Long-term Follow-up Study of Participants Following an Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/8-hCARp.hCNGB3 and AAV2/8-hG1.7p.coCNGA3) for Gene Therapy of Adults and Children With Achromatopsia Owing to Defects in CNGB3 or CNGA3
Conditions: Achromatopsia
Sponsor: MeiraGTx UK II Ltd

Page 1 of 37
MGT007_Protocol version 6.0 03Dec2021
Long-Term Follow-Up Gene Therapy Study for Achromatopsia CNGB3 and 
CNGA3
Long-term follow-up study of participants following open label, multi-centre, 
Phase I/II dose escalation trials of a recombinant adeno-associated virus vector 
(AAV8-hCARp.hCNGB3 or AAV8-hG1.7p.coCNGA3) for gene therapy of adults 
and children with achromatopsia owing to defects in CNGB3 or CNGA3
Version
6.0
Date
03 Dec 2021
Sponsor
MeiraGTx UK II Ltd.
Sponsor registration #
MGT007
Trial registration
EudraCT 2016-003856-59
Authorisation: Sponsor Representative 
Name
Role
Chief Medical Officer
Signature
Date

	

       
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MGT007_Protocol version 6.0_03Dec2021
Table of Contents
1
Administrative information.............................................................................................................6
1.1
Compliance .............................................................................................................................6
1.2
Sponsor ...................................................................................................................................7
1.3
Study Summary.......................................................................................................................7
1.4
Roles and responsibilities........................................................................................................8
2
Study Diagram.................................................................................................................................9
3
Abbreviations................................................................................................................................10
4
Introduction ..................................................................................................................................12
4.1
Background ...........................................................................................................................12
4.2
Rationale...............................................................................................................................12
4.3
Assessment and Management of Risk..................................................................................13
4.3.1
Risk of germline transmission.......................................................................................13
4.3.2
Risk of investigations performed during assessment and follow up ............................13
4.4
Explanation for Choice of Comparators................................................................................13
4.5
Objectives..............................................................................................................................13
4.5.1 Primary objective.................................................................................................................13
4.5.2 Secondary objective.............................................................................................................13
4.6
Study Design..........................................................................................................................14
5
Methods........................................................................................................................................14
5.1
Site Selection.........................................................................................................................14
5.1.1
Study Setting.................................................................................................................14
5.1.2
Site/Investigator Eligibility Criteria ...............................................................................14
5.1.2.1
Principal Investigator’s (PI) Qualifications and Agreements.....................................15
5.1.2.2
Resourcing at site...................................................................................................... 15
5.2
Site approval and activation .................................................................................................15
5.3
Eligibility Criteria...................................................................................................................15
5.3.1
Participant selection ..................................................................................................... 15
5.3.2
Participant Inclusion Criteria.........................................................................................16
5.3.3
Participant Exclusion Criteria .......................................................................................16
5.3.4
Enrolment into long term follow up study....................................................................16
5.3.5 Informed consent procedure............................................................................................... 16

       
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5.4 Participation................................................................................................................................17
5.4.1
Protocol Defined Clinical Schedule ...............................................................................17
5.4.1.1
Follow Up Assessments.............................................................................................17
5.4.1.1.1 Ocular examination and retinal imaging................................................................18
5.4.1.1.2 Functional and Participant-Related Outcome assessments ..................................18
5.4.1.1.3 Evaluation of immune responses...........................................................................19
5.4.2
Concomitant Care .........................................................................................................19
5.4.3
Protocol Discontinuation ..............................................................................................19
5.4.3.1 Participant withdrawal..................................................................................................19
5.4.3.2
Study Stopping Rules.................................................................................................19
5.5
Outcomes..............................................................................................................................19
5.5.1
Primary Outcomes ........................................................................................................19
5.5.2
Secondary Outcomes....................................................................................................19
5.6
Assessment Schedule............................................................................................................20
5.6.1
Early Stopping of Follow-up..........................................................................................21
5.6.2
Loss to Follow-up ..........................................................................................................21
5.6.3
Study Closure ................................................................................................................21
5.6.4 
Passive/Long Term Follow-Up After the End of the Study ...........................................21
5.7
Sample Size ...........................................................................................................................21
5.8
Recruitment and Retention ..................................................................................................21
5.8.1
Recruitment ..................................................................................................................21
5.8.2
Retention.......................................................................................................................21
5.9
Data Collection, Management and Analysis.........................................................................22
5.9.1
Data, management and entry.......................................................................................22
5.9.2
Non-Adherence and Non-Retention.............................................................................22
5.9.3
Statistical Methods ....................................................................................................... 22
5.9.3.1
Statistical Methods – Primary Outcome Analysis.....................................................23
5.9.3.2
Statistical Methods – Secondary Outcome Analysis.................................................23
5.9.3.3
Statistical Methods – Health Economic Analysis ......................................................23
5.10
Data Monitoring....................................................................................................................23
5.10.1
Independent Data Monitoring Committee...................................................................23
5.10.2
Safety Data Monitoring Committee CNGA3 .................................................................23
5.10.3
Interim Analyses............................................................................................................23
5.10.4
Data Monitoring for Harm ............................................................................................24

       
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MGT007_Protocol version 6.0_03Dec2021
5.10.4.1
Safety reporting ....................................................................................................24
5.10.4.2
Other Notifiable Adverse Events...........................................................................25
5.10.4.3
Procedures to follow in the event of female participants becoming pregnant....25
5.10.4.4
Procedures to follow in the event of the partners of male participants becoming 
pregnant
...............................................................................................................................26
5.10.4.5
Investigator responsibilities relating to safety reporting......................................26
5.10.4.5.1
Seriousness assessment....................................................................................27
5.10.4.5.2
Severity or grading of Adverse Events..............................................................27
5.10.4.5.3
Causality............................................................................................................ 27
5.10.4.5.4
Expectedness ....................................................................................................28
5.10.4.6
Notifications.......................................................................................................... 28
5.10.4.6.1
Notifications by the Investigator to PV.............................................................28
5.10.4.6.2
PV responsibilities.............................................................................................29
5.10.4.6.3 
Reporting SUSARs in International Studies......................................................29
5.10.4.6.4
Annual Progress Reports...................................................................................29
5.10.5
Quality Assurance and Control .....................................................................................29
5.10.5.1
Risk Assessment....................................................................................................29
5.10.5.2
Clinical Monitoring................................................................................................30
5.10.5.2.1
Direct access to participant records .................................................................30
5.10.5.3
Study Oversight.....................................................................................................30
5.10.5.3.1
Clinical Management Team ..............................................................................30
6
Ethics and Dissemination..............................................................................................................31
6.1
Research Ethics Approval......................................................................................................31
6.2
Regulatory Authority Approvals............................................................................................31
6.3
Other Approvals....................................................................................................................31
6.4
Protocol Amendments..........................................................................................................31
6.5
Consent or Assent.................................................................................................................32
6.6
Confidentiality.......................................................................................................................32
6.7
Declaration of Interests ........................................................................................................33
6.8
Indemnity..............................................................................................................................33
6.9
Finance..................................................................................................................................34
6.10
Archiving ...............................................................................................................................34
6.11
Access to Data.......................................................................................................................34
6.12
Ancillary and Post-study Care ............................................................................................... 34

       
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MGT007_Protocol version 6.0_03Dec2021
6.13
Publication Policy..................................................................................................................34
7. Ancillary Studies................................................................................................................................34
8
Protocol Amendments..................................................................................................................35
9
References ....................................................................................................................................36

       
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MGT007_Protocol version 6.0_03Dec2021
1
Administrative information
This document describes the longer-term Achromatopsia (CNGB3 and CNGA3) follow-up study, 
sponsored and co-ordinated by MeiraGTx UK II Ltd. 
It provides information about procedures for entering participants into the study, and provides 
sufficient detail to enable: an understanding of the background, rationale, objectives, study
population, intervention, methods, statistical analyses, ethical considerations, dissemination plans 
and administration of the study; replication of key aspects of study methods and conduct; and 
appraisal of the study’s scientific and ethical rigour from the time of ethics approval through to 
dissemination of the results. The protocol should not be used as an aide-memoire or guide for the 
follow up 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 study. 
MeiraGTx UK II Ltd. supports the commitment that its studies adhere to the SPIRIT guidelines. As such, 
the protocol template is based on an adaptation of the Standard Protocol Items: Recommendations 
for Interventional Trials (SPIRIT) 2012 Statement for protocols of clinical trials (Chan et Al. 2013a). The 
SPIRIT Statement Explanation and Elaboration document (Chan et Al. 2013b) can be referred to, or a 
member of MeiraGTx UK II Ltd. Clinical Operations team can be contacted for further detail about
specific items.
1.1
Compliance
The study will be conducted in compliance with the approved protocol, the Declaration of Helsinki 
(2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 
2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2006/1928
and subsequent amendments, Advanced Therapy Medicinal Products (ATMP) Regulations (EC) No 
1394/2007, the Human Tissue (Quality and Safety for Human Application) Regulations 2007, the UK 
Data Protection Act, and the National Health Service (NHS) Research Governance Framework for 
Health and Social Care (RGF). International sites will comply with the principles of GCP as laid down 
by ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the European Directive 
2001/20/EC (where applicable), and other local and national applicable regulations. The US sites will 
comply with 21 CFR 312 in the Code of Federal Regulations, and the NIH Guidelines for Research 
involving Recombinant or Synthetic Nucleic Acid Molecules (November 2013). Agreements that 
include detailed roles and responsibilities will be in place between participating sites and MeiraGTx
UK II Ltd.
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 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 study, or
x
The scientific value of the study.

       
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MGT007_Protocol version 6.0_03Dec2021
1.2
Sponsor
MeiraGTx UK II Ltd., 92 Britannia Walk, London N1 7NQ is the study sponsor. 
1.3
Study Summary
Primary 
Registry 
and 
study
Identifying Number
EudraCT 2016-003856-59
Secondary Identifying Numbers
MeiraGTx UK II Ltd. registration number: MGT007
Sponsor
MeiraGTx UK II Ltd.
Contact for Public Queries
ocularinfo@meiragtx.com
Contact for Scientific Queries
Professor of Retinal Studies
UCL Institute of Ophthalmology
11-43 Bath Street
London EC1V 9EL
Public Title
Long-Term Follow-Up Study of Gene Therapy for 
Achromatopsia CNGB3 and CNGA3
Scientific Title
Long-term follow-up study of participants following open 
label, multi-centre, Phase I/II dose escalation trials of a 
recombinant 
adeno-associated 
virus 
vector 
(AAV8-
hCARp.hCNGB3 or AAV8-hG1.7p.coCNGA3) for gene therapy 
of adults and children with achromatopsia owing to defects 
in CNGB3 or CNGA3
Countries of Recruitment
United Kingdom, United States of America
Health Condition(s) or Problem(s) 
Studied
Achromatopsia associated with defects in CNGB3 or CNGA3
Key Inclusion and Exclusion Criteria
Inclusion in the study will be limited to individuals who:
1.
Are able to give informed consent or assent, with or 
without the guidance of their parent(s)/guardian(s)
where appropriate
2.
Received 
AAV8-hCARp.hCNGB3
or 
AAV8-
hG1.7p.coCNGA3 by intraocular administration in the 
prior open-label, Phase I/II, dose escalation study
(EudraCT 2016-002290-35 or EudraCT 2018-003431-29)
3.
Are willing to adhere to the protocol and long-term 
follow-up
Individuals will be excluded who: 
Are unwilling or unable to meet with the requirements of the 
study
Study Type
Long-term follow-up study of the safety and efficacy of 
participants following an open label, non-randomised, two-
centre, dose escalation trial in adults and children with 
achromatopsia associated with defects in CNGB3 or CNGA3
Date of First Enrolment
October 2017
Target Sample Size
Up to 72 participants
Primary Outcome(s)
The primary outcome is longer term safety of subretinal 
administration of AAV8-hCARp.hCNGB3 (administered in the 

       
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MGT007_Protocol version 6.0_03Dec2021
CNGB3
clinical 
trial)
and 
AAV8-hG1.7p.coCNGA3
(administered in the CNGA3 clinical trial)
Safety will be assessed for 5 years after the intervention.
Key Secondary Outcomes
The secondary outcomes are measures of the longer-term 
efficacy of the original intervention:
1) Any improvement in visual function from baseline that is 
greater that the test-retest variation for that test and is 
sustained for at least two consecutive assessments.
2) Any improvement in retinal function from baseline that is 
measurable by electrophysiology and is greater than the 
test-retest variation.
3) Quality of life
1.4
Roles and responsibilities
Agreements that include detailed roles and responsibilities will be in place between participating sites 
and MeiraGTx UK II Ltd.

       
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MGT007_Protocol version 6.0_03Dec2021
2
Study Diagram 
At the 3 month follow up visit of the CNGB3 or 
CNGA3 Trial participants will be invited to join 
the longer-term follow-up study
Participant/parent/guardian (and child) 
given participant information sheet &
asked to provide informed 
consent/assent 
Visit 1 (9 months post-administration)
Visit 2 (12 months post-administration)
Visit 3 (18 months post-administration)
Visit 4 (24 months post-administration)
Visit 5 (36 months post-administration)
Visit 6 (48 months post-administration)
Visit 7 (60 months post-administration)
Tests that will be performed in all 
participants are:
x
Ocular examination
x
Colour fundus photography
x
Spectral 
Domain 
Optical 
Coherence Tomography (SD-
OCT)
x
Fundus 
Autofluorescence 
Imaging (FAF)
x
Best corrected visual acuity
x
Full-field 
electroretinography 
(ERG)
x
Pattern 
electroretinography 
(PERG) 
x
Serology tests (AAV8 antibody 
and transgene antibody testing)
x
Light-sensitivity 
testing/Photoaversion testing
x
Contrast sensitivity 
x
Static perimetry
x
Quality of Life
Tests that will be performed in all 
patients unless not possible due to lack 
of 
patient 
co-operation 
or 
equipment/facilities are:
x
Reading assessment
x
Colour vision testing
x
Adaptive optics (AO) imaging
x
Pregnancy test (up to 12 
months)
x
Full Field Stimulus Testing (FST)
Additional investigations may be 
performed for appropriate clinical 
management of any adverse events. 

       
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MGT007_Protocol version 6.0_03Dec2021
3
Abbreviations
AAV
Adeno-Associated Virus
Ad
Adenovirus
ADL
Activities of Daily Living
AE
Adverse Event
AF
Autofluorescence
AO
Adaptive Optics
AR
Adverse Reaction
ATIMP
Advanced Therapy 
Investigational Medicinal 
Product
ATMP
Advanced Therapy 
Medicinal Product
bps
Base pairs
BIOM
Binocular Indirect 
Ophthalmo Microscope
CA
Competent Authority
CCTV
Closed Circuit Television
cDNA
complementary 
Deoxyribonucleic Acid
CEO
Chief Executive Officer
CFR
Code of Federal 
Regulations
CI
Chief Investigator
CMT 
Clinical Management Team
CNGA3
Cyclic Nucleotide-Gated 
cation channel Alpha-3
CNGB3
Cyclic Nucleotide-Gated 
cation channel Beta-3
CRF
Case Report Form
CRO
Contract Research 
Organisation
CTA
Clinical Trial Authorisation
CTIMP
Clinical Trial of 
Investigational Medicinal 
Product
DLE
Dose-limiting event
DNA
Deoxyribonucleic acid
DSUR
Development Safety 
Update Report
ELISA
Enzyme-linked 
Immunosorbent Assay
ELISPOT
Enzyme-linked 
ImmunoSpot Assay
EMA
European Medicines 
Agency
ETDRS
Early Treatment Diabetic 
Retinopathy Study
ERG
Electroretinography
EU
European Union
EUCTD
European Clinical Trials 
Directive
EudraCT
European Clinical Trials 
Database
EudraVIGILANCE
European database for 
Pharmacovigilance
FAF
Fundus Autofluorescence
FDA
(US) Food and Drug 
Administration
FST
Full Field Stimulus Testing
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
H&E
haematoxylin and eosin
hCAR
Human Cone Arrestin
HIPAA
Health Insurance 
Portability and 
Accountability Act
HRA
Health Research Authority
HSE
Health and Safety 
Executive
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference 
on Harmonisation
IDMC
Independent Data 
Monitoring Committee
IMP
Investigational Medicinal 
Product
IMPD
Investigational Medicinal 
Product Dossier
IND
Investigational New Drug
IRB
Institutional Review Board
ISCEV
International Society for 
Clinical Electrophysiology 
of Vision
KEC
Kellogg Eye Centre
LCA
Leber congenital amaurosis
Ltd
Limited (Company)

MGT007 CNGB3 and CNGA3 Follow up study
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MGT007_Protocol version 6.0_03Dec2021
MHRA
Medicines and Healthcare 
Products Regulatory 
Agency
mL
Millilitre
ms
Millisecond
MTD
Maximum Tolerated Dose
mRNA
Messenger RNA
MP
Monitoring Plan
NHS
National Health Service
NIH
National Institutes of 
Health
NIMP
Non-Investigational
Medicinal Product
OBA
Office of Biotechnology 
Activities
OCT
Optical Coherence 
Tomography
ONL
Outer nuclear layer
PCT
Polymerase Chain Reaction
PERG
Pattern 
Electroretinography
PHI
Protected Health 
Information
PI
Principal Investigator
PIS
Participant Information 
Sheet
PPI
Patient and Public 
Involvement
QA
Quality Assurance
QALY
Quality Adjusted Life Year
QC
Quality Control
qds 
quarter die sumendus (four 
times a day)
QOL
Quality of Life
qPCR
Quantitative Polymerase 
Chain Reaction
QP
Qualified Person 
qPCR
Quantitative polymerase 
chain reaction
rAAV
Recombinant adeno 
associated virus
rAAV2/2
recombinant adeno-
associated virus serotype 2
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
SD-OCT
Spectral Domain Optical 
Coherence Tomography
SOP
Standard Operating 
Procedure
SmPC
Summary of Product 
Characteristics
SSAR
Suspected Serious Adverse 
Reaction
SUSAR
Suspected Unexpected 
Serious Adverse Reaction
SV40
Simian virus 40
TMF
Trial Master File
tRNA
Transfer ribonucleic acid
UAR
Unexpected Adverse 
Reaction
UCL
University College London
UK
United Kingdome of Great 
Britain & Northern Ireland
USA
United States of America
vg
Viral Genomes
 
WT
Wild type

MGT007 CNGB3 and CNGA3 Follow up study
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MGT007_Protocol version 6.0_03Dec2021
4
Introduction
4.1
Background
Achromatopsia is a recessively inherited condition characterised by a lack of cone photoreceptor 
function resulting in impairment of colour vision and visual acuity, central scotoma often with 
eccentric fixation, disabling hypersensitivity to light (photoaversion) and involuntary eye movements 
(nystagmus), (Kohl et Al., 2013; Aboshiha et Al., 2015; Michaelides et Al., 2004). In the United States, 
Achromatopsia is estimated to affect 9,566 individuals (Judd, 1943; Sharpe et Al., 1990; Sharpe et Al., 
1999), in 50% of whom (4,783) the condition results from mutations in the CNGB3 gene (Kohl et Al., 
2005). 
Achromatopsia resulting from mutations in CNGB3 and CNGA3 has several characteristics that make 
it a good candidate disease to demonstrate proof-of-principle in a first-in-man trial of gene therapy 
for photoreceptor disease. Effective improvement in cone photoreceptor function, which is otherwise 
absent (or markedly reduced) in this condition, would provide a clear, rapid and reliable measure of 
outcome. In addition, achromatopsia is largely non-progressive 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 cone-mediated vision. Although younger 
individuals 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 various ages will be included; children (as defined by 
age in section 4.3) will be included once an acceptable safety profile has been established in adults.
4.2
Rationale
There is currently no effective treatment available for most hereditary retinal disorders including 
achromatopsia. This condition is characterised by absent (or markedly reduced) cone function 
resulting in profound reduction in visual acuity, complete lack of (or markedly reduced) colour vision, 
marked Photoaversion and nystagmus. The CNGB3 gene encodes the beta subunit of the cone 
photoreceptor-specific cGMP-gated cation channel and the CNGA3 gene encodes the alpha subunit, 
both of which are critical for cellular responses to light. Absence of either the beta or the alpha subunit 
results in absent/extremely poor cone function and hence very poor daylight vision. Although loss of 
cone photoreceptor cells over time may occur in a limited number of patients, the rate of cell death 
appears to be very slow, resulting in retinas containing surviving but non-functioning cones. 
Improvement of cone function by provision of CNGB3 or CNGA3 (as appropriate) could provide a clear, 
rapid and reliable measure of outcome. Furthermore, the relatively non-progressive 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 cone-dependent 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 once 
an acceptable safety profile has been defined in adults. Older participants might benefit with relief 
from photoaversion even if limited cortical plasticity affects the potential for improved acuity or colour 
vision.

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MGT007_Protocol version 6.0_03Dec2021
The purpose of the CNGB3 and CNGA3 interventional trials and this longer term follow up study is to 
determine the safety and potential efficacy of the vector AAV8-hCARp.hCNGB3 and AAV8-
hG1.7p.coCNGA3 respectively.
4.3
Assessment and Management of Risk
There is minimal risk to a participant by participating in this study as the assessments taking place are 
routine and generally non-invasive. The schedule of assessments in this study are designed to 
evaluate for longer term durability and safety associated with the subretinal administration of the 
antecedent gene therapy.
4.3.1
Risk of germline transmission
This risk was assumed in the antecedent interventional trial. The risk of inadvertent germline 
transmission is very small. In a number of studies using a variety of animal models involving various 
routes of administration, including intraocular injection, inadvertent germline transmission by rAAV 
vectors has not been detected. Similarly, we detected no vector genomes in semen in our previous 
retinal gene therapy clinical trial (Bainbridge, et al 2008). Systemic intravascular administration of 
rAAV2 to deliver factor IX in haemophilia B, can lead to vector sequences detectable in semen, though 
not sperm for a short period (Manno et al 2006). However, in this instance doses ranging from
 
 
 
 were administered, considerably higher than the doses proposed for subretinal 
injection in this study. Whilst this indicates there may be some potential for inadvertent germline 
transmission following the systemic delivery of high doses of vector, the possibility of such an event 
following the microsurgical delivery of tiny amounts of vector to intraocular compartments is 
considered to be remote. Participants who are fertile and sexually active will be requested to use 
double-barrier contraception for at least 12 months following ATIMP administration.
4.3.2
Risk of investigations performed during assessment and follow up 
These investigations are routine clinical tests and present no significant risk. Venepuncture causes 
temporary discomfort, occasionally bruising/swelling and rarely infection at the site of puncture.
4.4
Explanation for Choice of Comparators
This is a follow-up study to gene therapy studies MGT006 and MGT012, and is non-interventional. 
There is no comparator used in this study.
4.5
Objectives
4.5.1 Primary objective
The primary research objective is to assess the longer term safety of AAV8-hCARp.hCNGB3 for CNGB3
gene replacement and AAV8-hG1.7p.coCNGA3 for CNGA3 gene replacement in the retina 
administered to participants in the CNGB3 and CNGA3 trials, measured by the presence or absence of 
adverse events, the assessment of visual acuity, and loss of light perception.
4.5.2 Secondary objective
The secondary research objective is to explore the longer-term efficacy of AAV8-hCARp.hCNGB3 and 
AAV8-hG1.7p.coCNGA3 in improving visual and retinal function, and quality of life. 

MGT007 CNGB3 and CNGA3 Follow up study
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MGT007_Protocol version 6.0_03Dec2021
4.6
Study Design
Participants will be invited to provide consent for this longer-term follow-up study during the CNGB3
(MGT006) trial or CNGA3 (MGT012) trial. During this longer-term follow-up study participants will be 
assessed for safety for up to 60 months following AAV8-hCARp.hCNGB3 or AAV8-hG1.7p.coCNGA3 
administration in the MGT006 or MGT012 trial.
The duration of long-term follow-up is therefore consistent with the recommendations of the current 
CHMP Guideline on Follow-up of Patients Administered with Gene Therapy Medicinal Products 
(EMEA/CHMP/GTWP/60436/2007) of 22 October 2009, where it is stated that, for viral vectors 
without integration, latency or reactivation potential, a brief clinical history and sample testing should 
be performed pre-treatment, at 3, 6 and 12 months after treatment, and then yearly thereafter for a 
minimum of 5 years (and, if non-clinical tests or evidence from other clinical trials using identical 
vectors or modifications of vectors indicate a potential for integration or late re-activation, the 
monitoring should be extended to continue yearly after those 5 years until data indicate that there is 
no longer any risk to be followed). Further, although the Food and Drug Administration (FDA) Guidance 
for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events (November 
2006) recommends a standard 15-year period of follow-up, it is also noted that a shorter period of 
follow up may be possible if the vector does not integrate and has no potential for latency and 
reactivation.  The follow up study will be a non-intervention study designed to collect data on longer 
term safety and efficacy at the equivalent of 9, 12, 18, 24, 36, 48 and 60 months following ATIMP 
administration; as such, participants in both studies will be followed up more frequently than 
recommended in the guidance, as additional assessments following ATIMP administration are 
included in the initial studies of MGT006 and MGT012 (at Weeks 1, 2, 4 and 6) and in the long-term 
follow up study (at Months 9 and 18). 
5
Methods
5.1
Site Selection
The study sponsor MeiraGTx UK II Ltd. has overall responsibility for site and investigator selection.
5.1.1
Study Setting
The study sites are academic hospitals and academic research centres selected for their ability to 
perform the intervention and assessments required of the CNGB3 and CNGA3 trials and this protocol. 
Participants will be recruited from centres participating in the CNGB3 trial MGT006 and CNGA3 trial 
MGT012.
5.1.2
Site/Investigator Eligibility Criteria
All investigative sites will be provided with a copy of this protocol and the ATIMP Investigator 
Brochures (IB). 
To participate in this study, investigators and trial sites must have been participating sites in the 
CNGB3 or CNGA3 trial as appropriate. They will be issued with the CNGB3 and CNGA3 long-term 
follow-up study TMF documentation to use when applying for HRA or other local approval in the USA
as applicable. 

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5.1.2.1 Principal Investigator’s (PI) Qualifications and Agreements
The investigator(s) must be willing to sign a Clinical Trial Agreement and an Investigator Agreement to 
comply with the clinical study protocol (confirming their specific roles and responsibilities relating to 
the study, and that their site is willing and able to comply with the requirements of the study). This 
includes confirmation of appropriate qualifications, agreement to comply with the principles of GCP, 
to permit monitoring and audit as necessary at the site, and to maintain documented evidence of all
staff at the site who have been delegated significant study-related duties.
5.1.2.2 Resourcing at site
The investigator(s) should have an adequate number of qualified staff and facilities available for the 
foreseen duration of the study to enable them to conduct the study properly and safely. 
Sites will be expected to complete a delegation of responsibilities log and provide contact details of 
trial personnel. 
5.2
Site approval and activation
The regulatory authorisations for the study require that the Medicines and Healthcare products 
Regulatory Agency (MHRA) in the UK and FDA are supplied with the names and addresses of all 
participating site Principal Investigators. Clinical operations staff at MeiraGTx UK II Ltd. will ensure this 
information is provided to both the MHRA and FDA. 
On receipt of the signed Clinical Trial Agreement and Investigator Agreement, approved delegation of 
responsibilities log and staff contact details, written confirmation will be sent to the site PI. The trial 
manager or delegate will notify the PI in writing of the plans for site initiation. Sites will not be
permitted to recruit any participants until a letter for activation has been issued. 
The site must conduct the study 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 
(HRA) and local Institutional Review Board (IRB) in the US. The PI or delegate must document and 
explain any deviation from the approved protocol, and communicate this to the trial team at MeiraGTx 
UK II Ltd.
5.3
Eligibility Criteria
5.3.1
Participant selection
The eligibility criteria for this clinical study have been carefully considered and are the standards used 
to ensure that only medically appropriate participants are entered. Participants not meeting the 
criteria should be excluded to ensure that the study 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 study if they fulfil all the inclusion and 
none of the exclusion criteria as defined below.

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5.3.2
Participant Inclusion Criteria
Inclusion in the study will be limited to individuals who meet the following criteria:
x
Are able to give informed consent or assent, with or without the guidance of their 
parent/guardian where appropriate
x
Were enrolled and treated in the prior open-label, Phase I/II, dose escalation study involving
intraocular administration of AAV8-hCARp.hCNGB3 or AAV8-hG1.7p.coCNGA3
x
Are willing to adhere to the protocol and long-term follow-up
5.3.3
Participant Exclusion Criteria
Individuals will be excluded if they are unwilling or unable to meet with the requirements of the study.
5.3.4
Enrolment into long term follow up study
Participants will be informed of the long term follow up study at the time of initial enrolment into the 
interventional CNGB3 or CNGA3 Phase I/II trials.  Initial informed consent to participate in the long 
term follow up study will be initiated during the interventional trials. Each participant’s consent to 
participate in the long term follow up study will be reconfirmed at the time of their first visit on this
long term follow study (approximately 9 months after vector administration on the CNGB3 or CNGA3
trial).  Written informed consent to enter into the study must be obtained from participants, or 
parents/guardians/person with legal responsibility (including legal authorities) for children, after 
explanation of the aims, methods, benefits and potential hazards of the study and before any study-
specific procedures are performed. Participants who fulfil the inclusion criteria and who provide 
informed consent will be enrolled in the study. 
5.3.5 Informed consent procedure
Written informed consent will be taken from each participant (or parent/guardian if the subject is a 
child) by the chief/principal investigator or delegated clinician following appropriate explanation of 
the aims, methods, possible benefits and risks of the study. The Investigator or designee will explain 
that the participants are under no obligation to enter the study and that they can withdraw at any 
time during the study, without having to give a reason, and without their clinical care being affected. 
The consent process will be managed by presenting information to potential participants in a form 
appropriate to their level of understanding. In the case of children, they and their legal guardian(s) 
will be offered the support of an independent counsellor or advisor. Potential participants will be 
provided with the relevant participant information sheets (or audio versions) and given time to 
consider their decision. They will be provided with the opportunity to ask questions and to sign the
consent form. Children will be invited to give their verbal (and noted in their medical notes) or written 
assent to participation where this is age appropriate (i.e. children aged over 6 years). A copy of the 
signed Informed Consent form will be provided to the participant. The original signed form will be 
retained at the study site and a copy placed in the medical notes.
If new safety information results in significant changes in the risk/benefit assessment, the participant 
information sheet and consent form will be reviewed and updated if necessary, and participants will 
be re-consented as appropriate.
Children who become of adult age (i.e. 16 in the UK, 18 in the US) during the study will be re-consented 
as adults at the time of the next visit.

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5.4 Participation
5.4.1
Protocol Defined Clinical Schedule
5.4.1.1 Follow Up Assessments
Both safety and efficacy of the ATIMP will be evaluated at various time points, between 6 months and 
5 years after ATIMP delivery, in this study. Evaluation will occur primarily by ocular assessments that 
will be read at independent reading centres in the UK and USA. Clinical assessments will be scheduled 
over a consecutive period of up to 3 days for each visit. The nature and schedule (Section 5.6, 
Assessment Schedule) of the follow up assessments is described below. 
In addition, a serology test sample for evaluation of immune response will be drawn at each visit in 
this study (described as serology test in the Assessments Schedule table in Section 5.6).
There is wide variability in the ability of children of different ages to undertake some of the proposed 
tests; the evaluations for children will be restricted to those tests that they are able to perform 
reliably.
Tests that will be performed in all participants are:
x
Ocular examination
x
Colour fundus photography
x
Spectral Domain Optical Coherence Tomography (SD-OCT)
x
Fundus Autofluorescence Imaging (FAF)
x
Best corrected visual acuity
x
Full-field electroretinography (ERG)
x
Pattern electroretinography (PERG) 
x
Serology tests (AAV8 antibody and transgene antibody testing)
x
Light-sensitivity testing/Photoaversion testing
x
Contrast sensitivity 
x
Static perimetry
x
Quality of Life
Tests that will be performed in all patients unless not possible due to lack of patient co-operation or 
equipment/facilities are:
x
Reading assessment
x
Colour vision testing
x
Adaptive optics (AO) imaging
x
Pregnancy test (up to 12 months)
x
Full Field Stimulus Testing (FST)
Additional investigations may be performed for appropriate clinical management of any adverse 
events. Further details of clinical assessments can be found in the Gene Therapy for Achromatopsia 
(CNGB3 and CNGA3) study manuals. Images taken at all timepoints will be sent for independent 
reading and analysis at centres in both the UK and the US and to the sponsor and research 

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development partners. ERG assessments may be performed under general anaesthetic where 
considered appropriate.
5.4.1.1.1 Ocular examination and retinal imaging
Ocular examination by slit lamp biomicroscopy will be used to assess the anatomical integrity of the 
eyes and quantify any intra-ocular inflammation. During the examination, intra-ocular pressure will 
be determined by tonometry.
Prolonged or recurrent intra-ocular inflammation will be managed conventionally by further 
topicaland/or systemic immunosuppression.
Retinal imaging includes colour fundus photography, FAF, SD-OCT, and AO imaging. FAF imaging allows 
visualisation of the retinal pigment epithelium (RPE) by taking advantage of its intrinsic fluorescence 
derived from its lipofuscin content. SD-OCT imaging enables measurement of retinal thickness and 
provides information about the integrity of the layers of the retina. AO imaging provides direct 
visualization of the photoreceptor and RPE mosaics in vivo.
5.4.1.1.2 Functional and Participant-Related Outcome assessments
Where possible the participant will complete an age appropriate Impact of Visual Impairment (IVI) 
vision-specific quality of life questionnaire, and EQ5D-5L questionnaire.
Reading ability including reading acuity, maximum reading rate, and critical print size will be assessed 
with MNRead and International Reading Speed Texts.
The degree of light sensitivity (photoaversion) will be investigated in 2 ways (i) Objectively by 
measurement of palpebral aperture narrowing in response to gradually increasing light intensity and 
(ii) Subjectively by participant reported symptomatology.
Best-corrected ETDRS visual acuity will be measured in each eye. Contrast sensitivity will be 
measured using the Pelli-Robson chart or computerised (achromatic) spatial contrast sensitivity 
function tests.
Colour vision will be assessed comprehensively using plate tests and computerised tests probing 
colour discrimination along all 3 axes of colour and other testing methods may also be used as 
appropriate.
Retinal sensitivity will be determined using static perimetry and full field stimulus testing (FST) where 
available. 
Full-field electroretinography (ERG), pattern ERG (PERG) will be performed according to the 
International Society for Clinical Electrophysiology of Vision (ISCEV) standards to assess both 
generalised retinal (rod and cone systems) and isolated macular function. Modified ISCEV protocols 
may be necessary in young children using internationally recognised modified protocols. ERG 
assessments may be performed under general anaesthesia if considered appropriate. ERG data will 
be analysed and interpreted by dedicated full-time Clinical Visual Electrophysiology Consultants at 
Moorfields Eye Hospital, UK, with extensive experience and who are directly involved in determining 
ISCEV standards.

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5.4.1.1.3 Evaluation of immune responses
Up to 4 mL of blood will be sampled to measure immune response (AAV8 antibody and transgene 
antibody) at each visit (described as serology test in the Assessments Schedule table in Section 5.6). 
Blood serum for immune response will be processed by a central laboratory. Antibody responses to 
AAV8 capsid proteins (for all subjects) and to CNGB3 protein (for CNGB3 subjects administered AAV8-
hCARp.hCNGB3) or CNGA3 protein (for CNGA3 subjects administered AAV8-hG1.7p.coCNGA3) will be 
investigated by ELISA. Blood serum samples are prepared and stored under appropriate storage 
conditions (as described in the Sample Management Plan/Laboratory Manual) batched, and subject 
to periodic bioanalysis. Bioanalysis will be performed on collected samples in each subject until 
antibody levels comparable to baseline are seen in that subject, at which time no subsequent samples 
will be collected from the subject.
5.4.2
Concomitant Care
There are no restrictions around the concomitant use of other medications.
5.4.3
Protocol Discontinuation
5.4.3.1 Participant withdrawal
In consenting to the study, participants are consenting to study follow-up assessments and data 
collection. 
As participation in the study is entirely voluntary, the participant may choose to discontinue study
participation at any time without penalty or loss of benefits to which they would otherwise be entitled. 
Although not obliged to give a reason for discontinuing their participation, a reasonable effort should 
be made to establish this, whilst remaining fully respectful of the participant’s rights.
Should a participant withdraw from the study, a withdrawal CRF documenting the reason for 
withdrawal will be completed.
5.4.3.2 Study Stopping Rules
The Chief Investigator and Sponsor retain the right to terminate the study. However, given the nature 
of the study assessing the safety and efficacy of the ATIMP administered in the CNGB3 or CNGA3 trial, 
it is not considered likely that this will occur.
5.5
Outcomes
5.5.1
Primary Outcomes
The primary study outcome is the long-term safety of the subretinal administration of the ATIMP.
5.5.2
Secondary Outcomes
The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an 
individual participant basis and will be descriptive in nature:
1)
Any improvements in visual function from baseline that are greater than the test-retest 
variation and are sustained for at least two consecutive assessments. 
2)
Any improvement in retinal function from baseline that is greater than test-retest variation 
and measurable by electrophysiology (pattern ERG, or full-field ERG).

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3)
Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire and the 
EQ5D-5L.
5.6
Assessment Schedule
Timings are since ATIMP administration. 
CNGB3/
CNGA3
M31
M9
M12
M18
M24
M36
M48
M60
Visit no.
1
2
3
4
5
6
7
Informed consent
•
•
Medical history
•
•
•
•
•
•
•
Pregnancy test
•
•
Adverse event review 
•
•
•
•
•
•
•
Concomitant medication review 
•
•
•
•
•
•
•
Serology test (AAV8 antibody and
Transgene antibody testing)
•
•
•
•
•
•
•
QoL questionnaires (IVI and EQ5D-
5L)
•
•
•
•
•
Static perimetry
•
•
•
•
•
•
•
Visual acuity
•
•
•
•
•
•
•
Contrast sensitivity
•
•
•
•
•
•
•
Reading speed
•
•
•
•
•
•
•
Colour vision
•
•
•
•
•
•
•
Ocular examination
•
•
•
•
•
•
•
Fundus photography
•
•
•
•
•
•
•
Optical coherence tomography
•
•
•
•
•
•
•
Adaptive optics imaging
•
•
•
•
•
•
•
Fundus autofluorescence
•
•
•
•
•
•
•
Full field electroretinography2
•
•
•
•
•
Pattern electroretinography2
•
•
•
•
•
Photoaversion assessments3
•
•
•
•
•
Full Field Stimulus Testing4
•
•
•
•
•
•
•
Flexibility of schedule (±days)
21
21
60
60
60
60
60
1 Initial consent for the long term follow up study will be obtained at the 3 or 6 month visit of the active CNGB3
or CNGA3 trial (or anytime thereafter).

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2 Electroretinography testing will be discontinued after M12 if responses remain undetectable
3 To include testing with Photoaversion device and questionnaires
4 Full Field Stimulus Testing will be discontinued after M12 if responses remain undetectable
5.6.1
Early Stopping of Follow-up
If a participant chooses to withdraw from the study, they should continue to be followed up as closely 
as possible to the follow-up schedule defined in the protocol, providing they are willing. If, however,
the participant exercises the view that they no longer wish to be followed up, this view must be 
respected. MeiraGTx UK II Ltd. should be informed of the withdrawal in writing using the appropriate 
study documentation. Data already collected will be kept and included in analyses according to the 
intention-to-treat principle for all participants who stop follow up early. 
5.6.2
Loss to Follow-up
This is a highly motivated patient group who are likely to remain committed to the research. Continued 
follow up of all participants will be strongly encouraged whilst being mindful of the importance of 
ensuring the autonomy of participants in regard to their treatment decisions and willingness to 
continue to participate in the study. 
5.6.3
Study Closure
The end of the study is considered the last follow-up visit of the last participant. For each participant, 
the study will terminate at the last scheduled visit 5 years following ATIMP administration. The MHRA
and FDA will be notified of the end of the study within 90 days of its completion. 
5.6.4 
Passive/Long Term Follow-Up After the End of the Study
After the end of this study participants will return to their usual standard of care in their originating 
care teams.
5.7
Sample Size
This is a long term follow up study to establish safety and assess indicators of potential efficacy of the 
ATIMP administered in the CNGB3 trial and CNGA3 trial, therefore there is no formal sample size 
calculation.
The CNGB3 and CNGA3 trials will each include up to 36 participants (up to 18 in the dose escalation 
phase and at least a further 9 at the established maximum tolerated dose). We estimate that inclusion 
of up to 36 participants for each gene therapy will be sufficient to determine the safety and tolerability 
of the intervention. All participants enrolled in the CNGB3 MGT006 and the CNGA3 MGT012 trials will 
be invited to participate in this follow up study.
5.8
Recruitment and Retention
5.8.1
Recruitment
All participants will be recruited through participating sites from the CNGB3 MGT006 and CNGA3
MGT012 trial. Participants entering the CNGB3 and CNGA3 trials will be informed about this follow-
up study during the consenting process. 
5.8.2
Retention
Participants will be encouraged to remain in follow-up by regular contact as per the protocol. 

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5.9
Data Collection, Management and Analysis
5.9.1
Data, management and entry
 will be responsible for data management activities for the study.
Data will be captured in a fully validated, 21 CRF Part 11 compliant Electronic Data Capture (EDC) 
system provided by
.
will grant authorised site staff with access to the EDC system following system training and a 
successful competency assessment.  
Data required by the protocol will first be recorded on source documents (e.g. medical records and 
study-specific data capture tools as needed) and then entered by site staff into the EDC system.  All 
information in EDC must be traceable to these source documents.  Any data recorded directly into 
EDC will be defined prior to the start of data collection. All data is currently anticipated to be 
associated with source data records.
Data validation checks will be activated during data entry to identify data discrepancies. Appropriate 
error messages will be displayed to allow modification or verification of data by the site staff.
Monitoring staff will review the data for completeness and accuracy, instructing site staff to make any 
required corrections or additions via data queries.  
will run further automated validation checks 
and review the data, raising further data queries to the sites for resolution of any inconsistencies.
The Investigator will review the eCRFs for completeness and accuracy then electronically approve the 
data, retaining full responsibility for its accuracy and authenticity.
Medical history and adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) terminology.  Prior and concomitant medication will be coded using the World Health 
Organization Drug (WHO)-Drug Dictionary which employs the Anatomical Therapeutic Chemical (ATC) 
classification system.  Further coding details and data management processes will be described in a 
Data Management Plan (DMP).  
All actions within the EDC system are captured within an audit trail.  After all data have been entered, 
validated and signed off, the database will be locked.
At the end of the study, PDF copies of the eCRFs for each subject and supporting information will be 
provided to sites and the Sponsor.  The electronic data will be provided to the Sponsor.
5.9.2
Non-Adherence and Non-Retention
Participants who withdraw from the study after enrolment will be encouraged to participate in any of 
the planned follow-up scheduled with their consent, and data from these participants collected prior 
to withdrawal may be included in the interpretation of results. 
5.9.3
Statistical Methods
A formal Statistical Analysis Plan (SAP) will be written by the Sponsor for each gene defect programme. 
Analysis of the primary and secondary outcomes will be descriptive in nature. All outcomes for each 
product will be analysed and reported separately.

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5.9.3.1 Statistical Methods – Primary Outcome Analysis
The primary outcome of each trial is safety of subretinal administration of the ATIMP.
The CNGB3 trial will include up to 36 participants (up to 18 in the dose escalation phase and a further 
9 at the maximum tolerated dose) in whom safety will be assessed. 
The CNGA3 trial will include up to 36 participants (up to 18 in the dose escalation phase and a further 
9 at the maximum tolerated dose) in whom safety will be assessed.
5.9.3.2 Statistical Methods – Secondary Outcome Analysis
The secondary outcomes are measures of the efficacy of each ATIMP; these will be performed on an 
individual participant basis and will be primarily descriptive in nature. Standard assessments will be 
used to measure visual function and established methods of analysis, appropriate for the assessment 
will be used to evaluate the data. For specialist assessments, data will be analysed by the expert team 
member(s) who developed the assessment. Final data will be reported descriptively.
Efficacy will be indicated by:
1) Any improvement in visual function from baseline that is greater that the test-retest variation for 
that test and is sustained for at least 2 consecutive assessments.
2) Any improvement in retinal function from baseline that is greater than test-retest variation and 
measurable by electrophysiology (pattern ERG, or full-field ERG).
Measures will be reported individually and aggregated across participants as the proportion who 
satisfy the above criteria.
Quality of life patient reported outcome measures will be used to correlate a participant’s feeling 
about their own wellbeing with clinical observations.
Any deviations from the original statistical plan will be described in the final report, as appropriate.
5.9.3.3 Statistical Methods – Health Economic Analysis
No health economic evaluation is planned but the collection of EQ5D would allow Quality Adjusted 
Life Years (QALYs) to be calculated.
5.10 Data Monitoring
5.10.1 Independent Data Monitoring Committee 
There is not an Independent Data Monitoring Committee for this trial. 
5.10.2 Safety Data Monitoring Committee CNGA3
There is not a Safety Data Monitoring Committee for this trial. 
5.10.3 Interim Analyses
No formal interim analysis is planned within the trial.   

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5.10.4 Data Monitoring for Harm
5.10.4.1
Safety reporting
The pharmacovigilance (PV) service provider will be responsible for pharmacovigilance services. 
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP apply 
to this study. 
Table 1: Adverse Event Definitions
Adverse Event (AE)
Any untoward medical occurrence in a clinical trial participant 
administered a medicinal product and which does not 
necessarily have a causal relationship with this product.
Adverse Reaction (AR)
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered.
Unexpected Adverse Reaction 
(UAR)
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g.,
Investigator’s Brochure for an unauthorised product or 
summary of product characteristics (SPC) for an authorised 
product.
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR)
Any AE or AR that at any dose:
x
results in death 
x
is life threatening* 
x
requires 
hospitalisation 
or 
prolongs 
existing 
hospitalisation**
x
results in persistent or significant disability or incapacity
x
is a congenital anomaly or birth defect
x
or is another important medical condition***
Unexpected Adverse Reaction
An adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
(a) In the case of a product with a marketing authorization, 
in the summary of product characteristics for that 
product, 
(b) In the case of any other investigational medicinal 
product, in the investigator’s brochure relating to the 
study in question
SUSAR
Suspected Unexpected Serious Adverse Reaction 
* the term life threatening here refers to an event in which the participant is at risk of death at the 
time of the event; it does not refer to an event that might hypothetically cause death if it was more 
severe (e.g., a silent myocardial infarction)
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisation for pre-
existing conditions (including elective procedures that have not worsened) do not constitute an SAE
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other 
situations. Important AEs or ARs that may not be immediately life threatening or result in death or 
hospitalisation, but may seriously jeopardise the participant by requiring intervention to prevent 
one of the other outcomes listed in the table (e.g., a secondary malignancy, an allergic 

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bronchospasm requiring intensive emergency treatment, seizures or blood dyscrasias that do not 
require hospitalisation, or development of drug dependency).
Adverse events include:
x
an exacerbation of a pre-existing illness
x
an increase in the frequency or intensity of a pre-existing episodic event or condition
x
a condition (regardless of whether PRESENT prior to the start of the CNGB3 or CNGA3 trial) 
that is DETECTED after administration. (This does not include pre-existing conditions recorded 
as such at baseline – as they are not detected after the administration of study drug.)
x
continuous persistent disease or a symptom present at baseline that worsens following 
administration of study drug
Adverse events do NOT include:
x
Medical or surgical procedures: the condition that leads to the procedure is the adverse event
x
Pre-existing disease or a condition present before treatment 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
5.10.4.2
Other Notifiable Events
Pregnancy is the only additional notifiable event that requires expedited reporting as detailed in 
Sections 5.10.4.3 and 5.10.4.4.
5.10.4.3
Procedures to follow in the event of female participants becoming pregnant
A pregnancy test is conducted for all females of childbearing age and the results are recorded in the 
medical notes before enrolling a volunteer to the CNGB3 or CNGA3 trial. Females with a positive 
pregnancy test at the time of planned ATIMP administration are to be excluded from the trial prior to 
administration of the ATIMP. 

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Participants are instructed to use barrier contraception for 12 months after ATIMP administration. 
However, it is difficult to 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 in the 12 
months following ATIMP administration, the participant’s GP will be notified that she is participating 
in a gene therapy trial and that, although the risks involved are minimal, there is a chance of gene 
transfer to the unborn child. With the participant’s consent, we will ask the GP/obstetrician to provide 
us with regular reports about the pregnancy until delivery. The pregnancy will be reported to The PV 
service provider on a pregnancy report form within 24 hours of the investigator becoming aware of 
the event, following the instructions on the pregnancy form. The participant will continue to be 
followed-up until outcome of the pregnancy. However, if the participant is unable or unwilling to 
participate further in the study, she will be encouraged to continue clinical monitoring visits to assess 
ocular health.
5.10.4.4
Procedures to follow in the event of the partners of male participants 
becoming pregnant
Participants are instructed to use double barrier contraception for 12 months after ATIMP 
administration. However, it is difficult to exclude entirely that the partner of a participant might 
become pregnant after administration of the ATIMP. In the unlikely event that the partner of a 
participant is found to be pregnant in the 12 months following ATIMP administration, the participant’s 
GP will be notified that he is participating in a gene therapy trial and that, although the risks involved 
are minimal, there is a chance of gene transfer to the unborn child. With the participant’s consent, we 
will contact the partner to ascertain the status of the pregnancy and the outcome. The pregnancy will 
be reported to The PV service provider on a pregnancy report form within 24 hours of the investigator 
becoming aware of the event, following the instructions on the pregnancy form.
.
5.10.4.5
Investigator responsibilities relating to safety reporting
The Investigator will assume overall responsibility for evaluating and reporting adverse events. In 
urgent situations another member of the study team may report on their behalf, while making every 
effort to discuss the event with them. All non-serious AEs and ARs, whether expected or not, should 
be recorded in the participant’s medical notes and reported in the toxicity (symptoms) section of the 
eCRF. These should be entered on to the database according to the timelines defined in the Data 
Management Plan to allow appropriate monitoring by the Clinical Management Team (CMT). SAEs 
and SARs should be notified to the PV service provider immediately after the investigator becomes 
aware of the event and in no circumstance should this notification take longer than 24 hours.
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 also be recorded in the hospital notes and the CRF. Adverse events will 
be recorded with clinical symptoms and accompanied with a simple, brief description of the event, 
including dates as appropriate. All adverse events will be recorded until the end of the study, or until 

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pregnancy outcome in the case of pregnancy. All SAEs will be recorded, fully investigated and 
appropriately managed until resolution or stabilisation and CI sign off. 
5.10.4.5.1
Seriousness assessment 
When an AE or AR occurs, the investigator responsible for the care of the participant must first assess 
whether or not the event is serious using the definition given in Table 1. If the event is classified as 
‘serious’ then an SAE form must be completed and emailed to the PV service provider (or delegated 
body) notified within 1 working day.
5.10.4.5.2
Severity or grading of Adverse Events
The severity of all AEs and/or ARs (serious and non-serious) in this study should be graded using the 
toxicity gradings in NIH CTCAE Version 4.0 (NIH 2009).
Table2: Grading of Adverse Events
Category
Definition
Mild (Grade I)
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Moderate (Grade II)
Minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental ADL*
Severe (Grade III)
Severe or medically significant but not immediately life 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care ADL**
Grade IV
Life threatening consequences; urgent intervention indicated
Grade V
Death related to AE
* Instrumental ADL (Activities of Daily Living) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
5.10.4.5.3
Causality
Causality will be assessed in terms of the ATIMP, the surgical procedures and any of the other 
procedures in the study. Based on all available information at the time of completion of the case report 
form, the investigator must assess the causality of all serious events or reactions. It is of particular
importance in this study to capture and differentiate events related to:
x
The ATIMP administration surgery
x
The ATIMP
The differentiated causality assessments will be captured in the study-specific CRF and SAE form using 
the definitions in Table 3. 
Table 3: 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 
Unrelated SAE

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time after administration of study drug). There is another 
reasonable explanation for the event (e.g., the participant’s 
clinical condition or other concomitant treatment)
Possibly related
There is some evidence to suggest a causal relationship (e.g.,
because the event occurs within a reasonable time after 
administration of study drug). However, the influence of other 
factors may have contributed to the event (e.g., the participant’s 
clinical condition or other concomitant treatment) 
SAR
Probably related
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely
SAR
Definitely related
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out.
SAR
5.10.4.5.4
Expectedness
This is a long-term follow-up study to the prior interventional studies, and no intervention is given to 
participants in this study. Any expectedness assessment will be related to ATIMP and surgery given in 
the prior interventional study.
Table 4: Assessment of expectedness 
Category
Definition
Expected
An adverse event that is classed in nature as serious and which 
is consistent with the information in the Investigator Brochure. 
In view of the very limited clinical experience with the ATIMP 
there are at present no events considered as expected for the 
ATIMP and surgery listed in the current Investigator Brochure.
Unexpected
An adverse event that is classed in nature as serious and which 
is not consistent with the information about the ATIMP and 
surgery listed in the Investigator Brochure*.
*This includes listed events that are more frequently reported or more severe than previously 
reported
The reference document to be used to assess expectedness of any SAE related to the ATIMP and/or
administrative surgical procedure is the Reference Safety Information (RSI) section of the current 
Investigator Brochure (IB) for each programme respectively at the time the event started. The RSI 
section of the IB lists all the expected adverse reactions.
5.10.4.6
Notifications
5.10.4.6.1
Notifications by the Investigator to PV
All adverse events will be recorded in the hospital notes and the CRF.  
PV must be notified of all SAEs within 24 hours of the investigator becoming aware of the event. The 
investigator will respond to any SAE queries raised by the PV provider as soon as possible. 
Investigators should notify the PV service provider of any SAE occurring from ICF signature. Any events
known to investigator that occur after the end of the study and that may be attributed to ATIMP 

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administration 
should 
be 
reported 
to 
the 
MHRA 
using 
the 
yellow 
card 
system 
(https://yellowcard.mhra.gov.uk/the-yellow-card-scheme/). 
The SAE CRF must be completed by the investigator (the consultant named on the delegation of 
responsibilities list who is responsible for the participant’s care) with attention paid to the grading and
causality of the event. In the absence of the responsible investigator, the SAE form should be 
completed and signed by a member of the site study 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. Systems will be in place at the site to enable the 
investigator to check the form for clinical accuracy as soon as possible.
The minimum criteria required for reporting an SAE are the study number, patient number, year of 
birth, name of reporting investigator and sufficient information on the event to confirm seriousness. 
Any further information regarding the event that is unavailable at the time of the first report should 
be entered as soon as it becomes available.
The SAE form must be scanned and sent by email to PV service provider as listed on the SAE form.
Participants must be followed up until clinical recovery is complete and laboratory results have 
returned to normal or baseline values, or until the event has stabilised. Follow-up should continue 
after completion of study follow-up (i.e., 5 years after delivery of ATIMP) if necessary. Follow-up SAE 
forms (clearly marked as follow-up) should be completed and emailed to the PV service provider as 
further information becomes available. Additional information and/or copies of test results etc may 
be provided separately. The participant’s name must not be used on any correspondence and if the 
name does appear it must be blacked out and replaced with study identifiers on any test results. Any 
occurrence of a subjects’name must be reported to the clinical trial manager and investigated and 
remediated to prevent reoccurrence.
5.10.4.6.2
PV responsibilities
PV will follow their own Standard Operating Procedures and a study specific Safety Management to 
ensure that case processing of events occurs within appropriate regulatory timeframes. PV will submit 
Development Safety Update Reports (DSURs) to competent authorities.
5.10.4.6.3
Reporting SUSARs in International Studies
The mechanism for reporting SUSARs that occur outside of the UK to the MHRA, and those that occur 
outside of the US to the FDA will be covered in the trial specific safety management plan.
5.10.4.6.4
Annual Progress Reports
An annual progress report (APR) will be submitted by the sponsor to the UK REC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is declared 
ended. Annual IRB applications for continuing review will be submitted with sufficient time to allow 
review and approval of trial continuation. 
5.10.5 Quality Assurance and Control
5.10.5.1
Risk Assessment
The Quality Assurance (QA) and Quality Control (QC) considerations for this study are based on the 
MeiraGTx UK II Ltd. Quality Management strategy that includes a formal Risk Assessment, and that 

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acknowledges the risks associated with the conduct of the study and proposals of how to mitigate 
them through appropriate QA and QC processes. Risks are defined in terms of their impact on: the 
rights and safety of participants; project concept including trial design, reliability of results and 
institutional risk; project management; and other considerations.
5.10.5.2
Clinical Monitoring 
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the
Long-Term Follow-Up Gene Therapy Study for Achromatopsia owning to defects in CNGB3 and CNGA3 
Monitoring Plan (MP) respectively. The MP will also detail the procedures for review and sign-off of 
monitoring reports. In the event of a request for a trial site inspection by any regulatory authority 
MeiraGTx UK II Ltd. must be notified as soon as possible.
5.10.5.2.1
Direct access to participant records
Participating investigators must agree to allow trial related monitoring, including audits, REC review
and regulatory inspections, by providing access to source data and other study related documentation 
as required. Participant consent for this will be obtained as part of the informed consent process for 
the study.
5.10.5.3
Study Oversight
Study oversight is intended to preserve the integrity of the study by independently verifying a variety 
of processes and prompting corrective action where necessary. The processes reviewed relate to
participant enrolment, consent and eligibility; adherence to policies to protect participants, including 
reporting of harms; completeness, accuracy and timeliness of data collection; and will verify 
adherence to applicable policies detailed in the Compliance section of the protocol.
In multi-centre studies oversight is considered and described both overall and for each recruiting 
centre by exploring the study dataset or performing site visits as described in the study Monitoring 
Plan.
5.10.5.3.1
Clinical Management Team
A Clinical Management Team (CMT) will be set up to assist with developing the design, co-ordination 
and strategic management of the trial. The membership, frequency of meetings, activity (including 
study conduct and data review) and authority will be covered in a CMT terms of reference.

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6
Ethics and Dissemination
6.1
Research Ethics Approval
Before initiation of the study at any clinical site, the protocol, all informed consent forms and any 
material to be given to the prospective participant will be submitted to the Health Research Authority 
(HRA) for approval. 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 study, the clinician remains free to give alternative 
treatment to that specified in the protocol, at any stage, if the clinician feels it to be in the best interest 
of the participant. The reasons for doing so must be recorded. The participant remains free to change 
their mind at any time about the protocol follow-up without giving a reason and without prejudicing 
their further treatment.
6.2
Regulatory Authority Approvals
This protocol will be submitted to the national competent or equivalent authority (i.e. MHRA in the 
UK and FDA in the USA).
This study does not involve the administration of an ATIMP. However, as the intention is to collect 
safety and efficacy data on participants administered an Advanced Therapy Investigational Medicinal 
Product in a previous trial (CNGB3 or CNGA3), which involves the application of monitoring procedures 
that are outside of the course of current practice for the management of achromatopsia, a CTA 
approval is required in the UK and an Investigational New Drug (IND) Application approval is required
in the United States.
The progress of the study, safety issues and reports, including expedited reporting of SUSARs, will be 
reported by the sponsor or authorised delegate to the Competent Authority, regulatory agency or 
equivalent in accordance with relevant national and local requirements and practices. 
6.3
Other Approvals
A copy of the confirmation of local capacity and capability review (or other relevant approval as above) 
and of the Participant Information Sheet (PIS) and consent form on local headed paper must be 
forwarded to MeiraGTx UK II Ltd. as part of the site initiation process prior to the site being designated 
‘open to recruitment’ status. 
Participating sites receiving funding or support from the US government will obtain a Federal Wide 
Assurance (FWA).
6.4
Protocol Amendments
MeiraGTx UK II Ltd. will be responsible for amendments to the protocol. MeiraGTx UK II Ltd. will be 
responsible for ensuring that protocol amendments are submitted to national competent authorities, 
and to investigators at each study site. 
Investigators at each clinical site will be responsible for submitting protocol amendments to the 
relevant REC/IRBs for approval, as well as any additional competent authorities in each country that 
require notification (e.g. the NIH OBA). 

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6.5
Consent or Assent
Potential participants will be provided with a Participant Information Sheet (PIS) and consent form, 
and given time to read it fully. Following a discussion with a medically qualified investigator or suitable 
trained and authorised delegate, any questions will be satisfactorily answered and if the participant is 
willing to participate, written informed consent will be obtained. During the consent process it will 
be made completely and unambiguously clear that the participant (or parent or guardian of a child) is 
free to refuse to participate in all or any aspect of the study, at any time and for any reason, without 
incurring any penalty or affecting their treatment (or that of their child).
Minors (as defined by local law) who are unable to consent for themselves will not be enrolled in the 
study without the consent of their parent(s) or legal guardian(s). Children or adolescents will be asked 
to assent or agree. A Participant Information and Assent sheet that describes the details of the study, 
study procedures, and risks in simplified form will be provided to minors who have the capacity to 
provide informed assent. Participation will 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, then he/she will be 
reconsented as an adult at the time of their next scheduled visit.
Consent will be re-sought if new information becomes available that affects the participant’s consent 
in any way. This will be documented in a revision to the participant information sheet and the 
participant will be asked to sign an updated consent form. These will be approved by the appropriate 
ethics committee prior to their use. Consent will also be re-sought in the event that a child’s carer 
changes. 
A copy of the approved consent form is available from MeiraGTx UK II Ltd. study team. 
6.6
Confidentiality
All data will be handled in accordance with the UK General Data Protection Regulation 2018 (GPDR) ,
the Health Insurance Portability and Accountability Act of 1996 (HIPAA) or appropriate local data 
protection requirements.
These regulations require a signed subject authorization informing the participants of the following: 
•
What protected health information (PHI) will be collected from participants in this trial
•
Who will have access to that information and why
•
Who will use or disclose that information
•
The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the subject is alive) at the end of 
their scheduled trial period.
Participant confidentiality will be held strictly in trust by the investigators, study 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 

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relating to participants. All laboratory specimens, evaluation forms, reports, and other records that 
leave the site will be identified only by a coded number to maintain subject confidentiality.  All records 
will be kept locked and all computer entry and networking programs will use coded numbers only. 
Participants will not be identified in any publicly released reports of this trial. 
Access to study 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 study-related monitoring, audits, REC/IRB review, and regulatory 
inspections by University or government entities. In these cases, the clinical site will provide direct 
access to all source data, documents, and records maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) for the study participants. Study participants will 
be informed of this during the informed consent process. 
No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of MeiraGTx UK II Ltd.
The Case Report Forms (CRFs) will not bear the participant’s name or other personal identifiable data. 
The participant’s initials, date of birth and study identification number, will be used for identification.
6.7
Declaration of Interests
This study is funded by MeiraGTx UK II Ltd.
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt of 
payment for consultancy services.
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt 
of payment from MeiraGTx UK II Ltd. for consultancy services.
6.8
Indemnity
MeiraGTx UK II Ltd. holds insurance to cover participants for injury caused by their participation in the 
clinical study. Participants may be able to claim compensation if they can prove that MeiraGTx UK II
Ltd. has been negligent. However, as this clinical study is being carried out in a hospital, the hospital 
continues to have a duty of care to the participant in the study. MeiraGTx UK II Ltd. does not accept 
liability for any breach in the hospital’s duty of care, or any negligence on the part of hospital 
employees. This applies whether the hospital is an NHS Trust or not.  This does not affect the 
participant’s right to seek compensation via the non-negligence route. 
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of MeiraGTx UK II Ltd. or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in 
the first instance to the Chief Investigator, who will pass the claim to MeiraGTx UK II Ltd’s insurers.
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.

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6.9
Finance
This follow up study is fully funded by MeiraGTx UK II Ltd. It is not expected that any further external 
funding will be sought.
6.10 Archiving
Study documents should be retained for a minimum of 2 years after an FDA marketing application is 
approved and until there are no pending or contemplated marketing applications, or if an application 
is not approved, until 2 years after shipment and delivery of the drug for investigational use has been 
discontinued and FDA is notified. For gene therapy trials, current Federal and State of Michigan 
requirements state that research records should be kept indefinitely, until further notice. Archiving of 
REC/IRB notices should be maintained according to local and/or institutional requirements. 
Essential documents are those which enable both the conduct of the study and the quality of the data 
produced to be evaluated and show whether the site complied with the principles of Good Clinical 
Practice and all applicable regulatory requirements. 
MeiraGTx UK II Ltd. will notify sites when trial documentation can be archived and which documents 
must be archived for the longer 30-year period. All archived documents must continue to be available 
for inspection by appropriate authorities upon request. 
Destruction of essential documents will require authorisation from the Sponsor.
6.11 Access to Data
The investigators/ institutions will permit study-related monitoring, audits, REC review, and regulatory 
inspections, providing direct access to source data/documents. Study participants are informed of this 
during the informed consent discussion. Participants will consent to provide access to their medical 
notes.
Requests for access to study data will be considered, and approved in writing where appropriate, after 
formal application to MeiraGTx UK II Ltd. 
6.12 Ancillary and Post-study Care
At the end of the follow up study, participants will resume usual standard of care within their primary 
care teams.
6.13 Publication Policy
All proposed scientific publications will be discussed with the Sponsor prior to publication. Study 
progress reports and significant findings may be presented at scientific forums/meetings and/or 
published during the course of the study. The results of the study will be disseminated regardless of 
the direction of effect.
7. Ancillary Studies
There are no currently planned ancillary studies. Any future ancillary studies will be subject to separate 
funding and will be submitted for ethical and regulatory review as appropriate. 

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8
Protocol Amendments
Protocol Version and Date
Reason for Amendment
Protocol v1.0 dated 10 February 2017
Initial version
Protocol v2.0 dated 05 June 2019
Addition of Full Field Stimulus Testing at all visits 
in line with interventional protocol.
Reduction in assessment burden in line with 
interventional protocols 
Addition of CNGA3 Achromatopsia trial 
Protocol v3.0 dated 26 June 2019
Administrative error
Protocol v4.0 dated 07 Sep 2020
Vector names updated 
Assessment and Management of risks updated
Evaluation of immune responses section added 
and Serology tests (AAV8 antibody and 
transgene 
antibody 
testing) 
added 
to 
assessments in protocol text and in assessments 
schedule.
Independent Data Monitoring Committee and 
Safety Data Monitoring Committee information 
updated
Administrative errors corrected
Protocol v5.0 dated 02Dec2021
Update to include patients and data from the 
MGT012 trial. 
Addition 
of 
Light-sensitivity 
testing/Photoaversion 
testing, 
Contrast 
sensitivity, Static perimetry and Quality of Life
assessments to be performed in all participants
New wording to the expectedness of AE/SAE. 
Protocol v6.0 dated 03Dec2021
Administrative error

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9
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