An Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/5-hRKp.RPGR) for Gene Therapy of Adults and Children With X-linked Retinitis Pigmentosa Owing to Defects in Retinitis Pigmentosa GTPase Regulator (RPGR)
Phase: PHASE1
Conditions: X-Linked Retinitis Pigmentosa
Sponsor: MeiraGTx UK II Ltd

MGT009, Gene Therapy for XLRP RPGR 
 
Protocol version 11.0, 01May2020 
 
Page 1 of 101 
 
Gene Therapy for XLRP RPGR 
An open label, multi-centre, Phase I/II dose escalation trial of a 
recombinant adeno-associated virus vector (AAV2/5-hRKp.RPGR) for 
gene therapy of adults and children with X-linked Retinitis Pigmentosa 
owing to defects in Retinitis Pigmentosa GTPase Regulator (RPGR) 
 
Version 
11.0 
Date 
1st May 2020   
Sponsor 
MeiraGTx UK II Ltd 
Sponsor registration # 
MGT009 
Trial registration 
EudraCT 2016 003967 21 
CTA # 
45522/0004/001 0001 
NRES # 
218294 
 
Authorisation: Co-ordinating Investigator 
Name 
Role 
Signature 
Date 
 
Authorisation: Sponsor Representative  
Name 
Role 
Signature 

MGT009, Gene Therapy for XLRP RPGR 
OJ MEI RA GTx 
Gene Therapy for XLRP RPGR 
An open label, multi-centre, Phase 1/11 dose escalation trial of a 
recombinant adeno-associated virus vector (AAV2/5-hRKp.RPGR) for 
gene therapy of adults and children with X-linked Retinitis Pigmentosa 
owing to defects in Retinitis Pigmentosa GTPase Regulator (RPGR) 
Version 
Date 
Sponsor 
Sponsor registration# 
Trial registration 
CTA# 
NRES# 
11.0 
1st May 2020 
MeiraGTx UK II Ltd 
MGT009 
EudraCT 2016-003967 21 
45522/0004/001 0001 
218294 
Authorisation: Co-ordinating Investigator 
Name 
Role 
Signature 
Date 
Authorisation: Sponsor Representative 
Name 
Role 
Signatur 
Date 
Protocol version 11.0, 01May2020 
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Table of Contents 
1 
Administrative information ............................................................................................................ 7 
1.1 
Compliance ..................................................................................................................................... 7 
1.2 
Sponsor ........................................................................................................................................... 8 
1.3 
Structured trial summary ............................................................................................................... 9 
1.4 
Roles and responsibilities ............................................................................................................. 11 
1.4.1 
Protocol contributors ........................................................................................................... 11 
1.4.2 
Independent Data Monitoring Committee .......................................................................... 11 
2 
Trial Diagram ................................................................................................................................ 12 
3 
Abbreviations ............................................................................................................................... 13 
4 
Introduction ................................................................................................................................. 16 
4.1 
Background and Rationale ........................................................................................................... 16 
4.1.1 
Background .......................................................................................................................... 16 
4.1.2 
Preclinical Data ..................................................................................................................... 17 
4.1.3 
Rationale .............................................................................................................................. 18 
4.1.4 
Risk/Benefit .......................................................................................................................... 19 
4.1.5 
Assessment and Management of Risk ................................................................................. 19 
4.1.5.1 
Risk of immune responses to AAV2/5-hRKp.RPGR ...................................................... 19 
4.1.5.2 
Risk of vector transmission to other organs ................................................................ 20 
4.1.5.3 
Risk of insertional mutagenesis and oncogenesis ....................................................... 20 
4.1.5.4 
Risk of germline transmission ...................................................................................... 21 
4.1.5.5 
Risk of surgical adverse effects .................................................................................... 21 
4.1.5.6 
Risk of adverse effects of corticosteroids .................................................................... 22 
4.1.5.7 
Risk of investigations performed during assessment and follow up ........................... 22 
4.1.5.8 
Conclusion on the risk-benefit ratio ............................................................................ 23 
4.1.6 
Explanation for Choice of Comparators ............................................................................... 23 
4.2 
Objectives ..................................................................................................................................... 23 
4.2.1 
Primary Objective ................................................................................................................. 23 
4.2.2 
Secondary Objective ............................................................................................................ 24 
4.3 
Trial Design ................................................................................................................................... 24 
4.3.1 
Separate longer term follow up study ................................................................................. 25 

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4.3.2 
IMP Administration Review and Dose Escalation Criteria and Process ............................... 26 
4.3.2.1 
Dose Escalation Criteria and Dose Limiting Events ...................................................... 26 
4.3.2.2 
Dosing Process ............................................................................................................. 27 
4.3.2.2.1 Cohort 1 [administration and immediate follow up is now complete in this cohort]
 .................................................................................................................................. 27 
4.3.2.2.2 Cohort 2 [administration and immediate follow up is now complete in this cohort]
 .................................................................................................................................. 27 
4.3.2.2.3 Cohort 3 [administration and immediate follow up is now complete in this cohort]
 .................................................................................................................................. 27 
4.3.2.2.4 Additional considerations ......................................................................................... 28 
4.3.2.2.5 Confirmatory Safety Phase ....................................................................................... 30 
5 
Methods ....................................................................................................................................... 32 
5.1 
Site Selection ................................................................................................................................ 32 
5.1.1 
Study Setting ........................................................................................................................ 32 
5.1.2 
Site/Investigator Eligibility Criteria ...................................................................................... 32 
5.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ........................................ 33 
5.1.2.2 
Resourcing at site ......................................................................................................... 33 
5.2 
Site approval and activation ......................................................................................................... 33 
5.3 
Participants................................................................................................................................... 34 
5.3.1 
Eligibility Criteria .................................................................................................................. 34 
5.3.1.1 
Participant selection .................................................................................................... 34 
5.3.1.2 
Participant Inclusion Criteria ........................................................................................ 34 
5.3.1.3 
Participant Exclusion Criteria ....................................................................................... 35 
5.3.1.4 
Eligibility Criteria for Individuals Performing the Interventions .................................. 36 
5.3.1.5 
Co-enrolment Guidance ............................................................................................... 36 
5.3.1.6 
Screening Procedures .................................................................................................. 36 
5.3.1.6.1 Informed consent procedure .................................................................................... 37 
5.3.1.6.2 Screening Period ....................................................................................................... 38 
5.3.1.6.3 Rescreening ............................................................................................................... 39 
5.3.1.6.4 Enrolment (Randomisation) ...................................................................................... 40 
5.4 
Interventions ................................................................................................................................ 40 
5.4.1 
Products ............................................................................................................................... 40 

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5.4.1.1 
Name and description of Investigational Medicinal Products ..................................... 40 
5.4.1.2 
ATIMPs Classified as Genetically Modified Organisms ................................................ 41 
5.4.1.3 
Source of ATIMPs ......................................................................................................... 41 
5.4.1.4 
Preparation and labelling of the ATIMP ....................................................................... 41 
5.4.1.5 
Description and Justification of Route of Administration and Dose ............................ 42 
5.4.1.6 
Name and Description of Each Non-Investigational Medicinal Product (NIMP) ......... 43 
5.4.2 
Protocol Defined Clinical Schedule ...................................................................................... 45 
5.4.2.1 
Baseline Assessments .................................................................................................. 45 
5.4.2.2 
ATIMP Administration Procedures .............................................................................. 52 
5.4.2.2.1 Pre-operative procedure........................................................................................... 52 
5.4.2.2.2 Operative procedure ................................................................................................. 52 
5.4.2.3 
Subsequent Assessments ............................................................................................. 54 
5.4.2.4 
Laboratory Procedures ................................................................................................ 56 
5.4.3 
Dispensing ............................................................................................................................ 57 
5.4.3.1 
Receipt and storage of the Investigational Medicinal Product .................................... 57 
5.4.4 
Dosage and dosage modifications ....................................................................................... 57 
5.4.5 
Accountability ...................................................................................................................... 58 
5.4.6 
Compliance and Adherence ................................................................................................. 59 
5.4.7 
Concomitant Care ................................................................................................................ 59 
5.4.8 
Overdose of Trial Medication............................................................................................... 59 
5.4.9 
Protocol Treatment Discontinuation ................................................................................... 59 
5.4.9.1 
Participant withdrawal ................................................................................................. 59 
5.4.9.2 
Trial Stopping Rules...................................................................................................... 60 
5.5 
Outcomes ..................................................................................................................................... 60 
5.5.1 
Primary Outcomes ............................................................................................................... 60 
5.5.2 
Secondary Outcomes ........................................................................................................... 61 
5.6 
Trial Assessments ......................................................................................................................... 62 
5.6.1 
Early Stopping of Follow-up ................................................................................................. 69 
5.6.2 
Loss to Follow-up ................................................................................................................. 69 
5.6.3 
Trial Closure ......................................................................................................................... 69 
5.6.4 
Passive/Long Term Follow-Up After the End of the Trial ..................................................... 69 
5.7 
Sample Size ................................................................................................................................... 69 

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5.8 
Recruitment and Retention .......................................................................................................... 70 
5.8.1 
Recruitment ......................................................................................................................... 70 
5.8.2 
Retention .............................................................................................................................. 70 
5.9 
Assignment of Intervention .......................................................................................................... 70 
5.9.1 
Allocation ............................................................................................................................. 70 
5.10 Data Collection, Management and Analysis ................................................................................ 71 
5.10.1 
Data collection, management and entry ............................................................................. 71 
5.10.2 
Non-Adherence and Non-Retention .................................................................................... 72 
5.10.3 
Statistical Methods .............................................................................................................. 72 
5.10.3.1 
Statistical Analysis Plan ................................................................................................ 72 
5.10.3.2 
Statistical Methods – Outcomes .................................................................................. 72 
5.10.3.3 
Statistical Methods – Secondary Outcome Analysis .................................................... 73 
5.10.3.4 
Economic evaluations .................................................................................................. 74 
5.11 Data Monitoring ........................................................................................................................... 74 
5.11.1 
Independent Data Monitoring Committee .......................................................................... 74 
5.11.2 
Interim Analyses ................................................................................................................... 74 
5.11.3 
Data Monitoring for Harm ................................................................................................... 74 
5.11.3.1 
Safety reporting ........................................................................................................... 74 
5.11.3.2 
Other Notifiable Adverse Events ................................................................................. 76 
5.11.3.3 
Procedures to follow in the event of the partners of male participants becoming 
pregnant ....................................................................................................................... 76 
5.11.3.4 
Investigator responsibilities relating to safety reporting ............................................ 76 
5.11.3.4.1 Seriousness assessment ............................................................................................ 77 
5.11.3.4.2 Severity or grading of Adverse Events ...................................................................... 77 
5.11.3.4.3 Causality .................................................................................................................... 78 
5.11.3.4.4 Expectedness ............................................................................................................ 79 
5.11.3.5 
Notifications ................................................................................................................. 80 
5.11.3.5.1 Notifications by the Investigator to 
 ................................................................ 80 
5.11.3.5.2 
 responsibilities ................................................................................................ 81 
5.11.3.5.4 Reporting SUSARs in International Trials .................................................................. 81 
5.11.3.5.5 Annual Progress Reports ........................................................................................... 81 
5.11.4 
Quality Assurance and Control............................................................................................. 82 

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5.11.4.1 
Risk Assessment ........................................................................................................... 82 
5.11.4.2 
Clinical Monitoring ....................................................................................................... 82 
5.11.4.2.1 Direct access to participant records ......................................................................... 82 
5.11.4.3 
Trial Oversight .............................................................................................................. 82 
5.11.4.3.1 Independent Data Monitoring Committee ............................................................... 83 
6 
Ethics and Dissemination ............................................................................................................. 83 
6.1 
Research Ethics Approval ............................................................................................................. 83 
6.2 
Regulatory Authority Approvals ................................................................................................... 83 
6.3 
Other Approvals ........................................................................................................................... 84 
6.4 
Protocol Amendments ................................................................................................................. 84 
6.5 
Consent or Assent ........................................................................................................................ 84 
6.6 
Confidentiality .............................................................................................................................. 85 
6.7 
Declaration of Interests ................................................................................................................ 86 
6.8 
Indemnity ..................................................................................................................................... 87 
6.9 
Finance ......................................................................................................................................... 87 
6.10 Archiving ....................................................................................................................................... 87 
6.10.1 
Archiving of essential trial documentation relating to traceability ..................................... 87 
6.10.2 
Archiving of Other Essential Trial Documentation ............................................................... 88 
6.11 Access to Data .............................................................................................................................. 89 
6.12 Ancillary and Post-trial Care ......................................................................................................... 89 
6.13 Publication Policy ......................................................................................................................... 89 
6.13.1 
Trial Results .......................................................................................................................... 89 
7 
Ancillary Studies ........................................................................................................................... 90 
8 
Appendix 1: Guidance on Study Conduct during the COVID-19 Pandemic.................................. 91 
9 
Protocol Amendments ................................................................................................................. 94 
10 
References .................................................................................................................................... 96 
 
 

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1 
Administrative information 
This document describes the Gene Therapy trial for X-linked Retinitis Pigmentosa (XLRP) caused by 
mutations in the gene encoding Retinitis Pigmentosa GTPase Regulator (RPGR), 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 the treatment of 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. 20131). The SPIRIT 
Statement Explanation and Elaboration document (Chan et Al. 20132) 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 all applicable regulations. UK 
sites will comply with the principles of Good Clinical Practice (GCP) as laid down by the Commission 
Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 
2006/1928 and subsequent amendments, Advanced Therapy Medicinal Products (ATMP) Regulations (EC) 
No 1394/2007, the Human Tissue (Quality and Safety for Human Application) Regulations 2007, and the 
UK Data Protection Act.  US sites will comply with 21 CFR 312 in the Code of Federal Regulations, and the 
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (November 2013). 
 
The participating sites will inform MeiraGTx UK II Ltd. as soon as they are aware of a possible serious 
breach of compliance, so that MeiraGTx UK II Ltd. can fulfil its requirement to report the breach if 

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necessary, 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 
EudraCT 2016-003967-21 
Secondary Identifying Numbers 
MeiraGTx UK II Ltd. registration number: MGT009 
Sponsor 
MeiraGTx UK II Ltd. 
Contact for Public Queries 
ocularinfo@meiragtx.com 
Contact for Scientific Queries 
 
  
 
 
 
 
 
 
Public Title 
RPGR XLRP trial 
Scientific Title 
An open label, multi-centre, Phase I/II dose escalation trial of a 
recombinant 
adeno-associated 
virus 
vector 
AAV2/5-
hRKp.RPGR for gene therapy of adults and children with X-
linked Retinitis Pigmentosa owing to defects in RPGR 
Countries of Recruitment 
United Kingdom, United States of America 
Health Condition(s) or Problem(s) 
Studied 
X-linked Retinitis Pigmentosa 
Intervention(s) 
Open label, dose-escalation 
• 
 
  
 
 
  
 
 
 
Key Inclusion and Exclusion Criteria 
Key Inclusion Criteria:  
• 
Males aged 5 years or older (children will be included only 
once the maximal tolerated dose has been determined) 
• 
With Retinitis Pigmentosa caused by mutations in RPGR 
• 
Evidence of relative preservation of retinal structure at the 
macula 
• 
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:  
• 
Intra-ocular surgery within 3 months of screening 
• 
Ocular or systemic disorder that may preclude subretinal 
surgery and/or interfere with interpretation of the study 
results. 
• 
Participated in another research study involving an 
investigational therapy for ocular disease within the last 6 
months 

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• 
Have any other condition that the Principal Investigator (PI) 
considers makes them inappropriate for entry into the trial 
• 
Are unwilling to consider the possibility of entry into a 
subsequent longer term follow up study 
Study Type 
Phase I/II, open-label, multi-centre, dose escalation in adults, 
followed by dose confirmation in children, followed by further   
randomised dose confirmation against a control arm in adults 
and children with XLRP owing to defects in RPGR 
Date of First Enrolment 
Q3 2017 
Target Sample Size 
Up to 71 participants 
Primary Outcome(s) 
The primary outcome is safety of subretinal administration of 
AAV2/5-hRKp.RPGR.  
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 12 months after the intervention in 
this study, and a further 4 years in a separate follow on study 
(for deferred arm patients’ safety will be assessed for 6 months 
after the intervention in this study and a further 4½ years in a 
separate follow on study). 
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.  
Efficacy will be assessed at several time points between 3 to 12 
months after the intervention:  
1) Slowing or halting of progressive deterioration in 
retinal structure or visual function that is greater than 
the baseline variation for that test and is sustained for 
at least two consecutive assessments. Slowing or 
halting of progression over time may be facilitated by 
comparing 
identical 
structural 
and 
functional 
assessments acquired prior to intervention/injection 
to better determine rate of change over time in this 
slowly progressive disease. 
2) Any improvement in visual function from baseline that 
is greater than the baseline variation for that test and 
is sustained for at least two consecutive assessments. 
3) Any improvement in retinal function from pre-
intervention that is greater than baseline variation and 
measurable by electrophysiology (pattern ERG, 
multifocal ERG or full-field ERG). 
4) Health- and vision-related quality of life measures 
(HRQoL, VRQoL). 

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1.4 
Roles and responsibilities 
Agreements that include detailed roles and responsibilities will be in place between participating sites and 
MeiraGTx UK II Ltd. 
 
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  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.2 
Independent Data Monitoring Committee  
Name 
Affiliation 
Role and responsibilities 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
BNF 
British National Formulary 
CAI 
Codon Adaptation Index 
cDNA 
complementary 
Deoxyribonucleic Acid 
CGIC 
Clinician Global Impression of 
Change 
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 
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 
hEBs 
Human embryonic bodies 
HEK293T 
human 
embryonic 
kidney 
epithelial cell line 
hRPE65 
human 
retinal 
pigment 
epitheliumspecific 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 

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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 
 
 
LCA 
Leber congenital amaurosis 
LCA2 
Retinal dystrophy associated 
with defects in RPE65 
LLQ 
Low Luminance Questionnaire 
LREC 
Local Research Ethics 
Committee  
MA 
Marketing authorisation 
Main REC 
Main Research Ethics 
Committee  
MHRA 
Medicines and Healthcare 
products Regulatory Agency 
MRI 
Magnetic Resonance Imaging 
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 
NRES 
NHS National Research Ethics 
Service 
NZW 
New Zealand White 
OBA 
Office of Biotechnology 
Activities 
OCT 
Optical Coherence Tomography 
ONL 
Outer nuclear layer 
ORF15 
open reading frame 15 
PCT 
Polymerase Chain Reaction 
PERG 
Pattern Electroretinogram 
PGIC 
Patient Global Impression of 
Change 
PGIS 
Patient Global Impression of 
Severity 
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 
rAAV 
Recombinant adeno associated 
virus 
rAAV2 
recombinant adeno-associated 
virus serotype 2 
R&D 
Research and Development 
REC 
Research Ethics Committee 
RG 
Research grade 
RK  
Rhodopsin Kinase 
RNA 
Ribonucleic acid 
RPE 
Retinal Pigment Epithelium 
RPE65 
retinal pigment 
epitheliumspecific protein 65 
(all-trans-retinyl isomerase) 
RPGR 
retinitis pigmentosa GTPase 
regulator 
rt-PCR 
reverse transcription 
polymerase 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 
TEI 
Treatment Experience 
Interview 

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TMF 
Trial Master File 
ToR 
Terms of Reference 
tRNA 
Transfer ribonucleic acid 
UAR 
Unexpected Adverse Reaction 
 
 
USA 
United States of America 
vg 
Viral Genomes 
 
 
WT 
Wild type 
XLRP 
X-linked retinitis pigmentosa 

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4 
Introduction 
4.1 
Background and Rationale 
4.1.1 
Background 
Retinitis pigmentosa (RP) is a group of inherited diseases of the retina, first described by Donders in 1857 
(Donders, 1857). The condition is characterised by a progressive reduction in vision, initially manifest as 
night blindness which usually becomes apparent in childhood or early adulthood and is progressive 
throughout the subject’s life-time. Owing to a number of X-linked forms, RP affects more men than 
women.   
 
The prevalence of RP is estimated to be 1:3000 with 30-40% of cases inherited via an autosomal dominant 
route, 45-60% via an autosomal recessive route and 5-15% as an X linked (XL) trait. RP occurs most 
commonly in isolation (non-syndromic). Less frequently, RP may present as part of a syndrome such as 
Usher syndrome and Bardet-Biedl syndrome. 
 
RP is characterised initially by night blindness (nyctalopia), progressive visual field constriction and finally 
decreased central vision in the advanced stage. The condition can manifest at any age from early 
childhood. Nyctalopia is commonly the first symptom, with difficulties in performing tasks in dark places 
or at night, such as navigating through dark rooms (e.g. cinemas), with a markedly impaired and delayed 
ability to adapt to dim ambient illumination. There is also progressive peripheral visual field loss with 
increasingly constricted peripheral vision.  This results in ‘tunnel vision’ over time, which markedly 
restricts navigation / mobility and ability to undertake activities of daily living – with associated emotional, 
psychological and social impact. In the later stages continued retinal failure and degeneration results in 
central visual impairment and eventual blindness (Tee et Al. 2016). 
 
Seventy to 80% percent of X-linked RP (XLRP) arises from pathogenic mutations in the retinitis pigmentosa 
GTPase regulator (RPGR) gene. RPGR associated XLRP (RPGR XLRP) is a particularly severe type of RP with 
an early onset of disease in childhood and relatively rapid progression. 
 
For most forms of RP, including RPGR XLRP, the underlying mutations effect their pathological change 
through the dysfunction and subsequent loss of the photoreceptor cells, and thus the loss of light 
sensitivity. 

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4.1.2 
Preclinical Data 
Evidence for the medical plausibility of this gene therapy as a treatment for RPGR XLRP has been obtained 
from successful treatment in a mouse model of RPGR XLRP in which a slow progressive loss of 
photoreceptors is seen (Pawlyket al., 2016). In this study, a vector carrying the construct that is intended 
for this clinical trial was subretinally injected into Rpgr-deficient mice, leading to a rescue of 
photoreceptor cell loss and a preservation of photoreceptor function. These investigations followed on 
from earlier work in which functional and morphological rescue of both rod and cone photoreceptor cells 
in Rpgr-deficient mice was demonstrated using an abbreviated murine Rpgr ORF15 isoform as the 
transgene (Hong et al., 2005). This earlier study supported the theory that a shortened human RPGR 
ORF15 replacement gene, driven by a rhodopsin kinase (RK) promoter, is sufficient to rescue 
photoreceptor degeneration in Rpgr-null mice. This is important as the long purine-rich repetitive 
sequence of the ORF15 exon is unstable in many recombinant DNA manipulation procedures, presenting 
significant challenges to cloning a full-length cDNA from retinal RNA and, consequently, the ability to 
manufacture viral vector constructs packaging such a full length cDNA predictably and reproducibly to 
GMP. 
 
The available data demonstrate that robust protein expression occurs with both of the abbreviated forms 
of RPGR.ORF15 studied (Pawlyk et al., 2016,Hong et al., 2005) as evidenced by immunocytochemistry and 
western blotting data, with the latter showing that both forms of RPGR.ORF15 were expressed at levels 
that were similar to or slightly above that seen for the full length RPGR protein in a normal human retina. 
Both forms were seen exclusively in the photoreceptor cells but not in the retinal pigment epithelium 
(RPE) or the inner retina, indicating that the use of the RK promoter drives rod and cone photoreceptor 
cell specific expression at levels that are likely appropriate for clinical trials.  Importantly, the data show 
that delivery of a human RPGR.ORF15 gene in which around one-third of the purine-rich repetitive region 
is removed (RPGR.ORF15-L) results in RPGR protein that correctly localises to the connecting cilia of 
photoreceptors and corrects the disease phenotype (and therefore retains RGPR function in vivo). In 
contrast, use of the shorter isoform, RPGR.ORF15-S form, where most of the purine-rich region is 
removed, resulted in an inability of the protein to correctly localise to the connecting cilia and also failure 
to function correctly. In conclusion, the RGPR.ORF15-L gene, under the control of the RK promoter, results 
in expression of a functional RGPR protein and, subsequently, significant functional and morphological 
rescue of rods and cones in an animal model of RPGR XLRP. 

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Prior to the selection of AAV2/5 for the viral vector serotype, the Sponsor used human embryonic stem 
cell-derived cone photoreceptors (human ES cells differentiated into retinal cultures bearing human 
neuroepithelia containing human cones) to test the transduction efficiency of both AAV2/5 and AAV2/8 
carrying GFP. In this experiment, human embryonic bodies (hEBs) were differentiated to retinal cultures 
and titre matched viruses were added between days 90-100 of culture. The transduced hEBs were 
collected after 2 weeks for immunohistochemistry and flow cytometry. The results showed that GFP+ cells 
were observed in all virally transduced human ESC-derived EBs and, analogous to their position in the 
human outer nuclear layer of the retina, these positive cells were mostly observed at the apical edge of 
the neuroepithelium. 
 
To determine transduction efficiency of cone photoreceptors transduced by either the AAV2/5 or AAV2/8, 
vector-derived GFP co-localisation with red and green (L+M) opsins (MOPSIN) was assessed by 
immunofluorescence. Co-localisation of MOPSIN and GFP+ cells was observed in the neuroepithelium 
with both AAV viral vectors. Quantification of MOPSIN+/GFP+ cone cells by flow cytometry showed a non-
significant difference in transduction efficacy between AAV2/5 and AAV2/8 serotypes. 
 
Therefore, in the absence of any significant difference between the 2 serotypes, it is considered that the 
data generated with the AAV2/8 serotype can be extrapolated to AAV2/5. As it is the viral vector genome 
that is the central element that determines the efficacy of the treatment, the absence of a significant 
difference in transduction efficiency between the 2 serotypes suggested that the 2 serotypes were 
comparable and would have analogous potency in vivo. Based on this and commercial considerations the 
AAV2/5 serotype was selected to advance into clinical development.   
 
4.1.3 
Rationale 
There is currently no licensed therapeutic treatment for RPGR XLRP. Among a variety of novel 
experimental strategies that are currently under investigation, gene therapy is considered the most 
promising. It is hypothesised that, in those subjects with RP associated with mutations in the RPGR gene, 
localised gene augmentation with a human RPGR-ORF15 variant will result in the production of a 
biochemically active RPGR-ORF15 protein and thereby facilitate functional and morphological rescue of 
both rod and cone photoreceptor cells and consequently improved vision.  

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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. RPGR XLRP is chronically debilitating as evidenced by the severe impairment in visual function 
from early childhood and the consequent relatively rapid progressive loss of retinal cells, leading to 
inexorable blindness in the 3rd and 4th decades of life. The condition is currently untreatable, but there is 
a real possibility that gene therapy could offer a significant benefit in terms of markedly slowing/halting 
progressive retinal loss thereby preserving central vision, improved sight and quality of life (QOL). This is 
reinforced by our own experience from the 1st gene therapy trial for inherited retinal disease (Bainbridge, 
et Al. 2008), as well as subsequent ocular gene therapy trials by others (Maguire, et al 2008; Cideciyan, 
AV et al 2008 and 2013), and pre-clinical data demonstrating improved outcome in animal models of RPGR 
XLRP.  
 
The safety of the proposed approach will be enhanced by restricting transgene expression to the target 
tissue by virtue of the photoreceptor-specific promoter, the inherent tropism of the AAV 2/5 vector, the 
direct administration to the sub-retinal delivery space and by restricting the intervention to one eye only 
in each participant.  
 
4.1.5 
Assessment and Management of Risk 
The risk to participant safety in relation to AAV2/5-hRKp.RPGR, the ATIMP, is MHRA Type C (i.e. markedly 
higher than the risk of standard medical care). General risk management will include the detailed review 
of all 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 AAV2/5-hRKp.RPGR 
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, peri and post-operative prophylactic administration of topical and systemic 

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corticosteroids. In our 1st 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 our subsequent trial of gene 
therapy, (including herein for low dose and intermediate dose AAV2/5-hRKp.RPGR) intraocular 
administration of an AAV2/5 has been well tolerated in the majority of participants to date. Some  
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 AAV, anterograde and trans-synaptic 
transport of small amounts of vector genome from the retina to central visual structures may occur 
(Stieger, et al 2008). This is considered most likely to result from off target transduction of retinal ganglion 
cells following reflux of vector suspension into the vitreous. Since only tiny amounts of vector are likely to 
reach the brain and a photoreceptor-specific promoter will be used, the possibility of transgene 
expression causing toxicity in the brain is considered to be highly unlikely. Minimal vector amounts (i.e. a 
few hundred vector genome copies) might be traced in other organs like lymph nodes, spleen and liver 
but similarly to the brain, transgene expression causing toxicity is highly unlikely due to the human 
photoreceptor-specific promoter. 
 
4.1.5.3 Risk 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) AAV vector genomes integrate 
into host chromosomes at a very low frequency (Nowrouzi, et al 2012), (ii) a limited number of AAV 
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 AAV into thousands of rodent eyes. Even when we injected AAV vectors intraocularly in a large 
number of tumour-prone p53-/- mice, we found no evidence of malignant transformation of retinal cells 
(Balaggan, et al2012).  In the highly unlikely event that an intraocular tumour does arise, the 
comprehensive monitoring procedures described in the protocol will enable early detection and thus 
prompt appropriate management.  
 

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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 AAV vectors has not been detected. Similarly, we detected no vector genomes in semen 
in our previous retinal gene therapy clinical trial (Bainbridge, et al 2008). Systemic intravascular 
administration of AAV2 to deliver factor IX in haemophilia B, can lead to vector sequences detectable in 
semen, though not sperm for a short period (Manno et al 2006). However, in this instance doses ranging 
from 8 x 1010 to 2 x 10 12 vg/kg were administered, considerably higher than the doses proposed for 
subretinal injection in this study. Whilst this indicates there may be some potential for inadvertent 
germline transmission following the systemic delivery of high doses of vector, 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 barrier 
and spermicide 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, including bleeding in the eye, infection and increased pressure inside the 
eye.  To manage the risk of surgical adverse events, only highly experienced surgeons will perform the 
procedure. Complications of surgery are typically managed effectively by medication or further surgical 
intervention, but can rarely result in lasting harm to sight. The risk of lasting severe impairment of sight 
from vitrectomy surgery is approximately 1 in 1000. We have identified some reduction in outer retinal 
thickness and deterioration in acuity in 2 of the 12 participants in our previous clinical trial of gene therapy 
for LCA RPE65, believed to result from temporary retinal detachment which is a deliberate consequence 
of targeted administration of the vector suspension, but no other significant surgical adverse effects.  
 
Delivery of ATIMP to the subretinal space will be performed by standard surgical vitrectomy. This will 
involve a 3-port pars plana vitrectomy followed by injection of ATIMP using a fine cannula through small 
retinotomies, resulting in a temporary retinal detachment. Previous gene therapy clinical trials have 
shown that the bleb of subretinal ATIMP 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.  
 

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Potential complications of this surgery specifically include persistence of the subretinal vector bleb, the 
development of retinal tears, elevated intraocular pressure and persistent postoperative intraocular 
inflammation. Persistently elevated intraocular pressure may result in glaucoma and vision loss; likewise, 
persistent inflammation may result in vision loss.  We will minimise any risk to visual function by limiting 
ATIMP delivery to the area of retina most likely to benefit, and by leaving the contralateral eye untreated. 
Retinal detachment caused by persistent vector bleb or intraoperative retinal tear is expected to occur in 
fewer than 1 in 100 procedures and can be effectively managed in the majority by retinopexy, with or 
without intraocular tamponade. Persistent intraocular inflammation will be managed by topical 
corticosteroid therapy, with systemic corticosteroids where indicated.  Elevated intraocular pressure will 
be managed by topical therapy; with systemic therapy where indicated with specialist advice sought as 
required. 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 in 
surgery for subretinal haemorrhage, and an adjunctive technique in the management of retinal 
detachment. 
 
4.1.5.6 Risk of adverse effects of corticosteroids 
Candidates will be screened for contra-indications to transient immune suppression by corticosteroids. 
Possible adverse effects of short-term systemic corticosteroid use include increases in blood pressure and 
blood sugar, weight gain, changes in mood or behaviour, increased risk of infections, increased intraocular 
pressure and cataracts. Local steroids used on or near the eye can cause increased intraocular pressure 
and cataracts.   
 
The possibility of steroid-induced adverse effects will be monitored regularly. In particular, blood pressure 
on day 1, day 3, day 7, week 2, week 4, week 6, and week 9, and blood glucose, renal function and liver 
function (at baseline and day 1, day 7, week 2, week 4, week 6 and week 9 after surgery).  
 
4.1.5.7 Risk 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.  

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4.1.5.8 Conclusion on the risk-benefit ratio 
In summary, the risks associated with the intervention are justified by the potential for individual 
participants to benefit, and by the scientific value of the trial to the development of treatments for other 
individuals similarly affected.  
 
4.1.6 
Explanation for Choice of Comparators 
There is no currently approved treatment for XLRP caused by mutations in RPGR thus there are no 
comparators in this study. The contralateral fellow eye will be left untreated to minimise the risk to visual 
function and may also serve as a control given the relative inter-ocular symmetry of disease. There are no 
currently approved treatments for any forms of RP. 
 
4.2 
Objectives 
4.2.1 
Primary Objective 
The primary research objective is to assess the safety of the ATIMP, AAV2/5-hRKp.RPGR, for RGPR-ORF15 
gene replacement in the retina of patients with RPGR XLRP.  
 
Safety is defined as the absence of 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) 
 
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 6 week period. 

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4.2.2 
Secondary Objective 
The secondary research objective is to determine whether AAV2/5-hRKp.RPGR for RGPR-ORF15 gene 
replacement in the retina can slow/halt progressive deterioration in retinal structure or visual function, 
and improve retinal function, visual function and quality of life in patients with RPGR XLRP. 
 
4.3 
Trial Design 
This is an open-label phase I/II dose-escalation trial to determine the safety and efficacy of subretinal 
administration of AAV2/5-hRKp.RPGR in participants with XLRP caused by mutations in RPGR.  
 
In the dose escalation phase, up to 18 adult participants will be administered one of 3 different doses of 
the ATIMP in cohorts of 3 participants at a time. Based on toxicity data, the IDMC will make a 
recommendation on the dose to administer to the next cohort of 3 participants.  
 
Adults are defined as participants aged 16+ in the UK and aged 18+ in the US. 
 
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 the study. This maximum 
acceptable dose will be confirmed in paediatrics in the first instance.  
 
Subsequent participants in the expansion phase will be randomised to one of 3 treatment groups (low 
dose administration: intermediate dose administration: deferred administration). Participants 
randomised to the deferred administration arm will also be randomised to receive either the low or 
intermediate dose. The eye selected for administration will also be randomised. All aspects of 
randomisation will be performed on completion of screening. Baseline assessments will be completed as 
soon as possible after randomisation and will be valid for 3 months1. See Section 5.9.1 for further details 
regarding randomisation. The deferred administration treatment group will perform baseline 
assessments as soon as possible after randomisation. At the end of baseline assessments, a day 0 will be 
applied and deferred administration follow up will be counted from this date. The deferred treatment 
group will be considered as a control group. 
                                                          
1 For patients who surgery dates were postponed due to COVID 19 please refer to appendix 1 

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Safety and efficacy will be assessed for 12 months following the intervention by clinical examination and 
special investigations according to the schedule in section 5.6. 
 
4.3.1 
Separate longer term follow up study 
Safety will be assessed in this study for 12 months following ATIMP administration (6 months for patients 
in the deferred arm). Participants will be invited to enrol in a separate subsequent 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, 9 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 February 2020 (Long Term Follow-up After 
Administration of Human Gene Therapy Products: Guidance for Industry) recommends a standard 15-year 
period of follow-up, it is also noted that a shorter period of follow up may be appropriate if the ATIMP 
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  12 (deferred treatment control group only), 18, 24, 36, 48 and 60 months 
following ATIMP administration; as such, participants will be followed up more frequently than 
recommended in the CHMP guidance, as additional assessments following ATIMP administration are 
included in the initial study (at weeks 1, 2, 4, 6, 9 and month 9). The-follow up study will have a separate 
protocol, participant information and consent process, and will be submitted for separate ethical review. 
Participants in the current study will be strongly 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 elect not to participate in the long-term follow-up study; 
however, in this motivated population, where individuals are typically monitored by their specialist closely 
and regularly, this is considered highly unlikely. 

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4.3.2 
IMP Administration Review and Dose Escalation Criteria and Process 
Up to 18 adult participants (as defined in section 5.3) will be administered one of 3 doses of ATIMP in a 
total maximal volume of 1mL, according to the dose-escalation criteria: 
1) low dose  
 
 
 
2) intermediate dose  
 
 
3) high dose  
 
 
 
Once a maximal tolerated dose is established, up to 53 further participants aged 5 years or older will 
continue to be administered ATIMP up to the highest dose observed to be tolerated in adults. This includes 
up to 5 paediatric participants in the confirmation phase and up to 48 in the randomised phase. 
 
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 patients. 
 
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 (defined below) 
• 
Infective endophthalmitis 
• 
Ocular malignancy 
• 
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 6 week period. 

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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 anticipated therapeutic ATIMP 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 [administration and immediate follow up is now complete in this cohort] 
ATIMP 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, ATIMP will continue to be administered at the same dose to 2 further adult participants. In 
the event of a DLE in the 1st adult in the cohort, the cohort will be expanded to a possible total of 6 
participants.  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 up to 9 weeks following ATIMP 
administration to the 3rd participant.  
 
4.3.2.2.2 
Cohort 2 [administration and immediate follow up is now complete in this cohort] 
In the event that there is no DLE in any participant, the IDMC will recommend administering ATIMP at the 
intermediate dose level to a single adult participant.  If there is no DLE after a minimum of 4 weeks, ATIMP 
will continue to be administered at the same dose to 2 further adult participants. In the event of a DLE in 
the 1st adult in the cohort, an additional 3 participants will may be treated at this dose level. 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 
ATIMP administration to the 3rd participant. 
 
4.3.2.2.3 
Cohort 3 [administration and immediate follow up is now complete in this cohort] 
If the IDMC recommends it is safe to dose escalate to the highest dose, then ATIMP will be administered 
at the highest dose level to a single adult participant.  If there is no DLE after a minimum of 4 weeks, 
ATIMP will be administered at the same dose to 2 further adult participants. In the event of a DLE in one 
of the 3 participants at this dose, the cohort may be expanded to up to 3 additional participants at this 
dose level. A discussion will be held with the IDMC to agree a plan of action for administering the ATIMP 
to further adults.  

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4.3.2.2.4 
Additional considerations 
In the event of a DLE in 1 of the 3 participants at a given dose, the cohort may be expanded and additional 
participants treated at the dose level. The IDMC will review the safety data and confirm that additional 
participants may be treated at this dose. The dose escalation will continue until:  
• 
On review of the accumulating data the IDMC recommend a maximum dose to be administered 
in the expansion phase; 
• 
3 participants have been 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 
patients with a DLE at that dose level), in which case the recommended maximum anticipated 
therapeutic dose will be the level below.  
 
In the event that 1 or 2 DLEs are seen at the 1st 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 and confirmation table 
Number of DLEs 
Low dose 
Participants 1-
3 
Participants 4-
6 
Action 
Details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intermediate dose 
Participants 1-
3 
Participants 4-
6 
Action 
Details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
High dose 
Participants 1-
3 
Participants >3 
Action 
Details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MGT009, Gene Therapy for XLRP RPGR 
Figure 1: Dose escalation Flow chart 
4.3.2.2.5 
First participant recruited to a 
cohort 
Confirmatory Safety Phase 
0J ME I RA GTx 
The adult dose escalation component of the study is complete at the t ime of protocol amendment v9.0. 
Review of the data collected to date with the IDMC led to a decision not to pursue the higher dose level 
and to commence administration for confirmation in paediatrics at the intermediate dose level. Children 
are defined as those aged 15 and under in the UK, and 17 and under in the US. These participants in the 
paediatric confirmation phase are administered the intermediate dose -
- -- which has 
Protocol version 11.0, 01May2020 
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been shown to be well tolerated in adults. Having identified children who may be willing to participate in 
the study, the CI will prioritise ATIMP administration to older candidates in the 1st instance. The 1st child 
administered ATIMP will be monitored for safety for a period of 4 weeks. If there is no adverse event 
consistent with the above definition of a DLE after 4 weeks, ATIMP will be administered to further 
children. 
 
In order to fully explore dose levels and make optimal use of the expansion phase of the study, a treatment 
group randomisation will subsequently occur to either low or intermediate dose; to achieve up to 32 
participants receiving intervention at baseline, and up to 16 further participants receiving deferred 
intervention at 6 months following baseline (control group). The expansion phase will include up to 48 
participants in total, who may be adults or children.  
 
Therefore, participants will be randomised to 1 of 3 arms in a 1:1:1 ratio (immediate low dose 
administration (n= up to 16): immediate intermediate dose administration (n= up to 16): deferred 
administration (n= up to 16)). Participants randomised to the deferred administration group will be further 
randomised to receive the low or intermediate dose in a 1:1 ratio (deferred low dose administration (n= 
up to 8): deferred intermediate dose administration (n= up to 8)). The eye selected for administration will 
also be randomised. All aspects of randomisation will occur on completion of screening. (Figure 2: 
Randomisation Timeline).  Baseline assessments will be completed as soon as possible after 
randomisation and will be valid for 3 months2. In the deferred treatment group, a day 0 will be applied at 
the end of baseline assessments and deferred treatment follow up will be calculated from this date.  The 
three treatment groups of the randomised expansion phase will be stratified by age at date of informed 
consent (<25 years, ≥25 years) to balance for disease severity between treatment groups with age used 
as a surrogate for severity. 
 
 
                                                          
2 For patients who surgery dates were postponed due to COVID 19 please refer to appendix 1 

MGT009, Gene Therapy for XLRP RPGR 
0J ME I RA GTx 
Figure 2: Randomisation Timeline 
Time (months) 
0 
Participant completes screening 
Randomisat ion 1: Eye selected for administ rat ion 
Randomisat ion 2: Treat ment Group 
• 
Low 
• 
Int ermediate 
• 
Deferred (Control Group) 
Randomisat ion 3: Dose selected for administration to Deferred (Cont rol 
Group) 
• 
Low 
• 
Int ermediate 
6 months after completion of 
Cont rol group administered low or intermediate dose 
baseline assessments in deferred 
Interim analysis performed 3 and 6 months post- surgery of t he last 
treatment group 
participant in the low or intermediate treatment arm 
12 
Follow-up complete 
5 
Methods 
5.1 
Site Selection 
The trial sponsor MeiraGTx UK II Ltd. 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 t his protocol. Data is anticipated to be collected 
from centres in t he United Kingdom and the United States of America. 
5.1.2 Site/Investigator Eligibility Criteria 
Once a site has been assessed as being suitable to part icipate in t he trial, they w ill be provided with a copy 
of t his protocol and t he ATIMP Investigator Brochure. 
To part icipate in the RPGR XLRP trial, investigators and trial sites must fulfil a set of criteria that have been 
agreed by t he Clinical 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 
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• 
The site has access to all specialised equipment/devices needed for clinical assessments 
• 
The site is able to archive traceability data for a minimum 30 years post expiry date of the ATIMP 
• 
The site has a pharmacy that can store, prepare and dispense ATIMP appropriately 
• 
The site can store, prepare 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 RPGR XLRP 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 Clinical Trial 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, 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 potential for recruiting the required number of suitable 
participants within the agreed recruitment period (i.e. the investigator(s) regularly treat(s) 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.  

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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 of formal 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 Research Ethics Committee (REC) 
in the UK 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. 
 
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 will 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 and none of 
the exclusion criteria as defined below. 
 
5.3.1.2 Participant Inclusion Criteria 
Inclusion in the trial will be limited to individuals who meet the following criteria: 
1. Are males aged 5 years or older 
2. Have X-linked retinitis pigmentosa confirmed by a retinal specialist (CI or PI) 
3. Have relatively symmetrical retinal disease - both structurally and functionally defined as < 15 
letters [Best Corrected Visual Acuity (BCVA)] difference between eyes 
4. Have a predicted disease-causing missense or null mutation in RPGR confirmed in an accredited 
laboratory 
5. Evidence of relative preservation of retinal structure at the macula 

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6. Evidence of impaired navigation in dim illumination on Mobility assessment in both eyes 
monocularly; defined by either an inability to complete the visual mobility maze at the 1 lux level, 
or the time taken to complete the maze at either 1 or 4 lux being greater or equal to 12 seconds. 
7. Are able to give informed consent or assent, with the guidance of their parent/guardian where 
appropriate: children aged 5-6 years will not be asked to provide assent 
8. Are able to undertake age appropriate clinical assessments at the trial sites as specified in the 
protocol 
9. Are willing to use barrier and spermicide form of contraception or will be sexually abstinent (when 
this is in line with the participant’s preferred and usual lifestyle) for at least 12 months following 
ATIMP administration 
10. Are willing to give consent for the use of blood and blood components collected through the trial 
for the investigation of immune responses to the ATIMP 
 
5.3.1.3 Participant Exclusion Criteria 
Individuals will be excluded if they meet any of the following criteria: 
1. Have a known allergy to any of the non-investigational drugs to be used in the trial as defined in 
Section 5.4.1. 
2. Have participated in another research study involving an investigational medicinal therapy for 
ocular disease within the last 6 months. 
3. Have any other condition that the CI/PI considers makes them inappropriate for entry into the 
trial, inclusive of but not limited to a history of the following:  
o Uncontrolled hypertension defined as a systolic value ≥160mmHg or diastolic value 
≥100mmHg. 
o Uncontrolled diabetes mellitus defined as an HbA1c ≥9% (75mmol/mol) at screening. 
o Uncontrolled heart failure (NYHA class II-IV). 
o Any history of tuberculosis 
o Chronic kidney disease (defined as eGFR ≤60ml/min calculated using Cockroft Gault or 
MDRD equations. 
o Immunocompromised state (including long term immunosuppressant therapy). 
o Osteoporosis (defined as presence of 1 or more non-traumatic “fragility” fractures or 
proven BMD of 2.5SD less than anticipated as demonstrated on DEXA scan). 
o Active peptic ulcer disease or uncontrolled gastro-oesophageal reflux. 

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o Severe affective disorder or past history of drug induced psychosis 
4. Use of high dose regular non-steroidal anti-inflammatory drugs at the time of screening. 
5. Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere with 
interpretation of the study results. 
6. Have had intraocular surgery within 3 months of screening. 
7. Have recently (within 4 weeks of last dose of concomitant immunosuppressive therapy) received 
a live vaccine. 
8. Have a condition that requires glucocorticoid replacement therapy, such as in endocrine diseases, 
if this would interfere with the immunosuppressive regime. 
9. Have known chronic hepatitis B infection as indicated by detectable surface antigen. Entry with 
negative surface antigens but positive hepatitis core antibody will be allowed; however additional 
monitoring throughout the trial may be required. 
10. 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 the interventions. 
 
Surgery will only be performed by a qualified vitreo-retinal surgeon. The ATIMP will be administered 
designated individuals at each 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 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 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, benefits and potential hazards of the trial and before any trial-specific 

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procedures are performed or any blood is taken for the trial.  However, results of any procedures that 
were performed as part of the usual standard of care within the screening/baseline window of MGT009 
and prior to enrolment on this study may be used for baseline/screening if the subjects provided informed 
consent for the use of the prior obtained results. Any participant entering the study with a known genetic 
confirmation of disease-causing missense or null mutation in RPGR from an accredited laboratory does 
not need to have this assessment repeated during screening. In addition, data obtained previously from 
subjects enrolled on the MGT011 RPGR Natural History Study may be used for screening and/or baseline 
data 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 CI/PI 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 interactions on at least 2 occasions. The 1st occasion will 
involve information being 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 occasion, 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). 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. 
 

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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.  Reconsent may be conducted by telephone if appropriate or in person at 
the participant’s next scheduled study visit.  If reconsent is taken by telephone, the designated site staff 
taking reconsent must explain the need for reconsent and give the participant an opportunity to ask 
questions. The informed consent process and information provided to the participant by telephone must 
be documented in the patient notes including details of the information provided, by whom, and date of 
the interaction.  
 
Children who become of adult age (i.e., 16 in the UK, 18 in the US) during the study will be re-consented 
as adults at the time of the next visit. Younger children who become 11 years of age during the study will 
be given the information sheet and assent form for older children to assent at the time of their next study 
visit. Likewise, younger children (aged 6 or less) who become old enough to provide assent during the 
course of the study will be asked to assent at their next visit. 
 
5.3.1.6.2 
Screening Period 
Screening procedures will only take place after the informed consent form has been signed by the 
participant/parent/guardian. However, if test results are available from the subject’s routine clinical 
examination or participation in the MGT011 RPGR 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 RPGR mutations at an accredited laboratory prior to 
enrolment. Any participant entering the study with a known genetic confirmation from an accredited 
laboratory does not need to have this assessment repeated during screening. 
 
Participants will be screened to ensure there are no contra-indications for transient immune suppression, 
in particular: uncontrolled hypertension, uncontrolled diabetes mellitus, uncontrolled heart failure, 
tuberculosis, chronic kidney disease, immunocompromised state, osteoporosis, active peptic ulcer 
disease or uncontrolled gastro-oesophageal reflux, severe affective disorder or past history of drug-
induced psychosis. 
 

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Screening assessments are listed below (and set out under the column headed ‘Screening’ in the Trial 
Assessments Table 3, Trial Assessments (Dose Escalation Phase, Paediatric Dose Confirmation Phase, and 
Immediate Treatment Arms of Dose Expansion Phase) and Table 4: Trial assessments (Deferred Treatment 
Group)):  
1. Genetic testing (if unconfirmed at an accredited laboratory prior to screening) 
2. Medical history and concomitant medication 
3. Physical examination  
4. Vital signs including blood pressure 
5. Ocular examination 
6. Visual acuity 
7. Contrast sensitivity 
8. Spectral Domain Optical Coherence Tomography (SD-OCT) (+/- Adaptive Optics (AO) imaging 
depending on age, as a greater degree of co-operation is needed compared to SD-OCT) 
9. Visual Mobility 
 
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 4 months prior to enrolment.  
 
Historical images will be collected wherever possible, with written informed consent from the 
participants, in order to assess the slowing or halting of progression over time, and to compare the 
identical structural and functional assessments acquired prior to intervention and determine rate of 
change over time in this progressive disease. If genetic confirmation from an accredited laboratory has 
been obtained prior to the participant consenting to the trial this assessment does not to be repeated 
during screening. 
 
5.3.1.6.3 
Rescreening 
Patients who have failed screening under a previous version of the protocol may be reconsidered for 
eligibility. All subjects who are rescreened must signed the updated ICF.  Any tests that have been 
completed within 4 months of rescreening date will not need to be repeated.   

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5.3.1.6.4 
Enrolment (Randomisation) 
Participants who fulfil the study entry criteria based on the results of all screening assessments will be 
enrolled (randomised) in the trial. ATIMP will be administered within 3 months of enrolment for 
participants randomised to immediate treatment. If the ATIMP is not delivered within 3 months of 
enrolment, all screening tests with the exception of genetic testing, visual mobility and 
electrophysiological assessment will be repeated and eligibility for enrolment re-assessed3.   For 
participants randomised to the control (deferred treatment) arm, study assessments will be performed 
per the Table 4: Trial Assessments (Deferred treatment arm).  
 
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 Products 
AAV2/5-hRKp.RPGR is an advanced therapy investigational medicinal product (ATIMP): specifically, a gene 
therapy product. 
 
AAV2/5-hRKp.RPGR is a gene therapy product to be developed for the treatment of a form of retinitis 
pigmentosa caused by defects in the gene encoding RPGR. This is the retinitis pigmentosa GTPase 
regulator protein that plays an essential role in the structure and function of rod and cone photoreceptors. 
Disruption of the gene prevents normal translocation of phototransduction cascade proteins to the 
photoreceptor outer segment, leading to a phototransduction dysfunction and cell death. Recombinant 
adeno-associated virus (rAAV) mediated gene transfer of a copy of the normal RPGR gene to the 
photoreceptors, results in stable, long term transgene expression and improves photoreceptor survival 
and vision in rodents with RPGR gene defects.  
 
AAV2/5-hRKp.RPGR consists of a linear single strand of DNA packaged in a rAAV protein capsid of serotype 
5. The AAV2/5-hRKp.RPGR genome incorporates 290 nucleotides of the wild-type AAV2 ITR (Inverted 
                                                          
3 For patients whose surgery dates were postponed due to COVID 19 please refer to appendix 1  
 

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Terminal Repeats) sequences that provide in cis the packaging signal, a cDNA encoding human RPGR-
ORF15, driven by a human photoreceptor-specific genomic promoter (Rhodopsin Kinase, RK, GRK1). The 
icosahedral capsid consists of three related capsid proteins, VP1, VP2, and VP3. AAV has a compact 
macromolecular structure and forms stable viral particles 20nm in diameter. The vector particles are 
replication incompetent. 
 
5.4.1.2 ATIMPs Classified as Genetically Modified Organisms 
The ATIMP (AAV2/5-hRKp.RPGR) 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 USA must obtain Institutional Biosafety Committee 
approval in addition to Institutional Review Board (IRB) approval to administer recombinant nucleic acid 
molecule material to human participants. 
 
5.4.1.3 Source of ATIMPs 
The ATIMP has been manufactured at the 
 
 in accordance with current Good Manufacturing 
Practice for clinical trial materials. 
 
5.4.1.4 Preparation and labelling of the ATIMP 
Preparation and labelling of the ATIMP will be completed in accordance with the relevant GMP and 
national guidelines.  
 
The ATIMP is a recombinant serotype 2/5 adeno-associated viral vector containing a human RPGR-ORF15 
cDNA, with a 378 bp (in-frame) deletion in the purine-rich tract in the ORF15 region. The transgene is 
driven by a fragment of the human Rhodopsin Kinase promoter. The manufacturer 
 will perform 
analytical testing and provide certification. Aliquoting into vials and labelling of the ATIMP was the 

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responsibility of 
 The 
was responsible for testing, release and storage of the final ATIMP. 
This responsibility for ATIMP storage and stability testing and subsequent expiry dating extension and 
labelling has been transferred to MeiraGTx.  
 
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 ATIMP 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.  
 
A detailed ATIMP management plan and manual describing the preparation of the vector prior to 
administration will be followed. 
 
5.4.1.5 Description and Justification of Route of Administration and Dose 
Efficient transduction of photoreceptor cells requires the ATIMP (AAV2/5-hRKp.RPGR) to be administered 
to the subretinal space. 
 
Delivery of vector suspension to the subretinal space will be performed by 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 into the subretinal space, resulting in a transient 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 ATIMP delivery, and by leaving the contralateral eye untreated.  
 
The highest ATIMP dose that is intended to be delivered to the trial participants is based on dose-limiting 
toxicity that was seen in an earlier trial of AAV2-mediated gene therapy for LCA2, where 1 mL of ATIMP 
at 
 
 was found to be the highest safe dose that could be administered subretinally. However, 
more recent data from a trial using AAV2/5 indicate that this serotype can elicit an inflammatory reaction 
to the dose of 
 
 that could pose a risk. As toxicity in this context is a complex interaction between 
local retinal effects, wider ocular effects and systemic effects, the decision was taken to use the confirmed 
safe volume (1 mL) and a titre of 
 
 
. As AAV2/5-mediated transduction of photoreceptors in 
dogs and non-human primates is efficient over a wide range of titres, including lower titres than used in 

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this study we are confident that the RPGR transgene can be delivered to the photoreceptors effectively 
at 
. 
 
5.4.1.6 Name and Description of Each Non-Investigational Medicinal Product (NIMP) 
1. Cefuroxime can be administered subconjuctivally at 50mg in 0.5ml normal saline, or 125mg in 1.0mL 
normal saline according to local practice. or cefazolin at 50 mg/0.5mL or vancomycin at 25 mg/0.5 
mL antibiotic given at usual dose at end of surgery (standard (as per British National Formulary) 
dose as prophylaxis for post-operative infection) or any other antibiotic prescribed as per local 
hospital practices. 
2. Long acting steroid in the sub-tenon space following sclerotomy closure according to local 
guidelines/standard of care. 
3. Betamethasone can be administered subconjunctivally at 2mg - 5mg in 0.5mL, according to local 
practice. or dexamethasone can be administered subconjuctivally at 1.5mg- 2.0mg in 0.5mL, 
according to local practice.at end of surgery (standard dose as prophylaxis for post-operative 
inflammation)) or any other steroid prescribed as per local hospital practices. 
4. Chloramphenicol 0.5% or ofloxacin (topical antibiotic) 4 times daily for 7 days following ATIMP 
administration. 
5. Dexamethasone 0.1% (topical steroid) or topical prednisolone drops  1.0% should be administered 
4 times daily for 4 weeks, then 2 times daily for a further 2 weeks (weeks 4 to 6) following ATIMP 
administration. 
• 
3and 4 above will be administered to minimise inflammation and protect against infection 
postoperatively. 
6. Omeprazole:  
• 
In adults 20mg per day for the duration of the steroid treatment 
• 
In children aged up to 16 weighing 5 kg to less than 10 kg (11 lb to less than 22 lb): 5 mg taken 
once per day for the duration of the steroid treatment 
• 
In children aged up to 16 weighing 10 kg to less than 20 kg (22 lb to less than 44 lb): 10 mg taken 
once per day for the duration of the steroid treatment 
• 
In children aged up to16 weighing 20 kg (44 lb) or more: 20 mg taken once per day for the 
duration of the steroid treatment 
7. Prednisolone or Prednisone (oral steroid) as prophylaxis against potential intraocular immune 
responses: 

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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 than 
1g). A further dose of methylprednisolone may be administered at week 4 in the presence of signs of 
intraocular inflammation. The regimen is described below: 
• 
0.5 mg/kg daily for one week prior to ATIMP administration 
• 
1 mg/kg daily for the first week following ATIMP administration 
• 
0.8 mg/kg daily for the second week following ATIMP administration 
• 
0.7 mg/kg daily for the third week following ATIMP administration 
• 
0.6 mg/kg daily for the fourth week following ATIMP administration 
• 
0.5 mg/kg daily for the fifth week following ATIMP administration 
• 
0.4 mg/kg daily for the sixth week following ATIMP administration 
• 
0.25 mg/kg daily for the seventh week following ATIMP administration 
• 
0.125 mg/kg daily for the eighth week following ATIMP administration 
• 
 
Following completion of steroid treatment, testing (if required), will be performed to confirm Hepatitis B 
viral load. 
 
All Non-Investigational Medicinal Products (NIMPs) are licensed within the EU and US and will be procured 
from standard hospital stock. 

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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 compliance 
where necessary. 
 
5.4.2 
Protocol Defined Clinical Schedule 
5.4.2.1 Baseline Assessments 
A detailed assessment of visual function and retinal imaging of both eyes will be performed preoperatively 
as outlined in Section 5.6 (Table 3: Trial assessments Dose Escalation Phase, Paediatric Dose Confirmation 
Phase, and Immediate Treatment Arms of Dose Expansion Phase and Table 4: Trial assessments Deferred 
Treatment Group). 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 baseline 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 MGT011 RPGR natural history study or as a part of 
routine clinical examination.  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.   
 
Baseline assessments will be completed as soon as possible after randomisation and will be valid for 3 
months4. In the deferred treatment group, a day 0 will be applied at the end of baseline assessments and 
deferred treatment follow up will be calculated from this date.   
 
Up to 10 mL of blood will be collected and to obtain serum samples in order to assess baseline levels of 
circulating antibodies against AAV serotype 5 and RPGR so that immunological responses to vector capsids 
and transgene product might be determined following vector administration (collectively described as 
serology in Table 3: Trial assessments). It is anticipated that the majority of participants will have no 
detectable pre-existing circulating antibodies against AAV5 or RPGR. The presence or absence of 
circulating antibodies will not affect recruitment of the participant. All serology tests will be performed at 
the Institutional Laboratory in the UK. 
                                                          
4 For patients who surgery dates were postponed due to COVID 19 please refer to appendix 1 

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There is wide variability in the abilities of individual children to perform certain of the proposed 
investigations; the evaluations for children will be restricted to those tests that individuals are able to 
perform reliably. 
 
Tests that will be performed in all participants are: 
1. Serological tests 
2. Blood pressure 
3. Haematology 
4. Biochemistry 
5. Hepatitis B testing** 
6. Best corrected visual acuity and low luminance visual acuity 
7. Contrast sensitivity testing 
8. Ocular examination 
9. Static visual field testing  
10. Spectral-domain optical coherence tomography (SD-OCT)  
11. Fundus autofluorescence imaging 
12. Colour fundus photography 
13. Full-field electroretinography (ERG) 
14. Pattern electroretinography (PERG) 
15. Visual mobility assessment 
16. Patient-Reported Outcome (PRO) questionnaires 
17. Treatment Experience Interview 
 
    ** Hepatitis B testing will be performed if required by local practice   
        
Tests that will be performed where possible are: 
18. Mesopic and scotopic microperimetry 
19. Detailed psychophysical/colour vision assessments 
20. Multifocal electroretinography (mfERG) 
21. Adaptive Optics imaging 
22. Reading assessment 
 

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Further details of clinical assessments can be found in the RPGR XLRP study manual. Images taken at all 
timepoints will be sent for independent reading and analysis at centres in both the UK and US.  
 
With the participant’s consent, information collected during their assessments in the format of videos, 
pictures or similar may be sent to the site where the participant enrolled in the main part of the study, as 
study records.   Copies of this non-identifiable information in the format of videos, pictures or similar may 
be sent to a third-party provider or to the sponsor and may be used for educational purposes.  
 
(i) Ocular examination and retinal imaging.  
Ocular examination using slit lamp biomicroscopy will assess the anatomical integrity of the eyes and allow 
quantification of intraocular inflammation. During the examination, intraocular pressure will be 
determined by tonometry.  
 
Retinal imaging includes colour fundus photography, fundus autofluorescence (FAF) imaging, SD-OCT, and 
adaptive optics (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 mosaics in vivo. 
 
(ii) Patient-Reported Outcome (PRO) Assessments.  
Patient-reported outcomes should be completed before any other assessments including physician 
assessments, treatment administration or provision of results in order to reduce the potential to influence 
the subject’s response. The following patient- and clinician-reported outcomes will be assessed as 
outlined in Section 5.6 - Table 3: Trial assessments (Dose Escalation Phase, Paediatric Dose Confirmation 
Phase, and Immediate Treatment Arms of Dose Expansion Phase) and Table 4: Trial assessments (Deferred 
Treatment Group).   
 
Participants will complete age appropriate versions of the Impact of Visual Impairment (IVI) vision-related 
quality of life (VRQoL) questionnaire, a Low Luminance Questionnaire (LLQ), an age appropriate EQ5D 
health-related quality of life (HRQoL) questionnaire (EQ-5D-5L or EQ-5D-Y), Patient Global Impression of 
Severity (PGIS) and Patient Global Impression of Change (PGIC) items.  A sample of each of the PROs and 
instructions for completion are provided in the PRO Completion guide.   

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Impact of Visual Impairment – Adult (IVI-A) Questionnaire 
The IVI-A and IVI-C questionnaires assess vision-related quality of life (VRQoL) in adults and children 
(respectively) with low vision.   
 
The IVI-A is a 28-item questionnaire comprised of three subscales: (i) mobility & independence, (ii) 
emotional well-being and (iii) reading & accessing information. (Lamoureux et al., 2006) Response options 
include 3 and 4 -point Likert Scales (4 items are rated on a 3-point Likert scale: 0 = A lot; 1 = A fair 
amount; 2 = Not at all; the remaining items are rated on a 4-point Likert scale: 0 = A lot; 1 = A fair 
amount; 2 = A little; 3 = Not at all ). An extra response option 'Don't do this for other reasons' (excluded 
from analysis) is possible for some items. The recall period is the last month.  The IVI-A is scored by domain 
by taking the average of the items in each domain to obtain an IVI raw score (3 IVI raw scores in total).  
Higher IVI scores reflect greater visual ability/less vision-related quality of life impairment within the 
subjects. 
 
Impact of Visual Impairment - Child (IVI-C) Questionnaire 
The IVI-C is a 24-item questionnaire developed for use in children and adolescents that assesses the 
impact of vision loss on specific components of VRQoL, including orientation, mobility and social 
interaction (Cochrane et al., 2008). Subjects are asked to rate the impact of visual impairment on a 5-point 
Likert scale: always (5), almost always (4), sometimes (3), almost never (2), never (1), and no, for other 
reasons.(Cochrane 2011). The final response is excluded from the analysis.  The measure is unidimensional 
and a global score is calculated ranging from 0-120, with higher scores reflecting less vision 
impairment/greater vision-related quality of life.  Six of the items are reverse scored to reduce response 
bias. 
 
The Low Luminance Questionnaire (LLQ) 
The Low Luminance Questionnaire (LLQ) is a 32-item disease-specific questionnaire for use in eye diseases 
to assess self-reported visual problems under low luminance and at night. The LLQ consists of six domains 
including Driving (5 items), Extreme lighting (8 items), Mobility (6 items), Emotional distress (4 items), 
General dim lighting (6 items), and Peripheral vision (3 items). Response options include 5- and 6-point 
Likert Scales ranging from “no difficulty at all” or “none of the time” to “stopped doing because of your 
vision”. Two additional response options represent non-applicable or missing data: “stopped for other 
reasons” and “don’t do”.  The recall period is ‘at the present time’.  Time to complete the measure is 

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approximately 5-10 minutes.  The instrument is scored by domain, computed by scaling individual items 
from 0 to 100 and then averaging the individual items for each domain.  A higher score reflects higher 
functional level (Owsley et al., 2006).   
 
EQ-5D Descriptive System 
The EuroQol 5-Dimension (EQ-5D) Descriptive System is a standardized measure of health status. 
Applicable to a wide range of health conditions and treatments, it provides a simple descriptive profile 
and a single index value for health status that can be used in the clinical and economic evaluation of health 
care. 
 
The EQ-5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ-VAS). The EQ-
5D descriptive system is comprised of 5 items across the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression, and can be completed in 2-3 minutes. The EQ-5D-Y 
uses 3-point Likert response options and has 3 levels of severity for each dimension: No Problems, Some 
Problems and A Lot of Problems. The EQ-5D-5L uses 5-point Likert response options and has 5 levels of 
severity: No problems, Slight problems, Moderate problems, Severe problems, and Extreme problems. 
The recall period is ‘Today’.  Respondents are asked to indicate their health by placing a cross in the box 
next to the response that best represents their current health for each of the 5 dimensions.  This results 
in a 1-digit number expressing the level of severity selected for that dimension.  The responses for the 5 
dimensions can be combined into a 3-digit number (for the EQ-5D-Y) or 5-digit number (for the EQ-5D-5L) 
describing the respondent’s health state (e.g. 11233). The EQ-5D-5L health states, defined by the EQ-5D 
descriptive system, can be converted into a single index value using country-specific value sets. Index 
values range from 0 to 1, with higher scores representing better health-related quality of life.  The index 
value facilitates the calculation of quality-adjusted life years (QALYS) that are used to inform economic 
evaluations of health care interventions.  Country-specific value sets are not available for the EQ-5D-Y so 
an index value cannot be calculated for the child subjects. 
 
The EQ-5D also includes a 20cm visual analog scale (EQ VAS) that has endpoints labelled “best imaginable 
health state” and “worst imaginable health state” anchored at 100 and 0, respectively. For the EQ-5D-Y, 
respondents are asked to indicate how they rate their own health by drawing a line from an anchor box 
to that point on the EQ VAS which best represents their own health on that day.  For the EQ-5D-5L, 
respondents are asked to mark an X at that point on the EQ VAS which best represents their own health 

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on that day, and entering the number they marked on the line into the box.  This can be used as a 
quantitative measure of health outcome that reflects the patient’s own judgement.  Completion of the 
EQ-5D instruments will take approximately 2-3 minutes. 
 
Patient Global Impression of Severity (PGIS) 
The Patient Global Impression of Severity (PGIS) is a 1-item questionnaire based on the clinical global 
impression scale developed by Guy (1976), designed to assess a patient’s impression of disease severity. 
The PGIS asks the patient to select the one response, ranging from ‘No Symptoms’ to ‘Very Severe’, that 
best describes the overall severity of their retinitis pigmentosa ‘at this time’ 
 
Completion will take approximately 1 minute or less.  The PGIS will be assessed at baseline and at 3, 6 and 
12 months post-treatment administration (for the low and intermediate-dose group), and at baseline and 
at 3 and 6 months post-treatment administration (for the deferred treatment group).  The PGIS will be 
evaluated for change over time and used to validate change over time reported on the Patient Global 
Impression of Change (PGIC) item, to mitigate any potential recall bias on the PGIC. 
 
Patient Global Impression of Change (PGIC) 
The Patient Global Impression of Change (PGIC) is a one-item patient-reported measure of perceived 
change in the patient’s health condition following a study/treatment intervention. The PGIC assesses the 
extent to which a person’s health condition has improved, worsened or remained unchanged since the 
start of their treatment using a scale ranging from 1 = Very much improved to 7 = Very much worse (where 
4 = No change).   The instructions ask the subject to select the one response that best describes the overall 
change in their retinitis pigmentosa since treatment was administered.  Completion will take 
approximately 1 minute or less.  The PGIC will be assessed at 3, 6 and 12 months post-treatment 
administration (for the low- and intermediate-dose group), and at 3 and 6 months post treatment 
administration (for the deferred treatment group). 
 
Clinician Global Impression of Change (CGIC) 
The Clinician Global Impression of Change (CGIC) is a generic global measure of change in a patient’s 
health status assessed by a clinician following a study/treatment intervention. The CGIC asks the clinician 
to rate on a scale from 1 (=very much improved) to 7 (=very much worse) the overall change in the 
patient’s retinitis pigmentosa since treatment was initiated. The CGIC will be assessed at 3, 6 and 12 

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months post-treatment administration (for the low- and intermediate-dose group), and at 3 and 6 months 
post treatment administration (for the deferred treatment group). 
 
Treatment Experience Interview 
Treatment experience interviews will be administered to all study participants. Subjects in the low- and 
intermediate dose active treatment group will participate in two interviews: one interview will be 
conducted at the month 6 / Visit 14 study visit (6 months post-treatment), and the second interview will 
be conducted at or within 14 days of the month 12/Visit 16  study visit (12 months post-treatment), or 
upon early withdrawal. The deferred treatment group subjects will participate in one interview at or 
within 14 days of the month 12 /Visit 16 study visit (6 months post-treatment), or upon early withdrawal. 
The questions included in the interview will be designed to more fully understand the subject’s experience 
with the study treatment, the aspects of the condition that are most important to them, and the perceived 
efficacy of the study treatment. The interview will be conducted by telephone and will last 15 to 20 
minutes. Subjects will be asked to consent to the treatment experience interview within the study 
informed consent form (ICF).   
 
A specialist contract research organisation (CRO) will be commissioned to conduct the treatment 
experience interview sub-study. The study site will facilitate scheduling of the interviews, and the CRO will 
conduct the interviews by telephone using an experienced qualitative interviewer. For the month 12/ Visit 
16 study visit interviews, the interviews may be conducted at the study site during the final study visit, or 
the subject may participate from their home within 14 days of the final study visit. Interviews will be audio 
recorded for the purposes of accurate transcription and analysis. The interviews will be transcribed by a 
third-party transcription agency. The transcripts will have any personally identifying information removed 
and any errors corrected, after which the audio recording will be permanently deleted by both the CRO 
and the transcription agency, and the interview transcript will serve as the source document.   
 
The qualitative data collected during the patient treatment experience interviews will be analysed by the 
CRO and summarised in a final report.  
 
(iii) Functional Assessments 
Reading ability including reading acuity, maximum reading rate, and critical print size will be assessed. 

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Colour vision will be assessed comprehensively using plate tests and computerised tests probing colour 
discrimination along all 3 axes of colour.  
 
Retinal sensitivity will be determined using static perimetry, and microperimetry (mesopic and scotopic). 
The retinal locus of fixation will also be determined using microperimetry.  
 
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 (rod and cone systems) and isolated macular function. Modified ISCEV protocols 
may be necessary in young children using internationally recognised modified protocols. ERG data will be 
analysed and interpreted by dedicated full-time Clinical Visual Electrophysiology Consultants with 
extensive experience and who are directly involved in defining ISCEV standards. 
 
5.4.2.2 ATIMP Administration Procedures 
The protocol describes the intended surgical technique for ATIMP administration. The surgical procedure 
may be modified on a case-by-case basis in the interests of safety: any modification 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 as described in 
the consent process. Relevant recordings and images will be stored alongside the trial database. 
 
5.4.2.2.1 
Pre-operative procedure 
For prophylaxis against potential intraocular immune responses to the ATIMP, participants will be 
prescribed a course of daily oral prednisolone commencing at a dose of 30mg daily for one week prior to 
ATIMP administration.  
 
Preoperative procedures and intraocular administration of ATIMP will be as described in the Gene Therapy 
for X linked RPGR Study Manual.  
 
5.4.2.2.2 
Operative procedure 
In the dose escalation and dose confirmation in paediatric participants phases of the study, the choice of 
eye for ATIMP administration will be the poorer-seeing eye as identified by the participant and CI/PI taking 
account of ocular dominance and visual acuity. In the randomised expansion phase, the eye to be 

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administered vector will be determined via randomisation to preserve objectivity. In order for this to be 
safely performed participants are required to have relatively symmetrical visual acuity. 
 
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 
include a 3-port pars plana vitrectomy followed by injection of ATIMP using a fine cannula through small 
retinotomies into the subretinal space. 
 
Surgery will be performed under general anaesthesia. The eye and face will be prepared using povidone 
iodine solution as per routine intraocular surgery. 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 (when applicable) 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. 3 pars plana sclerotomies will be sited 
to enable intraocular infusion, endoillumination probe and surgical instruments. The fundus will be 
viewed by means of a wide field indirect viewing system or a contact lens. To minimise the possibility of 
unplanned retinal detachment or preretinal fibrosis, vitrectomy (aspiration of vitreous gel) will be 
performed using a disposable cutter.  
 
Intraocular administration of the viral vector suspension (AAV2/5-hRKp.RPGR) will be performed using a 
subretinal cannula advanced through the retina. Under direct visualisation, the ATIMP will be injected 
under the neurosensory retina, causing a localised retinal detachment with a self-sealing non-expanding 
retinotomy. If appropriate, the bleb of ATIMP will be manipulated to the target area using a fluid-air 
exchange. The site and extent of the subretinal bleb of ATIMP suspension will be documented by video 
recording.  
 
Following intraocular administration of ATIMP, the retinal periphery will be examined for any unplanned 
retinal breaks for appropriate management by retinopexy with or without intraocular tamponade at the 
discretion of the operating surgeon. Intraocular instruments used subsequent to ATIMP delivery are 
disposable and will be destroyed after a single use. Sclerotomies may be secured using a vicryl suture. 
Standard doses of antibiotic and steroid will be administered subconjunctivally as prophylaxis against 
postoperative infection and inflammation respectively. Bupivacaine will be administered for analgesia. 

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The surgical procedure may be modified on a case-by-case basis in the interests of safety; any modification 
will be documented in the operation notes and CRF.  
 
On the basis of experience, it is anticipated that the subretinal ATIMP bleb will resolve spontaneously 
during the first 48 hours. 
 
Surgery may be performed, as is conventional for intra-ocular procedures, on a day-case basis and 
participants will be managed subsequently as out-patients, although hospital-based accommodation may 
be used for convenience. 
 
5.4.2.3 Subsequent Assessments 
On the 1st postoperative day, a full clinical ocular examination will be performed. Visual acuity, intraocular 
pressure, the degree of postoperative intraocular inflammation and the area of any residual retinal bleb 
will be documented. Fundus photography, ocular examination, intraocular pressure and SD-OCT will be 
performed at day 1 and each subsequent visit post ATIMP administration. 
 
A standard post-vitrectomy treatment regimen of topical antibiotic (chloramphenicol 0.5% qds for 7 days) 
and steroid (dexamethasone 0.1% qds for 4 weeks and then bd for a further 2 weeks) will be prescribed 
to minimise inflammation and protect against infection postoperatively.  
 
Intraocular pressure of greater than 30 mmHg will be managed with systemic therapy where indicated 
with specialist advice sought as required. 
 
Participants will be maintained on oral prednisolone (or other as appropriate) for 8 weeks following 
administration of ATIMP as described above (Section 5.4.2.2.1: Pre-operative procedure). The possible 
development of steroid-induced adverse effects will be monitored regularly. In particular, blood pressure 
will be measured, and blood glucose, renal function and liver function will be evaluated through blood 
biochemistry at the time points specific in Table 3, Trial Assessments (Dose Escalation Phase, Paediatric 
Dose Confirmation Phase, and Immediate Treatment Arms of Dose Expansion Phase) and Table 4: Trial 
assessments (Deferred Treatment Group) 
 

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Both safety and efficacy of the ATIMP will be evaluated at various time points up to 12 months after ATIMP 
delivery. Evaluations will comprise primarily ocular assessments. The nature and schedule (Section 5.6: 
Trial Assessments) of these is described below. 
 
(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 expected 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+ cells) intensity. The degree of intraocular inflammation is expected to decline over the 
course of the first 4 weeks following the surgical procedure, at which time the routine topical and systemic 
immunosuppression will be discontinued. Prolonged or severe intraocular inflammation, or deterioration 
in visual acuity that may be related to intraocular inflammation, will be investigated and managed 
conventionally with further topical and/or systemic immunosuppression. 
 
(ii) Evaluation of immune responses 
Up to 10 mL of blood will be collected to obtain serum samples to measure immune response. Antibody 
responses to AAV capsid proteins will be investigated by ELISA at baseline and at 4 weeks, 3 months and 
6 months.  
 
(iii) Evaluation of biodistribution 
Systemic biodistribution of vector genomes will be assessed by PCR analysis of tears (a compressed 
cellulose sponge placed under the eye lid until swollen), saliva (a minimum of 100 μL) and serum (1 mL) 
for patients in the immediate treatment arm at baseline 1, prior to intraocular ATIMP administration and  
day 1, week 1, week 2, week 4,week 6 and week 9  following intraocular ATIMP administration. For 
patients on the deferred treatment arm at baseline 1, month 6 prior to intraocular ATIMP administration 
and day 1, week 1, week 2, week 4, week 6 and week 9.  
 
(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). They will be carried out with the same methods applied for the baseline tests (see section 
5.6 for details) to allow direct comparison of the data sets. These assessments will be scheduled over a 
period of a day for visits at day 1, day 3, day 7, week 2, week 4, week 6, and week 9 after surgery, and up 

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to 4 days for baseline examinations, and 3 months, 6 months, 9 months and 12 months following ATIMP 
administration. For the deferred treatment arm, assessments will be performed at day 1, day 3, day 7, 
week 2, week 4, week 6, week 9, month 3 and month 6 after surgery.  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 reliable visual acuity testing, SD-OCT, 
retinal sensitivity testing (static visual fields, and visual mobility assessment, which are the principal 
clinical assessments both for safety and efficacy. Other clinical assessments will be undertaken as 
appropriate for the ability of individual participants, since there is wide variation in the abilities of 
individual children to perform such tests reliably; the evaluations for individuals may be restricted to those 
tests that they are able to perform reliably.  
 
Additional assessments may be performed if considered appropriate for the management of any 
unexpected adverse effects. These may be submitted as urgent safety measures and protocol 
amendments performed where required. Conversely, tests that cannot be reliably performed by a 
participant may be discontinued for that participant. This is not anticipated for the aforementioned key 
clinical assessments because participants who are unable to perform such tests will be excluded from the 
study at the screening phase. Evaluation of safety and efficacy will also be performed on an individual 
participant basis. We do not anticipate that any discontinuation will affect significantly the overall quality 
of the safety and efficacy evaluation. 
 
5.4.2.4 Laboratory Procedures 
Serum will be processed to investigate any immune responses to the ATIMP: 
1. anti-AAV5 neutralising antibodies 
2. anti-AAV5 antibodies by ELISA  
3. anti-human RPGR antibodies by ELISA 
 
Serum, saliva and lacrimal fluid will be processed  to assess dissemination of ATIMP after delivery, where 
the number of rAAV vector genome copies will be measured using a polymerase chain reaction (PCR) 
approach.  
 

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Whole blood will be processed at the 
, or a CLIA-
accredited molecular diagnostic laboratory in the US, for RPGR mutation screening. Haematology and 
biochemistry samples and screen will be carried out at the 
, or 
an accredited laboratory in the US (Table 2 Haematology and Biochemistry).  
 
Table 2: Haematology and Biochemistry 
Haematology 
Biochemistry 
Haemoglobin 
Sodium 
Haematocrit 
Potassium 
Erythrocytes 
Chloride 
Mean Corpuscular Volume 
Bilirubin 
Mean Corpuscular Haemoglobin 
Alkaline Phosphatase  
Platelet 
Aspartate Aminotransferase 
Leukocytes 
Alanine Aminotransferase 
Absolute Neutrophils 
Lactate Dehydrogenase  
Absolute Lymphocytes 
Gamma Glutamyl Transferase 
Absolute Neutrophils 
Protein 
Absolute Eosinophils 
Albumin 
Absolute Basophils 
Calcium 
 
Magnesium 
 
Phosphate 
 
Urea 
 
Urate 
 
Creatinine 
 
Glucose 
 
5.4.3 
Dispensing 
5.4.3.1 Receipt and storage of the Investigational Medicinal Product 
 
 
.  
 
The ATIMP vector will be dispensed on the same day as administration according to study specific working 
instructions, with a 1-hour window for administration after ATIMP has thawed at room temperature.    
 
5.4.4 
Dosage 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.  

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1) low dose  
 
 
 
2) intermediate dose  
 
 
3) high dose  
 
 
 
The ATIMP will be diluted as appropriate for the specific dose intended immediately prior to intraocular 
administration in Hartmann’s solution at the time of administration. The CI/PI will prepare the appropriate 
dilution, and this will be checked in the operating theatre by a second individual prior to administration. 
The check will be recorded in the patient’s source data notes. 
 
Further details for dose-escalation criteria are included in Sections 4.3.2. 
 
5.4.5 
Accountability 
The ATIMP will be prescribed and handled according to the ATIMP management plan applicable for the 
site.  
 
For accurate accountability, the following information will be recorded when the ATIMP is administered: 
i. 
date 
ii. 
participant identification 
iii. 
batch number 
iv. 
volume and dose of ATIMP administered 
v. 
name of CI/PI 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 participant and destruction. A comprehensive ATIMP management plan and 
associated forms will be in place to ensure that the required accountability and traceability data is 
retained.  

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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, should be used with 
caution, and appropriately documented on study logs where used. All concomitant medications (including 
steroids) must be recorded in the CRF from the day of informed consent. 
 
5.4.8 
Overdose of Trial Medication 
A single 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 scale 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 participant 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. 
 
5.4.9 
Protocol Treatment Discontinuation 
5.4.9.1 Participant 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. 

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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 (12 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 participant 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 safety and efficacy 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 participant who withdraws after vector administration.  
 
5.4.9.2 Trial Stopping Rules 
The CI 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 safety outcome is defined as absence of 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 

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• 
Severe unresponsive inflammation  
• 
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.  
• 
Slowing or halting of progressive deterioration in retinal structure or visual function that is greater 
than the baseline variation for that test and is sustained for at least 2 consecutive assessments. 
Slowing or halting of progression over time may be facilitated by comparing identical structural 
and functional assessments acquired prior to intervention/injection to better determine rate of 
change over time in this slowly progressive disease. 
Historical images will be collected wherever possible with written informed consent from the 
participants 
• 
Any improvements in visual function from baseline that are greater than the baseline variation 
and are sustained for at least two consecutive assessments.  
• 
Any improvement in retinal function from pre-intervention that is greater than baseline variation 
and measurable by electrophysiology (pattern ERG, multifocal ERG or full-field ERG). 
• 
Health- and Vision-Related Quality of life (HRQoL, VRQOL) will be assessed by the Impact of Visual 
Impairment (IVI) questionnaire, the Low Luminance Questionnaire (LLQ), the EQ5D HRQoL 
questionnaire (EQ-5D-5L or EQ-5D-Y), changes in disease severity and health status will be 
assessed by the Patient Global Impression of Severity (PGIS), the Patient Global Impression of 
Change (PGIC) and the Clinician Global Impression of Change (CGIC) measures. 

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5.6 
Trial Assessments 
Table 3: Trial assessments (Dose Escalation Phase, Paediatric Dose Confirmation Phase, and Immediate Treatment Arms of Dose 
Expansion Phase)* 
Screening 
Randomisation 
Baseline1• 2 
ATIMP 
admin 
D1 
D3 
Wl 
W2 
W4 
W6 
W9 
M3 
M6 
M9 
Flexibility of schedule {:t 
Upto 4 
- 3 months 
DayO 
days) 
months prior 
to 
± 
± 
± 
± 
± 
.:!: 70 
.:!: 70 
± 
± 
± 
randomisation 
OD 
10 
20 
40 
70 
140 
140 
140 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent 
• 
Physical exam 
• 
Medical history 
• 
• 
• 
• 
• 
• • 
• 
• 
Eligibility determination 
• 
IMP administration 
* 
Adverse event review 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• • 
• 
• 
Concomitant 
medication • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• • 
• 
• 
review 
Genetic screening 
• 
Vital 
signs 
(including • 
• 
• 
• 
• 
• 
• 
• 
• 
height and weight)3 
Randomisation 
* 
Haematology 
• 
• 
• 
• 
• 
• 
Biochemistry/glucose 
• 
• 
• 
• 
• 
• 
., 
Hepatitis B (HBV) testing 6 • 
• 
Serology 
• 
• 
• 
• 
PCR 
• 
• 
QoL questionnaires (IVI 
and EQSD-SL and EQSD-Y, 
Low Luminance 
• 
• 
• 
Questionnaire) Patient 
Global Impression of 
Severity 
Protocol version 11.0, 01May2020 
Page 62 of 100 
M12 
± 
140 
16 
• 
• 
• 
• 

MGT009, Gene Therapy for XLRP RPGR 
0J ME I RA GTx 
Screening 
Randomisation 
Baseline1• 2 
ATIMP 
admin 
01 
0 3 
Wl 
W2 
W4 
W6 
W9 
M3 
M6 
M9 
M 12 
Flexibility of schedule (:!: 
Upto4 
- 3 months 
0ay0 
days) 
months prior 
to 
± 
± 
± 
± 
± 
:!: 70 
± 70 
± 
± 
± 
± 
randomisation 
OD 
10 
20 
40 
70 
140 
140 
140 
140 
Patient Global Impression 
of Change and Clinician 
• 
• 
• 
Global Impression of 
Change 
Treatment Experience 
lnterview9 
• 
• 
Visual acuity4 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Low Luminance Visual 
• 
• 
• 
• 
• 
• 
• 
Acuity 
Contrast sensitivity 
• 
• 
• 
• 
• 
• 
• 
• 
Reading speed 
• 
• 
• 
• 
• 
• 
• 
Colour vision assessments 
• 
• 
• 
• 
• 
• 
Static visual fields 
• 
• 
• 
• 
• 
• 
Microperimetrv 
• 
• 
• 
• 
• 
• 
Ocular examination 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Fundus photography 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Optical coherence 
• 
• 
• 
• 
tomography 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adaptive optics imaging 
• 
• 
• 
Fundus autofluorescence 
• 
• 
• 
• 
• 
• 
Full field 
• 
electroretinography5 
• 
• 
Pattern 
• 
electroretinograohv5 
• 
• 
Multifocal 
• 
electroretinograohv5 
• 
• 
Visual mobility 
• 
assessment8 
• 
• 
• 
Protocol version 11.0, 01May2020 
Page 63 of 100 

MGT009, Gene Therapy for XLRP RPGR 
 
Protocol version 11.0, 01May2020 
 
Page 64 of 100 
 
1Baseline assessments may be performed on the same day where considered logistically and clinically appropriate.  All assessments should be 
performed as soon as possible; however, all baseline assessments must be done within a 3 month period.  
 
2Additional baseline assessments are permitted if there is inconsistency between the screening and first baseline assessment 
3Measurements for vital signs include: blood pressure, pulse, respiration rate, arterial oxygen saturation, temperature, height and weight 
4Visual acuity at day 1 and 3 will be assessed using the previous refraction. 
5ERG assessments may be performed under general anaesthesia if considered appropriate 
6 HBV testing is only mandatory for participants if required by local practice.  Participants with chronic hepatitis B virus infection as indicated by 
detectable surface antigen will be excluded from the study.  For those with negative surface antigen, but positive hepatitis B core antibody, testing 
will be performed to confirm Hepatitis B viral load following completion of steroid treatment.   
7 Additional monitoring of liver enzymes will be performed following steroid treatment 
8 Patients who screened failed under a previous version of the protocol may be reconsidered for eligibility and will not be required to repeat tests 
provided these were performed within the visit window from the original screening date. 
9 Two Treatment Experience interviews will be administered to the low and intermediate dose active treatment group at 6 months (Visit 14) and 
at 12 months post-treatment (either at the visit or within 14 days of the final study visit - visit 16), or upon early withdrawal.  
*Per section 5.4.2.1 assessments listed as “performed in all participants” must be performed, every effort must be made to perform all other 
assessments where possible 

MGT009, Gene Therapy for XLRP RPGR 
0J ME I RA GTx 
Table 4: Trial Assessments (Deferred Treatment arm) * 
Screening 
Randomisation 
Baseline1• 2 
ATIMP 
D1 
D3 
Wl 
W2 
W4 
W6 
W9 
M3 
M6 
Up to4 
M38 
M68 
admin after 
post-
post-
post-
post-
post-
post-
post-
post 
post 
months prior 
M6 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
to 
assessments 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
randomisation 
Flexibility of 
± 
14D 
+14D 
± OD 
± lD 
± 2D 
± 4D 
± 7D 
± 7D 
± 
± 
± 
schedule{± days) 
14D 
7D 
14D 
14D 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed consent 
• 
Physical exam 
• 
• 
Medical history 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Eligibility 
• 
determination 
• 
IMP administration 
* 
Adverse event 
• • • 
• 
review 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant 
medication review 
• 
• • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Genetic screening 
• 
Vital signs {including • 
• 
height and weight)3 
• 
• 
• 
• 
• 
• 
• 
• 
Randomisation 
* 
Haematology 
• 
• 
• 
• 
• 
• 
• 
Biochemistry/ 
• 
glucose 
• 
• 
• 
• 
• 
• 
. 1 
Hepat itis B {HBV) 
• 
testing 6 
• 
Serology 
• 
• 
• 
• 
PCR 
• 
• 
Protocol version 11.0, 0 1May2020 
Page 65 of 100 

MGT009, Gene Therapy for XLRP RPGR 
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Screening 
Randomisation 
Baseline1• 2 
ATIMP 
D1 
D3 
Wl 
W2 
W4 
W6 
W9 
M3 
M6 
Upto4 
M38 
M68 
admin after 
post-
post-
post-
post-
post-
post-
post-
post 
post 
months prior 
M6 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
to 
assessments 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
randomisation 
Flexibility of 
± 
14D 
+14D 
± OD 
± lD 
±2D 
± 4D 
±7D 
± 7D 
± 
± 
± 
schedule (± days) 
14D 
7D 
14D 
14D 
QoL quest ionnaires 
(IVI, EQSD-SL, EQSD-
Y, Low Luminance 
Quest ionnaire), 
• 
• 
• 
• 
Patient Global 
Impression of 
Severity 
Patient Global 
Impression of 
Change and Clinician 
• 
• 
Impression of 
Change 
Treatment 
Experience 
• 
lnterview10 
Visual acuity4 
• 
• • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Low Luminance 
• • • 
• 
• 
Visual Acuity 
Contrast sensitivity 
• 
• • • 
• 
• 
• 
• 
Reading speed 
• • • 
• 
• 
• 
• 
Colour vision 
• • • 
assessments 
• 
• 
• 
• 
Stat ic visual fields 
• • • 
• 
• 
• 
• 
Microperi met ry 
• • • 
• 
• 
• 
• 
Ocular examinat ion 
• 
• • • 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Fundus photography 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Protocol version 11.0, 01May2020 
Page 66 of 100 

MGT009, Gene Therapy for XLRP RPGR 
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Screening 
Randomisation 
Baseline1• 2 
ATIMP 
D1 
D3 
Wl 
W2 
W4 
W6 
W9 
M3 
Upto4 
M38 
M68 
admin after 
post-
post-
post-
post-
post-
post-
post-
post 
months prior 
M6 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
ATIMP 
to 
assessments 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
admin 
randomisat ion 
Flexibility of 
± 
14D 
+14D 
± OD 
± lD 
±2D 
± 4D 
±7D 
± 7D 
± 
± 
schedule (± days) 
14D 
7D 
14D 
Optical coherence 
• 
• • • 
tomography 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Adaptive optics 
• 
imaging 
• 
Fundus 
• • • 
autofluorescence 
• 
• 
• 
Full field 
• 
electroretinography5 
• 
Pattern 
• 
electroretinography5 
• 
Multifocal 
• 
e lectroretinography5 
• 
Visual mobility 
assessment8 9 
• 
• 
• 
• 
1Baseline assessments may be performed on t he same day w here considered logistically and clinically appropriate. All assessments should be 
performed as soon as possible however all baseline assessments must be done w ithin a 4 month period. 
2Additional baseline assessments are permitted if there is inconsistency between t he screening and first baseline assessment 
3Measurements for vital signs include: blood pressure, pulse, respiration rate, arterial oxygen saturation, temperature, height and weight 
4 Visual acuity at day 1 and 3 post-ATIMP administration will be assessed using t he previous refraction. 
5ERG assessments may be performed under general anaesthesia if considered appropriate 
Protocol version 11.0, 01May2020 
Page 67 of 100 
M6 
post 
ATIMP 
admin 
± 
14D 
• 
• 
• 
• 
• 
• 
• 

MGT009, Gene Therapy for XLRP RPGR 
 
Protocol version 11.0, 01May2020 
 
Page 68 of 100 
 
6 HBV testing is only mandatory for participants if required by local practice.  Participants with chronic hepatitis B virus infection as indicated by 
detectable surface antigen will be excluded from the study.  For those with negative surface antigen, but positive hepatitis B core antibody, testing 
will be performed to confirm Hepatitis B viral load following completion of steroid treatment.   
7 Additional monitoring of liver enzymes will be performed following steroid treatment 
8 Month 3 and 6 assessments should be planned for +3 months and +6 months after the last baseline assessment (Baseline visit 4) 
9 Patients who screened failed under a previous version of the protocol may be reconsidered for eligibility and will not be required to repeat tests 
provided these were performed within the visit window from the original screening date. 
10 Treatment Experience interviews will be administered to all subjects either at or within 14 days of the final study visit (month 6 / visit 16), or 
upon early withdrawal.  
 
*Per section 5.4.2.1 assessments listed as “performed in all participants” must be performed, every effort must be made to perform all other 
assessments where possible

MGT009, Gene Therapy for XLRP RPGR 
 
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5.6.1 
Early Stopping of Follow-up 
If a participant chooses to discontinue their trial treatment, 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 regard 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 12 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 longer term follow-up study to determine 
longer term safety and efficacy up to 60 months post treatment administration. 
 
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 71 participants (up to 18 in 
the dose escalation phase, up to 5 in the dose confirmation in paediatric phase, and up to 48 in the 
randomised expansion phase), as described in section 4.3.2.2. We estimate that inclusion of up to 53 
participants will be sufficient to determine the safety and tolerability of the intervention.  

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5.8 
Recruitment and Retention 
5.8.1 
Recruitment 
Participants will be recruited through research sites in the US and in the UK or on referral by 
ophthalmologists within or outside the UK or 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. 
Potential participants may also contact the trial team independently. We expect to recruit up to 71 
participants within a period of 48 months. 
 
5.8.2 
Retention 
Participants will be supported to remain in follow-up by regular contact as per the protocol and the 
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 ofAAV2/5-hRKp.RPGR to 1 eye. The dose received by each participant will depend on the 
order of their enrolment in the trial according to the sequence of dose escalation, and the extent of dose-
limiting events. Children will not be enrolled in the trial until the safety profile and recommended dose 
have been established in adults.  
 
In the randomised expansion phase, a target of up to 48 eligible participants will be randomised in a 1:1:1 
ratio to receive immediate low dose administration (n=up to 16), immediate intermediate dose 
administration (n=up to 16) or deferred administration (n=up to 16). Within the deferred administration 
treatment group, participants will be further randomised in a 1:1 ratio to deferred low dose administration 
(n=up to 8) or deferred intermediate dose administration (n=up to 8). The randomisation of treatment 
will be stratified by age at informed consent (<25 years, ≥25 years), the rationale for the stratification 
levels is described in Section 4.3.2.2.5 of this document. Thus, the overall randomisation ratio will be 
2:2:1:1 (immediate low dose: immediate intermediate dose: deferred low dose: deferred intermediate 
dose). 
 

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The eye of treatment will also be randomised in a 1:1 ratio; this aspect of the randomisation is considered 
administrative so will not be stratified or balanced across treatment groups, the rationale for this is 
described in Section 5.4.2.2.2 of this document.  
 
The randomisations will be produced by an independent statistician. The treatment and eye will be 
allocated in the web-based EDC system. 
 
5.10 Data Collection, Management and Analysis 
5.10.1 Data collection, management and entry 
 will be responsible for data management activities for the study. 
 
Data will be captured in a fully validated, 21 CRF Part 11 compliant Electronic Data Capture (EDC) system 
provided by 
.   
 
 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.  
 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. 

MGT009, Gene Therapy for XLRP RPGR 
 
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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) 
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. 
 
5.10.2 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. Data collected prior to withdrawal will 
be considered 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 (12 month) assessments with the participant’s consent. 
 
5.10.3 Statistical Methods 
5.10.3.1 
Statistical Analysis Plan 
A formal Statistical Analysis Plan (SAP) will be written by the 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. 
 
5.10.3.2 
Statistical Methods – Outcomes 
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 (defined below) 

MGT009, Gene Therapy for XLRP RPGR 
 
Protocol version 11.0, 01May2020 
 
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• 
Infective endophthalmitis 
• 
Ocular malignancy 
• 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
 
The number of DLEs at each dose level will be summarised by cohort and overall. 
 
Safety data relating to participants at all dose levels will allow estimation of an upper bound for the true 
event rate through a 95% confidence interval. 
 
5.10.3.3 
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) Slowing or halting of progressive deterioration in retinal structure or visual function that is greater than 
the baseline variation for that test and is sustained for at least 2 consecutive assessments. 
2) Any improvement in visual function from baseline that is greater than the baseline variation for that 
test and is sustained for at least 2 consecutive assessments. 
3) Any improvement in retinal function from baseline that is measurable by electroretinography (ERG) 
 
Measures will be reported individually, in each dose, and aggregated across participants as the proportion 
who satisfy the above criteria.  
 
Health- and vision-related quality of life (HRQoL, VRQoL) patient reported outcome and treatment 
experience interview data 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 IDMC and described in the final 
report, as appropriate. 

MGT009, Gene Therapy for XLRP RPGR 
 
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5.10.3.4 
Economic evaluations 
No health economic evaluation is planned, but the collection of EQ5D would allow Quality Adjusted Life 
Years (QALYs) to be calculated. 
 
5.11 Data Monitoring 
5.11.1 Independent Data Monitoring Committee 
To ensure the safety and efficacy and overall trial conduct, an Independent Data Monitoring Committee 
(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 in the UK or under 
18 in the US, being dosed 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 RPGR XLRP 
IDMC Charter. 
 
5.11.2 Interim Analyses 
An interim analysis may be scheduled when all patients in the immediate treatment arms (n= up to 32) of 
the randomised expansion phase of the trial reach 3 and 6-months post-surgery.    
 
5.11.3 Data Monitoring for Harm 
5.11.3.1 
Safety reporting 
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.  
 
 
 

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Table 5: 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. 
Unexpected Adverse Reaction 
(UAR) 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg 
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*** 
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 one 
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) 

MGT009, Gene Therapy for XLRP RPGR 
 
Protocol version 11.0, 01May2020 
 
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• 
continuous persistent disease or a symptom present at baseline that worsens following 
administration of the trial treatment 
 
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 treatment 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 trial Data Management Plan.  
 
5.11.3.3 
Procedures to follow in the event of the partners of male participants becoming 
pregnant 
Although participants are instructed to use barrier and spermicide 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 
on a pregnancy report form within 
24 hours of the investigator becoming aware of the event.  
 
5.11.3.4 
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, whether expected or not, should be recorded in the 
participant’s medical notes and adverse events section of the eCRF. These should be entered on to the 
database according to the timelines defined in the Data Management Plan to allow appropriate 
monitoring by the CMT. SAEs should be notified to 
immediately the investigator becomes aware of 
the event (in no circumstance should this notification take longer than 24 hours). 

MGT009, Gene Therapy for XLRP RPGR 
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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. 
All serious adverse events will be recorded in the hospital notes and on a paper SAE form. 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 if this extends beyond 
the end of the study. All SAEs will be recorded, fully investigated and appropriately managed until 
resolution or stabilisation and Cl sign off. 
5.11.3.4.1 
Seriousness assessment 
When an AE or AR occurs, the investigator responsible for the care of the participant must assess whether 
or not the event is serious using the definition given in Table 5: Adverse Event Definitions. If the event is 
classified as 'serious' then an SAE form must be completed and emailed to -
(or delegated body) 
within 24 hours. 
5.11.3.4.2 
Severity or grading of Adverse Events 
The severity of all AEs in this trial should be graded using the toxicity gradings in NIH CTCAE Version 4.0 
(NIH 2009) (Table 6: Grading of Adverse Events). 
Table 6: Grading of Adverse Events 
Category 
De&inition 
Mild (Grade I) 
Asymptomatic or mild 
symptoms; 
clinical or diagnostic 
observations only; intervention not indicated 
Moderate (Grade II) 
M inimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental AOL* 
Severe (Grade Ill) 
Severe or medically significant but not immediately life 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care AOL** 
Grade IV 
Life threatening consequences; urgent intervention indicated 
Grade V 
Death related to AE 
* Instrumental AOL (Activit ies of Daily Living) refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
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**Self-care AOL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
5.11.3.4.3 
Causality 
Causality will be assessed in terms of both the ATIMP and the surgical procedures. Based on all available 
information at the t ime 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 
• 
TheATIMP 
The differentiated causality assessments will be captured in the trial specific CRF and SAE form using the 
definitions in Table 7: Causality Definit ions. 
Ta ble 7: Causality Definitions 
Relationship 
Description 
Event Type 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely 
to 
be 
There is little evidence to suggest that there is a causal 
Unrelated SAE 
related 
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 
part icipant's 
clinical 
condition 
or other 
concomitant 
treatment) 
Possibly related 
There is some evidence to suggest a causal relationship (e.g. 
SAR 
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 condit ion or other concomitant 
treatment) 
Probably related 
There is evidence to suggest a causal relationship and the 
SAR 
influence of other factors is unlikely 
Definitely related 
There is clear evidence to suggest a causal relationship and 
SAR 
other possible contributing factors can be ruled out. 
For each AE/ SAE, a causality assessment for the ATIMP administration surgery must also be provided. Any 
events related to the surgery alone w ill not be reported to the relevant regulatory agencies. 
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5.11.3.4.4 
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 M HRA, REC/I BC, FDA, and NIH 
reporting guidelines apply (see Notifications sections of the protocol). 
Table 8: 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 
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 attributable 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 w ill not cause undue 
discomfort to the participants. Therefore, we have defined the success criteria for the primary outcome 
for 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 (to hand movements or better for a period of up 
to 8 weeks), due to detachment of the retina or post-surgical inflammation 
• 
Ocular discomfort 
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• 
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  
 
5.11.3.5 
Notifications 
5.11.3.5.1 
Notifications by the Investigator to 
 
All adverse events will be recorded in the participant’s medical notes and the CRF from the date of written 
informed consent until last study visit.  
must be notified of all SAEs and SUSARs within 24 hours of 
the investigator becoming aware of the event during this period. The investigator will respond to any SAE 
queries raised by 
 as soon as possible. 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. 
 
 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, and 
causality 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 

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necessary, sign and then email to 
. 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 
 
 
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 if necessary. Follow-up SAE forms (clearly marked as follow-up) should be completed 
and emailed to 
as further information becomes available. Additional information and/or copies of 
test results etc may be provided separately. The participant must be identified by trial number and date 
of birth only. The participant’s name must not be used on any correspondence and must be blacked out 
and replaced with trial identifiers on any test results should they be provided. 
 
5.11.3.5.2 
 responsibilities 
will follow 
Standard Operating Procedures and a study specific Safety Management Plan to 
ensure that case processing of events occurs within appropriate regulatory timeframes. 
 will submit 
Development Safety Update Reports (DSURs) to regulatory authorities. 
 
5.11.3.5.4 
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. 
 
5.11.3.5.5 
Annual Progress Reports 
An annual progress report (APR) will be submitted to the UK 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.  

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5.11.4 Quality Assurance and Control 
5.11.4.1 
Risk Assessment 
The Quality Assurance (QA) and Quality Control (QC) considerations for the 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 relevant 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. 
 
5.11.4.2.1 
Direct access to participant records 
Participating investigators must agree to allow trial related monitoring, including audits, research ethics 
committee (REC) review and regulatory inspections, by providing access to source data and other trial 
related documentation as required. Participant consent for this must be obtained as part of the informed 
consent process for the trial. 
 
5.11.4.3 
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, and eligibility; adherence to trial intervention 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 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 trial monitoring plan. 
 

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5.11.4.3.1 
Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (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 an IDMC Charter. The IDMC will consider data in 
accordance with the statistical analysis plan and will advise the CMT. 
 
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 Health Research Authority (HRA) for 
approval and to the relevant REC/IRB for approval. Any subsequent amendments to these documents will 
be submitted for further approval.  
 
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. However, the participant remains free to change their mind 
at any time about the protocol treatment and follow-up without giving a reason and without prejudicing 
their further treatment. 
 
6.2 
Regulatory 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 USA). 
 
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 21 CFR 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 site's 
Institutional Biosafety Committee.  
 
The progress of the trial, safety issues and reports, including expedited reporting of SUSARs, will be 
submitted to the Regulatory Authorities 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 relevant local department of each 
participating site or to other local departments for approval as required in each country. A copy of the 
local approval 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 (e.g. 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.  
 
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 

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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.  
 
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 General Data Protection Regulation 2016/679 or the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). 
 
These regulations require a signed participant 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 participant 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 participant 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 participant is alive) at the end of their scheduled 
trial period. 

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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 and date of birth in order to maintain participant 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 participant, 
except as necessary for trial-related monitoring, audits, REC/IRB review, and regulatory inspections by 
University or government entities. In these 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 MeiraGTx UK II Ltd. 
 
The Case Report Forms (CRFs) will not bear the participant’s name or other personal identifiable data. The 
participant’s date of birth and trial identification number, will be used for identification. 
 
6.7 
Declaration of Interests 
The trial is funded by MeiraGTx UK II Ltd. 
 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt of 
payment for consultancy services. 
 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt of 
payment for consultancy services. 
 

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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 CI, who will pass the claim to MeiraGTx UK II Ltd.’s insurers. 
 
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 trial is fully funded by MeiraGTx UK II Ltd. It is not expected that any further external 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) 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.  
 

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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 
• 
Participant 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 

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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 or per your local guidance, the longer guidance should be followed. All 
archived documents must continue to be available for inspection by appropriate authorities upon request.  
 
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 MeiraGTx UK II Ltd.  
 
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. 
 

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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. 
 
 

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8 
Appendix 1: Guidance on Study Conduct during the COVID-19 
Pandemic 
 
The measures outlined in this Appendix are temporary, while access to sites is restricted during the 
COVID 19 pandemic.  As restrictions are lifted, the decision to revert back to the protocol in effect 
prior to the pandemic should be discussed and agreed with the sponsor. 
 
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on the 
conduct of this clinical study due to, for example, self-isolation/quarantine by participants and study-site 
personnel; travel restrictions/limited access to public places, including hospitals; study site personnel 
being reassigned to critical tasks. 
 
In alignment with recent health authority guidance, the sponsor is providing options for study related 
participant management in the event of disruption to the conduct of the study. This guidance does not 
supersede any local or government requirements or the clinical judgement of the investigator to protect 
the health and well-being of participants and site staff.  
 
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow up. Modifications to protocol-required assessments may be permitted after 
consultation between the participant and investigator, and with the agreement of the sponsor. Missed 
assessments/visits will be captured in the EDC for protocol deviations. Discontinuations of study 
interventions and withdrawal from the study should be documented with the prefix “COVID-19-related” 
in the case report form (CRF). 
 
Scheduled visits that cannot be conducted in person at the study site will be performed remotely/virtually, 
and site -based evaluations may be delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy and safety endpoint 
assessments should be performed as feasible. Participants will also be questioned regarding general 
health status to fulfill any physical examination requirement. 
 

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The sponsor will continue to monitor the conduct and progress of the clinical study and any changes (eg, 
delay or discontinuation in recruitment, site monitoring and audits) will be communicated to the sites and 
health authorities according to local guidance. If a participant has tested positive for COVID 19, the 
investigator should contact the sponsor’s responsible medical officer to discuss plans for study 
intervention and follow-up. Modifications made to the study conduct as a result of the COVID-19 
pandemic should be summarized in the clinical study report. 
 
GUIDANCE SPECIFIC TO THIS PROTOCOL 
Each patient will be risk assessed on a case by case basis by the PI and his/her research team to decide 
the appropriate care for the patient.  
 
Item 
no  
Item  
Management of Item  
1 
Missed assessments 
Missed assessments will be captured in the EDC system as a 
deviation with the prefix COVID 19 RELATED. 
2 
Protocol Deviations  
Any deviations to the study protocol due to COVID 19 
pandemic will be captured in the EDC system will be entered 
with the prefix COVID 19 RELATED. 
3 
Patient missing any scheduled visits  
If scheduled visits cannot be conducted within the visit 
window the site can schedule an additional visit at the earliest 
opportunity the patient is able to travel,  
4 
Baseline Assessments  
Baseline assessments for those patients who have had 
surgery postponed due to COVID 19 - these baseline 
assessments will be valid up to 6 months expect for 
Haematology, Biochemistry and Glucose which will need 
repeating.   
5 
Patients may be unable to attend study 
visit during visit window. 
It is acknowledged that this is a global crisis and patients may 
be put at more risk attending hospital appointments due to 
route of travel into research facility. If appropriate the 
sponsor will offer expenses for taxi fares to avoid busy train 
or bus routes. 
 
If patients are unable to reach their research facility but are 
able to seek help at a local ophthalmologist for urgent 
concerns this is acceptable, and the sponsor will encourage 
patients to show any non-trial staff conducting assessments 
the contact details for the trial staff so that conversations can 
be had between the trial and non-trial medical staff 
6 
Patients visits conducted outside of 
visit window 
Patients will be assessed individually by the sites on a case by 
case basis and phone interviews may be conducted by sites 
for all follow up visits up until at least 3 months post-surgery.   

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Patients undergoing telephone assessment will be asked to 
provide information on any adverse events or other safety 
concerns. 
7 
Patients 
self-quarantined 
or 
government implemented quarantine.  
If patients and/or their carer are under quarantine and unable 
to leave home, their cases will be assessed by medical 
monitors and PI as to risk of delayed appointment. (e.g 
ongoing AEs, date of last appointment, less than 3 months 
since intervention). 
8 
Potential 
lack 
of 
reporting 
of 
symptoms due to delayed visits 
 
Delayed reporting of SAEs, SARs & 
SUSARs- Potential for events to not be 
reported within 24 hours of occurrence 
Delayed 
Participant 
reporting 
of 
Adverse Events 
All participants are provided with emergency cards on 
enrolment to the study to enable 24-hour contact with study 
investigators. 
 
All events should be reported by an Investigator (as assigned 
on the delegation log) or another member of the site team, in 
the Investigators absence and where delegated, within 24 
hours of the event occurring. 
Reminder of importance to report any new AEs/symptoms to 
be communicated to patients by the sites during this time.  
9 
Emergencies during the study and the 
provision 
of 
emergency 
contact 
arrangements:   
 
If the participants facing difficulties in contacting the Trial 
Team in the event of emergencies, they have been provided 
with an alert card to inform other healthcare providers of 
their participation in the gene therapy trial.   The Trial card 
includes the 24/7-hour contact number, patients trial code, 
trial number, brief details of the trial intervention and 
EudraCT number.   
10 
Patients may require NIMPs that they 
would have collected a scheduled 
study visit.  
Site research staff will be in regular contact with their study 
patients and should they require NIMPs, the site pharmacy 
will be able to courier them to the patient and charge the cost 
to the sponsor.  
11 
Assessment results outside of window 
not true representation of protocol 
stated timepoints 
Patient safety will be most important factor to consider. 
Patients will be invited as close to visit window as possible and 
deviations recorded where applicable. 
12 
Questionnaire responses could be 
incorrect due to expected visit vs 
actual visit attended. 
Patient may confuse true answers if questionnaire asks for 
certain timepoints.  Site research staff will explain 
questionnaire details before patient answers. 
13 
Clinician/s and site research staff 
unavailable due to contraction of virus 
Site to ensure appropriate staff are available and 
documented on the delegation log to provide medical cover 
if the PI is unavailable. 
14 
Monitor may not be allowed on site or 
may be quarantined and unable to 
visit. 
Monitors will be encouraged to attend site where possible, if 
unable will conduct remote monitoring as much as possible 
and arrange as many visits as is required to get back on track 
once site re-opens. 
 
 
 

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9 
Protocol Amendments 
 
Protocol Version and Date 
Reason for Amendment  
Protocol Version 1  
NA 
Protocol Version 2 10 March 2017  
To incorporate the flow chart for the dose 
escalation, dose of drugs used at the time of 
administration of the ATIMP and reconsenting the 
children as they progress through the age 
brackets.    
Protocol Version 3 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 Version 4 25 May 2017 
To add additional 2 exclusion criteria, and to refer 
to a barrier and spermicide form of contraception, 
rather than double barrier method and also to 
clarify that only males will be included in the trial 
Protocol Version 5 13 November 2017 
To update the medium and high dose. To reduce 
the gap between participant 1 and 2/3 in a cohort 
from 9 weeks to 4 weeks and update the 
prophylactic post-administrative steroid regimen 
in children, and clarify safety reporting and 
confirmatory safety dose for children 
Protocol Version 6 27 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 
Protocol Version 7.0 26 April 2018 
To clarify number of visual mobility assessments 
required  
 
To reduce the specificity of anti-biotics that may 
be prescribed on the trial. 
Protocol Version 7.1 19 September 2018       (MEEI 
Specific) 
This amendment was specific to Massachusetts 
Eye and Ear Institute to include the need for 
Hepatitis B screening. 
Protocol Version 9.0 11 February 2019 
To include a randomised component to the 
expansion phase of the study 
 
To include further QOL measurement tool  
 
To reduce the follow up from 18 to 12 months 

MGT009, Gene Therapy for XLRP RPGR 
 
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To include an Interim Analysis at 3 and 6 months 
post 
treatment 
for 
patients 
in 
the 
low/intermediate dose treatment arms of the 
randomised component of the trial 
Protocol Version 10.0 09 August 2019 
To amend and clarify the inclusion and exclusion 
criteria for the trial 
 
To remove FST at all assessments and to remove 
ERG at screening to reduce the assessment burden 
on patients 
 
To add in Low Luminance Visual Acuity testing 
 
To include additional Patient Reported Outcomes 
and to add a Clinician Reported Outcome. To 
include Treatment Experience interviews. 
 
To correct minor errors in the Patient Visit 
Schedule 
Protocol v11.0 01 May  2020  
Included guidance on the management of patients 
during COVID 19 pandemic  
 
Corrected minor errors in the protocol v10.0 
 
Updated Steroids risks 
 
Included update local steroid use 
 
 

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10 
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