An Open-label, Multi-centre, Phase I/II Dose Escalation Trial of an Adeno Associated Virus Vector for Gene Therapy of Adults And Children With Retinal Dystrophy Associated With Defects in RPE65 (LCA)
Phase: PHASE1
Conditions: Leber Congenital Amaurosis
Sponsor: MeiraGTx UK II Ltd



MGT003, Gene Therapy Trial for LCA OPTIRPE65                                       
 
 
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Table of Contents 
1. 
Administrative information ................................................................................................................... 7 
1.1 
Compliance ................................................................................................................................... 7 
1.2 
Sponsor ......................................................................................................................................... 7 
1.3 
Structured trial summary .............................................................................................................. 8 
1.4 
Roles and responsibilities.............................................................................................................. 9 
1.4.1 
Protocol contributors ................................................................................................................ 9 
1.4.2 
Independent Data Monitoring Committee ............................................................................. 10 
2 
Trial Diagram ....................................................................................................................................... 11 
3 
Abbreviations ...................................................................................................................................... 12 
4 
Introduction ........................................................................................................................................ 15 
4.1 
Background and Rationale .......................................................................................................... 15 
4.1.1 
Background ............................................................................................................................. 15 
4.1.2  
Preclinical Data ........................................................................................................................ 16 
4.1.3 
Rationale ................................................................................................................................. 16 
4.1.4  
Risk/Benefit ............................................................................................................................. 17 
4.1.5  
Assessment and Management of Risk .................................................................................... 17 
4.1.5.1 Risk of immune responses to AAV capsid proteins or expressed RPE65 protein ....................... 17 
4.1.5.2 Risk of vector transmission to other organs ............................................................................... 17 
4.1.5.3 Risks of insertional mutagenesis and oncogenesis ..................................................................... 18 
4.1.5.4 Risk of germline transmission ..................................................................................................... 18 
4.1.5.5Risk of surgical adverse effects .................................................................................................... 18 
4.1.5.6Risk of adverse effects of short-term corticosteroids ................................................................. 19 
4.1.5.7Risks of investigations performed during assessment and follow up ......................................... 19 
4.1.5.8 Conclusion on the risk-benefit ratio ........................................................................................... 19 
4.1.6 
Explanation for Choice of Comparators .................................................................................. 20 
4.2 
Objectives........................................................................................................................................ 20 
4.2.1  
Primary Objective .................................................................................................................... 20 
4.2.2  
Secondary Objective ............................................................................................................... 20 
4.3 
Trial Design ...................................................................................................................................... 20 

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4.3.1  
Overall Design ......................................................................................................................... 20 
4.3.1.1 Separate longer term follow up study ........................................................................................ 21 
4.3.2  
IMP administration Review and Dose Escalation Criteria and Process .................................. 21 
4.3.2.1 Dose escalation criteria and Dose Limiting Events ..................................................................... 22 
4.3.2.2 
Dosing process ........................................................................................................................ 22 
4.3.2.2.1 Cohort 1 ................................................................................................................................... 22 
4.3.2.2.2 Cohort 2 ................................................................................................................................... 23 
4.3.2.2.3 Cohort 3 ................................................................................................................................... 23 
4.3.2.2.4 Additional considerations ........................................................................................................ 23 
4.3.2.2.5 Confirmatory safety phase ....................................................................................................... 25 
5 
Methods .............................................................................................................................................. 25 
5.1 
Site Selection ............................................................................................................................... 25 
5.1.1 
Study Setting ........................................................................................................................... 25 
5.1.2 
Site/Investigator Eligibility Criteria ......................................................................................... 25 
5.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ................................................... 26 
5.1.2.2 
Resourcing at site .................................................................................................................... 26 
5.2 
Site approval and activation ....................................................................................................... 26 
5.3 
Participants ................................................................................................................................. 27 
5.3.1 
Eligibility Criteria ..................................................................................................................... 27 
5.3.1.1 
Participant selection ............................................................................................................... 27 
5.3.1.2 
Participant Inclusion Criteria ................................................................................................... 27 
5.3.1.3 
Participant Exclusion Criteria .................................................................................................. 28 
5.3.1.4 
Eligibility Criteria for Individuals Performing the Interventions ............................................. 28 
5.3.1.5 
Co-enrolment Guidance .......................................................................................................... 28 
5.3.1.6 
Screening Procedures ............................................................................................................. 28 
5.3.1.6.1  
Informed Consent Procedure .............................................................................................. 29 
5.3.1.6.2 
Screening Period ................................................................................................................. 29 
5.3.1.6.3 
Enrolment ........................................................................................................................... 30 
5.4 
Interventions ................................................................................................................................... 30 
5.4.1  
Products .................................................................................................................................. 30 
5.4.1.1 
Name and Description of Investigational Medicinal Product(s) ............................................. 30 

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5.4.1.2 
ATIMPs Classified as Genetically Modified Organisms ........................................................... 31 
5.4.1.3 
Source of ATIMPs .................................................................................................................... 31 
5.4.1.4  
Preparation and Labelling of the Investigational Medicinal Product ................................. 31 
5.4.1.5 
Description and Justification of Route of Administration and Dose ....................................... 32 
5.4.1.6 
Name and Description of Each Non-Investigational Medicinal Drug (NIMP) ......................... 33 
5.4.2 
Protocol defined clinical schedule .......................................................................................... 34 
5.4.2.1 
Baseline Assessments ............................................................................................................. 34 
5.4.2.2 
ATIMP administration Procedures .......................................................................................... 36 
5.4.2.2.1 Preoperative procedure ........................................................................................................... 36 
5.4.2.2.2 Operative procedure ................................................................................................................ 37 
5.4.2.3 
Subsequent Assessments ........................................................................................................ 38 
5.4.2.4 
Laboratory Procedures ............................................................................................................ 39 
5.4.3 
Dispensing ............................................................................................................................... 40 
5.4.3.1 
Receipt and Storage of the Investigational Medicinal Product .............................................. 40 
5.4.4 
Dosages ................................................................................................................................... 40 
5.4.4.1 
Dosages and dosage modifications ......................................................................................... 40 
5.4.5 
Accountability ......................................................................................................................... 40 
5.4.6 
Compliance and Adherence .................................................................................................... 41 
5.4.7 
Concomitant Care ................................................................................................................... 41 
5.4.8 
Overdose of Trial Medication ................................................................................................. 41 
5.4.9 
Protocol Discontinuation ........................................................................................................ 42 
5.4.9.1 
Subject Withdrawal ................................................................................................................. 42 
5.4.9.2 
Trial Stopping Rules ................................................................................................................. 42 
5.5 
Outcomes .................................................................................................................................... 42 
5.5.1 
Primary Outcomes .................................................................................................................. 42 
5.5.2 
Secondary Outcomes .............................................................................................................. 43 
5.6 
Trial Assessments ........................................................................................................................ 44 
5.6.1 
Early Stopping of Follow-up .................................................................................................... 46 
5.6.2 
Loss to Follow-up .................................................................................................................... 46 
5.6.3 
Trial Closure ............................................................................................................................ 46 
5.6.4 
Passive/Long Term Follow-Up After the End of the Trial ........................................................ 46 

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5.7 
Sample Size ..................................................................................................................................... 46 
5.8 
Recruitment and Retention ............................................................................................................ 46 
5.8.1 
Recruitment ............................................................................................................................ 46 
5.8.2 
Retention................................................................................................................................. 47 
5.9 
Assignment of Intervention ............................................................................................................ 47 
5.9.1 
Allocation ................................................................................................................................ 47 
5.10 
Data Collection, Management and Analysis ............................................................................... 47 
5.10.1 
Data Collection,Management and Entry ................................................................................. 47 
5.10.3 
Non-Adherence and Non-Retention ....................................................................................... 48 
5.10.4 
Statistical Methods ................................................................................................................. 48 
5.10.4.1 
Statistical Analysis Plan ....................................................................................................... 48 
5.10.4.2 
Statistical Methods – Primary Outcome Analysis ............................................................... 48 
5.10.4.3 
Statistical Methods - Secondary Outcome Analysis ............................................................ 49 
5.10.4.4 
Statistical Methods – Health Economic Analysis ................................................................ 49 
5.11 
Data Monitoring .......................................................................................................................... 50 
5.11.1 
Independent Data Monitoring Committee (IDMC) ................................................................. 50 
5.11.2 
Interim Analyses ...................................................................................................................... 50 
5.11.3 
Data Monitoring for Harm ...................................................................................................... 50 
5.11.3.1 
Safety reporting .................................................................................................................. 50 
5.11.3.2 
Other Notifiable Adverse Events ......................................................................................... 51 
5.11.3.3 
Procedures to follow in the event of female participants becoming pregnant .................. 52 
5.11.3.4 
Procedures to follow in the event of the partners of male participants becoming pregnant
 
52 
5.11.3.5 
Investigator responsibilities relating to safety reporting .................................................... 52 
5.11.3.5.1 
Seriousness assessment .................................................................................................. 53 
5.11.3.5.2 
Severity or grading of Adverse Events ............................................................................ 53 
5.11.3.5.3 
Causality .......................................................................................................................... 53 
5.11.3.5.4 Expectedness .......................................................................................................... 54 
5.11.3.6 
Notifications ........................................................................................................................ 55 
5.11.3.6.1 
Notifications by the Investigator to EMAS ...................................................................... 55 
5.11.3.6.2  
Reporting Urgent Safety Measures ................................................................................. 56 

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5.11.3.6.3 
EMAS responsibilities ...................................................................................................... 56 
5.11.3.6.4 
Reporting SUSARs in International Trials ........................................................................ 56 
5.11.3.6.5 
Annual Progress Reports ................................................................................................. 57 
5.11.4 
Quality Assurance and Control ................................................................................................... 57 
5.11.4.1 
Risk Assessment .................................................................................................................. 57 
5.11.4.2 Clinical Monitoring .................................................................................................................... 57 
5.11.4.3.1 
Direct access to participant records ............................................................................... 57 
5.11.4.4 
Trial Oversight ..................................................................................................................... 57 
5.11.4.4.1 
Clinical Management Team ............................................................................................ 58 
5.11.4.4.2 
Independent Data Monitoring Committee ..................................................................... 58 
5.11.4.4.3 
Trial Sponsor ................................................................................................................... 58 
6 
Ethics and Dissemination .................................................................................................................... 58 
6.1 
Research Ethics Approval ............................................................................................................ 58 
6.2 
Competent Authority Approvals ................................................................................................. 58 
6.3 
Other Approvals .......................................................................................................................... 59 
6.4 
Protocol Amendments ................................................................................................................ 59 
6.5 
Consent or Assent ....................................................................................................................... 59 
6.6 
Confidentiality ............................................................................................................................. 60 
6.7 
Declaration of Interests .............................................................................................................. 61 
6.8 
Indemnity .................................................................................................................................... 61 
6.9 
Finance ........................................................................................................................................ 61 
6.10 
Archiving ..................................................................................................................................... 61 
6.10.1 
Archiving of Essential Trial Documentation Relating to Traceability ...................................... 61 
6.10.2 
Archiving of Other Essential Trial Documentation .................................................................. 62 
6.11 
Access to Data ............................................................................................................................. 63 
6.12 
Ancillary and Post-Trial Care ....................................................................................................... 63 
6.13 
Publication Policy ........................................................................................................................ 63 
6.13.1 
Trial Results ......................................................................................................................... 63 
7 
Ancillary Studies .................................................................................................................................. 63 
8 
Revision History .................................................................................................................................. 63 
9 
References .......................................................................................................................................... 65 

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1. 
Administrative information 
This document was constructed using the MeiraGTx UK II Ltd. Protocol template. It describes the Gene 
Therapy Trial for LCA OPTIRPE65 trial, sponsored and co-ordinated by MeiraGTx UK II Ltd.  
It provides information about procedures for entering participants into the trial, and provides sufficient 
detail to enable: an understanding of the background, rationale, objectives, trial population, 
intervention, methods, statistical analyses, ethical considerations, dissemination plans and 
administration of the trial; replication of key aspects of trial methods and conduct; and appraisal of the 
trial’s scientific and ethical rigour from the time of ethics approval through to dissemination of the 
results. The protocol should not be used as an aide-memoire or guide for ATIMP administration to other 
patients. Every care has been taken in drafting this protocol, but corrections or amendments may be 
necessary. These will be circulated to registered investigators in the trial.  
MeiraGTx UK II Ltd. supports the commitment that its trials adhere to the SPIRIT guidelines. As such, the 
protocol template is based on an adaptation of the Standard Protocol Items: Recommendations for 
Interventional Trials (SPIRIT) 2012 Statement for protocols of clinical trials (Chan et al. 2013a). The 
SPIRIT Statement Explanation and Elaboration document (Chan et al. 2013b) can be referred to, or a 
member of MeiraGTx UK II Ltd. Clinical Operations team can be contacted for further detail about 
specific items. 
1.1 
Compliance 
The trial will be conducted in compliance with the approved protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
• 
Applicable laws and regulations 
MeiraGTx UK II Ltd. will be informed of any possible serious breach of compliance as soon as it is 
identified, so that the requirement to report the breach can be fulfilled within the relevant applicable 
timelines specified in each country in which the study is being conducted. 
For the purposes of reporting, a ‘serious breach’ is one that is likely to affect to a significant degree: 
• 
The safety or physical or mental integrity of the participants in the trial, or 
• 
The scientific value of the trial. 
1.2 
Sponsor 
MeiraGTx UK II Ltd., 92 Britannia Walk, London N1 7NQ is the study sponsor. 
 

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1.3 
Structured trial summary 
 
Primary Registry and Trial 
Identifying Number 
Clinical trials.gov (NCT02781480) 
 
Secondary Identifying Numbers 
EudraCT: 2015-003418-25 
Sponsor protocol number: MGT003 
Source of Monetary or Material 
Support 
Medical Research Council (MRC grant reference: 
MR/M015815/1) 
MeiraGTx UK II Ltd. 
Sponsor 
MeiraGTx UK II Ltd. 
Contact for Public Queries 
ocularinfo@meiragtx.com 
Contact for Scientific Queries 
James Bainbridge MA PhD FRCOphth 
Professor of Retinal Studies  
UCL Institute of Ophthalmology 
11-43 Bath Street 
London EC1V 9EL 
Tel: 020 7608 6889 
Fax: 020 7608 6991 
Email: j.bainbridge@ucl.ac.uk 
Public Title 
Gene Therapy Trial for LCA OPTIRPE65 
Scientific Title 
An Open-label, Multi-Centre, Phase I/II Dose Escalation Trial 
of an Adeno-Associated Virus Vector (AAV2/5-OPTIRPE65) for 
Gene Therapy of Adults and Children with Retinal Dystrophy 
associated with Defects in RPE65 (LCA2) 
Countries of Recruitment 
United Kingdom, United States of America 
Health Condition(s) or Problem(s) 
Studied 
Retinal dystrophy associated with defects in RPE65 
Intervention(s) 
Open label, non-randomised, dose-escalation (low dose at 
1.0 x1011 vg/mL; intermediate dose at 3.0 x1011 vg/mL; high 
dose at 1.0 x1012 vg/mL), phase I/II study, by subretinal 
administration of AAV2/5-OPTIRPE65 in up to 27 participants 
with LCA caused by mutations in RPE65.  
Key Inclusion and Exclusion Criteria 
Key Inclusion Criteria:  
• Aged 3 years or older  
• Early-onset severe retinal dystrophy consistent with RPE65 
deficiency 
• Homozygous or compound heterozygous missense or null 
mutations in RPE65 
• Functional or structural evidence of photoreceptor 
preservation 
• Able to undertake age-appropriate clinical assessments  
• Willing to give consent for the use of blood and blood 
components collected throughout the trial for the 
investigation of immune response to ATIMP 
 
Key Exclusion Criteria:  
• Females who are pregnant or breastfeeding 
• Contraindications for transient immune-suppression (i.e. 
history of diabetes mellitus, gastric or duodenal ulceration, 

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hiatus hernia, uncontrolled gastro-oesophageal reflux in the 
past or are using non-steroidal anti-inflammatory drugs on a 
regular basis at the time of screening)  
Have participated in another research study involving an 
investigational therapy for ocular disease within the last 6 
months.  
• Have had intraocular surgery within 6 months of screening. 
• Have an ocular or systemic disorder that may preclude 
subretinal surgery and/or interfere with interpretation of 
the study results 
Study Type 
Phase I/II, open-label, non-randomised, 2 centre, dose 
escalation in adults and children with retinal dystrophy 
associated with defects in RPE65 
Date of First Enrolment 
April 2016 
Target Sample Size 
Up to 27 participants 
Primary Outcome(s) 
The primary outcome is safety of subretinal administration of  
AAV2/5-OPTIRPE65.  
 
Safety is defined as the absence of ATIMP related: 
• 
reduction in visual acuity by 15 ETDRS letters or more 
• 
severe unresponsive inflammation 
• 
infective endophthalmitis 
• 
ocular malignancy 
• 
Grade III or above non-ocular SUSAR Safety will be 
assessed for 6 months after the intervention.  
Key Secondary Outcomes 
The secondary outcomes are measures of the efficacy of the 
intervention, which will be performed on an individual 
participant basis and will be descriptive in nature.  
 
1) Any improvement in visual function from baseline that is 
greater that the test-retest variation for that test and is 
sustained for at least two consecutive assessments. 
 
2) Any improvement in retinal function from pre intervention 
that is greater than the test-retest variation and measurable 
by electroretinography (ERG). 
 
3) Quality of life measures 
1.4 
Roles and responsibilities 
These membership lists are correct at the time of writing; please see terms of reference documentation 
in the TMF for current lists. 
1.4.1 Protocol contributors 
Name 
Affiliation 
Role 
James Bainbridge 
University 
College London 
CI - Protocol development including surgical 
considerations 
Michel Michaelides 
University 
College London 
Protocol development including clinical assessments 

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Stuart Naylor 
MeiraGTx UK 
Ltd. 
Protocol development 
Julie Bakobaki 
MeiraGTx UK 
Ltd. 
Protocol development and co-ordination 
Victoria McCudden 
UCL CCTU 
Clinical Project Manager 
Simon Skene 
UCL CCTU 
Principal Statistician 
Neruban Kumaran 
University 
College London 
Protocol development 
Praseeda Thaikalloor 
MeiraGTx UK 
Ltd 
Protocol development and co-ordination 
1.4.2 Independent Data Monitoring Committee 
Name 
Affiliation 
Role and responsibilities 
Professor Hatice Nida 
Sen 
National 
Institutes of 
Health 
Independent Chair, Clinical Professor of 
Ophthalmology 
Graeme MacLennan 
University of 
Aberdeen 
Independent statistician 
Emma Morris 
UCL Institute of 
Immunity and 
Transplantation 
Independent member, Professor of Clinical Cell and 
Gene Therapy 
Andrew Baker 
University of 
Edinburgh 
BHF Professor of Translational Cardiovascular Sciences 
 
 

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2 
Trial Diagram 
 
 
 
 
 
 
 
 

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3 
Abbreviations 
AAV 
Adeno-Associated 
Virus 
Ad 
Adenovirus 
AE 
Adverse Event 
AF 
Autofluorescence 
AO 
Adaptive Optics 
AR 
Adverse Reaction 
ATIMP 
Advanced Therapy 
Investigational 
Medicinal Product 
bps 
Basepairs 
BGL65p 
hRPE65 promoter 
fragment that is less 
efficient than the 
NA65p promoter 
CA 
Competent Authority 
CAI 
Codon Adaptation 
Index 
cDNA 
complementary 
Deoxyribonucleic Acid 
CLIA 
Clinical Laboratory 
Improvement 
Amendments  
CI 
Chief Investigator 
CMT 
Clinical Management 
Team 
CMV 
Cytomegalovirus 
CNS 
Central nervous 
system 
CRF 
Case Report Form 
CRO 
Contract Research 
Organization 
CTA 
Clinical Trial 
Authorisation 
CTCAE 
Common Terminology 
Criteria for Adverse 
Events  
CTIMP 
Clinical Trial of 
Investigational 
Medicinal Product 
DAPI 
4',6-diamidino-2-
phenylindole 
DLE 
Dose-limiting event 
DNA 
Deoxyribonucleic acid 
DSUR 
Development Safety 
Update Report 
EC 
European Commission  
eGFP 
enhanced green 
fluorescent protein 
ELISA 
Enzyme-linked 
Immunosorbent Assay 
ELISPOT 
Enzyme-linked 
ImmunoSpot Assay 
EMA 
European Medicines  
Agency 
EOSRDs 
early-onset severe 
retinal dystrophies 
EQ-5D-5L 
EuroQOL Quality of 
Life 5 dimension 5 
level 
ERG 
Electroretinography 
ETDRS 
Early Treatment 
Diabetic Retinopathy 
Study 
EU 
European Union 
EUCTD 
European Clinical Trials 
Directive 
EudraCT 
European Clinical Trials 
Database 
EudraVIGILANCE 
European database for 
Pharmacovigilance 
FAF 
Fundus 
Autofluorescence 
FDA 
(US) Food and Drug 
Administration 
FWA 
Federal Wide 
Assurance 
GCP 
Good Clinical Practice 
GFP 
Green Fluorescent 
Protein 
GLP 
Good Laboratory 
Practice 
GMO 
Genetically Modified 
Organism 
GMP 
Good Manufacturing 
Practice 
GMSC 
Genetic Modification 
Safety Committee 
GTAC 
Gene Therapy Advisory 
Committee 
H&E 
haematoxylin and 
eosin 
HEK293T 
human embryonic 
kidney epithelial cell 
line 
hRPE65 
human retinal pigment 
epithelium-specific 

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protein 65 (all-trans-
retinyl isomerase) 
HSE 
Health and Safety 
Executive 
HTA 
Human Tissue 
Authority 
H2B 
histone H2B 
IB 
Investigator Brochure 
ICF 
Informed Consent 
Form 
ICH 
International 
Conference on 
Harmonisation 
IDMC 
Independent Data 
Monitoring Committee 
IMP 
Investigational 
Medicinal Product 
IMPD 
Investigational 
Medicinal Product 
Dossier 
IND 
Investigational New 
Drug 
IRB 
Institutional Review 
Board 
ISF 
Investigator Site File 
ISRCTN  
International Standard 
Randomised Trial 
Number 
ITRs 
Inverted terminal 
repeats 
ITT 
Intention to Treat 
IV (or iv) 
Intravenously 
IVI 
Impact of Visual 
Impairment 
KEC 
Kellogg Eye Centre 
LCA 
Leber congenital 
amaurosis 
LCA2 
Retinal dystrophy 
associated with defects 
in RPE65 
LREC 
Local Research Ethics 
Committee  
MA 
Marketing 
authorisation 
Main REC 
Main Research Ethics 
Committee  
mGMP 
Manner-of-good 
manufacturing practice 
MHRA 
Medicines and 
Healthcare products 
Regulatory Agency 
MRI 
Magnetic Resonance 
Imaging 
MTD 
Maximum Tolerated 
Dose  
mRNA 
Messenger RNA 
NA65p 
Optimised hRPE65 
promoter 
NHS R&D 
National Health Service 
Research & 
Development 
NIH 
National Institutes of 
Health 
NIMP 
Non Investigational 
Medicinal Product 
NZW 
New Zealand White 
OBA 
Office of Biotechnology 
Activities 
OCT 
Optical Coherence 
Tomography 
ONL 
Outer nuclear layer 
PCT 
Polymerase Chain 
Reaction 
PERG 
Pattern 
Electroretinogram 
PHI 
Protected Health 
Information 
PI 
Principal Investigator 
PIS 
Participant Information 
Sheet 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life 
Year 
QC 
Quality Control 
qds  
quarter die sumendus 
(four times a day) 
QOL 
Quality of Life 
QMMP 
Quality Management 
and Monitoring Plan 
qPCR 
Quantitative 
Polymerase Chain 
Reaction 
QP 
Qualified Person for 
release of CTIMP 
qPCR 
Quantitative 
polymerase chain 
reaction 

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rAAV 
Recombinant adeno 
associated virus 
rAAV2/2 
recombinant adeno-
associated virus 
serotype 2 
R&D 
Research and 
Development 
REC 
Research Ethics 
Committee 
RG 
Research grade 
RNA 
Ribonucleic acid 
RPE 
Retinal Pigment 
Epithelium 
RPE65 
retinal pigment 
epithelium-specific 
protein 65 (all-trans-
retinyl isomerase) 
rt-PCR 
reverse 
transcription- polymer
ase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse 
Reaction 
SD 
standard deviation 
SDV 
Source Data 
Verification 
SOP 
Standard Operating 
Procedure 
SmPC 
Summary of Product 
Characteristics 
SSA 
Site Specific Approval 
SSAR 
Suspected Serious 
Adverse Reaction 
SUSAR 
Suspected Unexpected 
Serious Adverse 
Reaction 
SV40 
Simian virus 40 
TMF 
Trial Master File 
ToR 
Terms of Reference 
tRNA 
Transfer ribonucleic 
acid 
UAR 
Unexpected Adverse 
Reaction 
UCL 
University College 
London 
UCLH 
University College 
London Hospital 
UK 
United Kingdom 
US 
United States of 
America 
vg 
Viral Genomes 
WGTU 
Wolfson Gene Therapy 
Unit 
WT 
Wild type 

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4 
Introduction 
4.1 
Background and Rationale 
4.1.1 Background 
Inherited retinal degenerations cause sight impairment in approximately 1 in 3000 people in the 
Western world. There are currently no effective treatments. Leber congenital amaurosis (LCA) is a 
severe, early-onset form of inherited retinal degeneration involving both rod and cone photoreceptors 
(Perrault et al. 1999; Koenekoop, 2004). LCA is caused by mutations in one of at least 19 different genes 
(see https://sph.uth.edu/retnet). Mutations in RPE65, which is expressed in the retinal pigment 
epithelium (RPE), are responsible in 3 to 16 % of people affected. The RPE65 gene encodes a 65-kDa 
retinal pigment epithelium (RPE)-specific protein that is required for the conversion of vitamin A to 11-
cis-retinal by the RPE and is essential for the regeneration of the rod visual pigment (Hamel et al. 1993; 
Redmondet al. 2008). Mice and dogs that are homozygous for RPE65 null mutations have abnormally 
low levels of 11-cis-retinal, resulting in very poor vision and depressed light- and dark-adapted 
electroretinogram responses (Ekesten et al. 2001; Dekomien et al. 2003). Children with RPE65 mutations 
lack rod function from birth; residual cone function is typically extinguished by early adulthood 
(Marlhens et al. 1997; Cremers et al. 2002). 
Proof-of-principle for RPE65 gene replacement therapy has been demonstrated using recombinant 
adeno-associated virus serotype 2 (rAAV2/2) vectors in animal models (Acland et al. 2001; Acland et al. 
2005; Jacobson et al. 2006; Le Meur et al. 2007; Bennicelli et al. 2008) of the condition and in 3 previous 
clinical trials (Bainbridge et al. 2008; Maguire et al. 2008; Cideciyan et al. 2008).  In these 3 studies, 
adults and children as young as 6 years of age, were administered AAV vectors by sub-retinal 
administration at viral doses ranging from 1.5x1010 to 1x1012. Although vector administration was 
generally well-tolerated, a minority of participants who were administered 1012 viral genomes 
developed transient intraocular inflammation and immune responses to AAV indicating dose-limiting 
toxicity (Bainbridge et al. 2015). In all instances, intraocular inflammation resolved following more 
extended administration of corticosteroid treatment. 
In all 3 clinical trials, subsets of participants benefitted with improved visual function to varying extents 
during the first year. However, longer-term follow-up demonstrated that progressive degeneration 
continued unabated, and the maximal improvements in retinal sensitivity were not maintained 
(Cideciyan et al. 2013; Bainbridge et al. 2015). Additional pre-clinical studies have shown that 
endogenous expression of RPE65 in humans is greater than in the animal models, and support the 
hypothesis that continued degeneration reflects suboptimal RPE65 expression in the human retina 
(Bainbridge et al. 2015).  
To increase the availability of RPE65 for affected humans we have developed a new optimized AAV 
vector. Having identified in our previous clinical trial the maximal tolerated AAV2/2 vector dose, we 
have optimized the therapeutic vector to drive more efficient transgene expression. We have achieved 
this by optimization of the construct and the Kozak sequence, inclusion of an exogenous intron, and 

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codon optimization. We will use an AAV2/5 vector to deliver the construct because we have determined 
that AAV2/5 vectors are more effective than AAV2/2 vectors for gene therapy in Rpe65-deficient mice. 
The aim of this trial is to determine the safety of this new optimised AAV2/5 vector in humans and to 
explore its potential efficacy. 
4.1.2  Preclinical Data  
Our new optimised vector, AAV2/5-OPTIRPE65, provides 300-fold greater efficacy in animal models 
compared with that used in our previous trial.  
The toxicity of a single dose of AAV2/5-OPTIRPE65 administered as a subretinal injection has been 
evaluated in mice and rabbits.  Long-term (9-month) overexpression of RPE65 protein in the mouse RPE 
did not result in gross toxicity, as determined by clinical observations of health and behaviour or by 
increased mortality, or in ocular toxicity, as determined by functional and structural assessments of 
retinal health (Study RPE65-02/01).  In 8-week single dose studies in mice (Study RPE65-02/02) and 
rabbits (Study RPE65-02/04), subretinal administration of AAV2/5-OPTIRPE65 did not result in local 
adverse effects on retinal structure or function.  No overt systemic effects on health, as assessed by 
appearance or behaviour of the animals, or by macroscopic examination of the major organs post-
mortem, were observed.  Low level dissemination of vector to the liver, adrenal glands, and draining 
lymph nodes was detected in mice, and low level dissemination of vector to the liver and tissues of the 
optic tract was detected in rabbits.  This low level dissemination of vector did not result in pathological 
changes.  Subretinal administration of AAV2/-OPTIRPE65 in an Rpe65-deficient mouse strain did not 
result in adverse local or systemic effects (Study RPE65-02/03). 
No immune responses against the RPE65 protein were detected in a 4-week, single dose study of 
bilateral subretinal injection in the Rpe65-deficient (Rpe65−/−) mouse Study (RPE65-02/03). There were 
some immune responses against the vector capsid in this study and in the 8-week single dose toxicity 
and biodistribution studies of AAV2/5-OPTIRPE65 in mice (Study RPE65-02/02) and rabbits (Study 
RPE65-02/04), as would be expected after administration of AAV vector.  These were only detectable 
using the neutralising antibody assay.  Anti-AAV5 immune responses were not more pronounced in the 
Rpe65-deficient (Rpe65−/−) mouse compared with WT mice, and did not correlate with any changes in 
any of the other assessments.   
4.1.3 Rationale 
Inherited defects in the gene encoding RPE65 cause night blindness and progressive loss of sight in 
children. There is currently no approved treatment available. In previous clinical trials we and others 
have shown that subretinal administration of recombinant AAV2/2 vectors containing the cDNA for 
human RPE65 is generally well-tolerated and can improve low-luminance vision (night vision) in affected 
children and young adults (Bainbridge et al. 2008; Maguire et al. 2008; Cideciyan et al. 2008; Bainbridge 
et al. 2015). However, the efficacy of the intervention in humans is lower than that measured in mice 
and dogs with a similar condition. We hypothesise that higher efficacy can be achieved in affected 
humans by improving the efficiency of expression of RPE65 through optimisation of the vector 
construct. The purpose of this trial is to determine whether administration of a new version of the 

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vector (AAV2/5-OPTRPE65), which has been optimised for efficiency of both transduction and RPE65 
protein production, is safe and can result in greater efficacy. 
4.1.4  Risk/Benefit 
A gene therapy trial in human volunteers should not put the participants at disproportionate risk and for 
this reason should be restricted to individuals with serious disorders where effective treatments are not 
available. Children with RPE65 mutations lack rod function and night vision from birth; residual cone 
function and daylight vision is severely impaired by early adulthood. There is no established treatment. 
Although younger individuals in particular stand to benefit from gene supplementation therapy by virtue 
of their visual plasticity to accommodate an improvement in retinal function, we anticipate that people 
of a range of ages may benefit – as seen in the three aforementioned Phase 1 clinical trials. To define 
this range we will include participants of various ages in the trial; once an acceptable safety profile has 
been established in adults, we will include children. We will enhance the safety of the proposed 
approach by restricting transgene expression to the target tissue by virtue of rAAV vector tropism and 
the promoter sequence used, and by restricting the intervention to only one eye of each participant. The 
risk of adverse effects on foveal function will be further minimised by preferentially targeting the vector 
surgically to the extrafoveal retina. 
4.1.5  Assessment and Management of Risk 
The MHRA risk categorisation to participant safety in relation to the ATIMP is Type C (i.e. markedly 
higher than the risk of standard medical care). General risk management will include the detailed review 
of participants, appropriate intervals between ATIMP administration to successive participants, the dose 
escalation plan, and limiting the risks to children by initially demonstrating an acceptable safety profile 
in adults. In addition, the schedule of participants’ assessments has been designed to identify the short-
term and the long-term risks. Details of specific risks and their management strategies are outlined 
below. 
4.1.5.1 Risk of immune responses to AAV capsid proteins or expressed RPE65 
protein 
There is a risk that inflammation will occur following intra-ocular administration of rAAV in participants. 
The risk of inflammation is likely to be highest during the early postoperative period after ATIMP 
administration, before vector capsids are degraded. The risk of inflammation during this period will be 
minimised by pre- and post-operative prophylactic administration of topical and systemic 
corticosteroids. In our first clinical trial of gene therapy, intra-ocular delivery of an AAV2/2 vector was 
followed by transient intraocular inflammation in 3 of 12 participants. In this current protocol, 
intraocular administration of an AAV2/5 has been well tolerated in the majority of participants to 
date. A minority of participants developed an episode of intraocular inflammation involving the 
posterior segment, which responded to further administration of systemic corticosteroids. 
4.1.5.2 Risk of vector transmission to other organs 
Biodistribution studies suggest that following subretinal injection of rAAV, there may be anterograde 
and trans-synaptic transport of small amounts of vector genome from the retina to central visual 

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structures (Stieger et al. 2008). This is likely to result from inadvertent transduction of retinal ganglion 
cells following reflux of vector into the vitreous. Since only tiny amounts of vector are likely to reach the 
brain, the possibility of transgene expression causing toxicity in the brain is likely to be very low. 
4.1.5.3 Risks of insertional mutagenesis and oncogenesis 
The possibility of oncogenic events due to vector-mediated insertional mutagenesis cannot be excluded 
with certainty, but available evidence suggests it to be unlikely given that (i) rAAV vector genomes 
integrate into host chromosomes at a very low frequency (Nowrouzi et al. 2012), (ii) a relatively low 
number of rAAV particles will be administered, and (iii) the eye predominantly contains non-dividing 
cells and consequently ocular tumours are very rare. Furthermore, oncogenesis has not been reported 
following injection of rAAV into thousands of rodent eyes. Even when we injected AAV vectors into a 
large number of tumour-prone p53-/- mice, we did not observe malignant transformation of retinal cells 
(Balaggan et al. 2012).   
In the highly unlikely event that an intraocular tumour does arise in a participant, comprehensive 
monitoring procedures will enable early detection and thus prompt and appropriate management.  
4.1.5.4 Risk of germline transmission 
The risk of inadvertent germline transmission is very small. In a number of studies using a variety of 
animal models involving various routes of administration, including intraocular injection, inadvertent 
germline transmission by rAAV vectors has not been detected. Similarly, we detected no vector 
genomes in semen of participants in our previous retinal gene therapy clinical trial (Bainbridge et al. 
2008). However, in a Phase I clinical trial where rAAV2 was used to deliver factor IX in participants with 
haemophilia B, vector sequences have been detected in semen samples, though not sperm, from 6 (of 7) 
participants for a short period after vector delivery (Manno et al. 2006). Although this indicates there 
may be some potential for inadvertent germline transmission following the systemic delivery of high 
doses of vector suspension, the possibility of such an event following the microsurgical delivery of tiny 
amounts of vector to intraocular compartments is considered to be remote. Participants who are fertile 
and sexually active will be requested to use double-barrier contraception for at least 12 months 
following ATIMP administration.  
4.1.5.5 Risk of surgical adverse effects 
The risk of significant surgical adverse effects is similar to the standard surgical care for other common 
forms of vitreo-retinal disorders.  Only highly experienced surgeons will perform the procedure to limit 
the risk of surgical adverse events. These complications can normally be treated effectively by 
medication or further surgery and rarely result in a permanent effect on eyesight. The risk of permanent 
severe visual loss from vitrectomy surgery is approximately 1 in 1000. We have identified no significant 
surgical adverse effects in any of the 12 participants in our previous clinical trial performed using the 
same surgical procedure.  
Delivery of vector suspension to the subretinal space will be performed following a standard surgical 
vitrectomy. This will involve a 3-port pars plana vitrectomy followed by injection of vector suspension 
using a fine cannula through small retinotomies, resulting in a transient retinal detachment. Previous 

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gene therapy clinical trials have shown that the bleb of subretinal vector suspension will resolve 
spontaneously over the course of the first 24 to 48 hours postoperatively as the fluid is absorbed by the 
underlying retinal pigment epithelium.  
The aim of the intervention is to improve and/or to protect photoreceptor cell function. Previous trials 
have identified a risk of retinal thinning at the fovea, which is the site of greatest cone density, following 
subfoveal vector delivery. Although such thinning is not clearly associated with an adverse effect on 
foveal function in the short-term, we cannot exclude the possibility in the longer-term, and for this 
reason we aim to exclude the fovea from the area of vector delivery in the proposed trial.  
Potential complications of surgery specifically include persistence of the subretinal vector bleb, the 
development of retinal tears, and persistent postoperative intraocular inflammation. We will minimise 
any risk to overall visual function by leaving the contralateral fellow eye untreated. Retinal detachment 
caused by persistent vector bleb or intraoperative retinal tear is expected to occur in fewer than 1 in 100 
cases and can be effectively managed in the majority of participants by retinopexy with or without 
appropriate intraocular tamponade. Persistent intraocular inflammation will be managed by topical 
corticosteroid therapy with systemic steroids where indicated.  
Vitrectomy surgery is a standard technique, commonly performed for a wide range of indications. 
Injection of fluids under the retina is less commonly performed but injection of Hartmann’s solution 
(similar in composition to lactated Ringer's solution) is a standard step in surgery for macular 
degeneration. 
4.1.5.6 Risk of adverse effects of short-term corticosteroids 
Candidates will be screened to ensure there are no contra-indications for transient immune suppression 
by corticosteroids; in particular, a history of uncontrolled hypertension, diabetes mellitus, tuberculosis, 
renal impairment, osteoporosis, gastric ulceration, severe affective disorder and immunocompromised 
status. The possibility of steroid-induced adverse effects will be monitored regularly. In particular, blood 
pressure and blood glucose will be measured on Baseline, Day 1, Week 1, Week 2 and Week 4, as will 
renal function and liver function (at baseline and 1 day, 7 days, 2 weeks and 4 weeks and 6 weeks after 
surgery).  
4.1.5.7 Risks of investigations performed during assessment and follow up 
The majority of investigations are non-invasive routine clinical tests and present no significant risk. 
Venepuncture causes temporary discomfort, occasionally bruising/swelling and rarely infection at the 
site of puncture.  
4.1.5.8 Conclusion on the risk-benefit ratio 
In conclusion, the clinical benefit of delivery of the RPE65 gene to the retinal epithelium was 
demonstrated in the clinical trial conducted with the first generation product (AAV2/2-hRPE65).  Based 
on the specific modifications to that product (both regulatory elements that control gene expression, 
and sequences to enhance translation), it is hypothesised that AAV2/5-OPTIRPE65 will produce higher 
levels of RPE65 protein than AAV2/2-hRPE65, leading to greater improvements in visual function in 

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patients with LCA2. The investigators judge the scientific value of the trial and potential for individual 
participants to benefit outweigh the risks associated with the intervention. 
4.1.6 Explanation for Choice of Comparators 
There is no currently approved treatment for retinal dystrophy caused by mutations in RPE65, thus 
there are no comparators in this study. The contralateral fellow eye will be left untreated to minimize 
the risk to visual function and may also serve as a control.  
4.2 
Objectives 
4.2.1  Primary Objective 
The primary research objective is to assess the safety of a new optimised virus vector for RPE gene 
replacement in the retina. Safety is defined as an ATIMP related: 
• 
Reduction in visual acuity by 15 ETDRS letters or more 
• 
Severe unresponsive inflammation (defined below) 
• 
Infective endophthalmitis)  
• 
Ocular malignancy 
• 
Grade III or above non-ocular SUSAR (See Section 5.11.3) 
Classification of severe unresponsive inflammation will be according to the SUN (standardisation of 
uveitis nomenclature) Working Group grading system (Am J Ophthalmol. 2005 Sep;140(3):50916.) i.e  
• 
anterior chamber cells 3+ (26-50 cells in a field size of 1mm x 1-mm slit-beam), or  
• 
anterior chamber flare 3+ (marked, iris and lens details hazy) or 
• 
vitreous haze 3+ (Ophthalmology 1985; 92:467-71)  
that fail to improve by 2 steps (or to grade 0) during a 6 week period. 
4.2.2  Secondary Objective 
The secondary research objective is to determine whether a new optimised virus vector for RPE65 gene 
replacement in the retina is effective at improving sight in terms of both visual and retinal function, and 
quality of life. 
4.3 
Trial Design 
4.3.1  Overall Design 
This is an open-label phase I/II dose-escalation trial to determine the safety and efficacy of a single 
subretinal administration of the ATIMP in participants with RPE65-related retinal dystrophy.  
In the dose escalation phase, up to 18 adult participants will be administered one of 3 different doses of 
vector in cohorts of 3 participants at a time, using a 3+3 design. Based on toxicity data, the IDMC will 

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make a recommendation on the dose to administer to the next cohort of 3 participants. The IDMC may 
recommend   additional participants be treated at a given dose before deciding how to proceed. 
Adults are defined as participants aged 16+ in the UK and aged 18+ in the US. 
Up to 9 children or adults (aged 3 or older) will then be included once an acceptable safety profile has 
been established in adults. The IDMC will agree the maximum tolerated dose in adults before 
recommending administering up to this dose in children. 
Safety and efficacy will be assessed by clinical examination and special investigations according to the 
schedule in section 5.6 of the protocol for 6 months following the intervention. 
4.3.1.1 Separate longer term follow up study 
Participants will subsequently be invited to enrol in a separate 5-year follow-up study where they will be 
assessed for safety up to 60 months following ATIMP administration.  The duration of long-term follow-
up is therefore consistent with the recommendations of the current CHMP Guideline on Follow-up of 
Patients Administered with Gene Therapy Medicinal Products (EMEA/CHMP/GTWP/60436/2007) of 22 
October 2009, where it is stated that, for viral vectors without integration, latency or reactivation 
potential, a brief clinical history and sample testing should be performed pre-treatment, at 3, 6 and 12 
months after treatment, and then yearly thereafter for a minimum of 5 years (and, if non-clinical tests or 
evidence from other clinical trials using identical vectors or modifications of vectors indicate a potential 
for integration or late re-activation, the monitoring should be extended to continue yearly after those 5 
years until data indicate that there is no longer any risk to be followed). Further, although the FDA 
Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events 
(November 2006) recommends a standard 15-year period of follow-up, it is also noted that a shorter 
period of follow up may be possible if the vector does not integrate and has no potential for latency and 
reactivation. The follow up study will be a non-intervention study designed to collect data on longer 
term safety and efficacy at the equivalent of 9, 12, 18, 24, 36, 48 and 60 months following ATIMP 
administration; as such, participants in both studies will be followed up more frequently than 
recommended in the guidance, as additional assessments following ATIMP administration are included 
in the initial study (at weeks 1, 2, 4, 6 and 9) and in the long-term follow up study (at months 9 and 18). 
The follow up study will be supported by a different source of funding, will have a separate protocol, 
participant information and consent processes, and will be submitted for separate ethical review. 
Participants in the current study will be encouraged to join the follow up study as part of their ongoing 
clinical review, but there will be no obligation on their part to do so.  It is acknowledged that despite 
encouragement participants may choose not to participate in the long-term follow-up study; however, 
in this motivated population, where individuals are closely and regularly monitored by their specialist, 
this number is expected to be very small. Moreover, we anticipate that participants are more likely to 
join a long-term study at 6 months than at 2 years following intervention. 
4.3.2  IMP administration Review and Dose Escalation Criteria and Process 
Up to 18 adult participants (as defined in Section 4.3.1) will be administered 1 of 3 doses according to 
the dose-escalation criteria: 

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1) low dose  
 
1mL at 1.0x1011 vg/mL 
2) intermediate dose  
1mL at 3.0x1011 vg/mL 
3) high dose  
 
1mL at 1.0x1012 vg/mL 
Once a maximal tolerated dose is established, up to a further 9 participants aged 3 or above will continue 
to be administered vector up to the highest dose observed to be well tolerated in adults. 
4.3.2.1 Dose escalation criteria and Dose Limiting Events 
Dose escalation will be undertaken in adults, based on an escalation rule around Dose-Limiting Events 
(DLEs). An IDMC will review data from a minimum of 9 weeks of follow up from each cohort of 3 
participants, before recommending the next dose to be assessed in a further cohort of participants. 
A DLE is defined as any of the below occurring during the 9 weeks following administration, at least 
possibly related to the ATIMP, not surgery alone: 
• 
Reduction in visual acuity by 15 ETDRS letters or more 
• 
Severe unresponsive inflammation 
• 
Infective endophthalmitis 
• 
Ocular malignancy or 
• 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
Severe unresponsive inflammation will be defined according to the Standardisation of Uveitis 
Nomenclature (SUN) Working Group grading system (Jabs et Al.  2005) i.e. 
• 
anterior chamber cells 3+ (26-50 cells in a field size of 1mm x 1-mm slit-beam), or  
• 
anterior chamber flare 3+ (marked, iris and lens details hazy), or  
• 
vitreous haze 3+ (Ophthalmology 1985; 92:467-71) 
that fails to improve by 2 steps (or to grade 0) during a 9-week period. 
Review of safety data will be undertaken by the IDMC prior to each dose escalation. Children will be 
included at up to the highest safe vector dose recommended by the IDMC, once a safety profile has 
been established in adult participants.   
4.3.2.2 
Dosing process 
4.3.2.2.1 Cohort 1 
Vector will first be administered at the lowest dose to 1 adult participant only. This participant will be 
monitored for signs of toxicity for a period of 9 weeks.  If there is no DLE as defined above after a minimum 
of 9 weeks, vector will continue to be administered at the same dose to 2 further adult participants. In 
the event of a DLE in the first adult in the cohort, a discussion will be held with the IDMC to agree a 
plan of action for administering the ATIMP to further adults. The IDMC will review the data collected on 
this cohort of participants up to 9 weeks following vector administration to the 3rd participant.  

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4.3.2.2.2 Cohort 2 
In the event that there is no DLE in any participant, the IDMC will recommend administering vector at the 
intermediate dose level to a single adult participant.  If there is no dose-limiting toxicity after a minimum 
of 9 weeks, vector will continue to be administered at the same dose to 2 further adult participants. In 
the event of a DLE in the first adult in the cohort, a discussion will be held with the IDMC to agree a 
plan of action for administering the ATIMP to further adults. The IDMC will again review the data available 
on this next cohort of adult participants up to 9 weeks following vector administration to the 3rd 
participant.  
4.3.2.2.3 Cohort 3 
In the event that there is no DLE in any participant, the IDMC will recommend administering vector at the 
highest dose level to a single adult participant.  If there is no DLE after a minimum of 9 weeks, vector will 
be administered at the same dose to 2 further adult participants. In the event of a DLE in the first adult 
in the cohort, a discussion will be held with the IDMC to agree a plan of action for administering the 
ATIMP to further adults. 
4.3.2.2.4 Additional considerations 
In the event of a DLE in one of the 3 participants at any given dose, the cohort will be expanded at the 
same dose level. The IDMC will review the safety data and confirm that additional participants may be 
treated at this dose. The IDMC may recommend that the same dose of ATIMP is administered to 
additional participants. The dose escalation will continue until 3 participants have been either 
administered the highest dose without any DLEs, or until at least 2 participants among a cohort of 3 to 6 
participants experience DLEs (i.e., ≥33% of participants with a DLE at that dose level), in which case the 
recommended dose will be the level below this toxic dose. In the event that 1 or 2 DLEs are seen at the 
first dose level, the IDMC may recommend administering a lower dose to that described in the protocol 
to a cohort of participants. 
 
 

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Table 1: Dose escalation table 
Number of 
DLEs 
 
Action 
Details 
Low dose 
 
 
 
Participants 1-3 
Participants 4-6 
 
 
0/3 
 
Increase 
Give intermediate dose to next cohort of 
participants 
1/3 
 
Remain 
Give low dose to another cohort of participants (Pt 
4-6) 
≥ 2/3 
 
Stop 
MTD not found. Consider lower dose 
 
≤ 1/6 
Increase/stop 
Has higher dose been tried? 
No: Give intermediate dose to next cohort of 
participants 
Yes: MTD found – low dose 
 
≥ 2/6 
Stop 
MTD not found. Consider lower dose 
Intermediate 
dose 
 
 
 
Participants 1-3 
Participants 4-6 
Action 
Details 
0/3 
 
Increase 
Give high dose to next cohort of participants 
1/3 
 
Remain 
Give intermediate dose to participants 4-6 
≥ 2/3 
 
Decrease/stop 
Give low dose to 3 more participants. If 6 
participants already had low dose, stop. MTD found 
– low dose. 
 
≤ 1/6 
Increase/stop 
Has higher dose been tried? 
No: Give high dose to participants 1-3 
Yes: MTD found – intermediate dose 
 
≥ 2/6 
Decrease/stop 
Give low dose to participants 4-6. If 6 participants 
already had low dose, stop. MTD found – low dose 
High dose 
 
 
 
Participants 1-3 
Participants 4-6 
Action 
Details 
0/3 
 
Remain 
MTD found – give high dose to participants in 
confirmation phase 
 1/3 
 
Remain 
Give high dose to participants 4-6 
≥ 2/3 
 
Decrease/stop 
Give intermediate dose to participants 4-6. If 6 
participants already had intermediate dose, stop. 
MTD found – intermediate dose 
 
 1/6 
Stop 
MTD found – high dose 
 
≥ 2/6 
Decrease/Stop 
Give intermediate dose to participants 4-6. If 6 
participants already had intermediate dose, stop. 
MTD found – intermediate dose 
 

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4.3.2.2.5 Confirmatory safety phase 
MeiraGTx will seek IDMC agreement on the highest dose that can be administered in the expansion 
cohort.  This may include up to 9   participants who may be adults or children. Recruitment into this 
expansion cohort can begin at any dose level up to the IDMC agreed highest dose level.  Children are 
defined as those aged 15 and under in the UK and 17 and under in the US.  Children will be administered 
up to the maximal tolerated dose identified in adults. Having identified a group of children who may be 
willing to participate in the study, the CI will prioritise ATIMP administration to older candidates in the 
first instance. The first child administered vector will be monitored for safety for a period of 9 weeks.  If 
there is no adverse event consistent with the above definition of a DLE after a minimum of 9 weeks, 
vector will continue to be administered to up to 8 further participants. In the event of a DLE as described 
above in the first child, a discussion will be held with the IDMC to agree a plan of action for 
administering the ATIMP to further children. 
5 
Methods 
5.1 
Site Selection 
The trial sponsor has overall responsibility for site and investigator selection. 
5.1.1 Study Setting 
The study settings are academic hospitals and academic research centres selected for their ability to 
perform the intervention and assessments required of this protocol. Participants will be recruited from 2 
clinical centres: one in the United Kingdom (UK) and one in the United States (US). However, 
participants recruited from the centre in the US will have one clinical assessment performed at a 
separate centre so data will be collected from 3 centres: 1 in the United Kingdom and 2 in the United 
States of America.  
5.1.2 Site/Investigator Eligibility Criteria 
Once a site has been assessed as being suitable to participate in the trial, the trial team will provide 
them with a copy of this protocol and the ATIMP Investigator Brochure.  
To participate in the Gene Therapy Trial for LCA OPTIRPE65, investigators and trial sites must fulfil a set 
of criteria that have been agreed by the Gene Therapy Trial for LCA OPTIRPE65Clinical Management 
Team (CMT) and that are defined below. 
Eligibility criteria: 
• 
A named clinician is willing and appropriate to take Principal Investigator responsibility 
• 
Suitably trained staff are available to recruit participants, enter data and collect samples 
• 
Suitably trained and certified staff are available to undertake clinical assessments 
• 
The site has access to all specialised equipment/devices needed for clinical assessments 
• 
The site should be able to archive traceability data for a minimum of 30 years post expiry date of 
the ATIMP 

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• 
The site should have a pharmacy that is able to store, prepare and dispense ATIMP 
appropriately 
• 
The site should be able to store, prepare, dispense, and administer ATIMP appropriately 
Trial sites meeting eligibility criteria and that are accepted by the CMT as being suitable to recruit to the 
trial, will be issued with the Gene Therapy Trial for LCA OPTIRPE65 Trial Master File (TMF) 
documentation to use when applying for local approvals as applicable.  
5.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements 
The investigator(s) must be willing to sign a sponsor’s Clinical Trial Site Agreement and an Investigator 
Agreement to comply with the trial protocol (confirming their specific roles and responsibilities relating 
to the trial, and that their site is willing and able to comply with the requirements of the trial). This 
includes confirmation of appropriate qualifications, familiarity with the appropriate use of any 
investigational products, agreement to comply with the principles of GCP, maintaining up to date GCP 
certification, to permit monitoring and audit as necessary at the site, and to maintain documented 
evidence of all staff at the site who have been delegated significant trial related duties. 
5.1.2.2 
Resourcing at site 
The investigator(s) should be able to demonstrate a potential for recruiting the required number of 
suitable volunteers within the agreed recruitment period (i.e. the investigator(s) regularly provide 
clinical care for the target population). They should also have an adequate number of qualified staff and 
facilities available for the foreseen duration of the trial to enable them to conduct the trial properly and 
safely.  
Sites will be expected to complete a delegation of responsibilities log and provide staff contact details.  
5.2 
Site approval and activation 
The regulatory authorisations for the trial requires that the Medicines and Healthcare products 
Regulatory Agency (MHRA) in the UK and US Food and Drug Administration (FDA) are supplied with the 
names and addresses of all participating site Principal Investigators. Clinical Operations staff at 
MeiraGTx UK II Ltd. will ensure this information is provided to both the MHRA and FDA.  
On receipt of the signed Clinical Trial Agreement and Investigator Agreement, approved delegation of 
responsibilities log and staff contact details, written confirmation will be sent to the site PI. The trial 
manager or delegate will notify the PI in writing of the plans for site initiation. Sites will not be permitted 
to recruit any participants until a letter for activation has been issued.  
The site must conduct the trial in compliance with the protocol as agreed by the Sponsor and, by the 
competent authorities, and which was given favourable opinion by the UK Research Ethics Committee 
(REC) and local Institutional Review Board (IRB) in the US. The PI or delegate must document and explain 
any deviation from the approved protocol, and communicate this to the clinical operations team at 
MeiraGTx UK II Ltd. 

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5.3 
Participants 
5.3.1 Eligibility Criteria 
5.3.1.1 
Participant selection 
The eligibility criteria for this trial have been carefully considered and are the standards used to ensure 
that only medically appropriate participants are entered. Participants not meeting the criteria should 
not be entered into the trial for their safety, and to ensure that the trial results can be appropriately 
used to make future treatment decisions for other people with similar diseases or conditions. It is 
therefore vital that exceptions are not made to these eligibility criteria. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria and 
none of the exclusion criteria as defined below. 
The trial CI will confirm the eligibility of all individual participants. 
5.3.1.2 
Participant Inclusion Criteria 
Inclusion in the trial will be limited to individuals who:  
1. Are aged 3 years or older (although children, as defined in Section 4.3.2.2.5 will only be enrolled 
once the MTD has been agreed) 
2. Have early-onset severe retinal dystrophy consistent with RPE65 deficiency 
3. Have homozygous or compound heterozygous missense or null mutations in RPE65 confirmed in 
an accredited laboratory 
4. Have functional or structural evidence of photoreceptor preservation as assessed by static 
perimetry (for visual field assessment) and SD-OCT scanning respectively* 
5. Are able to give informed consent or assent, with the guidance of their parent/guardian where 
appropriate: children aged 3-6 years will not be asked to provide assent.  
6. Are able to undertake age-appropriate clinical assessments at the trial sites as specified in the 
protocol 
7. If female and of child bearing potential, are willing to use an effective form of birth control 
(hormonal or barrier method of birth control; or abstinence) for at least 12 months following 
ATIMP administration;  
8. If male, are willing to use barrier and spermicide form of contraceptive or maintain sexual 
abstinence for 12 months following ATIMP administration  
9. Females of childbearing potential will have a negative pregnancy test on the day of ATIMP 
administration. Participants are considered not of childbearing potential if they are pre-
pubescent, surgically sterile (i.e. they have undergone a hysterectomy or bilateral 
oophorectomy) or post-menopausal 
10. Are willing to give consent for the use of blood and blood components collected throughout the 
trial for the investigation of immune responses to the ATIMP 
*if the tests having been performed within the 3 months of enrolment and the subject has consented to allow the 
use of those test results, then these tests will not need to be repeated. 

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5.3.1.3 
Participant Exclusion Criteria 
Individuals will be excluded who:  
1. Are females who are pregnant or breastfeeding 
2. Have contraindications for transient immune-suppression by systemic corticosteroids (including 
uncontrolled hypertension, diabetes mellitus, tuberculosis, renal impairment, osteoporosis, 
gastric ulceration, severe affective disorder) or are immunocompromised 
3. Have a previous (within 5 years) history of gastric or duodenal ulceration, hiatus hernia, 
uncontrolled gastro-oesophageal reflux or are using non-steroidal anti-inflammatory drugs on a 
regular basis at the time of screening 
4. Have a known allergy to any of the non-investigational drugs to be used in the trial as defined in 
Section 5.4.1 
5. Have participated in another research study involving an investigational medicinal therapy for 
ocular disease within the last 6 months 
6. Have any other condition that the PI considers makes them inappropriate for entry into the trial 
7. Have had intraocular surgery within 6 months of screening 
8. Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere with 
interpretation of the study results 
9. Are unwilling to consider the possibility of entry into a subsequent longer term follow up study 
5.3.1.4 
Eligibility Criteria for Individuals Performing the Interventions 
Individuals performing the interventions will be limited to those qualified by training and experience to 
perform those interventions. 
Surgery will only be performed by a qualified vitreo-retinal surgeon. The ATIMP will be administered by 
designated individuals at each study site to promote consistency of the intervention. The CI has 
developed a training programme that involves any designated individuals being trained in person by the 
CI. This may involve observations of the procedure being performed in the UK or the US. The completion 
of this training is one of the criteria that will be satisfied prior to site activation. 
5.3.1.5 
Co-enrolment Guidance 
Individuals who have participated in another research study involving an investigational medicinal 
therapy for ocular disease within the last 6 months, will not be eligible for enrolment in this study.  
5.3.1.6 
Screening Procedures 
Written informed consent to enter into the trial must be obtained from participants, or 
parents/guardians/person with legal responsibility (including legal authorities) for children, after 
explanation of the aims, methods, possible benefits and potential hazards of the trial and BEFORE any 
trial-specific procedures are performed or any blood is taken for the trial. The only procedures that may 
be performed in advance of written informed consent being obtained are those that would be 

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performed on all individuals in the same situation as a usual standard of care. Data obtained previously 
from subjects enrolled on the MGT005 LCA Natural history study may be used for screening and/ or 
baseline assessments if testing was performed within the screening/baseline window of this trial and 
the subjects have provided informed consent for the use of the prior obtained results.  
5.3.1.6.1  
Informed Consent Procedure 
Written informed consent will be taken from each participant (or parent/guardian if the participant is a 
child) by the chief/principal investigator or delegated clinician following appropriate explanation of the 
aims, methods, possible benefits and risks of the study. The Investigator or designee will explain that the 
participants 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, and without their clinical care being affected. No clinical trial 
procedure will be conducted prior to taking consent from the participant.  
The consent process will be managed during at least 2 meetings. At an initial meeting, information will 
be presented to potential participants in a form appropriate to their level of understanding. In the case 
of children, they and their legal guardian(s) will be offered the support of a family support counsellor (in 
the UK) or genetic counsellor (in the US). Potential participants will be provided with the relevant 
participant information sheets (or audio versions) and given time (a minimum of 24 hours) to consider 
their decision. 
At a subsequent meeting, potential participants will be provided with a further opportunity to ask 
questions and to sign the consent form. Children will be invited to give their verbal (and noted in their 
medical notes) or written assent to participation where this is age appropriate (i.e. children aged over 6 
years). Where children aged over 6 years do not assent, they will not be entered into the trial. A copy of 
the signed Informed Consent form will be provided 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 participant 
information sheet and consent form will be reviewed and updated if necessary, and participants will be 
re-consented as appropriate. 
Children who become of adult age (i.e. 16 in the EU, 18 in the US) during the study will be reconsented 
as adults at the time of their next visit. 
5.3.1.6.2 
Screening Period 
Screening procedures will take place only after the informed consent form has been signed by the 
participant/parent/guardian.  However, if test results are available from the subject’s participation in 
the MGT005 LCA natural history study, and the subject has consented to allow the use of those test 
results, then those screening tests will not need to be repeated. 
Participants will undergo genetic screening for RPE65 mutations at an accredited laboratory prior to 
enrolment. 

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Participants will be screened to ensure there are no contra-indications for transient immune 
suppression, in particular: hypertension, diabetes mellitus, tuberculosis, renal impairment, 
immunocompromised status, osteoporosis, gastric ulceration or severe affective disorder.  
Screening assessments are listed below (and set out under the column headed ‘Screening’ in the Trial 
Assessments Table 2, Section 5.6):  
1. Genetic testing 
2. Medical history and concomitant medication 
3. Physical examination  
4. Vital signs (including height and weight) 
5. Ocular examination 
6. Visual acuity 
7. Contrast Sensitivity 
8. Spectral Domain Optical Coherence Tomography (SD-OCT) imaging depending on age, as a 
greater degree of co-operation is needed compared to SD-OCT) 
9. Electrophysiological assessment 
A letter from the general practitioner detailing the health status of the participant may be requested if 
the clinician deems it appropriate to confirm eligibility for the trial.  
These assessments must have been completed within 3 months prior to enrolment. In addition, females 
of child bearing potential will undergo a pregnancy test at screening and again on the day of  ATIMP 
administration. 
5.3.1.6.3 
Enrolment 
Participants who fulfil the inclusion criteria based on the results of all screening assessments and 
pregnancy test will be enrolled in the trial. The ATIMP will be administered within 3 months of 
enrolment. If the ATIMP is not delivered within 3 months of enrolment, all screening tests with the 
exception of genetic testing and electrophysiological assessment will be repeated and eligibility for 
enrolment re-assessed. 
Participants who withdraw or are withdrawn from the study for any reason prior to ATIMP 
administration may be substituted in the study. 
5.4 
Interventions 
5.4.1  Products 
5.4.1.1 
Name and Description of Investigational Medicinal Product(s) 
AAV2/5-OPTIRPE65 is an advanced therapy investigational medicinal product; specifically, a gene 
therapy product. 

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It consists of a linear single strand of DNA packaged in a recombinant adenovirus-associated virus (rAAV) 
protein capsid of serotype 5. The rAAV.hRPE65p.hRPE65 incorporates the wild-type AAV inverted 
terminal repeats that provide the packaging signal, a cDNA encoding human RPE65, the human RPE65 
promoter, a SV40 intron sequence, and a SV40 polyadenylation signal. The icosahedral capsid consists of 
three related AAV5 capsid proteins, VP1, VP2, and VP3. AAV has a compact macromolecular structure 
and forms stable viral particles approximately 20 nm in diameter. The vector particles are replication-
incompetent.  
RPE65 is an isomerase expressed in the retinal pigment epithelium (RPE) that catalyses the isomerization 
of all-trans-retinyl esters to 11-cis-vitamin A, and is a critical component of the visual biochemical cycle 
that regenerates visual pigment after light exposure. The lack of functional RPE65 leads to a deficiency in 
11-cis-retinal, the light-sensitive chromophore that binds to opsin, and results in diminished rod 
photoreceptor function. Recombinant AAV-mediated gene transfer of a normal RPE65 gene to the RPE 
leads to stable, long-term transgene expression and improves visual function in rodent and dog models 
of disease. The study agent is based on the virus vector that led to improved night vision in a previous 
clinical trial (Bainbridge et al. 2008, Bainbridge et al. 2015); the original configuration has been modified 
to improve efficiency of RPE65 gene expression at least 300-fold.  
5.4.1.2 
ATIMPs Classified as Genetically Modified Organisms 
The ATIMP (AAV2/5-OPTIRPE65) is classified as a genetically modified organism under the Genetically 
Modified Organisms (Contained Use) Regulations 2000. 
The Health and Safety Executive (HSE) must be notified of each UK clinical trial site administering the 
ATIMP for first use of premises for genetic modification activities before the activities commence. A risk 
assessment of the activities has been carried out and has been reviewed by the local Genetic 
Modification Safety Committee (GMSC). Internal approval at site for the GMO activities has been gained. 
Each clinical trial site administering the ATIMP in the US must obtain local Institutional Biosafety 
Committee approval to administer recombinant nucleic acid molecule material to human subjects. Trial 
sites that receive support for recombinant or synthetic nucleic acid molecule research from the National 
Institutes of Health (NIH) must submit the protocol to the NIH Office of Biotechnology Activities (OBA) 
for review prior to initiating trial activities.  
5.4.1.3 
Source of ATIMPs 
The ATIMP has been manufactured at the Wolfson Gene Therapy Unit (WGTU) facility of the UCL Gene 
Therapy Consortium at the UCL Cancer Institute in accordance with current Good Manufacturing 
Practice for clinical trial materials. The manufacturer will perform analytical testing and provide QP 
certification for release.  
5.4.1.4  
Preparation and Labelling of the Investigational Medicinal 
Product 
Preparation and labelling of the investigational medicinal product will be completed in accordance with 
the relevant GMP guidelines and MeiraGTx UK II Ltd. procedures.  

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The ATIMP is a recombinant serotype 2/5 adeno-associated viral vector containing a human RPE65 cDNA 
driven by a fragment of the human RPE65 promoter. The manufacturer (WGTU) will perform analytical 
testing and provide QP certification for release. Aliquoting into vials and labelling of the ATIMP is the 
responsibility of WGTU. The WGTU is also responsible for testing, QP release and storage of the final 
ATIMP. Performance of certain release assays is contracted to approved contractors of the WGTU.  
US Federal regulations require that a drug should be the subject of an approved marketing application 
before it is transported or distributed across state lines. As such, in order to ship INDs to investigators, 
the sponsor will submit an IND application in order to obtain an exemption from the FDA with regard to 
the marketing approval requirement. 
5.4.1.5 
Description and Justification of Route of Administration and Dose 
Efficient transduction of the target retinal pigment epithelial cells requires the ATIMP (AAV2/5-
OPTIRPE65) to be administered to the subretinal space. Delivery of vector suspension to the subretinal 
space will be performed following a standard surgical vitrectomy. This will involve a 3-port pars plana 
vitrectomy followed by injection of vector suspension using a fine cannula through 1 or more small 
retinotomies into the subretinal space, resulting in temporary retinal detachment. Previous gene 
therapy clinical trials have shown that the bleb of subretinal vector suspension can be expected to 
resolve spontaneously over the course of the first 24 to 48 hours postoperatively as the fluid is absorbed 
by the underlying retinal pigment epithelium. Risks to visual function will be minimized by controlling 
the area of vector delivery, and by leaving the contralateral fellow eye untreated. Vitrectomy surgery is 
a standard technique, commonly performed for a wide range of indications. Injection of fluids under the 
retina is less commonly performed but is a standard step for delivery of surgical dyes and therapeutic 
thrombolytic agents to the subretinal space. 
Comparative experiments in Rpe65-deficient mice have shown that AAV2/5-OPTIRPE65 is 300-fold more 
potent than the AAV2/2-hRPE65 vector used previously.  Given that AAV2/5-OPTIRPE65 is at least 300 
fold more potent in mouse rescue experiment than AAV2/2-hRPE65, administration of 1 x 1011 vg/eye of 
AAV2/5-OPTIRPE65 would thus result in an approximately 30-fold increase in effective RPE65 delivery 
compared with that resulting from administration of 1 x 1012 vg/eye of AAV2/2-hRPE65 
(rAAV2/2.hRPE65p.hRPE65) in the first clinical study (10-fold lower dose of a vector that is 300-fold more 
potent).  In addition, as a 7-fold more efficient translation is seen with the optimized vector in human 
cells, it is possible that greater improvements in ERG and retinal survival may be observed at the proposed 
starting dose.  Importantly, based on existing knowledge, it is not anticipated that this enhanced 
translation efficiency and potency of the vector would be detrimental to the patients.  This approach is 
intended to maximize potential benefit for patients participating in the study by commencing dosing at a 
level that is theoretically effective. 
The intended administration volume of 1mL is considered appropriate to enable optimal exposure of 
target RPE cells to the vector, even in young children. The location of retinotomies will be determined 
with the aim of exposing those RPE cells that support overlying viable photoreceptor cells as determined 
by optical imaging. Whilst the surgical technique is designed to optimise the possibility of benefit, any 

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concern arising intra-operatively about possible adverse events will be appropriately addressed in the 
interests of safety, and any deviations from protocol recorded. 
5.4.1.6 
Name and Description of Each Non-Investigational Medicinal Drug 
(NIMP) 
1. Cefuroxime or cefazolin or vancomycin antibiotic given at usual dose at end of surgery (standard dose 
as prophylaxis for post-operative infection) 
2. Betamethasone or dexamethasone given at usual dose at end of surgery (standard dose as 
prophylaxis for post-operative inflammation) 
3. Chloramphenicol 0.5% or ofloxacin (topical antibiotic) 4 times daily for 7 days following ATIMP 
administration  
4. Dexamethasone 0.1% (topical steroid) 4 times daily for 4 weeks, then 2 times daily for a further 2 
weeks (weeks 4 to 6) following ATIMP administration  
3 and 4 above will be administered to minimise inflammation and protect against infection 
postoperatively. 
5. Omeprazole:  
• 
In adults 20mg per day for 8 weeks 
• 
In children weighing 5 kg to less than 10 kg (11 lb to less than 22 lb): 5 mg taken once per day  
• 
In children weighing 10 kg to less than 20 kg (22 lb to less than 44 lb): 10 mg taken once per day  
In children weighing 20 kg (44 lb) or more: 20 mg taken once per day 
6. Prednisolone or Prednisone (oral steroid) as prophylaxis against potential intraocular immune 
responses: 
For adults 30 mg daily for one week prior to ATIMP administration 
Following the ATIMP administration as follows: 
• 
60 mg daily in week 1 
• 
40 mg daily in week 2 
• 
30 mg daily in week 3 
• 
20 mg daily in week 4 
• 
15 mg daily in week 5 
• 
10 mg daily in week 6 
• 
5 mg daily in week 7 
• 
2.5 mg daily in week 8 
 
Children will be prescribed a tapering regimen of prednisolone tailored according to age and weight, and 
in addition intravenous methylprednisolone 30mg/kg on the day of surgery (maximum total no more 

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than 1g). A further dose of methylprednisolone may be administered at week 4 in the presence of signs 
of intraocular inflammation. The detailed treatment regimen is described in a clinical management plan. 
All Non Investigational Medicinal Products (NIMPs) are licensed within the EU and US and will be 
procured from standard hospital stock. 
Sites will maintain a system that allows adequate reconstruction of NIMP movements and permits 
recording of which participants received which NIMPs during the trial, with an evaluation of the 
compliance where necessary. 
5.4.2 Protocol defined clinical schedule 
5.4.2.1 
Baseline Assessments 
Assessment of visual function and retinal imaging of both eyes will be performed preoperatively as 
outlined in Section 5.6 (Table 2, Trial Assessments). For assessments requiring multiple baselines, testing 
is preferred on separate days within a maximum 3-month period to allow for day to day variation and 
test retest variability for individual participants. However, it is acknowledged that a balance will be 
achieved between what is pragmatic and appropriate for the different tests on an individual basis. Each 
set of baseline measurements may take up to 3 days to perform in total.  In some instances, results for 
protocol specified baseline tests may be available through a subject’s prior participation on the MGT005 
LCA natural history study.  As such, if the subject provides informed consent to use the results from the 
previously conducted tests, then these assessments will not need to be repeated at baseline.   
Visual assessments results will be sent for reading and analysis to independent reading centres within 
the UK and US.  For both sites Imaging for OCT and Fundus photography will be reviewed by the site 
teams but also sent for independent analysis by the Reading Centre, Queens University, Belfast during 
the course of the trial. Adaptive optics images will be sent to the Medical College of Wisconsin for 
reading and Octopus perimetry and Microperimetry will be sent to the Oregon Health and Science 
University Casey Eye Institute reading centre. All images will be saved under pseudo anonymised patient 
identifiers and images will only be taken of the patient’s eye to ensure that patients will remain 
unidentified.  
Up to 10 mL of blood will be sampled in order to assess baseline levels of T-cell responses to AAV5 and 
of circulating antibodies against AAV serotype 5 and RPE65 so that immunological responses to vector 
capsids and transgene product might be determined following vector administration (collectively 
described as serology in Table 2, Trial A assessments). We anticipate that the majority of participants 
will have no detectable pre-existing circulating antibodies against AAV5 or RPE65. The presence or 
absence of circulating antibodies will not affect recruitment of the participant. All serology tests will be 
carried out at the sponsor’s approved Laboratory in the UK. 
There is wide variability in the ability of children of different ages to undertake some of the proposed 
tests; the evaluations for children will be restricted to those tests that they are able to perform reliably. 
Tests that will be performed in all participants are: 

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1. Serological tests 
2. Blood pressure 
3. Haematology 
4. Biochemistry 
5. Ocular examination 
6. Intraocular pressure 
7. Colour fundus photography 
8. Spectral Domain Optical coherence tomography (SD-OCT) 
9. Fundus Autofluorescence imaging (FAF) 
10. Best corrected visual acuity  
11. Full-field electroretinography (ERG) 
12. Pattern electroretinography (PERG) 
 
Tests that will be performed where possible are: 
13. Contrast sensitivity  
14. Reading assessment 
15. Colour vision testing 
16. Microperimetry (mesopic and scotopic) 
17. Octopus900 full-field static perimetry 
18. Vision-guided mobility 
19. Multifocal electroretinography (mfERG) 
20. Adaptive optics (AO) imaging 
21. QOL questionnaires 
Further details of clinical assessments can be found in the OPTIRPE65 study manual.  
(i) Ocular examination and retinal imaging 
Ocular examination by slit lamp biomicroscopy will be used to assess the anatomical integrity of the 
eyes and quantify any intraocular inflammation. During the examination, intraocular pressure will be 
determined by tonometry.  
Retinal imaging includes colour fundus photography (ETDRS 7 standard fields), FAF, SD-OCT, and AO 
imaging. FAF imaging allows visualisation of the retinal pigment epithelium (RPE) by taking advantage of 
its intrinsic fluorescence derived from its lipofuscin content. SD-OCT imaging enables measurement of 
retinal thickness and provides information about the integrity of the layers of the retina. AO imaging 
provides direct visualization of the photoreceptor and RPE mosaics in vivo. 
(ii) Functional and Participant-Related Outcome assessments 
Where possible the participant will complete an age-appropriate Impact of Visual Impairment (IVI) vision-
specific quality of life questionnaire, and EQ5D-5L and EQ-5D-Y questionnaires. 

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Reading ability, including reading acuity, maximum reading rate, and critical print size will be assessed 
with MNRead and International Reading Speed Texts. 
Best-corrected ETDRS visual acuity will be measured in each eye. Contrast sensitivity will be measured 
using the Pelli-Robson chart.  
Colour vision testing will be undertaken using plate tests and computerised tests probing colour 
discrimination. 
Retinal sensitivity will be determined using Octopus 900 full-field static perimetry and/or full field 
stimulus testing (FST) where available, and microperimetry (mesopic and scotopic). Where available, FST 
may be performed for enrolled paediatric patients at participating sites. The retinal locus of fixation will 
also be accurately determined using microperimetry. 
Vision-guided mobility will be assessed by measuring the ability of each participant to navigate a simple 
route in a range of controlled illuminances. 
Full-field electroretinography (ERG), pattern ERG (PERG) and multifocal ERG (mfERG) will be performed 
according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standards to assess 
both generalised retinal (RPE, rod and cone systems) and isolated macular function. Modified ISCEV 
protocols may be necessary in young children using internationally recognised modified protocols. For 
young children, this procedure may be performed under general anaesthesia. ERG data will be analysed 
and interpreted by dedicated full-time Clinical Visual Electrophysiology Consultants with extensive 
experience and who are directly involved in determining ISCEV standards. 
5.4.2.2 
ATIMP administration Procedures 
The ATIMP administration procedures described in the protocol are what is broadly intended to occur 
during surgery. Anticipated procedures may be modified on a case-by-case basis in the interests of 
safety, and these modifications will be documented in the operation notes and CRF. Consent to record 
the surgery will be requested of the participant. Intraocular surgery will be recorded using a video 
camera via the operating microscope. Relevant recordings and images will be stored alongside the trial 
database. 
5.4.2.2.1 Preoperative procedure 
For prophylaxis against potential intraocular immune responses to the ATIMP, participants will be 
prescribed a course of daily oral prednisolone (or other as appropriate) commencing at a dose of 30mg 
daily for 1 week prior to ATIMP administration.  
Preoperative procedures and intraocular administration of ATIMP will be as described in the 
OPTIRPE65 study manual  

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5.4.2.2.2 Operative procedure 
The choice of eye that the vector is delivered to will be made between the participant and PI. It is 
anticipated that this will be the poorer-seeing eye but this will be decided upon in discussion with the 
participant.  
The recombinant vector will be delivered in the form of a suspension of viral vector particles injected 
intraocularly (subretinally) under direct observation using an operating microscope. This procedure will 
involve 3-port pars plana vitrectomy followed by injection of vector suspension using a fine cannula 
through 1 or more small retinotomies into the subretinal space. The procedure may be performed under 
general or local anaesthesia at the discretion of the operating surgeon and the participant. 
The eye and face will be prepared using povidone iodine solution. The face and eye will be covered with 
an adhesive sterile plastic drape. An opening will be made at the point of the palpebral fissure and a 
wire speculum inserted to retract the upper and lower eyelids. The speculum and all intraocular 
instruments will be sterilised according to standard local operating procedures. An intraocular infusion 
cannula will be placed to maintain a normal globe volume by infusion of fluid. 2 further pars plana 
sclerotomies will be placed to accommodate an endo-illumination probe and vitreous cutter. The fundus 
will be viewed by means of a BIOM indirect viewing system or a contact lens. The posterior hyaloid will 
be peeled anteriorly and the vitrectomy completed using the vitreous cutter.  
The specific area of retina to be targeted in each participant will be pre-determined according to the 
degree and distribution of retinal degeneration defined by pre-operative assessments. Intraocular 
administration of the viral vector suspension (AAV2/5-OPTIRPE65) will be performed using a cannula 
attached to a syringe. The cannula will be advanced through the retina at sites pre-determined in each 
participant according to the area of retina to be targeted. Where possible, the vector will be targeted to 
exclude the fovea. If appropriate, the bleb of vector may be manipulated to the target area using a fluid-
air exchange. Under direct visualisation the vector suspension (1.0 x1011 to 1.4 x1012 vg/mL; up to a 
maximum volume of 1 mL) will be injected under the neurosensory retina causing a localised retinal 
detachment. The first 3 adult participants will receive the low dose (1.0 x1011 vg/mL), with 3 subsequent 
adults receiving the intermediate dose (3.0 x1011 vg/mL) and 3 subsequent adults receiving the high 
dose (1.0 x1012 vg/mL) according to the dose-escalation criteria. Children will be included only after 
safety has been appropriately determined in adults. The injection of vector suspension may be preceded 
by injection of a small volume of saline solution (0.1 to 0.5 mL) to establish a “bleb” facilitating targeted 
delivery of vector suspension to the subretinal space and minimising possible exposure of the choroid 
and vitreous cavity to vector. The injection retinotomy is designed to be self-sealing with minimal reflux. 
Following administration of vector suspension, the area of the induced retinal detachment will be 
documented by fundus photography. 
On the basis of the findings of previous clinical studies, it is predicted that retinal blebs (localised retinal 
detachments) generated by subretinal vector delivery will resolve spontaneously with retinal re-
attachment during the first 48 hours, without the need for retinopexy or intraocular tamponade. 
However, any unplanned peripheral retinal breaks will be managed appropriately using cryo- or laser-
retinopexy and injection of an appropriate tamponade agent at the time of surgery, or as part of a 

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subsequent procedure. Sclerotomies may be closed using sutures at the surgeon’s discretion. Standard 
doses of cefuroxime antibiotic and betamethasone or their equivalent will be administered 
subconjunctivally as prophylaxis against postoperative infection and inflammation respectively. The 
operated eye will be dressed with a pad and shield. 
5.4.2.3 
Subsequent Assessments 
Surgery may be performed, as is conventional for intra-ocular procedures, on a day-case basis. 
Participants will subsequently be managed as outpatients, though hospital-based accommodation may 
be used for convenience. 
On the first postoperative day a clinical ocular examination will be performed. In particular, visual acuity, 
intraocular pressure, any postoperative intraocular inflammation and the area of any residual retinal 
bleb will be documented. Fundus photography and SD-OCT scanning will be performed on the day 1 and 
subsequent assessments.  
A standard post-vitrectomy treatment regimen of topical antibiotic (e.g., chloramphenicol 0.5% qds for 7 
days), and corticosteroid (e.g. dexamethasone 0.1% qds for 4 weeks and then bd for a further 2 weeks) 
will be commenced to minimise inflammation and protect against infection postoperatively. Intraocular 
pressure of greater than 30 mmHg will be managed using appropriate ocular antihypertensive therapy. 
Participants will be maintained on oral prednisolone (or other as appropriate) for 8 weeks following 
administration of vector suspension as described above (Section 5.4.2.2, Preoperative procedure). The 
possible development of steroid-induced adverse effects will be monitored regularly. In particular, blood 
pressure, blood glucose, renal function and liver function will be measured.  
Female participants of childbearing potential and male participants with partners of childbearing 
potential will be advised to use a double barrier method of contraception for 12 months after surgery. 
Both safety and efficacy of the ATIMP will be evaluated at various time points up to 6 months after 
ATIMP delivery. Evaluation will occur primarily by ocular assessments. The nature and schedule (Section 
5.6, Study assessments) of these is described below.  
Participants will subsequently be invited to enrol in a 5-year follow-up study to determine longer term 
safety and efficacy. 
(i) Clinical assessment of intraocular inflammation 
The degree of intraocular inflammation will be assessed by slit-lamp biomicroscopy at each time point. A 
temporary intraocular inflammatory response is predictable following vitrectomy surgery. This is 
typically evident clinically on slit lamp biomicroscopy as ‘flare’ and cells in the anterior chamber and can 
be of moderate (2+) intensity. The degree of intraocular inflammation is expected to decline during the 
course of the first 8 weeks following the surgical procedure at which time the routine topical and 
systemic immunosuppression will be discontinued. Prolonged or recurrent intraocular inflammation will 
be managed conventionally by further topical and/or systemic immunosuppression. 

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(ii) Evaluation of immune responses 
Up to 10mL of blood will be sampled to measure immune response. Blood serum will be isolated and 
analysed. Residual samples will be stored in an approved laboratory designated by the sponsor for use in 
future ethically approved research, with the participant’s consent. Immunological assays will be 
performed as outlined in Section 5.6 (Trial Assessments) to investigate antibody responses to AAV 
capsid proteins and to RPE65 protein. Investigators performing these analyses will be masked to 
participant’s identity. 
(iii) Evaluation of biodistribution 
Systemic biodistribution of vector genomes will be assessed at as outlined in Section 5.6 (Trial 
Assessments) by PCR analysis of tears from the study eye (a compressed cellulose sponge placed under 
the eye lid until swollen), saliva (a minimum of 100 μL) and serum (100 μL). This test will be carried out 
in the institutional laboratory in the UK. 
(iv) Assessment of visual function and retinal imaging 
Assessment of visual function and retinal imaging will be performed as outlined in Section 5.6 (Trial 
Assessments) at baseline and at intervals following intervention. These assessments will be scheduled 
over a period of a day for visits at day 1, day 3, week 1, week 2, week 4 and week 6 after surgery, and up 
to 4 days for baseline examinations, and 3 months and 6 months following intervention.  For day 1 and 3 
refraction cannot reliably be measured. Therefore, the most recent refraction measurement will be 
used. 
All participants (adults and children) will need to be able to perform visual acuity testing and SD-OCT 
imaging reliably. Other clinical assessments will be undertaken as appropriate for each participant’s 
ability; since there is wide variability in the ability of children of different ages to undertake these tests, 
the evaluations for children may be restricted to those tests that they are able to perform reliably. 
Additional investigations may be performed for appropriate clinical management of any adverse events. 
5.4.2.4 
Laboratory Procedures 
Blood serum will be processed within the UCL Institute of Ophthalmology to assess any immune 
responses to the ATIMP. Serum will be analysed for:  
1. anti-AAV5 antibodies by ELISA 
2. anti-human RPE65 antibodies by ELISA 
3. anti-AAV5 neutralising antibodies 
Blood serum, saliva and lacrimal fluid will be processed at the UCL Institute of Ophthalmology to assess 
dissemination of vector after delivery, where the number of rAAV vector genome copies will be 
measured by polymerase chain reaction (PCR).  

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Whole blood will be processed at the National Genetics Reference Laboratory in the UK, or a CLIA-
accredited molecular diagnostic laboratory in the US, for RPE65 mutation screening. Standard 
haematology and biochemistry screen will be carried out at the Trust associated laboratories, or an 
accredited laboratory in the United States.  
5.4.3 Dispensing 
5.4.3.1 
Receipt and Storage of the Investigational Medicinal Product 
The product, which is stable at ≤–50° Celsius, will be stored at < -70° Celsius in secure temperature 
controlled and monitored -800 Celsius freezers at the sponsor’s delegated storage facility. Shipping of 
ATIMP to study sites will be on dry ice, accompanied by a temperature-monitoring device.  
On the day of administration of the ATIMP, the prescribed number of vials will be transferred to the 
operating theatre according to study specific working instructions. The ATIMP will not be refrozen upon 
thawing prior to the surgical procedure and any remaining product will be discarded according to local 
procedures.  
5.4.4 Dosages 
5.4.4.1 
Dosages and dosage modifications 
Trial participants will receive 1 of 3 different doses of ATIMP within the range proven to be safe in the 
preclinical animal studies.  
1) low dose  
 
1mL at 1.0 x1011 vg/mL 
2) intermediate dose  
1mL at 3.0 x1011 vg/mL 
3) high dose  
 
1mL at 1.0 x1012 vg/mL 
The ATIMP has been produced and stored at the concentration of 1.4 x 1012 vg/mL. Vector will be 
diluted immediately prior to intraocular administration in Hartmann’s solution at the time of 
administration for all 3 doses. For participants receiving the low dose of 1.0 x1011 vg/mL, the ATIMP will 
be diluted 14-fold in Hartmann's solution. For participants receiving the intermediate dose of 3.0 x1011 
vg/mL, the ATIMP will be diluted 4.6-fold in Hartmann's solution. For participants receiving the high 
dose of 1.0 x1012 vg/mL, the ATIMP will be administered diluted 1.4-fold. In each case, up to 1.0 mL 
ATIMP at the appropriate titre will be administered to the target area. The CI/PI will prepare the 
appropriate dilution and this will be checked in the operating theatre by a second clinician prior to 
administration. The check will be recorded in the participant’s source data notes. 
Further details for dose-escalation criteria are included in Section 4.3.2. 
5.4.5 Accountability 
The ATIMP will be prescribed for a particular participant by 1 of the Investigators and handled according 
to the ATIMP Management Plan applicable for each site.  
For accurate accountability, the following information will be recorded when the ATIMP is administered: 

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i. 
Date 
ii. 
Participant identification number 
iii. 
Batch number 
iv. 
Volume and dose of vector administered 
v. 
Name of Principal Investigator or delegated surgeon administering ATIMP 
vi. 
ATIMP name/code 
vii. 
Trial reference code 
viii. 
Expiry date 
Surplus ATIMP will be destroyed according to existing SOPs, using methods suitable for destruction of 
genetically modified organisms. 
A system will be set-up to ensure the traceability of the ATIMP from the starting material, through to 
administration to the subject and destruction or final disposition. A comprehensive ATIMP management 
plan and associated SOPs and forms will be in place to ensure that the required accountability and 
traceability data is collected and retained.  
5.4.6 Compliance and Adherence 
Full compliance is expected since the ATIMP will be surgically delivered by the CI or a delegated vitreo-
retinal surgeon. The aim is to target the administered volume into the subretinal space. Any deviation 
from this will be noted in the CRF. See section 5.4.8 (Overdose of trial medication) about the assessment 
of adherence to the protocol defined delivery of the product.  
5.4.7 Concomitant Care 
Concomitant use of other medications should be avoided unless clinically necessary and should be used 
with caution, and appropriately documented on study logs where used. All concomitant medications 
(including steroids) must be recorded in the eCRF from the day of informed consent.  
5.4.8 Overdose of Trial Medication 
An intraocular administration of ATIMP will be performed by the operating surgeon (CI or a delegated 
vitreo-retinal surgeon). The volume of vector delivered to the target site will be measured by the syringe 
plunger and recorded in the CRF.  
Any overdose will be reported to the sponsor. This is a Phase I/II exploratory study and the possible 
impact of any overdose will be considered in the final analysis. Given that this is a single administration 
study, the trial subject will not be withdrawn but the collected data will be analysed separately in 
comparison with the data from the participant’s baseline assessments and from other treated 
participants. Any concern about accurate dosing may warrant suspension of the trial pending 
appropriate investigation. 
Overdose of ATIMP may result in development of Adverse Events of various severities that will be 
recorded and reported as outlined in Section 5.11.3. 

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5.4.9 Protocol Discontinuation 
5.4.9.1 
Subject Withdrawal 
In consenting to the trial, participants are consenting to ATIMP administration, trial follow-up and data 
collection.  
As participation in the trial is entirely voluntary, the participant may choose to discontinue trial 
participation at any time without penalty or loss of benefits to which they would otherwise be entitled. 
Although not obliged to give a reason for discontinuing their participation, a reasonable effort should be 
made to establish this, whilst remaining fully respectful of the participant’s rights. 
Should a participant withdraw from the study, a withdrawal CRF documenting the reason for withdrawal 
will be completed, in addition to the procedures and CRF for the final visit (6 month) assessments, with 
the participant’s consent. However, participants will be encouraged to participate in any of the planned 
schedule for the trial whilst arranging a visit for routine (annual) clinical follow-up. 
Participants who withdraw prior to vector administration will be regarded as off-protocol and their 
primary ophthalmologist will resume normal standard of care. Any subject who withdraws prior to 
administration of ATIMP may be replaced in the study. Participants who withdraw from the study after 
vector administration will be encouraged to have follow-up investigations with their consent, so that the 
consequences of vector administration can be documented and the data analysed. The CMT may choose 
to replace a subject who withdraws after vector administration.  
5.4.9.2 
Trial Stopping Rules 
The Chief Investigator and Sponsor retain the right to terminate the study. Specific circumstances that 
may precipitate such termination are as follows: 
1. 
Unanticipated adverse medical experience in this or other studies indicating a potential health 
hazard caused by the ATIMP 
2. 
Significant protocol deviation and lack of compliance and cooperation on the part of an 
investigator, which endangers the safety of the participants or the validity of the trial 
3. 
Death of a participant at any time point after ATIMP administration that is possibly, probably, or 
definitely related to the ATIMP 
4. 
The occurrence of a non-ocular malignancy at any point after gene transfer that is possibly, 
probably, or definitely related to the ATIMP 
5.5 
Outcomes 
5.5.1 Primary Outcomes 
The primary outcome is defined as any of the below occurring during the 9 weeks following 
administration, at least possibly related to the ATIMP, not surgery alone: 
• 
Reduction in visual acuity by 15 ETDRS letters or more 
• 
Severe unresponsive inflammation 

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• 
Infective endophthalmitis)  
• 
Ocular malignancy 
• 
Grade III or above non-ocular SUSAR. (See Section 5.11.3) 
5.5.2 Secondary Outcomes 
The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an 
individual participant basis and will be descriptive in nature. Secondary outcomes are: 
• 
Any improvements in visual function from baseline that are greater than the test-retest 
variationand are sustained for at least two consecutive assessments. 
• 
Any improvement in retinal function from pre-intervention that is greater than the test-retest 
variation and measurable by electroretinography (ERG). 
If no ERG is previously detectable, then the presence of any reproducible response with appropriate 
waveform would be significant. If an ERG is there to start with, any of the following would be significant: 
an improvement in amplitude of >50 % in DA 0.01 b-wave (rod system sensitivity); bright flash DA 10 a- 
wave (photoreceptor improvement); the 30Hz flicker; and the LA 3.0 photopic a- and b-waves. In terms 
of timing: > 3ms improvement in photopic parameters and bright flash DA 10 a-wave; 3-6ms for the DA 
0.01 and DA 10.0 b-waves. 
• 
Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire and the 
EQ5D- 5Land EQ-5D-Y

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5.6 
Trial Assessments 
Table 2: Trial assessments 
 
Screening 
Baseline 
ATIMP 
admin 
D1   
D3  
W1  
W2  
W4  
W6  W9 
W12 
W24 
Flexibility of schedule (+ days) 
- 3 
months 
Day 0 
+ 
0D 
+ 
1D 
+ 
2D 
+ 
4D 
+ 
7D 
+ 
7D 
+ 
7D 
+ 
14D 
+  
14D 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Informed consent 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
• 
 
 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
Eligibility determination 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration 
 
 
 
 
★ 
 
 
 
 
 
 
 
 
 
Adverse event review 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant medication review 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Genetic screening 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
 
Vital signs (including height and 
weight)5 
• 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
 
Haematology/Renal Function 
 
• 
 
 
 
• 
 
• 
• 
• 
• 
 
 
 
 
Biochemistry/glucose 
 
• 
 
 
 
• 
 
• 
• 
• 
•  
 
 
 
Serology 
 
• 
 
 
 
 
 
 
 
• 
 
 
• 
• 
PCR 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
 
QoL questionnaires (IVI and EQ5D-5L) 
 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Visual acuity6 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Contrast sensitivity 
• 
• 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Reading speed 
 
• 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Colour vision 
 
• 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Octopus perimetry 
 
• 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Full field Stimulus Testing7  
 
• 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Microperimetry (mesopic and 
scotopic) 
 
• 
• 
• 
 
 
 
 
 
 
• 
 
• 
• 

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Visual mobility (PAMELA or Michigan 
maze)1 
 
•2 
 
 
 
 
 
 
 
 
 
 
 
• 
Ocular examination 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Fundus photography 
 
• 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Optical coherence tomography 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adaptive optics imaging3 
 
• 
• 
 
 
 
 
 
 
 
 
 
 
• 
Fundus autofluorescence 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
• 
Flash electroretinography4 
• 
• 
 
 
 
 
 
 
 
 
• 
 
• 
• 
Pattern electroretinography4 
• 
• 
 
 
 
 
 
 
 
 
• 
 
• 
• 
Multifocal electroretinography4 
• 
• 
 
 
 
 
 
 
 
 
• 
 
• 
• 
1 A 6-week window period is permitted around the visual mobility assessments. 
2 Multiple baseline PAMELA assessments may be performed on the same day if considered logistically and clinically appropriate 
3 Adaptive optics imaging baseline assessments may be performed on the same day where considered logistically and clinically appropriate 
4 Additional baseline assessments are permitted if there is inconsistency between the screening and first baseline assessment 
5Measurements for vital signs include: blood pressure, pulse, respiration rate, arterial oxygen saturation, temperature, height and weight 
6 Visual acuity at day 1 and 3 will be assessed by using the previous refraction. 
7 FST test results will be collected retrospectively (with written consent) for paediatric participants if the assessment has been performed 
previously  
ERG assessments may be performed under general anaesthesia if considered appropriate 

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5.6.1 Early Stopping of Follow-up 
If a participant chooses to withdraw from the trial, they should continue to be followed up as closely as 
possible to the follow-up schedule defined in the protocol, providing they are willing. If, however, the 
participant exercises the view that they no longer wish to be followed up either, this view must be 
respected. Data already collected will be kept and included in analyses according to the intention-to-
treat principle for all participants who stop follow up early.  
Participants who stop trial follow-up early may be replaced. 
5.6.2 Loss to Follow-up 
This is a highly motivated patient group who are likely to remain committed to the research. Continued 
follow up of all participants will be strongly encouraged whilst being mindful of the importance of 
ensuring the autonomy of participants in regards to their treatment decisions and willingness to 
continue to participate in the trial.  
5.6.3 Trial Closure 
The end of the entire trial is considered the last follow-up visit of the last participant. For each 
participant, the trial will terminate at the last scheduled visit 6 months following ATIMP administration. 
The MHRA will be notified of the end of the trial within 90 days of its completion.  
5.6.4 Passive/Long Term Follow-Up After the End of the Trial 
At the end of this trial, participants will be invited to enrol in a 5-year follow-up study to determine 
longer term safety and efficacy. 
5.7 
Sample Size 
This is a Phase I/II trial to establish safety and assess indicators of potential efficacy of the ATIMP, 
therefore there is no formal sample size calculation. The trial will enrol up to 27 participants (up to 18 in 
the dose escalation phase and a further 9 in the confirmatory phase), as described in section 4.3.2.2. The 
limited number of participants is necessitated by the rare nature of the disease under investigation. We 
estimate that inclusion of up to 27 participants will be sufficient to determine the safety and tolerability 
of the intervention.  
5.8 
Recruitment and Retention 
5.8.1 Recruitment 
Most participants will be recruited through Moorfields Eye Hospital or the Kellogg Eye Center, or on 
referral by ophthalmologists within or outside the UK or the US. Members of their direct clinical care 
team will approach potential participants in the first instance to discuss whether they would like to 
consider participating. Alternatively, potential participants may contact the trial team independently. 
We expect to recruit up to 27 participants within a period of 36 months.  

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5.8.2 Retention 
Participants will be supported to remain in follow-up by regular contact as per the protocol, provision of 
a 24-hour hotline to a member of the trial team 
5.9 
Assignment of Intervention 
5.9.1 Allocation 
All participants will receive the same intervention in this open label, non-randomised trial: subretinal 
administration of AAV2/5-OPTIRPE65. The dose received by each participant will depend on the 
time/order of their enrolment in the trial, and the extent to which dose-limiting events observed in 
earlier participants during the dose-escalation phase (See Sections 4.3.2 and 5.4.4 for dose escalation 
information). Children will not be enrolled in the trial until the safety profile and recommended dose 
have been established in adults.  
5.10 Data Collection, Management and Analysis 
5.10.1 
Data Collection, Management and Entry 
Syne qua non will be responsible for data management activities for the study. 
Data will be captured in a fully validated, 21 CFR Part 11 compliant Electronic Data Capture (EDC) system 
provided by Syne qua non.   
Syne qua non will grant authorised site staff with access to the EDC system following system training and 
a successful competency assessment.   
Data required by the protocol will first be recorded on source documents (e.g. medical records and 
study-specific data capture tools as needed) and then entered by site staff into the EDC system.  All 
information in EDC must be traceable to these source documents.  Any data recorded directly into EDC 
will be defined prior to the start of data collection. All data is currently anticipated to be associated with 
source data records. 
Data validation checks will be activated during data entry to identify data discrepancies. Appropriate 
error messages will be displayed to allow modification or verification of data by the site staff. 
Monitoring staff will review the data for completeness and accuracy, instructing site staff to make any 
required corrections or additions via data queries.  Syne qua non will run further automated validation 
checks and review the data, raising further data queries to the sites for resolution of any inconsistencies. 
The Investigator will review the eCRFs for completeness and accuracy then electronically approve the 
data, retaining full responsibility for its accuracy and authenticity. 
Medical history and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.  Prior and concomitant medication will be coded using the World Health 
Organization Drug (WHO)-Drug Dictionary which employs the Anatomical Therapeutic Chemical (ATC) 

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classification system.  Further coding details and data management processes will be described in a Data 
Management Plan (DMP).   
All actions within the EDC system are captured within an audit trail.  After all data have been entered, 
validated and signed off, the database will be locked. 
At the end of the study, PDF copies of the eCRFs for each subject and supporting information will be 
provided to sites and the Sponsor.  The electronic data will be provided to the Sponsor. 
5.10.3 
Non-Adherence and Non-Retention 
Participants who withdraw from the trial after the intervention will be encouraged to participate in any 
of the planned follow-up scheduled for the trial with their consent, and data from these subjects 
collected prior to withdrawal may be included in the interpretation of results.  
Reasons for withdrawal from the trial will be documented on a withdrawal CRF where possible, in 
addition to the procedures and CRF for the final visit (6 month) assessments with the participant’s 
consent.  
5.10.4 
Statistical Methods 
5.10.4.1 
Statistical Analysis Plan 
A formal statistical analysis plan will be written by the trial sponsor and approved by the IDMC. This trial 
is an open label, no crossover, Phase I/II trial involving a small number of participants, and analysis of 
the primary and secondary outcomes will be descriptive in nature.  
5.10.4.2 
Statistical Methods – Primary Outcome Analysis 
The primary outcome is safety of subretinal administration of the ATIMP, defined as any of the below 
occurring during the 9 weeks following administration, at least possibly related to the ATIMP, not 
surgery alone: 
• 
Reduction in visual acuity by 15 ETDRS letters or more 
• 
Severe unresponsive inflammation 
• 
Infective endophthalmitis  
• 
Ocular malignancy 
• 
Grade III or above non-ocular SUSAR (See Section 5.11). 
The number of DLEs at each dose level will be summarised by cohort and overall. 
It is anticipated that the vector will be administered at the MTD in up to 15 participants (6 adults in the 
dose escalation phase and up to 9 further adults and children in the confirmatory safety phase). Safety 
data relating to these participants will allow estimation of an upper bound for the true event rate 
through a 95% confidence interval. 

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5.10.4.3 
Statistical Methods - Secondary Outcome Analysis 
The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an 
individual participant basis and will be primarily descriptive in nature. Standard assessments will be used 
to measure visual function and established methods of analysis, appropriate for the assessment will be 
used to evaluate the data. For specialist assessments, data will be analysed by the expert team 
member(s) who developed the assessment. Final data will be reported descriptively. 
Efficacy will be indicated by: 
1) Any improvement in visual function from baseline that is greater that the test-retest variation for that 
test and is sustained for at least two consecutive assessments. 
2) Any improvement in retinal function from pre-intervention assessment that is greater than the test-
retest variation and measurable by electroretinography (ERG) 
If no ERG was previously detectable, then the presence of any reproducible response with appropriate 
waveform would be clinically significant. If an ERG was there to start with, any of the following would be 
significant:  
• 
an improvement in amplitude of >50 % in DA 0.01 b-wave (rod system sensitivity);  
• 
bright flash DA 10 a- wave (photoreceptor improvement);  
• 
the 30Hz flicker; and  
• 
the LA 3.0 photopic a- and b-waves.  
In terms of timing: > 3ms improvement in photopic parameters and bright flash DA 10 a-wave; 6ms for 
the DA 0.01 and DA 10.0 b-waves. 
Measures will be reported individually and aggregated across participants as the proportion who satisfy 
the above criteria.  
Quality of life patient reported outcome measures will be used to correlate a participant’s feeling about 
their own wellbeing with clinical observations. 
Any deviations from the original statistical plan will be approved by the CMT and IDMC and described in 
the final report, as appropriate. 
5.10.4.4 
Statistical Methods – Health Economic Analysis 
No health economic evaluation is planned, but the collection of EQ5D would allow QALYs to be 
calculated. 

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5.11 Data Monitoring 
5.11.1 
Independent Data Monitoring Committee (IDMC) 
To ensure the safety and efficacy and overall trial conduct, an IDMC will be established and take part in 
the data monitoring. The IDMC will consist of members with specific expertise in ophthalmology and 
molecular genetics. The IDMC will make recommendations on the safety data prior to any dose change, 
and prior to the first participant aged under 16 being included in the trial.  
Further details of the roles and responsibilities of the IDMC, including membership, relationships with 
other committees, decision making processes, and the timing and frequency of interim analyses (and 
description of stopping rules and/or guidelines where applicable) are described in detail in the Gene 
Therapy Trial for LCA OPTIRPE65 IDMC charter. 
5.11.2 
Interim Analyses 
No formal interim analysis is planned within the trial, but periodic reports concerning participant safety 
and key efficacy outcomes will be prepared for the IDMC as agreed in the Terms of Reference.    
5.11.3 
Data Monitoring for Harm 
5.11.3.1 
Safety reporting 
EMAS Pharma will be responsible for pharmacovigilance services.  
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply to 
this trial.  
Table 3: Adverse Event Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical trial participant 
administered a medicinal product and which does not 
necessarily have a causal relationship with this product. 
Adverse Reaction (AR) 
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered 
This includes medication errors, uses outside of protocol 
(including misuse and abuse of product) 
Unexpected Adverse Reaction 
(UAR) 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. 
Investigator’s Brochure for an unauthorised product or summary 
of product characteristics (SPC) for an authorised product. 
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR) 
Any AE or AR that at any dose: 
• 
results in death  
• 
is life threatening* 
• 
requires hospitalisation or prolongs existing 
hospitalisation** 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect 
• 
or is another important medical condition*** 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction  
*the term life threatening here refers to an event in which the participant is at risk of death at the 
time of the event; it does not refer to an event that might hypothetically cause death if it was more 
severe (e.g. a silent myocardial infarction) 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisation for pre-existing 
conditions (including elective procedures that have not worsened) do not constitute an SAE 
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other 
situations. Important AEs or ARs that may not be immediately life threatening or result in death or 
hospitalisation, but may seriously jeopardise the participant by requiring intervention to prevent 1 of 
the other outcomes listed in the table (e.g. a secondary malignancy, an allergic bronchospasm 
requiring intensive emergency treatment, seizures or blood dyscrasias that do not require 
hospitalisation, or development of drug dependency). 
 
Adverse events include: 
• 
an exacerbation of a pre-existing illness 
• 
an increase in the frequency or intensity of a pre-existing episodic event or condition 
• 
a condition (regardless of whether PRESENT prior to the start of the trial) that is DETECTED after 
trial drug administration. (This does not include pre-existing conditions recorded as such at 
baseline – as they are not detected after trial drug administration) 
• 
continuous persistent disease or a symptom present at baseline that worsens following ATIMP 
administration 
Adverse events do NOT include: 
• 
Medical or surgical procedures: the condition that leads to the procedure is the adverse event 
• 
Pre-existing disease or a condition present before ATIMP administration that does not worsen 
• 
Hospitalisation where no untoward or unintended response has occurred e.g. elective cosmetic 
surgery 
• 
Overdose of medication without signs or symptoms 
5.11.3.2 
Other Notifiable Adverse Events 
In order to manage the safety risks associated with administration of the vector, all safety events will be 
reviewed within a short time frame for all participants, as described in the OPTIRPE65 Data 
Management Plan. Pregnancy is the only additional notifiable event that requires expedited reporting. 
 

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5.11.3.3 
Procedures to follow in the event of female participants becoming 
pregnant 
A pregnancy test will be conducted for all females of child bearing age and the results will be recorded in 
the medical notes before enrolling a volunteer to the trial. Females with a positive pregnancy test at this 
point will be excluded from the trial.  
A further pregnancy test will be performed on the day of administration of the ATIMP. Female 
participants with a positive pregnancy test at this point will be excluded from the trial prior to 
administration of the ATIMP.  
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that a participant might become pregnant after administration of the ATIMP. In the unlikely event that a 
participant is found to be pregnant we will notify their GP that she is participating in a gene therapy trial 
and that, although the risks involved are minimal, there is a chance of gene transfer to the unborn child. 
With the participant’s consent, we will ask the GP/obstetrician to provide us with regular reports about 
the pregnancy until delivery. The pregnancy will be reported to EMAS Pharma within 24 hours of the 
investigator becoming aware of the event. We will continue follow-up of the participant until outcome 
of the pregnancy. However, if the participant is unable or unwilling to participate further in the trial, she 
will be encouraged to continue clinical monitoring visits to assess ocular health. In that situation, we 
may choose to enrol another participant to ensure the scientific validity of the trial. 
5.11.3.4 
Procedures to follow in the event of the partners of male 
participants becoming pregnant 
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that the partner of a participant might become pregnant after administration of the ATIMP. In the 
unlikely event that this occurs we will notify the participant’s GP that he is participating in a gene 
therapy trial and that, although the risks involved are minimal, there is a chance of gene transfer to the 
unborn child. With the participant’s consent, we will contact the partner to ascertain the status of the 
pregnancy and the outcome. The pregnancy will be reported to EMAS Pharma 
5.11.3.5 
Investigator responsibilities relating to safety reporting 
The Investigator will assume overall responsibility for evaluating and reporting adverse events. In urgent 
situations a member of the trial team may report on their behalf, while making every effort to discuss 
the event with them. All non-serious AEs and ARs including all events observed following ATIMP 
administration, whether expected or not, should be recorded in the participant’s medical notes and in 
the eCRF. These should be entered on to the database according to the timelines defined in the Gene 
Therapy for LCA OPTIRPE65 Data Management Plan to allow appropriate monitoring by the CMT. SAEs 
and SARs should be notified to EMAS Pharma within 24 hours of the investigator becoming aware of the 
event. 
Clinically significant abnormalities in the results of objective tests will also be recorded as adverse 
events. If the results are not expected as part of disease or surgery these will also be recorded as 
unexpected. There are currently no expected events associated with the ATIMP. 

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All serious adverse events will be recorded in the hospital notes and the CRF. 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 the end of the trial (refer to 
Section 5.6.3 for definition), or until pregnancy outcome in the case of pregnancy. All SAEs will be 
recorded, fully investigated and appropriately managed until resolution or stabilisation and CI sign off.  
5.11.3.5.1 
Seriousness assessment 
When an AE or AR occurs, the investigator responsible for the care of the participant must first assess 
whether or not the event is serious using the definition given in Table3. If the event is classified as 
‘serious’ an SAE form must be completed and emailed to EMAS Pharma, notified within 24-hours of the 
investigator becoming aware of the event.  
5.11.3.5.2 
Severity or grading of Adverse Events 
The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the 
toxicity grading in NIH CTCAE Version 4.0 (NIH, 2009). 
Table 4: Grading of Adverse Events 
Category 
Definition 
Mild (Grade I) 
 
 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate (Grade II) 
Minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental ADL* 
Severe (Grade III) 
Severe or medically significant but not immediately life 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care ADL** 
Grade IV 
Life threatening consequences; urgent intervention indicated 
Grade V 
Death related to AE 
* Instrumental ADL (Activities of Daily Living) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
5.11.3.5.3 
Causality 
Causality will be assessed in terms of both the ATIMP and the surgical procedures. Based on all available 
information at the time of completion of the case report form, the investigator must assess the causality 
of all serious events or reactions. It is of particular importance in this trial to capture and differentiate 
events related to: 
• 
The ATIMP administration surgery 
• 
The ATIMP 

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The differentiated causality assessments will be captured in the trial specific CRF and SAE form using the 
definitions in Table 5.  
Table 5: Causality definitions 
Relationship 
Description 
Event Type 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely to be related 
There is little evidence to suggest that 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 
participant’s clinical condition or other concomitant treatment) 
Unrelated SAE 
Possibly related 
There is some evidence to suggest a causal relationship (e.g. 
because the event occurs 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 
participant’s clinical condition or other concomitant treatment)  
SAR 
Probably related 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely 
SAR 
Definitely related 
There is clear evidence to suggest a causal relationship and 
other possible contributing factors can be ruled out. 
SAR 
 
 
5.11.3.5.4 
Expectedness 
In view of the very limited clinical experience with the ATIMP there are at present no events considered 
as expected for the ATIMP. Therefore, any SAEs that are related to the ATIMP (i.e., considered a SAR) 
will be deemed a SUSAR (suspected, unexpected, serious adverse reaction) and MHRA, REC/IBC, FDA, 
and NIH reporting guidelines apply (see Notifications sections of the protocol). 
Table 6: Assessment of expectedness  
Category 
Definition 
Expected 
 
 
An adverse event that is classed in nature as serious and which 
is consistent with the information about the surgery listed in the 
Investigator Brochure or clearly defined in the protocol. In view 
of the very limited clinical experience with the ATIMP there are 
at present no events considered as expected for the ATIMP 
listed in the current Investigator Brochure. 
Unexpected 
An adverse event that is classed in nature as serious and which 
is not consistent with the information about the ATIMP and 
surgery listed in the Investigator Brochure*or clearly defined in 
the protocol. 
*This includes listed events that are more frequently reported or more severe than previously reported 

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The reference document to be used to assess expectedness against the ATIMP and surgery is the 
Investigator Brochure. Procedure-related adverse events cannot be considered expected to the ATIMP. 
Previous experience with AAV-mediated gene therapy in the retina indicates that the risks are largely 
limited to the eye. A temporary and/or mild decrease in visual acuity, due to detachment of the retina 
or post-surgical inflammation, is to be expected after intraocular surgery and will not cause undue 
discomfort to the participants. Therefore, we have defined the success criteria for the primary outcome 
(safety) as the absence of an adverse event that has a substantial and sustained negative impact on 
vision, as well as the absence of any non-ocular SUSAR. 
Expected events associated with surgery: 
• 
Temporary and/or mild decrease in visual acuity, due to detachment of the retina or post-
surgical inflammation 
• 
Ocular discomfort 
• 
Epiphora 
• 
Periocular swelling 
• 
Diplopia 
• 
Ptosis 
• 
Subconjunctival or intraocular haemorrhage 
• 
Corneal abrasion 
• 
Retinal tear or detachment 
• 
Wound leak 
• 
Ocular hypotony or raised intraocular pressure 
• 
Overfill or underfill of any intraocular gas tamponade 
• 
Mild intra- or extra-ocular inflammation 
• 
Scleral or conjunctival suture granuloma 
• 
Lens opacity or dislocation 
• 
Systemic adverse events related to sedation or general anaesthesia, including nerve or vascular 
injury 
5.11.3.6 
Notifications 
5.11.3.6.1 
Notifications by the Investigator to EMAS 
All adverse events will be recorded in the hospital notes and the CRF from the date of written informed 
consent until last study visit.  Investigators should notify EMAS of any SAEs occurs during this period.    
After last visit, any SAE reported to the investigator and considered causally related to trial treatment 
should be reported as part of the follow up study. For any participants that do not go into the follow up 
study, then SAEs that occur after the end of the trial and that may be attributed to ATIMP 
administration should be reported to the relevant regulatory agencies.  
 

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EMAS must be notified of all SAEs and SUSARs within 24 hours of the investigator becoming aware of 
the event. The investigator will respond to any SAE queries raised by the sponsor as soon as possible.  
The SAE form must be completed by the investigator (the consultant named on the delegation of 
responsibilities list who is responsible for the participant’s care) with attention paid to the grading, 
causality and expectedness of the event. In the absence of the responsible investigator, the SAE form 
should be completed and signed by a member of the site trial team and emailed as appropriate within 
the timeline. The responsible investigator should check the SAE form at the earliest opportunity, make 
any changes necessary, sign and then email to EMAS. Detailed written reports should be completed as 
appropriate. Systems will be in place at the site to enable the investigator to check the form for clinical 
accuracy as soon as possible. 
The minimum criteria required for reporting an SAE are the trial number and date of birth, name of 
reporting investigator and sufficient information on the event to confirm seriousness. Any further 
information regarding the event that is unavailable at the time of the first report should be sent as soon 
as it becomes available. 
The SAE form must be scanned and sent by email to the trial team on drug.safety@emaspharma.com 
Participants must be followed up until clinical recovery is complete and laboratory results have returned 
to normal or baseline values, or until the event has stabilised. Follow-up should continue after 
completion of trial follow-up (i.e. 6 months after delivery of ATIMP) if necessary. Follow-up SAE forms 
(clearly marked as follow-up) should be completed and emailed to EMAS as further information 
becomes available. Additional information and/or copies of test results may be provided separately. The 
participant must be identified by trial number and date of birth only. The participant’s name should not 
be used on any correspondence and must be blacked out and replaced with trial identifiers on any test 
results if the name is shown. 
5.11.3.6.2  Reporting Urgent Safety Measures 
The sponsor or investigator may take appropriate urgent safety measures in order to protect research 
participants against any immediate hazard to their health or safety. 
If any urgent safety measures are taken, MeiraGTx UK II Ltd. shall immediately (no later than 3 days 
from the date the measures are taken), give written notice to the MHRA, the relevant REC and the 
Sponsor of the measures taken and the circumstances giving rise to those measures. 
5.11.3.6.3 
EMAS responsibilities 
EMAS will follow EMAS Standard Operating Procedures and a study specific Safety Management Plan to 
ensure that case processing of events occurs within appropriate regulatory timeframes. EMAS will 
submit Development Safety Update Reports (DSURs) to regulatory authorities. 
5.11.3.6.4 
Reporting SUSARs in International Trials 
The mechanism for reporting SUSARs that occur outside of the UK to the MHRA, and those that occur 
outside of the US to the FDA will be covered in the trial specific Safety Management Plan. 

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5.11.3.6.5 
Annual Progress Reports 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date on 
which the favourable opinion was given, and annually until the trial is declared ended. Annual IRB 
applications for continuing review will be submitted with sufficient time to allow review and approval of 
trial continuation.  
5.11.4 
Quality Assurance and Control 
5.11.4.1 
Risk Assessment 
The Quality Assurance (QA) and Quality Control (QC) considerations for the Gene Therapy for LCA 
OPTIRPE65 trial are based on the MeiraGTx UK II Ltd. Quality Management Policy that includes a formal 
Risk Assessment, and that acknowledges the risks associated with the conduct of the trial and proposals 
of how to mitigate them through appropriate QA and QC processes. Risks are defined in terms of their 
impact on: the rights and safety of participants; project concept including trial design, reliability of 
results and institutional risk; project management; and other considerations. 
5.11.4.2 Clinical Monitoring 
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the trial 
Monitoring Plan (MP). The MP will also detail the procedures for review and sign-off of monitoring 
reports. In the event of a request for a trial site inspection by any regulatory authority MeiraGTx UK II 
Ltd. must be notified as soon as possible. 
5.11.4.3.1 
Direct access to participant records 
Participating investigators must agree to allow trial related monitoring, including audits, REC/IRB review 
and regulatory inspections, by providing access to source data and other trial related documentation as 
required. Participant consent for this will be obtained as part of the informed consent process for the 
trial. 
5.11.4.4 
Trial Oversight 
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of 
processes and prompting corrective action where necessary. The processes reviewed relate to 
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial interventions 
and policies to protect participants, including reporting of harms; completeness, accuracy and timeliness 
of data collection; and will verify adherence to applicable policies detailed in the Compliance section of 
the protocol. 
In multi-centre trials this oversight is considered and described both overall and for each recruiting 
centre by exploring the trial dataset or performing site visits as described in the Monitoring Plan. 

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5.11.4.4.1 
Clinical Management Team 
A Clinical Management Team (CMT) will be set up to assist with developing the design, co-ordination 
and strategic management of the trial. The membership, frequency of meetings, activity (including trial 
conduct and data review) and authority will be covered in the CMT terms of reference. 
5.11.4.4.2 
Independent Data Monitoring Committee 
The IDMC is responsible for safeguarding the interests of trial participants, monitoring the accumulating 
data and making recommendations to the CMT on whether the trial should continue as planned. The 
membership, frequency of meetings, activity (including review of trial conduct and data) and authority 
will be covered in the IDMC terms of reference. The IDMC will consider data in accordance with the 
statistical analysis plan and will advise the CMT through its Chair. 
5.11.4.4.3 
Trial Sponsor 
The role of the sponsor is to undertake regulatory responsibilities, and to secure arrangements to 
initiate, manage and finance the trial. MeiraGTx UK II Ltd. is the trial sponsor. 
6 
Ethics and Dissemination 
6.1 
Research Ethics Approval 
Before initiation of the trial at any clinical site, the protocol, all informed consent forms and any material 
to be given to the prospective participant will be submitted to the relevant REC/IRB for approval. Any 
subsequent amendments to these documents will be submitted for further approval. Before initiation of 
the trial at each additional clinical site, the same/amended documents will be submitted for local 
approval. An annual progress report or application for annual Continuing Review will be submitted to 
the relevant REC/IRB at each clinical trial site.  
The rights of the participant to refuse to participate in the trial without giving a reason must be 
respected. After the participant, has entered the trial, the clinician remains free to give alternative 
treatment to that specified in the protocol, at any stage, if the clinician feels it to be in the best interest 
of the participant. The reasons for doing so must be recorded. The participant remains free to change 
their mind at any time about the ATIMP administration (before administration) and follow-up (at any 
time) without giving a reason and without prejudicing their further treatment. 
6.2 
Competent Authority Approvals 
This protocol will be submitted to the national competent or equivalent authority (i.e. MHRA in the UK 
and Food and Drug Administration (FDA) in the US). 
This is a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive 
2001/20/EC. Therefore, a CTA is required in the UK.  
This is a Clinical Trial of an Investigational New Drug as defined by 21CFR Part 312 of the Code of Federal 
Regulations. Therefore, an Investigational New Drug Application (IND) is required in the US. 

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This trial is a human gene transfer study and therefore in the US must be reviewed by the initial site's 
Institutional Biosafety Committee and possibly by the Recombinant DNA Advisory Committee (RAC) of 
the NIH's Office of Biotechnology Activities (OBA). 
The progress of the trial, safety issues and reports, including expedited reporting of SUSARs, will be 
reported to the Competent Authority, regulatory agency or equivalent in accordance with relevant 
national and local requirements and practices.  
6.3 
Other Approvals 
The protocol will be submitted by those delegated to do so to the local department of each participating 
site. A copy of the local approval (or other relevant approval as above) and of the Participant 
Information Sheet (PIS) and consent form on local headed paper must be forwarded to MeiraGTx UK II 
Ltd. as part of the site initiation process prior to the site being designated ‘open to recruitment’ status. 
Participating sites receiving funding or support from the US government will obtain a Federal Wide 
Assurance (FWA). For ATIMP trials using Genetically Modified Organisms, organisations should also 
receive approval from their relevant national body to use the product (i.e. notification to the HSE in the 
UK). 
6.4 
Protocol Amendments 
MeiraGTx UK II Ltd. will be responsible for amendments to the protocol. MeiraGTx UK II Ltd. will be 
responsible for ensuring that protocol amendments are submitted to national competent authorities, 
and to investigators at each clinical trial site.  
Investigators at each clinical site will be responsible for submitting protocol amendments to the relevant 
REC/IRBs for approval, as well as any additional competent authorities in each country that require 
notification (e.g. the NIH OBA).  
6.5 
Consent or Assent 
Potential participants will be provided with a Participant Information Sheet (PIS) and given time to read 
it fully. Following a discussion with a medically qualified investigator or suitable trained and authorised 
delegate, any questions will be satisfactorily answered and if the participant is willing to participate, 
written informed consent will be obtained. During the consent process it will be made completely and 
unambiguously clear that the participant (or parent or guardian of a child) is free to refuse to participate 
in all or any aspect of the trial, at any time and for any reason, without incurring any penalty or affecting 
their treatment (or that of their child). 
 
Minors who are unable to consent for themselves will not be enrolled in the trial without the consent of 
their parent(s) or legal guardian(s). Children or adolescents will be asked to assent or agree. A 
Participant Information and Assent sheet that describes the details of the trial, trial procedures, and 
risks in simplified form will be provided to minors who have the capacity to provide informed assent. 
Participation must be refused in the event that assent is not given. Assent forms do not substitute for 
the consent form signed by the participant’s legally authorized representative.  

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Consent will be re-sought if new information becomes available that affects the participant’s consent in 
any way. This will be documented in a revision to the participant information sheet and the participant 
will be asked to sign an updated consent form. These will be approved by the appropriate ethics 
committee prior to their use. Consent will also be re-sought in the event that a child’s carer changes.  
A copy of the approved consent form is available from MeiraGTx UK II Ltd.  
6.6 
Confidentiality 
All data will be handled in accordance with the UK Data Protection Act 1998 and 2018  or the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). 
These regulations require a signed subject authorization informing the participants of the following:  
• 
What protected health information (PHI) will be collected from participants in this trial 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of 
their scheduled trial period. 
Participant confidentiality will be held strictly in trust by the investigators, trial staff, and the sponsor 
and their agents, to the extent provided by Federal, state, and local law.  This confidentiality is extended 
to cover testing of biological samples and genetic tests in addition to any trial information relating to 
participants. All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified only by a coded number in order to maintain subject confidentiality.  All records will be 
kept locked and all computer entry and networking programs will use coded numbers only. Participants 
will not be identified in any publicly released reports of this trial.  
Access to trial records will be limited to the minimum number of individuals necessary for quality 
control, audit and analysis. Clinical information will not be released without written permission of the 
subject, except as necessary for trial-related monitoring, audits, REC/IRB review, and regulatory 
inspections by University or government entities. In such cases, the clinical trial site will provide direct 
access to all source data, documents, and records maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) for the trial participants. Trial participants will be 
informed of this during the informed consent process.  
No information concerning the trial or the data will be released to any unauthorized third party without 
prior written approval of the MeiraGTx UK II Ltd. 

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The Case Report Forms (CRFs) will not bear the subject’s name or other personal identifiable data. The 
date of birth and participant identification number, will be used for identification. 
6.7 
Declaration of Interests 
The trial is funded by MeiraGTx UK II Ltd. 
James Bainbridge declares a financial interest in the company and receipt of payment for consultancy 
services. 
Michel Michaelides declares a financial interest in the company and receipt of payment for consultancy 
services. 
6.8 
Indemnity 
MeiraGTx UK II Ltd. holds insurance to cover participants for injury caused by their participation in the 
clinical trial. Participants may be able to claim compensation if they can prove that MeiraGTx UK II Ltd. 
has been negligent. However, as this clinical trial is being carried out in a hospital, the hospital continues 
to have a duty of care to the participant in the clinical trial. MeiraGTx UK II Ltd. does not accept liability 
for any breach in the hospital’s duty of care, or any negligence on the part of hospital employees. This 
applies whether the hospital is an NHS Trust or not.  This does not affect the participant’s right to seek 
compensation via the non-negligence route.  
 
Participants may also be able to claim compensation for injury caused by participation in this clinical trial 
without the need to prove negligence on the part of MeiraGTx UK II Ltd. or another party.  Participants 
who sustain injury and wish to make a claim for compensation should do so in writing in the first instance 
to the Chief Investigator, who will pass the claim to MeiraGTx UK II Ltd.’s insurers, via the Sponsor’s office. 
 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover for 
harm caused by their employees and a copy of the relevant insurance policy or summary shall be provided 
to MeiraGTx UK II Ltd., upon request. 
6.9 
Finance 
The Gene Therapy Trial for LCA OPTIRPE65 is funded by Medical Research Council grant number 
MR/M015815/1 and by MeiraGTx UKII Ltd. It is not expected that any further funding will be sought. 
6.10 Archiving 
6.10.1 
Archiving of Essential Trial Documentation Relating to 
Traceability 
Requirements for a traceability system and document archiving will be met in line with Regulation 
1394/2007 on Advanced Therapy Medicinal Products and the applicable Directives therein. To comply 
with the regulatory requirements, each responsible party (the sponsor of the trial, the manufacturer and 
the investigator(s)/institution(s) where the ATIMP is used) will ensure that the information relating to 
the traceability and accountability, from the production of ATIMPs to the recipient (participant) 

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receiving the ATIMPs, are archived for a minimum of 30 years after the expiry date of the ATIMP. These 
requirements will be set out in contractual agreements between the parties and the sponsor.  
The following essential documents/traceability data will be retained by the investigator and institution 
responsible for the human application of the ATIMP:  
• 
Shipping Records for the ATIMP  
• 
Certificate of Analysis of the ATIMP 
• 
Subject identification code list 
• 
ATIMP accountability at the site including final disposition of both used and unused product 
These records contain relevant information for traceability purposes and at least the following minimum 
data set from these records should be kept for 30 years after the expiry date of the product, or longer if 
required by the terms of the clinical trial authorisation or by the agreement with the sponsor: 
• 
Identification of the investigator/institution  
• 
Identification of the sponsor  
• 
Identification of the manufacturing site  
• 
Product name/code  
• 
Pharmaceutical form, route of administration, quantity of dosage units and strength  
• 
Batch number  
• 
Trial reference code  
• 
Trial Participant code  
• 
Participant identification code list (links name of recipient to the trial participant code)  
• 
Product expiry/retest date  
• 
Date of administration  
• 
Participant medical record should also contain the product name/code, the trial reference code, 
trial participant code and administration dates and doses  
• 
Records of any product that was unused or destroyed at site and its final status 
6.10.2 
Archiving of Other Essential Trial Documentation 
Trial documents should be retained for a minimum of 2 years after an FDA marketing application is 
approved for the ATIMP and until there are no pending or contemplated marketing applications for the 
ATIMP, or if an application is not approved for the ATIMP, until 2 years after shipment and delivery of 
the drug for investigational use has been discontinued and FDA is notified. For gene therapy trials, 
current Federal and State of Michigan requirements state that research records should be kept 
indefinitely, until further notice. Archiving of REC/IRB notices should be maintained according to local 
and/or institutional requirements.  
Essential documents are those which enable both the conduct of the trial and the quality of the data 
produced to be evaluated and show whether the site complied with the principles of Good Clinical 
Practice and all applicable regulatory requirements.  
MeiraGTx UK II Ltd. will notify sites when trial documentation can be archived, and which documents 
must be archived for the 30-year period. All archived documents must continue to be available for 
inspection by appropriate authorities upon request.  

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Destruction of essential documents will require authorisation from the Sponsor. 
6.11 Access to Data 
The investigators/ institutions will permit trial-related monitoring, audits, REC review, and regulatory 
inspections, 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. 
Requests for access to trial data will be considered, and approved in writing where appropriate, after 
formal application to the CMT. Considerations for approving access are documented in the CMT Terms 
of Reference. 
6.12 Ancillary and Post-Trial Care 
Participants will be invited to participate in a follow-up study after completion of this trial. 
6.13 Publication Policy 
6.13.1 Trial Results 
All proposed scientific publications will be discussed with the Sponsor prior to publication. Since this is 
an exploratory, open-label, Phase I/II trial, progress and significant findings may be presented at 
scientific forums/meetings and/or published during the course of the trial. 
The results of the trial will be disseminated regardless of the direction of effect. 
7 
Ancillary Studies 
There are no currently planned ancillary studies. Any future ancillary studies will be subject to separate 
funding, and will be submitted for ethical and regulatory review as appropriate. 
8 
Revision History 
Protocol Version and  Date 
Reason for Amendment  
Protocol V1.1 dated 28.01.2016 
 Clarify safety reporting procedures as requested 
by MHRA 
Protocol V2 dated 6th June 2016 
Further clarification of safety reporting 
procedures as requested by the MHRA. 
Updated inclusion/exclusion criteria as requested 
by the US FDA. 
Enhanced description of the method of 
measuring the primary objective and outcome 
Enhanced description of the dose limiting criteria 

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Minor modification to wording and language to 
correct typographical errors and ensure 
consistency throughout 
Change in name of funder from Athena Vision 
Ltd. to MeiraGTx UK Ltd. 
Protocol V3 dated 2nd August 2016 
Visual acuity assessments at day 1 and day 3 
post-treatment had been erroneously omitted 
from V2. These were replaced.  
UCL CCTU Clinical Project Manager was replaced 
and details updated. 
Protocol V4 dated 10 February 2017  
To reflect the change in sponsor from UCL to 
MeiraGTx UK II Ltd. 
Minor modification to wording and language to 
correct typographical errors and ensure 
consistency throughout 
To clarify the DLE and safety definitions 
 
To clarify the primary objective and outcome 
measures  
To describe the outsourcing of data management, 
pharmacovigilance and clinical monitoring to 
CROs 
Protocol V5 dated 12 April 2017  
To extend the course of post-surgery 
prophylactic steroids from 4 weeks to 8 weeks. 
Consequently, the duration for considering dose 
limiting events has been extended from 6 weeks 
to 9 weeks to cover the period of steroid 
administration and one additional week and 
other minor clarifications  
Protocol V6 dated 21 August 2017  
To update the prophylactic steroid regimen in 
children, and clarify safety reporting and safety 
dose for children  
Protocol V7 dated 23 February 2018  
To clarify the allowance of data obtained from 
the natural history study be used for screening 
and or baseline assessments (with consent from 
subjects) in order to avoid unnecessary testing of 
subjects. 
 
Clarify that more than 1 surgeon at a site may 
inject vector 

MGT003, Gene Therapy Trial for LCA OPTIRPE65
 
MGT003, Protocol version 8.0 11 June 2018  Page 65 of 67 
 
 
Expand the number of categories for ATIMP 
administration surgery from related or unrelated 
to: unrelated, unlikely, possibly, probably or 
definitely 
Protocol V8 dated 11 June 2018  
To add Full field Stimulus Testing as an 
assessment for children  
9 
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