A Randomised, Open Label, Outcomes-Assessor Masked, Prospective, Parallel Controlled Group, Phase 3 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1)
Phase: PHASE3
Conditions: Choroideremia
Sponsor: Biogen

COVER PAGE 
Official Title: 
A Randomised, Open Label, Outcomes-Assessor Masked, 
Prospective, Parallel Controlled Group, Phase 3 Clinical Trial of 
Retinal Gene Therapy for Choroideremia Using an Adeno-Associated 
Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1) 
NCT Number: 
NCT03496012 
Document Date: 
Protocol Version 5.0: 15 March 2019 
 
 

Phase 3 Study of AAV2-REP1 in CHM 
Clinical Study Protocol NSR-REP-01 
Version 5.0 (Amendment 4.0) 
15 Mar 2019 
 
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CLINICAL STUDY PROTOCOL  
NSR-REP-01 (TIMREPIGENE EMPARVOVEC) 
 
AAV2-REP1 
A Randomised, Open Label, Outcomes-Assessor Masked, 
Prospective, Parallel Controlled Group, Phase 3 Clinical Trial 
of Retinal Gene Therapy for Choroideremia Using an Adeno-
Associated Viral Vector (AAV2) Encoding Rab Escort 
Protein 1 (REP1) 
 
STAR Study 
INDICATION: 
 
 
Choroideremia 
STUDY PHASE: 
 
 
3 
EUDRACT NUMBER: 
 
2015-003958-41 
Clintrials.gov 
 
 
NCT03496012 
SPONSOR: 
NightstaRx Ltd 
2nd Floor 
10 Midford Place 
London W1T 5BJ UK 
Telephone:  +44 (0) 020 7062 2777 
 
ORIGINAL PROTOCOL DATE: 
17 September 2015 
DATE OF AMENDMENT 1: 
10 November 2015 
DATE OF AMENDMENT 2: 
26 February 2016 
DATE OF AMENDMENT 3: 
01 August 2017 
DATE OF AMENDMENT 4: 
15 March 2019 
CONFIDENTIALITY STATEMENT 
This protocol is the property of NightstaRx Ltd. It is not to be transmitted, copied or published without written 
permission from NightstaRx and must be kept in a confidential manner. Persons to whom the information is 
disclosed must be informed that the information is CONFIDENTIAL and may not be further disclosed by them. 

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SPONSOR APPROVAL PAGE 
 
Clinical Study Protocol Number:  
NSR-REP-01, Amendment 4.0, Version 5.0 
Protocol Title: 
A Randomised, Open Label, Outcomes-
Assessor Masked, Prospective, Parallel 
Controlled Group, Phase 3 Clinical Trial of 
Retinal Gene Therapy for Choroideremia Using 
an Adeno-Associated Viral Vector (AAV2) 
Encoding Rab Escort Protein 1 (REP1) 
Protocol Date: 
 
 
 
15 Mar 2019 
 
Approved By: 
 
 
 
, MD 
 
 
 
 
 
 
 
 
The person listed above is authorised to sign the protocol on behalf of NightstaRx Ltd.  The 
wet-ink signature is on file and available upon request.  
 
 
 
 
 

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INVESTIGATOR’S SIGNATURE PAGE 
Clinical Study Protocol Number: 
NSR-REP-01, Amendment 4.0, Version 5.0 
Protocol Title: 
A Randomised, Open Label, Outcomes-Assessor 
Masked, Prospective, Parallel Controlled Group, 
Phase 3 Clinical Trial of Retinal Gene Therapy 
for Choroideremia Using an Adeno-Associated 
Viral Vector (AAV2) Encoding Rab Escort 
Protein 1 (REP1) 
Protocol Date: 
15 Mar 2019 
I have read the Investigator’s Brochure for AAV2-REP1 and I have read Protocol NSR-REP-
01 and agree to conduct the study as outlined and in compliance with the Declaration of 
Helsinki (where required) and/or the International Council on Harmonization (ICH) guideline 
for Good Clinical Practice, and all applicable local and federal regulatory requirements and 
state/local laws. I agree to maintain confidentiality of my subjects and all information 
received or developed in relation to this protocol. 
Signed: 
Date: 
Name 
Title 
Institution 
City, State (as applicable), Country 

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2 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: NightstaRx, Ltd 
Name of Test Product: AAV2-REP1 (timrepigene emparvovec) 
Protocol Title:  A Randomised, Open-Label, Outcomes-Assessor Masked, Prospective, Parallel- 
Controlled Group, Phase 3 Clinical Trial of Retinal Gene Therapy for Choroideremia Using an 
Adeno-Associated Viral Vector (AAV2) Encoding Rab Escort Protein 1 (REP1) 
Protocol Number: NSR-REP-01 
Study centres: The study will be conducted at approximately 20 study centres located in, but not 
limited to, North America and Europe. 
Study period:  
Screening, treatment and follow-up are approximately 14 
months per subject 
Phase of development: Phase 3 
Study Objective: The objective of the study is to evaluate the efficacy and safety of a single sub-
retinal injection of AAV2-REP1 in subjects with choroideremia (CHM). 
Primary Endpoint: The primary efficacy endpoint is the proportion of subjects with a ≥15-letter 
improvement from Baseline in best corrected visual acuity (BCVA) at Month 12 as measured by 
the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. 
Key Secondary Efficacy Endpoints:  
There are 3 key secondary efficacy endpoints: 
1. Change from Baseline in BCVA at Month 12 measured by the ETDRS chart 
2. Proportion of subjects with a ≥10-letter improvement from Baseline in BCVA at Month 
12 measured by the ETDRS chart 
3. Proportion of subjects with no decrease from Baseline in BCVA or a decrease from 
Baseline in BCVA of <5 ETDRS letters at Month 12 in BCVA measured by the ETDRS 
chart 
Other Secondary Endpoints: 
• 
Change from Baseline in BCVA at Months 4 and 8  
• 
Change from Baseline in total area of preserved autofluorescence (AF) at Month 12 
• 
Change from Baseline in the area of preserved ellipsoid zone (spectral domain optical 
coherence tomography [SD-OCT]) at Month 12 
• 
Change from Baseline in microperimetry at Month 12 
• 
Change from Baseline in contrast sensitivity score at Month 12 
• 
Change from Baseline in colour vision at Month 12 
• 
Change from Baseline in reading speed test at Month 12 
• 
Change from Baseline in the 25-item Visual Function Questionnaire (VFQ-25) at Month 
12 
Exploratory Efficacy Endpoint: 
• 
 
Safety Endpoint: 
• 
Evaluation of safety assessments, including adverse events (AEs), clinical laboratory 
assessments, vital signs 
Study Design: This is an outcomes-assessor-masked, prospective, randomised, parallel-controlled 
group, multi-centre, global, interventional study.  The study consists of 8 visits with a 12-month 
evaluation period.  During the Screening/Baseline period, each subject will be assessed for 

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eligibility.  For eligible subjects, a study eye will be assigned, and the subjects will be randomised 
in a 2:1:2 ratio to receive either AAV2-REP1 high dose (1.0×10^11 genome particles [gp]), 
AAV2-REP1 low dose (1.0×10^10 gp) or to enter the untreated Control group. 
On the Injection Day Visit (Visit 2, Day 0), subjects in the AAV2-REP1 high- and low-dose 
treatment arms will undergo vitrectomy and receive a sub-retinal injection of the assigned 
treatment dose of AAV2-REP1 in their study eye; these subjects will then return to the surgical 
site for 2 post-operative follow up visits on Day 1 (Visit 3) and, possibly for Day 7 (Visit 4; Day 7 
can occur at either the surgical site or the home site depending on the clinical status of the 
subject).  Subjects in the Control group will not undergo surgery, receive any study drug in their 
study eye (i.e., Control-study eye) or attend the 2 on-site post-operative visits.  Instead, a 
telephone contact from the site will occur for the Control group on Day 0 (Visit 2), Day 1 
(Visit 3) and Day 7 (± 3 days; Visit 4).   
Day 0 (Visit 2) will be defined as the projected surgical day, whether the subject is randomised to 
treated or control groups.  
All subjects will be followed for 12 months from Visit 2 (Day 0). 
Study data will be collected for both eyes of each subject.  Since AAV2-REP1 treatment requires 
an invasive surgical procedure under general anaesthesia, the sponsor, investigator and the subject 
will be unmasked to the study procedure (i.e., vitrectomy and sub-retinal injection), however 
within the treated groups, the sponsor, investigator and subject will be masked to the assigned 
dose (1.0×10^11 gp or 1.0×10^10 gp).  To further minimise the potential bias of the treated and 
untreated eye evaluations, all subjective ophthalmic assessments from the Screening/Baseline 
Period (Visit 1) and from Month 1 (Visit 5) onwards (including the Month 12 Primary Endpoint 
evaluation) will be conducted by a masked assessor. 
Subjects will be assessed for efficacy and safety throughout the study as indicated in the Schedule 
of Study Procedures.  Subjects who develop cataracts may undergo cataract surgery if deemed 
clinically necessary; if surgery is performed, it should be carried out at least 4 weeks before the 
Month 12 Visit/End of Study (EOS) Visit. 
Number of subjects (planned): Approximately 160 subjects randomised in a 2:1:2 ratio; 
64 subjects in the AAV2-REP1 high dose (1.0×10^11 gp) group, 32 subjects in the AAV2-REP1 
low dose (1.0×10^10 gp) and 64 subjects in the untreated control group. 
Inclusion Criteria: Subjects are eligible for study participation if they meet all of the following 
inclusion criteria. 
1. Are willing and able to give informed consent for participation in the study 
2. Are male and ≥18 years of age 
3. Have a documented genetically-confirmed diagnosis of CHM  
4. Have active disease clinically visible within the macular region in the study eye  
5. Have a BCVA of 34-73 ETDRS letters (equivalent to worse than or equal to 6/12 or 
20/40 Snellen acuity, but better than or equal to 6/60 or 20/200 Snellen acuity) in the 
study eye. 
Exclusion Criteria: Subjects are not eligible for study participation if they meet any of the 
following exclusion criteria. 
1. Have a history of amblyopia in the eligible eye 
2. Are unwilling to use barrier contraception methods, or abstain from sexual intercourse, 
for a period of 3 months, if treated with AAV2-REP1 
3. Have had previous intraocular surgery performed in the study eye within 3 months of 
Visit 1 
4. Have any significant ocular or non-ocular disease/disorder which, in the opinion of the 
investigator, may either put the subjects at risk because of participation in the study, or 

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may influence the results of the study, or the subject’s ability to participate in the study.  
This includes but is not limited to, a subject: 
a. with a contraindication to oral corticosteroid (e.g. prednisolone/prednisone) 
b. with a clinically significant cataract 
c. who, in the clinical opinion of the Investigator, is not an appropriate candidate for 
sub-retinal surgery 
5. Have participated in another research study involving an investigational product in the 
past 12 weeks or received a gene/cell-based therapy at any time previously.  
Test product, dosage, and mode of administration: All subjects receiving active treatment will 
undergo vitrectomy and receive a volume of up to 100 µL sub-retinally of either high dose 
(1.0×10^11 gp) AAV2-REP1 or low dose (1.0×10^10 gp) AAV2-REP1 in their study eye.  
Reference therapy (Comparator), dosage, and mode of administration: The reference therapy 
in this study is no study medication/surgical procedure. 
Criteria for Evaluation: 
Efficacy: The efficacy evaluation will be based on BCVA, fundus AF, SD-OCT, microperimetry, 
contrast sensitivity, colour vision, reading speed test assessments, VFQ-25 and 
 
. 
Safety: The safety evaluation will be based on full ophthalmic examination (including intraocular 
pressure, slit lamp examination, lens opacity grading, and dilated ophthalmoscopy), fundus 
photography, AE reporting, immunogenicity, and vital signs. 
Any safety information collected as a result of the efficacy assessments (e.g., BCVA) will also be 
used in the overall safety evaluation, as appropriate. 
Statistical Methodology:  
Statistical tests will be performed at the alpha level of 0.05 (unless otherwise specified). Statistical 
tests and 95% confidence intervals (CIs) will be 2-sided. 
Continuous variables will be summarised over time using descriptive statistics (i.e., mean, 
standard deviation, 95% CI, median, first and third quartiles, fifth and ninety-fifth percentiles, 
minimum, and maximum).  Categorical variables will be described over time using counts, 
percentages, and 95% CIs. 
The proportion of subjects with a ≥15-letter improvement from Baseline in BCVA at the 
Month 12 visit will be compared between study arms (high dose vs control, low dose vs control) 
using the Fisher’s Exact test. The primary approach will be the unstratified analysis, and a 
supportive analysis will be conducted with the Cochran-Mantel-Haenszel approach by stratifying 
by Surgery Group. As Fisher’s Exact test is overly conservative when the number of events is 
low, a supportive analysis will be conducted using Fisher’s Exact-Boschloo test with a Berger-
Boos correction of beta=0.001. To maintain the test at 0.05 two-sided level, the reported p-value 
will be 2 times the one-sided p-value from the Fisher’s Exact-Boschloo test.  The primary 
approach will be the unstratified analysis, and a supportive analysis will be conducted by 
stratifying by Surgery Group. 
The primary analysis of the primary endpoint will be based on the ITT population, and a 
supportive analysis will be performed based on the PP population. 
For continuous endpoints, point estimates and statistical comparisons will be generated based on 
an analysis of covariance (ANCOVA) model including Surgery Group, baseline value of the 
assessment, and study arms as covariates.  
The protection of the type I error will be achieved for the comparison between the high dose and 
the untreated control under a hierarchical procedure.  The primary efficacy endpoint will be first 
tested. If the p-value is <0.05, the study will be declared positive and the key secondary endpoints 
will be tested in the pre-specified order.  The comparison between the low-dose arm and the 

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untreated control is considered as supportive, and will be performed only if significance is 
achieved between the high dose and the untreated control. 
Adverse events will be summarised by system organ class, preferred term, and group.  Both the 
number of eyes/subjects experiencing an AE and the number of events will be summarised.  
Similar summaries will be produced for study drug/procedure-related AEs, AEs leading to 
discontinuation, and serious adverse events (SAEs).  AEs will also be summarised by maximum 
severity, relationship to study drug/procedure, and time to onset and resolution. 

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3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
 
TITLE PAGE .............................................................................................................................1 
2 
PROTOCOL SYNOPSIS .......................................................................................5 
3 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...........9 
4 
ABBREVIATIONS AND DEFINITIONS ...........................................................13 
5 
INTRODUCTION ................................................................................................14 
5.1 
Choroideremia ...................................................................................................... 14 
5.2 
Gene Therapy with Adeno-Associated Viral Vectors .......................................... 14 
5.3 
Study Rationale ..................................................................................................... 14 
5.4 
Benefit / Risk Assessment .................................................................................... 15 
6 
STUDY OBJECTIVES AND ENDPOINTS ........................................................17 
6.1 
Objective ............................................................................................................... 17 
6.2 
Endpoints .............................................................................................................. 17 
6.2.1 
Primary Endpoint ..................................................................................................17 
6.2.2 
Key Secondary Efficacy Endpoints ......................................................................17 
6.2.3 
Other Secondary Endpoints ..................................................................................17 
6.2.4 
Exploratory Efficacy Endpoints ...........................................................................17 
6.2.5 
Safety Endpoints ...................................................................................................17 
7 
INVESTIGATIONAL PLAN ...............................................................................19 
7.1 
Overall Study Design ............................................................................................ 19 
7.2 
Discussion of Design ............................................................................................ 20 
8 
SELECTION AND WITHDRAWAL OF SUBJECTS ........................................22 
8.1 
Inclusion Criteria .................................................................................................. 22 
8.2 
Exclusion Criteria ................................................................................................. 22 
8.3 
Subject Withdrawal Criteria ................................................................................. 22 
9 
STUDY TREATMENT ........................................................................................24 
9.1 
Treatments Administered ...................................................................................... 24 
9.2 
Description of Study Drug .................................................................................... 24 
9.3 
Packaging, Labelling, and Storage ....................................................................... 24 
9.4 
Vitrectomy Procedure and Injection of AAV2-REP1 .......................................... 24 
9.5 
Randomisation ...................................................................................................... 26 
9.6 
Study Masking and Minimisation of Bias ............................................................ 26 
9.6.1 
AAV2-REP1 Treatment Groups vs Untreated Control Group, Assessor Masking
 ..............................................................................................................................27 
9.6.2 
AAV2-REP1 Treatment Groups, Dose Masking ..................................................28 

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9.7 
Study Drug Accountability ................................................................................... 28 
9.8 
Concomitant Therapy ........................................................................................... 28 
9.9 
Treatment Compliance .......................................................................................... 29 
10 
STUDY VISITS AND PROCEDURES ...............................................................30 
10.1 
Visit 1 (Screening/Baseline Period) ...................................................................... 30 
10.2 
Visit 2 (Day 0, Injection Day Visit or Telephone Contact) .................................. 32 
10.3 
Visit 3 (Day 1 Post-Operative Visit) .................................................................... 32 
10.4 
Visit 4 (Day 7 Post-Operative Visit ± 3 Days) ..................................................... 33 
10.5 
Visit 5 (Month 1 ± 7 Days) ................................................................................... 34 
10.6 
Visit 6 (Month 4 ± 7 Days) ................................................................................... 34 
10.7 
Visit 7 (Month 8 ± 14 Days) ................................................................................. 35 
10.8 
Visit 8 (Month 12 ± 14 Days, End of Study Visit) ............................................... 35 
10.9 
Early Termination Visit ........................................................................................ 36 
10.10 
Unscheduled Visits ............................................................................................... 36 
11 
ASSESSMENT OF EFFICACY ..........................................................................38 
11.1 
VFQ-25 Questionnaire .......................................................................................... 38 
 
 38 
11.3 
Best Corrected Visual Acuity ............................................................................... 38 
11.4 
Contrast Sensitivity ............................................................................................... 38 
11.5 
Colour Vision........................................................................................................ 39 
11.6 
Reading Speed Test .............................................................................................. 39 
11.7 
Microperimetry ..................................................................................................... 39 
11.8 
Fundus Autofluorescence ..................................................................................... 39 
11.9 
Spectral Domain Optical Coherence Tomography (SD-OCT) ............................. 39 
12 
ASSESSMENT OF SAFETY ...............................................................................40 
12.1 
Full Ophthalmic Examination ............................................................................... 40 
12.2 
7-Field Colour Fundus Photography .................................................................... 40 
12.3 
Evaluation, Recording, and Reporting Adverse Events ....................................... 40 
12.3.1 
Definitions ............................................................................................................40 
12.3.1.1 
Adverse Event ....................................................................................................... 40 
12.3.1.2 
Serious Adverse Event .......................................................................................... 41 
12.3.2 
Recording of Adverse Events ...............................................................................42 
12.3.3 
Follow-up of Adverse Events ...............................................................................43 
12.3.4 
Reporting of Serious Adverse Events ...................................................................43 
12.3.5 
Procedures for Unmasking ...................................................................................43 
12.3.6 
Data Monitoring Committee .................................................................................44 

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12.4 
Pregnancy ............................................................................................................. 44 
12.5 
Laboratory Assessments ....................................................................................... 44 
12.5.1 
Immunogenicity ....................................................................................................44 
12.6 
Vital Signs ............................................................................................................ 45 
13 
STATISTICAL CONSIDERATIONS .................................................................46 
13.1 
Sample Size .......................................................................................................... 46 
13.2 
Procedure for Accounting for Missing Data ......................................................... 46 
13.3 
Analysis Population .............................................................................................. 46 
13.3.1 
Intent-to-Treat Population ....................................................................................46 
13.3.2 
Per Protocol Population ........................................................................................47 
13.3.3 
Safety Population ..................................................................................................47 
13.4 
Descriptive Statistics ............................................................................................ 47 
13.5 
Demographics and Baseline Characteristics ......................................................... 47 
13.6 
Efficacy Analyses ................................................................................................. 47 
13.6.1 
Primary Efficacy Endpoint ...................................................................................47 
13.6.2 
Key Secondary Efficacy Endpoints ......................................................................48 
13.6.3 
Other Secondary Efficacy Endpoints ....................................................................48 
13.6.4 
Multiplicity Control ..............................................................................................48 
13.7 
Safety Analyses .................................................................................................... 49 
13.7.1 
Adverse Events .....................................................................................................49 
13.7.2 
Full Ophthalmic Examination ...............................................................................49 
13.7.3 
7-Field Colour Fundus Photography ....................................................................49 
13.7.4 
Laboratory Assessments and Vital Signs .............................................................49 
14 
INFORMED CONSENT, ETHICAL REVIEW AND REGULATORY 
CONSIDERATIONS ............................................................................................50 
14.1 
Informed Consent ................................................................................................. 50 
14.2 
Ethical/Regulatory Review ................................................................................... 50 
14.3 
Regulatory Considerations .................................................................................... 50 
15 
ADMINISTRATIVE PROCEDURES .................................................................52 
15.1 
Data Quality Control and Assurance .................................................................... 52 
15.2 
Data Handling and Records Management ............................................................ 52 
15.3 
Access to Source Documentation and Subject Privacy ........................................ 53 
15.4 
Time and Schedule of the Study ........................................................................... 53 
15.5 
Policy for Publication and Presentation of Data ................................................... 53 
16 
REFERENCE LIST ..............................................................................................54 
17 
APPENDICES ......................................................................................................56 

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17.1 
Schedule of Study Procedures .............................................................................. 56 
LIST OF TABLES 
Table 1 
Assessor Masked Ophthalmic Assessments .........................................................28 
Table 2 
Statistical Tests for Key Secondary Efficacy Endpoints ......................................48 
Table 3 
Schedule of Study Procedures ..............................................................................57 
 
LIST OF FIGURES 
Figure 1 
Overall Study Schematic ......................................................................................19 
Figure 2 
Vitrectomy and Sub-retinal Injection of AAV2 Vector .......................................26 
 

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4 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation or Term 
Definition 
AAV 
adeno-associated virus 
AAV2 
AAV serotype 2 
AAV2-REP1 
AAV2 virus particle encapsulating 1.962kB cDNA of the wild-type human 
REP1 gene 
AE 
adverse event 
AF 
autofluorescence 
ANCOVA 
analysis of covariance 
BCVA 
best corrected visual acuity 
BGH-polyA 
bovine growth hormone polyadenylation 
BSS 
balanced salt solution 
CBA 
chicken β actin 
(c)DNA 
(complementary) deoxyribonucleic acid 
CHM 
choroideremia 
CI 
confidence interval 
CRC 
Central Reading Centre 
DMC  
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
EOS 
end of study 
ET 
early termination 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
gp 
genome particle 
ICH 
International Council on Harmonisation 
ID 
identification 
IEC 
Independent Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IReST 
International Reading Speed Texts 
 
 
 
LOCF 
last observation carried forward 
REP1 
Rab escort protein 1 
SAE 
serious adverse event 
SD-OCT 
spectral domain optical coherence tomography 
SUSAR 
suspected, unexpected, serious adverse reaction 
UK 
United Kingdom 
VA 
 
visual acuity 
VFQ-25 
25-item Visual Function Questionnaire 
WPRE 
woodchuck hepatitis post-transcriptional regulatory element 

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5 
INTRODUCTION 
5.1 
Choroideremia 
Choroideremia (CHM) is a rare, untreatable retinal degeneration that begins in childhood 
with loss of night vision and gradually progresses to blindness by middle age.  CHM is 
caused by loss of function of the gene encoding Rab escort protein 1 (REP1) which is located 
on the X-chromosome (Cremers 1990; Seabra 1993).  The disease has an X-linked recessive 
mode of inheritance and affects approximately 1 in 50,000 people, mostly due to loss of 
function (null) mutations (Sankila 1992; MacDonald 2009). 
5.2 
Gene Therapy with Adeno-Associated Viral Vectors 
Adeno-associated virus (AAV) is a parvovirus containing single stranded deoxyribonucleic 
acid (DNA).  There are many different AAV subtypes, each with slightly different DNA 
sequences and capsid proteins.  AAV serotype 2 (AAV2) is the vector to be used in this 
study.  The wild type AAV2 genome lacks many of the viral sequences necessary for 
replication and packaging of viral particles and has evolved to become dependent on a helper 
virus (e.g. adenovirus or herpes simplex virus) for replication and spread from infected cells.  
In the absence of a helper virus, the AAV2 genome must remain dormant in the host cell 
which may have helped it to evolve to remain undetected by the eukaryotic immune system, 
although wild type AAV2 antibodies can be detected in about 30% of humans 
(Mingozzi 2007).  Over time, the wild type AAV2 genome may become integrated into 
chromosome 19; however, this is not believed to occur in recombinant AAV because the 
integration mechanism involves part of the wild type sequence that is removed during cloning 
(Dutheil 2009). 
The non-immunogenic features of AAV2 make it ideal for gene therapy.  The principle is to 
remove the wild type AAV2 genome and replace it with a specific therapeutic transgene, 
thereby creating a “recombinant vector” which can deliver the therapeutic gene to diseased 
cells.  The maximum size of the AAV2 genome is 4,700 base pairs and this must include the 
inverted terminal repeat sequences which remain at either end of the transgene (Lusby 1980).  
Hence the main drawback of AAV2 is the relatively small size of gene it can carry.  At 
1,900 base pairs however the REP1 complementary DNA (cDNA) coding sequence is well 
within this carrying capacity.  
Gene therapy to the retina has advantages compared to other organs because the target area is 
small and much lower doses of vector can be applied by injection into the sub-retinal space, 
which is an enclosed natural anatomical compartment.  Furthermore, the eye is a relatively 
immune-privileged organ which reduces further the degree of immune-mediated reactions to 
the AAV2 vector.  AAV vectors target neurons effectively and AAV2 can infect rods, cones 
and the retinal pigment epithelium after sub-retinal injection in non-human primates 
(Jacobson 2006; Stieger 2006; Vandenberghe 2011).  The retinal pigment epithelium is the 
cell layer that is primarily affected by the absence of REP1 in CHM, which correlates with 
the natural targeting of AAV2 delivered by sub-retinal injection.  Hence, the AAV2 serotype 
is an ideal vector to treat this condition. 
5.3 
Study Rationale 
CHM is a disease that causes blindness, with no available treatment option.  The initial 
results from 6 patients included in a Phase 1/2 investigator-sponsored study (MacLaren 2014) 
show the investigational gene therapy medicinal product being generally well tolerated and 

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although the Phase 1/2 study was not powered to show efficacy, there were functional 
improvements in vision following retinal detachment and sub-retinal injection of AAV2-
REP1 (0.6-1.0×10^10 genome particles [gp]), performed under general anaesthesia.  In 
addition, long term maintenance of effect has been established for the 6 patients in the Phase 
1 / 2 study for up to 4 years post treatment (Edwards 2016). 
Three other open-label, single-dose, contralateral-control eye, Phase 2 investigator-sponsored 
studies were initiated and aimed to evaluate the effects of AAV2-REP1 over a 24-month 
period in adult male patients with a clinical and confirmed molecular diagnosis of CHM.  The 
primary objective was to assess the safety and tolerability of AAV2-REP1.  Across these 
studies, 18 patients (6 patients in each of the studies) have received 1.0×10^11 gp of AAV2-
REP1 administered by sub-retinal injection into the macula following retinal detachment via 
vitrectomy.  All studies utilised broadly the same protocol and trial design as the NSR-REP-
01 study.   
Additional data from the MacLaren study, including 8 patients treated with the high dose 
(1.0×10^11 gp) of AAV2-REP1, along with up to 48 months of efficacy results for the first 6 
subjects who received the lower dose (1.0×10^10 gp), reveal encouraging efficacy and safety 
results.  These data, together with up to 12 months of efficacy results for the 18 patients who 
received 1.0×10^11 gp of AAV2-REP1 in the Phase 2 trials (Dimopoulos 2018; Lam 2018; 
Xue 2018; Fischer 2018), reveal consistent findings with efficacy and safety, including no 
reported dose-limiting toxicities.  
The initial results of these investigational retinal gene therapy trials are consistent with 
improved rod and cone function and overcome any negative effects of vitrectomy followed 
by retinal detachment induced during sub-retinal injection of vector.  These findings 
demonstrate functional improvements in vision in a range of doses (1.0×10^11 gp and 
1.0×10^10 gp) and lend support to the further assessment of AAV2-REP1 gene therapy in the 
treatment of CHM. 
5.4 
Benefit / Risk Assessment 
No treatment currently exists for CHM. 
The non-clinical studies conducted with AAV2-REP1 showed that it provides efficient and 
functional transgene expression in CHM mouse and human cells, as well as in mouse and 
human RPE and photoreceptors, without overt toxicity.  Results from the 26-week single-
dose combined toxicity/biodistribution study conducted in rats indicate that administration of 
AAV2-REP1 by single sub-retinal injection to both eyes is well tolerated at dose levels of 
1×10^9 and 6×10^9 gp/eye (equal to 1×10^11 and 6×10^11 gp/eye in humans) when 
evaluated 4 and 26 weeks after injection.  Minor reductions in some ERG parameters, ocular 
inflammation, and microscopic signs of retinal/corneal degeneration were observed and were 
considered procedure-related or not biologically significant. 
In humans, application of AAV2-REP1 to the surface of the retina requires retinal 
detachment via vitrectomy.  The 2-step procedure employed in delivering AAV2-REP1 sub-
retinally (see Section 9.4), allows the management of unexpected surgical complications of 
retinal detachment before the AAV2-REP1 is applied. Furthermore, since the volume of fluid 
required to detach the fovea is variable, by excluding the vector from the first step, and 
administering the vector after successful retinal detachment has been achieved, a precise, 
consistent dose in terms of genome particles can be applied into the sub-retinal space.   

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Sub-retinal injection of AAV2-REP1 does carry the risks associated with vitrectomy and 
retinal detachment, which include intra-operative and post-operative complications; infection 
(most notably infectious endophthalmitis); low and elevated IOP; choroidal detachment; 
persistent retinal detachment, retinal tears, holes and breaks; macular hole and macular 
oedema; vitreous haemorrhage; visual impairment; metamorphopsia; and photopsia (Park 
1995; Thompson 1996; Banker1997; Cheng 2001; Anderson 2006; Stein 009; Recchia  
2010).  Post-operative intraocular inflammation caused by vitrectomy is often associated 
with transient and sometimes permanent visual impairment.  Another complication of 
vitrectomy is cataract formation, which may require an additional surgical procedure 
(cataract extraction) (Park 1995; Cheng 2001; Recchia 2010). In addition, the surgical 
procedure is performed under general anesthesia, which includes the risks of dizziness, 
confusion, nausea and vomiting. 
Loss of visual acuity (VA) has been observed post-treatment with AAV2-REP1. This VA 
loss was determined by investigators to be plausibly related to the administration of AAV2-
REP1, however without definitively attributing the cause to either the study procedure or the 
GTMP.  Loss of VA is, therefore, considered a Potential Risk of AAV2-REP1 treatment, in 
addition to the above-described potential and anticipated surgical risks.  See the 
Investigator’s Brochure for AAV2-REP1 for further details. 
Thus, although there are risks associated with the administration of the study treatment via 
vitrectomy and retinal detachment, the potential for benefit in the form of improved VA 
potentially provided to subjects with CHM following treatment with AAV2-REP1 provides 
an acceptable benefit-risk profile for participation in this study. 

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•
Clinical laboratory evaluations
•
Vital signs including diastolic blood pressure, systolic blood pressure, and pulse

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7 
INVESTIGATIONAL PLAN 
7.1 
Overall Study Design 
This is an outcomes-assessor-masked, prospective, randomised, parallel-controlled group, 
multi-centre, global, interventional Phase 3 study, consisting of 8 visits with a 12-month 
evaluation period.  A study schematic is presented below. 
Figure 1 
Overall Study Schematic 
During the Screening/Baseline period (Visit 1), each subject will be assessed for eligibility.  
If a subject has only 1 eligible eye, that eye will be designated as the “study eye” and the 
subject’s other (non-eligible) eye will be designated as the “fellow eye.” If a subject has 
2 eligible eyes, the selection of the “study eye” will be made on clinical grounds and will 
generally be the worse eye affected.  This will be discussed in detail and agreed with each 
subject as part of the informed consent process.  Subject choice will be considered in cases 
where the degeneration is relatively symmetrical between the two eyes. 
During the Screening/Baseline period, eligible subjects will be randomised in a 2:1:2 ratio to 
either the AAV2-REP1 high-dose group (1.0×10^11 gp), the AAV2-REP1 low-dose group 
(1.0×10^10 gp) or the untreated Control group.  To facilitate understanding of the study 
design, eyes will be classified into 4 categories based on treatment-group assignment and 
designation of study/fellow eye: AAV2-REP1-study eye (includes high and low dose); 
AAV2-REP1-fellow eye (includes high and low dose); Control-study eye; and Control-fellow 
eye.  Once a subject has been randomised, a change in “study eye” designation is not 
permitted. 
At the time of randomisation, a projected surgical date should be defined for each subject. 
For each subject randomised to the control group, this projected surgical date (+/- 1 day) 
should remain the Day 0 (Visit 2) date.  For each subject randomised to a treated group, Day 
0 (Visit 2) will be the actual date of surgery.  The Screening / Baseline period must occur 
within 8 weeks prior to dosing (Week 2, Day 0).  
On this visit (Visit 2, Day 0), subjects in the AAV2-REP1-treatment groups will undergo 
vitrectomy and retinal detachment before receiving a sub-retinal injection of AAV2-REP1 
high dose (1.0×10^11 gp), or AAV2-REP1 low dose (1.0×10^10 gp) in their study eye (i.e., 
AAV2-REP1-study eye). 
These treated subjects will then return to the site for 2 post-operative follow up visits on 
Day 1 (Visit 3) and, possibly, Day 7 (Visit 4; Day 7 can occur either at the surgical site or the 
host site, depending on the clinical status of the subject).  Subjects in the Control group will 
not undergo surgery, receive study drug or attend the 2 on-site safety post-operative visits.  

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Instead, a telephone contact from the site will occur for the Control group on Day 0 (Visit 2), 
Day 1 (Visit 3) and Day 7 (± 3 days; Visit 4). 
All subjects will be followed for 12 months from Visit 2 (Day 0).  Study data will be 
collected for both eyes of each subject.   
Since AAV2-REP1 treatment requires an invasive surgical procedure under general 
anaesthesia, the sponsor, investigator and the subject will be unmasked to the study procedure 
(i.e. vitrectomy and sub-retinal injection), however within the treated groups, the sponsor, 
investigator and subject will be masked to the assigned dose (1.0×10^11 gp or 
1.0×10^10 gp).  To further minimise the potential bias of the treated and untreated eye 
evaluations, all subjective ophthalmic assessments from the Screening/Baseline period 
(Visit 1) and from Month 1 (Visit 5) onwards, will be conducted by a masked assessor.  
Subjects will be assessed for efficacy and safety throughout the study as indicated in the 
Schedule of Study Procedures (see Section 17.1).   
The efficacy evaluation will be based on BCVA, fundus AF, SD-OCT, microperimetry, 
contrast sensitivity, colour vision, reading speed test, VFQ-25 
 
.  The safety evaluation will be based on full ophthalmic examination 
(including IOP, slit lamp examination, lens opacity grading, and dilated ophthalmoscopy), 
fundus photography, adverse event (AE) reporting, laboratory assessments (immunogenicity), 
and vital signs.  Any safety information collected as a result of the efficacy assessments (e.g., 
BCVA) will also be used in the overall safety evaluation, as appropriate. 
Subjects who develop cataracts may undergo cataract surgery if deemed clinically necessary; 
if surgery is performed, it should be carried out at least 4 weeks before the Month 12 
Visit/End of Study (EOS) Visit (primary endpoint). 
A subject is considered to have completed the study if he completes the Month 12 
assessments.  The end of the trial is the date the last subject completes his Month 12 
assessments (or early termination [ET] assessments in the event of premature 
discontinuation) or the date of last data collection if the last subject is lost to follow-up.  After 
study completion, treated subjects will be invited to participate in a long term follow up study 
which will permit continued efficacy and safety monitoring over a period of 5 years post-
treatment. 
7.2 
Discussion of Design 
The subjects to be included in the study are representative of active CHM disease and are 
being selected in such a way as to optimise observance of meaningful change in the outcome 
measures (i.e., baseline BCVA 34-73 ETDRS letters avoids potential ceiling/floor effects for 
change from baseline BCVA measures).  The planned sample size (approximately 
160 subjects) is considered to be a comprehensive number of subjects considering the rarity 
of the disease and provides adequate power to observe the expected treatment effect (see 
Section 13.1 for details).  A prospective trial period of up to 12 months for efficacy and 
safety is considered a sufficient period of time to observe clinically relevant changes in 
disease status among subjects selected for the study and to assess the safety of the 
investigational drug.  In the AAV2-REP1 Investigator-Sponsored trials, efficacy has been 
observed as early as Month 1, with stabilisation of efficacy at Month 3 onwards in responders 
(patients with ≥ 15 letter gains versus baseline).  
The choice of control for this parallel-group study is no study medication/surgical procedure.  
Since administration of vector requires vitrectomy, an invasive surgical procedure under 
general anaesthesia, a similar sham treatment procedure was not ethically feasible.  A 

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parallel-group design was selected following feedback from regulatory authorities.  The 
choice of primary endpoint (proportion of patients with ≥ 15-letter gain) is well-accepted as a 
clinically meaningful improvement in visual function (Csaky 2017). 
The sponsor, investigator and subject will be unmasked to the study procedure and treatment 
(i.e. vitrectomy and sub-retinal injection).  However, within the treated groups, the sponsor, 
investigator and subject will be masked to the assigned dose (1.0×10^11 gp or 
1.0×10^10 gp).  To further minimise potential bias of the treated and non-treated eye 
evaluations, all subjective ophthalmic assessments collected during the Screening/Baseline  
period (Visit 1) and from Month 1 (Visit 5) onwards will be conducted by a masked assessor. 
The dose range of vector being employed in this study is based on previous clinical trials 
using the AAV2 vector with a chicken β actin (CBA) promoter (Maguire 2009; 
MacLaren 2014) and investigator-driven clinical studies in which AAV2-REP1 was 
administered to subjects with CHM (MacLaren 2014; Dimopoulos 2018; Lam 2018; 
Xue 2018).  Efficacy has been observed in doses of 1.0×10^10 gp or 1.0×10^11 gp in these 
Investigator-Sponsored trials, with approximately 17% of patients in the target population 
treated with 1.0×10^11 gp achieving ≥ 15 letter improvement at 12 months post-treatment.  
The high dose of 1.0×10^11 gp is planned to be administered in this study at a higher 
allocation ratio than the lower dose of 1.0×10^10 gp because the high dose provides optimal 
multiplicity of infection ratios, has been previously tested in the Investigator-Sponsored trials 
and has been generally well tolerated thus far.  In addition, randomisation is stratified by 
surgical group, to account for potential confounders (e.g., differences in care provided 
according to country/region). 
Application of AAV2-REP1 to the retina requires retinal detachment following vitrectomy.  
To improve visualization of the vector and facilitate dosing, surgeons are given the option of 
adding a minute quantity of trypan blue ophthalmic solution (~6 µL) to the vector solution.  
See the AAV2-REP1 Surgical Manual for further details.  
Sub-retinal injection of AAV2-REP1 carries the risks associated with vitrectomy and retinal 
detachment. These and other surgical risks are discussed in Section 5.4. To minimise 
inflammation resulting from potential immune responses to vector, subjects receiving AAV2-
REP1 will be given a course of oral corticosteroid (e.g., prednisolone / prednisone) (see 
Section 9.8 for details).   

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8 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The study will enroll approximately 160 subjects with CHM (see Section 13.1 for discussion 
of the sample size determination).  The majority of patients enrolled in this study will be from 
the preceding NIGHT observational study (Protocol NSR-CHM-OS1). 
8.1 
Inclusion Criteria 
Subjects are eligible for study participation if they meet all of the following inclusion criteria. 
1. Are willing and able to provide informed consent for participation in the study
2. Are male and ≥18 years of age
3. Have a documented genetically-confirmed diagnosis of CHM
4. Have active disease clinically visible within the macular region in the study eye
5. Have a BCVA of 34-73 ETDRS letters (equivalent to worse than or equal to 6/12 or
20/40 Snellen acuity, but better than or equal to 6/60 or 20/200 Snellen acuity) in the
study eye
8.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they meet any of the following exclusion 
criteria. 
1. Have a history of amblyopia in the eligible eye
2. Are unwilling to use barrier contraception methods, or abstain from sexual intercourse,
for a period of 3 months, if treated with AAV2-REP1
3. Have had previous intraocular surgery performed in the study eye within 3 months of
Visit 1
4. Have any significant ocular or non-ocular disease/disorder which, in the opinion of the
investigator, may either put the subjects at risk because of participation in the study, or
may influence the results of the study, or the subject’s ability to participate in the study.
This includes but is not limited to, a subject:
•
with a contraindication to oral corticosteroid (e.g., prednisolone/prednisone)
•
with a clinically significant cataract
•
who, in the clinical opinion of the Investigator, is not an appropriate candidate
for sub-retinal surgery
5. Have participated in another research study involving an investigational product in the
past 12 weeks or received a gene/cell-based therapy at any time previously
8.3 
Subject Withdrawal Criteria 
Each subject has the right to withdraw from the study at any time without prejudice.  In 
addition, the investigator may discontinue a subject from the study at any time if the 
investigator considers it necessary for any reason, including: 
•
Significant protocol deviation
•
Significant non-compliance with study requirements

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• AE which results in an inability to continue to comply with study assessments 
• Lost to follow up 
• Death 
• Other (to be specified on the electronic case report form [eCRF]). 
In the event that a subject discontinues the study, the reason for withdrawal is to be recorded 
in the eCRF.  In the event that a subject discontinues the study early, the site should use every 
reasonable effort to ensure that an ET Visit is conducted as outlined in the Schedule of Study 
Procedures (see Section 17.1).  If the subject is withdrawn due to an AE, the investigator will 
arrange for follow-up until the event has resolved or stabilised.  For subjects who withdraw 
consent, data will be collected through their last available study visit.  Subjects withdrawn 
from the study may possibly be replaced. 
Withdrawal from the study will not result in the exclusion of a subject’s data acquired up to 
the point of withdrawal. 
The study may be discontinued if the Sponsor deems it necessary for medical, safety, 
regulatory, business or other reasons consistent with applicable or regulations. 

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9 
STUDY TREATMENT 
9.1 
Treatments Administered 
During the Screening/Baseline period, eligible subjects will be randomised in a 2:1:2 ratio to 
receive either AAV2-REP1 high dose (1.0×10^11 gp), AAV2-REP1 low dose 
(1.0×10^10 gp) or to enter the untreated Control group.  The “study eye” must be selected 
prior to randomisation.  Once a subject has been randomised, a change in “study eye” 
designation is not permitted. 
At the time of randomisation, a projected surgical date should be defined for each subject. 
For each subject randomised to the control group, this projected surgical date (+/- 1 day) 
should remain the Day 0 (Visit 2) date.  For each subject randomised to a treated group, Day 
0 will be the actual date of surgery. 
For those randomized to treated groups, at this visit (Visit 2, Day 0), subjects will be 
administered AAV2-REP1 as a sub-retinal injection after vitrectomy (See Section 9.4 for 
details). Subjects in the untreated Control group will receive no sham surgery or study 
medication. 
9.2 
Description of Study Drug 
The AAV2 vector contains recombinant human cDNA encoding REP1 (AAV2-REP1).  The 
vector genome (AAV2-CBA-hREP1-WPRE-BGH) is comprised of a strong constitutive 
expression cassette, a hybrid CBA promoter, the human cDNA encoding REP1, a modified 
woodchuck hepatitis post-transcriptional regulatory element (WPRE) sequence, and a bovine 
growth hormone polyadenylation (BGH-polyA) sequence flanked by AAV2 inverted 
terminal repeats.  The cDNA fragment was originally isolated from a human retinal cDNA 
library from unaffected individuals. 
The AAV2-REP1 drug product is formulated in a sterile, 20 mM Tris-buffered solution, 
pH 8.0, and contains 1 mM MgCl2, 200 mM NaCl, and 0.001% PF68.  The drug product is a 
clear to slightly opalescent, colourless, sterile-filtered suspension with a target concentration 
of 1.0 × 10^12 gp/mL. 
9.3 
Packaging, Labelling, and Storage 
AAV2-REP1 is currently supplied in sterile, single-use, clear glass or plastic vials, stoppered, 
and capped with plastic overseals, with each vial containing 300 µL vector suspension.  Each 
vial contains 3.0×10^11 gp in total.  Prior to shipment, each vial will be placed in a labeled 
secondary container.  The drug product is to be stored at <−60oC (<−76oF) in a controlled 
access, temperature monitored freezer. 
The Investigational Medicinal Product will be labeled in compliance with regulatory 
standards. 
9.4 
Vitrectomy Procedure and Injection of AAV2-REP1 
Injection of AAV2-REP1 is to be performed by an appropriately qualified and experienced 
retinal surgeon.  All surgeons must have completed all study-specific surgical training and 
obtained certification by NightstaRx to perform the study procedure, before treating a study 
participant. 

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Due to the complexity and unpredictability of detaching the retina in end-stage CHM, in 
which the retina and choroid are extremely thin and fused in places, a modification to the 
technique of sub-retinal gene therapy has been developed.  This involves performing the 
vector delivery in 2 steps after vitrectomy.  An advantage of a 2-step procedure is that any 
unexpected complications of retinal detachment can be managed conservatively, minimising 
concerns about the vector escaping into the vitreous.  Further, the injection could be deferred 
until a later date if, for instance, a macular hole was created which required treatment with 
gas.  Also, since the volume of fluid required to detach the fovea is variable, by removing the 
vector from the first step, a precise consistent dose in terms of genome particles can still be 
applied into the sub-retinal space. 
Initially, subjects will undergo a standard vitrectomy and detachment of the posterior hyaloid 
(Figure 2).  All surgery will be conducted using the standard BIOM vitrectomy system.  A 
23-gauge sutured approach is usually favoured to avoid any potential risks of wound leakage.  
The retina will be detached with 100-500 µL of balanced salt solution (BSS) injected through 
a 41-gauge sub-retinal cannula connected to a vitreous injection set (this is the first step of the 
2-step procedure). 
In the second step of the procedure, the BSS cannula is removed from the eye and AAV2-
REP1 is prepared for injection.  The dilution process for the 1.0×10^10 gp dose is outlined in 
the Pharmacy Manual.  A dose of either 1.0×10^11 or 1.0×10^10 AAV2-REP1 gp (injection 
of a volume of up to 100 µL vector suspension) will be injected into the sub-retinal fluid 
through the same entry site.  To improve visualization of the vector and facilitate dosing, 
surgeons are given the option of adding a minute quantity of trypan blue ophthalmic solution 
(~6 µL) to the vector solution.  See the AAV2-REP1 Surgical Manual for further details (see 
Figure 2).  The vector needs to be primed in the 1-mL syringe to avoid formation of air 
bubbles, and a connector is used so that the 1-mL syringe can be connected to the constant 
pressure line of the vitrectomy machine.  The sub-retinal injection will target any area of the 
macula but also include the fovea, if possible.  In each case, the vector will be injected so that 
the sub-retinal fluid overlies all edge boundaries of the central region that has yet to undergo 
chorioretinal degeneration, as identified by fundus AF.  After wound closure, care will be 
taken to dispose of all irrigating fluids that may have passed through the eye to limit potential 
vector spread. 
Subjects will be carefully monitored for the occurrence of AEs peri- and post-operatively.  
All AEs, irrespective of relationship to the study drug and/or the surgical procedure will be 
captured in the subject’s medical record and reported in the eCRF. 

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Figure 2 
Vitrectomy and Sub-retinal Injection of AAV2 Vector 
A 
B 
 
(A) A standard vitrectomy through the BIOM operating system to remove the vitreous gel is followed 
by (B) 2-step procedure: 1) retinal detachment by injection of BSS; 2) injection of a volume of up to 
100 µL vector suspension through a 41-gauge cannula into the sub-retinal space.  
9.5 
Randomisation 
During the Screening/Baseline period, all subjects will be assigned a screening identifier, 
which will include the centre number and subject number.  If the subject fulfils all eligibility 
criteria during the Screening/Baseline period, a study eye will be assigned (prior to 
randomisation) and the subject will be randomised in a 2:1:2 ratio to receive either AAV2-
REP1 high dose (1.0×10^11 gp), AAV2-REP1 low dose (1.0×10^10 gp) or to enter the 
untreated Control group.  
Randomisation will be generated using a validated system that automates the random 
assignment of treatment groups, and stratified by surgical group*.  Once a subject is deemed 
eligible, the investigative site (or authorised designee) will access the system, and the subject 
will be randomised using a standard blocked randomisation.   
Once a subject has been randomised, a change in “study eye” designation is not permitted. 
At the time of randomisation, a projected surgical date should be defined for each subject. 
For each subject randomised to the control group, this projected surgical date (+/- 1 day) 
should remain the Day 0 (Visit 2) date.  For each subject randomised to a treated group, Day 
0 will be the actual date of surgery. 
All subjects’ data (including screen failures) will be entered into the eCRF. 
* A surgical group will consist of a single ‘Surgical Site’ and ‘Non-surgical Sites’.  The Surgical Site will 
conduct baseline and follow-up visits for local subjects, as well as surgeries and immediate post-operative visits 
for all subjects treated in the surgical group.  The ‘Non-surgical Sites’ will only perform the baseline/screening 
visit and the follow-up visits from Day 7 (Visit 4) onwards for their respective local subjects. 
9.6 
Study Masking and Minimisation of Bias 
Randomisation of subjects aims to minimise potential selection bias.   
Given a double-masked design is not feasible (i.e. treatment involves invasive surgical 
procedure under general anaesthesia), the sponsor, investigator and the subject will be 

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unmasked to whether a subject has been assigned to the AAV2-REP1 treatment groups, or 
the untreated Control group.  However, within the treated groups, the sponsor, investigator 
and subject will be masked to the assigned dose (1.0×10^11 gp or 1.0×10^10 gp).  To further 
minimise potential performance/detection bias, all subjective ophthalmic assessments at the 
Screening/Baseline Period (Visit 1) and from Month 1 (Visit 5) onwards, will be conducted 
by a masked (outcomes) assessor. 
Additional measures to minimise potential performance/detection bias include standardised 
methodologies across participating sites (same equipment, assessor training/certification, 
surgical training), and an identical visit/assessment schedule for treated/untreated patients. 
9.6.1 AAV2-REP1 Treatment Groups vs Untreated Control Group, Assessor Masking 
All ophthalmic assessments conducted during the Screening/Baseline period will be 
performed by appropriately qualified masked assessors.  For the immediate post-operative 
visits, masking of the assessors will not be viable as clinical signs of surgery will be apparent 
(i.e. redness, swelling).  Therefore, unmasked assessors will perform all ophthalmic 
assessments at Visit 3 (Day 1) and Visit 4 (Day 7).  From Visit 5 (Month 1) onwards, masked 
assessors will be used, as any signs of surgery will have dissipated and it will not be possible 
clinically to differentiate between those subjects that have not undergone surgery, and those 
subjects that have undergone surgery and received active treatment. 
Subjects randomised to the untreated Control group will not be required to attend the site at 
Visit 2, 3 or 4.  As the key purpose of Visit 2 is surgery, and Visit 3 and 4, post-operative 
safety, there is limited utility in Control subjects attending.  This will also limit the study 
burden for Control subjects, thereby potentially reducing the risk of subject withdrawal at this 
stage, and reducing the possibility of further unmasking due to direct contact and 
communication with fellow participants.  Instead, a telephone contact from the site will occur 
for the Control group on Day 0 (Visit 2), Day 1 (Visit 3) and Day 7 (± 3 days; Visit 4).   
In order to minimise bias further, masked assessors will not have access to the subject’s 
medical records, source documentation or eCRF as data entries or notation (such as use of 
peri-operative corticosteroid) may be sources of unmasking.  From Visit 5 (Month 1) 
onwards, the masked assessor will also read a pre-written statement to each subject, 
regardless of randomisation, reminding them of the masked nature of the study, and to avoid 
any reference to prior surgery/non-surgery, which eye may have received treatment or to 
allude to any information that may unmask the assessor as to which group the subject has 
been assigned to. 
Furthermore, it is anticipated that a subset of the subjects participating in the trial will be 
active on social media.  Following appropriate approval by the Independent Ethics 
Committee (IEC) / Institutional Review Board (IRB), the patient information leaflet will 
request that subjects refrain from posting any details of study participation on social media, 
that may unmask the assessors to the group the subject has been assigned to.  This request 
will be reiterated at visits by the investigator and within the pre-written statement. 
Table 1 describes the ophthalmic assessments that are to be performed by masked assessors at 
Screening/Baseline (Visit 1) and Visits 5-8. 
 

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Table 1 
Assessor Masked Ophthalmic Assessments 
Assessment 
Masked Outcomes Assessors at  
Visit 1 and Visits 5-8 
BCVA 
 
Microperimetry 
 
Contrast Sensitivity 
 
Colour Vision 
 
Reading Speed 
 
VFQ-25 
 
Abbreviations: BCVA= best corrected visual acuity, 
, VFQ-25=25-item 
Visual Function Questionnaire 
9.6.2 AAV2-REP1 Treatment Groups, Dose Masking 
Subjects randomised to the AAV2-REP1 treatment groups, surgeons, the investigative team 
and the study sponsor will be masked as to which dose of AAV2-REP1 the subject has been 
assigned to.  All vector vials will be filled at 1.0 × 10^11 gp.  Therefore, for subjects who are 
due to receive the lower dose of 1.0 × 10^10 gp, a dilution step is required prior to surgery.  
Unmasked study site personnel will be assigned the responsibility of performing the dilution 
in accordance with the Pharmacy manual, in a designated area remote from the investigative 
team to preserve masking of the treatment arm.  Personnel delegated to perform the dilution 
will not be involved in any other aspect of the study (i.e., consent, safety/efficacy 
assessments, surgical procedure). 
9.7 
Study Drug Accountability 
Records of the receipt and dispensing of study drug, which should include the diluent if used, 
will be kept by each study centre until the end of the study to provide complete accounting of 
all used and unused study drug. Dispensation logs will be checked by the Sponsor (or its 
designee).  Study centres will destroy all used vials in accordance with local procedures, and 
will return all unused study drug to the Sponsor (or its designee) at the end of the study.  
Final drug accountability will be verified by the Sponsor (or its designee).   
9.8 
Concomitant Therapy 
Subjects cannot have participated in another research study involving an investigational 
product in the past 12 weeks or received a gene/cell-based therapy at any time previously. 
Throughout the study, subjects may be prescribed any concomitant medications, procedures, 
and/or treatments deemed necessary.  Details of concomitant medications, procedures, and 
treatments will be collected at the Screening/Baseline Visit and updated at every study visit 
(including the ET Visit, if applicable).  Concomitant medications, procedures and treatments 
(including corticosteroids) taken during the study are to be recorded in the subject’s medical 
records and eCRF; an exception to this is any medication used in the course of conducting a 
study assessment (e.g., ophthalmic dyes, topical anaesthesia, dilating eye drops). 

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To minimise inflammation resulting from surgery and potential or unexpected immune 
responses to vector/transgene, all subjects who receive AAV2-REP1 will be given a 21-day 
course of oral corticosteroid (e.g., prednisolone/prednisone), modified from the 17-day 
protocol established in the voretigene neparvovec-rzyl AAV gene therapy clinical trial for 
treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy 
(Maguire 2008), allowing an extra 4 days for tapering the dose at the end of the course.  
Hence, this will be 1 mg/kg/day prednisolone/prednisone for a total of 10 days, (beginning 
2 days before the vector injection, on the day of injection, and then for 7 days), followed by 
0.5 mg/kg/day for 7 days, then 0.25 mg/kg/day for 2 days and 0.125 mg/kg/day for 2 days 
(21 days in total).  Weight captured at Visit 1 (Screening/Baseline) will be used to calculate 
the required dose during the 21-day course, and all doses should be rounded to the nearest 
1 mg.  Compliance with the use of corticosteroid (e.g., prednisolone / prednisone) will be 
captured in a patient diary card and in the eCRF. 
9.9 
Treatment Compliance 
This study involves a single sub-retinal injection of a volume of up to 100 µL AAV2-REP1 
containing either 1×10^11 gp or 1×10^10 gp following vitrectomy by a qualified retinal 
surgeon.  The exact quantity injected at the time of surgery should be recorded on the eCRF.  
Measure of treatment compliance with AAV2-REP1 is therefore not necessary. 

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10 STUDY VISITS AND PROCEDURES 
The schedule of study procedures is presented in Table 3. 
10.1 Visit 1 (Screening/Baseline Period) 
The investigator will explain the study purpose, procedures, and subject responsibilities to 
each potential study subject.  The subject's willingness and ability to meet the protocol 
requirements will be determined. 
Prior to any study-specific procedure, written informed consent will be obtained.  The subject 
will sign and date one copy of the consent form in the presence of the investigator or his/her 
designee.  The original signed form will be retained at the study site and an additional copy 
will remain in the subject’s medical records; a copy will also be given to the subject.  The 
informed consent must be signed within 12 weeks prior to the treatment visit (Visit 2, Day 0).   
After informed consent has been obtained, the subject will be allocated a subject identifier 
number and evaluated to determine eligibility.  The Screening / Baseline Period (Visit 1) 
must be completed within 8 weeks prior to the treatment visit (Visit 2, Day 0).  
Subjects randomised to the AAV2-REP1 groups will be instructed to use barrier 
contraception, or abstain from sexual intercourse, for a period of 3 months from the time they 
are treated. 
In some cases, subjects randomised to receive AAV2-REP1 will travel to alternative qualified 
investigative sites to undergo the study surgical procedure, and then return back to the 
original (host) investigational site for study follow up.  The post-operative visits at Day 1 
(Visit 3) and possibly at Day 7±3 Days (Visit 4) will occur at the surgical site, while the 
remaining visits will occur at the original, host site.  The Sponsor will provide the 
investigational sites, subject and any appropriate caregiver with necessary logistical support, 
with arrangements made for Visits 2, 3 and 4 to allow for adequate planning and post-
operative follow-up. 
If the subject is randomised to the Control group, then Visit 2 will consist of a telephone call 
(see Section 10.2).   
For subjects who roll over from the observational NIGHT study (Protocol NSR-CHM-OS1) 
into this interventional study, the assessments and procedures conducted at the final visit 
(including the ET Visit) of the NIGHT study may be used for the Screening/Baseline Visit in 
the current study, as long as the visit occurred within 8 weeks of Visit 2 (dosing). 
If the subject was not previously enrolled in the NIGHT study, BCVA assessments at 
baseline must be performed in triplicate over a period of 2 days, as described above.  At least 
2 of the triplicate values must meet BCVA eligibility requirements for inclusion in the study, 
and the difference between the 3 assessments may not be ≥ 10 letters. 
Screening/baseline procedures will consist of the following (assessments can be spread over 
2 consecutive days if necessary): 
• Demography, medical and ocular history.  (Only subjects with a genetically 
confirmed diagnosis of CHM may enter the study.  Genetic confirmation must be 
documented prior to Visit 1) 
• VFQ-251 
• Vital signs 

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• Weight 
• Immunoassay sampling (enzyme-linked immunosorbent assay [ELISA], cell-based 
assay, and enzyme-linked immunospot [ELISPOT]) 
• 
 
• BCVA3 
• Contrast sensitivity test 
• Colour vision test 
• Reading speed test4 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• 7-field colour fundus photography (including stereo photographs for fields 1, 2, and 3) 
• Adverse event (AE) and serious adverse event (SAE) monitoring 
• Concomitant medication, procedures, and treatment review 
• Corticosteroid dispensing (if randomised to AAV2-REP1 groups) 
Subjects randomised to the AAV2-REP1 groups will be given a 21-day course of oral 
corticosteroid (e.g., prednisolone/prednisone) and instructed to start taking the drug 2 
days before their next study visit (Visit 2).   
• Randomisation 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will 
have a study eye assigned and be enrolled into the study (see Section 9.5 for details on 
randomisation and assignment of subject numbers).  At this time, subjects will be 
informed of the randomisation outcome (i.e., AAV2-REP1 treatment or the Control 
group) and instructed to not reveal their treatment group assignment to the masked 
assessors during the study.  Subjects randomised to the AAV2-REP1 treatment groups 
(along with the Investigators and sponsor) will remain masked to the assigned dose.   
At the time of randomisation, a projected surgical date should be defined for each 
subject.  For each subject randomised to the control group, this projected surgical date 
(+/- 1 day) should remain the Day 0 (Visit 2) date.  For each subject randomised to a 
treated group, Day 0 will be the actual date of surgery. 
Once a subject has been randomised, a change in “study eye” designation is not 
permitted. 
1. VFQ-25 must be completed by subjects at the beginning of the study visit, prior to any 
significant interaction with study staff; the questionnaire is used only in languages in which it 
is validated. 
 
3. In order to capture accurate BCVA values at Visit 1 (Screening/Baseline), the following 
conditions apply to the BCVA assessment: 

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• 
If the BCVA value at Visit 1 (Screening/Baseline) is ≥ ±10 letter gain or loss in the 
study eye compared to the previous NIGHT study visit (if applicable), then BCVA 
must be repeated an additional 2 times, resulting in a total of 3 BCVA measures at 
Visit 1.  To facilitate the additional BCVA measures this visit should be conducted 
over 2 days, with BCVA measured twice on Day 1 and once on Day 2.  All 
3 BCVA values must be recorded in the eCRF.  The highest score will be used to 
define subject eligibility. 
• 
If the BCVA value at Visit 1 (Screening/Baseline) is < ± 10-letter difference in the 
study eye compared to the previous NIGHT study visit (if applicable), then BCVA 
will be collected once and will not be repeated.  
If the subject was not previously in the NIGHT study, BCVA assessments at baseline must be 
performed in triplicate over a period of 2 days, as described above.  At least 2 of the triplicate 
values must meet BCVA eligibility requirements for inclusion in the study and the difference 
between the 3 assessments may not be greater than or equal to 10 letters.4. The International 
Reading Speed Texts (IReST) speed reading test is only conducted in languages in which a 
validated translation is available. 
10.2 Visit 2 (Day 0, Injection Day Visit or Telephone Contact) 
At Visit 2 (Day 0), all subjects in the AAV2-REP1-treated groups will visit the surgical site, 
and the following assessments will be performed: 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review  
• Corticosteroid compliance review 
It may be necessary for subjects to undergo a pre-surgical workup according to local hospital 
procedures (e.g., blood draw for anesthetist) which are outside of the protocol-defined 
assessments.  Any assessments performed outside of the protocol will not be collected as part 
of the study analyses. 
Subjects in the AAV2-REP1-treated groups will then undergo vitrectomy and receive a sub-
retinal injection of AAV2-REP1, containing either 1×10^11 gp or 1×10^10 gp (see 
Section 9.4 for details), in their study eye.  Subjects will be carefully monitored for the 
occurrence of AEs during and after the procedure.   
Subjects will return to the surgical site for Visit 3 (post-operative Day 1).  Visit 4, post-
operative Day 7, may occur at the surgical site or the host site depending on the clinical status 
of the subject. 
Subjects in the Control group will receive the Visit 2 (Day 0) Telephone Call at the agreed 
upon date and time.  Sites will conduct the following assessments during the telephone call: 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
10.3 Visit 3 (Day 1 Post-Operative Visit) 
At Visit 3 (Day 1), subjects in the AAV2-REP1 groups will return to the surgical site for a 
post-operative visit.  The following assessments will be performed: 
• Vital signs 

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• Immunoassay sampling (ELISA and cell-based assays only) 
• BCVA 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
• Corticosteroid compliance review 
Subjects will be reminded of the requirement to use barrier contraception for a period of 
3 months from the time of treatment. 
Subjects in the Control group will receive the Visit 3 Telephone Call at the agreed upon date 
and time.  Sites will conduct the following assessments during the telephone call: 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review  
10.4 Visit 4 (Day 7 Post-Operative Visit ± 3 Days) 
At Visit 4 (Day 7 ± 3 days), subjects in the AAV2-REP1 groups will return for a second post-
operative assessment.   
For subjects who traveled from a host site (i.e. same site where their Visit 1 
Screening/Baseline visit was performed) to a surgical site for their surgical procedure, this 
visit may occur either at the surgical site or the host site.  However, in the event of a post-
operative complication or for any other safety reason considered appropriate by the study 
surgeon and surgical site Investigator, Visit 4 should be conducted at the surgical site.  In this 
case, post-operative follow-up should continue at the surgical site until the surgeon/surgical 
site Investigator agrees to discharge the subject to the care of the non-surgical site.   
The following assessments will be performed: 
• Vital signs 
• Immunoassay sampling  
• 
 
• BCVA 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
• Corticosteroid compliance review 

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Subjects in the Control group will receive the Visit 4 Telephone Call at the agreed upon date 
and time (± 3 days of Day 7).  Sites will conduct the following assessments during the 
telephone call: 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review  
10.5 Visit 5 (Month 1 ± 7 Days) 
All subjects, regardless of treatment randomisation, will attend their host site (i.e. same site 
where their Visit 1 Screening/Baseline visit was performed) from Visit 5 onwards.  At Visit 5 
(Month 1 ± 7 days), the following assessments will be performed for all subjects 
(assessments can be spread over 2 consecutive days if necessary): 
• Vital signs 
• Immunoassay sampling 
• 
 
• BCVA 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
• Corticosteroid compliance review for treated subjects 
10.6 Visit 6 (Month 4 ± 7 Days) 
At Visit 6 (Month 4 ± 7 days), the following assessments will be performed (assessments can 
be spread over 2 consecutive days if necessary): 
• Immunoassay sampling  
• 
 
• BCVA 
• Contrast sensitivity test 
• Colour vision test 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 

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• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
10.7 Visit 7 (Month 8 ± 14 Days) 
At Visit 7 (Month 8 ± 14 days), the following assessments will be performed (assessments 
can be spread over 2 consecutive days if necessary): 
• Immunoassay sampling  
• 
 
• BCVA 
• Contrast sensitivity test 
• Colour vision test 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
10.8 Visit 8 (Month 12 ± 14 Days, End of Study Visit) 
At Visit 8 (Month 12 ± 14 days), the following assessments will be performed (assessments 
can be spread over 2 consecutive days if necessary): 
• VFQ-251 
• Vital signs 
• Immunoassay sampling  
• 
 
• BCVA 
• Contrast sensitivity test 
• Colour vision test 
• Reading speed test2 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• 7-field colour fundus photography (including stereo photographs for fields 1, 2, and 3) 

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• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 
1. VFQ-25 must be completed by subjects at the beginning of the study visit, prior to any 
significant interaction with study staff; the questionnaire is used only in languages in which it 
is validated. 
2. The IReST speed reading test is only conducted in languages of which a validated 
translation is available. 
10.9 Early Termination Visit 
In the event that a subject discontinues the study at any time, the site should use every 
reasonable effort to ensure that an ET Visit is conducted.  The following assessments should 
be performed: 
• VFQ-251 
• Vital signs 
• Immunoassay sampling   
• 
 
• BCVA 
• Contrast sensitivity test 
• Colour vision test 
• Reading speed test (if applicable)2 
• Microperimetry 
• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• 7-field colour fundus photography (including stereo photographs for fields 1, 2, and 3) 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review  
1. VFQ-25 must be completed by subjects at the beginning of the study visit, prior to any 
significant interaction with study staff; the questionnaire is also used only languages in which 
it is validated. 
2. The IReST speed reading test is only conducted in languages in which a validated 
translation is available. 
10.10 Unscheduled Visits 
If clinically indicated, subjects may need to return to the site for an unscheduled visit.  At a 
minimum, the following assessments will be performed. 
• BCVA 

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• Full ophthalmic examination, including IOP, a slit-lamp examination, lens opacity, 
and dilated fundus examination 
• SD-OCT 
• AF 
• AE/SAE monitoring 
• Concomitant medication, procedures, and treatment review 

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11.5 Colour Vision 
Colour vision will be tested for both eyes prior to pupil dilation at the times indicated in 
Table 3. 
Eyes will be tested separately and in the same order at each assessment.  Refer to the Study 
Operations Manual for details on the colour vision test to be used. 
11.6 Reading Speed Test 
Reading performance will be evaluated prior to pupil dilation at the times indicated in Table 
3 using International Reading Speed Texts (IReST), which provide standardised assessment 
of reading performance in 17 languages (Trauzettel-Klosinski 2012).  The IReST will be 
provided to each site by the Sponsor, and for complete user instructions refer to the Study 
Operations Manual (which will include the randomisation procedure for text selection).  The 
IReST will only be conducted in languages in which a validated translation is available. 
11.7 Microperimetry 
Microperimetry will be conducted for both eyes at the times indicated in Table 3. 
Microperimetry will be conducted by certified technicians to assess changes in retinal 
sensitivity within the macula.  All microperimetry images will be sent by the sites to a 
Central Reading Centre (CRC) for review.  For complete technical specifications for 
microperimetry, refer to the Study Operations Manual (which will include procedures from 
the CRC regarding how measurements are to be taken). 
11.8 Fundus Autofluorescence 
To assess changes in the area of viable retinal tissue, fundus AF will be performed for both 
eyes at the times indicated in Table 3. 
All fundus AF images will be performed by certified technicians at the site after dilation of 
the subject’s pupil and sent to a CRC for review.  For complete technical specifications for 
fundus AF, refer to the Study Operations Manual (which will include procedures from the 
CRC regarding how measurements are to be taken). 
11.9 Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT will be performed for both eyes at the times indicated in Table 3. 
SD-OCT measurements will be taken by certified technicians at the site after dilation of the 
subject’s pupil.  All OCT scans will be submitted by the sites to a CRC where the scans will 
be evaluated.  SD-OCT will be used to assess a number of variables, including quantifying 
the integrity of the ellipsoid zone and reduction in the signal from the outer nuclear layer and 
choroid.  In addition, since progressive foveal thickening has been noted in the early phase of 
CHM (Jacobson 2006), foveal changes will be assessed.  For complete technical 
specifications for SD-OCT, refer to the Study Operations Manual (which will include 
procedures from the CRC regarding how measurements are to be taken). 
 

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12 ASSESSMENT OF SAFETY 
12.1 Full Ophthalmic Examination 
A full ophthalmic examination will be conducted for both eyes at the times indicated in Table 
3. 
For subjects in the AAV2-REP1 groups, the full ophthalmic examination will be conducted 
prior to pupil dilation and prior to vitrectomy and administration of study medication at the 
applicable study visit. 
The ophthalmic examination will include IOP, slit lamp examination, lens opacity grading, 
and dilated ophthalmoscopy.  The same slit lamp machine and lighting conditions should be 
used across study visits for any given subject. 
In addition to the parameters listed above, relevant subjects will be carefully examined for the 
presence of intraocular inflammation after vector administration.  Cataract can also develop 
as a result of the vitrectomy procedure and can potentially affect VA.  Pre-operative grading 
of lens opacity and colour should therefore be documented by the established clinical lens 
opacities classification system.  A recent study has shown that cataract surgery is effective in 
subjects with CHM and without any specific risks (Edwards 2015).  Hence, if clinically 
indicated, subjects who develop cataracts may undergo cataract surgery.  If cataract surgery is 
performed, it should be carried out at least 4 weeks before the Month 12 Visit/EOS Visit. 
12.2 7-Field Colour Fundus Photography 
To aid in the objective clinical assessment of progressive retinal changes, 7-field colour 
fundus photography will be performed for both eyes at the times indicated in Table 3.  
Fundus photography will be performed by certified technicians following pupil dilation.  
Stereo photos should be performed for fields 1, 2, and 3.  All fundus photographs will be sent 
by the sites to the CRC for review.  For complete technical specifications for fundus 
photography, refer to the Study Operations Manual (which will include procedures from the 
CRC regarding how measurements are to be taken). 
12.3 Evaluation, Recording, and Reporting Adverse Events 
12.3.1 Definitions 
12.3.1.1 Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation subject, which does not 
necessarily have a causal relationship with the study medication/surgical procedure.  An AE 
can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the study medication / 
surgical procedure, whether or not related to the investigational product or with the surgical 
procedure described in this protocol. 
AEs are to also include any pre-existing condition (other than CHM) or illness which worsens 
during the study (i.e., increases in frequency or intensity). 

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12.3.1.2 Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Results in vision loss or is vision threatening 
• 
Is an other important medical event(s). 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
subject is at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might cause death if it were more severe. 
Hospitalisation for a pre-existing condition, including elective procedures, which has not 
worsened, does not constitute an SAE. 
Other events that may not result in death, are not life threatening or do not require 
hospitalisation, may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
Vision Loss to Be Reported as a Serious Adverse Event 
Vision Loss NOT TO BE Reported as an SAE: 
• Surgery-related BCVA decrease of ≥15 letters on ETDRS chart occurring within 1 
day of surgery, but recovering / resolving at post-operative Days 7 and 14.  
Vision Loss or Vision-Threatening Event TO BE Reported as an SAE: 
• Surgery-related BCVA decrease of ≥15 letters on ETDRS chart that occurs within 1 
day of surgery and that has not recovered* by the 1-Month Visit. 
• A decrease in BCVA of ≥15 letters on ETDRS chart that occurs within 1 day of 
surgery, however, in the investigator’s opinion: 
o Has an evolution not consistent with the expected post-operative course;  
o May be attributable to a complication that occurred during surgery, or another 
untoward event, or the study drug;  
o Actually or potentially requires any surgical or medical intervention to prevent 
permanent loss of vision. 
• Non-surgery-related, sustained (>48 hours duration) decrease from baseline in BCVA 
of ≥15 letters on ETDRS chart. 
*Recovery / Resolution of BCVA loss is defined as a return to baseline BCVA within 
5 letters on the ETDRS chart. 

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12.3.2 Recording of Adverse Events 
AEs/SAEs will be collected from the time the subject provides written informed consent 
through the EOS Visit (or ET Visit or Unscheduled Visits, if applicable).  
Subjects will be questioned on the occurrence of an AE at every visit including any 
unscheduled visit, by using non-leading questioning such as ‘How have you been since the 
last visit?’ This will include the telephone contact at Visits 2, 3 and 4 for subjects in the 
Control group. 
All AEs occurring during the study observed by the investigator or reported by the subject, 
whether or not attributed to study medication or the surgical procedure, will be recorded in 
the subject’s medical records and in the eCRF. 
The following information will be recorded in the eCRF for each AE: description, date of 
onset and end date, outcome, severity, assessment of relatedness to study medication/study 
procedure, the action taken and confirmation of whether the event is considered serious (see 
Section 12.3.1.2 for the definition of seriousness).  Follow-up information should be provided 
as necessary (see Section 12.3.3 for specifics on follow-up procedures). 
AE severity and relationship to the study medication or the surgical procedure will be 
assessed at the site by the investigator or a medically qualified designee. 
AE Severity 
The severity of events will be assessed on the following scale: 
1 = mild (awareness of sign or symptom, but easily tolerated) 
2 = moderate (discomfort sufficient to cause interference with normal activities) 
3 = severe (incapacitating, with inability to perform normal activities). 
AE Relationship 
When assigning relatedness of the AE, consideration will be given to whether there is a 
plausible relationship to either the study medication or the surgical procedure.  The following 
are definitions of relatedness that will be used in this study. 
Unrelated:  
It is not reasonably related in time to the administration of the 
study medication/surgical procedure or exposure of the study 
medication/surgical procedure has not occurred 
Related: 
A reasonable possibility exists that the study medication / study 
procedure caused the AE. A suspected AE can be further 
defined by: 
Possibly related:  
clinically or biologically reasonable 
relative to the administration of the study medication/surgical 
procedure, but the event could have been due to another equally 
likely cause 
Probably related:  
is clinically/biologically reasonable 
relative to the administration of the study medication/surgical 
procedure, and the event is more likely explained by exposure 
to/administration of the study medication/surgical procedure 
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Definitely related:  a causal relationship of the onset of the 
event, relative to administration of the study 
medication/surgical procedure exists and there is no other cause 
to explain the event. 
 
 
When a relationship is determined to exist, the investigator or medical designee will further 
define if that relationship is to the study medication, the study procedure, both, or unknown. 
12.3.3 Follow-up of Adverse Events 
AEs will be followed until the subject has recovered or the subject’s participation in the study 
is complete. 
Subjects who are withdrawn from the study as a result of a drug-related AE will be followed 
up until the event has resolved, subsided, stabilised, or the subject withdraws consent or is 
lost to follow-up. 
All SAEs, regardless of attribution to study medication or the surgical procedure, should be 
followed-up until the event has resolved, subsided, stabilised, or the subject withdraws 
consent or is lost to follow-up.  The Sponsor (or designee) will follow up SAE reports to 
completion.  Investigators are expected to provide the requested additional information for a 
complete assessment and documentation of the SAE reports within a timely manner. 
12.3.4 Reporting of Serious Adverse Events 
The investigator shall immediately (within 24 hours of learning of the event) report any SAE 
to the Sponsor (or its designee) by completing and emailing an SAE form.  The initial report 
shall be promptly followed up with a more detailed report providing specifics about the 
subject and the event.  Copies of hospital reports, autopsy reports, and other documents 
should be provided (if applicable).  
The sponsor may unmask any SAE reports that are serious, unexpected, and related to the 
study drug, as required, in accordance with safety reporting guidance and regulations. 
The Sponsor will report SAEs and Suspected, Unexpected, Serious Adverse Reactions 
(SUSARs) to investigative sites, IRBs/IECs and regulatory authorities in compliance with 
current legislation.  All cases that are fatal or life-threatening will be reported immediately 
after the Sponsor received the initial report from the Investigator.  All non-fatal or non-life-
threatening cases will be reported within a maximum of fifteen days after the initial 
Investigators report.  The Sponsor will also provide periodic safety reports to IRBs/IECs and 
regulatory authorities as applicable.  Follow-up SAE reports will be submitted within 15 days 
of receiving the information. 
A sample SAE form is provided in the Study Operations Manual, along with the SAE 
reporting contact information. 
12.3.5 
Procedures for Unmasking  
The Investigator has the ability to unmask an individual subject’s treatment assignment in 
order to provide emergency treatment.  Unmasking is appropriate when knowledge of the 
subject’s dose would affect the medical management of the subject. 
If the Investigator determines unmasking is required, then s/he unmasks the subject through 
the Electronic Data Capture (EDC) system, files the resulting confirmation in a restricted file 

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until the end of the study, and notifies the Medical Monitor within 24 hours that the subject’s 
treatment assignment has been unmasked. The Investigator will not communicate the 
treatment assignment to the Medical Monitor or to any sponsor or study team staff; nor 
should the treatment assignment be communicated to site staff other than those personnel 
who require that knowledge in order to treat the subject. 
The Investigator will ensure that the rationale, date, and time of unmasking is noted in the 
subject’s source documentation, but not the treatment assignment.  The medical emergency 
that necessitated unmasking must also be recorded in the source documentation and the case 
report form per standard study procedures. 
12.3.6 Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be used in this study to safeguard 
the safety and interests of study subjects and assess the safety and risk/benefit of the gene 
therapy intervention during the trial. 
At regular intervals during the study, the DMC will review the progress and accrued study 
data.  The DMC will inform the Sponsor if there is a consensus that the ongoing data show 
that the gene therapy, its method of administration, and/or the study design are no longer in 
the best interests of study subjects.  Details of DMC organisation and responsibilities are 
included within a DMC charter that has been approved by all committee members. 
12.4 Pregnancy 
Any pregnancy that occurs during the clinical study in a female partner of a study subject 
should be recorded on a Pregnancy Notification Form.  Subject consent is required prior to 
the collection of personal data, however, the investigator shall immediately (within 24 hours 
of learning of the event) report the pregnancy, with at least preliminary data, to the Sponsor 
(or its designee) by completing and emailing the Pregnancy Notification Form.  In addition, if 
possible, outcome of the pregnancy fathered by the subject should be recorded, including any 
congenital abnormality or birth defect. 
12.5 Laboratory Assessments 
12.5.1 Immunogenicity 
For the evaluation of immunogenicity, blood will be collected at the times indicated in Table 
3. Select samples may be analysed.  
Immunoassays are planned to assess antibody and cell-based responses against AAV2-REP1.  
Immunoassays may or may not be conducted on these samples, depending on safety findings 
from Investigator Sponsored studies and ongoing NighstaRx sponsored studies with AAV2-
REP1.  If immunoassays are conducted, ELISPOT assays will be used for T-cell mediated 
immune responses to transgene, and antibody responses will be assayed using ELISA- and 
cell-based methods. 
All immunogenicity samples will be sent to a central laboratory for analysis.  Refer to the 
Study Operations Manual for details on the shipping and handling of samples. 
Remaining samples may be stored for up to 15 years or per local regulations.  

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12.6 Vital Signs 
Vital signs (pulse and systolic and diastolic blood pressure) will be taken at the times 
indicated in Table 3. 
Vital signs should be taken after the subject is seated for at least 5 minutes. 
 

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13 STATISTICAL CONSIDERATIONS 
Details of the statistical analyses will be described separately in the STAR Statistical 
Analysis Plan. 
13.1 Sample Size 
Approximately 160 subjects will be enrolled in the study (64, high dose group; 32, low dose 
group; 64, control group).   
The sample size calculation is based on a Fischer’s exact test.  CHM is a degenerative 
disease, it is therefore assumed that a ≥15 letter BCVA gain would not be observed in 
subjects without CHM treatment.  Assuming that 16.7% of the treated subjects will gain 
≥15 letters BCVA at Month 12, 56 subjects in the high dose group and the control group 
provide at least 90% power at a 0.05 level of significance with a 2-sided test. To be 
conservative, 64 patients in the high dose group and 64 patients in the control group is needed 
to ensure 85% power in case 1 patient in the untreated control group has ≥15 letter BCVA 
gain by chance, which corresponds to a total of 160 patients completing the study.  
13.2 Procedure for Accounting for Missing Data 
All reasonable efforts will be made to obtain complete data for both eyes on all subjects.  
However, missing observations may occur.  Management of dropout and missing 
observations will depend on their nature and frequency. 
For binary efficacy endpoints (including the primary efficacy endpoint), missing data will be 
imputed as failure, to be conservative. For the continuous efficacy endpoints, the last 
observation carried forward (LOCF) approach will be utilized for handling missing data.  
To evaluate the robustness of the results of the main analyses, sensitivity analyses of the 
primary and secondary endpoints will be performed.  These analyses will include different 
imputation methods on different analysis sets and will be described in detail in the Statistical 
Analysis Plan. 
Safety data will be analysed on observed data.  Missing data will not be imputed. 
13.3 Analysis Population 
13.3.1 Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population is defined as all subjects who are randomised, receive 
the study treatment (or the phone call for those in the untreated control group), and have at 
one least one post-treatment BCVA measurement.  
The ITT population will be used for the efficacy, quality of life, and 
 
.  
The primary population for efficacy analysis is the ITT population.  Subjects will be analyzed 
based on the treatment to which they were randomised. 
 

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13.3.2 Per Protocol Population 
The Per Protocol (PP) population is a subset of the ITT Population, whereby subjects with 
major protocol deviations that may affect substantially the results of the efficacy endpoints, 
are excluded.  Subjects will be analysed according to their actual treatment received. 
The determination of the major protocol deviations, and therefore the composition of the Per 
Protocol Set, will be made prior to unmasking and will be documented separately.   
The PP population will be used to analyze the primary and key secondary efficacy endpoints. 
13.3.3 Safety Population 
The Safety population includes all subjects randomised and who attended Visit 2 (either 
received study treatment [AAV2-REP1] or a study visit Telephone Call [Control]).  
Subjects will be analysed according to their actual treatment received. 
The Safety population will be used for all safety analyses. 
13.4 Descriptive Statistics 
Continuous variables (including changes from Baseline) will be summarised over time using 
descriptive statistics (i.e., mean, standard deviation, 95% confidence interval [CI], median, 
first and third quartiles, fifth and ninety-fifth percentiles, minimum, and maximum).  
Categorical variables (including shifts from Baseline) will be described over time using 
counts, percentages, and 95% CIs. 
13.5 Demographics and Baseline Characteristics 
In order to establish whether treatment groups are comparable, demographics will be 
summarised by treatment group and overall subjects.  Baseline ocular characteristics will be 
summarised by eye and treatment group. 
In the event Baseline data from Visit 1 (prior to treatment) are missing or unavailable, then 
available data from Visit 2 (prior to treatment) will be used as the Baseline value. 
13.6 Efficacy Analyses 
Statistical tests will be performed at the alpha level of 0.05 (unless otherwise specified).  
Statistical tests and 95% CIs will be 2-sided. 
13.6.1 Primary Efficacy Endpoint 
The primary endpoint will be calculated as the proportion of subjects with a ≥15-letter 
increase from baseline in BCVA at the Month 12 visit.   
The primary endpoint will be summarised using the summary statistics for categorical data 
including the 95% CI. 
The primary endpoint will be compared between study arms (high dose vs control, low dose 
vs control) using the Fisher’s Exact test.  The primary approach will be the unstratified 
analysis, and a supportive analysis will be conducted with the Cochran-Mantel-Haenszel 
approach by stratifying by Surgery Group. As Fisher’s Exact test is overly conservative when 
the number of events is low, a supportive analysis will be conducted using Fisher’s Exact-
Boschloo test with a Berger-Boos correction of beta=0.001 (Berger 1994). To maintain the 

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be tested in the pre-specified order.  The comparison between the low dose arm and the 
untreated control is considered as supportive, and will be performed only if significance is 
achieved between the high dose and the untreated control. 
No adjustment will be performed for DMC reviews. 
13.7 Safety Analyses 
No significance testing will be performed for safety analyses.  Safety analyses will be 
descriptive, with 95% CIs calculated where appropriate. 
13.7.1 Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Affairs version 21 or higher. 
Events will be summarised by system organ class, preferred term, and group.  Both the 
number of eyes/subjects experiencing an AE and the number of events will be summarised.  
Similar summaries will be produced for study drug/procedure-related AEs, AEs leading to 
discontinuation, and SAEs.  AEs will also be summarised by maximum severity, relationship 
to study drug/procedure, and time to onset and resolution. 
13.7.2 Full Ophthalmic Examination 
Intraocular pressure and change from Baseline in IOP will be summarised by visit, by 
treatment and by eye.  Abnormal slit lamp examination findings and dilated ophthalmoscopy 
findings, and shift from Baseline will be summarised by visit, by treatment and by eye. 
Lens opacity categories and shift from Baseline will be summarised by visit, by treatment and 
by eye. 
13.7.3 7-Field Colour Fundus Photography 
Categories of colour fundus photography findings and shift from Baseline will also be 
summarised by visit, by treatment and by eye. 
13.7.4 Laboratory Assessments and Vital Signs 
Laboratory assessments (immunogenicity) and vital signs will be summarised in a descriptive 
manner. 

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14 INFORMED CONSENT, ETHICAL REVIEW AND REGULATORY 
CONSIDERATIONS 
14.1 Informed Consent 
Subjects with CHM who meet all of the entry criteria will be invited to take part in the study.  
Subjects must personally sign and date the latest IEC/IRB approved version of the informed 
consent form before any study-specific procedures are performed.  
Written and verbal versions of the subject information and informed consent will be 
presented to the subjects detailing no less than: the exact nature of the study; the implications 
and constraints of the protocol; expectations of their participation and the known side effects 
and any risks involved in taking part.  It will be clearly stated that the subject is free to 
withdraw from the study at any time for any reason without prejudice to future care, and with 
no obligation to give the reason for withdrawal. 
The subject will be allowed as much time as needed to consider the information and the 
opportunity to question the investigator, their primary care physician/general practitioner or 
other independent parties to decide whether they will participate in the study.  Written 
informed consent will then be obtained by means of subject dated signature and dated 
signature of the person who presented and obtained the informed consent.  The person who 
obtained the consent must be suitably qualified and experienced and have been authorised to 
do so by the investigator.  A copy of the signed informed consent will be given to each 
subject.  The original signed form will be retained at the study site and an additional copy 
will remain in the subject’s medical records.  
This is a single-masked study.  Therefore, all subjects will be informed at the time of 
randomisation whether they have been randomised to the AAV2-REP1 or Control group.  
However, subjects in the AAV2-REP1 treatment groups will be masked to the assigned dose. 
For subjects in the AAV2-REP1 treatment groups having surgery at a different site, it may be 
necessary to sign a separate surgical consent form at that location. 
The informed consent must be signed within 12 weeks prior to the treatment visit (Visit 2, 
Day 0). 
14.2 Ethical/Regulatory Review 
The protocol, informed consent form, subject information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (IEC or IRB), 
regulatory authorities, and host institution(s) for approval.  If there are any changes to the 
approved protocol (with the exception of emergency modifications required for the subject’s 
safety), a protocol amendment will be issued by the Sponsor.  When required by local law, 
the IEC/IRB and Competent Authority must give approval of any amendments likely to affect 
the safety of subjects or study conduct.  Each site must maintain accurate and updated records 
of all correspondence with the IEC/IRB. 
14.3 Regulatory Considerations 
The study will be conducted in full conformity with all applicable laws and regulations, 
including the International Council on Harmonisation (ICH) Guidelines for Good Clinical 
Practice (GCP) (CPMP/ICH/135/95). 

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As permitted, the study will be conducted in accordance with the relevant articles of the 
Declaration of Helsinki as adopted by the 18th World Medical Assembly in 1964 and as 
revised in Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Scotland 
(2000), Washington (2002), Tokyo (2004), Seoul (2008), and Brazil (2013). 
 

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15 ADMINISTRATIVE PROCEDURES 
15.1 Data Quality Control and Assurance 
The study will be conducted in accordance with the current approved protocol, ICH GCP, 
relevant regulations and standard operating procedures.  
The Sponsor and its selected vendors have systems in place for implementing and 
maintaining quality assurance and quality control systems, with written Standard Operating 
Procedures to ensure that all aspects of the trial will be conducted in compliance with this 
protocol and data will be generated, documented and reported in compliance with this 
protocol. 
Data will be entered into a validated clinical study database and subject to programmed 
validation checks and manually verified for accuracy and completeness by a Sponsor’s 
representative, both remotely and during on-site monitoring visits.  Any discrepancies will be 
resolved with the investigator or designee, as appropriate. 
Regular monitoring will be performed by the Sponsor or its designee according to ICH GCP.  
Data will be evaluated for compliance with the protocol and accuracy in relation to source 
documents.  Following written standard operating procedures, the monitors will verify that 
the study is conducted and data are generated, documented, and reported in compliance with 
the protocol, ICH GCP and applicable regulatory requirements. 
In addition, this study will be subject to quality assurance audits in order to independently 
verify compliance with the protocol.  
15.2 Data Handling and Records Management 
The investigator must maintain adequate and accurate source documents, which will be the 
basis of information for the eCRFs.  The source documents are to be separate and distinct 
from the eCRFs.  All study data will be entered on an encrypted electronic data capture 
system with pass-codes known to all investigators and appropriately delegated study team 
members only.  This electronic data entry system has been validated.  Incomplete or 
inconsistent data will result in data queries that require resolution by the investigator or 
designee.  
The investigator must ensure that clinical study records are retained according to national 
regulations.  The investigator must immediately inform the Sponsor if any documents are to 
be destroyed, transferred to another facility, or transferred to a different owner. 
In addition, files containing photos or digital outputs will be electronically transmitted to the 
reading centre for centralised, standardised review.   
Samples will also be provided to a central laboratory for potential analysis of 
immunogenicity.  Results from these analyses, if conducted, will also be provided as an 
external data set that will be loaded directly into the study database. 
The investigator must retain sufficient documentation that these images, outputs, and samples 
were handled and transmitted appropriately. 

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15.3 Access to Source Documentation and Subject Privacy 
Direct access will be granted to authorised representatives from the Sponsor (or designee), 
host institution, the IEC/IRB, and regulatory authorities to permit trial-related monitoring, 
audits and inspections. 
The trial staff will ensure that the subject’s anonymity is maintained.  All documents will be 
stored securely and only accessible by trial staff and authorised personnel.  Subjects will be 
identified by a subject ID number on the eCRF and any electronic database.  The subject’s 
name and any other identifying detail will NOT be included in any study data electronic file.  
The study will comply with the data protection laws which require data to be anonymised as 
soon as it is practical to do so. 
Subject medical information obtained in this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.  As required by Personal Information 
Protection and Electronics Documents Act and Personal Health Information Protection Act, 
upon the subject’s written permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or her welfare.  
Data generated by this study must be available for inspection by regulatory agencies, national 
and local health authorities, the Sponsor or their representative, and the IRB. 
15.4 Time and Schedule of the Study 
The study includes 12 months of follow-up post-treatment, and 8 weeks for screening, for a 
total of approximately 14 months per subject.  
15.5 Policy for Publication and Presentation of Data 
The detailed procedures for publications and data presentations are set out in the clinical trial 
agreement entered into with the Sponsor (or designee) in connection with this study. 
 

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16 REFERENCE LIST 
Anderson NG, Fineman MS, Brown GC. Incidence of intraocular pressure spike and other 
adverse events after vitreoretinal surgery. Ophthalmology. 2006;113(1):42-47. Epub 2005 
Dec 19. 
Banker AS, Freeman WR, Kim JW, et al. Vision-threatening complications of surgery for 
full-thickness macular holes. Vitrectomy for Macular Hole Study Group. Ophthalmology 
1997;104 (9):1442-1452; discussion 1452-1453. 
Berger RL, Boos DD. P values maximized over a confidence set for the nuisance parameter. J 
Am Stat Assoc 1994;89(427): 1012-1016. 
Cheng L, Azen SP, El-Bradey MH, et al. Duration of Vitrectomy and Postoperative Cataract 
in the Vitrectomy for Macular Hole Study. Am J Ophthalmol. 2001;132(6):881-887. 
Cremers FP, van de Pol DJ, van Kerkhoff LP, et al. Cloning of a gene that is rearranged in 
patients with choroideremia. Nature. 1990;347(6294):674–677. 
Csaky KG, Ferris FL, Chew EY, et al. Report from the NEI/FDA endpoints workshop on 
age- related macular degeneration and inherited retinal diseases. Invest Ophthalmol Vis Sci. 
2017;58:3456-3463 
Dimopoulos IS, Hoang SC. Radziwon A, Bincyk NM, et al. Two-year results after AAV2-
mediated gene therapy for choroideremia: the Alberta experience. Am J Ophthalmol 
2018;193:130-142. 
Dutheil N, Henckaerts E, Kohlbrenner E, et al. Transcriptional analysis of the adeno-
associated virus integration site. J Virol. 2009;83(23):12512-12525. 
Edwards TL, Jolly JK, Groppe M, et al. Visual acuity after retinal gene therapy for 
choroideremia. N Engl J Med. 2016;374(20):1996-1998. 
Edwards TL, Groppe M, MacLaren RE. Outcomes following cataract surgery in 
choroideremia. Eye (Lond). 2015 Jan 16. 10.1038. 
Fischer MD, Ochakovski GA, Beier B, et al. Changes in reitnal sensitivity after gene therapy 
in choroideremia. Retina 2018 Oct 9 (ahead of print) 
Jacobson SG, Boye SL, Aleman TS, et al. Safety in nonhuman primates of ocular AAV2-
RPE65, a candidate treatment for blindness in Leber congenital amaurosis. Hum Gene Ther. 
2006;17:845-858. 
Lam BL, Davis JL, Gregori NZ, et al. Choroideremia gene therapy phase 2 clinical trial: 24-
month results. Am J Ophthalmol 2019; 197:65-73. 
Lusby E, Fife KH, Berns KI. Nucleotide sequence of the inverted terminal repetition in 
adeno-associated virus DNA. J Virol 1980;34:402-409. 
Macdonald IM, Russell L, Chan CC. Choroideremia: new findings from ocular pathology and 
review of recent literature. Surv Ophthalmol. 2009;54(3):401-407. 

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MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with 
choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383(9923):1129-
1137. 
Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for 
Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597-
1605. 
Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s 
congenital amaurosis. N Engl J Med. 2008;358(21):2240-2248. 
Mangione CM, Lee PP, Gutierrez PR, et al. Development of the 25-item National Eye 
Institute Visual Function Questionnaire. Arch Ophthalmol 2001;119:1050-1058. 
Mingozzi F, Maus MV, Hui DJ, et al. CD8(+) T-cell responses to adeno-associated virus 
capsid in humans. Nat Med. 2007;13(4):419-422. 
Park SS, Marcus DM, Duker JS, et al. Posterior Segment Complications After Vitrectomy for 
Macular Hole. Ophthalmology. 1995;102:775-781. 
Recchia FM, Scott IU, Brown GC, et al. Small-Gauge Pars Plana Vitrectomy: A Report by 
the American Academy of Ophthalmology. Ophthalmology 2010;117(9):1851-1857. 
Sankila EM, Tolvanen R, van den Hurk JA, et al. Aberrant splicing of the CHM gene is a 
significant cause of choroideremia. Nat Genet. 1992;1(2):109-113. 
Seabra MC, Brown MS, Goldstein JL. Retinal degeneration in choroideremia: deficiency of 
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Stieger K, Le Meur G, Lasne F et al. Long-term doxycycline-regulated transgene expression 
in the retina of nonhuman primates following subretinal injection of recombinant AAV 
vectors. Mol Ther. 2006;13:967-975. 
Thompson JT, Sjaarda RN, Glaser BM, et al. Increased Intraocular Pressure after Macular 
Hole Surgery. Am J Ophthalmol. 1996;121(6):615-622. 
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Vandenberghe LH, Bell P, Maguire AM et al. Dosage thresholds for AAV2 and AAV8 
photoreceptor gene therapy in monkey. Sci Transl Med. 2011; 22:88ra54. Erratum in: Sci 
Transl Med. 2011;3:112er9. 
Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal 
gene therapy for choroideremia. Nat Med 2018;24:1507-1512. 
 

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17 APPENDICES 
17.1 Schedule of Study Procedures 
Table 3 presents a schedule of study procedures. 

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Visit 
Visit 1a 
Visit 2b 
Visit 3b 
Visit 4b 
Visit 5 a 
Visit 6 a 
Visit 7 a 
Visit 8 a, c 
Early 
Terminationd 
Unscheduled 
Visite 
Study Day/Visit Window 
Screening/ 
Baselinef 
Day 0 
Injection 
Day 
Day 1 
Post op 
Day 7 
Post op 
± 3d 
Month 
1 ± 7d 
Month 
4 
± 7d 
Month 
8  
± 14d 
Month 12 
± 14d 
 
 
Concomitant medication, procedures and 
treatment review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; BCVA=best corrected visual acuity; ELISA=enzyme-linked immunosorbent assay: ELISPOT=enzyme-linked immunospot; 
ET=early termination; IOP=intraocular pressure; 
; SAE=serious adverse event; SD-OCT=spectral domain optical coherence 
tomography; VFQ-25=25-item Visual Function Questionnaire. 
NOTE:  An attempt should be made to perform all procedures in both eyes, unless otherwise specified. Each eye should be tested separately. If the subject is 
unable to complete a procedure due to poor vision in either eye, this should be documented in the source notes and the assessment not completed for that eye. 
Assessments with gray shading are to be assessor-masked. 
a 
Visit may be performed over 2 consecutive days if necessary. 
b 
Study Visits 2, 3, and 4 only apply to subjects in the AAV2-REP1 groups. For subjects in the Control group, a telephone contact will be made at Visits 2, 3, 
and 4, and information regarding AEs/SAEs and concomitant medications, procedures, and treatments will be recorded. 
c 
End of Study Visit. 
d 
An ET visit should be performed if a subject discontinues at any time.  
e 
If clinically indicated, subjects may need to return to the site for an unscheduled visit. At a minimum, all assessments listed will be performed.  
f 
Informed consent must be signed within 12 weeks prior of dosing (Visit 2).  The Screening/Baseline Visit must be performed within 8 weeks of dosing (Visit 
2). Assessments and procedures conducted in the final visit of the NIGHT study (including the ET Visit) may be used for the Screening/Baseline Visit if the 
final NIGHT study occurs within 8 weeks prior to dosing (Visit 2). 
g 
Samples will be taken and retained for analyses, if necessary.  
h 
VFQ-25: to be completed only at sites where a validated translation is available. VFQ-25 must be completed by subjects at the beginning of the study visit, 
before any significant interaction with the study staff. 
i 
Weight is assessed for dose calculation for 21-day corticosteroid regimen. 
 
 
k 
In order to capture accurate BCVA values at Visit 1 (Screening/Baseline), the following conditions apply to the BCVA assessment: 
If the BCVA value at Visit 1 (Screening/Baseline) is ≥ ±10 letter gain or loss in the study eye compared to the previous NIGHT study visit (if applicable), 
then BCVA must be repeated an additional 2 times, resulting in a total of 3 BCVA measures at Visit 1.  To facilitate the additional BCVA measures this visit 
should be conducted over 2 days, with BCVA measured twice on Day 1 and once on Day 2.  All 3 BCVA values must be recorded in the eCRF.  The highest 
score will be used to define subject eligibility. 

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If the BCVA value at Visit 1 (Screening/Baseline) is < ± 10-letter difference in the study eye compared to the previous NIGHT study visit (if applicable), 
then BCVA will be collected once and will not be repeated.  
If the subject was not previously in the NIGHT study, BCVA assessments at baseline must be performed in triplicate over a period of 2 days, as described 
above.  At least 2 of the triplicate values must meet BCVA eligibility requirements for inclusion in the study and the difference between the 3 assessments 
may not be ≥ 10 letters. 
l 
The full ophthalmic examination will include assessments of IOP and lens opacity, a slit lamp examination, and dilated ophthalmoscopy. The same slit lamp 
machine and lighting conditions should be used across the study for each subject. 
m 
Pelli Robson chart will be used for contrast sensitivity. 
n 
Stereo photos for Fields 1, 2, 3. 
o 
International Reading Speed Texts. To be completed only in languages for which a validated translation is available. 
p 
 For AAV2-REP1-treated subjects, only: corticosteroid (prednisone/prednisolone) will be dispensed at Visit 1 or at least 2 days prior to Visit 2 with 
instruction to start treatment 2 days before the planned surgical date, and to continue for 21 days in total. 
q 
AEs/SAEs will be collected from the time the subject provides written informed consent through the End of Study Visit (or ET Visit or Unscheduled Visits, 
if applicable).  
r 
For subjects in the AAV2-REP1 groups only. On the Injection Day Visit (Visit 2, Day 0), all subjects in the AAV2-REP1 groups will undergo vitrectomy 
and treatment with AAV2-REP1.