An Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/8-hG1.7p.coCNGA3) for Gene Therapy of Children and Adults With Achromatopsia Owing to Defects in CNGA3
Phase: PHASE1
Conditions: Achromatopsia
Sponsor: MeiraGTx UK II Ltd

 
 
  
 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ Page 1 of ϲϴ 
 
 
Gene Therapy for Achromatopsia ;CNGAϯͿ 
An open label, multiͲcentre, Phase IͬII dose escalation trial of a 
recombinant adenoͲassociated virus vector ;AAVϴͲhGϭ.ϳp.coCNGAϯͿ 
for gene therapy of children with Achromatopsia owing to defects in 
CNGAϯ 
Version
Version ϲ.Ϭ
Date 
ϭϲAprϮϬϮϭ 
Sponsor 
MeiraGTx UK II Ltd. 
Sponsor’s Protocol Number
MGTϬϭϮ
Trial registration 
EudraCT ϮϬϭϴͲϬϬϯϰϯϭͲϮϵ
 
 
Authorisation: Chief Investigator 
Name 
Role
Professor of Retinal Studies 
UCL Institute of Ophthalmology 
Signature 
Date 
 
Authorisation: Sponsor Representative  
Name 
Role 
MeiraGTx Chief Medical Officer 
Signature 
 
Date 
 
 
 
 
	


   
 
 
  
CNGAϯ MGTϬϭϮ Protocol version ϱ.Ϭ ϬϵJulϮϬϮϬ Page 2 of ϲϴ 
 
 
Tabe f Ce 
1 
Administrative information ................................................................................................... ϳ 
1.1 
Compliance ................................................................................................................... ϳ 
1.2 
Sponsor ........................................................................................................................ ϴ 
1.3 
Structured trial summary ............................................................................................... ϵ 
1.ϰ 
Roles and responsibilities ............................................................................................ 11 
2 
Trial Diagram ...................................................................................................................... 12 
3 
Abbreviations ..................................................................................................................... 13 
ϰ 
Introduction ....................................................................................................................... 1ϱ 
ϰ.1 
Background and Rationale ........................................................................................... 1ϱ 
ϰ.1.1 
 Background ......................................................................................................... 1ϱ 
ϰ.1.2 
Pre-clinical data ................................................................................................... 1ϱ 
ϰ.1.3 
Clinical data ......................................................................................................... 1ϲ 
ϰ.1.ϰ 
Rationale ............................................................................................................. 1ϳ 
ϰ.1.ϱ 
Assessment and management of risk .................................................................... 1ϳ 
ϰ.1.ϱ.1 
 Risk of immune responses to AAVϴ-hG1.ϳp.coCNGA3 ....................................... 1ϴ 
ϰ.1.ϱ.2 
 Risk of vector transmission to other organs ...................................................... 1ϴ 
ϰ.1.ϱ.3 
 Risks of insertional mutagenesis and oncogenesis ............................................ 1ϵ 
ϰ.1.ϱ.ϰ 
 Risk of germline transmission .......................................................................... 1ϵ 
ϰ.1.ϱ.ϱ 
 Risk of surgical adverse effects ........................................................................ 1ϵ 
ϰ.1.ϱ.ϲ 
 Risk of adverse effects of corticosteroids ......................................................... 20 
ϰ.1.ϱ.ϳ 
 Risks of investigations performed during assessment and follow up ................. 21 
ϰ.1.ϱ.ϴ 
 Risk of rod photoreceptor dysfunction ............................................................. 21 
ϰ.1.ϱ.ϵ 
 Risk of thinning of the fovea ............................................................................ 21 
ϰ.1.ϱ.10 
Risk of visual imbalance ................................................................................ 21 
ϰ.1.ϱ.11 
 Conclusion on the risk-benefit ratio .............................................................. 22 
ϰ.1.ϲ 
Explanation for Choice of Comparators ................................................................. 22 
ϰ.2 
Objectives ................................................................................................................... 22 
ϰ.2.1  
Primary Objective ................................................................................................ 22 
ϰ.2.2  
Secondary Objective ............................................................................................ 22 
ϰ.3 
Trial Design ................................................................................................................. 22 
ϰ.3.1.1 Separate longer term follow up study .................................................................. 23 

   
 
 
  
CNGAϯ MGTϬϭϮ Protocol version ϱ.Ϭ ϬϵJulϮϬϮϬ Page 3 of ϲϴ 
 
ϰ.3.2  
IMP administration Review and Dose Escalation Criteria and Process .................... 2ϰ 
ϰ.3.2.1 
 Dose escalation criteria and Dose Limiting Events ............................................ 2ϰ 
ϰ.3.2.2 
Dosing process ................................................................................................. 2ϰ 
ϰ.3.2.2.1 Cohort 1 ........................................................................................................ 2ϰ 
ϰ.3.2.2.2 Cohort 2 ........................................................................................................ 2ϱ 
ϰ.3.2.2.3 Cohort 3 ........................................................................................................ 2ϱ 
ϰ.3.2.2.2.ϰ Adult Cohort-United States ......................................................................... 2ϱ 
ϰ.3.2.2.ϱ Additional considerations .............................................................................. 2ϱ 
ϱ 
Methods............................................................................................................................. 2ϲ 
ϱ.1 
Site Selection .............................................................................................................. 2ϲ 
ϱ.1.1 
Study Setting ....................................................................................................... 2ϲ 
ϱ.1.2 
Site/Investigator Eligibility Criteria ....................................................................... 2ϲ 
ϱ.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ............................... 2ϳ 
ϱ.1.2.2 
Resourcing at site ............................................................................................. 2ϳ 
ϱ.2 
Site approval and activation ........................................................................................ 2ϳ 
ϱ.3 
Participants ................................................................................................................. 2ϴ 
ϱ.3.1 
Eligibility Criteria.................................................................................................. 2ϴ 
ϱ.3.1.1 
Participant selection ......................................................................................... 2ϴ 
ϱ.3.1.2 
Participant Inclusion Criteria ............................................................................. 2ϴ 
ϱ.3.1.3 
Participant Exclusion Criteria ............................................................................ 2ϵ 
ϱ.3.1.ϰ 
Eligibility Criteria for Individuals Performing the Interventions .......................... 30 
ϱ.3.1.ϱ 
Co-enrolment Guidance .................................................................................... 30 
ϱ.3.1.ϲ 
Screening Procedures ....................................................................................... 30 
ϱ.3.1.ϲ.1  Informed Consent Procedure ..................................................................... 30 
ϱ.3.1.ϲ.2 Screening Period ........................................................................................ 31 
ϱ.3.1.ϲ.3 Enrolment .................................................................................................. 32 
ϱ.ϰ 
Intervention ................................................................................................................ 32 
ϱ.ϰ.1 
Name and Description of Investigational Medicinal Product .................................. 32 
ϱ.ϰ.1.1 
ATIMPs Classified as Genetically Modified Organisms ....................................... 33 
ϱ.ϰ.1.2 
Source of ATIMPs ............................................................................................. 33 
ϱ.ϰ.1.3 
Preparation and Labelling of the Investigational Medicinal Product ................... 33 
ϱ.ϰ.1.ϰ 
Description and Justification of Route of Administration and Dose .................... 33 
ϱ.ϰ.1.ϱ 
Name and Description of Each Non-Investigational Medicinal Drug (NIMP)........ 3ϰ 

   
 
 
  
CNGAϯ MGTϬϭϮ Protocol version ϱ.Ϭ ϬϵJulϮϬϮϬ Page ϰ of ϲϴ 
 
ϱ.ϰ.2 
Protocol defined clinical schedule ......................................................................... 3ϱ 
ϱ.ϰ.2.1 
Baseline Assessments ....................................................................................... 3ϱ 
ϱ.ϰ.2.2 
ATIMP administration Procedures .................................................................... 3ϳ 
ϱ.ϰ.2.2.1 Pre-operative Procedures ........................................................................... 3ϳ 
ϱ.ϰ.2.2.2 Technique for intraocular administration of ATIMP ..................................... 3ϴ 
ϱ.ϰ.2.3 
Subsequent Assessments .................................................................................. 3ϴ 
ϱ.ϰ.2.ϰ 
Laboratory Procedures ..................................................................................... ϰ0 
ϱ.ϰ.3  
Dispensing ........................................................................................................... ϰ1 
ϱ.ϰ.3.1 
Receipt and Storage of the Advanced Therapy Investigational Medicinal Product .. 
 
 ........................................................................................................................ ϰ1 
ϱ.ϰ.ϰ 
Dosages ............................................................................................................... ϰ1 
ϱ.ϰ.ϰ.1 
Dosages and dosage modifications ................................................................... ϰ1 
ϱ.ϰ.ϱ 
Accountability ...................................................................................................... ϰ2 
ϱ.ϰ.ϲ 
Compliance and Adherence .................................................................................. ϰ2 
ϱ.ϰ.ϳ 
Concomitant Care ................................................................................................ ϰ2 
ϱ.ϰ.ϴ 
Overdose of Trial Medication ............................................................................... ϰ2 
ϱ.ϰ.ϵ 
Protocol Discontinuation ...................................................................................... ϰ2 
ϱ.ϰ.ϵ.1 
Participant Withdrawal .................................................................................... ϰ2 
ϱ.ϰ.ϵ.2 
Trial Stopping Rules .......................................................................................... ϰ3 
ϱ.ϱ 
Outcomes ................................................................................................................... ϰ3 
ϱ.ϱ.1 
Primary Outcomes ............................................................................................... ϰ3 
ϱ.ϱ.2 
Secondary Outcomes ........................................................................................... ϰϰ 
ϱ.ϲ 
Trial Assessments ........................................................................................................ ϰϱ 
ϱ.ϲ.1 
Early Stopping of Follow-up .................................................................................. ϰϳ 
ϱ.ϲ.2 
Loss to Follow-up ................................................................................................. ϰϳ 
ϱ.ϲ.3 
Trial Closure ......................................................................................................... ϰϳ 
ϱ.ϲ.ϰ 
 Long Term Follow-Up After the End of the Trial .................................................... ϰϳ 
ϱ.ϳ 
Sample Size ................................................................................................................. ϰϳ 
ϱ.ϴ 
Recruitment and Retention ......................................................................................... ϰϳ 
ϱ.ϴ.1 
Recruitment ......................................................................................................... ϰϳ 
ϱ.ϴ.2 
Retention ............................................................................................................ ϰϳ 
ϱ.ϵ 
Assignment of Intervention ......................................................................................... ϰϴ 
ϱ.ϵ.1 
Allocation ............................................................................................................ ϰϴ 

   
 
 
  
CNGAϯ MGTϬϭϮ Protocol version ϱ.Ϭ ϬϵJulϮϬϮϬ Page ϱ of ϲϴ 
 
ϱ.10 
Data Collection, Management and Analysis.................................................................. ϰϴ 
ϱ.10.1 
Data collection, management and entry ............................................................... ϰϴ 
ϱ.10.2 
Non-Adherence and Non-Retention ...................................................................... ϰϵ 
ϱ.10.3 
Statistical Methods .............................................................................................. ϰϵ 
ϱ.10.3.1 
Statistical Analysis Plan ................................................................................. ϰϵ 
ϱ.10.3.2 
Statistical Methods – Primary Outcome Analysis ........................................... ϰϵ 
ϱ.10.3.3 
Statistical Methods – Secondary Outcome Analysis ....................................... ϰϵ 
ϱ.10.3.ϰ 
Statistical Methods – Health Economics Analysis ........................................... ϱ0 
ϱ.11 
Data Monitoring .......................................................................................................... ϱ0 
ϱ.11.1 
 Safety Data Monitoring Committee ..................................................................... ϱ0 
ϱ.11.2 
Interim Analyses .................................................................................................. ϱ0 
ϱ.11.3 
Data Monitoring for Harm .................................................................................... ϱ0 
ϱ.11.3.1 
Safety reporting ............................................................................................ ϱ0 
ϱ.11.3.2 
Other Notifiable Adverse Events ................................................................... ϱ2 
ϱ.11.3.3 
Procedures to follow in the event of female participants becoming pregnant . ϱ2 
ϱ.11.3.ϰ 
Procedures to follow in the event of the partners of male participants becoming 
pregnant 
 .................................................................................................................... ϱ2 
ϱ.11.3.ϱ 
Investigator responsibilities relating to safety reporting ................................ ϱ3 
ϱ.11.3.ϱ.1 Seriousness assessment ............................................................................ ϱ3 
ϱ.11.3.ϱ.2 Severity or grading of Adverse Events ....................................................... ϱ3 
ϱ.11.3.ϱ.3 Causality .................................................................................................. ϱϰ 
ϱ.11.3.ϱ.ϰ Expectedness ........................................................................................... ϱϰ 
ϱ.11.3.ϲ 
Notifications ................................................................................................. ϱϲ 
ϱ.11.3.ϲ.1 Notifications by the Investigator to Pharmacovigilance ............................. ϱϲ 
ϱ.11.3.ϲ.2  
Reporting Urgent Safety Measures ........................................................... ϱϲ 
ϱ.11.3.ϲ.3 PV Service Provider responsibilities .......................................................... ϱϳ 
ϱ.11.3.ϲ.ϰ  
Reporting SUSARs in International Trials .................................................. ϱϳ 
ϱ.11.3.ϲ.ϱ Annual Progress Reports ........................................................................... ϱϳ 
ϱ.11.ϰ 
Quality Assurance and Control ............................................................................. ϱϳ 
ϱ.11.ϰ.1 
Risk Assessment ........................................................................................... ϱϳ 
ϱ.11.ϰ.2  
Clinical Monitoring ....................................................................................... ϱϳ 
ϱ.11.ϰ.3 
Direct access to participant records ............................................................. ϱϳ 
ϱ.11.ϰ.ϰ 
Trial Oversight .............................................................................................. ϱϳ 

   
 
 
  
CNGAϯ MGTϬϭϮ Protocol version ϱ.Ϭ ϬϵJulϮϬϮϬ Page ϲ of ϲϴ 
 
ϱ.11.ϰ.ϰ.1 Clinical Management Team ....................................................................... ϱϴ 
ϱ.11.ϰ.ϰ.2 Safety Data Monitoring Committee........................................................... ϱϴ 
ϲ.1 
Research Ethics Approval ............................................................................................. ϱϴ 
ϲ.2 
Regulatory Authority Approvals ................................................................................... ϱϴ 
ϲ.3 
 Other approvals ......................................................................................................... ϱϵ 
ϲ.ϰ 
Protocol Amendments ................................................................................................. ϱϵ 
ϲ.ϱ 
Consent or Assent ....................................................................................................... ϱϵ 
ϲ.ϲ 
Confidentiality ............................................................................................................ ϲ0 
ϲ.ϳ 
Declaration of Interests ............................................................................................... ϲ1 
ϲ.ϴ 
Indemnity ................................................................................................................... ϲ1 
ϲ.ϵ 
Finance ....................................................................................................................... ϲ1 
ϲ.10 
Archiving ..................................................................................................................... ϲ1 
ϲ.10.1 
Archiving of Essential Trial Documentation ........................................................... ϲ1 
ϲ.11 
Access to Data ............................................................................................................. ϲ2 
ϲ.12 
Ancillary and Post-trial Care ........................................................................................ ϲ2 
ϲ.13 
Publication Policy ........................................................................................................ ϲ2 
ϲ.13.1 
Trial Results ......................................................................................................... ϲ2 
ϳ 
Ancillary Studies ................................................................................................................. ϲ3 
ϴ  
Appendix: Guidance on Study Conduct during the COVID-1ϵ Pandemic ................................ ϲ3 
ϵ 
 Protocol Amendments ....................................................................................................... ϲϲ 
10 
References ...................................................................................................................... ϲϳ 
 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page ϳ of ϲϴ 
ͳ 
Adiiaie ifai 
This document describes the Gene Therapy for Achromatopsia ;CNGAϯͿ trial, sponsored and coͲ
ordinated by MeiraGTx UK II Ltd. In early ϮϬϭϵ, MeiraGTx UK II Ltd. ;MeiraGTxͿ entered into a 
worldwide collaboration and license agreement with Janssen Research and Development, LLC ;JRDͿ, 
which is based in the US. The partnership seeks to develop, manufacture, and commercialize gene 
therapy treatments for inherited retinal diseases ;IRDsͿ. MeiraGTx and JRD are collaborating on the 
development of AAVϴͲhGϭ.ϳp.coCNGAϯ formerly known as AAVϮͬϴͲhGϭ.ϳp.coCNGAϯ. 
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 aideͲmemoire 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. Sites entering participants 
for the first time should confirm they have the correct version through a member of the trial team at 
MeiraGTx UK II Ltd. 
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 ;SPIRITͿ ϮϬϭϮ Statement for protocols of clinical trials ;Chan et Al͘ ϮϬϭϯaͿ. The 
SPIRIT Statement Explanation and Elaboration document ;Chan et Al͘ ϮϬϭϯbͿ can be referred to, or a 
member of the MeiraGTx UK II Ltd. Clinical Operations team can be contacted for further detail about 
specific items.  
ͳǤͳ 
Ciace 
The trial will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
;ϮϬϬϴͿ, the principles of Good Clinical Practice ;GCPͿ as laid down by the Commission Directive 
ϮϬϬϱͬϮϴͬEC with implementation in national legislation in the UK by Statutory Instrument ϮϬϬϲͬϭϵϮϴ 
and subsequent amendments, Advanced Therapy Medicinal Products ;ATMPͿ Regulations ;ECͿ No 
ϭϯϵϰͬϮϬϬϳ, the Human Tissue ;Quality and Safety for Human ApplicationͿ Regulations ϮϬϬϳ, the 
General Data Protection Regulations ϮϬϭϲͬϲϳϵ, and the National Health Service ;NHSͿ Research 
Governance Framework for Health and Social Care ;RGFͿ. US sites will comply with Ϯϭ CFR ϯϭϮ in the 
Code of Federal Regulations, and the NIH Guidelines for Research Involving Recombinant or Synthetic 
Nucleic Acid Molecules ;November ϮϬϭϯͿ.  
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 
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: 
x 
The safety or physical or mental integrity of the participants in the trial, or 
x 
The scientific value of the trial. 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page ϴ of ϲϴ 
ͳǤʹ 
S 
MeiraGTx UK II Ltd., ϵϮ Britannia Walk, London Nϭ ϳNQ, is the study sponsor.  
 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page ϵ of ϲϴ 
ͳǤ͵ 
Sced ia a 
 
Primary 
Registry 
and 
Trial 
Identifying Number 
EudraCT  ϮϬϭϴͲϬϬϯϰϯϭͲϮϵ 
Secondary Identifying Numbers 
MeiraGTx UK II Ltd. registration number: MGTϬϭϮ 
Source of Monetary or Material 
Support 
MeiraGTx UK II Ltd. 
Sponsor
MeiraGTx UK II Ltd.
Contact for Public Queries
ocularinfoΛmeiragtx.com
Contact for Scientific Queries 
  
Chief Medical Officer ;MeiraGTxͿ 
ϰϱϬ East Ϯϵth Street 
ϭϰth Floor 
New York, NY ϭϬϬϭϲ 
Tel : ϲϰϲͲϴϲϵͲϳϯϳϵ 
Email : 
  
Public Title 
Gene Therapy for Achromatopsia ;CNGAϯͿ 
Scientific Title 
An open label, multiͲcentre, Phase IͬII dose escalation trial of 
an adenoͲassociated virus vector ;AAVϴͲhGϭ.ϳp.coCNGAϯͿ 
for gene therapy of children with Achromatopsia owing to 
defects in CNGAϯ 
Countries of Recruitment 
United Kingdom, United States of America 
Health Condition 
Achromatopsia 
Intervention;sͿ 
Open label, nonͲrandomised, doseͲescalation 
 
 
 
  
Phase IͬII doseͲescalation study, by subretinal administration 
of AAVϴͲhGϭ.ϳp.coCNGAϯ in up to ϭϴ paediatric participants 
with Achromatopsia owing to mutations in the CNGAϯ gene. 
Key Inclusion and Exclusion Criteria 
Key Inclusion Criteria:  
x 
Aged ϯ to ϭϱ years old  
x 
Achromatopsia caused by mutations in CNGAϯ 
x 
Evidence of relative preservation of photoreceptors at 
the macula 
x 
Able to undertake ageͲappropriate clinical assessments 
x 
Willing to give consent for the use of blood and blood 
components collected throughout the trial for the 
investigation of immune response to Advanced Therapy 
Investigational Product ;ATIMPͿ. 
 
Key Exclusion Criteria:  
x 
Female adolescents who are pregnant or breastfeeding 
x 
IntraͲocular surgery within ϵ months of screening 
x 
Ocular or systemic disorder that may preclude subretinal 
surgery andͬor interfere with interpretation of the study 
results. 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page 10 of ϲϴ 
x 
Participated in another research study involving an 
investigational therapy for ocular disease within the last 
ϲ months 
x 
Use of high dose regular nonͲsteroidal antiͲinflammatory 
drugs at the time of screening 
x 
Have any other condition that the Principal Investigator 
;PIͿ considers makes them inappropriate for entry into 
the trial 
x 
Are unwilling to consider the possibility of entry into a 
subsequent longer term follow up study 
x 
During the ϲ weeks prior to baseline, have had any  
confirmed SARSͲCoVͲϮ ;COVIDͲϭϵͿ infection 
Study Type 
Phase IͬII, openͲlabel, nonͲrandomised, multiͲcentre, dose 
escalation study, followed by dose confirmation in children 
with Achromatopsia owing to defects in CNGAϯ 
Date of First Enrolment
Anticipated Qϭ ϮϬϭϵ
Target Sample Size 
Up to ϭϴ participants 
Primary Outcome;sͿ 
The primary outcome is safety of subretinal administration of 
AAVϴͲhGϭ.ϳp.coCNGAϯ.  
 
Safety is defined as the absence of ATIMPͲrelated: 
x 
Reduction in visual acuity by ϭϱ ETDRS letters or 
more that fails to resolve to within ϭϱ letters of 
baseline in a ϰͲweek period once prophylactic 
treatment commences  
x 
Severe unresponsive inflammation 
x 
Infective endophthalmitis 
x 
Ocular malignancy 
x 
Grade III or above nonͲocular SUSAR 
Safety will be assessed for ϲ months after the intervention in 
this study, and a further optional ϰ.ϱ years in a separate 
subsequent 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 ϯ to ϲ months 
after the intervention:  
 
ϭͿ 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. 
 
ϮͿ Any improvement in retinal function from preͲintervention 
that is greater than the baseline variation and measurable by 
electroretinography ;ERGͿ. 
 
ϯͿ Quality of life measures including EQͲϱD and IVI or 
equivalent as appropriate. 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page 11 of ϲϴ 
ͳǤͶ 
Re ad eibiiie 
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. 
 
Name 
Affiliation 
Role and responsibilities 
 
University 
College 
London 
Chief Investigator, Moorfield’s Eye Hospital 
 
 
University 
College 
London 
Co ʹ Investigator, Moorfields’s Eye Hospital 
 
University 
College 
London 
Senior Scientist 
 
MeiraGTx UK II Ltd. 
Chief Medical Officer 
 
MeiraGTx UK II Ltd.
Chief Development Officer
 
 
MeiraGTx UK II Ltd. 
Senior Director Clinical Operations 
 
 
MeiraGTx UK II Ltd. 
Clinical Project Manager 
 
 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
Page 12 of ϲϴ 
ʹ 
Tia Diaga   
 
 
 
Children with cone dysfuction syndrome consistent with CNGAϯ deficiency
Genetic screening for CNGAϯ by accredited laboratory ;before or after 
consentͿ
Participantͬparentͬguardian ;and childͿ given participant information sheet 
and asked to provide informed consentͬassent
Screeningͬbaseline tests ;genetic testing, health status, physical examination, 
vital signs, ocular examination, visual acuity, OCT, Full Field Stimulus 
electrophysiology, pregnancy
Oral Steriods prescribed ϭ week BEFORE Surgery
ATIMP administration surgery ;ϭ of ϯ dosesͿ
Pregnancy test if applicable
ϭ day postͲoperative follow up
ϯ days postͲoperative follow up
ϭ week postͲoperative follow up
Ϯ weeks postͲoperative follow up
ϰ weeks postͲoperative follow up
ϲ weeks postͲoperative follow up
ϯ months postͲoperative follow up
ϲ months postͲoperative follow up
Recruitment to LongͲterm Follow Up Study
Clinical assessments during follow up period including ocular exam, labs Θ visual 
assessments 
Antibiotic Θ corticosteroid prescribed ϭͲ
ϰ weeks postͲsurgery 
Ineligibleͬ
unwilling to 
consent  

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
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͵ 
Abbeiai 
AAV 
AdenoͲAssociated Virus 
Ad
Adenovirus
AE
Adverse Event
AF 
Autofluorescence 
AO 
Adaptive Optics 
AR 
Adverse Reaction 
ATIMP 
Advanced Therapy 
Investigational Medicinal 
Product 
ATMP 
Advanced Therapy 
Medicinal Products 
Bd 
Bis die twice daily 
BIOM 
Binocular Indirect 
Ophthalmo Microscope 
CA 
Competent Authority 
cDNA 
complementary 
Deoxyribonucleic Acid 
CEO 
Chief Executive Officer 
cGMP 
cyclic guanosine 
monophosphate 
CI 
Chief Investigator 
CMT 
Clinical Management 
Team 
CNGAϯ 
Cyclic NucleotideͲGated 
cation channel BetaͲϯ 
CRF 
Case Report Form 
CRO 
Contract Research 
Organization 
CTA 
Clinical Trial 
Authorisation 
CTIMP 
Clinical Trial of 
Investigational Medicinal 
Product 
DLE
DoseͲlimiting event
DNA 
Deoxyribonucleic acid 
DSUR 
Development Safety 
Update Report 
ELISA 
EnzymeͲlinked 
Immunosorbent Assay 
ELISPOT
EnzymeͲlinked 
ImmunoSpot Assay 
EMA
European Medicines 
Agency 
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 
;USͿ Food and Drug 
Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMO 
Genetically Modified 
Organism 
GMP
Good Manufacturing 
Practice 
GMSC
Genetic Modification 
Safety Committee 
GTAC 
Gene Therapy Advisory 
Committee 
hCAR 
Human Cone Arrestin 
HIPAA
Health Insurance 
Portability and 
Accountability Act 
HRA  
Health Research 
Authority 
HSE 
Health and Safety 
Executive 
IB
Investigator Brochure
ICF
Informed Consent Form
ICH 
International Conference 
on Harmonisation 
ISe 
Inner Segment Ellipsoid 
SDMC 
Safety andData 
Monitoring Committee 
IMP 
Investigational Medicinal 
Product 
IMPD
Investigational Medicinal 
Product Dossier 
IND 
Investigational New Drug 
IRB 
Institutional Review 
Board 
ISCEV 
International Society for 
Clinical Electrophysiology 
of Vision 
KEC 
Kellogg Eye Centre 
LCA 
Leber congenital 
amaurosis 
MHRA 
Medicines and 
Healthcare products 
Regulatory Agency 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
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mL
Millilitre 
ms
Millisecond
mRNA
Messenger RNA 
MTD 
Maximum Tolerated 
Dose 
NHS 
National Health Service 
NIH 
National Institutes of 
Health 
NIMP 
NonͲInvestigational 
Medicinal Product 
OBA 
Office of Biotechnology 
Activities 
OCT 
Optical Coherence 
Tomography 
PCR 
Polymerase Chain 
Reaction 
PERG 
Pattern 
Electroretinogram 
PHI 
Protected Health 
Information 
PI 
Principal Investigator 
PIS 
Participant Information 
Sheet 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life Year
QC 
Quality Control 
qds 
quarter die sumendus 
;four times dailyͿ 
QOL 
Quality of Life 
QP 
Qualified Person for 
release of ATIMP 
rAAV 
Recombinant adeno 
associated virus 
REC
Research Ethics 
Committee 
RG 
Research grade 
RGF 
Research Governance 
Framework 
RNA 
Ribonucleic acid 
RPE 
Retinal Pigment 
Epithelium 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
SAR
Serious Adverse Reaction
SDͲOCT
Spectral Domain Optical 
Coherence Tomography 
SOP 
Standard Operating 
Procedure 
SSA 
Site Specific Approval 
SSAR
Suspected Serious 
Adverse Reaction 
SUSAR 
Suspected Unexpected 
Serious Adverse Reaction 
SVϰϬ 
Simian virus ϰϬ 
TMF 
Trial Master File 
tRNA 
Transfer ribonucleic acid 
UAR 
Unexpected Adverse 
Reaction 
UCL
University College 
London 
UK 
United Kingdom of Great 
Britain Θ Northern 
Ireland 
US 
United States 
vg 
Viral Genomes 
WGTU 
Wolfson Gene Therapy 
Unit 
WT 
Wild type 
 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
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Ͷ 
Idci 
ͶǤͳ 
Backgd ad Raiae 
ͶǤͳǤͳ 
 Backgd 
Achromatopsia is a hereditary autosomal recessive condition characterized by intact rod function and 
absent cone function.  As a consequence of loss of cone function in the retina, Achromatopsia patients 
present with reduced or complete loss of colour vision, reduced visual acuity, involuntary backͲandͲ
forth eye movements ;pendular nystagmusͿ, a disabling increase in sensitivity to light ;photophobiaͿ, 
and a central scotoma ;Kohl et al͘, ϮϬϭϯ; Aboshiha et al͘, ϮϬϭϲ; Michaelides et al͘, ϮϬϬϰͿ.  In the United 
States, ACHM is estimated to affect approx. ϵ,ϳϬϬ individuals ;Judd, ϭϵϰϯ; Sharpe et al͘, ϭϵϵϬ; Sharpe 
et al͘, ϭϵϵϵͿ, in ϮϱйͲϯϱй of whom the condition results from mutations in the CNGAϯ gene ;Kohl et 
al͘, ϮϬϬϱ; Aboshiha et al͘, ϮϬϭϲͿ; similarly, it is estimated that approximately ϰ,ϬϬϬ people are affected 
in the EU. 
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IRU JHQH WKHUDS\ (DD\D DQG BHUQV, 2008).  SXEUHWLQDO DGPLQLVWUDWLRQ RI AAV2/8 YHFWRU LQ WKH PRXVH 
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DIWHU VXEUHWLQDO LQMHFWLRQ LQ WKH H\HV RI QRQ-KXPDQ SULPDWHV (NHPV) VKRZHG AAV2/8 WR EH DPRQJ 
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VDQGHQEHUJKH HW aO., 2011). 
Achromatopsia resulting from mutations in CNGAϯ has several characteristics that make it an 
appropriate candidate disease to demonstrate proofͲofͲprinciple in a firstͲinͲman trial of gene therapy 
for photoreceptor disease. Effective improvement in cone photoreceptor function, which is otherwise 
absent ;or markedly reducedͿ in this condition, would provide a clear, rapid and reliable measure of 
outcome. In addition, Achromatopsia is largely nonͲprogressive and the extended survival of cones, 
despite their profound lack of function, presents a wide window of opportunity during which gene 
supplementation could lead to significant benefit in coneͲmediated vision. Although younger children 
may benefit most from gene supplementation therapy by virtue of their greater visual plasticity, we 
anticipate that the intervention may offer benefit across a range of ages and we aim to define this 
range. For this reason, participants of a range of ages will be included. 
ͶǤͳǤʹ 
PeǦciica daa 
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Gene Therapy for Achromatopsia (CNGAϯ) 
CNGAϯ MGTϬϭϮ Protocol version ϲ.Ϭ ϭϲAprϮϬϮϭ  
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DPHQDEOH WR JHQH VXSSOHPHQWDWLRQ WKHUDS\. 
The efficacy and safety of AAVϴͲhGϭ.ϳp.coCNGAϯ is also the subject of an ongoing ϴͲweek toxicology 
and biodistribution rodent study and ongoing ϲͲmonth long term gross and ocular toxicity rodent 
study. In addition, a series of nonclinical pharmacology and toxicologyͬbiodistribution studies have 
been conducted with a closely related vector ;AAVϮͬϴͲhCARp.hCNGBϯͿ containing the human CNGBϯ 
gene. As this vector is comprised of the same vector backbone and capsid ;serotype ϴͿ as AAVϴͲ
hGϭ.ϳp.coCNGAϯ ;albeit with a different promoter and transgeneͿ, these data are considered 
relevant, supportive and representative of the nonclinical programme for AAVϴͲhGϭ.ϳp.coCNGAϯ. 
 
ͶǤͳǤ͵ 
Ciica daa 
No clinical studies using AAVϴͲhGϭ.ϳp.coCNGAϯ have been conducted to date in any country. 
However, proofͲofͲprinciple for gene replacement therapy in the retina has been demonstrated using 
recombinant adenoͲassociated virus serotype Ϯ ;rAAVϮͬϮͿ vectors delivering the retinal pigment 
epitheliumͲspecific protein ϲϱ ;RPEϲϱͿ gene in several completed clinical trials in Leber Congenital 
Amaurosis ;LCAϮͿ patients ;Bainbridge et al., ϮϬϬϴ; Maguire et al., ϮϬϬϴ; Cideciyan et al., ϮϬϬϵ; Russell 
et al͘, ϮϬϭϱ; Russell et al͘, ϮϬϭϳͿ.  
In these studies, adults and children as young as ϲ years of age were administered AAV vectors by 
subretinal administration, using analogous methods ;but with differing doses and volumesͿ to those 
proposed for the planned clinical study, at viral doses ranging from ϭ.ϱ x ϭϬϭϬ vgͬeye to ϭ x ϭϬϭϮ vgͬeye, 
with injection volumes ranging from Ϭ.ϭϱ to ϭ mL. In one of these clinical studies the vector was 
delivered by subretinal administration that in many cases encompassed the fovea ;Bainbridge et al., 
ϮϬϬϴͿ. 
This protocol describes MeiraGTx’s ϱth clinical trial of a gene supplementation therapy for inherited 
retinal disease using a recombinant AAV ;rAAVͿ vector.  
We are currently investigating the safety and potential efficacy of new optimized vectors in trials with 
a similar design and protocol to this proposed trial: 
x 
In MGTϬϬϯ we are investigating an optimized rAAVϮͬϱ vector for delivery of RPEϲϱ to adults 
and children with Leber Congenital Amaurosis caused by mutations in RPEϲϱ ;Chief 
Investigator:
Ϳ 
x 
In MGTϬϬϲ we are investigating an rAAVϮͬϴ vector for delivery of CNGBϯ to adults and 
children with Achromatopsia caused by mutations in CNGBϯ ;Chief Investigator: 
Ϳ 
x 
In MGTϬϬϵ we are investigating an rAAVϮͬϱ vector for delivery of RPGR to adults and children 
with XͲlinked Retinitis Pigmentosa caused by mutations in RPGR ;Chief Investigator: 
Ϳ 
 
Notably we will be using the same serotype in the trial herein for CNGAϯ ;AAVϮͬϴͿ as has been used 
in our completed human clinical trial for CNGBϯ ;AAVϮͬϴͿ. We administered AAVϴ vector to Ϯϯ 
participants in total ;ϭϭ adults and ϭϮ childrenͿ.  A total of ϯ serious adverse events ;SAE’sͿ were 
reported in the CNGBϯ study, Ϯ of which were considered at least possibly related to ATIMP. These 
were unexpected and were, therefore, reported as suspected unexpected serious adverse reactions 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
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;SUSARsͿ. They are further discussed in section ϰ.ϭ.ϱ. Overall, we judge that the safety profile supports 
the use of AAVϴ vector for children in this trial for CNGAϯ, given that children are more likely to benefit 
than adults. 
ͶǤͳǤͶ 
Raiae 
In CNGAϯͲrelated Achromatopsia, delivery of a cDNA sequence encoding a functional CNGAϯ protein 
using gene supplementation could lead to measurable improvements in visual function within ϲ 
months. 
There is currently no effective treatment available for most hereditary retinal disorders including 
Achromatopsia. This condition is characterised by absent ;or markedly reducedͿ cone function 
resulting in profound reduction in visual acuity, complete lack of ;or markedly reducedͿ colour vision, 
marked photophobia and nystagmus. The CNGAϯ gene encodes the alpha subunit of the cone 
photoreceptorͲspecific cGMPͲgated cation channel, which is critical for cellular responses to light. 
Absence of this alpha subunit results in absentͬextremely poor cone function and hence very poor 
daylight vision. Although loss of cone photoreceptor cells may occur in a limited number of patients, 
the rate of cell death is very slow, resulting in retinas containing surviving but nonͲfunctioning cones. 
Improvement of cone function by provision of CNGAϯ could provide a clear, rapid and reliable measure 
of outcome. Furthermore, the relatively nonͲprogressive nature of Achromatopsia, with extended 
survival of cone photoreceptors, means that the window of opportunity for effective intervention by 
gene supplementation may extend into adulthood. However, since Achromatopsia results in marked 
visual impairment from birth, associated abnormal development of physiological coneͲdependent 
neuronal circuits, including that of the visual cortex, may limit the potential for older individuals to 
benefit from therapeutic restoration of retinal function. Since visual cortical plasticity is known to be 
greater in younger children, we will recruit children into the dose escalation phase of the study to 
provide the greatest opportunity for benefit.  The totality of the data from paediatric subjects enrolled 
in the UK and adult subjects enrolled in the U.S. in this dose escalation study will be reviewed and 
inform the design of a future Phase ll interventional trial prior to its initiation. 
ͶǤͳǤͷ 
Aee ad aagee f ik 
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. CNGAϯͲrelated Achromatopsia results in profound sight impairment from birth or 
early infancy. The condition is currently untreatable, but there is a real possibility that gene therapy 
could offer a significant benefit in terms of improved sight and quality of life ;QOLͿ, based on own 
experience from the existing clinical trials for ocular gene therapy, subsequent ocular gene therapy 
trials elsewhere ;Maguire, et al ϮϬϬϴ; Cideciyan, AV et al ϮϬϬϴ and ϮϬϭϯͿ, the ongoing programme of 
work in ocular gene therapy trials investigating the safety and efficacy of CNGBϯ as a treatment for 
Achromatopsia, and preͲclinical data demonstrating improved outcome in both CNGBϯͲ and CNGAϯͲ
related Achromatopsia. Possible benefits of improved coneͲphotoreceptor function include, improved 
visual acuity, improved colour perception, and relief from disabling photophobia.  
The safety of the proposed approach will be enhanced by restricting transgene expression to the 
target tissue by virtue of rAAV vector tropism and the coneͲspecific promoter sequence used, and by 
restricting the intervention to one eye only in each participant. The risk of adverse effects will be 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
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further minimised by minimising the volume of vector suspension administered and by targeting it 
surgically to the cone rich region of the central retina. 
Risks to participant safety in relation to the ATIMP are classified using the MHRA definition as Type C 
;Markedly higher than the risk of standard medical careͿ. General risk management and the 
experience from all ongoing trials to date and will include, detailed review of all participants prior to 
administration of ATIMP, appropriate protocol design to identify potential short and long term risks 
appropriate time interval between ATIMP administration to successive participants and further 
limiting the risks to the child participants by first demonstrating an acceptable safety profile in both 
adults and children, with a similar vector, in a separate trial, MGTϬϬϲ. 
. Details of specific risks and their management strategies are outlined below.  
ͺǤͷǤͻǤͷ  Rik f ie ee  AAV;ǦhGͷǤͽǤcCNGA͹ 
The main risk of inflammation will be during the early postoperative period after ATIMP administration 
and before vector capsids are degraded. This risk will be minimised by preͲ and postͲoperative 
prophylactic treatment using topical and systemic corticosteroids. Any persistent intraocular 
inflammation will be managed by topical corticosteroid therapy and systemic corticosteroids where 
indicated. The participants will be closely followed up with a schedule of frequent assessments to 
identify and address any adverse events promptly. 
In the first clinical trial of gene therapy ;MGTϬϬϯͿ, intraͲocular delivery of an AAVϮͬϮ vector was 
followed by transient intraocular inflammation in ϯ of ϭϮ participants. In our subsequent trials with 
the intraocular administration of AAVϱ and AAVϴ vectors has been well tolerated in the majority of 
participants.  Similar episodes of intraocular inflammation involving the posterior segment in a 
minority of participants but all have responded to further administration of topical and systemic 
corticosteroids.  Of the Ϯ SUSARs reported in the CNGBϯ trial, the first, a panuveitis ;MRN ϮϬϭϳͲUKͲ
ϬϬϬϬϬϳͿ, met the definition of a dose limiting event ;DLEͿ  ;i.e. a reduction in visual acuity by greater 
than ϭϱ Early Treatment Diabetic Retinopathy Study ΀ETDRS΁ lettersͿ and responded favourably and 
promptly to treatment with additional corticosteroids. In the second SUSAR ;MRN ϮϬϭϴͲUKͲϬϬϬϬϬϯͿ, 
a ϭϯ year old female participant was administered vector at the higher dose of ϭ.Ϭ x ϭϬϭϮ vgͬmL. An 
anterior ͬ intermediate uveitis was reported, which did not itself constitute an SAE, but was associated 
with a temporary reduction in visual acuity by greater than ϭϱ ETDRS and was, therefore, a dose 
limiting event that responded favourably and promptly to treatment with additional corticosteroids.  
ͺǤͷǤͻǤ͸  Rik f ec aii  he ga 
Biodistribution studies suggest that following subretinal injection of AAV, anterograde and transͲ
synaptic transport of small amounts of vector genome from the retina to central visual structures may 
occur ;Stieger, et al ϮϬϬϴͿ. 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 cone photoreceptorͲspecific 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 copiesͿ 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 cone photoreceptorͲspecific promoter. 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
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ͺǤͷǤͻǤ͹  Rik f ieial ageei ad cgeei 
The possibility of oncogenic events due to vectorͲmediated insertional mutagenesis cannot be 
excluded with certainty, but available evidence suggests it to be unlikely given that ;iͿ AAV vector 
genomes integrate into host chromosomes at a very low frequency ;Nowrouzi, et al ϮϬϭϮͿ, ;iiͿ a limited 
number of AAV particles will be administered, and ;iiiͿ the eye predominantly contains nonͲdividing 
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 tumourͲprone pϱϯͲͬͲ mice, we found no evidence of malignant 
transformation of retinal cells ;Balaggan, et al ϮϬϭϮͿ.  In the highly unlikely event that an intraocular 
tumour does arise, the comprehensive monitoring procedures described in Section ϱ.ϰ.Ϯ.ϯ of the 
protocol will enable early detection and thus prompt appropriate management.  
ͺǤͷǤͻǤͺ  Rik f gelie aii 
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 ϮϬϬϴͿ. Systemic 
intravascular administration of rAAVϮ 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 ϮϬϬϲͿ. However, in 
this instance doses ranging from ϴ x ϭϬϭϬ to Ϯ x ϭϬϭϮ vgͬkg 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.  
 
Pregnant or nursing ;lactatingͿ women will be excluded. Female patients of childbearing potential 
;e.g., are menstruating or could reach menarche during the studyͿ should be counselled on the need 
for contraception should they be sexually active or, in the opinion of the Investigator, likely to be 
sexually active. Such subjects must agree to use an effective form of birth control ;hormonal or double 
barrier method of birth controlͿ for at least ϭϮ months following ATIMP administration. Male patients 
who are sexually active must agree to use barrier and spermicide form of contraceptive during 
intercourse while taking the IMP and for at least ϭϮ months after stopping treatment. Acceptable 
hormonal methods of contraception include combined pill, contraceptive implant, injection or patch, 
hormonal coil or progestogenͲonly pill.  
Despite similar advice and protocol requirements across all trials, one pregnancy ;MRN ϮϬϭϴͲUKͲ
ϬϬϬϬϬϮͿ has been reported in our MGTϬϬϰ trial, the longerͲterm followͲup trial for the MGTϬϬϯ retinal 
dystrophy trial of gene therapy for RPEϲϱ disease, with conception approximately ϱ months following 
vector administration and normal delivery of a healthy infant at fullͲterm. The most recent followͲup 
reports a positive outcome with both mother and infant being well. 
ͺǤͷǤͻǤͻ  Rik f gical adee effec 
The risk of significant surgical adverse effects is similar to the standard surgical care for other common 
forms of vitreoͲretinal 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 

 
 
Gene Therapy for Achromatopsia (CNGAϯ) 
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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 ϭ in ϭϬϬϬ. Reduction in foveal retinal thickness has 
been previously reported in a proportion of patients in both our first RPEϲϱ trial and other RPEϲϱ 
clinical trials, 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. 
However, in subsequent trials the use of a modified surgical technique that minimises the height of 
retinal detachment has resulted in no significant effect on foveal retinal thickness ʹ most notably 
retinal thickness has been stable postͲintervention in all Ϯϯ participants ;ϭϭ adults and ϭϮ childrenͿ in  
the CNGBϯ trial. 
Delivery of ATIMP to the subretinal space will be performed by standard surgical vitrectomy. This will 
involve a ϯͲport 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 Ϯϰ to ϰϴ hours postoperatively as the fluid is absorbed by the underlying 
retinal pigment epithelium.  
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. Elevated intraocular pressure will be 
managed by topical therapy; with systemic therapy where indicated with specialist advice sought as 
required.  Any potential risk to visual function will be minimised 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 ϭ in 
ϭϬϬ procedures and can be effectively managed in the majority by retinopexy, with or without 
intraocular tamponade. 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.  
ͺǤͷǤͻǤͼ  Rik f adee effec f ciceid 
Candidates will be screened for contraͲindications to transient immune suppression by 
corticosteroids; in particular, a history of uncontrolled hypertension, diabetes mellitus, tuberculosis, 
renal impairment, osteoporosis, gastric ulceration, severe affective disorder immunocompromised 
status and increased risk of infections.Possible adverse effects of shortͲterm 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 steroidͲinduced 
adverse effects will be monitored regularly. In particular, blood pressure and blood glucose will be 
measured, as will renal function and liver function ;at baseline, ϭ day, ϳ days, Ϯ weeks and ϰ weeks 
after surgeryͿ. Common and expected laboratory findings observed in the other ongoing studies 
utilising prophylactic corticosteroids have included but are not limited to: leucocytosis, neutrophilia, 
hyperglycaemia. If the latter should occur, then a referral to a diabetologist would occur. On occasion 

 
 
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mild transaminase changes have occurred but are mild and selfͲlimiting.  All the above have resolved 
with the tapering of the corticosteroids. 
ͺǤͷǤͻǤͽ  Rik f ieigai efed dig aee ad fll   
The majority of investigations are nonͲinvasive routine clinical tests and presents no significant risk. 
Venepuncture causes temporary discomfort, occasionally bruisingͬswelling and rarely infection at the 
site of puncture.  The participants will have all risks discussed during the consent process and are able 
to read them additionally in the Participant Information Sheet ;PISͿ. 
ͺǤͷǤͻǤ;  Rik f d hece dfci 
The aim of the intervention is to improve the function of cone photoreceptor cells. Rod 
photoreceptors exposed to the ATIMP are not expected to benefit but may be subject to adverse 
effects of the surgical intervention or ATIMP. We plan to minimize any adverse effect by targeting the 
ATIMP to the central retina where the cone photoreceptors predominate. In addition, the use of a 
cone specific promoter to drive CNGAϯ expression specifically in cones, will minimise inappropriate 
ectopic expression in rod photoreceptors. Moreover, should cone photoreceptorͲmediated vision be 
improved by the gene therapy, any dysfunction of rod photoreceptor cells is expected to be evident 
only in a dimly illuminated environment. 
No change in rod function has been described to date in the animal models ;mouse and dogͿ used to 
demonstrate the potential of gene supplementation therapy in CNGAϯͲassociated Achromatopsia. 
There has also been no change in rod function in any of the Ϯϯ participants ;ϭϭ adults and ϵ childrenͿ 
in our current CNGBϯ trial. 
ͺǤͷǤͻǤͿ  Rik f hiig f he fea  
Thinning of the retina in the macula ;macular thinningͿ has been detected in ϲͬϭϬ participants after 
subfoveal delivery of AAV vector in our previous RPEϲϱ clinical trial ;MGTϬϬϯͿ. Macular thinning was 
typically apparent within ϯ months and subsequently nonͲprogressive. Associated thinning of the 
photoreceptor cell ;outer nuclearͿ layer was evident, with variable disruption of the photoreceptor 
ellipsoid ;inner segmentͿ zone.  However, in subsequent current trials the use of a modified surgical 
technique that minimises the height of retinal detachment has resulted in no significant effect on 
retinal thickness ʹ most notably retinal thickness has been stable postͲintervention in all Ϯϯ 
participants ;ϭϭ adults and ϵ childrenͿ in the CNGBϯ trial. 
Since the central macula comprises predominantly of cone photoreceptor cells that have no function 
in achromatopsia, therefore it is not expected that macular thinning to affect vision significantly in this 
trial. The participants intensive schedule of assessments ;Table ϱ.ϲͿ has been designed to assess vision 
frequently. 
ͺǤͷǤͻǤͷͶ 
Rik f ial ibalace 
Individuals affected by Achromatopsia have severe sight impairment with no colour perception from 
birth. Improvement of retinal function by intervention later in development is expected to lead to new 
visual experiences. While these are expected to be positive, unpleasant visual sensations might also 
be experienced. The participants are made aware of this risk from the initial consenting process. 

 
 
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ͺǤͷǤͻǤͷͷ 
 Ccli  he ikǦbeefi ai 
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. Emerging safety data from the ongoing CNGBϯ Achromatopsia trial 
provides further justification for the administration of vector to children in the dose escalation part of 
the current trial. 
ͶǤͳǤ͸ 
Eaai f Chice f Caa 
There is no currently approved treatment for Achromatopsia caused by mutations in CNGAϯ͘ The 
comparator will be the contralateral eye and supplementary data collected as part of a prospective, 
parallel natural history study of patients with Achromatopsia.  
The totality of the data from paediatric subjects enrolled in the UK and adult subjects enrolled in the 
U.S. will be reviewed and inform the design of a future Phase ll interventional study. 
ͶǤʹ 
Objecie 
ͶǤʹǤͳ  Pia Objecie 
The primary research objective is to assess the safety of an AAVϮͬϴ vector for hCNGAϯ gene 
replacement in the retina. Safety is defined as: 
Safety is defined as the absence of an ATIMPͲrelated: 
x 
Reduction in visual acuity by ϭϱ ETDRS letters or more that fails to resolve to within ϭϱ letters 
of baseline in a ϰͲweek period once prophylactic treatment commences 
x 
Severe unresponsive inflammation ;defined belowͿ 
x 
Infective endophthalmitis 
x 
Ocular malignancy 
x 
Grade III or above nonͲocular SUSAR ;see section ϱ.ϭϭ.ϯͿ 
Severe unresponsive inflammation will be defined according to the Standardisation of Uveitis 
Nomenclature ;SUNͿ Working Group grading system ;Jabs et Al͘  ϮϬϬϱͿ i.e. 
x 
anterior chamber cells ϯн ;ϮϲͲϱϬ cells in a field size of ϭmm x ϭͲmm slitͲbeamͿ, or  
x 
anterior chamber flare ϯн ;marked, iris and lens details hazyͿ, or  
x 
vitreous haze ϯн ;Ophthalmology ϭϵϴϱ; ϵϮ:ϰϲϳͲϳϭͿ 
that fails to improve by Ϯ steps ;or to grade ϬͿ during a ϲͲweek period. 
ͶǤʹǤʹ  Secda Objecie 
The secondary research objective is to determine whether an AAVϮͬϴ vector for hCNGAϯ gene 
replacement in the retina can improve retinal function, visual function and quality of life. 
ͶǤ͵ 
Tia Deig 
This is an openͲlabel phase IͬII doseͲescalation trial to determine the safety and efficacy of subretinal 
administration of the ATIMP in children with CNGAϯͲrelated Achromatopsia. Paediatric participants 
for the purposes of this protocol are participants aged up to and inclusive of ϭϱ years of age. As part 
of the risk mitigation strategy for this protocol, ATIMP administration will first be administered to at 
least one older child participant ;ϭϭͲ ϭϱ years of ageͿ from each cohort before proceeding to younger 
participants. 

 
 
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In this dose escalation study, up to ϭϴ participants will be administered one of ϯ different doses of the 
ATIMP in cohorts of ϯ participants at a time in the first instance. Based on emerging safety data, the 
SDMC will make a recommendation on the dose to administer to the next cohort of participants. The 
SDMC may recommend additional participants at a given dose before making their recommendation 
on how to proceed to the next dose.  
Paediatric cases for the purposes of this protocol are defined as participants aged up to and inclusive 
of ϭϱ years. 
In addition to the paediatric cohorts in the UK, an additional cohort of Ϯ adult subjects will be enrolled 
in the US. The adult cohort will be administered the highest dose studied from the paediatric cohorts 
based on when the first adult subject is identified and ready to be enrolled.  The SDMC will review the 
data from all subjects ;paediatric and adultͿ in this dose escalation study. 
Safety and efficacy will be assessed for ϲ months following the intervention by clinical examination 
and special investigations according to the schedule in section ϱ.ϲ of the protocol. The totality of the 
data from paediatric subjects enrolled in the UK and adult subjects enrolled in the US will be reviewed 
and inform the design of  a future Phase ll interventional study. 
ͺǤ͹ǤͷǤͷ Seaae lge e fll  d 
In line with current CHMP and FDA guidance, the ATIMP safety is further assessed by a separate longer 
term follow up study of ϲϬ months duration, if the participants ͬ caregiver’s consent and only once 
they have reached the ϲͲmonth timepoint in the current study. The duration of longͲterm followͲup 
is therefore consistent with the recommendations of the current CHMP Guideline on FollowͲup of 
Patients Administered with Gene Therapy Medicinal Products ;EMEAͬCHMPͬGTWPͬϲϬϰϯϲͬϮϬϬϳͿ of 
ϮϮ October ϮϬϬϵ, where it is stated that, for viral vectors without integration, latency or reactivation 
potential, a brief clinical history and sample testing should be performed preͲtreatment, at ϯ, ϲ and 
ϭϮ months after treatment, and then yearly thereafter for a minimum of ϱ years ;and, if nonͲclinical 
tests or evidence from other clinical trials using identical vectors or modifications of vectors indicate 
a potential for integration or late reͲactivation, the monitoring should be extended to continue yearly 
after those ϱ years until data indicate that there is no longer any risk to be followedͿ. Further, although 
the FDA Guidance February ϮϬϮϬ ;Long Term FollowͲup After Administration of Human Gene Therapy 
Products: Guidance for IndustryͿ recommends a standard ϭϱͲyear period of followͲup, 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 followͲup study will be a nonͲintervention study designed to collect data on longer term safety 
and efficacy at the equivalent of ϵ, ϭϮ, Ϯϰ, ϯϲ, ϰϴ and ϲϬ months following ATIMP administration; as 
such, participants in both studies will be followed up more frequently than recommended in the 
guidance, as additional assessments following ATIMP administration are included in the initial study 
;at weeks ϭ, Ϯ, ϰ and ϲͿ and in the longͲterm follow up study ;at months ϵ and ϭϴͿ. TheͲfollow 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 longͲ
term followͲup study; however, in this motivated population, where individuals are typically 
monitored by their specialist closely and regularly, this is considered unlikely. 

 
 
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ͶǤ͵Ǥʹ  IMP adiiai Reie ad De Ecaai Cieia ad Pce 
Up to ϭϴ participants ;as defined in section ϰ.ϯͿ will be administered a single dose of ATIMP in a total 
volume of Ϭ.ϱmL, according to the below doseͲescalation criteria. These are anticipated to be as 
described below: 
ϭͿ low dose  
 
 
ϮͿ intermediate dose  
 
ϯͿ high dose  
 
 
In order to explore optimal dosing within safe limits, additional doses may be administered in order 
to maximise therapeutic effect, whilst maintaining the safety profile of the product. Any dose that 
differs from those described above will not exceed the highest titre of 
. The Chief 
Investigator, Medical Monitor and SDMC chair will confirm additional doses in advance of them being 
administered. The actual titre to be administered will be recorded in the eCRF.  
ͺǤ͹Ǥ͸Ǥͷ  De ecalai cieia ad De Liiig Ee 
Dose escalation will be managed according to review of available and emerging data on the subjects 
administered ATIMP top date and the occurrence, if any, of DLE’s or medically important events. An 
SDMC will review data from a minimum of ϲ weeks of follow up from each cohort of participants ;at 
least one older child, ϭϭͲϭϱ years of age per cohortͿ, before recommending the next dose to be 
assessed in a further cohort of participants or to additional participants at the same dose level.  
A DLE is defined as any of the below occurring during the ϲ weeks following administration, at least 
possibly related to the ATIMP, not surgery alone: 
x 
A reduction in visual acuity by ϭϱ ETDRS letters or more that fails to resolve to within ϭϱ letters 
of baseline in a ϰͲweek period once prophylactic treatment commences 
x 
Severe unresponsive inflammation ;defined belowͿΎ 
x 
Infective endophthalmitis 
x 
Ocular malignancy 
x 
Grade III or above nonͲocular SUSAR ;see section ϱ.ϭϭ.ϯͿ 
 
Ύ Severe unresponsive inflammation will be defined according to the Standardisation of Uveitis 
Nomenclature ;SUNͿ Working Group grading system ;Jabs et Al͘  ϮϬϬϱͿ i.e. 
x 
anterior chamber cells ϯн ;ϮϲͲϱϬ cells in a field size of ϭmm x ϭͲmm slitͲbeamͿ, or  
x 
anterior chamber flare ϯн ;marked, iris and lens details hazyͿ, or  
x 
vitreous haze ϯн ;Ophthalmology ϭϵϴϱ; ϵϮ:ϰϲϳͲϳϭͿ 
that fails to improve by Ϯ steps ;or to grade ϬͿ during a ϲͲweek period. 
Review of safety data will be undertaken by the SDMC prior to each dose escalation.  
ͺǤ͹Ǥ͸Ǥ͸ Dig ce 
ͶǤ͵ǤʹǤʹǤͳ Cohort ͳ 
ATIMP will first be administered at the lowest dose to at least one older paediatric ;aged ϭϭͲϭϱͿ 
participant only. This participant will be monitored for signs or evidence of visual andͬor systemic 
toxicity for a period of ϲ weeks and as per schedule of assessments ;section ϱ.ϲͿ. If there is no DLE as 

 
 
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defined above after a minimum of ϲ weeks, ATIMP will continue to be administered at the same dose 
to Ϯ additional paediatric participants. In the event of a DLE in the first cohort, a discussion will be held 
with the SDMC to agree a plan of action for the administration of ATIMP to further participants. The 
SDMC will review the data collected on this cohort up to ϲ weeks following ATIMP administration to 
the last participant in the cohort.  
ͶǤ͵ǤʹǤʹǤʹ Cohort ʹ 
In the event that there is no DLE or other event considered clinically relevant to the progression of the 
study and dose escalation in any participant in cohort ϭ the SDMC will provide a recommend to 
proceed administering ATIMP at the intermediate dose level. If dose escalation proceeds, at least a 
single older paediatric ;aged ϭϭͲϭϱͿ participant will be administered ATIMP.  If there is no DLE or other 
event considered clinically relevant after a minimum of ϲ weeks, ATIMP will continue to be 
administered at the same dose to Ϯ further participants. In the event of a DLE in the first participant 
in the cohort, a discussion will be held with the SDMC to agree a plan of action for administering the 
ATIMP to further participants. The SDMC will again review the data available on this next cohort of 
participants up to ϲ weeks following ATIMP administration to the last participant in the cohort.  
ͶǤ͵ǤʹǤʹǤ͵ Cohort ͵ 
In the event that there is no DLE ;or clinically relevant eventͿ in any participant in previous cohorts, 
the SDMC may recommend administering ATIMP at the highest dose level to a single older paediatric 
participant ;aged ϭϭͲϭϱ yearsͿ following review of all presented safety, toxicity and if relevant efficacy 
data. If there is no DLE or other event considered clinically relevant to the progression of the study 
after a minimum of ϲ weeks, ATIMP will be administered at the same dose to Ϯ further participants. 
In the event of a DLE in the first participant in the cohort, a discussion will be held with the SDMC to 
agree a plan of action for administering the ATIMP to further participants, the age and the dose.  
ͶǤ͵ǤʹǤʹǤʹǤͶ Adlt CohortǦUnited States 
In addition to the paediatric cohorts in the United Kingdom an additional cohort of Ϯ adult subjects, 
ϭϴ years of age or older will be administered ATIMP at the highest dose studied from the paediatric 
cohorts based on when the first adult subject is identified and ready to be enrolled.  The SDMC will 
also review the data from the adult cohort. 
ͶǤ͵ǤʹǤʹǤͷ Additional considerations 
In the event of a DLE in one of the participants at a given dose, the cohort may be expanded at the 
same dose level. The SDMC will review the safety data and recommend that additional participants 
may be treated at this dose. The SDMC may recommend that the same dose of ATIMP is administered 
to additional participants. The dose escalation will continue until SDMC are comfortable on review of 
the accumulating data, to recommend a maximum dose to be administered, or ϯ participants have 
been administered the highest dose without any DLEs, or until at least Ϯ participants among a cohort 
of ϯ to ϲ participants experience DLEs ;i.e., шϯϯй of patients with a DLE at that dose levelͿ, in which 
case the recommended dose will be the level below this dose. In the event that ϭ or Ϯ DLEs are seen 
at the first dose level, the SDMC may recommend administering a lower dose to that described in the 
protocol to a cohort of participants. 
 
 
 

 
 
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Table ϭ: Dose escalation table 
 
ͷ 
Mehd 
ͷǤͳ 
Sie Seeci 
The trial sponsor MeiraGTx UK II Ltd. has overall responsibility for site and investigator selection. 
ͷǤͳǤͳ 
Sd Seig 
The study settings are academic hospitals and academic research centres selected for their ability to 
perform the intervention and assessments required of this protocol. Data will be collected from 
multiple centres in the United Kingdom ;UKͿ and in the United States;USͿ.  
ͷǤͳǤʹ 
SieȀIeiga Eigibii Cieia 
Once a site has been assessed as being suitable to participate in the trial, the trial team will provide 
them with a copy of this protocol and the ATIMP Investigator Brochure.  
To participate in this trial of gene therapy for Achromatopsia ;CNGAϯͿ, investigators and trial sites 
must fulfil a set of criteria that have been agreed by the Clinical Management Team ;CMTͿ as defined 
below. 
Eligibility criteria: 
x 
A named clinician is willing and appropriate to take Principal Investigator responsibility 
x 
Suitably trained staff are available to recruit participants, enter data and collect samples 
x 
Suitably trained and certified staff are available to undertake clinical assessments 
x 
The site has access to a sufficient number of potential participants to meet their enrolment 
objectives  
x 
The site has access to all specialised equipmentͬdevices needed for clinical assessments 

 
 
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x 
The site should be able to archive traceability data for a minimum of ϯϬ years’ post expiry date 
of the ATIMP 
x 
The site should be able to store, prepare, dispense, and administer ATIMP appropriately 
 
Trial sites meeting eligibility criteria and that are accepted by the CMT as being suitable to recruit to 
the trial, will be issued with the Gene Therapy for Achromatopsia ;CNGAϯͿ Trial Master File ;TMFͿ 
documentation to use when applying for local approvals as applicable.  
ͻǤͷǤ͸Ǥͷ Picial Ieigaǯ ȋPIȌ Qalificai ad Ageee 
The investigator;sͿ 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 trialͿ. This includes 
confirmation of appropriate qualifications, familiarity with the appropriate use of any investigational 
products, agreement to comply with the principles of GCP, maintaining up to date GCP certification, 
to permit monitoring and audit as necessary at the site, and to supervise and maintain documented 
evidence of all staff at the site who have been delegated significant trial related duties. 
ͻǤͷǤ͸Ǥ͸ Recig a ie 
The investigator;sͿ should be able to demonstrate a potential for recruiting the required number of 
suitable participants within the agreed recruitment period ;i.e., the investigator;sͿ regularly provide 
clinical care for the target populationͿ. 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.  
ͷǤʹ 
Sie aa ad aciai 
The regulatory authorisations for the trial require that the Medicines and Healthcare products 
Regulatory Agency ;MHRAͿ and US Food and Drug Administration ;FDAͿ are supplied with the names 
and addresses of all participating site Principal Investigators. Clinical Operations staff at MeiraGTx UK 
II Ltd. will ensure this information is provided to both the MHRA and FDA.  
On receipt of the signed Clinical Trial Agreement and Investigator Agreement, approved delegation of 
responsibilities log and staff contact details, written confirmation will be sent to the site PI. The trial 
manager or delegate will notify the PI in writing of the plans for site initiation. Sites will not be 
permitted to recruit any patients until a letter for activation has been issued.  
The site must conduct the trial in compliance with the protocol as agreed by the Sponsor and, by the 
competent authorities, and which was given favourable opinion by the UK Health Research Authority 
;HRAͿ and local Institutional Review Board ;IRBͿ in the US. The PI or delegate must document and 
explain any deviation from the approved protocol, and communicate this to the trial team at MeiraGTx 
UK II Ltd. 

 
 
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ͷǤ͵ 
Paicia 
ͷǤ͵Ǥͳ 
Eigibii Cieia 
ͻǤ͹ǤͷǤͷ Paicia eleci 
The eligibility criteria for this trial have been carefully considered and are the standards used to ensure 
that only medically appropriate participants are entered. Participants not meeting the criteria should 
not be entered into the trial for their safety, and to ensure that the trial results can be appropriately 
used to make future treatment decisions for other people with similar diseases or conditions. It is 
therefore vital that exceptions are not made to these eligibility criteria. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria 
and none of the exclusion criteria as defined below. 
ͻǤ͹ǤͷǤ͸ Paicia Icli Cieia 
Inclusion in the trial will be limited to individuals who: 
ϭ. Are aged ϯͲϭϱ years  
Ϯ. Have Achromatopsia confirmed by a retinal specialist ;PIͿ 
ϯ. Have homozygous or compound heterozygous missense or null mutations in CNGAϯ 
confirmed in an accredited laboratory. Segregation is highly desirable but not essential if 
parental samples are not available. 
ϰ. Have evidence of relative photoreceptor preservation at the macula assessed by OCT нͬͲ AO. 
Participants with normal ISe or minimally disrupted ISe on OCT will be prioritised.  
ϱ. Are able to give informed consent or assent, with or without the guidance of their 
parentͬguardian where appropriate: children aged ϯͲϲ years will not be required to provide 
assent 
ϲ. Are able to undertake ageͲappropriate clinical assessments at the trial sites as specified in the 
protocol 
ϳ. If female and of childbearing potential and sexually active, are willing to use an effective form 
of birth control ;hormonal or double barrier method of birth control; or abstinenceͿ for at 
least ϭϮ months following ATIMP administration ;Section ϰ.ϭ.ϱ, Assessment and Management 
of RiskͿ  
ϴ. If male and sexually active, are willing to use barrier and spermicide form of contraceptive or 
maintain sexual abstinence for at least ϭϮ months following ATIMP administration 
ϵ. Females of childbearing potential will have a negative pregnancy test on the day of ATIMP 
administration. Participants are considered not of childbearing potential if they are preͲ
pubescent or surgically sterile ;i.e. they have undergone a hysterectomy or bilateral 
oophorectomyͿ  
ϭϬ. Are willing to give consent for the use of blood and blood components collected throughout 
the trial for the investigation of immune responses to the ATIMP 
 
 
 
 
 
 

 
 
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ͻǤ͹ǤͷǤ͹ Paicia Ecli Cieia 
Individuals will be excluded who: 
ϭ. Are females who are pregnant or breastfeeding 
Ϯ. Have uncontrolled gastroͲoesophageal reflux or are using nonͲsteroidal antiͲinflammatory 
drugs on a regular basis at the time of screening 
ϯ. Have a known allergy to any of the nonͲinvestigational drugs to be used in the trial as defined 
in Section ϱ.ϰ.ϭ 
ϰ. Have participated in another research study involving an investigational medicinal therapy for 
ocular disease within the last ϲ months 
ϱ. Have any other condition that the CIͬPI considers makes them inappropriate for entry into the 
trial, inclusive of but not limited to a history of the following:                                                                       
x 
 Uncontrolled hypertension defined as a systolic value шϭϲϬmmHg or diastolic value 
шϭϬϬmmHg. 
x 
Uncontrolled diabetes mellitus defined as an HbAϭc шϵй ;ϳϱmmolͬmolͿ at screening. 
x 
Any history of tuberculosis 
x 
Chronic kidney disease ;defined as eGFR чϲϬmlͬmin calculated using Cockroft Gault 
or MDRD equations. 
x 
Immunocompromised state ;including long term immunosuppressant therapyͿ. 
x 
Osteoporosis ;defined as presence of ϭ or more nonͲtraumatic “fragility” fractures or 
proven BMD of Ϯ.ϱSD less than anticipated as demonstrated on DEXA scanͿ. 
x 
Active peptic ulcer disease or uncontrolled gastroͲoesophageal reflux. 
x 
Severe affective disorder or past history of drug induced psychosis, and uncontrolled 
heart failure ;NYHA class IIͲIVͿ. 
ϲ. Use of high dose regular nonͲsteroidal antiͲinflammatory drugs at the time of screening 
Will be excluded from participating in the study protocol: 
x 
During the ϲ weeks prior to baseline, have had ANY of ;aͿ confirmed SARSͲCoVͲϮ ;COVIDͲϭϵͿ 
infection ;test positiveͿ, OR ;bͿ suspected SARSͲCoVͲϮ infection ;clinical features without 
documented test resultsͿ, OR ;cͿ close contact with a person with known or suspected SARSͲ
CoVͲϮ infection  
o Exception: may be included with a documented negative result for a validated SARSͲ
CoVͲϮ test 
;iͿ obtained at least Ϯ weeks after conditions ;aͿ, ;bͿ, ;cͿ above ;timed from 
resolution of key clinical features if present, e.g. fever, cough, dyspneaͿ 
AND 
;iiͿ with absence of ALL conditions ;aͿ, ;bͿ, ;cͿ above during the period between 
the negative test result and the baseline study visit  
 
 

 
 
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x 
NOTES on COVIDͲrelated exclusion: 
ϭ. If a patient is excluded due to recent COVIDͲϭϵͲrelated features, the reason for screen 
failure should be documented in the case report form under the exclusion criterion of 
having a condition for which participation would not be in the participant’s interest or 
could confound study assessments.  
Ϯ. The field of COVIDͲrelated testing ;for presence of, and immunity to, the SARSͲCoVͲϮ 
virusͿ is rapidly evolving. Additional testing may be performed as part of screening andͬor 
during the study if deemed necessary by the investigator and in accordance with current 
regulations ͬ guidance from authorities ͬ standards of care.  
ϯ. Have an ocular or systemic disorder that may preclude subretinal surgery andͬor 
interfere with interpretation of the study results 
ϰ. Have had intraocular surgery within ϲ months of screening 
ϱ. Are unwilling to consider the possibility of entry into a subsequent longer term follow up 
study 
ͻǤ͹ǤͷǤͺ Eligibili Cieia f Idiidal Pefig he Ieei 
Individuals performing the interventions will be limited to those qualified by training and experience 
to perform those interventions.  
Surgery will be performed only by a qualified vitreoͲretinal surgeon. The ATIMP will be administered 
by designated individuals at each study site to promote consistency of the intervention. A training 
programme has been developed that involves any designated individuals being trained in person by 
Professor 
 ;or an experienced surgeon who has been delegated this role by Prof 
Ϳ. This may involve observations of the procedure being performed in the UK or the US. The 
completion of this training is one of the criteria that will be satisfied prior to site activation. 
ͻǤ͹ǤͷǤͻ CǦele Gidace 
Individuals who have participated in another research study involving an investigational medicinal 
therapy for ocular disease within the last ϲ months, will not be eligible for enrolment in this study.  
ͻǤ͹ǤͷǤͼ Sceeig Pcede  
Written informed consent to enter the trial must be obtained from participants’ 
parentsͬguardiansͬperson with legal responsibility ;including legal authoritiesͿ, and written assent 
must be obtained from children aged over ϲ, after explanation of the aims, methods, possible benefits 
and potential hazards of the trial and before any trialͲspecific procedures are performed or any blood 
is taken for the trial. The only procedures that may be performed in advance of written informed 
consent being obtained are those that would be performed on all patients in the same situation as a 
usual standard of care. However, results of any procedures that were performed as part of the usual 
standard care within ϵ months of the screeningͬbaseline window of this study and prior to enrolment 
on this study may be used for baselineͬscreening if the subjects provide informed consent for the use 
of the prior obtained results. 
ͷǤ͵ǤͳǤ͸Ǥͳ  
Informed Consent Procedre 
Written assent and informed consent as appropriate will be taken from each participant and 
parentͬguardian by the chiefͬprincipal investigator or delegated clinician following appropriate 
explanation of the aims, methods, possible benefits and risks of the study. The Investigator or designee 

 
 
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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.  
The consent process will be managed during at least Ϯ meetings. At an initial meeting, information will 
be presented to potential participants in a form appropriate to their level of understanding. The 
support of an independent counsellor or advisor will also be offered. Potential participants will be 
provided with the relevant patient information and given time ;a minimum of Ϯϰ hoursͿ to consider 
their decision. 
At a subsequent meeting, potential participants and their parentsͬcarers will be provided with a 
further opportunity to ask questions and to sign the consent and assent forms. Children will be invited 
to give their verbal ;noted in their medical notesͿ or written assent to participation where this is age 
appropriate ;i.e., children aged over ϲ yearsͿ. Children aged over ϲ years will be included in the trial 
only if they assent to participate. Children under the age of ϲ are not required to provide assent. A 
copy of the signed assent and Informed Consent form will be provided to the participant. The original 
signed form will be retained at the study site and a copy placed in the medical notes. 
If new safety information results in significant changes in the riskͬbenefit assessment, the participant 
information sheet and consent form will be reviewed and updated if necessary, and participants will 
be reͲconsented as appropriate.  
Children who become of adult age ;i.e. ϭϲ in the EUͿ during the study will be reͲconsented as adults 
at the time of the next visit. 
ͷǤ͵ǤͳǤ͸Ǥʹ 
Screening Period 
Screening procedures will take place only after the informed consent form has been signed by the 
participantͬparentͬguardian. However, if test results are available from the subject’s routine clinical 
examination results within ϵ months of the screening visit and the subject has consented to allow the 
use of those tests, then those screening tests will not need to be repeated.  
Participants will undergo genetic screening for CNGAϯ mutations at an accredited laboratory prior to 
enrolment. If genetic screening has taken place as part of routine medical assessments the test may 
not be repeated, but the result will be reported in the CRF. 
Participants will be screened to ensure there are no contraͲindications for transient immune 
suppression, in particular: hypertension, diabetes mellitus, tuberculosis, renal impairment, 
immunocompromised state, osteoporosis, gastric ulceration or severe affective disorder. The study 
medical monitor should be consulted if the investigator is unsure or to discuss any other screening or 
eligibility issues. 
Screening assessments are listed below ;and set out under the column headed ‘Screening’ in the Trial 
Assessments Table Ϯ, Section ϱ.ϲͿ:  
ϭ. Genetic testing ;if no prior result availableͿ 
Ϯ. Medical history and concomitant medication ;include prescription medications and overͲ
theͲcounter preparationsͿ used by the patient from enrolment date, during the study, and 
at the study drug discontinuation visit will be documented and recorded on eCRF. 

 
 
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ϯ. Physical examination 
ϰ. Vital signs including blood pressure 
ϱ. Ocular examination 
ϲ. Visual acuity 
ϳ. Spectral Domain Optical Coherence Tomography ;SDͲOCTͿ  
ϴ. Electrophysiological assessment 
 
A letter from the general practitioner detailing the health status of the participant may be requested 
if the clinician deems it appropriate to confirm eligibility for the trial. 
These assessments must have been completed within ϵ months prior to enrolment. In addition, 
females of childbearing potential will undergo a pregnancy test at screening and again on the day of 
ATIMP administration. 
ͷǤ͵ǤͳǤ͸Ǥ͵ 
Enrolment 
Participants who fulfil the inclusion criteria based on the results of all screening assessments and 
pregnancy test will be enrolled in the trial. The ATIMP will be administered within ϵ months of 
enrolment. If the ATIMP is not delivered within ϵ months of enrolment, all screening tests with the 
exception of genetic testing and electrophysiological assessment will be repeated and eligibility for 
enrolment reͲassessed. 
Participants who withdraw or are withdrawn from the study for any reason prior to ATIMP 
administration may be substituted in the study. 
ͷǤͶ 
Ieei 
ͷǤͶǤͳ 
Nae ad Decii f Ieigaia Medicia Pdc 
AAVϴͲhGϭ.ϳp.coCNGAϯ is an advanced therapy investigational medicinal product: specifically, a gene 
therapy product. 
AAVϮͬϴͲhGϭ.ϳp.coCNGAϯ is a gene transfer agent developed for the treatment of a form of 
Achromatopsia caused by defects in the gene encoding CNGAϯ. This is the alpha subunit of the cGMPͲ
gated ion channel that plays an essential role in the cone phototransduction pathway. Disruption of 
the gene prevents the conversion of light to an electrical signal, leading to lack of cone function and 
visual dysfunction. Recombinant adenoͲassociated virus ;rAAVͿ mediated gene transfer of a copy of 
the normal CNGAϯ gene to the cone photoreceptors, results in stable, long term transgene expression 
and improves visual function significantly in both rodents and dogs with CNGAϯ gene defects.  
AAVϴͲhGϭ.ϳp.coCNGAϯ consists of a linear single strand of DNA packaged in a rAAV protein capsid of 
serotype ϴ. The AAVϴͲhGϭ.ϳp.coCNGAϯ genome incorporates ϮϵϬ nucleotides of the wildͲtype AAVϮ 
ITR ;Inverted Terminal RepeatsͿ sequences that provide in cis the packaging signal, a cDNA encoding 
codon optimised human CNGAϯ, a human opsin locus control region and green opsin promoter 
;OPNϭMWͿ and a SVϰϬ ;simian virus ϰϬͿ polyadenylation signal. The icosahedral capsid consists of 
three related capsid proteins, VPϭ, VPϮ, and VPϯ. AAV has a compact macromolecular structure and 
forms stable viral particles ϮϬnm in diameter. The vector particles are replication incompetent. 

 
 
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ͻǤͺǤͷǤͷ ATIMP Claified a Geeicall Mdified Ogai 
The ATIMP ;AAVϴͲhGϭ.ϳp.coCNGAϯͿ is classified as a genetically modified organism under the 
Genetically Modified Organisms ;Contained UseͿ Regulations ϮϬϬϬ. 
The Health and Safety Executive ;HSEͿ 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 ;GMSCͿ. Internal approval at site for the GMO activities has been 
gained.  
Each clinical trial site administering the ATIMP in the US must obtain local Institutional Biosafety 
Committee approval to administer recombinant nucleic acid molecule material to human participants. 
Trial sites that receive support for recombinant or synthetic nucleic acid molecule research from the 
National Institutes of Health ;NIHͿ must register the protocol with the NIH Office of Science Policy 
;OSPͿ for review prior to initiating trial activities.  
ͻǤͺǤͷǤ͸ Sce f ATIMP 
The ATIMP has been manufactured at the MeiraGTx II Ltd., ϵϮ Britannia Walk, London. Nϭ ϳNQ in 
accordance with current Good Manufacturing Practice for clinical trial materials. The product is 
released by an EU QP or as per country specific guidelines. 
ͻǤͺǤͷǤ͹ Peaai ad Labellig f he Ieigaial Medicial Pdc 
Preparation and labelling of the investigational medicinal product will be completed in accordance 
with the relevant GMP guidelines.  
The ATIMP is a recombinant serotype Ϯͬϴ adenoͲassociated viral vector containing a human CNGAϯ 
cDNA driven by a Ϭ.ϰ kb fragment of the human CAR promoter.  
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. 
ͻǤͺǤͷǤͺ Decii ad Jificai f Re f Adiiai ad De 
Efficient transduction of the cone photoreceptor cells requires the ATIMP ;rAAVϴͲhGϭ.ϳp.coCNGAϯͿ 
to be administered to the subretinal space. 
Delivery of vector suspension to the subretinal space will be performed by standard vitrectomy 
surgery. This will involve a ϯͲport 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 Ϯϰ to ϰϴ 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. Injection of fluids under the retina commonly performed delivery of surgical dyes and 
antithrombotic agents in the management of rhegmatogenous retinal detachment and macular 
degeneration. 

 
 
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The highest ATIMP dose that is intended to be delivered to the trial participants is based on doseͲ
limiting toxicity that was seen in an earlier trial of AAVϮͲmediated gene therapy for LCAϮ, where ϭ mL 
of ATIMP at ϭ x ϭϬϭϮ vgͬmL was found to be the highest safe dose that could be administered 
subretinally. As toxicity in this context is a complex interaction between local retinal effects, wider 
ocular effects and systemic effects, a conservative decision was taken to use the confirmed safe titre 
;ϭ x ϭϬϭϮ vgͬmLͿ, despite using a smaller maximal volume ;Ϭ.ϱ mLͿ and thus a slightly lower dose. As 
AAVϮͬϴͲmediated transduction of cone photoreceptors in nonͲhuman primates is efficient over a wide 
range of titres, including much lower titres than used in this study ;Vandenberghe et al, Sci Transl Med 
ϯ, ϴϴraϱϰͿ we are confident that the CNGAϯ transgene can be delivered to the cones effectively at ϭ x 
ϭϬϭϮ vgͬmL.  
ͻǤͺǤͷǤͻ Nae ad Decii f Each NǦIeigaial Medicial Dg ȋNIMPȌ 
ϭ. Cefuroxime can be administered subconjunctivally at Ϭ.ϱml normal saline, or ϭϮϱmg in ϭ.ϬmL 
normal saline according to local practice or cefazolin or vancomycin antibiotic given at usual dose at 
end of surgery ;standard dose as prophylaxis for postͲoperative infectionͿ 
Ϯ. Long acting steroid in the subͲtenon space following sclerotomy closure ;see details in CNGAϯ 
ATIMP Management PlanͿ. 
ϯ. Betamethasone can be administered subconjunctivally at Ϯ.mgͲ ϱmg in Ϭ.ϱmL, according to local 
practice, or dexamethasone can be administered subconjunctivally at ϭ.ϱmgͲϮ.Ϭmg in Ϭ.ϱmL, 
according to local practice  at end of surgery ;standard dose as prophylaxis for postͲoperative 
inflammationͿ 
ϰ. Chloramphenicol Ϭ.ϱй or ofloxacin ;topical antibioticͿ ϰ times daily for ϳ days following ATIMP 
administration  
ϱ. Dexamethasone Ϭ.ϭй ;topical steroidͿ or topical prednisolone drops ϭ.Ϭй should be administered 
ϰ times daily for ϰ weeks following ATIMP administration  
ϰ and ϱ above will be administered to minimise inflammation and protect against infection 
postoperatively. 
ϲ. Omeprazole:  
x 
In children aged up to ϭϱ weighing ϱ kg to less than ϭϬ kg ;ϭϭ lb to less than ϮϮ lbͿ: ϱ mg taken 
once per day  
x 
In children aged up to ϭϱ weighing ϭϬ kg to less than ϮϬ kg ;ϮϮ lb to less than ϰϰ lbͿ: ϭϬ mg 
taken once per day  
x 
In children aged up to ϭϱ weighing ϮϬ kg ;ϰϰ lbͿ or more: ϮϬ mg taken once per day 
 
Omeprazole will be administered as a gastroͲprotectant against corticosteroid therapy. 
 
 
 

 
 
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ϳ. Prednisolone or Prednisone ;oral steroidͿ as prophylaxis against potential intraocular immune 
responses: 
Ϭ.ϱ mgͬkg daily for one week prior to ATIMP administration 
ϭmgͬkg daily for the first week following ATIMP administration 
Ϭ.ϱmgͬkg daily for the second week following ATIMP administration 
Ϭ.Ϯϱmgͬkg daily for the third week following ATIMP administration 
Ϭ.ϭϮϱmgͬkg daily for the fourth week following ATIMP administration 
All NonͲ Investigational Medicinal Products ;NIMPsͿ are licensed within the EU and US and will be 
procured from standard hospital stock. 
Sites will maintain a system that allows adequate reconstruction of NIMP movements and permits 
recording of which participants received which NIMPs during the trial, with an evaluation of the 
compliance where necessary. 
ͷǤͶǤʹ 
Pc defied ciica chede 
ͻǤͺǤ͸Ǥͷ Baelie Aee 
A detailed assessment of visual function and retinal imaging of both eyes will be performed 
preoperatively as outlined in Section ϱ.ϲ ;Table Ϯ: Trial AssessmentsͿ. For assessments requiring 
multiple baselines, testing is preferred on separate days within a maximum ϵͲmonth period to allow 
for dayͲtoͲday variation and testͲretest variability for individual participants. However, it is 
acknowledged that a pragmatic balance will be achieved for what is appropriate for the different tests 
on an individual basis. Each set of baseline measurements may take up to ϱ days to perform in total. 
Where it is not possible to obtain reliable data for any given baseline assessment, further protocol 
defined timepoints for those assessments will not be taken, unless required for evaluation of safety. 
In some instances, results for protocol specified baseline tests may be available as a part of routine 
clinical examination within ϵ months. As such, if the subject provides informed consent to use the 
results from the previously conducted tests, then these assessments will not need to be repeated at 
baseline.   
Visual assessment results will be sent for reading and analysis to independent reading centres within 
the UK and US. For both UK and US sites imaging with OCT, fundus autofluorescence and fundus 
photography will be reviewed by the site teams but also sent for independent analysis by the Reading 
Centre, Queens University, Belfast, Ireland, during the course of the trial. Adaptive optics images will 
be sent to the Medical College of Wisconsin, US, for reading. Octopus perimetry will be sent to the 
Oregon Health and Science University Casey Eye Institute, US, reading centre. Photoaversion videos 
will be sent to MeiraGTx and their research development partners. All images will be saved under 
pseudoͲanonymised patient identifiers and surgical images will only be taken of the patient’s eye to 
ensure that patients remain unidentified. Images and videos obtained during photoaversion testing 
may reveal some facial characteristics. To the extent possible, images and videos will be anonymised 
by removing any personally identifiable information from the imaging or video files.   
Up to ϭϬ mL of blood will be sampled in order to assess baseline levels of circulating antibodies against 
AAVϴ and of circulating antibodies against rAAV serotype ϴ so that immunological responses to vector 
capsids can be determined following ATIMP administration ;collectively described as serology in Table 

 
 
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Ϯ: Trial AssessmentsͿ. We anticipate that that majority of participants will have no detectable preͲ
existing circulating antibodies against AAVϴ. The presence or absence of circulating antibodies will not 
affect recruitment of the participant. All serology tests will be performed at a laboratory approved by 
the sponsor and their research development partners. 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: 
x 
Serological tests 
x 
Blood pressure 
x 
Haematology 
x 
Biochemistry 
x 
Ocular examination 
x 
Colour fundus photography 
x 
Spectral Domain Optical coherence tomography ;SDͲOCTͿ 
x 
Fundus Autofluorescence ;FAFͿ imaging  
x 
Best corrected visual acuity  
x 
At least one of static perimetry and ͬ or fullͲfield stimulus testing.  
x 
LightͲsensitivity ;PhotoaversionͿ testing 
 
Tests that will be performed where possible unless lack of patient coͲoperation or equipmentͬ 
facilities are: 
x 
Contrast sensitivity  
x 
Reading assessment 
x 
Colour vision testing 
x 
Adaptive optics ;AOͿ imaging 
x 
QOL questionnaires 
 
Further details of clinical assessments can be found in the Gene Therapy for Achromatopsia ;CNGAϯͿ 
study manual. Images taken at all timepoints will be sent for independent reading and analysis at 
centres in both the UK and US.  
 
;iͿ 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 ;FAFͿ imaging, SDͲOCT, 
and adaptive optics ;AOͿ imaging. FAF imaging allows visualisation of the retinal pigment epithelium 
;RPEͿ by taking advantage of its intrinsic fluorescence derived from its lipofuscin content. SDͲOCT 

 
 
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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 ǀiǀo. 
;iiͿ Functional and ParticipantͲRelated Outcome Assessments.  
Where possible the participant will complete an age appropriate Impact of Visual Impairment ;IVIͿ 
visionͲspecific quality of life questionnaire, and EQϱDͲϱL questionnaire and EQϱDͲY questionnaire, or 
equivalent as appropriate. Reading ability including reading acuity, maximum reading rate, and critical 
print size will be assessed where possible. 
The degree of light sensitivity ;photoaversionͿ will be investigated in two ways ;iͿ Objectively by 
measurement of palpebral aperture narrowing in response to gradually increasing light intensity and 
;iiͿ Subjectively by participant reported symptomatology. 
BestͲcorrected ETDRS visual acuity will be measured in each eye. Contrast sensitivity will be measured 
using the PelliͲRobson chart.  
Colour vision will be assessed comprehensively using plate tests and computerised tests probing 
colour discrimination along all ϯ axes of colour.  
Retinal sensitivity will be determined using static perimetry andͬor full field stimulus testing ;FSTͿ 
where possible.  
FullͲfield electroretinography ;ERGͿ and pattern ERG ;PERGͿ will be performed according to the 
International Society for Clinical Electrophysiology of Vision ;ISCEVͿ standards to assess both 
generalised retinal ;rod and cone systemsͿ and isolated macular function. Modified ISCEV protocols 
may be necessary in young children using internationally recognised modified protocols. For young 
children, this procedure may be performed under general anaesthesia. 
ERG data will be analysed and interpreted by dedicated fullͲtime Clinical Visual Electrophysiology 
Consultants with extensive experience and who are directly involved in defining ISCEV standards.  
ͻǤͺǤ͸Ǥ͸ ATIMP adiiai Pcede 
 
The protocol describes the intended surgical technique for ATIMP administration. The surgical 
procedure may be modified on a caseͲbyͲcase basis in the interests of safety; any modification will be 
documented in the operation notes and eCRF. Consent to record the surgery will be requested of the 
participant.  Intraocular surgery will be recorded by video via the operating microscope as described 
in the consent process. Relevant anonymised video recordings and images will be stored alongside the 
trial database, with the sponsor and held by third party vendors. 
ͷǤͶǤʹǤʹǤͳ 
PreǦoperatie Procedres 
For prophylaxis against potential intraocular immune responses to the ATIMP, participants will be 
prescribed a course of oral prednisolone as described in section ϱ.ϰ.ϭ.ϱ. 
Preoperative procedures and intraocular administration of ATIMP will be as described in the Gene 
Therapy for Achromatopsia ;CNGAϯͿ study manual. 

 
 
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ͷǤͶǤʹǤʹǤʹ 
Techniqe for intraoclar administration of ATIMP 
The choice of eye for ATIMP administration will be the poorerͲseeing eye as identified by the 
participant and CIͬPI taking into account ocular dominance and visual acuity. 
The recombinant vector will be delivered in the form of a suspension of viral vector particles injected 
intraocularly ;subretinallyͿ under direct observation using an operating microscope. This procedure 
will involve a ϯͲport 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 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. Three pars plana 
sclerotomies will be sited to enable intraocular infusion, endoillumination probe and surgical 
instruments. The fundus will be viewed by means of a binocular indirect ophthalmo microscope 
;BIOMͿ viewing system or a contact lens. To minimise the possibility of unplanned retinal detachment 
or preretinal fibrosis, vitrectomy ;aspiration of vitreous gelͿ will be performed using a disposable 
cutter.  
Intraocular administration of the viral vector suspension ;AAVϴͲhGϭ.ϳp.coCNGAϯͿ 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 selfͲsealing nonͲ
expanding retinotomyͬretinotomies. The aim will be to target the ATIMP to the central macula. If 
appropriate, the bleb of ATIMP will be manipulated to the target area using a fluidͲair 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 cefuroxime antibiotic and betamethasone will be administered 
subconjunctivally as prophylaxis against postoperative infection and inflammation respectively. 
Bupivacaine will be administered for analgesia. The surgical procedure may be modified on a caseͲbyͲ
case basis in the interests of safety; any modification will be documented in the operation notes and 
CRF. 
On the basis of our own experience, we anticipate that the subretinal ATIMP bleb will resolve 
spontaneously during the first ϰϴ hours. 
Surgery may be performed, as is conventional for intraͲocular procedures, on a dayͲcase basis and 
participants will be managed subsequently as outͲpatients, although hospitalͲbased accommodation 
may be used for convenience. 
ͻǤͺǤ͸Ǥ͹ Sbee Aee 
On the first postoperative day a full clinical ocular examination will be performed. In particular, visual 
acuity, intraocular pressure, the degree of postoperative intraocular inflammation and the area of any 

 
 
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residual retinal bleb will be documented. Fundus photography, autofluorescence imaging, ocular 
examination, intraocular pressure and SDͲOCT will be performed at day ϭ and each subsequent visit 
post ATIMP administration. 
A standard postͲvitrectomy treatment regimen of topical antibiotic ;chloramphenicol Ϭ.ϱй qds for ϳ 
daysͿ and steroid ;dexamethasone Ϭ.ϭй qds for ϰ weeksͿ will be prescribed to minimise inflammation 
and protect against infection postoperatively.  
Intraocular pressure of greater than ϯϬ mmHg will be managed with topical medication and systemic 
therapy where indicated, with specialist advice sought as required.  
Participants will be maintained on oral prednisolone ;or other as appropriateͿ for ϰ weeks following 
administration of ATIMP as described above ;Section ϱ.ϰ.Ϯ.Ϯ.ϭ: PreͲoperative procedureͿ. The possible 
development of steroidͲinduced 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 Ϯ: Trial Assessments. 
Both safety and efficacy of the ATIMP will be evaluated at various time points up to ϲ months after 
ATIMP delivery. Evaluations will comprise primarily, ocular assessments. The nature and schedule 
;Section ϱ.ϲ: Trial AssessmentsͿ of these is described below. 
;iͿ Clinical assessment of intraocular inflammation 
The degree of intraocular inflammation will be assessed by slitͲlamp biomicroscopy at each time point. 
A temporary intraocular inflammatory response is expected following vitrectomy surgery. This is 
typically evident clinically on slitͲlamp biomicroscopy as ‘flare’ and cells in the anterior chamber and 
can be of moderate ;Ϯн cellsͿ intensity. The degree of intraocular inflammation is expected to decline 
over the course of the first ϰ 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 andͬor systemic immunosuppression. 
;iiͿ Evaluation of immune responses 
Up to ϭϬ mL of blood will be sampled to measure immune response. Antibody responses to AAV capsid 
proteins will be investigated by ELISA at baseline and at ϰ weeks, ϯ months, and ϲ months following 
ATIMP administration. 
;iiiͿ 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 swollenͿ, saliva ;a minimum of ϭϬϬ μLͿ and serum ;ϭ 
mLͿ at ϭ day and at ϰ weeks following intraocular ATIMP administration. The test will be carried out 
at a laboratory approved by the sponsor and their research development partners. 
;ivͿ Assessment of visual function and retinal imaging 
Assessment of visual function and retinal imaging will be performed as outlined in Section ϱ.ϲ ;Trial 
AssessmentsͿ. They will be carried out with the same methods applied for the baseline tests ;see 

 
 
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section ϱ.ϰ.Ϯ.ϭ for detailsͿ to allow direct comparison of the data sets. These assessments will be 
scheduled over a period of a day for visits at day ϭ, day ϯ, day ϳ, week Ϯ, week ϰ and week ϲ after 
surgery, and up to ϰ days for baseline examinations, and ϯ months, ϲ months following ATIMP 
administration.  For day ϭ and ϯ refraction cannot reliably be measured. Therefore, the most recent 
refraction measurement will be used. 
All participants will need to be able to perform reliable visual acuity testing and SDͲOCT imaging, 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 
particular participant may be discontinued for that participant. This is not anticipated for the key 
clinical assessments such as visual acuity test or SDͲOCT imaging 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. 
ͻǤͺǤ͸Ǥͺ Laba Pcede 
Blood serum will be processed, to investigate any immune responses to the ATIMP: 
ϭ. antiͲAAVϴ neutralising antibodies 
Ϯ. antiͲAAVϴ antibodies using an ELISA  
Blood serum, saliva and lacrimal fluid will be processed in the UCL Institute of Ophthalmology to assess 
dissemination of ATIMP after delivery, where the number of rAAV vector genome copies will be 
measured using a polymerase chain reaction ;PCRͿ approach.  
Whole blood will be processed at the National Genetics Reference Laboratory in the UK, or a CLIAͲ
accredited molecular diagnostic laboratory in the US, for CNGAϯ mutation screening. Haematology 
and biochemistry samples and screen will be carried out at the Trust associated laboratories, or an 
accredited laboratory in the US.  
Biochemistry and haematology parameters to be analysed are as per the table below: 
Haematology
Biochemistry
Haemoglobin 
Sodium 
Haematocrit
Potassium
Erythrocytes 
Chloride 
Mean Corpuscular Volume 
Bilirubin 
Mean Corpuscular Haemoglobin
Alkaline Phosphatase
Platelet 
Aspartate Aminotransferase 

 
 
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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 
 
ͷǤͶǤ͵  Dieig 
ͻǤͺǤ͹Ǥͷ Recei ad Sage f he Adaced Thea Ieigaial Medicial Pdc 
The batch of ATIMP will be stored at either the MeiraGTx II Ltd Manufacturing Facility ;MeiraGTx MFͿ, 
or other approved storage facility ;details of storage will be specified in the ATIMP Management PlanͿ.  
The product, which is stable at чʹϳϬΣ Celsius, will be stored at ͲϳϬΣ Celsius or below in secure 
temperature controlled and monitored ͲϴϬΣ Celsius freezers. No further manufacturing or testing will 
take place at the MeiraGTx MF. Shipping of ATIMP will be on dry ice, accompanied by a temperatureͲ
monitoring device.  
The ATIMP vector will be dispensed on the same day of administration according to study specific 
working instructions, with a ϭͲhour window for administration after ATIMP has thawed at room 
temperature.  
ͷǤͶǤͶ 
Dage  
ͻǤͺǤͺǤͷ Dage ad dage dificai 
Trial participants will receive a single dose of ATIMP within the range proven to be safe in the 
preclinical animal studies. These are anticipated to be as described below: 
ϭͿ low dose  
 
 
ϮͿ intermediate dose  
 
ϯͿ high dose  
 
  
In order to explore optimal dosing within safe limits, additional doses may be administered in order 
to maximise therapeutic effect, whilst maintaining the safety profile of the product. Any dose that 
differs from those described above will not exceed the highest titre of 
. The Chief 

 
 
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Investigator, Medical Monitor and SDMC chair will confirm additional doses in advance of them being 
administered. The actual titre to be administered will be recorded in the eCRF.  
The ATIMP will be produced and stored at a titre appropriate for the high dose 
Ϳ and 
diluted immediately prior to intraocular administration in Hartmann’s solution at the time of 
administration for lower doses. The appropriate dilution will be prepared in the operating theatre and 
this will be checked in by a second individual prior to administration. The check will be recorded in the 
patient’s source data notes. 
Further details for doseͲescalation criteria are included in Sections ϰ.ϯ.Ϯ. 
ͷǤͶǤͷ 
Accabii 
The ATIMP will be prescribed for a particular participant by one of the investigators and handled 
according to the ATIMP management plan applicable for each site.  
A comprehensive ATIMP management plan and associated Working Practices and forms will be in 
place to ensure that the required accountability and traceability data is collected and retained. 
ͷǤͶǤ͸ 
Ciace ad Adheece 
Full compliance is expected since the ATIMP will be surgically delivered by the CI or a delegated vitreoͲ
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 ϱ.ϰ.ϴ ;Overdose of trial medicationͿ about the 
assessment of adherence to the protocol defined delivery of the product.  
ͷǤͶǤ͹ 
Ccia Cae 
Concomitant use of other medications should be avoided unless clinically necessary and should be 
used with caution, and appropriately documented on study logs where used. All concomitant 
medications ;including steroidsͿ must be recorded in the eCRF from the day of informed consent. 
ͷǤͶǤͺ 
Oede f Tia Medicai 
Intraocular administration of the ATIMP will be performed by the operating surgeon ;CI or a delegated 
vitreoͲretinal surgeonͿ. The volume of ATIMP delivered to the target site will be measured from the 
scale located on syringeͬ plunger and recorded in the CRF.  
Any overdose will be reported to the sponsor. This is a Phase IͬII 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 ϱ.ϭϭ.ϯ. 
ͷǤͶǤͻ 
Pc Diciai 
ͻǤͺǤͿǤͷ Paicia Wihdaal 
In consenting to the trial, participants consent to ATIMP administration, trial followͲup and data 
collection.  

 
 
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As participation is entirely voluntary, participants may choose to withdraw from the trial at any time 
without penalty or loss of benefits to which they would otherwise be entitled. Although not obliged 
to give a reason for withdrawal, a reasonable effort should be made to establish and document this in 
the withdrawal eCRF, whilst fully respecting the participants rights.  
Should a participant withdraw from the study, a withdrawal eCRF documenting the reason for 
withdrawal ;if providedͿ will be completed, in addition to the procedures and eCRF for the final visit 
;ϲ monthͿ 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 ;annualͿ 
clinical followͲup.  
Participants who withdraw prior to ATIMP administration will be regarded as offͲprotocol 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 ATIMP administration will be strongly encouraged to 
have followͲup investigations with their consent, so that the consequences of ATIMP administration 
can be documented and the data analysed. The CMT may choose to replace a participant who 
withdraws after ATIMP administration.  
ͻǤͺǤͿǤ͸ Tial Sig Rle 
The Chief Investigator and Sponsor retain the right to terminate the study. Specific circumstances that 
may precipitate such termination are as follows: 
ϭ. 
Unanticipated severe adverse event in this or other studies indicating a potential health 
hazard caused by the ATIMP 
Ϯ. 
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 study 
ϯ. 
Death of a participant at any time point after ATIMP administration that is possibly, probably, 
or definitely related to the ATIMP 
ϰ. 
The occurrence of a nonͲocular malignancy at any point after gene transfer that is possibly, 
probably, or definitely related to the ATIMP 
ͷǤͷ 
Oce 
ͷǤͷǤͳ 
Pia Oce 
The primary outcome is defined as any of the below occurring during the ϲ weeks following 
administration, at least possibly related to the ATIMP, not surgery alone: 
x 
Reduction in visual acuity by ϭϱ ETDRS letters or more that fails to resolve to within ϭϱ letters 
of baseline in a ϰͲweek period once prophylactic treatment commences 
x 
Severe unresponsive inflammation  
x 
Infective endophthalmitis 
x 
Ocular malignancy 
x 
Grade III or above nonͲocular SUSAR ;see section ϱ.ϭϭ.ϯͿ 
 

 
 
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ͷǤͷǤʹ 
Secda Oce 
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.  
x 
Any improvements in visual function from baseline that are greater than the baseline variation 
and are sustained for at least two consecutive assessments.  
x 
Any improvement in retinal function from pre ʹ intervention that is greater than the baseline 
variation and measurable by electrophysiology ;pattern ERG or fullͲfield ERGͿ. Quality of life 
will be measured by the Impact of Visual Impairment ;IVIͿ questionnaire and the EQϱDͲϱL and 
EQϱDͲY, or equivalent as appropriate.  

 
 
 
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ͷǤ͸ 
Tia Aee 
Table Ϯ: Trial assessments 
 
Screening
Baselineϭ,  
ATIMP 
admin 
Dϭ  
Dϯ 
Wϭ 
WϮ 
Wϰ 
Wϲ 
WϭϮ 
WϮϰ 
Flexibility of schedule ;н daysͿ 
Ͳ ϵ months
Day Ϭ 
н 
ϬD 
н 
ϭD 
н 
ϮD 
н 
ϰD 
н 
ϳD 
н 
ϳD 
н 
ϭϰD 
н ϭϰD
Visit number 
ϭ 
Ϯ 
ϯ 
ϰ 
ϱ 
ϲ 
ϳ 
ϴ 
ϵ 
ϭϬ 
ϭϭ 
ϭϮ 
ϭϯ 
Informed consent
•
Physical exam
•
Medical history
•
Eligibility determination
•
ATIMP administration
 
★
Adverse event review 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant medication review 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Genetic screeningϮ
• 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
Vital signsϯ 
• 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Haematologyϰ
 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Biochemistryͬglucoseͬliver and renal functionϱ
 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Serology 
 
• 
 
 
 
 
 
 
 
• 
 
• 
• 
PCR 
 
 
 
 
 
• 
 
 
 
• 
 
 
 
QoL questionnaires ;IVI and EQϱDͲϱL, or 
equivalentͿ 
 
• 
 
 
 
 
 
 
 
 
 
 
• 
Visual acuityϲ
•
•
•
•
•
•
•
•
•
•
•
•
Colour vision assessments 
 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Contrast sensitivity 
 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Reading assessments 
 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Static perimetry
 
•
•
•
•
•
Full Field Stimulus Testing
 
•
•
•
•
•
Ocular examination 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 

 
 
 
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Screening
Baselineϭ,  
ATIMP 
admin 
Dϭ  
Dϯ 
Wϭ 
WϮ 
Wϰ 
Wϲ 
WϭϮ 
WϮϰ 
Flexibility of schedule ;н daysͿ
Ͳ ϵ months
Day Ϭ
н
ϬD 
н
ϭD 
н
ϮD 
н
ϰD 
н
ϳD 
н
ϳD 
н
ϭϰD 
н ϭϰD
Fundus photography 
 
• 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Optical coherence tomography 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
Adaptive optics imaging 
 
• 
• 
 
 
 
 
 
 
 
 
 
• 
Fundus autofluorescence 
 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Pattern Electroretinography,ϳ 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Full field Electroretinographyϳ 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Photoaversionͬ light sensitivity assessments 
;test and questionnairesͿ 
 
•ϴ
•ϴ
•ϴ
 
 
 
 
 
 
 
•ϵ
•ϵ
ϭ Baseline assessments may be performed on the same day where considered logistically and clinically appropriate 
Ϯ If result is available from prior testing, no repeat test mandated. Result will be reported into the CRF. 
3 Measurements for vital signs include: blood pressure, pulse, respiration rate, arterial oxygen saturation, temperature, height and weight 
ϰ Hematology to include the following parameters: Haemoglobin, Haematocrit, Erythrocytes, Mean Corpuscular Volume, Mean Corpuscular Haemoglobin, Platelet, 
Leukocytes, Absolute Neutrophils, Absolute Lymphocytes, Absolute Neutrophils, Absolute Eosinophils, Absolute Basophils 
ϱ Biochemistry to include the following parameters: Sodium, Potassium, Chloride, Bilirubin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine, Aminotransferase, 
Lactate Dehydrogenase, Gamma Glutamyl Transferase, Total Protein, Albumin, Calcium, Magnesium, Phosphate, UreaͬBUN, Urate, Creatinine, Glucose 
ϲ Visual acuity at day ϭ and ϯ will be assessed using the previous refraction. 
ϳ ERG assessments may be performed under general anaesthesia if necessary. 
ϴ Photoaversion Questionnaire only to be completed at one baseline visit, “Photoaversion Device Questionnaire ʹ Baseline” to be completed after every PA assessment 
ϵ “Photoaversion Device Questionnaire ʹ after Surgery” to be used at week ϭϮ and week Ϯϰ straight after Photoaversion assessments. 
For management of visits delayed due to COVID_1ϵ refer to appendix. 

 
 
 
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ͷǤ͸Ǥͳ 
Ea Sig f FǦ 
If a participant chooses to discontinue their trial treatment, they should continue to be followed up 
as closely as possible to the followͲup 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, and the participant withdrawn entirely from the trial. MeiraGTx UK II Ltd. 
should be informed of the withdrawal. Data already collected will be kept and included in analyses 
according to the intentionͲtoͲtreat principle for all participants who stop follow up early.  
Participants who stop trial followͲup early may be replaced. 
ͷǤ͸Ǥʹ 
L  FǦ 
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.  
ͷǤ͸Ǥ͵ 
Tia Ce 
The end of the entire trial is considered the last followͲup visit of the last participant. For each 
participant, the trial will terminate at the last scheduled visit ϲ months following ATIMP 
administration. The MHRA and FDA will be notified of the end of the trial within ϵϬ days of its 
completion. 
ͷǤ͸ǤͶ 
 Lg Te FǦU Afe he Ed f he Tia 
At the end of this trial, participants will be invited to enrol in a followͲup study to determine the longerͲ
term safety and efficacy up to ϲϬ months’ post treatment administration. 
ͷǤ͹ 
Sae Sie 
This is a Phase IͬII dose escalation 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 ϭϴ 
participants, as described in section ϰ.ϯ.Ϯ.Ϯ. The limited number of participants is necessitated by the 
rare nature of the disease under investigation. The information obtained in this dose escalation study 
will help inform the design of a future Phase ll interventional study.   
 
ͷǤͺ 
Recie ad Reei 
ͷǤͺǤͳ 
Recie 
Most participants will be recruited through Moorfields Eye Hospital, UK, or the Kellogg Eye Centre, US, 
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 ϭϴ participants in this dose escalation study.  
ͷǤͺǤʹ 
Reei 
Participants will be supported to remain in followͲup by regular contact as per the protocol, provision 
of a ϮϰͲhour hotline to a member of the trial team. 

 
 
 
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ͷǤͻ 
Aige f Ieei 
ͷǤͻǤͳ 
Acai 
All participants will receive the same intervention in this open label, nonͲrandomised trial: subretinal 
administration of AAVϴͲhGϭ.ϳp.coCNGAϯ to one eye. The dose received by each participant will 
depend on the timeͬorder of their enrolment in the trial according to the sequence of dose escalation, 
and the extent of dose limiting events ;see sections ϰ.ϯ.Ϯ and ϱ.ϰ.ϰ for dose escalation informationͿ.  
ͷǤͳͲ Daa Ceciǡ Maagee ad Aai 
ͷǤͳͲǤͳ Daa ceciǡ aagee ad e 
Syne qua non will be responsible for data management activities for the study. 
Data will be captured in a fully validated, Ϯϭ CFR Part ϭϭ compliant Electronic Data Capture ;EDCͿ 
system. 
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 
studyͲspecific data capture tools as neededͿ 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. Data Management will run further automated 
validation checks and review the data, raising further data queries to the sites for resolution of any 
inconsistencies. 
The Investigator will review the eCRFs for completeness and accuracy then electronically approve the 
data, retaining full responsibility for its accuracy and authenticity. 
Medical history and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
;MedDRAͿ terminology.  Prior and concomitant medication will be coded using the World Health 
Organization Drug ;WHOͿͲDrug Dictionary which employs the Anatomical Therapeutic Chemical ;ATCͿ 
classification system.    
Further coding details and data management processes will be described in a Data Management Plan 
;DMPͿ.   
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. 

 
 
 
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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. 
ͷǤͳͲǤʹ NǦAdheece ad NǦReei 
Participants who withdraw from the trial after the intervention will be encouraged to participate in 
any of the planned followͲup 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 ;ϲ monthͿ assessments with the participant’s 
consent. 
ͷǤͳͲǤ͵ Saiica Mehd 
ͻǤͷͶǤ͹Ǥͷ 
Saiical Aali Pla 
A formal Statistical Analysis Plan ;SAPͿ will be approved by the sponsor. This trial is an open label, no 
crossover, phase IͬII trial involving a small number of participants, and analysis of the primary and 
secondary outcomes will be descriptive in nature. 
ͻǤͷͶǤ͹Ǥ͸ 
Saiical Mehd Ȃ Pia Oce Aali 
The primary outcome is safety of subretinal administration of the ATIMP defined as any of the below 
occurring during the ϲ weeks following administration, at least possibly related to the ATIMP, not 
surgery alone: 
x 
Reduction in visual acuity by ϭϱ ETDRS letters or more that fails to resolve to within ϭϱ letters 
of baseline in a ϰͲweek period once prophylactic treatment commences 
x 
Severe unresponsive inflammation  
x 
Infective endophthalmitis 
x 
Ocular malignancy 
x 
Grade III or above nonͲocular SUSAR ;see section ϱ.ϭϭ.ϯͿ 
The number of DLEs at each dose level will be summarised by cohort and overall. 
It is anticipated that the ATIMP will be administered at the MTD in up to ϭϴ participants. Safety data 
relating to these participants will allow estimation of an upper bound for the true event rate through 
a ϵϱй confidence interval. 
ͻǤͷͶǤ͹Ǥ͹ 
Saiical Mehd Ȃ Secda Oce Aali 
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;sͿ who developed the assessment. Final data will be reported descriptively. 
Efficacy will be indicated by: 
ϭͿ 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. 

 
 
 
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ϮͿ Any improvement in retinal function from pre ʹ intervention assessment that is greater than 
baseline variation and measurable by electrophysiology ;pattern ERG or fullͲfield ERGͿ. 
Measures will be reported individually and aggregated across participants as the proportion who 
satisfy the above criteria.  
Quality of life patient reported outcome measures will be used to correlate a participant’s feeling 
about their own wellbeing with clinical observations. 
ͻǤͷͶǤ͹Ǥͺ 
Saiical Mehd Ȃ Healh Ecic Aali 
No health economic evaluation is planned, but the collection of EQϱD would allow Quality Adjusted 
Life Years ;QALYsͿ to be calculated.  
ͷǤͳͳ Daa Miig 
ͷǤͳͳǤͳ  Safe Daa Miig Ciee 
To ensure the safety and efficacy and overall trial conduct, an SDMC will be established and take part 
in the data monitoring. The SDMC will consist of an independent consultant in pharmaceutical 
medicine who will be supported by the medical monitor, principal investigator and medical retina 
expert, and other independent uveitis or medical experts as required. The SDMC will make 
recommendations on the safety data prior to any dose changes.  
Further details of the roles and responsibilities of the SDMC, including membership, decision making 
processes ;and description of stopping rules andͬor guidelines where applicableͿ are described in 
detail in the CNGAϯ Gene Therapy Trial for Achromatopsia SDMC Charter. 
ͷǤͳͳǤʹ Iei Aae 
No formal interim analysis is planned within the trial, but periodic reports concerning participant 
safety and key efficacy outcomes will be prepared for the SDMC as agreed in the SDMC charter.    
ͷǤͳͳǤ͵ Daa Miig f Ha 
ͻǤͷͷǤ͹Ǥͷ 
Safe eig 
Pharmacovigilance services will be delegated to an appropriately qualified and evaluated service 
provider.  
Definitions of harm of the EU Directive ϮϬϬϭͬϮϬͬEC Article Ϯ based on the principles of ICH GCP apply 
to this trial.  

 
 
 
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Table ϯ: Adverse Event Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical trial participant 
administered a medicinal product and which does not 
necessarily have a causal relationship with this product. 
Adverse Reaction (AR)
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered 
This inclƵdes medication errors͕ Ƶses oƵtside of protocol 
;inclƵding misƵse and abƵse of prodƵctͿ 
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 ;SPCͿ for an authorised 
product. 
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR) 
Any AE or AR that at any dose: 
x 
results in death  
x 
is life threateningΎ  
x 
requires 
hospitalisation 
or 
prolongs 
existing 
hospitalisationΎΎ 
x 
results in persistent or significant disability or incapacity
x 
is a congenital anomaly or birth defect 
x 
or is another important medical conditionΎΎΎ 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
Ύ 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 infarctionͿ 
ΎΎ Hospitalisation is defined as an inͲpatient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisation for preͲ
existing conditions ;including elective procedures that have not worsenedͿ do not constitute an SAE
ΎΎΎ 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 dependencyͿ. 
 
Adverse events include: 
x 
an exacerbation of a preͲexisting illness 
x 
an increase in the frequency or intensity of a preͲexisting episodic event or condition 
x 
a condition ;regardless of whether PRESENT prior to the start of the trialͿ that is DETECTED 
after trial drug administration. ;This does not include preͲexisting conditions recorded as such 
at baseline ʹ as they are not detected after trial drug administration.Ϳ 
x 
continuous persistent disease or a symptom present at baseline that worsens following ATIMP 
administration 
 

 
 
 
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Adverse events do NOT include: 
x 
Medical or surgical procedures: the condition that leads to the procedure is the adverse event 
x 
PreͲexisting disease or a condition present before ATIMP administration that does not worsen 
x 
Hospitalisation where no untoward or unintended response has occurred e.g. elective 
cosmetic surgery 
x 
Overdose of medication without signs or symptoms 
 
ͻǤͷͷǤ͹Ǥ͸ 
Ohe Nifiable Adee Ee 
In order to manage the safety risks associated with administration of the ATIMP, all safety events will 
be reviewed within a short time frame for all participants, as described in the CNGAϯ Gene Therapy 
Trial for Achromatopsia Data Management Plan.  
Pregnancy is the only additional notifiable event that requires expedited reporting. 
ͻǤͷͷǤ͹Ǥ͹ 
Pcede  fll i he ee f feale aicia becig ega 
A pregnancy test will be conducted for all females of childbearing age who are sexually active, and the 
results will be recorded in the medical notes before enrolling a volunteer to the trial. Females with a 
positive pregnancy test at this point will be excluded from the trial.  
Where appropriate, a further pregnancy test will be performed on the day of administration of the 
ATIMP. Female participants with a positive pregnancy test at this point will be excluded from the trial 
prior to administration of the ATIMP.  
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that a participant might become pregnant after administration of the ATIMP. In the unlikely event that 
a participant is found to be pregnant we will notify their GP that she is participating in a gene therapy 
trial and that, although the risks involved are minimal, there is a chance of gene transfer to the unborn 
child. With the participant’s consent, we will ask the GPͬobstetrician to provide us with regular reports 
about the pregnancy until delivery. The pregnancy will be reported to the pharmacovigilance service 
provider on a pregnancy report form within Ϯϰ hours of the investigator becoming aware of the event. 
The participant will continue to be assessed until outcome of the pregnancy. However, if the 
participant is unable or unwilling to participate further in the trial, she will be encouraged to continue 
clinical monitoring visits to assess ocular health. In this situation, we may choose to enrol another 
participant to ensure the scientific validity of the trial. 
ͻǤͷͷǤ͹Ǥͺ 
Pcede  fll i he ee f he ae f ale aicia 
becig ega 
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that the partner of a participant might become pregnant after administration of the ATIMP. In the 
unlikely event that this occurs we will notify the participant’s GP that he is participating in a gene 
therapy trial and that, although the risks involved are minimal, there is a chance of gene transfer to 
the unborn child. With the participant’s consent, we will request the partner to contact us to ascertain 
the status of the pregnancy and the outcome. The pregnancy will be reported to PV Service Provider 
on a pregnancy report form within Ϯϰ hours of the investigator becoming aware of the event. 

 
 
 
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ͻǤͷͷǤ͹Ǥͻ 
Ieiga eibiliie elaig  afe eig 
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. The investigator may consult the study medical monitor for advice, but 
they will assume overall responsibility for the evaluation, assignment of clinical significance and 
reporting of adverse events.  All nonͲserious AEs and ARs, whether expected or not, should be 
recorded in the participant’s medical notes, including all events observed following ATIMP 
administration, and in the eCRF. These should be entered on to the database according to the 
timelines defined in the CNGAϯ Gene Therapy trial for Achromatopsia Data Management Plan to allow 
appropriate monitoring by the CMT. SAEs and SARs should be notified to PV Service Provider 
immediately the investigator becomes aware of the event ;in no circumstance should this notification 
take longer than Ϯϰ hoursͿ.  
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 the eCRF. 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 ϱ.ϲ.ϯ for definitionͿ, or until pregnancy outcome in the case of pregnancy. All SAEs will be 
recorded, fully investigated and appropriately managed until resolution or stabilisation and CI sign off.  
ͷǤͳͳǤ͵ǤͷǤͳ 
Seriosness assessment  
When an AE or AR occurs, the investigator responsible for the care of the participant must first assess 
whether or not the event is serious using the definition given in Table ϯ. If the event is classified as 
‘serious’ an SAE form must be completed and emailed to PV Service Provider ;or delegated bodyͿ 
notified within Ϯϰ hours of the investigator becoming aware of the event. 
ͷǤͳͳǤ͵ǤͷǤʹ 
Seerit or grading of Aderse Eents 
The severity of all AEs andͬor ARs ;serious and nonͲseriousͿ in this trial should be graded using the 
toxicity grading in NIH CTCAE Version ϱ.Ϭ ;NIH, ϮϬϭϴͿ. 
Table ϰ: Grading of Adverse Events 
Category
Definition
Mild (Grade I)
 
 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate (Grade II) 
Minimal, local or nonͲinvasive intervention indicated; limiting 
age appropriate instrumental ADLΎ 
Severe (Grade III) 
Severe or medically significant but not immediately life 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting selfͲcare ADLΎΎ 
Grade IV 
Life threatening consequences; urgent intervention indicated 
Grade V 
Death related to AE 
Ύ Instrumental ADL ;Activities of Daily LivingͿ refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc 

 
 
 
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ΎΎSelfͲcare ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
ͷǤͳͳǤ͵ǤͷǤ͵ 
Casalit 
Causality will be assessed in terms of both the ATIMP and the surgical procedures. Based on all 
available information at the time of completion of the case report form, the investigator must assess 
the causality of all serious events or reactions. It is of importance in this trial to capture and 
differentiate events related to: 
x 
The ATIMP administration surgery 
x 
The ATIMP 
The differentiated causality assessments will be captured in the trial specific CRF and SAE form. If the 
event is related to the ATIMP, definitions in Table ϱ will be used to capture the information. Any event 
that is only related to the ATIMP administration surgery will be classified as an Adverse Event. The 
study medical monitor is available Ϯϰͬϳ to provide any advice as required 
Table ϱ: Causality definitions 
Relationship 
Description 
Event Type 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely to be related 
There is little evidence to suggest that there is a causal 
relationship ;e.g., the event did not occur within a reasonable 
time after administration of the trial medicationͿ. There is 
another reasonable explanation for the event ;e.g., the 
participant’s clinical condition or other concomitant treatmentͿ 
Unrelated SAE 
Possibly related
There is some evidence to suggest a causal relationship ;e.g., 
because the event occurs within a reasonable time after 
administration of the trial medicationͿ. However, the influence 
of other factors may have contributed to the event ;e.g., the 
participant’s clinical condition or other concomitant treatmentͿ  
SAR
Probably related 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely 
SAR 
Definitely related 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
SAR 
 
ͷǤͳͳǤ͵ǤͷǤͶ 
Epectedness 
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 SARͿ will be deemed a SUSAR ;suspected, unexpected, serious adverse reactionͿ and 
MHRA, RECͬIBC, FDA, and NIH reporting guidelines apply ;see Notifications sections of the protocolͿ. 
 
 
 

 
 
 
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Table ϲ: 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 BrochureΎ or clearly defined in 
the protocol. 
ΎThis includes listed events that are more frequently reported or more severe than previously 
reported 
The reference document to be used to assess expectedness against ATIMP and surgery is the 
Investigator Brochure. ProcedureͲrelated adverse events cannot be considered expected to the 
ATIMP. Previous experience with AAVͲmediated gene therapy in the retina indicates that the risks are 
largely limited to the eye. A temporary andͬor mild decrease in visual acuity, due to detachment of 
the retina or postͲsurgical inflammation, is to be expected after intraocular surgery and is not 
expected to cause undue discomfort. Therefore, we have defined the success criteria for the primary 
outcome ;safetyͿ as the absence of an adverse event that has a substantial and sustained negative 
impact on vision, as well as the absence of any nonͲocular SUSAR. 
Expected events associated with surgery: 
x 
Temporary andͬor mild decrease in visual acuity ;to hand movements or better for a period 
of up to ϴ weeksͿ, due to detachment of the retina or postͲsurgical inflammation 
x 
Ocular discomfort 
x 
Epiphora 
x 
Periocular swelling 
x 
Diplopia 
x 
Ptosis 
x 
Subconjunctival or intraocular haemorrhage 
x 
Corneal abrasion 
x 
Retinal tear or detachment 
x 
Wound leak 
x 
Ocular hypotony or raised intraocular pressure 
x 
Overfill or underfill of any intraocular gas tamponade 
x 
Mild intraͲ or extraͲocular inflammation 
x 
Scleral or conjunctival suture granuloma 
x 
Lens opacity or dislocation 
x 
Systemic adverse events related to sedation or general anaesthesia, including nerve or 
vascular injury  
 

 
 
 
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ͻǤͷͷǤ͹Ǥͼ 
Nificai 
 
ͷǤͳͳǤ͵Ǥ͸Ǥͳ 
Notifications b the Inestigator to Pharmacoigilance 
All adverse events will be recorded in the hospital notes and the eCRF from the date of written 
informed consent until last study visit.   
Investigators should notify PV service provider of any SAEs and SARs occurring during this period.   
After the 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.  
PV service provider must be notified of all SAEs and SARs within Ϯϰ hours of the investigator becoming 
aware of the event. The investigator will respond to any SAE queries raised by PV service provider as 
soon as possible. 
The SAE form must be completed by the investigator ;the consultant named on the delegation of 
responsibilities list who is responsible for the participant’s careͿ 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 necessary, sign and then email to PV service provider. 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:Ͳ 
x 
the trial number 
x 
Participant number 
x 
date of birth 
x 
name of reporting investigator, and  
x 
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. 
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. FollowͲup should continue 
after completion of trial followͲup ;i.e. ϲ months after delivery of ATIMPͿ if necessary. FollowͲup SAE 
forms ;clearly marked as followͲupͿ should be completed and emailed to PV service provider as further 
information becomes available. Additional information andͬor copies of test results etc may be 
provided separately. The participant must be identified by trial number, participant number and date 
of birth only. The participant’s name should not be used on any correspondence and should be blacked 
out and replaced with trial identifiers on any test results if it is displayed. Such instances must also be 
reported as per appropriate SOP. 
ͷǤͳͳǤ͵Ǥ͸Ǥʹ  
Reporting Urgent Safet Measres 
MeiraGTx UK II Ltd. or investigator may take appropriate urgent safety measures in order to protect 
research participants against any immediate hazard to their health or safety. 

 
 
 
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If any urgent safety measures are taken the CIͬPIͬ MeiraGTx UK II Ltd. shall immediately ;no later than 
ϯ days from the date the measures are takenͿ, give written notice as per local reporting requirements 
of the measures taken and the circumstances giving rise to those measures, according to the relevant 
SOP. 
ͷǤͳͳǤ͵Ǥ͸Ǥ͵ 
PV Serice Proider responsibilities 
PV service provider will follow PV service provider Standard Operating Procedures and a study specific 
Safety Management Plan to ensure that case processing of events occurs within appropriate 
regulatory timeframes. PV service provider will submit Development Safety Update Reports ;DSURsͿ 
to regulatory authorities. 
ͷǤͳͳǤ͵Ǥ͸ǤͶ  
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. 
ͷǤͳͳǤ͵Ǥ͸Ǥͷ 
Annal Progress Reports 
An annual progress report ;APRͿ will be submitted to the REC within ϯϬ 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.  
ͷǤͳͳǤͶ Qai Aace ad C 
ͻǤͷͷǤͺǤͷ 
Rik Aee 
The Quality Assurance ;QAͿ and Quality Control ;QCͿ considerations for the CNGAϯ Gene Therapy trial 
for Achromatopsia are based on MeiraGTx UK II Ltd. Quality Management Policy that includes a formal 
Risk Assessment, and that acknowledges the risks associated with the conduct of the trial and 
proposals of how to mitigate them through appropriate QA and QC processes. Risks are defined in 
terms of their impact on: the rights and safety of participants; project concept including trial design, 
reliability of results and institutional risk; project management; and other considerations. 
ͻǤͷͷǤͺǤ͸  
Cliical Miig 
The frequency, type and intensity of routine and triggered onͲsite monitoring will be detailed in the 
trial Monitoring Plan ;MPͿ. The MP will also detail the procedures for review and signͲoff 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. 
ͻǤͷͷǤͺǤ͹ 
Diec acce  aicia ecd 
Participating investigators must agree to allow trial related monitoring, including audits, 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. 
ͻǤͷͷǤͺǤͺ 
Tial Oeigh 
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of 
processes and prompting corrective action where necessary. The processes reviewed relate to 
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial 
interventions and policies to protect participants, including reporting of harms; completeness, 

 
 
 
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accuracy and timeliness of data collection; and will verify adherence to applicable policies detailed in 
the Compliance section of the protocol.  
In multiͲcentre 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. 
ͷǤͳͳǤͶǤͶǤͳ 
Clinical Management Team 
A Clinical Management Team ;CMTͿ will be set up to assist with developing the design, coͲordination 
and strategic management of the trial. The membership, frequency of meetings, activity ;including 
study conduct and data reviewͿ and authority will be covered in a CMT terms of reference. 
ͷǤͳͳǤͶǤͶǤʹ 
Safet Data Monitoring Committee 
The Safety Data Monitoring Committee ;SDMCͿ is responsible for safeguarding the interests of trial 
participants, monitoring the accumulating data and making recommendations to on whether the trial 
should continue as planned. The membership, frequency of meetings, activity ;including review of trial 
conduct and dataͿ and authority will be covered in the SDMC charter.  
͸ 
Ehic ad Dieiai 
͸Ǥͳ 
Reeach Ehic Aa 
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 
;HRAͿ 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 followͲup without giving a reason 
and without prejudicing their further treatment. 
͸Ǥʹ 
Rega Ahi Aa 
This protocol will be submitted to the national competent or equivalent authority ;i.e. MHRA in the 
UK and Food and Drug Administration ;FDAͿ in the USͿ. 
This is a Clinical Trial of an Investigational Medicinal Product ;IMPͿ as defined by the EU Directive 
ϮϬϬϭͬϮϬͬEC. Therefore, a Clinical Trial Application is required in the UK.  
This is a Clinical Trial of an Investigational New Drug as defined by ϮϭCFR Part ϯϭϮ of the Code of 
Federal Regulations. Therefore, an Investigational New Drug Application ;INDͿ is required in the US.  
This trial is a human gene transfer study and therefore in the US must be reviewed by the initial siteΖs 
Institutional Biosafety Committee and possibly by the Recombinant DNA Advisory Committee ;RACͿ 
of the NIHΖs Office of Biotechnology Activities ;OBAͿ. 

 
 
 
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The progress of the trial, safety issues and reports, including expedited reporting of SUSARs, will be 
reported to the Competent Authority, regulatory agency or equivalent in accordance with relevant 
national and local requirements and practices.  
͸Ǥ͵ 
 Ohe aa 
The protocol will be submitted by those delegated to do so to the local departments of each 
participating sites. A copy of the local approval letter ;or other relevant approval as aboveͿ and of the 
Participant Information Sheet ;PISͿ 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 ;FWAͿ. 
For ATIMP trials using Genetically Modified Organisms, organisations should also receive approval 
from their relevant national body to use the product ;i.e. notification to the HSE in the UKͿ. 
͸ǤͶ 
Pc Aede 
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 RECͬIRBs for approval, as well as any additional competent authorities in each country that 
require notification ;e.g. the NIH OBAͿ.  
͸Ǥͷ 
Ce  Ae 
The parents of potential participants will be provided with a Participant Information Sheet ;PISͿ 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 parent is 
willing for their child to participate, written informed consent will be obtained.  During the consent 
process it will be made completely and unambiguously clear that the 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 the treatment of their child. 
 
Children who are unable to consent for themselves will not be enrolled in the trial without the consent 
of their parent;sͿ or legal guardian;sͿ. Children or adolescents ;aged ϭϭͲϭϱͿ 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 children 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. If a 
child becomes an adult during their participation in the trial, the child will be reconsented as an adult 
at the time of their next scheduled visit. 
 
Consent will be reͲsought 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 

 
 
 
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participant legally authorised representative will be asked to sign an updated consent form and assent 
will be sought as appropriate. These will be approved by the appropriate ethics committee prior to 
their use. Consent will also be reͲsought in the event that a child’s carer changes and when the child 
reaches the age of ϭϲ.  
A copy of the approved consent and assent form are available from the MeiraGTx UK II Ltd. trial team.  
͸Ǥ͸ 
Cfideiai 
All data will be handled in accordance with the General Data Protection Regulation ϮϬϭϲͬϲϳϵ andͬor 
the Health Insurance Portability and Accountability Act of ϭϵϵϲ ;HIPAAͿ. 
These regulations require a signed participant authorization informing the participants of the 
following:  
ͻ 
What protected health information ;PHIͿ will be collected from participants in this trial 
ͻ 
Who will have access to that information and why 
ͻ 
Who will use or disclose that information 
ͻ 
The rights of a research participant to revoke their authorization for use of their PHI.  
x 
Where data will be heldͬstored 
x 
Rights that do not apply for research 
x 
How and why data is being used 
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 aliveͿ at the end 
of their scheduled trial period. 
Participant confidentiality will be held strictly in trust by the investigators, trial staff, and the sponsor 
and their agents, to the extent provided by Federal, state, and local law.  This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to any trial information 
relating to participants. All laboratory specimens, evaluation forms, reports, and other records that 
leave the site will be identified only by a coded number in order to maintain 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 trialͲrelated monitoring, audits, RECͬIRB review, and regulatory 
inspections by 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 hospitalͿ 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. 

 
 
 
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The Case Report Forms ;eCRFsͿ will not bear the participant’s name or other personal identifiable data. 
The participant’s date of birth and trial identificationͬparticipant number will be used for 
identification. 
For other information regarding Data Management please see Section ϱ.ϭϬ.Ϯ.  
͸Ǥ͹ 
Decaai f Iee 
The trial is funded by MeiraGTx UK II Ltd. 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt of 
payment from MeiraGTx UK II Ltd. for consultancy services. 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt 
of payment from MeiraGTx UK II Ltd. for consultancy services. 
͸Ǥͺ 
Idei 
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 does not affect the participant’s right to seek compensation via the nonͲnegligence 
route.  
 
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of MeiraGTx UK II Ltd. or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in 
the first instance to the Chief Investigator, who will pass the claim to MeiraGTx UK II Ltd‘s. insurers. 
 
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. 
͸Ǥͻ 
Fiace 
The trial is fully funded by MeiraGTx UK II Ltd. It is not expected that any further external funding will 
be sought. 
͸ǤͳͲ Achiig 
͸ǤͳͲǤͳ Achiig f Eeia Tia Dceai  
Requirements for a traceability system and document archiving will be met in line with Regulation 
ϭϯϵϰͬϮϬϬϳ on Advanced 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;sͿͬinstitution;sͿ where the ATIMP is usedͿ will ensure that the information relating to the 
traceability and accountability, from the production of ATIMPs to the recipient ;participantͿ receiving 
the ATIMPs, are archived for a minimum of ϯϬ 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 documentsͬtraceability data will be retained by the investigator and institution 
responsible for the human application of the ATIMP:  
x 
Shipping Records for the ATIMP  
x 
Certificate of Analysis of the ATIMP 
x 
Participant identification code list 
x 
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 ϯϬ 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: 
x 
Identification of the investigatorͬinstitution  
x 
Identification of the sponsor  
x 
Identification of the manufacturing site  
x 
Product nameͬcode  
x 
Pharmaceutical form, route of administration, quantity of dosage units and strength  
x 
Batch number  
x 
Trial reference code  
x 
Trial participant code  
x 
Participant identification code list ;links name of recipient to the trial participant codeͿ  
x 
Product expiryͬretest date  
x 
Date of administration  
x 
Participant medical record should also contain the product nameͬcode, the trial reference 
code, trial participant code and administration dates and doses  
x 
Records of any product that was unused or destroyed at site and its final status 
 
͸Ǥͳͳ Acce  Daa 
The investigatorsͬ institutions will permit trialͲrelated monitoring, audits, REC review, and regulatory 
inspections, providing direct access to source dataͬdocuments. 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.  
͸Ǥͳʹ Acia ad PǦia Cae 
Participants will be invited to participate in a followͲup study after completion of this trial. 
͸Ǥͳ͵ Pbicai Pic 
͸Ǥͳ͵Ǥͳ Tia Re 
All proposed scientific publications will be discussed with and approved by the MeiraGTx UK II Ltd. 
prior to publication. Since this is an exploratory, openͲlabel, Phase IͬII trial, progress and significant 
findings may be presented at scientific forumsͬmeetings andͬor published during the course of the 
trial. Where the presenter is not a MeiraGTx UK II Ltd. Representative, permission must be sought 
from MeiraGTx UK II Ltd. 
The results of the trial will be disseminated regardless of the direction of effect. 

 
 
 
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͹ 
Acia Sdie 
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. 
 
ͺ  
Aediǣ Gidace  Sd Cdc dig he COVIDǦͳͻ 
Padeic 
This Appendix is intended for all ongoing studies at sites worldwide impacted by COVIDͲϭϵ. The 
measures outlined in this Appendix are temporary, while access to sites is restricted. 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 recognised that the Coronavirus Disease ϮϬϭϵ ;COVIDͲϭϵͿ pandemic may have an impact on the 
conduct of this clinical study due to, for example, selfͲisolationͬquarantine by participants and studyͲ
site personnel; travel restrictionsͬlimited 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 wellͲbeing of participants and site staff. If at any time a 
participant’s safety is considered to be at risk, study intervention will be discontinued, and study 
followͲup will be conducted.  
Scheduled visits that cannot be conducted in person at the study site will be performed 
remotelyͬvirtually or delayed until such time that onͲsite visits can be resumed. At each contact, 
participants will be interviewed to collect safety data. Key efficacy endpoint assessments should be 
performed if required and as feasible. Participants will also be questioned regarding general health 
status to fulfil any physical examination requirement.  
If visits should be delayed past the visit window as per the schedule of events every effort should be 
made to see this patient as soon as it is deemed safe to do so whether this is due to the countries’ 
Governing bodies restrictions being uplifted or under the advice of the CI of that site and patient’s 
should not be made to wait until the next protocol visit.  
Every effort should be made to adhere to protocolͲspecified assessments for participants on study 
intervention, including follow up. Modifications to protocolͲrequired assessments may be permitted 
after consultation between the participant and investigator, and with the agreement of the sponsor. 
Missed assessmentsͬvisits will be captured in the eCRF for protocol deviations and should be titled 
‘COVIDͲϭϵ related’. Discontinuations of study interventions and withdrawal from the study should be 
documented with the prefix “COVIDͲϭϵͲrelated” in the case report form ;CRFͿ.  
 
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 auditsͿ will be communicated to the 
sites and health authorities according to local guidance. If a participant has tested positive for COVIDͲ 
ϭϵ, the investigator should contact the sponsor’s responsible medical officer to discuss plans for study 
intervention and followͲup. Modifications made to the study conduct as a result of the COVIDͲϭϵ 
pandemic should be summarised in the clinical study report. 
 
 
 
 
 

 
 
 
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GUIDANCE SPECIFIC TO THIS PROTOCOL 
 
 
Each patient will be risk assessed on a case by case basis by the PI and hisͬher research team to decide 
the appropriate care for the patient.  
 
Item 
no  
Item  
Management of Item  
ϭ 
Missed assessments 
Missed assessments will be captured in the EDC system as a 
deviation with the prefix COVID ϭϵ RELATED. 
Ϯ 
Protocol Deviations  
Any deviations to the study protocol due to COVID ϭϵ 
pandemic will be captured in the EDC system will be entered 
with the prefix COVID ϭϵ RELATED. 
ϯ 
Baseline Assessments  
Baseline assessments for those patients who have had 
surgery postponed due to COVID ϭϵ Ͳ these baseline 
assessments will be valid up to ϵ months except for 
Haematology, Biochemistry and Glucose which will need 
repeating.   
ϰ
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 scheduled visits cannot be conducted within the visit 
window the site can schedule an additional visit at the 
earliest opportunity the patients is able to travel, ensuring 
no visits are completely missed unless authorised by the 
sponsor. 
 
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 nonͲtrial staff conducting assessments 
the contact details for the trial staff so that conversations 
can be had between the trial and nonͲtrial medical staff 
ϲ 
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 ϯ months postͲ
surgery until onͲsite visits are possible.   
Patients undergoing telephone assessment will be asked to 
provide information on any adverse events or other safety 
concerns. 
 
ϳ 
Patients 
selfͲquarantined 
or 
government implemented quarantine. 
If patients andͬor their caregiver 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 

 
 
 
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ongoing AEs, date of last appointment, less than ϯ months 
since interventionͿ. 
ϴ 
Potential lack of reporting of 
symptoms due to delayed visits 
 
Delayed reporting of SAEs, SARs Θ 
SUSARsͲ Potential for events to not be 
reported within Ϯϰ hours of 
occurrence 
Delayed 
Participant 
reporting 
of 
Adverse Events 
All participants are provided with emergency cards on 
enrolment to the study to enable ϮϰͲhour contact with study 
investigators. 
 
All events should be reported by an Investigator ;as assigned 
on the delegation logͿ or another member of the site team, 
in the Investigators absence and where delegated, within Ϯϰ 
hours of the investigatorͬsite being made aware. Sites have 
been advised how to still maintain timelines for reporting if 
impeded by pandemic restrictions.   
 
ϵ
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 ϮϰͬϳͲhour contact number, patients trial code, 
trial number, brief details of the trial intervention and 
EudraCT number.   
ϭϬ 
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.  
ϭϭ 
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. 
ϭϮ 
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. 
ϭϯ
Clinicianͬs 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. 
ϭϰ 
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 reͲopens. 
 
 

 
 
 
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ͻ 
 Pc Aede 
 
Protocol Version and Date
Reason for Amendment 
Protocol vϭ.Ϭ ϭϲNovϮϬϭϴ 
Initial version 
Protocol vϮ.Ϭ ϮϵJanϮϬϭϵ 
Reduction of assessments based on analysis of 
CNGBϯ MGTϬϬϲ data to reduce assessment 
burden on participants and clinical sites and 
addition of optional MRI assessment.  
Protocol vϯ.Ϭ
Update to contraception wording on request of 
MHRA 
Protocol vϰ.Ϭ 
Change of baselineͬscreening window prior to 
surgery from ϲ months to ϵ months. Addition of 
Photoaversion Device Questionnaires. Removal 
of MRI assessment 
Protocol vϱ.Ϭ 
Updated steroid Θ surgical risks, and local 
steroid use detailed. 
Guidance included on the management of 
patients during COVIDͲϭϵ pandemic  
Further details added to exclusion criteria.  
ReͲillustration of dose escalation table ;no 
changes madeͿ 
Protocol vϲ.Ϭ
Removed dose expansion cohort ;as this will 
now take part as a separate Phase ll 
interventional studyͿ 
 
Included details on additional adult cohort 
taking place in the US. 
Corrected inconsistencies 
 
 

 
 
 
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ͳͲ 
Refeece 
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ϮϬϭϲ;ϭϬϬ;ϭͿ:ϭϭϱʹϭϮϭ. 
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