An Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/8-hCARp.hCNGB3) for Gene Therapy of Adults and Children With Achromatopsia Owing to Defects in CNGB3
Phase: PHASE1
Conditions: Achromatopsia
Sponsor: MeiraGTx UK II Ltd



   
 
 
  
Protocol V7.029Jan2019                                                                                                           Page 2 of 63 
 
 
Table of Contents 
1 
Administrative information ............................................................................................................. 7 
1.1 
Compliance ............................................................................................................................. 7 
1.2 
Sponsor ................................................................................................................................... 7 
1.3 
Structured trial summary ........................................................................................................ 8 
1.4 
Roles and responsibilities...................................................................................................... 10 
1.4.1 
Protocol contributors .................................................................................................... 10 
1.4.2 
Independent Data Monitoring Committee ................................................................... 10 
2 
Trial Diagram ................................................................................................................................. 11 
3 
Abbreviations ................................................................................................................................ 12 
4 
Introduction .................................................................................................................................. 14 
4.1 
Background and Rationale .................................................................................................... 14 
4.1.1 
 Background .................................................................................................................. 14 
4.1.2 
Pre-clinical data ............................................................................................................. 14 
4.1.3 
Clinical data ................................................................................................................... 14 
4.1.4 
Rationale ....................................................................................................................... 15 
4.1.5 
Assessment and management of risk ........................................................................... 15 
4.1.5.1 
 Risk of immune responses to AAV2/8-hCAR.hCNGB3 ............................................. 16 
4.1.5.2 
 Risk of vector transmission to other organs ............................................................ 16 
4.1.5.3 
 Risks of insertional mutagenesis and oncogenesis .................................................. 17 
4.1.5.4 
 Risk of germline transmission .................................................................................. 17 
4.1.5.5 
 Risk of surgical adverse effects ................................................................................ 17 
4.1.5.6 
 Risk of adverse effects of short-term corticosteroids .............................................. 18 
4.1.5.7 
 Risks of investigations performed during assessment and follow up ...................... 18 
4.1.5.8 
 Risk of rod photoreceptor dysfunction .................................................................... 18 
4.1.5.9 
 Risk of thinning of the fovea .................................................................................... 18 
4.1.5.10 
Risk of visual imbalance ........................................................................................ 19 
4.1.5.11 
 Conclusion on the risk-benefit ratio ..................................................................... 19 
4.1.6 
Explanation for Choice of Comparators ........................................................................ 19 
4.2 
Objectives.............................................................................................................................. 19 
4.2.1  
Primary Objective .......................................................................................................... 19 
4.2.2  
Secondary Objective ..................................................................................................... 19 

   
 
 
  
Protocol V7.029Jan2019                                                                                                           Page 3 of 63 
 
4.3 
Trial Design ............................................................................................................................ 19 
4.3.1.1 Separate longer term follow up study .......................................................................... 20 
4.3.2  
IMP administration Review and Dose Escalation Criteria and Process ........................ 21 
4.3.2.1 
 Dose escalation criteria and Dose Limiting Events .................................................. 21 
4.3.2.2 
Dosing process .......................................................................................................... 22 
4.3.2.2.1 Cohort 1 ................................................................................................................. 22 
4.3.2.2.2 Cohort 2 ................................................................................................................. 22 
4.3.2.2.3 Cohort 3 ................................................................................................................. 22 
4.3.2.2.4 Additional considerations ...................................................................................... 22 
4.3.2.2.5 Confirmatory safety phase ..................................................................................... 23 
5 
Methods ........................................................................................................................................ 24 
5.1 
Site Selection ......................................................................................................................... 24 
5.1.1 
Study Setting ................................................................................................................. 24 
5.1.2 
Site/Investigator Eligibility Criteria ............................................................................... 24 
5.1.2.1 
Principal Investigator’s (PI) Qualifications and Agreements ..................................... 24 
5.1.2.2 
Resourcing at site ...................................................................................................... 25 
5.2 
Site approval and activation ................................................................................................. 25 
5.3 
Participants ........................................................................................................................... 25 
5.3.1 
Eligibility Criteria ........................................................................................................... 25 
5.3.1.1 
Participant selection ................................................................................................. 25 
5.3.1.2 
Participant Inclusion Criteria ..................................................................................... 25 
5.3.1.3 
Participant Exclusion Criteria .................................................................................... 26 
5.3.1.4 
Eligibility Criteria for Individuals Performing the Interventions ............................... 26 
5.3.1.5 
Co-enrolment Guidance ............................................................................................ 27 
5.3.1.6 
Screening Procedures ............................................................................................... 27 
5.3.1.6.1  Informed Consent Procedure............................................................................. 27 
5.3.1.6.2 Screening Period ................................................................................................. 28 
5.3.1.6.3 Enrolment ........................................................................................................... 28 
5.4 
Intervention .......................................................................................................................... 29 
5.4.1 
Name and Description of Investigational Medicinal Product ....................................... 29 
5.4.1.1 
ATIMPs Classified as Genetically Modified Organisms ............................................. 29 
5.4.1.2 
Source of ATIMPs ...................................................................................................... 29 
5.4.1.3 
Preparation and Labelling of the Investigational Medicinal Product ....................... 29 

   
 
 
  
Protocol V7.029Jan2019                                                                                                           Page 4 of 63 
 
5.4.1.4 
Description and Justification of Route of Administration and Dose ......................... 30 
5.4.1.5 
Name and Description of Each Non-Investigational Medicinal Drug (NIMP) ........... 30 
5.4.2 
Protocol defined clinical schedule ................................................................................ 31 
5.4.2.1 
Baseline Assessments ............................................................................................... 31 
5.4.2.2 
ATIMP administration Procedures ............................................................................ 33 
5.4.2.2.1 Pre-operative Procedures ................................................................................... 33 
5.4.2.2.2 Technique for intraocular administration of ATIMP ........................................... 34 
5.4.2.3 
Subsequent Assessments .......................................................................................... 35 
5.4.2.4 
Laboratory Procedures .............................................................................................. 36 
5.4.3  
Dispensing ..................................................................................................................... 36 
5.4.3.1 
Receipt and Storage of the Advanced Therapy Investigational Medicinal Product . 36 
5.4.4 
Dosages ......................................................................................................................... 37 
5.4.4.1 
Dosages and dosage modifications ........................................................................... 37 
5.4.5 
Accountability ............................................................................................................... 38 
5.4.6 
Compliance and Adherence .......................................................................................... 38 
5.4.7 
Concomitant Care ......................................................................................................... 38 
5.4.8 
Overdose of Trial Medication ....................................................................................... 38 
5.4.9 
Protocol Discontinuation .............................................................................................. 39 
5.4.9.1 
Participant Withdrawal ............................................................................................. 39 
5.4.9.2 
Trial Stopping Rules ................................................................................................... 39 
5.5 
Outcomes .............................................................................................................................. 39 
5.5.1 
Primary Outcomes ........................................................................................................ 39 
5.5.2 
Secondary Outcomes .................................................................................................... 40 
5.6 
Trial Assessments .................................................................................................................. 41 
5.6.1 
Early Stopping of Follow-up .......................................................................................... 43 
5.6.2 
Loss to Follow-up .......................................................................................................... 43 
5.6.3 
Trial Closure .................................................................................................................. 43 
5.6.4 
 Long Term Follow-Up After the End of the Trial .......................................................... 43 
5.7 
Sample Size ........................................................................................................................... 43 
5.8 
Recruitment and Retention .................................................................................................. 43 
5.8.1 
Recruitment .................................................................................................................. 43 
5.8.2 
Retention....................................................................................................................... 43 
5.9 
Assignment of Intervention .................................................................................................. 44 

   
 
 
  
Protocol V7.029Jan2019                                                                                                           Page 5 of 63 
 
5.9.1 
Allocation ...................................................................................................................... 44 
5.10 
Data Collection, Management and Analysis ......................................................................... 44 
5.10.1 
Data collection, management and entry ...................................................................... 44 
5.10.2 
Non-Adherence and Non-Retention ............................................................................. 45 
5.10.3 
Statistical Methods ....................................................................................................... 45 
5.10.3.1 
Statistical Analysis Plan ......................................................................................... 45 
5.10.3.2 
Statistical Methods – Primary Outcome Analysis ................................................. 45 
5.10.3.3 
Statistical Methods – Secondary Outcome Analysis ............................................. 45 
5.10.3.4 
Statistical Methods – Health Economics Analysis ................................................. 46 
5.11 
Data Monitoring .................................................................................................................... 46 
5.11.1 
Independent Data Monitoring Committee ................................................................... 46 
5.11.2 
Interim Analyses ............................................................................................................ 46 
5.11.3 
Data Monitoring for Harm ............................................................................................ 46 
5.11.3.1 
Safety reporting .................................................................................................... 46 
5.11.3.2 
Other Notifiable Adverse Events ........................................................................... 48 
5.11.3.3 
Procedures to follow in the event of female participants becoming pregnant .... 48 
5.11.3.4 
Procedures to follow in the event of the partners of male participants becoming 
pregnant 
48 
5.11.3.5 
Investigator responsibilities relating to safety reporting ...................................... 49 
5.11.3.5.1 Seriousness assessment .................................................................................... 49 
5.11.3.5.2 Severity or grading of Adverse Events .............................................................. 49 
5.11.3.5.3 Causality ............................................................................................................ 50 
5.11.3.5.4 Expectedness .................................................................................................... 50 
5.11.3.6 
Notifications .......................................................................................................... 52 
5.11.3.6.1 Notifications by the Investigator to 
 ........................................................ 52 
5.11.3.6.2  Reporting Urgent Safety Measures .................................................................. 52 
5.11.3.6.3 
responsibilities ........................................................................................ 53 
5.11.3.6.4  Reporting SUSARs in International Trials ......................................................... 53 
5.11.3.6.5 Annual Progress Reports ................................................................................... 53 
5.11.4 
Quality Assurance and Control ..................................................................................... 53 
5.11.4.1 
Risk Assessment .................................................................................................... 53 
5.11.4.2 Clinical Monitoring ...................................................................................................... 53 
5.11.4.3 Direct access to participant records .................................................................... 53 

   
 
 
  
Protocol V7.029Jan2019                                                                                                           Page 6 of 63 
 
5.11.4.4 
Trial Oversight ....................................................................................................... 53 
5.11.4.4.1 Clinical Management Team .............................................................................. 54 
5.11.4.4.2 Independent Data Monitoring Committee ....................................................... 54 
6 
Ethics and Dissemination .............................................................................................................. 54 
6.1 
Research Ethics Approval ...................................................................................................... 54 
6.2 
Regulatory Authority Approvals............................................................................................ 54 
6.3 
 Other approvals ................................................................................................................... 55 
6.4 
Protocol Amendments .......................................................................................................... 55 
6.5 
Consent or Assent ................................................................................................................. 55 
6.6 
Confidentiality ....................................................................................................................... 56 
6.7 
Declaration of Interests ........................................................................................................ 57 
6.8 
Indemnity .............................................................................................................................. 57 
6.9 
Finance .................................................................................................................................. 57 
6.10 
Archiving ............................................................................................................................... 57 
6.10.1 
Archiving of Essential Trial Documentation Relating to Traceability ............................ 57 
6.10.2 
Archiving of Other Essential Trial Documentation ........................................................ 58 
6.11 
Access to Data ....................................................................................................................... 58 
6.12 
Ancillary and Post-trial Care .................................................................................................. 59 
6.13 
Publication Policy .................................................................................................................. 59 
6.13.1 
Trial Results ................................................................................................................... 59 
7 
Ancillary Studies ............................................................................................................................ 59 
8 
Protocol Amendments .................................................................................................................. 59 
9 
References .................................................................................................................................... 61 
 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 7 of 63 
 
1 
Administrative information 
This document describes the Gene Therapy for Achromatopsia (CNGB3) trial, sponsored and co-
ordinated by MeiraGTx UK II Ltd.  
It provides information about procedures for entering participants into the trial, and provides 
sufficient detail to enable: an understanding of the background, rationale, objectives, trial 
population, intervention, methods, statistical analyses, ethical considerations, dissemination plans 
and administration of the trial; replication of key aspects of trial methods and conduct; and appraisal 
of the trial’s scientific and ethical rigour from the time of ethics approval through to dissemination of 
the results. The protocol should not be used as an aide-memoire or guide for the treatment of other 
patients. Every care has been taken in drafting this protocol, but corrections or amendments may be 
necessary. These will be circulated to registered investigators in the trial. Sites entering participants 
for the first time should confirm they have the correct version through a member of the trial team at 
MeiraGTx UK II Ltd. 
MeiraGTx UK II Ltd. supports the commitment that its trials adhere to the SPIRIT guidelines. As such, 
the protocol template is based on an adaptation of the Standard Protocol Items: Recommendations 
for Interventional Trials (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 the MeiraGTx UK II Ltd. Clinical Operations team can be contacted for further detail 
about specific items.  
1.1 
Compliance 
The trial will be conducted in compliance with the approved protocol, 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 General Data Protection Regulation 2016/679, and the National Health Service 
(NHS) Research Governance Framework for Health and Social Care (RGF). US sites will comply with 
21 CFR 312 in the Code of Federal Regulations, and the NIH Guidelines for Research Involving 
Recombinant or Synthetic Nucleic Acid Molecules (November 2013).  
The participating sites will inform MeiraGTx UK II Ltd. as soon as they are aware of a possible serious 
breach of compliance, so that MeiraGTx UK II Ltd. can fulfil its requirement to report the breach if 
necessary, within the relevant applicable timelines specified in each country in which the study is 
being conducted. For the purposes of reporting, a ‘serious breach’ is one that is likely to affect to a 
significant degree: 
 
The safety or physical or mental integrity of the participants in the trial, or 
 
The scientific value of the trial. 
1.2 
Sponsor 
MeiraGTx UK II Ltd., 92 Britannia Walk, London N1 7NQ, is the study sponsor.  
  
 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 8 of 63 
 
1.3 
Structured trial summary 
 
Primary Registry and Trial 
Identifying Number 
EudraCT 2016-002290-35 
Secondary Identifying Numbers 
MeiraGTx UK II Ltd. registration number: MGT006 
Source of Monetary or Material 
Support 
MeiraGTx UK II Ltd. 
Sponsor
MeiraGTx UK II Ltd.
Contact for Public Queries
ocularinfo@meiragtx.com
Contact for Scientific Queries 
 
 
 
 
 
 
  
Public Title
Gene Therapy for Achromatopsia (CNGB3)
Scientific Title
An open label, multi-centre, Phase I/II dose escalation trial 
of an adeno-associated virus vector (AAV2/8-
hCARp.hCNGB3) for gene therapy of adults and children 
with achromatopsia owing to defects in CNGB3 
Countries of Recruitment
United Kingdom, United States of America
Health Condition
Achromatopsia
Intervention(s)
Open label, non-randomised, dose-escalation (
 
 
  
 
 
, Phase I/II study, by subretinal 
administration of AAV2/8-hCARp.hCNGB3 in up to 36 
participants with achromatopsia owing to mutations in the 
CNGB3 gene. 
Key Inclusion and Exclusion Criteria 
Key Inclusion Criteria:  
 
Aged 3 years or older (children will be included only 
once the maximal tolerated dose has been determined) 
 
Achromatopsia caused by mutations in CNGB3 
 
Evidence of preservation of photoreceptors at the 
macula 
 
Able to undertake age-appropriate clinical assessments 
 
Willing to give consent for the use of blood and blood 
components collected throughout the trial for the 
investigation of immune response to ATIMP 
 
Key Exclusion Criteria:  
 
Females who are pregnant or breastfeeding 
 
Intra-ocular surgery within 6 months of screening 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 9 of 63 
 
 
Ocular or systemic disorder that may preclude 
subretinal surgery and/or interfere with interpretation 
of the study results. 
 
Participated in another research study involving an 
investigational therapy for ocular disease within the last 
6 months 
 
Have any other condition that the PI considers makes 
them inappropriate for entry into the trial 
 
Are unwilling to consider the possibility of entry into a 
subsequent longer term follow up study 
Study Type 
Phase I/II, open-label, non-randomised, 2 centre, dose 
escalation in adults, followed by dose confirmation in adults 
and children with achromatopsia owing to defects in CNGB3
Date of First Enrolment 
Anticipated Q4 2016 
Target Sample Size 
Up to 36 participants 
Primary Outcome(s)
The primary outcome is safety of subretinal administration 
of AAV2/8-hCARp.hCNGB3.  
 
Safety is defined as the absence of ATIMP-related: 
 
Reduction in visual acuity by 15 ETDRS letters or 
more 
 
Severe unresponsive inflammation 
 
Infective endophthalmitis 
 
Ocular malignancy 
 
Grade III or above non-ocular SUSAR 
Safety will be assessed for 6 months after the intervention 
in this study, and a further 4.5 years in a separate 
subsequent study. 
Key Secondary Outcomes 
The secondary outcomes are measures of the efficacy of 
the intervention, which will be performed on an individual 
participant basis and will be descriptive in nature. Efficacy 
will be assessed at several time points between 3 to 6 
months after the intervention:  
 
1) Any improvement in visual function from baseline that is 
greater than the test-retest variation for that test and is 
sustained for at least two consecutive assessments. 
 
2) Any improvement in retinal function from pre 
intervention that is greater than the test-retest variation 
and measurable by electroretinography (ERG). 
 
3) Quality of life measures. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 10 of 63 
 
1.4 
Roles and responsibilities 
Agreements that include detailed roles and responsibilities will be in place between participating 
sites and MeiraGTx UK II Ltd. 
These membership lists are correct at the time of writing; please see terms of reference 
documentation in the TMF for current lists. 
1.4.1 
Protocol contributors 
Name 
Affiliation 
Role and responsibilities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.2 
Independent Data Monitoring Committee 
 
Name 
Affiliation 
Role and responsibilities 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 11 of 63 
 
2 
Trial Diagram  
 
 
 
Adults & children with cone dysfuction syndrome consistent with CNGB3
deficiency confirmed by CI & PI
Genetic screening for CNGB3 by accredited laboratory (before or after 
consent)
Participant/parent/guardian (and child) given participant information sheet 
and asked to provide informed consent/assent
Screening/baseline tests (genetic testing, health status, physical examination, 
vital signs, ocular examination, visual acuity, OCT, electrophysiology, 
pregnancy
Oral Steriods prescribed 1 week BEFORE Surgery
ATIMP administration surgery (1 of 3 doses)
1 day post-operative follow up
3 days post-operative follow up
1 week post-operative follow up
2 weeks post-operative follow up
4 weeks post-operative follow up
6 weeks post-operative follow up
3 months post-operative follow up
6 months post-operative follow up
Recruitment to Long-term Follow Up Study
Clinical assessments during follow up period including ocular exam, labs & visual 
assessments 
Antibiotic & corticosteroid prescribed 1-
4 weeks post-surgery 
Ineligible/
unwilling 
to consent  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 12 of 63 
 
3 
Abbreviations 
AAV 
Adeno-Associated Virus 
Ad
Adenovirus
AE
Adverse Event
AF 
Autofluorescence 
AO 
Adaptive Optics 
AR 
Adverse Reaction 
ATIMP 
Advanced Therapy 
Investigational Medicinal 
Product 
ATMP 
Advanced Therapy 
Medicinal Products 
Bd 
Bis die twice daily 
BIOM 
Binocular Indirect 
Ophthalmo Microscope 
CA 
Competent Authority 
cDNA 
complementary 
Deoxyribonucleic Acid 
CEO 
Chief Executive Officer 
cGMP 
cyclic guanosine 
monophosphate 
CI 
Chief Investigator 
CMT 
Clinical Management 
Team 
CNGB3 
Cyclic Nucleotide-Gated 
cation channel Beta-3 
CRF 
Case Report Form 
CRO 
Contract Research 
Organization 
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 
ERG
Electroretinography
ETDRS 
Early Treatment Diabetic 
Retinopathy Study 
EU
European Union
EUCTD
European Clinical Trials 
Directive 
EudraCT 
European Clinical Trials 
Database 
EudraVIGILANCE 
European database for 
Pharmacovigilance 
FAF
Fundus Autofluorescence
FDA 
(US) Food and Drug 
Administration 
FWA 
Federal Wide Assurance 
GCP 
Good Clinical Practice 
GLP
Good Laboratory Practice
GMO 
Genetically Modified 
Organism 
GMP
Good Manufacturing 
Practice 
GMSC
Genetic Modification 
Safety Committee 
GTAC 
Gene Therapy Advisory 
Committee 
hCAR 
Human Cone Arrestin 
HIPAA
Health Insurance
Portability and 
Accountability Act 
HRA  
Health Research 
Authority 
HSE 
Health and Safety 
Executive 
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference 
on Harmonisation 
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 
 
 
LCA 
Leber congenital 
amaurosis 
mfERG 
Multifocal 
Electroretinography 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 13 of 63 
 
MHRA
Medicines and 
Healthcare products 
Regulatory Agency 
mL 
Millilitre 
ms 
Millisecond 
mRNA 
Messenger RNA 
MTD 
Maximum Tolerated 
Dose 
NHS
National Health Service
NIH
National Institutes of 
Health 
NIMP 
Non-Investigational 
Medicinal Product 
OBA 
Office of Biotechnology 
Activities 
OCT 
Optical Coherence 
Tomography 
PCR 
Polymerase Chain 
Reaction 
PERG 
Pattern 
Electroretinogram 
PHI 
Protected Health 
Information 
PI
Principal Investigator
PIS
Participant Information 
Sheet 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life Year
QC 
Quality Control 
qds  
quarter die sumendus 
(four times daily) 
QOL 
Quality of Life 
QP 
Qualified Person for 
release of ATIMP 
rAAV 
Recombinant adeno 
associated virus 
REC
Research Ethics 
Committee 
RG 
Research grade 
RGF 
Research Governance 
Framework 
RNA 
Ribonucleic acid 
RPE 
Retinal Pigment 
Epithelium 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAR
Serious Adverse Reaction
SD-OCT
Spectral Domain Optical 
Coherence Tomography 
SOP 
Standard Operating 
Procedure 
SSA 
Site Specific Approval 
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 
 
 
UK
United Kingdom of Great 
Britain & Northern 
Ireland 
USA 
United States of America 
vg 
Viral Genomes 
 
 
 
WT
Wild type
 
 
 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 14 of 63 
 
4 
Introduction 
4.1 
Background and Rationale 
4.1.1 
 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 (photophobia) 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 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. 
4.1.2 
Pre-clinical data 
In preclinical studies using a murine model of CNGB3-deficiency, we have demonstrated that 
delivery of a functional copy of the hCNGB3 cDNA sequence to cone photoreceptors is associated 
with substantial improvements in cone function and morphology (Carvalho, et al 2011). Subretinal 
injection of AAV2/8-hCARp.hCNGB3 of (2.0 x 10 12 vg/mL) restores CNGB3 protein in cone outer 
segments, prolongs cone survival, and substantially improves photopic ERG amplitudes (cone-
mediated responses on electroretinography) in mice ranging in age from 15 days to 6 months. In 
younger animals improved cone function results in a complete recovery of cone-mediated vision as 
assessed by optomoter responses. These findings in mice demonstrate one of the most effective 
rescues of an animal model of a photoreceptor defect reported to date, suggesting that 
achromatopsia in humans may also benefit from gene supplementation therapy. These results are 
supported by a study by Komaromy and coworkers, demonstrating successful gene supplementation 
therapy in a dog model of the same condition (Komaromy, et al 2010).  
4.1.3 
Clinical data 
This protocol describes our group’s 3rd clinical trial of a gene supplementation therapy for inherited 
retinal disease using a recombinant AAV (rAAV) vector. In the first gene therapy trial (Bainbridge, et 
al 2008) 12 participants with severe early onset retinal dystrophy caused by mutations in the gene 
encoding RPE65 were administered rAAV vector subretinally. Vector administration was generally 
well tolerated and 6 of the 12 participants benefitted with improved visual function to varying 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 15 of 63 
 
extents during the first year. However, longer-term follow-up demonstrated that progressive 
degeneration continued and maximal improvements in retinal sensitivity were not maintained 
(Bainbridge, et al 2015). Similar observations have been described in other independent trials where 
rAAV2/2 vectors were administered for the same condition by sub retinal administration (Maguire, 
et al 2008; Cideciyan, et al 2008; Cideciyan, et al 2013). In these studies, subretinal administration of 
rAAV vectors resulted in visual improvement without significant safety concerns. We are currently 
investigating the safety and potential efficacy of a new optimized rAAV2/5 vector for delivery of 
RPE65 in a trial with a similar design and protocol to this proposed trial 
 
 in up to 27 adults and children with retinal dystrophy caused by mutations 
in RPE65. 
4.1.4 
Rationale 
We predict that in CNGB3-related Achromatopsia, delivery of a cDNA sequence encoding a 
functional CNGB3 protein using gene supplementation will lead to measurable improvements in 
visual function within 6 months. 
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 photophobia and nystagmus. The CNGB3 gene encodes the beta subunit of the cone 
photoreceptor-specific cGMP-gated cation channel, which is critical for cellular responses to light. 
Absence of this beta subunit results in absent/extremely poor cone function and hence very poor 
daylight vision. Although loss of cone photoreceptor cells may occur in a limited number of patients, 
the rate of cell death is very slow, resulting in retinas containing surviving but non-functioning cones. 
Improvement of cone function by provision of CNGB3 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 photophobia even if limited cortical plasticity affects the potential for 
improved acuity or colour vision. 
4.1.5 
Assessment and management of risk 
A gene therapy trial in human volunteers should not put the participants at disproportionate risk and 
for this reason should be restricted to individuals with serious disorders where effective treatments 
are not available. CNGB3-related Achromatopsia results in profound sight impairment from birth or 
early infancy. The condition is currently untreatable, but there is a real possibility that gene therapy 
could offer a significant benefit in terms of improved sight and quality of life (QOL), based on our 
own experience from the first clinical trial for ocular gene therapy, subsequent ocular gene therapy 
trials elsewhere (Maguire, et al 2008; Cideciyan, AV et al 2008 and 2013), and pre-clinical data 
demonstrating improved outcome in CNGB3-related achromatopsia. Possible benefits of improved 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 16 of 63 
 
cone-photoreceptor function include, improved visual acuity, improved colour perception, and relief 
from disabling photophobia.  
The safety of the proposed approach will be enhanced by restricting transgene expression to the 
target tissue by virtue of rAAV vector tropism and the cone-specific promoter sequence used, and by 
restricting the intervention to one eye only in each participant. The risk of adverse effects will be 
further minimised by minimising the volume of vector suspension administered and by targeting it 
surgically to the cone rich region of the central retina. 
Risks to participant safety in relation to the ATIMP is classified using the MHRA definition as Type C 
(Markedly higher than the risk of standard medical care). General risk management includes the 
detailed review of all participants, appropriate intervals between ATIMP administration to successive 
participants, the dose escalation plan, and limiting the risks to children by initially demonstrating an 
acceptable safety profile in adults. In addition, the schedule of participants’ assessments has been 
designed to identify the short term and the longer-term risks. Details of specific risks and their 
management strategies are outlined below. 
4.1.5.1  Risk of immune responses to AAV2/8-hCAR.hCNGB3 
The main risk of inflammation will be during the early postoperative period after ATIMP 
administration, before vector capsids are degraded. The risk of inflammation during this period will 
be minimised by pre- and post-operative prophylactic treatment using topical and systemic 
corticosteroids. . Persistent intraocular inflammation will be managed by topical corticosteroid 
therapy, with systemic corticosteroids where indicated.  
The risk of inflammation is likely to be highest during the early postoperative period after ATIMP 
administration, before vector capsids are degraded. The risk of inflammation during this period will 
be minimised by pre- and post-operative prophylactic administration of topical and systemic 
corticosteroids. In our first clinical trial of gene therapy, intra-ocular delivery of an AAV2/2 vector 
was followed by transient intraocular inflammation in 3 of 12 participants. In our subsequent trial of 
gene therapy, intraocular administration of an AAV2/5 has been well tolerated in majority of 
participants to date.  A minority of participants developed an episode of intraocular inflammation 
involving the posterior segment, which responded to further administration of systemic 
corticosteroids. 
4.1.5.2  Risk of vector transmission to other organs 
Biodistribution studies suggest that following subretinal injection of AAV, anterograde and trans-
synaptic transport of small amounts of vector genome from the retina to central visual structures 
may occur (Stieger, et al 2008). This is considered most likely to result from off target transduction of 
retinal ganglion cells following reflux of vector suspension into the vitreous. Since only tiny amounts 
of vector are likely to reach the brain and a cone photoreceptor-specific promoter will be used, the 
possibility of transgene expression causing toxicity in the brain is considered to be highly unlikely. 
Minimal vector amounts (i.e. a few hundred vector genome copies) might be traced in other organs 
like lymph nodes, spleen and liver but similarly to the brain; transgene expression causing toxicity is 
highly unlikely due to the cone photoreceptor-specific promoter. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 17 of 63 
 
4.1.5.3  Risks of insertional mutagenesis and oncogenesis 
The possibility of oncogenic events due to vector-mediated insertional mutagenesis cannot be 
excluded with certainty, but available evidence suggests it to be unlikely given that (i) AAV vector 
genomes integrate into host chromosomes at a very low frequency (Nowrouzi, et al 2012), (ii) a 
limited number of AAV particles will be administered, and (iii) the eye predominantly contains non-
dividing cells and consequently ocular tumours are very rare. Furthermore, oncogenesis has not 
been reported following injection of AAV into thousands of rodent eyes. Even when we injected AAV 
vectors intraocularly in a large number of tumour-prone p53-/- mice, we found no evidence of 
malignant transformation of retinal cells (Balaggan, et al 2012).  In the highly unlikely event that an 
intraocular tumour does arise, the comprehensive monitoring procedures described in Section 
5.4.2.3 of the protocol will enable early detection and thus prompt appropriate management.  
4.1.5.4  Risk of germline transmission 
The risk of inadvertent germline transmission is very small. In a number of studies using a variety of 
animal models involving various routes of administration, including intraocular injection, inadvertent 
germline transmission by AAV vectors has not been detected. Similarly, we detected no vector 
genomes in semen in our previous retinal gene therapy clinical trial (Bainbridge, et al 2008). 
Systemic intravascular administration of 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 8 x 1010 to 2 x 10 12 vg/kg were administered, 
considerably higher than the doses proposed for subretinal injection in this study. Whilst this 
indicates there may be some potential for inadvertent germline transmission following the systemic 
delivery of high doses of vector, the possibility of such an event following the microsurgical delivery 
of tiny amounts of vector to intraocular compartments is considered to be remote. Participants who 
are fertile and sexually active will be requested to use double-barrier contraception for at least 12 
months following ATIMP administration. 
4.1.5.5  Risk of surgical adverse effects 
The risk of significant surgical adverse effects is similar to the standard surgical care for other 
common forms of vitreo-retinal disorders.  To manage the risk of surgical adverse events, only highly 
experienced surgeons will perform the procedure. Complications of surgery are typically managed 
effectively by medication or further surgical intervention but can rarely result in lasting harm to 
sight. The risk of lasting severe impairment of sight from vitrectomy surgery is approximately 1 in 
1000. We have identified some reduction in outer retinal thickness and deterioration in acuity in 2 of 
the 12 participants in our previous clinical trial, believed to result from temporary retinal 
detachment which is a deliberate consequence of targeted administration of the vector suspension, 
but no other significant surgical adverse effects.  
Delivery of ATIMP to the subretinal space will be performed by standard surgical vitrectomy. This 
will involve a 3-port pars plana vitrectomy followed by injection of ATIMP using a fine cannula 
through small retinotomies, resulting in a temporary retinal detachment. Previous gene therapy 
clinical trials have shown that the bleb of subretinal ATIMP suspension can be expected to resolve 
spontaneously over the course of the first 24 to 48 hours postoperatively as the fluid is absorbed by 
the underlying retinal pigment epithelium.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 18 of 63 
 
Potential complications of surgery specifically include persistence of the subretinal vector bleb, the 
development of retinal tears, and persistent postoperative intraocular inflammation. We will 
minimise any risk to visual function by limiting ATIMP delivery to the area of retina most likely to 
benefit, and by leaving the contralateral eye untreated. Retinal detachment caused by persistent 
vector bleb or intraoperative retinal tear is expected to occur in fewer than 1 in 100 procedures and 
can be effectively managed in the majority by retinopexy, with or without intraocular tamponade. 
Vitrectomy surgery is a standard technique, commonly performed for a wide range of indications. 
Injection of fluids under the retina is less commonly performed but is a standard step in surgery for 
subretinal haemorrhage, and an adjunctive technique in the management of retinal detachment. 
4.1.5.6  Risk of adverse effects of short-term corticosteroids 
Candidates will be screened for contra-indications to transient immune suppression by 
corticosteroids; in particular, a history of uncontrolled hypertension, diabetes mellitus, tuberculosis, 
renal impairment, osteoporosis, gastric ulceration, severe affective disorder and 
immunocompromised status. The possibility of steroid-induced adverse effects will be monitored 
regularly. In particular, blood pressure and blood glucose will be measured, as will renal function and 
liver function (at baseline, 1 day, 7 days, 2 weeks and 4 weeks after surgery). 
4.1.5.7  Risks of investigations performed during assessment and follow up  
The majority of investigations are non-invasive routine clinical tests and present no significant risk. 
Venepuncture causes temporary discomfort, occasionally bruising/swelling and rarely infection at 
the site of puncture.  
4.1.5.8  Risk of rod photoreceptor dysfunction 
The aim of the intervention is to improve the function of cone photoreceptor cells. Rod 
photoreceptors exposed to the ATIMP are not expected to benefit but may be subject to adverse 
effects of the surgical intervention or ATIMP. We plan to minimize any adverse effect by targeting 
the ATIMP to the central retina where the cone photoreceptors predominate. In addition, the use of 
a cone specific promoter to drive CNGB3 expression specifically in cones, will minimise inappropriate 
ectopic expression in rod photoreceptors. Moreover, should cone photoreceptor-mediated vision be 
improved by the gene therapy, any dysfunction of rod photoreceptor cells is expected to be evident 
only in a dimly illuminated environment. 
No rod dysfunction has been described to date in the animal models (mouse and dog) used to 
demonstrate the potential of gene supplementation therapy in CNGB3-associated achromatopsia. 
4.1.5.9  Risk of thinning of the fovea  
Thinning of the retina in the macula (macular thinning) has been detected in 6/10 participants after 
subfoveal delivery of AAV vector in our previous clinical trial. Macular thinning was typically 
apparent within 3 months and subsequently non-progressive. Associated thinning of the 
photoreceptor cell (outer nuclear) layer was evident, with variable disruption of the photoreceptor 
ellipsoid (inner segment) zone. Participants in the proposed trial may develop macular thinning but 
since the central macula comprises predominantly cone photoreceptor cells that have no function in 
achromatopsia, we do not expect this to affect vision adversely. 
 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 19 of 63 
 
4.1.5.10 
Risk of visual imbalance 
Individuals affected by achromatopsia have severe sight impairment with no colour perception from 
birth. Improvement of retinal function by intervention later in development is expected to lead to 
new visual experiences. While these are expected to be positive, unpleasant visual sensations might 
also be experienced. 
4.1.5.11 
 Conclusion on the risk-benefit ratio 
In summary, the risks associated with the intervention are justified by the potential for individual 
participants to benefit, and by the scientific value of the trial to the development of treatments for 
other individuals similarly affected.  
4.1.6 
Explanation for Choice of Comparators 
There is no currently approved treatment for achromatopsia caused by mutations in CNGB3. The 
comparator will be the contralateral eye.  
4.2 
Objectives 
4.2.1  Primary Objective 
The primary research objective is to assess the safety of a AAV2/8 vector for hCNGB3 gene 
replacement in the retina. Safety is defined as: 
Safety is defined as the absence of an ATIMP-related: 
 
Reduction in visual acuity by 15 ETDRS letters or more 
 
Severe unresponsive inflammation (defined below) 
 
Infective endophthalmitis 
 
Ocular malignancy 
 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
Severe unresponsive inflammation will be defined according to the Standardisation of Uveitis 
Nomenclature (SUN) Working Group grading system (Jabs et Al.  2005) i.e. 
 
anterior chamber cells 3+ (26-50 cells in a field size of 1mm x 1-mm slit-beam), or  
 
anterior chamber flare 3+ (marked, iris and lens details hazy), or  
 
vitreous haze 3+ (Ophthalmology 1985; 92:467-71) 
that fails to improve by 2 steps (or to grade 0) during a 6-week period. 
4.2.2  Secondary Objective 
The secondary research objective is to determine whether a AAV2/8 vector for hCNGB3 gene 
replacement in the retina can improve retinal function, visual function and quality of life. 
4.3 
Trial Design 
This is an open-label phase I/II dose-escalation trial to determine the safety and efficacy of 
subretinal administration of the ATIMP in participants with CNGB3-related achromatopsia.  
In the dose escalation phase, up to 18 adult participants will be administered a single dose of the 
ATIMP in cohorts of 3 participants at a time. Based on toxicity data, the IDMC will make a 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 20 of 63 
 
recommendation on the dose to administer to the next cohort of 3 participants. The IDMC may 
recommend additional participants at a given dose before deciding how to proceed. 
Adults are defined as participants aged 16+ in the UK and aged 18+ in the US. 
Once an acceptable safety profile has been established in adults, up to 18 additional participants, 
who may be children or adults, will be included. The IDMC will agree the maximum tolerated dose in 
adults before recommending administering up to this dose in the expansion phase.  
Safety and efficacy will be assessed for 6 months following the intervention by clinical examination 
and special investigations according to the schedule in section 5.6 of the protocol. 
4.3.1.1 Separate longer term follow up study 
Safety will be assessed on an ongoing basis in this study. When the 6 months follow up time point 
has been reached in this study, participants will subsequently be invited to enrol in a separate 
follow-up study where they will be assessed for safety up to 60 months following ATIMP 
administration.  The duration of long-term follow-up is therefore consistent with the 
recommendations of the current CHMP Guideline on Follow-up of Patients Administered with Gene 
Therapy Medicinal Products (EMEA/CHMP/GTWP/60436/2007) of 22 October 2009, where it is 
stated that, for viral vectors without integration, latency or reactivation potential, a brief clinical 
history and sample testing should be performed pre-treatment, at 3, 6 and 12 months after 
treatment, and then yearly thereafter for a minimum of 5 years (and, if non-clinical tests or evidence 
from other clinical trials using identical vectors or modifications of vectors indicate a potential for 
integration or late re-activation, the monitoring should be extended to continue yearly after those 5 
years until data indicate that there is no longer any risk to be followed). Further, although the FDA 
Guidance for Industry: Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events 
(November 2006) recommends a standard 15-year period of follow-up, it is also noted that a shorter 
period of follow up may be appropriate if the ATIMP does not integrate and has no potential for 
latency and reactivation.    
The follow-up study will be a non-intervention study designed to collect data on longer term safety 
and efficacy at the equivalent of 9, 12, 18, 24, 36, 48 and 60 months following ATIMP administration; 
as such, participants in both studies will be followed up more frequently than recommended in the 
guidance, as additional assessments following ATIMP administration are included in the initial study 
(at weeks 1, 2, 4 and 6) and in the long-term follow up study (at months 9 and 18). The-follow up 
study will have a separate protocol, participant information and consent process, and will be 
submitted for separate ethical review. Participants in the current study will be strongly encouraged 
to join the follow up study as part of their ongoing clinical review, but there will be no obligation on 
their part to do so.  It is acknowledged that, despite encouragement, participants may elect not to 
participate in the long-term follow-up study; however, in this motivated population, where 
individuals are typically monitored by their specialist closely and regularly, this is considered unlikely. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 21 of 63 
 
4.3.2  IMP administration Review and Dose Escalation Criteria and Process 
Up to 18 adult participants (as defined in section 4.3) will be administered a single dose of ATIMP in 
a total volume of 0.5mL, according to the dose-escalation criteria: 
1) low dose  
 
 
2) intermediate dose  
 
3) high dose  
 
 
Once a maximal tolerated dose is established, up to 18 further participants aged 3 years or older will 
continue to be administered vector up to the highest dose observed to be tolerated in adults. 
In order to explore optimal dosing within safe limits (
 
), additional doses may be administered in order to maximise therapeutic effect, 
whilst maintaining the safety profile of the product. Any dose that differs from those described 
above will not exceed the highest titre of 
. The Chief Investigator, Medical Monitor 
and IDMC chair will confirm additional doses and participant numbers in advance of them being 
administered. The actual titre to be administered will be recorded in the eCRF. 
4.3.2.1  Dose escalation criteria and Dose Limiting Events 
Dose escalation will be undertaken in adults, based on an escalation rule around dose-limiting events 
(DLEs). An IDMC will review data from a minimum of 6 weeks of follow up from each cohort of 3 
participants, before recommending the next dose to be assessed in a further cohort of patients. 
A DLE is defined as any of the below occurring during the 6 weeks following administration, at least 
possibly related to the ATIMP, not surgery alone: 
 
Reduction in visual acuity by 15 ETDRS letters or more 
 
Severe unresponsive inflammation (defined below) 
 
Infective endophthalmitis 
 
Ocular malignancy 
 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
Severe unresponsive inflammation will be defined according to the Standardisation of Uveitis 
Nomenclature (SUN) Working Group grading system (Jabs et Al.  2005) i.e. 
 
anterior chamber cells 3+ (26-50 cells in a field size of 1mm x 1-mm slit-beam), or  
 
anterior chamber flare 3+ (marked, iris and lens details hazy), or  
 
vitreous haze 3+ (Ophthalmology 1985; 92:467-71) 
that fails to improve by 2 steps (or to grade 0) during a 6-week period. 
Review of safety data will be undertaken by the IDMC prior to each dose escalation. Children will be 
included at up to the highest safe ATIMP dose recommended by the IDMC, once a safety profile has 
been established in adult participants according to the dose escalation rules.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 22 of 63 
 
4.3.2.2 Dosing process 
4.3.2.2.1 Cohort 1 
ATIMP will first be administered at the lowest dose to one adult participant only. This participant will 
be monitored for signs of toxicity for a period of 6 weeks.  If there is no DLE as defined above after a 
minimum of 6 weeks, ATIMP will continue to be administered at the same dose to 2 further adult 
participants. In the event of a DLE in the first adult in the cohort, a discussion will be held with the 
IDMC to agree a plan of action for administering the ATIMP to further adults. The IDMC will review 
the data collected on this cohort up to 6 weeks following ATIMP administration to the 3rd participant.  
4.3.2.2.2 Cohort 2 
In the event that there is no DLE in any participant, the IDMC will recommend administering ATIMP at 
the intermediate dose level to a single adult participant.  If there is no DLE after a minimum of 6 weeks, 
ATIMP will continue to be administered at the same dose to 2 further adult participants. In the event 
of a DLE in the first adult in the cohort, a discussion will be held with the IDMC to agree a plan of action 
for administering the ATIMP to further adults. The IDMC will again review the data available on this 
next cohort of adult participants up to 6 weeks following ATIMP administration to the 3rd participant.  
4.3.2.2.3 Cohort 3 
In the event that there is no DLE in any participant, the IDMC may recommend administering ATIMP 
at the highest dose level to a single adult participant.  If there is no DLE after a minimum of 6 weeks, 
ATIMP will be administered at the same dose to 2 further adult participants. In the event of a DLE in 
the first adult in the cohort, a discussion will be held with the IDMC to agree a plan of action for 
administering the ATIMP to further adults.  
4.3.2.2.4 Additional considerations 
In the event of a DLE in one of the 3 participants at a given dose, the cohort will be expanded at the 
same dose level. The IDMC will review the safety data and confirm that additional participants may 
be treated at this dose. The IDMC may recommend that the same dose of ATIMP is administered to 
additional participants. The dose escalation will continue until IDMC are comfortable on review of 
the accumulating data, to recommend a maximum dose to be administered to children, or 3 
participants have been administered the highest dose without any DLEs, or until at least 2 
participants among a cohort of 3 to 6 participants experience DLEs (i.e., ≥33% of patients with a DLE 
at that dose level), in which case the recommended dose will be the level below this toxic dose. In 
the event that 1 or 2 DLEs are seen at the first dose level, the IDMC may recommend administering a 
lower dose to that described in the protocol to a cohort of participants. 
Table 1: Dose escalation table 
Number of DLEs 
Low dose 
Participants 1-3 
Participants 4-6 
Action 
Details 
0/3 
 
Increase 
Give intermediate dose to next cohort of 
participants 
1/3
Remain
Give low dose to another cohort of participants (Pt 
4-6) 
≥ 2/3 
 
Stop 
MTD not found. Consider lower dose 
 
≤ 1/6 
Increase/stop 
Has higher dose been tried? 
No: Give intermediate dose to next cohort of 
participants 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 23 of 63 
 
Yes: MTD found – low dose
≥ 2/6
Stop
MTD not found. Consider lower dose
Intermediate dose
Participants 1-3
Participants 4-6
Action
Details
0/3
Increase
Give high dose to next cohort of participants
1/3
Remain
Give intermediate dose to participants 4-6
≥ 2/3
Decrease/stop
Give low dose to 3 more participants. If 6 
participants already had low dose, stop. MTD found 
– low dose. 
 
≤ 1/6 
Increase/stop 
Has higher dose been tried? 
No: Give high dose to participants 1-3 
Yes: MTD found – intermediate dose 
 
≥ 2/6 
Decrease/stop 
Give low dose to participants 4-6. If 6 participants 
already had low dose, stop. MTD found – low dose 
High dose 
Participants 1-3 
Participants 4-6 
Action 
Details 
0/3 
 
Remain 
MTD found – give high dose to participants in 
confirmation phase 
1/3
Remain
Give high dose to participants 4-6
 
≥ 2/3 
 
Decrease/stop 
Give intermediate dose to participants 4-6. If 6 
participants already had intermediate dose, stop. 
MTD found – intermediate dose 
 
1/6 
Stop 
MTD found – high dose 
 
≥ 2/6 
Decrease/Stop 
Give intermediate dose to participants 4-6. If 6 
participants already had intermediate dose, stop. 
MTD found – intermediate dose 
 
4.3.2.2.5 Confirmatory safety phase 
MeiraGTx UK II Ltd. will seek IDMC agreement on the highest dose that can be administered in the 
expansion cohort.  This may include up to 18 participants who may be adults or children. 
Recruitment into this expansion cohort can begin at any dose level up to the IDMC agreed highest 
dose level. Children are defined as those aged 15 and under in the UK and 17 and under in the US. 
Children will be administered up to the maximal tolerated dose determined in adults. Having 
identified a group of children who may be willing to participate in the study, the CI will prioritise 
ATIMP administration to older candidates in the first instance. The first child administered ATIMP 
will be monitored for safety for a period of 6 weeks.  If there is no adverse event consistent with the 
above definition of a DLE after 6 weeks, ATIMP will continue to be administered to up to 17 further 
participants. In the event of an AE as described above in the first child, a discussion will be held with 
the IDMC to agree a plan of action for administering the ATIMP to further children. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 24 of 63 
 
5 
Methods 
5.1 
Site Selection 
The trial sponsor MeiraGTx UK II Ltd. has overall responsibility for site and investigator selection. 
5.1.1 
Study Setting 
The study settings are academic hospitals and academic research centres selected for their ability to 
perform the intervention and assessments required of this protocol. Data will be collected from 3 
centres: one in the United Kingdom (UK) and two in the United States (US).  
5.1.2 
Site/Investigator Eligibility Criteria 
Once a site has been assessed as being suitable to participate in the trial, the trial team will provide 
them with a copy of this protocol and the ATIMP Investigator Brochure.  
To participate in this trial of gene therapy for achromatopsia (CNGB3), investigators and trial sites 
must fulfil a set of criteria that have been agreed by the Clinical Management Team (CMT) as 
defined below. 
Eligibility criteria: 
 
A named clinician is willing and appropriate to take Principal Investigator responsibility 
 
Suitably trained staff are available to recruit participants, enter data and collect samples 
 
Suitably trained and certified staff are available to undertake clinical assessments 
 
The site has access to a sufficient number of potential participants to meet their enrolment 
objectives  
 
The site has access to all specialised equipment/devices needed for clinical assessments 
 
The site should be able to archive traceability data for a minimum of 30 years’ post expiry 
date of the ATIMP 
 
The site should have a pharmacy that is able to store, prepare and dispense ATIMP 
appropriately 
 
The site should be able to store, prepare, dispense, and administer ATIMP appropriately 
 
Trial sites meeting eligibility criteria and that are accepted by the CMT as being suitable to recruit to 
the trial, will be issued with the Gene Therapy for Achromatopsia (CNGB3) Trial Master File (TMF) 
documentation to use when applying for local approvals as applicable.  
5.1.2.1 Principal Investigator’s (PI) Qualifications and Agreements 
The investigator(s) must be willing to sign a Clinical Trial Agreement and an Investigator Agreement 
to comply with the trial protocol (confirming their specific roles and responsibilities relating to the 
trial, and that their site is willing and able to comply with the requirements of the trial). This includes 
confirmation of appropriate qualifications, familiarity with the appropriate use of any investigational 
products, agreement to comply with the principles of GCP, maintaining up to date GCP certification, 
to permit monitoring and audit as necessary at the site, and to supervise and maintain documented 
evidence of all staff at the site who have been delegated significant trial related duties. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 25 of 63 
 
5.1.2.2 Resourcing at site 
The investigator(s) should be able to demonstrate a potential for recruiting the required number of 
suitable participants within the agreed recruitment period (i.e., the investigator(s) regularly provide 
clinical care for the target population). They should also have an adequate number of qualified staff 
and facilities available for the foreseen duration of the trial to enable them to conduct the trial 
properly and safely.  
Sites will be expected to complete a delegation of responsibilities log and provide staff contact 
details.  
5.2 
Site approval and activation 
The regulatory authorisations for the trial requires that the Medicines and Healthcare products 
Regulatory Agency (MHRA) and US Food and Drug Administration (FDA) are supplied with the names 
and addresses of all participating site Principal Investigators. Clinical Operations staff at MeiraGTx UK 
II Ltd. will ensure this information is provided to both the MHRA and FDA.  
On receipt of the signed Clinical Trial Agreement and Investigator Agreement, approved delegation 
of responsibilities log and staff contact details, written confirmation will be sent to the site PI. The 
trial manager or delegate will notify the PI in writing of the plans for site initiation. Sites will not be 
permitted to recruit any patients until a letter for activation has been issued.  
The site must conduct the trial in compliance with the protocol as agreed by the Sponsor and, by the 
competent authorities, and which was given favourable opinion by the UK Health Research Authority 
(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 
Participants 
5.3.1 
Eligibility Criteria 
5.3.1.1 Participant selection 
The eligibility criteria for this trial have been carefully considered and are the standards used to 
ensure that only medically appropriate participants are entered. Participants not meeting the 
criteria should not be entered into the trial for their safety, and to ensure that the trial results can be 
appropriately used to make future treatment decisions for other people with similar diseases or 
conditions. It is therefore vital that exceptions are not made to these eligibility criteria. 
Participants will be considered eligible for enrolment in this trial if they fulfil all the inclusion criteria 
and none of the exclusion criteria as defined below. 
5.3.1.2 Participant Inclusion Criteria 
Inclusion in the trial will be limited to individuals who: 
1. Are aged 3 years or older (children, as defined in Section 4.3 will be enrolled only once the 
MTD has been determined) 
2. Have achromatopsia confirmed by a retinal specialist (CI or PI) 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 26 of 63 
 
3. Have homozygous or compound heterozygous missense or null mutations in CNGB3 
confirmed in an accredited laboratory 
4. Have evidence of relative photoreceptor survival at the macula, which will be assessed by 
OCT +/- AO 
5. Are able to give informed consent or assent, with or without the guidance of their 
parent/guardian where appropriate: children aged 3-6 years will not be asked to provide 
assent 
6. Are able to undertake age-appropriate clinical assessments at the trial sites as specified in 
the protocol 
7. If female and of child bearing potential, are willing to use an effective form of birth control 
(hormonal or double barrier method of birth control; or abstinence) for at least 12 months 
following ATIMP administration (Section 4.1.5, Assessment and Management of Risk)  
8. If male, are willing to use barrier and spermicide form of contraceptive or maintain sexual 
abstinence for at least 12 months following ATIMP administration 
9. Females of childbearing potential will have a negative pregnancy test on the day of ATIMP 
administration. Participants are considered not of childbearing potential if they are pre-
pubescent, surgically sterile (i.e. they have undergone a hysterectomy or bilateral 
oophorectomy) or post-menopausal 
10. Are willing to give consent for the use of blood and blood components collected throughout 
the trial for the investigation of immune responses to the ATIMP 
5.3.1.3 Participant Exclusion Criteria 
Individuals will be excluded who: 
1. Are females who are pregnant or breastfeeding 
2. Have uncontrolled gastro-oesophageal reflux or are using non-steroidal anti-inflammatory 
drugs on a regular basis at the time of screening 
3. Have a known allergy to any of the non-investigational drugs to be used in the trial as 
defined in Section 5.4.1 
4. Have participated in another research study involving an investigational medicinal therapy 
for ocular disease within the last 6 months 
5. Have any other condition that the CI/PI considers makes them inappropriate for entry into 
the trial, inclusive of but not limited to a history of the following:                                                                      
hypertension, diabetes mellitus, tuberculosis, renal impairment, immunocompromised 
state, osteoporosis, gastric ulceration or severe affective disorder 
6. Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere 
with interpretation of the study results 
7. Have had intraocular surgery within 6 months of screening 
8. Are unwilling to consider the possibility of entry into a subsequent longer term follow up 
study 
5.3.1.4 Eligibility Criteria for Individuals Performing the Interventions 
Individuals performing the interventions will be limited to those qualified by training and experience 
to perform those interventions.  
Surgery will be performed only by a qualified vitreo-retinal surgeon. The ATIMP will be administered 
by designated individuals at each study site to promote consistency of the intervention. The CI has 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 27 of 63 
 
developed a training programme that involves any designated individuals being trained in person by 
the CI. This may involve observations of the procedure being performed in the UK or the US. The 
completion of this training is one of the criteria that will be satisfied prior to site activation. 
5.3.1.5 Co-enrolment Guidance 
Individuals who have participated in another research study involving an investigational medicinal 
therapy for ocular disease within the last 6 months, will not be eligible for enrolment in this study.  
5.3.1.6 Screening Procedures  
Written informed consent to enter the trial must be obtained from participants, or 
parents/guardians/person with legal responsibility (including legal authorities) for children, after 
explanation of the aims, methods, possible benefits and potential hazards of the trial and before any 
trial-specific procedures are performed or any blood is taken for the trial. The only procedures that 
may be performed in advance of written informed consent being obtained are those that would be 
performed on all patients in the same situation as a usual standard of care. However, results of any 
procedures that were performed as part of the usual standard care within the screening/baseline 
window of this study and prior to enrolment on this study may be used for baseline/screening if the 
subjects provided informed consent for the use of the prior obtained results 
5.3.1.6.1  
Informed Consent Procedure 
Written informed consent will be taken from each participant (or parent/guardian if the participant 
is a child) by the chief/principal investigator or delegated clinician following appropriate explanation 
of the aims, methods, possible benefits and risks of the study. The Investigator or designee will 
explain that the participants are under no obligation to enter the trial and that they can withdraw at 
any time during the trial, without having to give a reason, and without their clinical care being 
affected. No clinical trial procedure will be conducted prior to taking consent from the participant. 
The consent process will be managed during at least 2 meetings. At an initial meeting, information 
will be presented to potential participants in a form appropriate to their level of understanding. In 
the case of children, they and their legal guardian(s) will be offered the support of an independent 
counsellor or advisor. Potential participants will be provided with the relevant patient information 
and given time (a minimum of 24 hours) to consider their decision. 
At a subsequent meeting, potential participants will be provided with a further opportunity to ask 
questions and to sign the consent form. Children will be invited to give their verbal (noted in their 
medical notes) or written assent to participation where this is age appropriate (i.e., children aged 
over 6 years). Children aged over 6 years will be included in the trial only if they assent to 
participate. A copy of the signed Informed Consent form will be provided to the participant. The 
original signed form will be retained at the study site and a copy placed in the medical notes. 
If new safety information results in significant changes in the risk/benefit assessment, the 
participant information sheet and consent form will be reviewed and updated if necessary, and 
participants will be re-consented as appropriate. 
Children who become of adult age (i.e. 16 in the EU, 18 in the US) during the study will be re-
consented as adults at the time of the next visit. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 28 of 63 
 
5.3.1.6.2 
Screening Period 
Screening procedures will take place only after the informed consent form has been signed by the 
participant/parent/guardian. However, if test results are available from the subject’s routine clinical 
examination results within 6 months of the screening visit and the subject has consented to allow 
the use of those tests, then those screening tests will not need to be repeated. 
Participants will undergo genetic screening for CNGB3 mutations at an accredited laboratory prior to 
enrolment. 
Participants will be screened to ensure there are no contra-indications for transient immune 
suppression, in particular: hypertension, diabetes mellitus, tuberculosis, renal impairment, 
immunocompromised state, osteoporosis, gastric ulceration or severe affective disorder.  
Screening assessments are listed below (and set out under the column headed ‘Screening’ in the 
Trial Assessments Table 2, Section 5.6):  
1. Genetic testing 
2. Medical history and concomitant medication (includes prescription medications and 
over-the-counter preparations) used by the patient from enrolment date, during the 
study, and at the study drug discontinuation visit will be documented and recorded on 
eCRF. 
3. Physical examination 
4. Vital signs including blood pressure 
5. Ocular examination 
6. Visual acuity 
7. Contrast sensitivity 
8. Spectral Domain Optical Coherence Tomography (SD-OCT)  
9. Electrophysiological assessment 
 
A letter from the general practitioner detailing the health status of the participant may be requested 
if the clinician deems it appropriate to confirm eligibility for the trial. 
These assessments must have been completed within 6 months prior to enrolment. In addition, 
females of childbearing potential will undergo a pregnancy test at screening and again on the day of 
ATIMP administration. 
5.3.1.6.3 
Enrolment 
Participants who fulfil the inclusion criteria based on the results of all screening assessments and 
pregnancy test will be enrolled in the trial. The ATIMP will be administered within 6 months of 
enrolment. If the ATIMP is not delivered within 6 months of enrolment, all screening tests with the 
exception of genetic testing and electrophysiological assessment will be repeated and eligibility for 
enrolment re-assessed. 
Participants who withdraw or are withdrawn from the study for any reason prior to ATIMP 
administration may be substituted in the study. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 29 of 63 
 
5.4 
Intervention 
5.4.1 
Name and Description of Investigational Medicinal Product 
AAV2/8-hCARp.hCNGB3 is an advanced therapy investigational medicinal product: specifically, a 
gene therapy product. 
AAV2/8-hCARp.hCNGB3 is a gene transfer agent to be developed for the treatment of a form of 
achromatopsia caused by defects in the gene encoding CNGB3. This is the beta subunit of the cGMP-
gated ion channel that plays an essential role in the cone phototransduction pathway. Disruption of 
the gene prevents the conversion of light to an electrical signal, leading to lack of cone function and 
visual dysfunction. Recombinant adeno-associated virus (rAAV) mediated gene transfer of a copy of 
the normal CNGB3 gene to the cone photoreceptors, results in stable, long term transgene 
expression and improves visual function significantly in both rodents and dogs with CNGB3 gene 
defects  
AAV2/8-hCARp.hCNGB3 consists of a linear single strand of DNA packaged in a rAAV protein capsid 
of serotype 8. The AAV2/8-hCARp.hCNGB3 genome incorporates 290 nucleotides of the wild-type 
AAV2 ITR (Inverted Terminal Repeats) sequences that provide in cis the packaging signal, a cDNA 
encoding human CNGB3, a human cone-specific genomic promoter (cone arrestin, CAR) and a SV40 
(simian virus 40) polyadenylation signal. The icosahedral capsid consists of three related capsid 
proteins, VP1, VP2, and VP3. AAV has a compact macromolecular structure and forms stable viral 
particles 20nm in diameter. The vector particles are replication incompetent. 
5.4.1.1 ATIMPs Classified as Genetically Modified Organisms 
The ATIMP (AAV2/8-hCARp.hCNGB3) is classified as a genetically modified organism under the 
Genetically Modified Organisms (Contained Use) Regulations 2000. 
The Health and Safety Executive (HSE) must be notified of each UK clinical trial site administering the 
ATIMP for first use of premises for genetic modification activities before the activities commence. A 
risk assessment of the activities has been carried out and has been reviewed by the local Genetic 
Modification Safety Committee (GMSC). Internal approval at site for the GMO activities has been 
gained.  
Each clinical trial site administering the ATIMP in the US must obtain local Institutional Biosafety 
Committee approval to administer recombinant nucleic acid molecule material to human 
participants. Trial sites that receive support for recombinant or synthetic nucleic acid molecule 
research from the National Institutes of Health (NIH) must register the protocol with the NIH Office 
of Science Policy (OSP) for review prior to initiating trial activities.  
5.4.1.2 Source of ATIMPs 
The ATIMP has been manufactured at the 
 
 in accordance with current Good 
Manufacturing Practice for clinical trial materials. The product is released by an EU QP. 
5.4.1.3 Preparation and Labelling of the Investigational Medicinal Product 
Preparation and labelling of the investigational medicinal product will be completed in accordance 
with the relevant GMP guidelines.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 30 of 63 
 
The ATIMP is a recombinant serotype 2/8 adeno-associated viral vector containing a human CNGB3 
cDNA driven by a 0.4 kb fragment of the human CAR promoter.  
US Federal regulations require that a drug should be the subject of an approved marketing 
application before it is transported or distributed across state lines. As such, in order to ship ATIMP 
to investigators, the sponsor will submit an IND application in order to obtain an exemption from the 
FDA with regard to the marketing approval requirement. 
5.4.1.4 Description and Justification of Route of Administration and Dose 
Efficient transduction of the cone photoreceptor cells requires the ATIMP (rAAV2/8-hCARp.hCNGB3) 
to be administered to the subretinal space. 
Delivery of vector suspension to the subretinal space will be performed by standard surgical 
vitrectomy. This will involve a 3-port pars plana vitrectomy followed by injection of vector 
suspension using a fine cannula through small retinotomies into the subretinal space, resulting in a 
transient retinal detachment. Previous gene therapy clinical trials have shown that the bleb of 
subretinal vector suspension can be expected to resolve spontaneously over the course of the first 
24 to 48 hours postoperatively as the fluid is absorbed by the underlying retinal pigment epithelium. 
Risks to visual function will be minimized by controlling the area of ATIMP delivery, and by leaving 
the contralateral eye untreated. Injection of fluids under the retina is less commonly performed but 
is a standard step for delivery of surgical dyes and in surgery for macular degeneration performed at 
 and elsewhere. 
The highest ATIMP dose that is intended to be delivered to the trial participants is based on dose-
limiting toxicity that was seen in an earlier trial of AAV2-mediated gene therapy for LCA2, where 1 
mL of ATIMP at 
 was found to be the highest safe dose that could be administered 
subretinally. As toxicity in this context is a complex interaction between local retinal effects, wider 
ocular effects and systemic effects, a conservative decision was taken to use the confirmed safe titre 
(
), despite using a smaller maximal volume (0.5 mL) and thus a slightly lower dose. As 
AAV2/8-mediated transduction of cone photoreceptors in non-human primates is efficient over a 
wide range of titres, including much lower titres than used in this study (Vandenberghe et al, Sci 
Transl Med 3, 88ra54) we are confident that the CNGB3 transgene can be delivered to the cones 
effectively at 
. 
5.4.1.5 Name and Description of Each Non-Investigational Medicinal Drug (NIMP) 
1. Cefuroxime or cefazolin or vancomycin antibiotic given at usual dose at end of surgery (standard 
dose as prophylaxis for post-operative infection) 
2. Betamethasone or dexamethasone given at usual dose at end of surgery (standard dose as 
prophylaxis for post-operative inflammation) 
3. Chloramphenicol 0.5% or ofloxacin (topical antibiotic) 4 times daily for 7 days following ATIMP 
administration  
4. Dexamethasone 0.1% (topical steroid) 4 times daily for 4 weeks following ATIMP administration  
3 and 4 above will be administered to minimise inflammation and protect against infection 
postoperatively. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 31 of 63 
 
5. Omeprazole:  
 
In adults 20mg per day for 4 weeks 
 
In children aged up to 16 weighing 5 kg to less than 10 kg (11 lb to less than 22 lb): 5 mg 
taken once per day  
 
In children aged up to 16 weighing 10 kg to less than 20 kg (22 lb to less than 44 lb): 10 mg 
taken once per day  
 
In children aged up to16 weighing 20 kg (44 lb) or more: 20 mg taken once per day 
6. Prednisolone or Prednisone (oral steroid) as prophylaxis against potential intraocular immune 
responses: 
0.5 mg/kg daily for one week prior to ATIMP administration 
1mg/kg daily for the first week following ATIMP administration 
0.5mg/kg daily for the second week following ATIMP administration 
0.25mg/kg daily for the third week following ATIMP administration 
0.125mg/kg daily for the fourth week following ATIMP administration 
All Non- Investigational Medicinal Products (NIMPs) are licensed within the EU and US and will be 
procured from standard hospital stock. 
Sites will maintain a system that allows adequate reconstruction of NIMP movements and permits 
recording of which participants received which NIMPs during the trial, with an evaluation of the 
compliance where necessary. 
5.4.2 
Protocol defined clinical schedule 
5.4.2.1 Baseline Assessments 
A detailed assessment of visual function and retinal imaging of both eyes will be performed 
preoperatively as outlined in Section 5.6 (Table 2: Trial Assessments). For assessments requiring 
multiple baselines, testing is preferred on separate days within a maximum 6-month period to allow 
for day-to-day variation and test-retest variability for individual participants. However, it is 
acknowledged that a balance will be achieved between what is pragmatic and appropriate for the 
different tests on an individual basis. Each set of baseline measurements may take up to 3 days to 
perform in total. In some instances, results for protocol specified baseline tests may be available as a 
part of routine clinical examination within 6 months.  As such, if the subject provides informed 
consent to use the results from the previously conducted tests, then these assessments will not 
need to be repeated at baseline.   
Visual assessment results will be sent for reading and analysis to independent reading centres within 
the UK and US.  For both sites imaging with OCT, fundus autofluorescence and fundus photography 
will be reviewed by the site teams but also sent for independent analysis by the 
 
, during the course of the trial. Adaptive optics images will be sent 
to the 
 for reading and Octopus perimetry and Microperimetry will 
be sent to the 
 reading centre. All 
images will be saved under pseudo anonymised patient identifiers and images will only be taken of 
the patient’s eye to ensure that patients remain unidentified.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 32 of 63 
 
Up to 10 mL of blood will be sampled in order to assess baseline levels of circulating antibodies 
against, AAV8 and of circulating antibodies against rAAV serotype 8 so that immunological responses 
to vector capsids can be determined following ATIMP administration (collectively described as 
serology in Table 2: Trial Assessments). We anticipate that that majority of participants will have no 
detectable pre-existing circulating antibodies against AAV8. The presence or absence of circulating 
antibodies will not affect recruitment of the participant. All serology tests will be performed at the 
Institutional Laboratory in the UK. 
There is wide variability in the abilities of individual children to perform certain of the proposed 
investigations; the evaluations for children will be restricted to those tests that individuals are able 
to perform reliably.  
Tests that will be performed in all participants are: 
 
Serological tests 
 
Blood pressure 
 
Haematology 
 
Biochemistry 
 
Ocular examination 
 
Colour fundus photography 
 
Spectral Domain Optical coherence tomography (SD-OCT) 
 
Fundus Autofluorescence (FAF) imaging  
 
Best corrected visual acuity  
 
Full-field electroretinography (ERG) 
 
Pattern electroretinography (PERG) 
 
Tests that will be performed where possible are: 
 
Contrast sensitivity  
 
Reading assessment 
 
Static perimetry 
 
Colour vision testing 
 
Light-sensitivity testing 
 
QOL questionnaire 
 
Further details of clinical assessments can be found in the Gene Therapy for Achromatopsia (CNGB3) 
study manual. Images taken at all timepoints will be sent for independent reading and analysis at 
centres in both the UK and US.  
 (i) Ocular examination and retinal imaging.  
Ocular examination using slit lamp biomicroscopy will assess the anatomical integrity of the eyes and 
allow quantification of intraocular inflammation. During the examination, intraocular pressure will 
be determined by tonometry.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 33 of 63 
 
Retinal imaging includes colour fundus photography, fundus autofluorescence (FAF) imaging and SD-
OCT. 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. 
(ii) Functional and Participant-Related Outcome Assessments.  
Where possible the participant will complete an age appropriate Impact of Visual Impairment (IVI) 
vision-specific quality of life questionnaire, and EQ5D-5L questionnaire and EQ5D-Y 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 two 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.  
Colour vision will be assessed comprehensively using plate tests and computerised tests probing 
colour discrimination along all 3 axes of colour.  
Retinal sensitivity will be determined using static perimetryand full field stimulus testing (FST) where 
available. FST may be performed for enrolled patients at participating sites. The retinal locus of 
fixation will also be determined using microperimetry.  
Full-field electroretinography (ERG) and 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. For young 
children, this procedure may be performed under general anaesthesia. 
ERG data will be analysed and interpreted by dedicated full-time Clinical Visual Electrophysiology 
Consultants with extensive experience and who are directly involved in defining ISCEV standards.  
5.4.2.2 ATIMP administration Procedures 
 
The protocol describes the intended surgical technique for ATIMP administration. The surgical 
procedure may be modified on a case-by-case basis in the interests of safety; any modification will 
be documented in the operation notes and eCRF. Consent to record the surgery will be requested of 
the participant.  Intraocular surgery will be recorded by video via the operating microscope as 
described in the consent process. Relevant video recordings and images will be stored alongside the 
trial database. 
5.4.2.2.1 
Pre-operative Procedures 
For prophylaxis against potential intraocular immune responses to the ATIMP, participants will be 
prescribed a course of oral prednisolone, commencing at a daily dose of 0.5 mg/kg one week prior to 
ATIMP administration; 1mg/kg for the first week following administration, 0.5mg/kg for the second 
week, 0.25mg/kg for the third week and 0.125mg/kg for the fourth week.  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 34 of 63 
 
Preoperative procedures and intraocular administration of ATIMP will be as described in the Gene 
Therapy for Achromatopsia (CNGB3) study manual. 
5.4.2.2.2 
Technique for intraocular administration of ATIMP 
The choice of eye for ATIMP administration will be the poorer-seeing eye as identified by the 
participant and CI/PI taking into account ocular dominance and visual acuity. 
The recombinant vector will be delivered in the form of a suspension of viral vector particles injected 
intraocularly (subretinally) under direct observation using an operating microscope. This procedure 
will include a 3-port pars plana vitrectomy followed by injection of ATIMP using a fine cannula 
through small retinotomies into the subretinal space. 
Surgery will be performed under general anaesthesia. The eye and face will be prepared using 
povidone iodine solution as per routine intraocular surgery. The face and eye will be covered with an 
adhesive sterile plastic drape. An opening will be made at the point of the palpebral fissure and a 
wire speculum inserted to retract the upper and lower eyelids. The speculum and all intraocular 
instruments will be sterilised according to standard local operating procedures. Three pars plana 
sclerotomies will be sited to enable intraocular infusion, endoillumination probe and surgical 
instruments. The fundus will be viewed by means of a binocular indirect ophthalmo microscope 
(BIOM) indirect viewing system or a contact lens. To minimise the possibility of unplanned retinal 
detachment or preretinal fibrosis, vitrectomy (aspiration of vitreous gel) will be performed using a 
disposable cutter.  
Intraocular administration of the viral vector suspension (AAV2/8-hCARp.hCNGB3) will be performed 
using a subretinal cannula advanced through the retina. 
Under direct visualisation, the ATIMP will be injected under the neurosensory retina, causing a 
localised retinal detachment with a self-sealing non-expanding retinotomy. The aim will be to target 
the ATIMP to the central macula. If appropriate, the bleb of ATIMP will be manipulated to the target 
area using a fluid-air exchange. The site and extent of the subretinal bleb of ATIMP suspension will 
be documented by video recording.  
Following intraocular administration of ATIMP, the retinal periphery will be examined for any 
unplanned retinal breaks for appropriate management by retinopexy with or without intraocular 
tamponade at the discretion of the operating surgeon. Intraocular instruments used subsequent to 
ATIMP delivery are disposable and will be destroyed after a single use. Sclerotomies may be secured 
using a vicryl suture. Standard doses of cefuroxime antibiotic and betamethasone will be 
administered subconjunctivally as prophylaxis against postoperative infection and inflammation 
respectively. Bupivacaine will be administered for analgesia. The surgical procedure may be modified 
on a case-by-case basis in the interests of safety; any modification will be documented in the 
operation notes and CRF. 
On the basis of our own experience, we anticipate that the subretinal ATIMP bleb will resolve 
spontaneously during the first 48 hours. 
Surgery may be performed, as is conventional for intra-ocular procedures, on a day-case basis and 
participants will be managed subsequently as out-patients, although hospital-based accommodation 
may be used for convenience. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 35 of 63 
 
5.4.2.3 Subsequent Assessments 
On the first postoperative day a full clinical ocular examination will be performed. In particular, 
visual acuity, intraocular pressure, the degree of postoperative intraocular inflammation and the 
area of any residual retinal bleb will be documented. Fundus photography, autofluorescence 
imaging, ocular examination, intraocular pressure and SD-OCT will be performed at day 1 and each 
subsequent visit post ATIMP administration. 
A standard post-vitrectomy treatment regimen of topical antibiotic (chloramphenicol 0.5% qds for 7 
days) and steroid (dexamethasone 0.1% qds for 4 weeks) will be prescribed to minimise 
inflammation and protect against infection postoperatively.  
Intraocular pressure of greater than 30 mmHg will be managed using appropriate ocular 
antihypertensive therapy.  
Participants will be maintained on oral prednisolone (or other as appropriate) for 4 weeks following 
administration of ATIMP as described above (Section 5.4.2.2.1: Pre-operative procedure). The 
possible development of steroid-induced adverse effects will be monitored regularly. In particular, 
blood pressure will be measured and blood glucose, renal function and liver function will be 
evaluated through blood biochemistry at the time points specific in Table 2: Trial Assessments. 
Both safety and efficacy of the ATIMP will be evaluated at various time points up to 6 months after 
ATIMP delivery. Evaluations will comprise primarily, ocular assessments. The nature and schedule 
(Section 5.6: Trial Assessments) of these is described below. 
(i) Clinical assessment of intraocular inflammation 
The degree of intraocular inflammation will be assessed by slit-lamp biomicroscopy at each time 
point. A temporary intraocular inflammatory response is expected following vitrectomy surgery. This 
is typically evident clinically on slit-lamp biomicroscopy as ‘flare’ and cells in the anterior chamber 
and can be of moderate (2+ cells) intensity. The degree of intraocular inflammation is expected to 
decline over the course of the first 4 weeks following the surgical procedure, at which time the 
routine topical and systemic immunosuppression will be discontinued. Prolonged or severe 
intraocular inflammation, or deterioration in visual acuity that may be related to intraocular 
inflammation, will be investigated and managed conventionally with further topical and/or systemic 
immunosuppression. 
(ii) Evaluation of immune responses 
Up to 10 mL of blood will be sampled to measure immune response. Antibody responses to AAV 
capsid proteins will be investigated by ELISA at baseline and at 4 weeks, 3 months, and 6 months 
following ATIMP administration. 
(iii) Evaluation of biodistribution 
Systemic biodistribution of vector genomes will be assessed by PCR analysis of tears a compressed 
cellulose sponge placed under the eye lid until swollen), saliva (a minimum of 100 μL) and serum (1 
mL) at 1 day and at 4 weeks following intraocular ATIMP administration. The test will be carried out 
in the
. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 36 of 63 
 
(iv) Assessment of visual function and retinal imaging 
Assessment of visual function and retinal imaging will be performed as outlined in Section 5.6 (Trial 
Assessments). They will be carried out with the same methods applied for the baseline tests (see 
section 8.6 for details) to allow direct comparison of the data sets. These assessments will be 
scheduled over a period of a day for visits at day 1, day 3, day 7, week 2, week 4 and week 6 after 
surgery, and up to 4 days for baseline examinations, and 3 months, 6 months following ATIMP 
administration.  For day 1 and 3 refraction cannot reliably be measured. Therefore, the most recent 
refraction measurement will be used. 
All participants (adults and children) will need to be able to perform reliable visual acuity testing and 
SD-OCT imaging, which are the principal clinical assessments both for safety and efficacy. Other 
clinical assessments will be undertaken as appropriate for the ability of individual participants, since 
there is wide variation in the abilities of individual children to perform such tests reliably; the 
evaluations for individuals may be restricted to those tests that they are able to perform reliably.  
Additional assessments may be performed if considered appropriate for the management of any 
unexpected adverse effects. These may be submitted as urgent safety measures and protocol 
amendments performed where required. Conversely, tests that cannot be reliably performed by a 
particular participant may be discontinued for that participant. This is not anticipated for the key 
clinical assessments such as visual acuity test or SD-OCT imaging because participants who are 
unable to perform such tests will be excluded from the study at the screening phase. Evaluation of 
safety and efficacy will also be performed on an individual participant basis. We do not anticipate 
that any discontinuation will affect significantly the overall quality of the safety and efficacy 
evaluation. 
5.4.2.4 Laboratory Procedures 
Blood serum will be processed within 
 to investigate any immune 
responses to the ATIMP: 
1. anti-AAV8 neutralising antibodies 
2. anti-AAV8 antibodies using an ELISA  
Blood serum, saliva and lacrimal fluid will be processed in the 
 to 
assess dissemination of ATIMP after delivery, where the number of rAAV vector genome copies will 
be measured using a polymerase chain reaction (PCR) approach.  
Whole blood will be processed at the 
, or a CLIA-
accredited molecular diagnostic laboratory in the US, for CNGB3 mutation screening. Haematology 
and biochemistry samples and screen will be carried out at the Trust associated laboratories, or an 
accredited laboratory in the US.  
5.4.3  Dispensing 
5.4.3.1 Receipt and Storage of the Advanced Therapy Investigational Medicinal Product 
The batch of ATIMP will be stored at either the 
 
 or other approved storage facility (details of storage will be specified in the 
ATIMP Management Plan).  

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 37 of 63 
 
The product, which is stable at ≤–50° Celsius, will be stored at -70° Celsius or below in secure 
temperature controlled and monitored -80° Celsius freezers. No further manufacturing or testing will 
take place at the 
. Shipping of ATIMP will be on dry ice, accompanied by a temperature-
monitoring device.  
The ATIMP vector will be dispensed on the same day of administration according to study specific 
working instructions, with a 1-hour window for administration after ATIMP has thawed at room 
temperature.  
5.4.4 
Dosages  
5.4.4.1 Dosages and dosage modifications 
Trial participants will receive a single dose of ATIMP within the range proven to be safe in the 
preclinical animal studies. These are anticipated to be as described below: 
1) low dose  
 
 
2) intermediate dose  
 
3) high dose  
 
  
In order to explore optimal dosing within safe limits (
 
), additional doses may be administered in order to maximise therapeutic effect, 
whilst maintaining the safety profile of the product. Any dose that differs from those described 
above will not exceed the highest titre of 
. The Chief Investigator, Medical Monitor 
and IDMC chair will confirm additional doses and participant numbers in advance of them being 
administered. The actual titre to be administered will be recorded in the eCRF.  
The ATIMP will be produced and stored at a titre appropriate for the high dose (
) 
and diluted immediately prior to intraocular administration in Hartmann’s solution at the time of 
administration for lower doses. The CI/PI will prepare the appropriate dilution and this will be 
checked in the operating theatre by a second individual prior to administration. The check will be 
recorded in the patient’s source data notes. 
Further details for dose-escalation criteria are included in Sections 5.3.2. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 38 of 63 
 
5.4.5 
Accountability 
The ATIMP will be prescribed for a particular participant by one of the investigators and handled 
according to the ATIMP management plan applicable for each site.  
For accurate accountability, the following information will be recorded when the ATIMP is 
administered: 
i. 
date 
ii. 
participant identification 
iii. 
batch number 
iv. 
volume and dose of ATIMP administered 
v. 
name of Principal Investigator administering ATIMP 
vi. 
ATIMP name/code 
vii. 
Trial reference code 
viii. 
Expiry date 
Surplus ATIMP will be destroyed according to existing SOPs, using methods suitable for destruction 
of genetically modified organisms. 
A system will be set-up to ensure the traceability of the ATIMP from the starting material, through to 
administration to the participant and destruction or final disposition. A comprehensive ATIMP 
management plan and associated Working Practices and forms will be in place to ensure that the 
required accountability and traceability data is collected and retained.  
5.4.6 
Compliance and Adherence 
Full compliance is expected since the ATIMP will be surgically delivered by the CI or a delegated 
vitreo-retinal surgeon. The aim is to target the administered volume into the subretinal space. Any 
deviation from this will be noted in the CRF. See section 5.4.8 (Overdose of trial medication) about 
the assessment of adherence to the protocol defined delivery of the product.  
5.4.7 
Concomitant Care 
Concomitant use of other medications should be avoided unless clinically necessary and should be 
used with caution, and appropriately documented on study logs where used. All concomitant 
medications (including steroids) must be recorded in the eCRF from the day of informed consent. 
5.4.8 
Overdose of Trial Medication 
Intraocular administration of the ATIMP will be performed by the operating surgeon (CI or a 
delegated vitreo-retinal surgeon). The volume of ATIMP delivered to the target site will be measured 
from the scale located on syringe/ plunger and recorded in the CRF.  
Any overdose will be reported to the sponsor. This is a Phase I/II exploratory study and the possible 
impact of any overdose will be considered in the final analysis. Given that this is a single 
administration study, the trial participant will not be withdrawn but the collected data will be 
analysed separately in comparison with the data from the participant’s baseline assessments and 
from other treated participants. Any concern about accurate dosing may warrant suspension of the 
trial pending appropriate investigation. 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 39 of 63 
 
Overdose of ATIMP may result in development of Adverse Events of various severities that will be 
recorded and reported as outlined in Section 5.11.3. 
5.4.9 
Protocol Discontinuation 
5.4.9.1 Participant Withdrawal 
In consenting to the trial, participants consent to ATIMP administration, trial follow-up and data 
collection.  
As participation is entirely voluntary, participants may choose to withdraw from the trial at any time 
without penalty or loss of benefits to which they would otherwise be entitled. Although not obliged 
to give a reason for withdrawal, a reasonable effort should be made to establish and document this 
in the withdrawal eCRF, whilst fully respecting the participants rights.  
Should a participant withdraw from the study, a withdrawal eCRF documenting the reason for 
withdrawal (if provided) will be completed, in addition to the procedures and eCRF for the final visit 
(6 month) assessments, with the participant’s consent. However, participants will be encouraged to 
participate in any of the planned schedule for the trial whilst arranging a visit for routine (annual) 
clinical follow-up.  
Participants who withdraw prior to ATIMP administration will be regarded as off-protocol and their 
primary ophthalmologist will resume normal standard of care. Any participant who withdraws prior 
to administration of ATIMP may be replaced in the study.  
Participants who withdraw from the study after ATIMP administration will be strongly encouraged to 
have follow-up investigations with their consent, so that the consequences of ATIMP administration 
can be documented and the data analysed. The CMT may choose to replace a participant who 
withdraws after ATIMP administration.  
5.4.9.2 Trial Stopping Rules 
The Chief Investigator and Sponsor retain the right to terminate the study. Specific circumstances 
that may precipitate such termination are as follows: 
 
1. 
Unanticipated severe adverse event in this or other studies indicating a potential health 
hazard caused by the ATIMP 
2. 
Significant protocol deviation and lack of compliance and cooperation on the part of an 
investigator, which endangers the safety of the participants or the validity of the study 
3. 
Death of a participant at any time point after ATIMP administration that is possibly, 
probably, or definitely related to the ATIMP 
4. 
The occurrence of a non-ocular malignancy at any point after gene transfer that is possibly, 
probably, or definitely related to the ATIMP 
5.5 
Outcomes 
5.5.1 
Primary Outcomes 
The primary outcome is defined as any of the below occurring during the 6 weeks following 
administration, at least possibly related to the ATIMP, not surgery alone: 
 
Reduction in visual acuity by 15 ETDRS letters or more 

 
 
Gene Therapy for Achromatopsia (CNGB3) 
Protocol V7.0 29Jan2019 
 
Page 40 of 63 
 
 
Severe unresponsive inflammation  
 
Infective endophthalmitis 
 
Ocular malignancy 
 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
5.5.2 
Secondary Outcomes 
The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an 
individual participant basis and will be descriptive in nature.  
 
Any improvements in visual function from baseline that are greater than the test-retest 
variation and are sustained for at least two consecutive assessments.  
 
Any improvement in retinal function from pre – intervention that is greater than test-retest 
variation and measurable by electrophysiology (pattern ERG, multifocal ERG or full-field 
ERG). Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire 
and the EQ5D-5L and EQ5D-Y.  

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 41 of 63 
 
5.6 
Trial Assessments 
Table 2: Trial assessments 
 
Screening
Baseline1,  
ATIMP 
admin 
D1  
D3  
W1 
W2 
W4 
W6 
W12 
W24 
Flexibility of schedule (+ days) 
- 6 months
Day 0 
+ 
0D 
+ 
1D 
+ 
2D 
+ 
4D 
+ 
7D 
+ 
7D 
+ 
14D 
+ 14D
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Informed consent
•
Physical exam
•
Medical history
•
•
•
•
•
•
•
Eligibility determination
•
ATIMP administration
★
Adverse event review 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Concomitant medication review 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Genetic screening6
• 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
• 
 
 
 
• 
 
 
 
 
 
 
 
 
Vital signs2 
• 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Haematology 
 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Biochemistry/glucose/liver and renal 
function 
 
• 
 
 
 
• 
 
• 
• 
• 
 
 
 
Serology
•
•
•
•
PCR
•
•
QoL questionnaires (IVI and EQ5D-5L)
•
•
Visual acuity3
•
•
•
•
•
•
•
•
•
•
•
•
Colour vision assessments 
 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Contrast sensitivity 
• 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Reading speed 
 
• 
• 
• 
 
 
 
 
 
 
 
• 
• 
Static perimetry
•
•
•
•
•
Full Field Stimulus Testing
•
•
•
•
•
•
Ocular examination 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 42 of 63 
 
 
Screening
Baseline1,  
ATIMP 
admin 
D1  
D3  
W1 
W2 
W4 
W6 
W12 
W24 
Flexibility of schedule (+ days)
- 6 months
Day 0
+
0D 
+
1D 
+
2D 
+
4D 
+
7D 
+
7D 
+
14D 
+ 14D
Fundus photography 
 
• 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Optical coherence tomography 
• 
• 
• 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
Adaptive optics imaging 
 
• 
• 
 
 
 
 
 
 
 
 
 
• 
Fundus autofluorescence 
 
• 
• 
 
 
 
 
 
 
 
 
• 
• 
Pattern Electroretinography,4  
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Full field Electroretinography,4
• 
 
 
 
 
 
 
 
 
 
 
 
• 
Photoaversion assessments 
 
•5
•5
•5
 
 
 
 
 
 
 
• 
• 
 
1 Baseline assessments may be performed on the same day where considered logistically and clinically appropriate 
2 Measurements for vital signs include: blood pressure, pulse, respiration rate, arterial oxygen saturation, temperature, height and weight 
3 Visual acuity at day 1 and 3 will be assessed using the previous refraction. 
4 ERG assessments may be performed under general anaesthesia if considered appropriate 
5 Photoaversion Questionnaire only to be completed at one baseline visit 
6 Not required to be repeated if previous result available from an accredited laboratory  
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 43 of 63 
 
5.6.1 
Early Stopping of Follow-up 
If a participant chooses to discontinue their trial treatment, they should continue to be followed up 
as closely as possible to the follow-up schedule defined in the protocol, providing they are willing. If, 
however, the participant exercises the view that they no longer wish to be followed up either, this 
view must be respected, and the participant withdrawn entirely from the trial. MeiraGTx UK II Ltd. 
should be informed of the withdrawal. Data already collected will be kept and included in analyses 
according to the intention-to-treat principle for all participants who stop follow up early.  
Participants who stop trial follow-up early may be replaced. 
5.6.2 
Loss to Follow-up 
This is a highly motivated patient group who are likely to remain committed to the research. 
Continued follow up of all participants will be strongly encouraged whilst being mindful of the 
importance of ensuring the autonomy of participants in regard to their treatment decisions and 
willingness to continue to participate in the trial.  
5.6.3 
Trial Closure 
The end of the entire trial is considered the last follow-up visit of the last participant. For each 
participant, the trial will terminate at the last scheduled visit 6 months following ATIMP 
administration. The MHRA and FDA will be notified of the end of the trial within 90 days of its 
completion. 
5.6.4 
 Long Term Follow-Up After the End of the Trial 
At the end of this trial, participants will be invited to enrol in a follow-up study to determine the 
longer-term safety and efficacy up to 60 months’ post treatment administration. 
5.7 
Sample Size 
This is a Phase I/II trial to establish safety and assess indicators of potential efficacy of the ATIMP, 
therefore there is no formal sample size calculation. The trial will enrol up to 36 participants (up to 
18 in the dose escalation phase and up to a further 18 in the confirmatory phase), as described in 
section 4.3.2.2. The limited number of participants is necessitated by the rare nature of the disease 
under investigation. We estimate that inclusion of up to 36 participants will be sufficient to 
determine the safety and tolerability of the intervention.  
5.8 
Recruitment and Retention 
5.8.1 
Recruitment 
Most participants will be recruited through 
, or the 
 
 or on referral by ophthalmologists within or outside the UK or US. Members of their direct 
clinical care team will approach potential participants in the first instance to discuss whether they 
would like to consider participating. Potential participants may also contact the trial team 
independently. We expect to recruit up to 36 participants within a period of 36 months.  
5.8.2 
Retention 
Participants will be supported to remain in follow-up by regular contact as per the protocol, 
provision of a 24-hour hotline to a member of the trial team. 
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 44 of 63 
 
5.9 
Assignment of Intervention 
5.9.1 
Allocation 
All participants will receive the same intervention in this open label, non-randomised trial: subretinal 
administration of AAV2/8-hCARp.hCNGB3 to one eye. The dose received by each participant will 
depend on the time/order of their enrolment in the trial according to the sequence of dose 
escalation, and the extent of dose limiting events (see sections 4.3.2 and 5.4.4 for dose escalation 
information). Children will be enrolled in the trial only once the safety profile and recommended 
dose have been established in adults. 
5.10 Data Collection, Management and Analysis 
5.10.1 Data collection, management and entry 
 will be responsible for data management activities for the study. 
Data will be captured in a fully validated, 21 CFR Part 11 compliant Electronic Data Capture (EDC) 
system provided by 
.   
 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. 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 45 of 63 
 
At the end of the study, PDF copies of the eCRFs for each subject and supporting information will be 
provided to sites and the Sponsor.  The electronic data will be provided to the Sponsor. 
5.10.2 Non-Adherence and Non-Retention 
Participants who withdraw from the trial after the intervention will be encouraged to participate in 
any of the planned follow-up scheduled for the trial with their consent. Data collected prior to 
withdrawal will be considered in the interpretation of results. 
Reasons for withdrawal from the trial will be documented on a withdrawal CRF where possible, in 
addition to the procedures and CRF for the final visit (6 month) assessments with the participant’s 
consent. 
5.10.3 Statistical Methods 
5.10.3.1 
Statistical Analysis Plan 
 A formal Statistical Analysis Plan (SAP) will be written by the sponsor and approved by the IDMC. 
This trial is an open label, no crossover, phase I/II trial involving a small number of participants, and 
analysis of the primary and secondary outcomes will be descriptive in nature. 
5.10.3.2 
Statistical Methods – Primary Outcome Analysis 
The primary outcome is safety of subretinal administration of the ATIMP defined as any of the below 
occurring during the 6 weeks following administration, at least possibly related to the ATIMP, not 
surgery alone: 
 
Reduction in visual acuity by 15 ETDRS letters or more 
 
Severe unresponsive inflammation  
 
Infective endophthalmitis 
 
Ocular malignancy 
 
Grade III or above non-ocular SUSAR (see section 5.11.3) 
The number of DLEs at each dose level will be summarised by cohort and overall. 
It is anticipated that the ATIMP will be administered at the MTD in up to 15 participants (6 adults in 
the dose escalation phase and up to 18 further adults and children in the confirmatory safety phase). 
Safety data relating to these participants will allow estimation of an upper bound for the true event 
rate through a 95% confidence interval. 
5.10.3.3 
Statistical Methods – Secondary Outcome Analysis 
The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an 
individual participant basis and will be primarily descriptive in nature. Standard assessments will be 
used to measure visual function and established methods of analysis, appropriate for the 
assessment will be used to evaluate the data. For specialist assessments, data will be analysed by 
the expert team member(s) who developed the assessment. Final data will be reported descriptively. 
Efficacy will be indicated by: 
1) Any improvement in visual function from baseline that is greater than the test-retest variation for 
that test and is sustained for at least two consecutive assessments. 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 46 of 63 
 
2) Any improvement in retinal function from pre – intervention assessment that is greater than test-
retest variation and measurable by electrophysiology (pattern ERG, multifocal 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 approved by the IDMC and described in the 
final report, as appropriate. 
5.10.3.4 
Statistical Methods – Health Economics Analysis 
No health economic evaluation is planned, but the collection of EQ5D would allow Quality Adjusted 
Life Years (QALYs) to be calculated.  
5.11 Data Monitoring 
5.11.1 Independent Data Monitoring Committee 
To ensure the safety and efficacy and overall trial conduct, an IDMC will be established and take part 
in the data monitoring. The IDMC will consist of members with specific expertise in ophthalmology 
and molecular genetics. The IDMC will make recommendations on the safety data prior to any dose 
changes in the dose escalation phase, and prior to the enrolment of the first participant in the dose 
expansion phase. 
Further details of the roles and responsibilities of the IDMC, including membership, relationships 
with other committees, decision making processes, and the timing and frequency of interim analyses 
(and description of stopping rules and/or guidelines where applicable) are described in detail in the 
CNGB3 Gene Therapy Trial for Achromatopsia IDMC Charter). 
5.11.2 Interim Analyses 
No formal interim analysis is planned within the trial, but periodic reports concerning participant 
safety and key efficacy outcomes will be prepared for the IDMC as agreed in the IDMC charter.    
5.11.3 Data Monitoring for Harm 
5.11.3.1 
Safety reporting 
 will be responsible for pharmacovigilance services.  
Definitions of harm of the EU Directive 2001/20/EC Article 2 based on the principles of ICH GCP 
apply to this trial.  
 
 
 
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 47 of 63 
 
Table 3: Adverse Event Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a clinical trial participant 
administered a medicinal product and which does not 
necessarily have a causal relationship with this product. 
Adverse Reaction (AR)
Any untoward and unintended response to an investigational 
medicinal product related to any dose administered 
This includes medication errors, uses outside of protocol 
(including misuse and abuse of product) 
Unexpected Adverse Reaction 
(UAR) 
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (eg 
Investigator’s Brochure for an unauthorised product or 
summary of product characteristics (SPC) for an authorised 
product. 
Serious Adverse Event (SAE) or 
Serious Adverse Reaction (SAR) 
Any AE or AR that at any dose: 
 
results in death  
 
is life threatening*  
 
requires hospitalisation or prolongs existing 
hospitalisation** 
 
results in persistent or significant disability or 
incapacity 
 
is a congenital anomaly or birth defect 
 
or is another important medical condition*** 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
* the term life threatening here refers to an event in which the participant is at risk of death at 
the time of the event; it does not refer to an event that might hypothetically cause death if it was 
more severe (e.g., a silent myocardial infarction) 
** Hospitalisation is defined as an in-patient admission, regardless of length of stay, even if the 
hospitalisation is a precautionary measure for continued observation. Hospitalisation for pre-
existing conditions (including elective procedures that have not worsened) do not constitute an 
SAE 
*** Medical judgement should be exercised in deciding whether an AE or AR is serious in other 
situations. Important AEs or ARs that may not be immediately life threatening or result in death or 
hospitalisation but may seriously jeopardise the participant by requiring intervention to prevent 
one of the other outcomes listed in the table (e.g., a secondary malignancy, an allergic 
bronchospasm requiring intensive emergency treatment, seizures or blood dyscrasias that do not 
require hospitalisation, or development of drug dependency). 
 
Adverse events include: 
 
an exacerbation of a pre-existing illness 
 
an increase in the frequency or intensity of a pre-existing episodic event or condition 
 
a condition (regardless of whether PRESENT prior to the start of the trial) that is DETECTED 
after trial drug administration. (This does not include pre-existing conditions recorded as 
such at baseline – as they are not detected after trial drug administration.) 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 48 of 63 
 
 
continuous persistent disease or a symptom present at baseline that worsens following 
ATIMP administration 
Adverse events do NOT include: 
 
Medical or surgical procedures: the condition that leads to the procedure is the adverse 
event 
 
Pre-existing disease or a condition present before ATIMP administration that does not 
worsen 
 
Hospitalisation where no untoward or unintended response has occurred e.g. elective 
cosmetic surgery 
 
Overdose of medication without signs or symptoms 
5.11.3.2 
Other Notifiable Adverse Events 
In order to manage the safety risks associated with administration of the ATIMP, all safety events 
will be reviewed within a short time frame for all participants, as described in the CNGB3 Gene 
Therapy Trial for Achromatopsia Data Management Plan.  
Pregnancy is the only additional notifiable event that requires expedited reporting. 
5.11.3.3 
Procedures to follow in the event of female participants becoming pregnant 
A pregnancy test will be conducted for all females of child bearing age and the results will be 
recorded in the medical notes before enrolling a volunteer to the trial. Females with a positive 
pregnancy test at this point will be excluded from the trial.  
A further pregnancy test will be performed on the day of administration of the ATIMP. Female 
participants with a positive pregnancy test at this point will be excluded from the trial prior to 
administration of the ATIMP.  
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that a participant might become pregnant after administration of the ATIMP. In the unlikely event 
that a participant is found to be pregnant we will notify their GP that she is participating in a gene 
therapy trial and that, although the risks involved are minimal, there is a chance of gene transfer to 
the unborn child. With the participant’s consent, we will ask the GP/obstetrician to provide us with 
regular reports about the pregnancy until delivery. The pregnancy will be reported to 
 
on a pregnancy report form within 24 hours of the investigator becoming aware of the event. The 
participant will continue to be assessed until outcome of the pregnancy. However, if the participant 
is unable or unwilling to participate further in the trial, she will be encouraged to continue clinical 
monitoring visits to assess ocular health. In this situation, we may choose to enrol another 
participant to ensure the scientific validity of the trial. 
5.11.3.4 
Procedures to follow in the event of the partners of male participants 
becoming pregnant 
Although participants are instructed to use double barrier contraception, we cannot exclude entirely 
that the partner of a participant might become pregnant after administration of the ATIMP. In the 
unlikely event that this occurs we will notify the participant’s GP that he is participating in a gene 
therapy trial and that, although the risks involved are minimal, there is a chance of gene transfer to 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 49 of 63 
 
the unborn child. With the participant’s consent, we will contact the partner to ascertain the status 
of the pregnancy and the outcome. The pregnancy will be reported to 
 on a pregnancy 
report form within 24 hours of the investigator becoming aware of the event. 
5.11.3.5 
Investigator responsibilities relating to safety reporting 
The Investigator will assume overall responsibility for evaluating and reporting adverse events. In 
urgent situations, a member of the trial team may report on their behalf, while making every effort 
to discuss the event with them. All non-serious AEs and ARs, whether expected or not, should be 
recorded in the participant’s medical notes, including all events observed following ATIMP 
administration, and in eCRF. These should be entered on to the database according to the timelines 
defined in the CNGB3 Gene Therapy trial for Achromatopsia Data Management Plan to allow 
appropriate monitoring by the CMT. SAEs and SARs should be notified to 
 immediately 
the investigator becomes aware of the event (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 be recorded in the hospital notes and the eCRF. Adverse events will be 
recorded with clinical symptoms and accompanied with a simple, brief description of the event, 
including dates as appropriate. All adverse events will be recorded until the end of the trial (refer to 
Section 5.6.3 for definition), or until pregnancy outcome in the case of pregnancy. All SAEs will be 
recorded, fully investigated and appropriately managed until resolution or stabilisation and CI sign 
off.  
5.11.3.5.1 
Seriousness assessment  
When an AE or AR occurs, the investigator responsible for the care of the participant must first 
assess whether or not the event is serious using the definition given in Table 3. If the event is 
classified as ‘serious’ an SAE form must be completed and emailed to 
 (or delegated 
body) notified within 24 hours of the investigator becoming aware of the event. 
5.11.3.5.2 
Severity or grading of Adverse Events 
The severity of all AEs and/or ARs (serious and non-serious) in this trial should be graded using the 
toxicity grading in NIH CTCAE Version 4.0 (NIH, 2009). 
Table 4: Grading of Adverse Events 
Category 
Definition 
Mild (Grade I) 
 
 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate (Grade II)
Minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental ADL* 
Severe (Grade III) 
Severe or medically significant but not immediately life 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care ADL** 
Grade IV 
Life threatening consequences; urgent intervention indicated 
Grade V 
Death related to AE 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 50 of 63 
 
* Instrumental ADL (Activities of Daily Living) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
5.11.3.5.3 
Causality 
Causality will be assessed in terms of both the ATIMP and the surgical procedures. Based on all 
available information at the time of completion of the case report form, the investigator must assess 
the causality of all serious events or reactions. It is of importance in this trial to capture and 
differentiate events related to: 
 
The ATIMP administration surgery 
 
The ATIMP 
The differentiated causality assessments will be captured in the trial specific CRF and SAE form. If the 
event is related to the ATIMP, definitions in Table 5 will be used to capture the information. Any 
event that is only related to the   ATIMP administration surgery will be classified as an Adverse 
Event.   
Table 5: Causality definitions 
Relationship 
Description 
Event Type 
Unrelated 
There is no evidence of any causal relationship 
Unrelated SAE 
Unlikely to be related 
There is little evidence to suggest that there is a causal 
relationship (e.g., the event did not occur within a reasonable 
time after administration of the trial medication). There is 
another reasonable explanation for the event (e.g., the 
participant’s clinical condition or other concomitant treatment) 
Unrelated SAE 
Possibly related 
There is some evidence to suggest a causal relationship (e.g., 
because the event occurs within a reasonable time after 
administration of the trial medication). However, the influence 
of other factors may have contributed to the event (e.g., the 
participant’s clinical condition or other concomitant treatment)  
SAR 
Probably related 
There is evidence to suggest a causal relationship and the 
influence of other factors is unlikely 
SAR 
Definitely related
There is clear evidence to suggest a causal relationship and 
other possible contributing factors can be ruled out. 
SAR
5.11.3.5.4 
Expectedness 
In view of the very limited clinical experience with the ATIMP there are at present no events 
considered as expected for the ATIMP. Therefore, any SAEs that are related to the ATIMP (i.e., 
considered a SAR) will be deemed a SUSAR (suspected, unexpected, serious adverse reaction) and 
MHRA, REC/IBC, FDA, and NIH reporting guidelines apply (see Notifications sections of the protocol). 
 
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 51 of 63 
 
Table 6: Assessment of expectedness  
Category 
Definition 
Expected 
 
 
An adverse event that is classed in nature as serious and which 
is consistent with the information about the surgery listed in 
the Investigator Brochure or clearly defined in the protocol. In 
view of the very limited clinical experience with the ATIMP 
there are at present no events considered as expected for the 
ATIMP listed in the current Investigator Brochure. 
Unexpected
An adverse event that is classed in nature as serious and which 
is not consistent with the information about the ATIMP and 
surgery listed in the Investigator Brochure* or clearly defined 
in the protocol. 
*This includes listed events that are more frequently reported or more severe than previously 
reported 
The reference document to be used to assess expectedness against ATIMP and surgery is the 
Investigator Brochure. Procedure-related adverse events cannot be considered expected to the 
ATIMP. Previous experience with AAV-mediated gene therapy in the retina indicates that the risks 
are largely limited to the eye. A temporary and/or mild decrease in visual acuity, due to detachment 
of the retina or post-surgical inflammation, is to be expected after intraocular surgery and is not 
expected to cause undue discomfort. Therefore, we have defined the success criteria for the primary 
outcome (safety) as the absence of an adverse event that has a substantial and sustained negative 
impact on vision, as well as the absence of any non-ocular SUSAR. 
Expected events associated with surgery: 
 
Temporary and/or mild decrease in visual acuity (to hand movements or better for a period 
of up to 8 weeks), due to detachment of the retina or post-surgical inflammation 
 
Ocular discomfort 
 
Epiphora 
 
Periocular swelling 
 
Diplopia 
 
Ptosis 
 
Subconjunctival or intraocular haemorrhage 
 
Corneal abrasion 
 
Retinal tear or detachment 
 
Wound leak 
 
Ocular hypotony or raised intraocular pressure 
 
Overfill or underfill of any intraocular gas tamponade 
 
Mild intra- or extra-ocular inflammation 
 
Scleral or conjunctival suture granuloma 
 
Lens opacity or dislocation 
 
Systemic adverse events related to sedation or general anaesthesia, including nerve or 
vascular injury  
 
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 52 of 63 
 
5.11.3.6 
Notifications 
5.11.3.6.1 
Notifications by the Investigator to 
 
All adverse events will be recorded in the hospital notes and the eCRF from the date of written 
informed consent until last study visit.   
Investigators should notify 
 of any SAEs and SARs occurring during this period.   After the last 
visit, any SAE reported to the investigator and considered causally related to trial treatment should 
be reported as part of the follow up study. For any participants that do not go into the follow up 
study, then SAEs that occur after the end of the trial and that may be attributed to ATIMP 
administration should be reported to the relevant regulatory agencies.  
must be notified of all SAEs and SARs within 24 hours of the investigator becoming aware of 
the event. The investigator will respond to any SAE queries raised by 
 as soon as possible. 
The SAE form must be completed by the investigator (the consultant named on the delegation of 
responsibilities list who is responsible for the participant’s care) with attention paid to the grading 
and causality of the event. In the absence of the responsible investigator, the SAE form should be 
completed and signed by a member of the site trial team and emailed as appropriate within the 
timeline. The responsible investigator should check the SAE form at the earliest opportunity, make 
any changes necessary, sign and then email to 
. Systems will be in place at the site to enable 
the investigator to check the form for clinical accuracy as soon as possible. 
The minimum criteria required for reporting an SAE are the trial number and date of birth, name of 
reporting investigator and sufficient information on the event to confirm seriousness. Any further 
information regarding the event that is unavailable at the time of the first report should be sent as 
soon as it becomes available. 
The SAE form must be scanned and sent by email to the trial team on 
 
Participants must be followed up until clinical recovery is complete and laboratory results have 
returned to normal or baseline values, or until the event has stabilised. Follow-up should continue 
after completion of trial follow-up (i.e. 6 months after delivery of ATIMP) if necessary. Follow-up SAE 
forms (clearly marked as follow-up) should be completed and emailed to 
 as further 
information becomes available. Additional information and/or copies of test results etc may be 
provided separately. The participant must be identified by trial number and date of birth only. The 
participant’s name should not be used on any correspondence and should be blacked out and 
replaced with trial identifiers on any test results if it is displayed. Such instances must also be 
reported to the CMT. 
5.11.3.6.2  
Reporting Urgent Safety Measures 
MeiraGTx UK II Ltd. or investigator may take appropriate urgent safety measures in order to protect 
research participants against any immediate hazard to their health or safety. 
If any urgent safety measures are taken the CI/PI/ MeiraGTx UK II Ltd. shall immediately (no later 
than 3 days from the date the measures are taken), give written notice as per local reporting 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 53 of 63 
 
requirements of the measures taken and the circumstances giving rise to those measures, according 
to the relevant SOP. 
5.11.3.6.3 
responsibilities 
 will follow 
 Standard Operating Procedures and a study specific Safety Management Plan 
to ensure that case processing of events occurs within appropriate regulatory timeframes. 
 will 
submit Development Safety Update Reports (DSURs) to regulatory authorities. 
5.11.3.6.4  
Reporting SUSARs in International Trials  
The mechanism for reporting SUSARs that occur outside of the UK to the MHRA, and those that 
occur outside of the US to the FDA will be covered in the trial specific Safety Management Plan. 
5.11.3.6.5 
Annual Progress Reports 
An annual progress report (APR) will be submitted to the REC within 30 days of the anniversary date 
on which the favourable opinion was given, and annually until the trial is declared ended. Annual IRB 
applications for continuing review will be submitted with sufficient time to allow review and 
approval of trial continuation.  
5.11.4 Quality Assurance and Control 
5.11.4.1 
Risk Assessment 
The Quality Assurance (QA) and Quality Control (QC) considerations for the CNGB3 Gene Therapy 
trial for Achromatopsia are based on MeiraGTx UK II Ltd. Quality Management Policy that includes a 
formal Risk Assessment, and that acknowledges the risks associated with the conduct of the trial and 
proposals of how to mitigate them through appropriate QA and QC processes. Risks are defined in 
terms of their impact on: the rights and safety of participants; project concept including trial design, 
reliability of results and institutional risk; project management; and other considerations. 
5.11.4.2 Clinical Monitoring 
The frequency, type and intensity of routine and triggered on-site monitoring will be detailed in the 
trial Monitoring Plan (MP). The MP will also detail the procedures for review and sign-off of 
monitoring reports. In the event of a request for a trial site inspection by any regulatory authority 
MeiraGTx UK II Ltd. must be notified as soon as possible. 
5.11.4.3 
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 trial related documentation 
as required. Participant consent for this must be obtained as part of the informed consent process 
for the trial. 
5.11.4.4 
Trial Oversight 
Trial oversight is intended to preserve the integrity of the trial by independently verifying a variety of 
processes and prompting corrective action where necessary. The processes reviewed relate to 
participant enrolment, consent, eligibility, and allocation to trial groups; adherence to trial 
interventions and policies to protect participants, including reporting of harms; completeness, 
accuracy and timeliness of data collection; and will verify adherence to applicable policies detailed in 
the Compliance section of the protocol.  

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 54 of 63 
 
In multi-centre trials oversight is considered and described both overall and for each recruiting 
centre by exploring the trial dataset or performing site visits as described in the trial monitoring 
plan. 
5.11.4.4.1 
Clinical Management Team 
A Clinical Management Team (CMT) will be set up to assist with developing the design, co-ordination 
and strategic management of the trial. The membership, frequency of meetings, activity (including 
study conduct and data review) and authority will be covered in a CMT terms of reference. 
5.11.4.4.2 
Independent Data Monitoring Committee 
The Independent Data Monitoring Committee (IDMC) is responsible for safeguarding the interests of 
trial participants, monitoring the accumulating data and making recommendations to on whether 
the trial should continue as planned. The membership, frequency of meetings, activity (including 
review of trial conduct and data) and authority will be covered in the IDMC charter. The IDMC will 
consider data in accordance with the statistical analysis plan and will advise the CMT. 
6 
Ethics and Dissemination 
6.1 
Research Ethics Approval 
Before initiation of the trial at any clinical site, the protocol, all informed consent forms and any 
material to be given to the prospective participant will be submitted to the Health Research 
Authority (HRA) for approval. Any subsequent amendments to these documents will be submitted 
for further approval.   
The rights of the participant to refuse to participate in the trial without giving a reason must be 
respected. After the participant has entered the trial, the clinician remains free to give alternative 
treatment to that specified in the protocol, at any stage, if the clinician feels it to be in the best 
interest of the participant. The reasons for doing so must be recorded. However, the participant 
remains free to change their mind at any time about the protocol treatment and follow-up without 
giving a reason and without prejudicing their further treatment. 
6.2 
Regulatory Authority Approvals 
This protocol will be submitted to the national competent or equivalent authority (i.e. MHRA in the 
UK and Food and Drug Administration (FDA) in the US). 
This is a Clinical Trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive 
2001/20/EC. Therefore, a CTA is required in the UK.  
This is a Clinical Trial of an Investigational New Drug as defined by 21CFR Part 312 of the Code of 
Federal Regulations. Therefore, an Investigational New Drug Application (IND) is required in the US.  
This trial is a human gene transfer study and therefore in the US must be reviewed by the initial 
site's Institutional Biosafety Committee and possibly by the Recombinant DNA Advisory Committee 
(RAC) of the NIH's Office of Biotechnology Activities (OBA). 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 55 of 63 
 
The progress of the trial, safety issues and reports, including expedited reporting of SUSARs, will be 
reported to the Competent Authority, regulatory agency or equivalent in accordance with relevant 
national and local requirements and practices.  
6.3 
 Other approvals 
The protocol will be submitted by those delegated to do so to the local departments of each 
participating sites. A copy of the local approval letter (or other relevant approval as above) and of 
the Participant Information Sheet (PIS) and consent form on local headed paper must be forwarded 
to MeiraGTx UK II Ltd. as part of the site initiation process prior to the site being designated ‘open to 
recruitment’ status.  
Participating sites receiving funding or support from the US government will obtain a Federal Wide 
Assurance (FWA). 
For ATIMP trials using Genetically Modified Organisms, organisations should also receive approval 
from their relevant national body to use the product (i.e. notification to the HSE in the UK). 
6.4 
Protocol Amendments 
MeiraGTx UK II Ltd. will be responsible for amendments to the protocol. MeiraGTx UK II Ltd. will be 
responsible for ensuring that protocol amendments are submitted to national competent 
authorities, and to investigators at each clinical trial site.  
Investigators at each clinical site will be responsible for submitting protocol amendments to the 
relevant REC/IRBs for approval, as well as any additional competent authorities in each country that 
require notification (e.g. the NIH OBA).  
6.5 
Consent or Assent 
Potential participants will be provided with a Participant Information Sheet (PIS) and given time to 
read it fully. Following a discussion with a medically qualified investigator or suitable trained and 
authorised delegate, any questions will be satisfactorily answered and if the participant is willing to 
participate, written informed consent will be obtained.  During the consent process it will be made 
completely and unambiguously clear that the participant (or parent or guardian of a child) is free to 
refuse to participate in all or any aspect of the trial, at any time and for any reason, without incurring 
any penalty or affecting their treatment (or that of their child). 
 
Minors who are unable to consent for themselves will not be enrolled in the trial without the 
consent of their parent(s) or legal guardian(s). Children or adolescents will be asked to assent or 
agree. A Participant Information and Assent sheet that describes the details of the trial, trial 
procedures, and risks in simplified form will be provided to minors who have the capacity to provide 
informed assent. Participation must be refused in the event that assent is not given. Assent forms do 
not substitute for the consent form signed by the participant’s legally authorized representative. If a 
child becomes an adult during their participation in the trial, the child will be reconsented as an 
adult at the time of their next scheduled visit. 
 
Consent will be 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 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 56 of 63 
 
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 the MeiraGTx UK II Ltd. trial team.  
6.6 
Confidentiality 
All data will be handled in accordance with the General Data Protection Regulation 2016/679 or the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
These regulations require a signed participant authorization informing the participants of the 
following:  
• 
What protected health information (PHI) will be collected from participants in this trial 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research participant to revoke their authorization for use of their PHI.  
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of participant 
authorization.  For participants that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the participant is alive) 
at the end of their scheduled trial period. 
Participant confidentiality will be held strictly in trust by the investigators, trial staff, and the sponsor 
and their agents, to the extent provided by Federal, state, and local law.  This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to any trial information 
relating to participants. All laboratory specimens, evaluation forms, reports, and other records that 
leave the site will be identified only by a coded number in order to maintain participant 
confidentiality.  All records will be kept locked and all computer entry and networking programs will 
use coded numbers only. Participants will not be identified in any publicly released reports of this 
trial.  
Access to trial records will be limited to the minimum number of individuals necessary for quality 
control, audit and analysis. Clinical information will not be released without written permission of 
the participant, except as necessary for trial-related monitoring, audits, REC/IRB review, and 
regulatory inspections by University or government entities. In these cases, the clinical trial site will 
provide direct access to all source data, documents, and records maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) for the trial participants. Trial 
participants will be informed of this during the informed consent process.  
No information concerning the trial, or the data will be released to any unauthorized third party 
without prior written approval of MeiraGTx UK II Ltd. 
The Case Report Forms (eCRFs) will not bear the participant’s name or other personal identifiable 
data. The participant’s date of birth and trial identification number, will be used for identification. 
For other information regarding Data Management please see Section 5.10.2.  

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 57 of 63 
 
6.7 
Declaration of Interests 
The trial is funded by MeiraGTx UK II Ltd. 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt of 
payment from MeiraGTx UK II Ltd. for consultancy services. 
 declares ownership of minority shareholdings in MeiraGTx UK II Ltd. and receipt 
of payment from MeiraGTx UK II Ltd. for consultancy services. 
6.8 
Indemnity 
MeiraGTx UK II Ltd. holds insurance to cover participants for injury caused by their participation in the 
clinical trial. Participants may be able to claim compensation if they can prove that MeiraGTx UK II Ltd. 
has been negligent. However, as this clinical trial is being carried out in a hospital, the hospital 
continues to have a duty of care to the participant in the clinical trial. MeiraGTx UK II Ltd. does not 
accept liability for any breach in the hospital’s duty of care, or any negligence on the part of hospital 
employees. This applies whether the hospital is an NHS Trust or not.  This does not affect the 
participant’s right to seek compensation via the non-negligence route.  
 
Participants may also be able to claim compensation for injury caused by participation in this clinical 
trial without the need to prove negligence on the part of MeiraGTx UK II Ltd. or another party.  
Participants who sustain injury and wish to make a claim for compensation should do so in writing in 
the first instance to the Chief Investigator, who will pass the claim to MeiraGTx UK II Ltd‘s. insurers. 
 
Hospitals selected to participate in this clinical trial shall provide clinical negligence insurance cover 
for harm caused by their employees and a copy of the relevant insurance policy or summary shall be 
provided to MeiraGTx UK II Ltd. upon request. 
6.9 
Finance 
The trial is fully funded by MeiraGTx UK II Ltd. It is not expected that any further external funding 
will be sought. 
6.10 Archiving 
6.10.1 Archiving of Essential Trial Documentation Relating to Traceability  
Requirements for a traceability system and document archiving will be met in line with Regulation 
1394/2007 on Advanced Medicinal Products and the applicable Directives therein. To comply with 
the regulatory requirements, each responsible party (the sponsor of the trial, the manufacturer and 
the investigator(s)/institution(s) where the ATIMP is used) will ensure that the information relating 
to the traceability and accountability, from the production of ATIMPs to the recipient (participant) 
receiving the ATIMPs, are archived for a minimum of 30 years after the expiry date of the ATIMP. 
These requirements will be set out in contractual agreements between the parties and the sponsor.  
The following essential documents/traceability data will be retained by the investigator and 
institution responsible for the human application of the ATIMP:  
 
Shipping Records for the ATIMP  
 
Certificate of Analysis of the ATIMP 
 
Participant identification code list 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 58 of 63 
 
 
ATIMP accountability at the site including final disposition of both used and unused product 
These records contain relevant information for traceability purposes and at least the following 
minimum data set from these records should be kept for 30 years after the expiry date of the 
product, or longer if required by the terms of the clinical trial authorisation or by the agreement with 
the sponsor: 
 
Identification of the investigator/institution  
 
Identification of the sponsor  
 
Identification of the manufacturing site  
 
Product name/code  
 
Pharmaceutical form, route of administration, quantity of dosage units and strength  
 
Batch number  
 
Trial reference code  
 
Trial participant code  
 
Participant identification code list (links name of recipient to the trial participant code)  
 
Product expiry/retest date  
 
Date of administration  
 
Participant medical record should also contain the product name/code, the trial reference 
code, trial participant code and administration dates and doses  
 
Records of any product that was unused or destroyed at site and its final status 
6.10.2 Archiving of Other Essential Trial Documentation 
Trial documents should be retained for a minimum of 2 years after an FDA marketing application is 
approved for the ATIMP and until there are no pending or contemplated marketing applications for 
the ATIMP, or if an application is not approved for the ATIMP, until 2 years after shipment and 
delivery of the drug for investigational use has been discontinued and FDA is notified. For gene 
therapy trials, current 
 requirements state that research records 
should be kept indefinitely, until further notice. Archiving of REC/IRB notices should be maintained 
according to local and/or institutional requirements.  
Essential documents are those which enable both the conduct of the trial and the quality of the data 
produced to be evaluated and show whether the site complied with the principles of Good Clinical 
Practice and all applicable regulatory requirements.  
MeiraGTx UK II Ltd. will notify sites when trial documentation can be archived, and which documents 
must be archived for the 30-year period. All archived documents must continue to be available for 
inspection by appropriate authorities upon request.  
Destruction of essential documents will require authorisation from the Sponsor. 
6.11 Access to Data 
The investigators/ institutions will permit trial-related monitoring, audits, REC review, and regulatory 
inspections, providing direct access to source data/documents. Trial participants are informed of this 
during the informed consent discussion. Participants will consent to provide access to their medical 
notes. 
Requests for access to trial data will be considered, and approved in writing where appropriate, after 
formal application to MeiraGTx UK II Ltd.  

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 59 of 63 
 
6.12 Ancillary and Post-trial Care 
Participants will be invited to participate in a follow-up study after completion of this trial. 
6.13 Publication Policy 
6.13.1 Trial Results 
All proposed scientific publications will be discussed with the Sponsor prior to publication. Since this 
is an exploratory, open-label, Phase I/II trial, progress and significant findings may be presented at 
scientific forums/meetings and/or published during the course of the trial. 
The results of the trial will be disseminated regardless of the direction of effect. 
7 
Ancillary Studies 
There are no currently planned ancillary studies. Any future ancillary studies will be subject to 
separate funding and will be submitted for ethical and regulatory review as appropriate. 
8 
Protocol Amendments 
 
 
Protocol Version and Date 
Reason for Amendment 
Protocol v1.0 dated 15 Jul 2017 
Initial version 
Protocol v2.0 dated 3 Mar 2017 
relevant changes in the operational 
responsibilities of the study.    
 
Protocol v3.0 dated 09 Oct 2017
Safety reporting clarification, 
Dose expansion clarifications 
Protocol v4.0 dated 01 May 2018
To clarify the allowance of data obtained from 
the usual standard of care be used for 
screening and or baseline assessments (with 
consent from subjects) in order to avoid 
unnecessary testing of subjects and also to 
extend the screening/baseline window from 3 
months to 6 months.  
 
Clarify that more than 1 surgeon at a site may 
inject vector 
 
To remove CI will confirm eligibility of all 
individual participants 
 
To add FST as a visual assessment 
 
Expand the number of categories for ATIMP 
administration surgery from related or 
unrelated to: unrelated, unlikely, possibly, 
probably or definitely 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 60 of 63 
 
 
To clarify ATIMP vector must be administered 
with a 1 hour window after ATIMP has thawed 
at room temperature. 
 
Protocol v5.0 dated 05 Dec 2018 
To increase the number of participants to be 
recruited in the dose expansion phase and to 
allow for additional doses of vector to those 
described to be explored. 
Protocol v6.0 17 Dec 2018 
Addition of wording to provide clarification 
regarding what is considered “safe limits”  
Protocol v7.0 29 Jan 2019 
Updated to remove assessments that have 
been reviewed and deemed to add no scientific 
value to continue testing, in order to reduce 
assessment burden to participants and clinical 
sites.  
 
 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 61 of 63 
 
9 
References 
Aboshiha J, Dubis AM, Carroll J, et al.  The cone dysfunction syndromes.  Br J Ophthalmol 
2016;100(1):115–121 
Amado D, Mingozzi F, Hui D, Bennicelli JL, Wei Z, Chen Y, Bote E, Grant RL, Golden JA, Narfstrom K, 
Syed NA, Orlin SE, High KA, Maguire AM, Bennett J. Safety and efficacy of gene transfer for Leber's 
congenital amaurosis. N Engl J Med, 2008, 358:2240-8. 
Annear,M.J., Bartoe,J.T., Barker,S.E., Smith,A.J., Curran,P.G., Bainbridge,J.W., Ali,R.R., and Petersen-
Jones,S.M. (2011). Gene therapy in the second eye of RPE65-deficient dogs improves retinal 
function. Gene Ther. 18, 53-61. 
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, 
Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, 
Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J 
Med, 2008, 358:2231-9 
Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, 
Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJL, 
Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, 
Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G and Ali RR. Long-
term effect of gene therapy on Leber Congenital amaurosis. N Eng J Med, 2015, 372: 1887-97. 
Barker,S.E., Broderick,C.A., Robbie,S.J., Duran,Y., Natkunarajah,M., Buch,P., Balaggan,K.S., 
MacLaren,R.E., Bainbridge,J.W., Smith,A.J., and Ali,R.R. (2009). Subretinal delivery of adeno-
associated virus serotype 2 results in minimal immune responses that allow repeat vector 
administration in immunocompetent mice. J. Gene Med. 11, 486-497. 
Baseler HA, Brewer AA, Sharpe LT, Morland AB, Jägle H, Wandell BA. Reorganization of human 
cortical maps caused by inherited photoreceptor abnormalities. Nat Neurosci, 2002, 5:364-70. 
Carvalho LS, Xu J, Pearson RA, Smith AJ, Bainbridge JW, Morris LM, Fliesler SJ, Ding XQ, Ali RR. Long-
term and age-dependent restoration of visual function in a mouse model of CNGB3-associated 
achromatopsia following gene therapy. Hum Mol Genet, 2011. 20:3161-75. 
Chan AW, Tetzlaff JM, Altman DG et Al. SPIRIT 2013 Statement: Defining Protocol Items for Clinical 
Trials. Ann Intern Med 2013; 158:200-207. 
Chan AW, Tetzlaff, Gotzsche et Al. SPIRIT 2013 explanation and elaboration: guidance for protocols 
of clinical trials. BMJ 2013; 346: e7586. 
Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ, Pang JJ, Sumaroka A, Windsor 
EA, Wilson JM, Flotte TR, Fishman GA, Heon E, Stone EM, Byrne BJ, Jacobson SG, Hauswirth WW. 
Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with 
slow rod kinetics. Proc Natl Acad Sci U S A, 2008.105:15112-7. 
Cideciyan AV, Jacobson SG, Beltran WA, Sumaroka A, Swider M, Iwabe S, Roman AJ, Olivares MB, 
Schwartz SB, Komáromy AM, Hauswirth WW, Aguirre GD. Human retinal gene therapy for Leber 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 62 of 63 
 
congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement. 
Proc Natl Acad Sci U S A, 2013, 110(6):E517-25. 
Gerstner A, Zong X, Hofmann F, Biel M.  Molecular cloning and functional characterization of a new 
modulatory cyclic nucleotide-gated channel subunit from mouse retina. J Neurosci. 2000, 20:1324-
32. 
Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of Uveitis Nomenclature (SUN) Working 
Group. Standardization of uveitis nomenclature for reporting clinical data: results of the First 
International Workshop. Am J Ophthalmol, 2005, 140:509–516. 
Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. 
Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet, 2004, 41:e20. 
Judd DB.  Facts of color-blindness.  J Opt Soc Amer 1943;33:294–307 
Kohl. S, Jagle. H, and Wissinger. B, 2013, Achromatopsia, GeneReviews® - NCBI Bookshelf: National 
Institute of Health 
Komáromy AM, Alexander JJ, Rowlan JS, Garcia MM, Chiodo VA, Kaya A, Tanaka JC, Acland GM, 
Hauswirth WW, Aguirre GD. Gene therapy rescues cone function in congenital achromatopsia. Hum 
Mol Genet, 2010 19:2581-93.  
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, 
Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, 
Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, 
McDonnell JW, Auricchio A, High KA, Bennett J. Safety and efficacy of gene transfer for Leber's 
congenital amaurosis. N Engl J Med, 2008, 358:2240-8. 
Manno CS, Pierce GF, Arruda VR, Glader B, Ragni M, Rasko JJ, Ozelo MC, Hoots K, Blatt P, Konkle B, 
Dake M, Kaye R, Razavi M, Zajko A, Zehnder J, Rustagi PK, Nakai H, Chew A, Leonard D, Wright JF, 
Lessard RR, Sommer JM, Tigges M, Sabatino D, Luk A, Jiang H, Mingozzi F, Couto L, Ertl HC, High KA, 
Kay MA.  Nat Med, 2006, 12:342-7 
Michaelides M, Hunt DM, and Moore AT.  The cone dysfunction syndromes.  Br J Ophthalmol 
2004;88(2):291–297. 
Natkunarajah M, Trittibach P, McIntosh J, Duran Y, Barker SE, Smith AJ, Nathwani AC, Ali RR. 
Assessment of ocular transduction using single-stranded and self-complementary recombinant 
adeno-associated virus serotype 2/8. Gene Ther, 2008, 15:463-7. 
Nowrouzi A, Penaud-Budloo M, Kaeppel C, Appelt U, Le Guiner C, Moullier P, Kalle CV, Snyder RO, 
Schmidt M. Integration Frequency and Intermolecular Recombination of rAAV Vectors in Non-human 
Primate Skeletal Muscle and Liver. Mol Ther, 2012, 20(6):1177-86. 
Rolling F. Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives. Gene 
Ther, 2004, 11 Suppl 1: S26-S32 

 
 
 
CNGB3 Gene Therapy trial for Achromatopsia   
Protocol V7.0 29Jan2019 
 
Page 63 of 63 
 
Sharpe LT and Nordby K.  Total colour-blindness: an introduction.  In:  Night Vision:  Basic, Clinical 
and Applied Aspects.  R. F. Hess, L. T. Sharpe and K. Nordby.  Cambridge, Cambridge University Press 
1990:253–289.  
Sharpe LT, Stockman A, Jägle H, et al.  Opsin genes, cone photopigments, color vision, and color 
blindness.  In:  Color Vision:  from Genes to Perception.  KR Gegenfurtner and Sharpe LT (Eds).  
Cambridge University Press 1999:1–51.  
Stieger K, Colle MA, Dubreil L, Mendes-Madeira A, Weber M, Le Meur G, Deschamps JY, Provost N, 
Nivard D, Cherel Y, Moullier P, Rolling F.  Subretinal delivery of recombinant AAV serotype 8 vector in 
dogs results in gene transfer to neurons in the brain. Mol Ther, 2008,16:916-23.