Mantel-Haenszel weighting scheme adjusted for region 
(North America vs. Japan) and baseline BCVA category (> 20/200 and ≤ 20/200) 
C) LS mean difference and 95% CI based on an ANCOVA model with treatment group, baseline BCVA 
category (> 20/200 and ≤ 20/200) and region (North America vs. Japan) as fixed effects, and baseline 
BCVA as covariate 
D) From Week 24 on the treatment interval in the Eylea treatment group was extended for all subjects 
from 4 weeks to 8 weeks through week 48. 
E) Beginning at Week 24 subjects in the Laser Group could receive rescue treatment with Eylea, if they 
met at least one pre-specified eligibility criterion. At total of 67 subjects in this group received Eylea 
rescue treatment. The fixed regimen for Eylea rescue was three times Eylea 2mg every 4 weeks 
followed by injections every 8 weeks. 
F) Nominal p-value 
Figure 3: Mean Change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in 
VIBRANT Study 


 
 
 
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At baseline, the proportion of perfused patients in the Eylea and laser groups was 
60% and 68%, respectively. At week 24 these proportions were 80% and 67%, 
respectively. In the Eylea group the proportion of perfused patients was maintained 
through week 52. In the laser group, where patients were eligible for rescue 
treatment with Eylea from week 24, the proportion of perfused patients increased to 
78% by week 52. 
 
Elderly population 
 
In the BRVO study, approximately 58% (53/91) of the patients randomised to 
treatment with Eylea were 65 years of age or older, and approximately 23% (21/91) 
were 75 years of age or older. 
 
Diabetic Macular Oedema 
 
The safety and efficacy of Eylea were assessed in two randomised, multi-center, 
double-masked, active-controlled studies in patients with DME. A total of 862 
randomised and treated patients were evaluable for efficacy. Of those, 576 were 


 
 
 
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randomised to the Eylea groups in two studies (VIVIDDME and VISTADME). In each 
study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:  
 
1) Eylea administered 2 mg every 8 weeks following 5 initial monthly injections 
(Eylea 2Q8);  
2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); and  
3) macular laser photocoagulation (active control).  
 
Beginning at week 24, patients meeting a pre-specified threshold of vision loss were 
eligible to receive additional treatment: patients in the Eylea groups could receive 
laser and patients in the laser group could receive Eylea. Patient ages ranged from 
23 to 87 years with a mean of 63 years. The majority of patients in both studies had 
Type II diabetes.  
 
In both studies, the primary efficacy endpoint was the mean change from baseline in 
BCVA at Week 52 as measured by ETDRS letter score. Both Eylea 2Q8 and Eylea 
2Q4 groups were shown to have efficacy that was statistically significantly superior 
to the laser control group. Detailed results from the analysis of the VIVIDDME and 
VISTADME studies are shown in Table 5 and Figure 4 below. 
 
Table 5: Efficacy Outcomes at Week 52 (Full Analysis Set with LOCF) in VIVIDDME 
and VISTADME Studies (Bayer plc., 2015) 
Efficacy Outcomes VIVIDDME 
VISTADME 
52 Weeks 
52 Weeks 
Eylea 
2 mg Q8 A 
(N = 135) 
Eylea 
2 mg Q4 
(N = 136) 
Active 
Control 
(laser) 
(N = 132) 
Eylea 
2 mg Q8 A 
(N = 151) 
Eylea 
2 mg Q4 
(N = 154) 
Active 
Control 
(laser) 
(N = 154) 
Mean change in 
BCVA as measured 
by ETDRS E letter 
score from Baseline  
10.7  
10.5  
1.2  
10.7  
12.5  
0.2  
Difference in LS 
mean B,C,E 
(97.5% CI)  
9.1 
(6.3, 11.8)  
9.3 
(6.5, 12.0)  
  
10.45  
(7.7, 13.2)  
12.19  
(9.4, 15.0)  
  
Proportion of patients 
who gained at least 
33%  
32%  
9%  
31%  
42%  
8%  


 
 
 
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15 letters in BCVA E 
from Baseline  
Adjusted Difference 
D,C,E 
(97.5% CI)  
24% 
(13.5, 34.9)  
23% 
(12.6, 33.9)  
  
23% 
(13.5, 33.1)  
34% 
(24.1, 44.4)  
  
 
 
A After treatment initiation with 5 monthly injections  
B LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and 
a factor for treatment group. Additionally, region (Europe/Australia vs. Japan) had been included as 
factor for VIVIDDME, and history of MI and/or CVA as a factor for VISTADME). 
C Difference is Eylea group minus active control (laser) group 
D Difference with confidence interval (CI) and statistical test is calculated using Mantel-Haenszel 
weighting scheme adjusted by region (Europe/Australia vs. Japan) for VIVIDDME and medical history of 
MI or CVA for VISTADME 
E BCVA: Best Corrected Visual Acuity 
ETDRS: Early Treatment Diabetic Retinopathy Study 
LOCF: Last Observation Carried Forward 
LS: Least square means derived from ANCOVA 
CI: Confidence interval 
 
Figure 3: Mean change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52 in 
VIVIDDME and VISTADME Studies (Bayer plc., 2015) 


 
 
 
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The VISTADME second year outcomes are in line with the results from the primary 
and secondary endpoints obtained at week 52. 
Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, 
baseline visual acuity, prior anti-VEGF therapy) in each study and in the combined 
analysis were generally consistent with the results in the overall populations.  
 
In the VIVIDDME and VISTADME studies, 36 (9%) and 197 (43%) patients received 
prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. 
Treatment effects in the subgroup of patients who had previously been treated with a 
VEGF inhibitor prior to study participation were similar to those seen in patients who 
were VEGF inhibitor naïve prior to study participation. 


 
 
 
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Patients with bilateral disease were eligible to receive anti-VEGF treatment in their 
fellow eye if determined to be necessary by the physician. In the VISTADME study, 
198 (65%) of Eylea patients received bilateral Eylea injections; in the VIVIDDME 
study, 70 (26%) of Eylea patients received a different anti-VEGF treatment in their 
fellow eye. 
 
Elderly population 
In the DME phase III studies, approximately 47% (268/576) of the patients 
randomised to treatment with Eylea were 65 years of age or older, and 
approximately 9% (52/576) were 75 years of age or older. Efficacy and safety 
outcomes were consistent with the outcomes of the overall population. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of 
studies with Eylea in all subsets of the paediatric population in wet AMD, CRVO, 
BRVO and DME (see section 4.2 for information on paediatric use). 
 
3.5     Assessment and management of risk 
 
Risk management: 
 
Risk*                                                 How the risk will be minimised 
Sub-conjunctival haemorrhage  
Avoid injecting around vascular area 
Endophthalmitis  
Perform intravitreal injection (IVT) under aseptic 
conditions. Provide patients with post-IVT anti-biotic drops 
Intraocular inflammation 
Exclude patients with active severe intraocular 
inflammation 
Rhegmatogenous retinal detachment, 
retinal tear and iatrogenic traumatic 
cataract 
Perform IVT at 3.5mm from the limbus in pseudo-phakic 
patients and 4.0mm from the limbus in phakic patients  
Non-ocular haemorrhages and arterial 
thromboembolic events 
Exclude patients who have suffered a thromboembolic 
event (MI/CVA/Unstable Angina) within 3 months  
Raised intra-ocular pressure 
Exclude patients with uncontrolled IOP >24mmHg for 


 
 
 
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ocular hypertension (on topical IOP lowering medications) 
or those with advanced glaucoma (in the opinion of a 
glaucoma specialist). IOP check to be performed before 
the patient goes home on the day of IVT.  
 
*Risks as per current use in wet AMD and macular oedema secondary to CRVO, 
BRVO and DMO. 
 
Logistics 
All patients will receive 3 loading injections of Eylea at monthly intervals followed by 
a treat and extend protocol up to 12 months. 
Extension from monthly to 6, 8 and 12 week follow-up will occur when there is 
evidence of OCT stability in the view of the investigator i.e. there is no further 
reduction in macular fluid compared to the previous visit. 
Injections will be administered by Dr. Stacey Strong (Clinical Research Fellow) who 
is experienced in the administration of intravitreal injections. If, for any reason, Dr. 
Strong is absent on a day that a patient has a scheduled visit, another clinical trial 
fellow who is also GCP trained and experienced in the administration of intravitreal 
injections will be appointed to perform the procedure. Decisions regarding extension 
from monthly to 6, 8 and 12 weeks will be taken in consultation with Professor Michel 
Michaelides. All injections will be carried out at the Clinical Research Facility, 
Moorfields Eye Hospital. 
 
This trial is categorised as:  
• Type B = Somewhat higher than the risk of standard medical care  
(being an invasive procedure rather than the current treatment of oral/topical 
medications) 


 
 
 
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4 
Objectives 
To assess the efficacy and safety of Eylea in patients with Retinitis 
Pigmentosa associated with cystoid macular oedema.   
Primary Objective: To report mean Central Macular Thickness (CMT) at 12 
months as measured with SDOCT in eyes of patients with Retinitis 
Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend 
protocol between baseline and twelve months. 
 
Secondary Objectives:  
To report mean Central Macular Thickness (CMT) at 6 months as measured 
with SDOCT in eyes of patients with Retinitis Pigmentosa associated with 
cystoid macular oedema treated with three loading doses of Eylea at 
monthly intervals followed by a treat and extend protocol between baseline 
and twelve months. 
 
To report mean change in Central Macular Thickness (CMT) as measured 
with SDOCT in eyes of patients with Retinitis Pigmentosa associated with 
cystoid macular oedema treated with three loading doses of Eylea at 
monthly intervals followed by a treat and extend protocol between baseline 
and six months, and baseline and twelve months. 
 
To report the mean BCVA ETDRS letter score at 6 and 12 months in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and twelve months. 
 


 
 
 
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To report the mean change in BCVA ETDRS letter score in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated 
with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and 6 months, and baseline and twelve 
months. 
 
To report mean macular volume at 6 and 12 months as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid 
macular oedema treated with three loading doses of Eylea at monthly 
intervals followed by a treat and extend protocol between baseline and 
twelve months. 
 
To report mean change in macular volume as measured with SDOCT in 
eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals 
followed by a treat and extend protocol between baseline and six months, 
and baseline and twelve months. 
 
To report all AEs and SAEs at any time point during the 12 month study of 
using intravitreal Eylea in eyes of patients with Retinitis Pigmentosa 
associated with cystoid macular oedema. 
 
To report the mean retinal sensitivity at 6 and 12 months using 
Microperimetry in eyes of patients with Retinitis Pigmentosa associated with 
cystoid macular oedema treated with three loading doses of Eylea at 
monthly intervals followed by a treat and extend protocol between baseline 
and twelve months. 
 


 
 
 
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To report the mean change in retinal sensitivity using Microperimetry in eyes 
of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals 
followed by a treat and extend protocol between baseline and 6 months, and 
baseline and twelve months 
 
To report the mean number of intravitreal injections administered in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and twelve months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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5 
Trial design 
5.1 
Overall design       
• 
    Purpose of research: 
To assess the safety and efficacy of Eylea in patients with Retinitis 
Pigmentosa associated with cystoid macular oedema.  
 
• 
    Trial design 
Ø  Open label, prospective, non-randomised 
Ø  30 patients with RP associated CMO 
Ø 16 years of age  
Ø Molecularly confirmed patients prioritised (to be able to potentially 
explore any pharmacogenetic aspects) 
Ø Recruited over a 9 month period, with each patient having 12 month 
follow-up 
Ø  All patients receive 3 loading injections of Eylea at monthly intervals 
followed by a treat and extend protocol up to 12 months 
Ø Extension from monthly to 6, 8 and 12 week follow-up will occur when 
there is evidence of OCT stability in the view of the investigator i.e. 
there is no further reduction in macular fluid compared to the previous 
visit 
Ø  All patients will receive 5 injections before considering them non-
responders 
Ø  BCVA and SDOCT undertaken at every visit 
Ø  Microperimetry undertaken at Baseline, 6 months and 12 months 
Ø  Fundus Autofluorescence (FAF) Imaging Baseline, 6 and 12 months 
Ø  Refracted BCVA at baseline, 6 months and 12 months 
Ø  SDOCTs will be graded by Moorfields Eye Hospital Reading Centre 


 
 
 
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6 
Selection of Subjects 
6.1 
Inclusion criteria 
• CMO in association with RP 
• > 16 years of age  
• Unilateral or Bilateral CMO (the worse eye only will be treated – defined as 
the eye with a greater central macular thickness (CMT) on OCT) 
• No previous oral treatment for CMO for last 3 months 
• No previous peribulbar or intravitreal treatment for CMO in the study eye for 
last 3 months 
• No previous topical treatment for CMO in the study eye for last 1 month  
• Central visual impairment that in the view of the Principal Investigator is due 
to CMO 
• 
BCVA better than 3/60  
 
6.2 
Exclusion criteria 
• Insufficient patient cooperation or media clarity to allow adequate fundus 
imaging. 
• Evidence of visually significant vitreo-retinal traction or epiretinal membrane 
on OCT that in the Principal Investigator’s opinion is highly likely to 
significantly limit the efficacy of intravitreal therapy. 
• History of cataract surgery within prior 3 months or cataract surgery 
anticipated within 6 months of starting the study. 
• Any anti-VEGF treatment to study eye within 3 months. 
• History of YAG capsulotomy performed within 3 months.  
• Uncontrolled IOP > = 24 mmHg for ocular hypertension (on topical IOP 
lowering medications)  
• Advanced glaucoma (in the opinion of a glaucoma specialist). 


 
 
 
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• Patients with active or suspected ocular or periocular infections 
• Patients with active severe intraocular inflammation. 
• Patients with a new, untreated retinal tear or detachment 
• Patients with a stage 3 or 4 macular hole 
• Thromboembolic event (MI/CVA/Unstable Angina) within 6 months. 
• Pregnancy or family planned within 15 months 
• Females who are breast feeding 
• Known allergy or hypersensitivity to anti-VEGF products 
 
Females of childbearing potential and males must be willing to use an 
effective method of contraception (hormonal or barrier method of birth control; 
abstinence) from the time consent is signed until 12 weeks after treatment 
discontinuation. The MHRA advise double contraception.  
 
Females of childbearing potential must have a negative pregnancy test within 
7 days prior to being registered for trial treatment. NOTE:  Subjects are 
considered not of child bearing potential if they are surgically sterile (i.e. they 
have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are postmenopausal.  
 
 
 
 
 
 
 
 
 
7 
Recruitment 
Patients will be approached at medical retina clinics at Moorfields Eye Hospital, or 
contacted by phone, email or post.  


 
 
 
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8 
Study procedures and schedule of assessments 
8.1 
Informed consent procedure 
 


 
 
 
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Dr. Stacey Strong is GCP trained, suitably qualified and experienced to deliver 
intravitreal injections and be delegated the duty of taking informed consent by the 
CI/PI (Professor Michel Michaelides). Written informed 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.  
 
“Adequate time” must be given for consideration by the patient before taking part. 
The PI must record when the patient information sheet (PIS) has been given to the 
patient. The Investigator or designee will explain the patients are under no obligation 
to enter the trial and that they can withdraw at any time during the trial, without 
having to give a reason. 
 
No clinical trial procedures will be conducted prior to taking consent from the 
participant. Consent will not denote enrolment into trial.  
 
A copy of the signed Informed Consent form will be given to the participant.  The 
original signed form will be retained at the study site and a copy placed in the 
medical notes. 
If new safety information results in significant changes in the risk/benefit 
assessment, the consent form will be reviewed and updated if necessary and 
subjects will be re-consented as appropriate 
8.2 
Randomisation procedures 
Non-applicable as this is a non-randomised trial 
 
8.3 
Unmasking 
Non-applicable as this is an open label trial 
 


 
 
 
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8.4 
Screening Period 
Patients will be recruited over a 6 to 12 month period. Within a week of being 
approached in the medical retina clinics or by telephone and having been provided 
with information about the trial, our research manager will contact the patient and 
invite them to attend a screening appointment. This screening appointment 
(‘Screening’) should occur within 28 days of being contacted. At the screening 
appointment the patient will have the opportunity to ask any further questions before 
informed consent is taken, their medical/drug history reviewed, a general physical 
examination performed together with vital signs including blood pressure and 
temperature measurements. If they are deemed fit to enter the trial, their 1st Eylea 
intravitreal injection will be given on the same day (‘Visit 1’). 
 
a. Screening visit to take place within 28 days of being contacted by 
research manager 
 
b. If for any reason the patient cannot attend their scheduled visit, an 
alternative appointment will be arranged. This must occur within 14 days of 
the original scheduled date.  
 
c. The follow up period should be 28 days after Visits 1 and 2. The follow up 
period after visit 3 will depend on whether there is evidence of OCT stability 
in the view of the investigator (i.e. there is no further reduction in macular 
fluid compared to the previous visit) in which case extension from 4 to 6, 8 
and 12 week follow up will occur.  
 
d. Follow up will occur up until 12 months after the first treatment was 
initiated. 
 
Screen failures i.e. patients who do not meet eligibility criteria at time of screening 
may be eligible for rescreening subject to acceptable parameters. For example, if a 


 
 
 
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patient was breast-feeding at the initial screening and decided to stop a few months 
later, she could be invited for a second screening appointment. 


 
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8.5 
Baseline and subsequent assessments  
 
 
Screening 
and 
Baseline 
Treatment phase and follow-up* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 
Baseli
ne 
4 wks 
post 
baseli
ne 
8 wks 
post 
baseli
ne 
12 
wks 
post 
baseli
ne
4 - 12 
wks 
post 
visit 4 
4 - 12 
wks 
post 
visit 5 
4 - 12 
wks 
post 
visit 6 
4 - 12 
wks 
post 
visit 7 
4 - 12 
wks 
post 
visit 8 
4 - 12 
wks 
post 
visit 9 
4 - 12 
wks 
post 
visit 10 
4 - 12 
wks 
post 
visit 11 
4 - 12 
wks 
post 
visit 12 
Patient demographics 
confirmed 
X 
X 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
X 
General medical and 
ocular history 
X 
 
 
 
 
 
 
 
 
 
 
Medication review 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Pregnancy status 
confirmed 
 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs: Blood 
pressure, heart rate and 
temperature 
X 
X 
x 
X 
x 
x 
x 
x 
x 
x 
x 
x 
X 
Best corrected 
ETDRS visual acuity 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Refracted best 
corrected ETDRS visual 
acuity 
X 
 
 
 
X ( at 6 
months) 
 
 
 
 
 
X (at 12 
months) 
Colour vision 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Contrast sensitivity 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Microperimetry 
X 
 
 
 
X ( at 6 
months) 
 
 
 
 
 
X (at 12 
months) 
Dilation of the patient 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Slit lamp 
examination 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IOP check (pre- 
injection) 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
SDOCT  in both eyes 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Fundus 
Autofluorescence 
X 
 
 
 
x( at 6 
months)
 
 
 
 
 
x 
Administration of Eylea  Possibly X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IOP check (post- 
injection) 
X 
X 
X 
X 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   *Number of total visits will vary between patients as follow-up appointments will be any time   
    between 4 – 12 weeks.  


 
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8.6 
Treatment procedures 
 
Eylea 2 mg (0.05mL) administered by intravitreal injection every 4 weeks (monthly) 
for the first 12 weeks (3 months), followed by 2 mg once every 4-12 weeks 
depending on whether there is evidence of OCT stability in the view of the 
investigator (i.e. there is no further reduction in macular fluid compared to the 
previous visit) 
8.7 
Flowchart of study assessments 
 
Patient demographics confirmed (at all scheduled visits) 
General medical and ocular history (taken at baseline only) 
Medication review (at all scheduled visits) 
Pregnancy status confirmed (taken at baseline only) 
Eligibility check (taken at baseline only)  
Informed consent (taken at baseline only) 
Vital signs inc: blood pressure, heart rate and temperature (at all 
scheduled visits) 
BCVA (at all scheduled visits) 
Refracted BCVA (Baseline, 6 and 12 months) 
Colour vision (at all scheduled visits) 
Contrast Sensitivity (at all scheduled visits) 
Microperimetry (Baseline, 6 and 12 months) 
Dilation of the patient (at all scheduled visits) 
Slit lamp examination to check for cataract (at all scheduled visits) 
Pre-injection IOP check (at all scheduled visits) 
SDOCT (at all scheduled visits)  
Fundus Autofluorescence Imaging (Baseline, 6 and 12 months) 
Administration of Eylea (at all scheduled visits) 
Post-injection IOP check (at all scheduled visits) 


 
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8.8 
  Methods 
8.8.1 
Laboratory procedures 
No samples are to be processed for this trial 
 
 
8.9 Definition of end of trial 
28 days following the last visit by the last participant.   
 
8.10      Discontinuation/withdrawal of participants and ‘stopping rules’ 
Circumstances in which subjects will be withdrawn from the trial, include: Mortality, 
CVA/TIA/MI/Unstable angina, Hypersensitivity/Allergy to anti-VEGF and if for any 
reason the patient no longer wishes to be involved with the trial. This will be 
confirmed in writing and documentation sent to both patient and GP informing them 
why they have been withdrawn from the trial and thanking them for their participation 
up to that point. Withdrawn subjects will only be replaced if their withdrawal is 
deemed unrelated to the trial, for example, if a patient needs to relocate for work 
purposes/sick family member and can no longer physically attend their appointments. 
Replacement patients will be recruited in an identical fashion to those who originally 
enrolled in the study. Recruitment of these patients must occur within the designated 
8 month recruitment period.  Patients who withdraw for reasons deemed related to 
the trial e.g. intolerable side effects, will not be replaced. Patients who withdraw from 
the study will be asked to attend an exit follow-up review at 12 months, which will 
involve the same tests to be undertaken as those still remaining in the study.  
 
In the event of a retinal break the dose should be withheld and treatment should  
not be resumed until the break is adequately repaired  
 
The trial will be stopped prematurely: 
1) if serious adverse effects are shown to be caused by Eylea and the trial 
safety is deemed to have unacceptable  


 
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9        Name and description of all drugs used in the trial 
Eylea: 
Eylea is currently licenced for use in wet AMD and Macular Oedema secondary to 
CRVO, BRVO and DMO. Please see below for information regarding safety and 
efficacy of Eylea. There is some evidence in the literature that anti-VEGF therapy 
may be effective in patients with Reitnitis Pigmentosa associated with cystoid 
macular oedema – Artunay et al (Journal of Ocular Pharmacology and Therapeutics 
2009,25(6)545-550) observed significant response to a single injection of Lucentis in 
15 eyes of 15 patients with RP and CMO over a 6 month follow-up period. By 
undertaking the proposed protocol-driven prospective study we will obtain reliable 
data to potentially plan a randomised controlled trial – potentially multi-centre. 
 
Mechanism of action - Aflibercept is a recombinant fusion protein consisting of 
portions of human VEGF receptor 1 and 2 extracellular domains fused to the Fc 
portion of human IgG1. Aflibercept is produced in Chinese hamster ovary (CHO) K1 
cells by recombinant DNA technology. Aflibercept acts as a soluble decoy receptor 
that binds VEGF-A and PlGF with higher affinity than their natural receptors, and 
thereby can inhibit the binding and activation of these cognate VEGF receptors. 
Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) 
are members of the VEGF family of angiogenic factors that can act as potent 
mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF 
acts via two receptor tyrosine kinases; VEGFR-1 and VEGFR-2, present on the 
surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on 
the surface of leucocytes. Excessive activation of these receptors by VEGF-A can 
result in pathological neovascularisation and excessive vascular permeability. PlGF 
can synergize with VEGF-A in these processes, and is also known to promote 
leucocyte infiltration and vascular inflammation.  
 
Tropicamide 1% eye drops: 
 
Tropicamide is an eye drop used to dilate (enlarge) the pupil of the eye. This allows 
for easier examination of the back of a patients eye by an eye doctor. Tropicamide  


 
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also effects the muscle that controls the lens of the eye, which results in reduced 
accommodation (being able to focus on close objects). Due to the effects of 
tropicamide, some people may find bright light uncomfortable and have blurred 
vision, which may affect the ability to drive. The effects of tropicamide are only 
temporary lasting between 4-6 hours, however, it is possible for the effects to last 
longer. 
 
Each carton of tropicamide contains 20 minim units, measuring approximately 0.5ml 
of the active ingredient tropicamide 1% w/v (5mg). Other ingredients are sodium 
hydroxide, hydrochloric acid (for pH adjustment) and purified water. There is no 
preservative. 
 
Tropicamide should not be used in patients with known allergy to tropicamide or any 
of its ingredients. It should also not be used in patients with a history of closed angle 
glaucoma (a particular type of glaucoma) or patients with a narrow chamber at the 
front of the eye. This can be confirmed on examinaton by the doctor prior to its 
usage. Tropicamide can cause temporary stinging upon its administration into the 
eye. It is also possible for this medication to cause a patient to have a dry mouth.  
 
Phenylepherine 2.5% eye drops: 
Phenylepherine 2.5% is an eye drop used to dilate (enlarge) the pupil of the eye. This 
allows for easier examination of the back of a patients eye by an eye doctor. Due to 
the effects of phenylephrine, some people may find bright light uncomfortable and 
have blurred vision, which may affect the ability to drive. The effects of 
phenylepherine are only temporary lasting between 4-6 hours, however, it is possible 
for the effects to last longer. 
 
Each carton of phenylephrine 2.5% contains 20 minim units, measuring 
approximately 0.5ml solution of phenylephrine hydrochloride 2.5% w/v (12.5mg).  
 


 
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Other ingredients are sodium metabisulphite (E223), disodium edetate and purified 
water. There is no preservative. 
 
Phenylepherine should not be used in patients with known allergy to phenylepherine 
or any of its ingredients. It should also not be used in patients with a history of heart 
disease, fast heartbeats (tachycardia), high blood pressure, bulges in major blood 
vessels (aneurysms), overactive thyroid gland (hyperthyroidism) or high sugar level 
(diabetes mellitus). It should also not be used in patients with a history of closed 
angle glaucoma (a particular type of glaucoma) or patients with a narrow chamber at 
the front of the eye. This can be confirmed on examination by the doctor prior to its 
usage. 
 
Proxymetacaine eye drops: 
Proxymetacaine is an eye drop used before the giving of an intravitreal injection, in 
order to produce an anaesthetic effect on the eye. Each pack contains 20 units 
(minims) containing the active ingredient Proxymetacaine Hydrochloride. Each unit 
contains approximately 0.5 ml eye drops solution of proxymetacaine hydrochloride 
0.5% (2.5 mg). The other ingredients are hydrochloric acid, sodium hydroxide and 
purified water. This medicine does not contain a preservative as it is a sterile single 
use unit. 
 
Allergic reactions can occasionally occur that affect the cornea (a transparent 
membrane covering the iris and pupil of the eye) and the iris. The following reactions 
have been reported very rarely and usually wear off quickly:  
- 
widening of the pupil (center of the iris)  
- 
transient loss of lens movement (inability to read)  
- 
irritation of the conjunctiva (a membrane which lines the inside of the eyelid)  
 
In rare circumstances, a defect or inflammation of the cornea (whitening of the deep 
cornea, immunology-mediated disorder) and/or inflammation of the iris may occur. 


 
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Iodine eye drops and skin preparation 
Iodine has a powerful bactericidal action and is used for disinfecting unbroken 
skin before operations. Iodine is active against fungi, viruses, protozoa, cysts 
and spores. The product is suitable for use by adults, children and the elderly. 
Excipients include: purified water and ethanol (96%). Its use is contraindicated in 
patients with hypersensitivity to iodine or iodides, newborn infants and in patients 
with thyroid disorders or those receiving lithium therapy. 
 
Allergic reactions that can occur, include: urticaria, angioedema, cutaneous 
haemorrhage or purpuras, fever, arthralgia, lymphadenopathy and eosinophilia. 
 
Chloramphenicol eye drops 
Chloramphenicol eye drops will be prescribed to each patient in order to prevent an 
infection occurring following intravitreal injection. It will be prescribed for use four 
times a day to the treated eye, for a total of 5 days. It is contra-indicated for use in 
patients with a known hypersensitivity to chloramphenicol or to any other component 
of the preparation and if there is a family or personal history of blood dyscrasias 
including aplastic anaemia. 
 
Adverse local effects: Sensitivity reactions such as transient irritation, burning, 
stinging, itching and dermatitis have been reported. Sometimes the eye drops can be 
tasted or affect taste as they drain from the eye into the back of the mouth. The 
prolonged use of eye drops containing a phenylmercuric preservative has been 
associated with skin irritation, primary atypical band keratopathy (changes to the 
cornea) and mercurialentis (pigmentation of the anterior capsule of the lens). 
 
Adverse systemic effects: Rarely cases of adverse haematological events (bone 
marrow depression, aplastic anaemia and death) have been reported following ocular 
use of chloramphenicol. 
 
 


 
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9.1      Concomitant medication 
No interaction studies have been performed, however, medication(s)/treatment(s) not 
permitted before and/or during the trial (specify time restrictions) include: 
• Any intravitreal (anti-VEGF) treatment to the study eye within 3 months of 
starting the trial or during the trial itself 
• Any oral carbonic anhydrase inhibitors within 3 months of starting the trial or 
during the trial itself 
• Any topical carbonic anhydrase inhibitors to the study eye within 1 month of 
starting the trial or during the trial itself 
• Any peri-bulbar treatment to the study eye within 3 months of starting the trial 
or during the trial itself 
 
 
Medication(s)/treatment(s) permitted before and/or during the trial (specify time 
restrictions) include: 
• Any intravitreal (anti-VEGF) treatment to the study eye given more than 3 
months before the 1st injection of Eylea is due to take place 
• Any oral carbonic anhydrase inhibitors taken more than 3 months before the 
1st injection of Eylea is due to take place 
• Any topical carbonic anhydrase inhibitors taken more than 1 month before the 
1st injection of Eylea is due to take place. It may be used throughout the trial in 
the non-study eye. 
• Any peri-bulbar treatment to the study eye given more than 3 months before 
the 1st injection of Eylea is due to take place 
• Any medication that the patient was on before the trial started, or is required to 
take during the trial period, as long as it is not in the list mentioned above 
 
 
 
 
 


 
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10      Investigational Medicinal Product  
 
10.1    Name and description of Investigational Medicinal Product(s)  
Eylea solution is supplied in a vial (40mg/ml). Each vial contains 100 microlitres, 
equivalent to 4 mg aflibercept. This provides a usable amount to deliver a single dose 
of 50 microlitres containing 2 mg aflibercept. The dose used in this trial will be 0.05ml 
(2mg) per intravitreal injection and will be supplied free of charge by the 
manufacturer Bayer plc. Eylea is already licenced for use in these quantities for wet 
AMD and oedema secondary to CRVO, BRVO and DMO.  Please see section 3.4. 
 
10.2     Name and description of each Non-IMP (NIMP) 
N/A 
 
 
10.3      Summary of findings from non-clinical studies 
Please refer to: 
https://www.medicines.org.uk/emc/medicine/27224/SPC/Eylea+40mg+ml+solution+f
or+injection+in+a+vial/ 
 
10.4       Summary of findings from clinical studies 
Please refer to: 
https://www.medicines.org.uk/emc/medicine/27224/SPC/Eylea+40mg+ml+solution+f
or+injection+in+a+vial/ 
 
10.5        Summary of known and potential risks and benefits 
Please refer to: 
https://www.medicines.org.uk/emc/medicine/27224/SPC/Eylea+40mg+ml+solution+f
or+injection+in+a+vial/ 


 
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10.6         Description and justification of route of administration and dosage 
Eylea is a solution that needs to be placed in the vitreous cavity of the eye in order 
for it to have localised effects with minimal systemic absorption.  This is achieved in 
the form of an intravitreal injection. No other form of drug delivery is deemed 
acceptable in this trial. 
 
10.7          Dosages, dosage modifications and method of administration 
 
Please see the following link for The Royal College of Ophthalmologist Guidelines for 
Intravitreal Injections Procedure (2009): https://www.rcophth.ac.uk/wp-
content/uploads/2015/01/2009-SCI-
012_Guidelines_for_Intravitreal_Injections_Procedure_1.pdf 
Eylea solution is supplied in a vial (40mg/ml). Each vial contains 100 microlitres, 
equivalent to 4 mg aflibercept. A 23G blue needle is fitted onto a 1ml insulin syringe 
and the entire contents of the vial withdrawn. Care is taken to expel any air bubbles 
from the syringe. The 23G blue needle is then replaced with a 30G needle and any 
excess drug expelled until exactly 0.05ml is contained within the syringe. The 
contents are injected into the vitreous cavity of the eye using an infero-temporal 
approach as a first preference. This will be 3.5mm away from the limbus in pseudo-
phakic patients, and 4mm away from the limbus in phakic patients. No reconstitution 
is required. This dose remains identical for any injection of Eylea that is given. All 
patients will receive 3 loading injections of Eylea at monthly intervals followed by a 
treat and extend protocol up to 12 months. 
 
Extension from monthly to 6, 8 and 12 week follow-up will occur when there is 
evidence of OCT stability in the view of the investigator i.e. there is no further 
reduction in macular fluid compared to the previous visit. 
 


 
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10.8            Preparation and labelling of Investigational Medicinal Product 
Preparation and labelling of the investigational medicinal products will be completed 
in accordance with the relevant GMP guidelines. Text for labels used for the 
Investigational Medicinal Product may be obtained by the Pharmacist. 
Due to the primary packaging containing a small vial of medication on which 
particulars cannot be displayed, a second sheet will bear a label containing the 
following information:  
 
(a) name of sponsor, or investigator 
(b) route of administration, the name/identifier and strength/potency 
(c) batch and/or code number to identify the contents and packaging operation; 
(d) a trial reference code allowing identification of the trial, site, investigator and 
sponsor if not given elsewhere 
(e) the trial subject identification number/treatment number and where relevant, 
the visit number 
10.9           Drug accountability 
The drug, Eylea, will be provided by the manufacturer Bayer who will be responsible 
for the shipment and receipt of the product. All units will be held at the pharmacy 
within Moorfields Eye Hospital. The contact person is Racheal Yoon 
(racheal.yoon@moorfields.nhs.uk). Once the product has been used, the glass vial 
and any sharps will be disposed of into a designated yellow sharps bin located within 
the treatment room of the clinical research facility. Any unused vials will be returned 
to the manufacturer or destroyed. 
 
10.10 Source of IMPs including placebo 
The drug Eylea will be provided for use in this trial at no cost to the hospital.  
 
 


 
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10.11     Dose modifications 
All patients will receive 3 loading injections of Eylea at monthly intervals followed by a 
treat and extend protocol up to 12 months. Each injection will contain 2mg of the 
active ingredient. Extension from monthly to 6, 8 and 12 week follow-up will occur 
when there is evidence of OCT stability in the view of the investigator i.e. there is no 
further reduction in macular fluid compared to the previous visit. 
 
In the case of a serious adverse event, no further injections of Eylea will be given. 
 
10.12       Assessment of compliance 
Compliance includes both adherences to IMP and Protocol study procedures.  
Noncompliance to the Protocol study procedures will be documented by the 
investigator and reported to the Sponsor as agreed. Persistent noncompliance may 
lead the patient to be withdrawn from the study. 
 
Procedures defined for: 
• Monitoring: Patient will be observed having intravitreal injection  
• Recording of subject compliance: date of attendance will be recorded  
• Details of follow-up of non-compliant subjects: A list of patients that 
have been deemed to be non-compliant will be kept. Non-compliant 
patients will be invited to attend an Exit Visit at 12 months post initial 
intravitreal injection. 
10.13        Post-trial IMP arrangements 
Even if the results of this trial were favourable, the drug would still likely need to 
undergo further testing using a multi-centre placebo-controlled approach in order to 
consider licencing of the product for use in RP associated CMO. Patients involved in 
the trial will therefore be unable to continue receiving Eylea at the end of the trial. 
Patients will continue to be seen in their regular clinics, where a decision will be 
taken by the team, whether previous treatment should be re-started or not. 


 
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11         Recording and reporting of adverse events and reactions 
11.1  Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product and which 
does not necessarily have a causal relationship with this 
treatment. 
Adverse Reaction 
(AR) 
Any untoward and unintended response in a subject to 
an investigational medicinal product which is related to 
any dose administered to that subject.  
This includes medication errors, uses outside of protocol 
(including misuse and abuse of product) 


 
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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, 
• 
results in persistent or significant disability or 
incapacity, or 
• 
consists of a congenital anomaly or birth 
defect 
Important Medical 
Event 
These events may jeopardise 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 information about the medicinal 
product in question set out: 
 (a) in the case of a product with a marketing 
authorization, in the summary of product 
characteristics 
for 
that 
product,  
(b) in the case of any other investigational 
medicinal product, in the investigator's brochure 
relating to the trial in question. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
 
 
 
 
 
 
 
 


 
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11.2         Recording adverse events 
 
All adverse events will be recorded in the medical records, Case Report Form (CRF) 
and Adverse Event form following consent.  
 
If the investigator suspects that the subjects’ disease has progressed faster due to 
the administration of Eylea, it will be recorded and reported as an unexpected 
adverse event. 
 
Clinically significant abnormalities in the results of objective tests (e.g. visual acuity, 
temperature, blood-pressure) will also be recorded as adverse events. If the results 
are not expected as part of disease or from the injection of Eylea in accordance with 
the SPC, these will also be recorded as unexpected.  
 
All adverse events will be recorded with clinical symptoms and accompanied with a 
simple, brief description of the event, including dates as appropriate.  
 
All adverse events will be recorded until 12 months post 1st IVT. 
 
Each adverse event will be assessed for the following criteria: 


 
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11.2.1     Severity  
 
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 
 
 
11.2.2        Causality 
The assessment of relationship of adverse events to the administration of Eylea 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 
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 the trial medication). 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 
medication). There is another reasonable explanation for 
the event (e.g. the patient’s clinical condition, other 
concomitant treatments). 


 
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Not related 
There is no evidence of any causal relationship. 
Not Assessable 
Unable to assess on information available. 
 
 
11.2.3        Expectedness 
 
 
Category 
Definition 
Expected 
An adverse event the nature or severity of which is 
consistent with the information about Eylea listed in the 
Investigator Brochure (or SmPC if Licensed IMP) or 
clearly defined in this protocol. 
Unexpected 
An adverse event, the nature or severity of which is not 
consistent with the information about Eylea listed in the 
Investigator Brochure (or SmPC if Licensed IMP)  
 
 
11.2.4        Seriousness 
 
All AEs/ARs will be assessed to see is they meet the definition of serious as 
per section 11.1 
 
11.3 Procedures for recording and reporting Serious Adverse  
 
All serious adverse events will be recorded in the patient notes, CRF and on the 
sponsor SAE form. The SAE form will be submitted immediately (within 24hrs) to the 
sponsor on the email address:  pharmacovigilance@moorfields.nhs.uk. All SAEs will 
be recorded with clinical symptoms and accompanied with a simple, brief description 
of the event, including dates as appropriate. The description of the event must 
ensure the clinical picture is captured accurately. 
All SAEs will be recorded until 30 days after  the last injection of Eylea is given. 
 


 
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The Chief or Principal Investigator will respond to any SAE queries raised by the 
sponsor as soon as possible.  
 
 
SUSARs 
The Principal Investigator or sub/co-investigator will complete the sponsor’s serious 
adverse event form indicating a SUSAR and the form will be emailed to the sponsor 
using 
the 
following 
email 
address: 
pharmacovigilance@moorfields.nhs.uk 
immediately (within 24hours) of his / her becoming aware of the event. The Chief or 
Principal Investigator will respond to any SUSAR queries raised by the sponsor as 
soon as possible.   
 
 
11.3.1    Notification of deaths 
 All deaths will be reported to the sponsor irrespective of whether the death is related 
to disease progression, the injection of Eylea, or an unrelated event. These will be 
reported up until 12 months post 1st injection of the last patient, or 30 days after the 
giving of the last injection of Eylea (whichever is the furthest away).  
 
 
11.3.2     Reporting SUSARs 
The sponsor will notify the main REC and MHRA of all SUSARs.  SUSARs that are 
fatal or life-threatening must be notified to the MHRA and REC within 7 days after the 
sponsor has learned of them.  Other SUSARs must be reported to the REC and 
MHRA within 15 days after the sponsor has learned of them. 
   


 
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11.3.2.1      Reporting SUSARs in International Trials  
N/A 
 
 
11.3.3         Development Safety Update Reports 
The sponsor will provide the main REC and the MHRA with Development Safety 
Update Reports (DSUR) which will be written in conjunction with the trial team and 
the Sponsor’s office. The report will be submitted within 60 days of the 
Developmental International Birth Date (DIBD) of the trial each year until the trial is 
declared ended 
 
11.3.4        Annual progress reports 
An annual progress report (APR) will be submitted to the REC that gave favourable 
opinion 12 months after the date on which the favourable opinion was given. The 
chief investigator will prepare the APR. 
 
11.3.5       Pregnancy (If applicable) 
If a patient becomes pregnant at any point during the duration of the trial: 
• 
It will be recorded in both the patient notes, case report form (CRF) and 
the sponsor will be notified using the sponsor’s SOP 
• 
Immediate cessation of further intravitreal injections will take place 
• 
A letter will be written to the GP (with permission from the patient) 
recommending that the patient be referred to their local obstetrics and 
gynaecology team for monitoring 
• 
A letter will be written to the GP (with permission from the patient) asking 
for correspondence about the health and well-being of any child born to a 
patient that became pregnant during the trial, or within 6 months of their  


 
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last intravitreal injection with Eylea. This includes a child born to a 
woman who was the partner of a male trial patient.  
The patient will be asked to attend an exit follow-up review at 12 months, 
which will involve the same tests to be undertaken as those still 
remaining in the study.  
 
 11.3.6        Overdose  
• 
Injecting the entire volume of the prefilled syringe could result in 
overdose.  
• 
If an overdose occurs, it will be recorded in both the patient notes, case 
report form (CRF) and the sponsor notified (placed on the deviation log) 
• 
Patients that receive an overdose of Eylea will be withdrawn from the trial 
as it will be unknown to what extent the effects on CMT/BCVA are 
attributable to the increased amount of drug injected  
• 
If a SAE is associated with an overdose, it will be fully described in the 
SAE report form 
 
 
11.3.7          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 
to the MHRA and the relevant REC of the measures taken and the circumstances 
giving rise to those measures. 
 
 
11.4 The type and duration of the follow-up of subjects after adverse events. 
Subjects who have experienced an adverse drug reaction will continue to be 
followed-up until 12 months after the 1st IVT.  
Adverse events and reactions will be recorded and reported for up to 30 days  
 


 
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following the last injection of Eylea.  
 
Any SUSAR related to Eylea will need to be reported to the Sponsor irrespective of 
how long after Eylea administration the reaction has occurred. 
 
 
11.4.1      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.   
 
 
 
 
 
 
 
 


 
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10 
Data management and quality assurance 
12.1 Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998. 
The Case Report Forms (CRFs) will not bear the subject’s name or other personal 
identifiable data.   
A 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 will be kept on a password protected 
computer 
 
12.2 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 Vision charts, 
OCT scans etc. 
 
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 trial 
statistician, senior data manager 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 initialled and dated by the person making the alteration. 
Overwriting or use of correction fluid will not be permitted.  
 


 
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It will be the responsibility of the investigator to ensure the accuracy of all data 
recorded on the CRFs. The delegation log will identify all those personnel with 
responsibilities for data collection and handling. The completion of CRFs will be 
signed off by the Chief Investigator or delegated authorised individual (Principal 
Investigator) as outlined in the delegation log.  
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). 
 
Methods used to maximise completeness of data include: telephoning subjects who 
have not attended for their appointment and data collection forms will be included as 
appendices. 
 
12.3 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. 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 and MEH SOPs for data management. 
 
The database will be produced using a file/server system. The front end will use a 
bespoke Microsoft Visual Studio application and the back end (data storage) will be  


 
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Microsoft SQL server. All database development is carried out by the R&D IT team 
and the database will be validated to GAMP 5 standards. 
 
The back end database is an installation of Microsoft SQL Server. The database is 
only available within the MEH WAN/Intranet area. All servers are backed up daily and 
with multiple restore points every day. Backup copies exist in more than one place as 
tapes are sent securely to another of our sites. There is to be no sending of trial data 
externally. All MEH clinical trial databases are part of the MEH disaster recovery 
strategy and have a 5 day Recovery Time Objective. 
 
This is a single-site trial so data will not be transferred to another site. However, if for 
any reason the data is required for electronic transfer, it will be transferred in 
accordance with the UK Data Protection Act 1998 as well as MEH Information 
Security Policy and Trust Information Governance Policy.  Documented record of 
data transfer and measures will be in place for the recovery of original information 
after transfer. 
 
 
 
 
 
 
 
 
 
 
 


 
AMOUR Protocol version 3.0    20th November 2015        
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13 
Record keeping and archiving 
Archiving will be authorised by the Sponsor following submission of the end of study 
report. In line with Moorfields Eye Hospital SOP, the retention periods outlined below 
should be adhered to: 
 
Document  
Minimum Retention period 
Reference  
CTIMP TMF & 
medical files of 
trial subjects (UK 
trial only) 
5 years after conclusion of the trial 
UK SI 2004/1031 (as 
amended) 31A (7 and 8) 
Commission Directive 
2005/28/EC 
CTIMP TMF & 
medical files of 
trial subjects 
where data is 
used to support a 
marketing 
authorisation 
15 years after completion or 
discontinuation of trial OR for at least 2 
years after the granting of the last 
marketing authorisation in the EEA OR for 
at least 2 years after formal 
discontinuation of clinical development of 
the investigational product.** 
Commission Directive 
2003/63/EC (amending 
Directive 2001/83/EC) 
ICH Guideline for Good 
Clinical Practice E6 (R1) 
 
The essential documents and trial database will be kept in a locker within the Clinical 
Research Facility at Moorfields Eye Hospital.  
 
Chief Investigators/Principal Investigators are responsible for the secure archiving of 
essential trial documents contained within the site file and the trial database as per 
their trust policy. All essential documents will be retained for a minimum of 5 years 
after completion of trial including the subject’s medical notes. 
 
Destruction of essential documents will require authorisation from the Sponsor.   
 


 
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14 
Statistical Considerations  
Catey Bunce is the trial statistician who will be responsible for all statistical aspects of 
the trial from design through to analysis and dissemination.     
 
14.1 Outcomes 
14.1.1 Primary outcomes 
 
Primary Objective:  
To report mean Central Macular Thickness (CMT) at 12 months as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and twelve months. 
 
14.1.2 Secondary outcomes 
 
To report mean Central Macular Thickness (CMT) at 6 months as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and twelve months. 
 
To report mean change in Central Macular Thickness (CMT) as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and six months, and baseline and twelve 
months. 
To report the mean BCVA ETDRS letter score at 6 and 12 months in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated with three 


 
AMOUR Protocol version 3.0    20th November 2015        
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loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and twelve months. 
To report the mean change in BCVA ETDRS letter score in eyes of patients with 
Retinitis Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and six months, and baseline and twelve months. 
To report mean macular volume at 6 and 12 months as measured with SDOCT in 
eyes of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and twelve months. 
To report mean change in macular volume as measured with SDOCT in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema treated 
with three loading doses of Eylea at monthly intervals followed by a treat and extend 
protocol between baseline and six months, and baseline and twelve months. 
To report all AEs and SAEs at any time point during the 12 month study of using 
intravitreal Eylea in eyes of patients with Retinitis Pigmentosa associated with cystoid 
macular oedema. 
To report the mean retinal sensitivity at 6 and 12 months using Microperimetry in 
eyes of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and twelve months. 
 
To report the mean change in retinal sensitivity using Microperimetry in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema treated 
with three loading doses of Eylea at monthly intervals followed by a treat and extend 
protocol between baseline and six months, and baseline and twelve months. 
 
To report the mean number of intravitreal injections administered in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and twelve months. 


 
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14.2 Sample size and recruitment 
14.2.1 Sample size calculation  
This is an exploratory study which aims to assess the safety and efficacy of Eylea 
in patients with RP and CMO.  We have chosen a sample size of 30 patients which 
is justified on the basis that 30 subjects will provide an estimate of the mean 
change in CMT from baseline to 12 months with reasonable precision as advocated 
by Browne (1995) and Hertzog (2008). 
14.2.2 Planned recruitment rate 
We plan to start recruiting patients from 5th December 2015 for a period of 9 months. 
This would equate to 3 to 4 patients being recruited per month if a total of 30 patients 
are required. This figure has been deemed to be attainable in practice. 
14.3 Statistical analysis plan 
The statistical analysis plan will be written in advance of the data analysis by a trial 
statistician.  All statistical tests will use a two-sided P value of 0.05.  All confidence 
intervals will be 95 % and two sided.   
14.3.1 Summary of baseline data and flow of patients 
 
Baseline characteristics will be presented to provide an overview of patient 
characteristics at baseline.  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. 
 
A consort flow chart will be constructed.  
14.3.2 Primary outcome analysis 
 


 
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Ø Mean Central Macular Thickness (CMT) at 12 months as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid 
macular oedema treated with three loading doses of Eylea at monthly intervals 
followed by a treat and extend protocol will be estimated with a 95 % 
confidence interval. 
14.3.3 Secondary outcome analysis 
 
Summary statistics for all secondary outcomes will be presented.  Where appropriate 
the standard error and two-sided 95 % confidence interval will also be presented 
alongside these.  For the case of any outcome measures which are presented as a 
proportion, a 95 % confidence interval will be computed by the exact binomial 
method.   
Ø To report mean Central Macular Thickness (CMT) at 6 months as measured 
with SDOCT in eyes of patients with Retinitis Pigmentosa associated with 
cystoid macular oedema treated with three loading doses of Eylea at monthly 
intervals followed by a treat and extend protocol between baseline and twelve 
months. 
 
Ø To report the mean change in Central Macular Thickness (CMT) as measured 
with SDOCT in eyes of patients with Retinitis Pigmentosa associated with 
cystoid macular oedema treated with three loading doses of Eylea at monthly 
intervals followed by a treat and extend protocol between baseline and six 
months, and baseline and twelve months. 
 
Ø To report the mean BCVA ETDRS letter score at 6 and 12 months in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol. 
 


 
AMOUR Protocol version 3.0    20th November 2015        
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Ø To report the mean change in BCVA ETDRS letter score in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated  
with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and six months, and baseline and twelve 
months. 
Ø To report mean macular volume at 6 and 12 months as measured with 
SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid 
macular oedema treated with three loading doses of Eylea at monthly intervals 
followed by a treat and extend protocol between baseline and twelve months. 
 
Ø To report mean change in macular volume as measured with SDOCT in eyes 
of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and six months, and baseline and 
twelve months. 
 
Ø To report all AEs and SAEs at any time point during the 12 month study of 
using intravitreal Eylea in eyes of patients with Retinitis Pigmentosa 
associated with cystoid macular oedema. 
 
Ø To report the mean retinal sensitivity at 6 and 12 months using Microperimetry 
in eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals 
followed by a treat and extend protocol between baseline and twelve months. 
 
Ø To report the mean change in retinal sensitivity using Microperimetry in eyes 
of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and six months, and baseline and 
twelve months. 
 


 
AMOUR Protocol version 3.0    20th November 2015        
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Ø To report the mean number of intravitreal injections administered in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a 
treat and extend protocol between baseline and twelve months. 
 
 
14.3.4 Sensitivity and other planned analyses 
It is inevitable that some patients will be lost to follow up.  If data are missing for any 
patients, reasons for this may be important and these will be examined and dealt with 
as appropriate.   
 
A detailed statistical analysis plan will be written by the trial statistician at the 
beginning of the trail (before any analysis begins) detailing all of the planned 
baseline, primary, secondary, safety and sensitivity analyses. 
 
14.4 Randomisation methods 
Not applicable 
 
14.5 Interim analysis 
There are no planned interim analyses. 
 
14.6 Other statistical considerations 
Statistical analysis will be done according to the statistical analysis plan.  Any 
deviation(s) from the original statistical analysis plan will be described and justified in 
the final report. 
 
 
 


 
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15 
Name of Committees involved in trial 
The Trial Management Group (TMG) will oversee recruitment and data management.  
The trial will also include a Trial Steering Committee (TSC) and a Independent Data 
Monitoring Commmittee (IDMC).  
 
 
 
 
16 
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.  Trial participants are informed of this during the informed consent 
discussion.  Participants will consent to provide access to their medical notes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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17 
Ethics and regulatory requirements 
 
Ethical issues that may arise, include: 
 
- 
Participants may be approached in a public space 
Patients may be recruited from the medical retina clinics, in which case 
discussion about the trial will be undertaken in a private cubicle to maintain 
privacy  
 
- 
Fear or pain / distress / discomfort to the participant  
A full explanation about intravitreal injections will be given to the patient, both 
verbally and written down in the patient information sheet. The patient will 
make an informed decision whether they would like to be involved with the trial 
or not. Reasons such as fear of having the intravitreal injections would be an 
understandably valid reason for a patient to choose not to enter the trial. No 
coercion will occur. 
 
- 
Issues of confidentiality and privacy, or lack of anonymity 
Patient information kept in the Case Report Forms (CRF) will be anonymised 
by using only their subject number, hospital number and date of birth. Their 
name will not appear on this data. 
 
- 
Security of personal data, retention and disposal of the data 
Clinical Report Forms are kept in a locked filing cabinet, in a locked room. 
Access to this information is only permitted to those people who are named 
and involved in the trial.  
 


 
AMOUR Protocol version 3.0    20th November 2015        
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The sponsor will ensure that the trial protocol, patient information sheet, consent 
form, GP letter and submitted supporting documents have been approved by the 
appropriate regulatory body (MHRA in UK) and 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 and regulatory 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 11.3.7 for reporting 
urgent safety measures). 
 
Within 90 days after the end of the trial, the Sponsor will ensure that the main REC 
and the MHRA 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 an end of study report of the clinical trial, which 
will then be submitted to the MHRA and main REC within 1 year after the end of trial 
declaration has been submitted. 
 
 
 
 


 
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18 
Monitoring requirement for the trial 
A trial specific monitoring plan will be established for studies as part of the oversight 
planning. The trial will be monitored in accordance with the agreed plan. 
 
19 
Finance 
Bayer, the manufacturer of Eylea, will be funding this trial 
 
20 
Insurance 
MEH participates in the Clinical Negligence Scheme for Trusts (CNST), run by the 
NHS Litigation Authority, which pools the risk of clinical negligence claims. 
NHS indemnity (for negligent harm) will cover MEH 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. MEH will 
not accept liability for any activity that has not been properly registered and Trust 
approved. 
 
21 
Publication policy 
All proposed publications will be discussed with Sponsor prior to publishing other 
than those presented at scientific forums/meetings. Publications and or study report 
findings will be submitted onto the European clinical trials database in line with 
current EU guidance. 
http://ec.europa.eu/health/files/eudralex/vol-10/2012_302-03/2012_302-03_en.pdf 
 
 


 
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22 
Statement of compliance 
The trial will be conducted in compliance with the approved protocol, the UK 
Regulations, EU GCP and the applicable regulatory requirement(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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23 
References 
 
Artunay, O., Yuzbasioglu, E., Rasier, R., Sengul, A., and Bahcecioglu, H. (2009) 
Intravitreal Ranibizumab in the Treatment of Cystoid Macular Edema Associated 
With Retinitis Pigmentosa. Journal of Ocular Pharmacology and Therapeutics. 25 (6) 
:  p.545-550.  
 
Bauch & Lomb. 2015. Minims® Chloramphenicol 0.5% w/v [ONLINE] Available at: 
https://www.medicines.org.uk/emc/medicine/418 [Accessed 24 August 15]. 
 
Bauch & Lomb. 2015. Minims® Phenylephrine Hydrochloride 2.5% w/v [ONLINE] 
Available at: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1435298230505.p
df . [Accessed 24 August 15]. 
 
Bauch & Lomb. 2015. Minims® Proxymetacaine Hydrochloride 0.5% w/v [ONLINE] 
Available at: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1420436246764.p
df  [Accessed 24 August 15]. 
 
Bauch & Lomb. 2015. Minims® Tropicamide 1% w/v [ONLINE] Available at: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1429249156463.p
df [Accessed 24 August 15]. 
 
Bayer plc. 2015. Eylea 40mg/ml solution for injection in a vial. [ONLINE] Available at: 
https://www.medicines.org.uk/emc/medicine/27224. [Accessed 21 August 15]. 
 
Browne, R (1995) On the use of a pilot sample for sample size determination. Stat 
Med. 14 (17) : p 1933 - 40  
 


 
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Page 92 of 93 
 
 
 
 
 
Campochiaro, PA., Clark, WL., Boyer, DS., Heier, JS., Brown, DM., Vitti, R., Kazmi, 
H., Berliner, AJ., Erickson, K., Chu, KW., Soo, Y., Cheng, Y., Haller, JA. (2015) 
Intravitreal aflibercept for macular edema following branch retinal vein occlusion: the 
24-week results of the VIBRANT study. Ophthalmology. 122 (3) : p. 538-44.  
 
Heier, JS., Clark, WL., Boyer, DS., Brown, DM., Vitti, R., Berliner, AJ., Kazmi, H., Ma, 
Y., Stemper, B., Zeitz, O., Sandbrink, R., Haller, JA. (2014) Intravitreal aflibercept 
injection for macular edema due to central retinal vein occlusion: two-year results 
from the COPERNICUS study. Ophthalmology. 121 (7) : p. 1414-1420.  
 
Hertzog (2008) Considerations in determining sample size for pilot studies. Research 
in Nursing and Health. 31 (2): p 180 - 191 
 
Korobelnik, JF., Holz, FG., Roider, J., Ogura, Y., Simader, C., Schmidt-Erfurth, U., 
Lorenz, K., Honda, M., Vitti, R., Berliner, AJ., Hiemeyer, F., Stemper, B., Zeitz, O., 
Sandbrink, R., GALILEO Study Group. (2014) Intravitreal Aflibercept Injection for 
Macular Edema Resulting from Central Retinal Vein Occlusion: One-Year Results of 
the Phase 3 GALILEO Study. Ophthalmology. 121(1) : p.202-8.  
 
Korobelnik, JF., Do, DV., Schmidt-Erfurth, U., Boyer, DS., Holz, FG., Heier, JS., 
Midena, E., Kaiser, PK., Terasaki, H., Marcus, DM., Nguyen, QD., Jaffe, GJ., Slakter, 
JS., Simader, C., Soo, Y., Schmelter, T., Yancopoulos, GD., Stahl,N., Vitti, R., 
Berliner, AJ., Zeitz, O., Metzig, C., Brown DM. (2014) Intravitreal aflibercept for 
diabetic macular edema. Ophthalmology. 121 (11) : p.2247-54.  
 


 
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Page 93 of 93 
 
MHRA.gov.uk. 2015. Summary of product Characteristics. [ONLINE] Available at: 
http://www.mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1430459463775.p
df [Accessed 24 August 15]. 
 
 
Moustafa, G.A. and Moschos, M.M (2015) Intravitreal aflibercept (Eylea) injection for 
cystoid macular edema secondary to retinitis pigmentosa - a first case report and 
short review of the literature. BMC Ophthalmol. [Online] Available at: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482192/ (Accessed: 24 August 2015) 
 
Schmidt-Erfurth, U., Kaiser, PK., Korobelnik, JF., Brown, DM., Chong, V., Nguyen, 
QD., Ho, AC., Ogura, Y., Simader, C., Jaffe, GJ., Slakter, JS., Yancopoulos, GD., 
Stahl, N., Vitti, R., Berliner, AJ., Soo, Y., Anderesi, M., Sowade, O., Zeitz, O., 
Norenberg, C., Sandbrink, R., Heier JS. (2014) Intravitreal aflibercept injection for 
neovascular age-related macular degeneration: ninety-six-week results of the VIEW 
studies. Ophthalmology. 121 (1) : p.193-201.  
 
 
 

SAP_001.pdf: 
Moorfields Eye Hospital, Statistical Analysis Plan 
MICM1014 
MICM1014_SAP_Final_v1.0_08062016.pdf 
CONFIDENTIAL  
Page 1 of 11 
08/06/2016 
 
 
Full title of trial 
 
 
Prospective non-randomised exploratory study 
to assess the safety and efficacy of Eylea in 
cystoid macular oedema associated with 
Retinitis Pigmentosa 
 
Short title 
 
 
 
Aflibercept for Macular Oedema with Underlying 
Retinitis Pigmentosa (AMOUR) study 
 
Version and date of protocol 
 
Version 2.0   26th November2015 
Sponsor: 
Moorfields Eye Hospital NHS Foundation Trust 
Sponsor protocol number 
MICM1014 
Funder (s) : 
Bayer PLC 
EudraCT no 
2015-003723-65  
ACTIVE IMP(s): 
Aflibercept (Eylea) 
PLACEBO IMP(s): 
N/A 
Phase of trial 
Therapeutic exploratory trial (phase II) 
Sites(s) 
Single site – Moorfields Eye Hospital 
 
 
 
Chief investigator: 
 
Professor Michel Michaelides 
Moorfields Eye Hospital 
City Road 
London 
EC1V 2PD 
UK 
  
 
Department of Genetics 
UCL Institute of Ophthalmology  
11-43 Bath Street 
London  
EC1V 9EL 
UK   
 
 
Sponsor Representative: 
 
Gisela Barreto 
Research Portfolio Manager  
Moorfields Eye Hospital NHS Foundation Trust 
162 City Road 
London 
EC1V 2PD 
 
 


Moorfields Eye Hospital, Statistical Analysis Plan 
MICM1014 
MICM1014_SAP_Final_v1.0_08062016.pdf 
CONFIDENTIAL  
Page 2 of 11 
08/06/2016 
 
 
 
Statistical Analysis Plan (SAP) 
 
This document has been developed in accordance with the approved MEH SOP documents developed by the 
Research & Development department at Moorfields. 
 


Moorfields Eye Hospital, Statistical Analysis Plan 
MICM1014 
MICM1014_SAP_Final_v1.0_08062016.pdf 
CONFIDENTIAL  
Page 3 of 11 
08/06/2016 
 
Prospective non-randomised exploratory study to assess the 
safety and efficacy of Eylea in cystoid macular oedema associated 
with Retinitis Pigmentosa 
 (MICM1014 – The AMOUR study)  
SAP SIGN-OFF SHEET 
 
 
Trial Forms  
Version Number  
Version Date 
MICM1014_SAP_Final_v1.0_08062016.pdf 
1.0 
08/06/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I have reviewed the trial’s SAP and approved the use of the above documents 
 
 
 
Name 
Position  
Signature  
Date 
 
Delegated Statistician 
 
__ __ / __ __ / __ __ __ __ 
 
Trial Statistician 
 
 
__ __ / __ __ / __ __ __ __ 
 
Chief Investigator 
  
 
__ __ / __ __ / __ __ __ __ 
 
 
 
Comments 
 
 
 


Moorfields Eye Hospital, Statistical Analysis Plan 
MICM1014 
MICM1014_SAP_Final_v1.0_08062016.pdf 
CONFIDENTIAL  
Page 4 of 11 
08/06/2016 
 
Prospective non-randomised exploratory study to assess the 
safety and efficacy of Eylea in cystoid macular oedema associated 
with Retinitis Pigmentosa 
 (MICM1014 – The AMOUR study) 
 
 
 
 
1. Summary 
 
1.1  Primary research question (formal testing will not be conducted) 
 
The aim of the AMOUR study is to assess the efficacy and safety of Eylea in patients with 
Retinitis Pigmentosa associated with cystoid macular oedema. 
 
 
1.2  Study design  
 
Therapeutic exploratory trial (phase II), prospective, non-randomised, single site 
exploratory trial in patients with Retinitis Pigmentosa associated with cystoid macula 
oedema. 
 
1.2.1 Treatment arm details  
 
Eylea 2 mg (0.05mL) administered by intravitreal injection every 4 weeks (monthly) for the 
first 12 weeks (3 months), followed by 2 mg once every 4-12 weeks depending on whether 
there is evidence of OCT stability in the view of the investigator (i.e. there is no further 
reduction in macular fluid compared to the previous visit). 
 
1.3  Unit of analysis 
 
Only one eye per patient will be included in the study (the study eye). Unilateral or Bilateral 
CMO (the worse eye only will be treated – defined as the eye with a greater central macular 
thickness (CMT) on OCT). 
 
2. Outcome measures 
 
In all sections below, baseline refers to the time of baseline visit. 
 
2.1  Primary outcome measure: 
 
The primary outcome is the mean Central Macular Thickness (CMT) at 12 months as measured 
with SDOCT in eyes of patients with Retinitis Pigmentosa associated with cystoid macular 
oedema treated with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and twelve months. 


Moorfields Eye Hospital, Statistical Analysis Plan 
MICM1014 
MICM1014_SAP_Final_v1.0_08062016.pdf 
CONFIDENTIAL  
Page 5 of 11 
08/06/2016 
 
 
2.2  Secondary outcome measures 
 
2.2.1 To report mean Central Macular Thickness (CMT) at 6 months as measured with SDOCT 
in eyes of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and twelve months  
2.2.2 To report mean change in Central Macular Thickness (CMT) as measured with SDOCT 
in eyes of patients with Retinitis Pigmentosa associated with cystoid macular oedema 
treated with three loading doses of Eylea at monthly intervals followed by a treat and 
extend protocol between baseline and six months, and baseline and twelve months  
2.2.3 To report the mean BCVA ETDRS letter score at 6 and 12 months in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and twelve months  
2.2.4 To report the mean change in BCVA ETDRS letter score in eyes of patients with Retinitis 
Pigmentosa associated with cystoid macular oedema treated with three loading doses of 
Eylea at monthly intervals followed by a treat and extend protocol between baseline and 
six months, and baseline and twelve months  
2.2.5 To report mean macular volume at 6 and 12 months as measured with SDOCT in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema treated with 
three loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and twelve months  
2.2.6 To report mean change in macular volume as measured with SDOCT in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and six months, and baseline and twelve months  
2.2.7 To report all AEs and SAEs at any time point during the 12 month study of using 
intravitreal Eylea in eyes of patients with Retinitis Pigmentosa associated with cystoid 
macular oedema  
2.2.8 To report the mean retinal sensitivity at 6 and 12 months using Microperimetry in eyes of 
patients with Retinitis Pigmentosa associated with cystoid macular oedema treated with 
three loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and twelve months  
2.2.9 To report the mean change in retinal sensitivity using Microperimetry in eyes of patients 
with Retinitis Pigmentosa associated with cystoid macular oedema treated with three 
loading doses of Eylea at monthly intervals followed by a treat and extend protocol 
between baseline and six months, and baseline and twelve months 
2.2.10 To report the mean number of intravitreal injections administered in eyes of patients with 
Retinitis Pigmentosa associated with cystoid macular oedema treated with three loading 
doses of Eylea at monthly intervals followed by a treat and extend protocol between 
baseline and twelve months 


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3. CRFs, data collection, data validation and management 
 
3.1  CRFs and variables 
 
Full details of data collection and timing are described in the trial protocol.  A copy of the 
CRF is held in the Trial Master File. 
 
3.2  Data coding  
 
Variable coding lists are available from the applications manager. 
 
3.3  Data Entry 
 
The completed CRFs will be checked for completion by the research nurse / trial 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. The data entry clerk will 
double data enter for at least 10% of all data randomly, plus 100% of primary outcome data 
(Central Macular Thickness (CMT) at 12 months after baseline). 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. 
 
3.4  Data verification 
 
Data verification, consistency and range checks are performed at data entry to the trial 
database, as well as checks for missing data (a complete list of these checks can be found in 
the Trial Master File).  
Additional range, consistency and missing data checks will be performed, as appropriate, when 
the analysis is performed (and when the datasets for analysis are constructed). All variables will 
be examined for unusual, outlying, unlabelled or inconsistent values. Any problems with trial 
data will be queried with the Trial Managers or Data Entry Clerks, as appropriate. If possible, 
data queries will be resolved; although it is accepted that due to administrative reasons and 
data availability a small number of problems may continue to exist. This will be minimised, any 
outliers remaining after the extensive data verification processes will continue to be reported 
and not replaced as missing.  
 
3.5  Management of datasets 
 
At the time of analysis a copy of each dataset will be made and moved to a designated area of 
CTU network (data locked) by the CTU Applications Manager.  If necessary, new data can be 
entered on the main, unfrozen copy of the dataset.  If any outstanding data queries are resolved 
during the analysis that relate to data in the frozen dataset (eg problems that are found during 
analysis or amended CRFs that are returned to CTU), the main and the locked datasets should 
both be changed under the oversight of the Trial Manager.  If any outstanding data queries are 
resolved while the analysis files are being prepared (i.e. when only a practice dataset has so far 
been copied), the changes need only be made to the main datasets and an updated, locked 
copy made available on the CTU statisticians’ area. 


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4. Sample size calculation 
 
This is an exploratory study which aims to assess the safety and efficacy of Eylea in patients 
with RP and CMO.  We have chosen a sample size of 30 patients which is justified on the basis 
that 30 subjects will provide an estimate of the mean change in CMT from baseline to 12 
months with reasonable precision as advocated by Browne (1995) and Hertzog (2008). 
 
5. Data Analysis 
 
5.1  Analysis Principles 
 
5.1.1 ITT or PP 
Data will be analysed based on the ITT principle. 
 
5.1.2 Significance levels of tests 
No statistical tests will be performed. All confidence intervals will be 95% and two sided. 
 
5.1.3 Recruitment, randomisation and follow-up (to be prepared by research manager)  
Recruitment and follow-up will be summarised in a CONSORT flow-diagram. 
 
5.1.4 Follow-up and losses to follow-up: missing data   
It is inevitable that some patients may be lost to follow-up. If data are missing for any patients, 
reasons for missingness may be important and these will be examined using logistic regression 
of covariates (i.e. gender, age and ethnicity and all other variables listed in Table 1) and on an 
indicator of missingness. 
 
5.1.5 Adjustment for design factors 
No adjustment for design factors will be made. 
 
5.1.6 Masking in the analysis stage 
Not applicable as this is an open-label non-randomised study. 


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5.2  Planned Analysis   
 
Summary statistics for the primary and all secondary endpoints will be presented using mean 
and standard deviation for continuous (approximate) normally distributed variables, medians 
and interquartile ranges for non-normally distributed variables, and frequencies and 
percentages for categorical variables. 
 
5.2.1 Baseline characteristics 
Baseline characteristics will be summarised using mean and standard deviation for continuous 
(approximate) normally distributed variables, medians and interquartile ranges for non-normally 
distributed variables, and frequencies and percentages for categorical variables. 
 
 
5.2.2 Primary Endpoint Analysis 
The mean Central Macular Thickness (CMT) at 12 months after baseline will be estimated with 
a 95% confidence interval. 
 
5.2.3 Secondary Endpoint Analysis  
Summary statistics for all secondary outcomes will be presented. Where appropriate, the 
standard error and two-sided 95% confidence interval will also be presented alongside these. 
For the case of any outcome measures which are presented as a proportion, a 95% confidence 
interval will be computed by the exact binomial method. 
 
5.2.4 Subgroup Analyses  
No subgroup analyses will be performed.  
 
 
5.2.5 Sensitivity and other planned analyses  
No sensitivity or planned analyses will be performed. 
 
5.3  Toxicity / Symptoms (to be prepared by CI/research manager) 
All adverse events will be reported in full detail. 


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Appendix 1: Dummy tables for AMOUR 
 
In all tables, missing data will be reported when applicable. 
 
Figure 1. Consort flow chart (to be prepared by CI/research manager) 
 
Table 1.  Non-Ocular Baseline Characteristics 
 
Eylea  
(N=) 
Number of Patients (Eyes), 
n (%) 
 
 
Male / Female, n (%) 
 
Age (years),  
Mean(SD)/Median(IQR) 
 
Ethnicity, n (%): 
  White 
  Asian 
  Mixed 
  Other 
 
 
 
 
 
 
Table 2. Ocular Baseline Characteristics 
 
Eylea  
(N=) 
Duration of CMO (weeks), Mean 
(SD)/Median (IQR) 
 
Lens status, n (%): 
  Aphakic 
  Pseudophakic 
  Phakic 
 
ETDRS BCVA,  Mean (SD) 
 
Colour vision, Mean (SD)/Median (IQR)  
 
Contrast sensitivity, Mean (SD)/Median 
(IQR) 
 
IOP (mmHg),  Mean (SD) 
 
Central macular thickness on OCT,  
Mean (SD) 
 
Macular Volume on OCT, Mean (SD) 
 
Mean Retinal sensitivity on 
microperimetry,  
Mean (SD)/Median (IQR) 
 
BCVA = best corrected visual acuity; OHT = ocular hypertension; IOP = intraocular pressure; 
mmHg = millimetre of mercury 


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Table 3. Primary outcome measures 
 
Eylea 
(N=) 
95% CI 
Central Macular thickness on 
SDOCT, Mean (SD) at 12 
months 
 
 
 
 
 
ETDRS = early treatment diabetic retinopathy study; BCVA = best corrected visual acuity; CI = 
confidence interval 
 
Table 4. Secondary outcome measures 
 
Eylea 
 (N =) 
95% CI 
Central Macular thickness on SDOCT, Mean (SD) at 6 
months  
 
 
 
Change in Central Macular thickness on SDOCT from 
- 
Baseline to 12 months, Mean (SD) 
- 
Baseline to 6 months, Mean (SD) 
 
 
ETDRS BCVA, Mean (SD) at 6 months  
 
 
ETDRS BCVA, Mean (SD) at 12 months  
 
 
Change in ETDRS BCVA from 
- 
Baseline to 12 months, Mean (SD) 
- 
Baseline to 6 months, Mean (SD) 
 
 
Macular Volume on SDOCT, Mean (SD) at 6 months  
 
 
 
Macular Volume on SDOCT, Mean (SD) at 12 months  
 
 
 
Change in Macular Volume on SDOCT from 
- 
Baseline to 12 months, Mean (SD) 
- 
Baseline to 6 months, Mean (SD) 
 
 
Retinal Sensitivity, Mean (SD) at 6 months  
 
 
 
Retinal Sensitivity, Mean (SD) at 12 months  
 
 
 
Change in Retinal Sensitivity from 
- 
Baseline to 12 months, Mean (SD) 
- 
Baseline to 6 months, Mean (SD) 
 
 
Total number of injections received over the study 
period (12 months), Mean (SD) /Median (IQR) 
 
 
BCVA = best-corrected visual acuity; CMT = central macular thickness; OCT = Optical 
coherence tomography 
 


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Table 5. Ocular and Non-Ocular Adverse Events (AEs) and Serious Adverse Events 
(SAEs) – at 6 months and 12 months (to be prepared by CI/research manager) 
 
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