A Randomized, Double-Masked, Sham-Controlled Clinical Trial to Evaluate the Efficacy of a Single Intravitreal Injection of GS010 in Subjects Affected for 6 Months or Less by LHON Due to the G11778A Mutation in the Mitochondrial ND4 Gene
Phase: PHASE3
Conditions: Optic, Atrophy, Hereditary, Leber
Sponsor: GenSight Biologics

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CLINICAL RESEARCH PROTOCOL 
DRUG: 
GS010 (rAAV2/2-ND4) 
STUDY NUMBER(S): 
GS-LHON-CLIN-03A 
PROTOCOL TITLE: 
A Randomized, Double-Masked, Sham-Controlled, 
Pivotal Clinical Trial to Evaluate the Efficacy of a 
Single Intravitreal Injection of GS010 (rAAV2/2-
ND4) in Subjects Affected for 6 Months or Less by 
Leber Hereditary Optic Neuropathy Due to the 
G11778A Mutation in the Mitochondrial NADH 
Dehydrogenase 4 Gene 
STUDY NAME: 
RESCUE 
PHASE: 
III 
SPONSOR: 
GenSight Biologics 
74 rue du Faubourg Saint-Antoine 
75012 Paris 
France 
 
 
 
 
 
 
 
  
 
EudraCT NUMBER: 
2015-001265-11 
IND NUMBER: 
16538 
Clinical Trials.gov NUMBER: 
NCT02652767 
ORIGINAL PROTOCOL 
DATE: 
08 May 2015 
VERSION NUMBER: 
4.0 
VERSION DATE: 
07 November 2016 

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STUDY GS-LHON-CLIN-03A 
RESCUE STUDY 
A 
RANDOMIZED, 
DOUBLE-MASKED, 
SHAM-CONTROLLED, 
PIVOTAL CLINICAL TRIAL TO EVALUATE THE EFFICACY OF A 
SINGLE INTRAVITREAL INJECTION OF GS010 (rAAV2/2-ND4) IN 
SUBJECTS AFFECTED FOR 6 MONTHS OR LESS BY LEBER 
HEREDITARY OPTIC NEUROPATHY DUE TO THE G11778A 
MUTATION IN THE MITOCHONDRIAL NADH DEHYDROGENASE 4 
GENE 
 
CONFIDENTIALITY AND INVESTIGATOR STATEMENT 
The information contained in this protocol and all other information relevant to GenSight 
Biologics is the confidential and proprietary information of GenSight Biologics, and except 
as may be required by federal, state or local laws or regulation, may not be disclosed to 
others without prior written permission of GenSight Biologics. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described. I will conduct 
this study as outlined herein, in accordance with the regulations stated in the guidelines for 
Good Clinical Practice and International Conference on Harmonization guidelines, and 
will make a reasonable effort to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by GenSight Biologics or specified 
designees. I will discuss the material with them to ensure that they are fully informed about 
GS010 and the study. 
 
 
 
 
Investigator Name 
 
 
 
 
 
Investigator Signature 
___________ ___________ 
Date 
Site Number 

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STUDY SUMMARY 
Title:  
RESCUE Study: A Randomized, Double-Masked, Sham-Controlled, 
Pivotal Clinical Trial to Evaluate the Efficacy of a Single Intravitreal 
Injection of GS010 (rAAV2/2-ND4) in Subjects Affected for 6 Months 
or Less by Leber Hereditary Optic Neuropathy Due to the G11778A 
Mutation in the Mitochondrial NADH Dehydrogenase 4 Gene  
Rationale:  
Leber Hereditary Optical Neuropathy (LHON) is an inherited 
mitochondrial disease of partial penetrance affecting both genders with 
predominance in males (~80%). The pathophysiology of LHON mainly 
affects the retinal ganglion cells (RGCs). The ND4 G11778A mutation 
is responsible for the majority of cases (~70%). Vision loss classically 
occurs in a bilateral sequential fashion, the second eye becoming 
involved after the first one with a median delay of 2 months. GenSight 
Biologics’ strategy to specifically treat LHON is based on a gene therapy 
approach by the development of GS010. The scientific basis behind this 
Investigational Medicinal Product consists of rescuing mitochondrial 
function by reaching the nucleus of the target cell, forming intranuclear 
episomes that can be read and produce specific mRNA inducing ND4 
protein synthesis and targeting of the ND4 protein to the mitochondria. 
This is expected to significantly improve the respiratory chain function. 
Preclinical studies performed in rats strongly suggest that GS010 
displays a potential to restore wild-type ND4 expression. 
Study 
Treatment: 
GS010 is a recombinant adeno-associated viral vector serotype 2 
(rAAV2/2) containing the wild-type ND4 gene (rAAV2/2-ND4). In this 
study, subjects will receive a single dose of GS010 via intravitreal (IVT) 
injection containing 9E10 vg in 90µL balanced salt solution (BSS) plus 
0.001% Pluronic F68®. 
Target 
Population: 
The study population will be subjects with LHON due to the G11778A 
ND4 mutation who have been affected by vision decline for 180 days or 
less. 
Number of 
Subjects: 
It is planned that approximately 40 subjects will be screened in order to 
randomize 36 into the study at 7 sites (one each in France, Germany, 
Italy, and the United Kingdom and 3 in the United States). 
Objectives:  
Primary Objective:  
To evaluate the efficacy of GS010 compared with sham at Week 48 in 
the change from baseline of the Log of the Minimal Angle of Resolution 
(LogMAR) in subjects affected for 6 months or less by LHON. 

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Secondary Objectives:  
• To evaluate the efficacy of GS010 compared with sham over the 
follow-up period and at Week 96 in the change from baseline of the 
LogMAR. 
• To verify whether the efficacy at Week 48 and at Week 96 of GS010 
compared with sham and measured by the change from baseline in 
the LogMAR is dependent upon the treatment of the better- or 
worse-seeing-eye. 
• To verify whether the rate of responders at Week 48 and 96 is 
dependent upon the treatment received and whether the magnitude 
of the treatment effect is dependent the treatment of the better- or 
worse-seeing eye at entry. 
• To assess the effect of GS010 on parameters measured with high 
resolution spectral-domain optical coherence tomography (SD-
OCT).  
• To assess the effect of GS010 on standardized automated visual 
fields obtained with the Humphrey Visual Field (HVF) Analyzer II. 
• To assess the effect of GS010 on contrast sensitivity measured with 
the Pelli-Robson chart. 
• To assess the effect of GS010 on color vision measure with the 
Farnsworth-Munsell 100 Hue color test. 
 
 
 
 
 
 
 
 
 
 
 
Study 
Design: 
GS-LHON-CLIN-03A is a Phase III double-masked, sham-controlled, 
multicenter, multi-country study. Recruitment is competitive.  
Both eyes will receive standard antiseptic preparation, administration of 
topical local ocular anesthetic agents and will undergo pupillary dilation. 
Administration of an intra-ocular pressure lowering agent will precede 
treatment. GS010 will be administered once during the study via a single 
IVT injection. Sham IVT injection will be performed by applying 
pressure to the eye at the location of a typical procedure using the blunt 
end of a syringe without a needle. 
The right eye of each subject will be randomly allocated to receive either 
GS010 or sham treatment in a 1:1 allocation ratio. The fellow (left) eye 
will receive the treatment not allocated to the right eye. Therefore, each 

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subject will receive GS010 in one eye and sham treatment in the fellow 
eye.  
 
 
 
 
 
 
 
 
 
An algorithm with a testing hierarchy will be employed to determine the 
better- and worse-seeing eye of each subject prior to randomization. The 
randomization will be based on the right and left eye, because if the right 
eye is treated the left eye will receive sham and vice versa the treatment 
groups will be automatically balanced. However, the better- or worse-
seeing eye at entry can be a confounding factor, and it cannot be 
discarded that the treatment effect will be the same in the better and 
worse seeing-eye. Secondarily, in order to verify this hypothesis, an 
adaptive randomization technique called Efron’s minimization method 
will be used to minimize the imbalance of treatment groups between the 
better-seeing eyes treated and worse-seeing eyes treated. 
Masking will be accomplished with sham injection of the fellow eye. 
Thus treatment allocation will be double-masked for both the subject 
and the investigation (follow-up) team. The pharmacy team, as well as 
the physician and medical team performing the GS010 administration 
and sham injection will be unmasked to treatment allocation. This 
treating, unmasked medical team will also perform the first follow-up 
visit (Visit 4), as well as focused follow up of ocular adverse events 
(AEs) commencing at Visits 3 and 4 until resolution of the AE or the 
determination that no further clinical evolution is expected. Centralized 
analysis of the Early Treatment Diabetic Retinopathy Study (ETDRS) 
visual acuity results, automated visual fields, SD-OCT, color vision and 
contrast sensitivity will be performed. 
Trial visits: 
The trial is divided into the following visits: 
• Screening Visit (Visit 1): From 28 to 2 days before the 
investigational medicinal product (IMP) administration. This visit 
will allow Investigators to assess subject eligibility based on 
selection and non-selection criteria. 
• Inclusion Visit (Visit 2): 1 day before the IMP administration. 
Screening 
visit 
Randomization 
W0 
W48 
W96 
Treatment groups: 
Right eye - GS010 / Left eye - SHAM 
Right eye - SHAM / Left eye - GS010 

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This visit will allow Investigators to confirm the subject’s eligibility 
based on inclusion and exclusion criteria. Subjects will undergo 
baseline ophthalmological testing.  
After the subject is confirmed to be eligible for the study, the right 
eye will be randomized to GS010 or sham treatment based on a pre-
defined central randomization scheme. 
• Treatment Visit (Visit 3): Day of the IMP administration. 
Subjects will receive GS010 by IVT injection according to the 
randomized treatment assigned. The fellow eye will receive the 
alternative treatment. 
• Follow-up visits (Visits 4 to 12): Nine follow-up visits after the IVT 
procedure will be conducted at 24 hours and 2, 4, 8, 12, 24, 48, 72, 
and 96 weeks. 
The study plan is shown in Section 4.2. 
A Data and Safety Monitoring Board meeting will be convened at least 
every 6 months to review the safety data. 
Study duration: 
Initiation of the trial with the first subject’s first visit is planned for late 
Q4 2015. The estimated recruitment period is 12 months and will be 
dependent on recruitment rate. Total study follow-up is 96 weeks and 
the study will end with the last subject’s last visit. The last subject’s last 
visit is estimated to occur late Q4 2018. Therefore, the estimated study 
duration is 3 years. 
At the end of this initial study period, a long-term safety and efficacy 
study as detailed in a future separate protocol will be initiated for further 
evaluation of the safety and efficacy durability. The long term safety 
study duration will be conducted according to current regulatory 
authority recommendation. 
Primary 
Efficacy 
Endpoint:  
The primary endpoint will be the ETDRS visual acuity (quantitative 
score) at Week 48 after IVT injection. The subjects’ LogMAR scores, 
which are derived from the number of letters they read on the ETDRS 
chart, will be used for statistical analysis purposes. The change from 
baseline in each eye will be the primary response of interest. 
Secondary 
Efficacy 
Endpoints: 
• ETDRS visual acuity (quantitative score) over the follow-up period 
and at Week 96 after IVT injection. Change from baseline of the 
LogMAR scores will be used for statistical analysis purposes. 
• Response status to treatment at Week 48 and 96 after IVT injection. 
Responder will be defined by an improvement of at least 15 letters 
in the visual acuity score obtained with ETDRS or being greater than 
a Snellen acuity equivalent of 20/200.   
• Measure of parameters of high resolution SD-OCT of the posterior 
pole and optic nerve at Week 48 and Week 96. 

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• Measure of the standardized automated visual fields obtained with 
HVF Analyzer II. Mean Deviation (MD) in decibels of sensitivity 
will be used at Week 48 and Week 96. 
• Measure of contrast sensitivity with the Pelli-Robson chart at Week 
48 and Week 96. 
• Measure of color vision with the Farnsworth-Munsell 100 Hue color 
vision test at Week 48 and Week 96. 
 
 
 
 
 
 
Safety 
Endpoints: 
• AEs and serious adverse events (SAEs), including those that are 
treatment-emergent and non-treatment-emergent, throughout the 
study period and at each study visit. Incidence and severity of 
systemic and local (ocular) AEs and SAEs will be determined at each 
clinical site and for the entire study cohort.  
 
 
 
 
 
 
 
  
 
 
 
 

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TABLE OF CONTENTS 
Contents 
Study Summary ..................................................................................................................4 
Table of Contents ...............................................................................................................9 
List of Tables ....................................................................................................................12 
List of Abbreviations .......................................................................................................13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2 
Study Objectives .......................................................................................................28 
2.1 
Primary .................................................................................................................28 
2.2 
Secondary..............................................................................................................28 
 
 
2.4 
Safety .....................................................................................................................28 
3 
Study Endpoints ........................................................................................................29 
3.1 
Primary .................................................................................................................29 
3.2 
Secondary..............................................................................................................29 
 
 
3.4 
Safety .....................................................................................................................29 
4 
Study Plan ..................................................................................................................30 
4.1 
Study Design .........................................................................................................30 
4.2 
Schedule of Events ...............................................................................................32 
4.2.1 
Overall Schedule of Events ...........................................................................32 
4.2.2 
Schedule of Events to be conducted by the Unmasked Site Team ............35 
5 
Population ..................................................................................................................36 
5.1 
Number of Subjects..............................................................................................36 
5.2 
Selection for the Study .........................................................................................36 
5.2.1 
Selection Criteria ...........................................................................................36 
5.2.2 
Non-Selection Criteria ...................................................................................36 

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5.3 
Inclusion Criteria .................................................................................................37 
5.4 
Exclusion criteria .................................................................................................37 
5.5 
Deviation from Inclusion/Exclusion Criteria ....................................................38 
6 
Study Conduct ...........................................................................................................39 
6.1 
Study Procedures by Time Point ........................................................................39 
6.1.1 
Visit 1 – Screening Visit .................................................................................39 
6.1.2 
Visit 2 – Inclusion Visit ..................................................................................40 
6.1.3 
Visit 3 - Treatment Visit ................................................................................41 
6.1.4 
Follow-up Visits ..............................................................................................41 
6.2 
Premature Discontinuation .................................................................................46 
6.3 
Unscheduled Visits ...............................................................................................47 
6.4 
Additional Care of Subjects ................................................................................47 
7 
Description of Study Procedures .............................................................................48 
7.1 
Informed Consent ................................................................................................48 
7.2 
Demographics and Other Clinical Evaluations .................................................49 
7.2.1 
Demographics, Medical History, and Prior Medications ...........................49 
7.2.2 
Pregnancy Testing ..........................................................................................49 
7.2.3 
Virology ...........................................................................................................49 
7.2.4 
ND4 (G11778A) Genotyping .........................................................................49 
7.3 
Ophthalmic Evaluations ......................................................................................50 
7.3.1 
Visual Acuity ..................................................................................................50 
7.3.2 
Refraction for Best Corrected Visual Acuity ..............................................50 
7.3.3 
Spectral Domain Optical Coherence Tomography .....................................50 
7.3.4 
Visual Field Assessment ................................................................................51 
7.3.5 
Contrast Sensitivity ........................................................................................51 
7.3.6 
Color Vision ....................................................................................................51 
7.3.7 
Color Fundus Photos .....................................................................................51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7 
Protocol Deviations ..............................................................................................54 
8 
Study Drug Management .........................................................................................55 

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8.1 
Description of GS010 ...........................................................................................55 
8.1.1 
Formulation ....................................................................................................55 
8.1.2 
Storage ............................................................................................................55 
8.2 
Packaging and Labeling ......................................................................................55 
8.3 
Dose and Administration .....................................................................................55 
8.4 
Dispensing and Accountability ...........................................................................56 
8.5 
Prior and Concomitant Therapy ........................................................................56 
8.6 
Method of Assigning Treatment .........................................................................57 
8.7 
Masking .................................................................................................................58 
8.8 
Procedure for Unmasking ...................................................................................58 
9 
Adverse Events ..........................................................................................................59 
9.1 
Reporting and Documentation of Adverse Events ............................................59 
9.1.1 
Reporting ........................................................................................................59 
9.1.2 
Documentation ...............................................................................................61 
9.2 
Ocular Inflammation ...........................................................................................61 
9.3 
Clinical Laboratory Changes ..............................................................................64 
9.4 
Concomitant Medication Assessments ...............................................................64 
9.5 
Adverse Event Follow-up ....................................................................................65 
9.6 
Pregnancy .............................................................................................................65 
10 Serious Adverse Events ............................................................................................66 
10.1 
Definition of Serious Adverse Event ..................................................................66 
10.2 
Definition of Terms ..............................................................................................66 
10.3 
Reporting Serious Adverse Events .....................................................................67 
10.3.1 
Follow-up ........................................................................................................67 
10.3.2 
Post-Study Serious Adverse Events ..............................................................67 
10.3.3 
Notification to Regulatory Authorities/Gene Therapy 
Bodies/IRBs/IECs ...........................................................................................67 
10.3.4 
Information to Investigator ...........................................................................67 
10.3.5 
Documentation ...............................................................................................68 
11 Quality Control and Assurance ...............................................................................69 
11.1 
Quality Control ....................................................................................................69 
11.2 
Quality Assurance ................................................................................................69 
12 Statistics .....................................................................................................................70 
12.1 
General Considerations .......................................................................................70 
12.2 
Sample Size ...........................................................................................................70 
12.3 
Analysis Populations ............................................................................................71 
12.3.1 
Intent-to-Treat Population ............................................................................71 
12.3.2 
Safety Population ...........................................................................................71 
12.4 
Statistical Methods ...............................................................................................71 
12.4.1 
Primary Analysis and Associated Planned Analyses ..................................71 
12.4.2 
Secondary Analysis ........................................................................................72 
12.4.3 
Analysis of Vision-Related Secondary Endpoints .......................................72 
 
 
12.4.5 
Analysis of Safety ...........................................................................................72 
12.4.6 
Demographic and Baseline Characteristics .................................................73 
12.5 
Interim Analysis ...................................................................................................74 

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12.6 
Timing of Primary Analysis ................................................................................74 
12.7 
Handling of Missing Data ....................................................................................74 
13 Ethics and Responsibilities .......................................................................................76 
13.1 
Good Clinical Practice .........................................................................................76 
13.2 
Data and Safety Monitoring Board ....................................................................76 
13.3 
Institutional Review Board/Independent Ethics Committee ...........................76 
13.4 
Informed Consent ................................................................................................76 
13.5 
Case Report Forms and Study Records Management .....................................77 
13.6 
Access to Source Documentation ........................................................................78 
13.7 
Study Files and Record Retention ......................................................................79 
13.8 
Data Generation and Analysis ............................................................................79 
13.8.1 
Data Collection and Data Management .......................................................79 
13.8.2 
Database Quality Assurance .........................................................................79 
13.9 
Financial Disclosure .............................................................................................80 
14 Auditing and Monitoring .........................................................................................81 
15 Amendments ..............................................................................................................82 
16 Study Report and Publications ................................................................................83 
17 Study Discontinuation ..............................................................................................84 
18 Confidentiality ...........................................................................................................85 
 
20 Appendices .................................................................................................................89 
 
 
20.2 
APPENDIX II – Declaration of Helsinki ...........................................................91 
 
 
 
 
 
20.5 
APPENDIX V – Masking of the Treated Eye and Performance of the 
Primary Analysis ................................................................................................116 
 
LIST OF TABLES 
 
Table 1 
Anatomic Classification of Uveitis (SUN Working Group) .................62 
Table 2 
Grading Scheme for Anterior Chamber Cells (SUN Working Group)62 
Table 3 
Grading Scheme for Anterior Chamber Flare (SUN Working Group)63 
Table 4 
Activity of Uveitis Terminology (SUN Working Group)......................63 
Table 5 
National Institutes of Health Grading System for Vitreous Haze .......64 
 
 

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LIST OF ABBREVIATIONS 
AAV 
adeno-associated viral vector, serotype 2 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
BCVA 
best corrected visual acuity 
BP 
blood pressure 
BSS 
balanced salt solution 
cDNA 
complementary DNA 
CI 
mitochondrial respiratory chain complex I 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria For Adverse Events 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
 
 
GCL 
ganglion cell layer 
GCP 
Good Clinical Practice 
GGT/γGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
GMO 
genetically modified organism 
HIV 
human immunodeficiency virus 
HVF 
Humphrey Visual Field 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 

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IOP 
intra-ocular pressure 
IPL 
inner plexiform layer 
IRB 
Institutional Review Board 
IRS 
interactive response system 
IVT 
intravitreal 
LHON 
Leber Hereditary Optic Neuropathy 
LogMAR 
Log of the minimal angle of resolution 
MD 
mean deviation 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
messenger ribonucleic acid 
mtDNA 
mitochondrial deoxyribonucleic acid 
NADH 
reduced nicotinamide adenine dinucleotide 
ND4 
NADH dehydrogenase 4 
NHP 
Non-Human Primate 
OCT 
optical coherence tomography 
 
 
qPCR 
quantitative polymerase chain reaction 
rAAV2/2 
recombinant adeno-associated viral vector, serotype 2 
RGC 
retinal ganglion cell 
RNFL 
retinal nerve fiber layer 
SAE 
serious adverse event 
SD-OCT 
spectral domain optical coherence tomography 
 
 
SOP 
Standard Operating Procedure 
SUN 
Standardization of Uveitis Nomenclature 
TEAE 
Treatment-Emergent Adverse Event 
 
 
WHO 
World Health Organization 

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2 STUDY OBJECTIVES 
2.1 
Primary 
To evaluate the efficacy of GS010 compared with sham at Week 48 in the change from 
baseline of the Log of the minimal angle of resolution (LogMAR) in subjects affected for 
6 months or less by LHON. 
2.2 
Secondary 
• To evaluate the efficacy of GS010 compared with sham over the follow-up period and 
at Week 96 in the change from baseline of the LogMAR. 
• To verify whether the efficacy at Week 48 and at Week 96 of GS010 compared with 
sham and measured by the change from baseline in the LogMAR is dependent upon the 
treatment of the better- or the worse-seeing eye.  
• To verify whether the rate of responders at Week 48 and 96 is dependent upon the 
treatment received and whether the magnitude of the treatment effect is dependent the 
treatment of the better- or worse-seeing eye at entry. 
• To assess the effect of GS010 on parameters measured with high resolution SD-OCT.  
• To assess the effect of GS010 on visual fields obtained with the Humphrey Visual Field 
(HVF) Analyzer II. 
• To assess the effect of GS010 on contrast sensitivity measured with the Pelli-Robson 
chart. 
• To assess the effect of GS010 on color vision measure with the Farnsworth-Munsell 
100 Hue color test. 
 
 
 
 
 
2.4 
Safety 
• To assess the safety and tolerability of GS010. 
 
 
 
 

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3 STUDY ENDPOINTS  
3.1 
Primary 
The primary endpoint will be the ETDRS visual acuity (quantitative score) at Week 48 
after IVT injection. The subjects’ LogMAR scores, which are derived from the number of 
letters they read on the ETDRS chart, will be used for statistical analysis purposes. The 
change from baseline in each eye will be the primary response of interest. 
3.2 
Secondary 
• ETDRS visual acuity (quantitative score) over the follow-up period and at Week 96 
after IVT injection. Change from baseline of the LogMAR scores will be used for 
statistical analysis purposes. 
• Response status to treatment at Week 48 and 96 after IVT injection. Responder will be 
defined by an improvement of at least 15 letters in the visual acuity score obtained with 
ETDRS or being greater than a Snellen acuity equivalent of 20/200.   
• Measure of parameters of high resolution SD-OCT of the posterior pole and optic nerve 
at Week 48 and Week 96. 
• Measure of the standardized automated visual fields obtained with HVF Analyzer II. 
Mean Deviation (MD) in decibels of sensitivity will be used at Week 48 and Week 96. 
• Measure of contrast sensitivity with the Pelli-Robson chart at Week 48 and Week 96. 
• Measure of color vision with the Farnsworth-Munsell 100 Hue color vision test at Week 
48 and Week 96. 
 
 
 
 
 
 
3.4 
Safety 
• Adverse events (AEs) and serious adverse events (SAEs), including those that are 
treatment-emergent and non-treatment-emergent, throughout the study period and at 
each study visit. Incidence and severity of systemic and local (ocular) AEs and SAEs 
will be determined at each clinical site and for the entire study cohort.  
 
 
 
 
 
 
  
 
 

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4 STUDY PLAN 
4.1 
Study Design 
GS-LHON-CLIN-03A is a Phase III double-masked, sham-controlled, multicenter, multi-
country, study. Recruitment is competitive. 
Both eyes will receive standard antiseptic preparation, administration of topical local 
ocular anesthetic agents and will undergo pupillary dilation. Administration of an IOP 
lowering agent will precede treatment. GS010 will be administered once during the study 
via a single IVT injection. Sham IVT injection will be performed whereby pressure will be 
applied to the eye at the site of a typical procedure using the blunt end of a syringe without 
a needle. 
The right eye of each subject will be randomly allocated to receive either GS010 or sham 
treatment in a 1:1 allocation ratio. The fellow (left) eye will receive the treatment not 
allocated to the right eye. Therefore, each subject will receive GS010 in one eye and sham 
treatment in the fellow eye.  
 
 
 
 
 
 
 
An algorithm with a testing hierarchy will be employed to determine the better- and worse-
seeing eye of each subject prior to randomization. The randomization will be based on the 
right and left eye, because if the right eye is treated the left eye will receive sham and vice 
versa the treatment groups will be automatically balanced. However, the better- or worse-
seeing eye at entry can be a confounding factor, and it cannot be discarded that the 
treatment effect will be the same in the better and worse seeing-eye. Secondarily, in order 
to verify this hypothesis, an adaptive randomization technique called Efron’s minimization 
method will be used to minimize the imbalance of treatment groups between the better-
seeing eyes treated and worse-seeing eyes treated. 
Masking will be accomplished with sham injection of the fellow eye. Thus, treatment 
allocation will be double-masked for both the subject and the investigation (follow-up) 
team. The pharmacy team, as well as the physician and medical team performing the 
GS010 administration and sham injection will be unmasked to treatment allocation. This 
treating, unmasked medical team will also perform the first follow-up visit (Visit 4), as 
well as focused follow up of ocular adverse events commencing at Visits 3 and 4 until 
Screening 
visit 
Randomization 
W0 
W48 
W96 
Right eye - SHAM / Left eye - GS010 
Treatment groups: 
Right eye - GS010 / Left eye - SHAM 

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resolution of the AE or the determination that no further clinical evolution is expected. 
Centralized analysis of ETDRS, automated visual fields, SD-OCT, color vision and 
contrast sensitivity will be performed. 
Trial visits: 
The trial is divided into the following visits: 
• Screening Visit (Visit 1): From 28 to 2 days before IMP administration. 
This visit will allow Investigators to assess subject eligibility based on selection and 
non-selection criteria. 
• Inclusion Visit (Visit 2): 1 day before IMP administration. 
This visit will allow Investigators to confirm the subject’s eligibility based on inclusion 
and exclusion criteria. Subjects will undergo baseline ophthalmological testing.  
After the subject is confirmed to be eligible for the study, the right eye will be 
randomized to GS010 or sham treatment based on a pre-defined central randomization 
scheme. 
• Treatment Visit (Visit 3): Day of IMP administration. 
Subjects will receive GS010 by IVT injection according to the randomized treatment 
assigned. The fellow eye will receive the alternative treatment. 
• Follow-up visits (Visits 4 to 12): Nine follow-up visits after-IVT procedure will be 
conducted at 24 hours and 2, 4, 8, 12, 24, 48, 72, and 96 weeks. 
An overall schedule of events for the study is in Section 4.2.1. A schedule of events for 
Visits 3 and 4 (those visits that will be conducted by the unmasked study site team) are in 
Section 4.2.2. 
A DSMB meeting will be convened at least every 6 months to review the safety data. 
Study duration: 
Initiation of the trial with the first subject’s first visit is planned for late Q4 2015. The 
estimated recruitment period is 12 months and will be dependent on recruitment rate. Total 
study follow-up is 96 weeks and the study will end with the last subject’s last visit. The 
last subject’s last visit is estimated to occur late Q4 2018. Therefore, the estimated study 
duration is 3 years. 
At the end of this initial study period, a long-term safety and efficacy study as detailed in 
a future separate protocol will be initiated for further evaluation of the safety and efficacy 
durability. The long-term safety study will be conducted according to current regulatory 
authority recommendation. 

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4.2 
Schedule of Events 
4.2.1 
Overall Schedule of Events 
 
Evaluation 
Screening 
Visit 
Inclusion 
Visit 
Treatment 
visit 
Study Follow-up Visits 
Visit 
1 
2 
31 
41 
5 
6 
7 
8 
9 
10 
11 
12 
EOS2 
Week(s) 
-4 to -1 
 
 
 
2 
4 
8 
12 
24 
48 
72 
96 
Day(s) 
-28 to -2 
-1 
0 
1 
14 
(±2D) 
28 
(±3D) 
56 
(±6D) 
84 
(±9D) 
168 
(±17D) 
336 
(±30D) 
502 
(±30D) 
672 
(±30D) 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Selection/non-selection criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics3 
X 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments 
 
 
 
 
 
 
 
 
 
ND4 (G11778A) genotyping7,8, 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum HIV testing8 
X9 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (for women of 
childbearing potential)8 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ocular Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Refraction for BCVA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Evaluation 
Screening 
Visit 
Inclusion 
Visit 
Treatment 
visit 
Study Follow-up Visits 
Visit 
1 
2 
31 
41 
5 
6 
7 
8 
9 
10 
11 
12 
EOS2 
Week(s) 
-4 to -1 
 
 
 
2 
4 
8 
12 
24 
48 
72 
96 
Day(s) 
-28 to -2 
-1 
0 
1 
14 
(±2D) 
28 
(±3D) 
56 
(±6D) 
84 
(±9D) 
168 
(±17D) 
336 
(±30D) 
502 
(±30D) 
672 
(±30D) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ETDRS visual acuity 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Humphrey visual field 30-2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spectral domain optical coherence 
tomography 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
Pelli-Robson contrast sensitivity 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Farnsworth-Munsell 100 Hue color 
testing 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Color Fundus Photos 
X13 
 
 
X14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administration16 
 
 
X 
 
 
 
 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
AE and SAE assessment 
X 
D = day; AE = adverse event; 
 ETDRS = Early Treatment Diabetic Retinopathy Study;
 SAE = Serious adverse event; AAV2 = adeno-associated viral vector, serotype 2; EOS = end of 
study; ND4 = NADH dehydrogenase 4; BCVA = best corrected visual acuity; 
 IMP = investigational medicinal product. 
1 Visits 3 and 4 will be conducted by the unmasked site team.  A schedule of events for these visits is below. 
2 Subjects who discontinue participation in the study prematurely (i.e. prior to Visit 12) will complete an end-of-study (EOS) visit including all procedures 
listed for Visit 12. 
3 
Includes gender and date of birth. 

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7 
All subjects will be required to have a blood sample taken for genotyping analysis by the central study laboratory. Subjects with previously documented 
G11778A ND4 mitochondrial mutation can proceed to visit 2 without the results of the central laboratory genotyping. Subjects without previously 
documented G11778A ND4 mitochondrial mutation will be required to have the results of the central laboratory genotyping available for Visit 2. 
 
 
 
 
 
 
10 
 
11 At Visit 3, baseline assessments should be done 60-120 minutes prior to IVT injection. 
12 
 
13 Obtained as baseline for future comparison if necessary. 
14 Obtained only if necessary for grading ocular inflammation. 
 
 
16 Via intravitreal injection with fellow-eye sham IVT procedure. 
17
 
 
 
 
 

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4.2.2 
Schedule of Events to be conducted by the Unmasked Site Team 
 
Evaluation 
Treatment Visit 
Follow-up 
Visit 
Visit 
3 
4 
Day(s) 
0 
1 
Hour(s) 
0 
0.5 
1 
2 
4 
 
 
 
 
 
Refraction for best corrected visual 
acuity 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ETDRS visual acuity 
 
 
 
 
 
X 
Humphrey visual field 30-2 
 
 
 
 
 
X 
Pelli-Robson contrast sensitivity 
 
 
 
 
 
X 
Farnsworth-Munsell 100 Hue color 
vision testing 
 
 
 
 
 
X 
Color Fundus Photos 
 
 
 
 
 
X9 
Investigational medicinal product 
(IMP) administration7 
X 
 
 
 
 
 
Concomitant medications 
X 
AE and SAE assessment10 
X 
 
 
 
AE = adverse event; ETDRS = Early Treatment Diabetic Retinopathy Study; SAE = Serious adverse event; 
AAV2 = adeno-associated viral vector, serotype 2; IOP = intra-ocular pressure; 
 
 
 
 
 
 
 
 
3 
 
 
 
5 ±15 minutes 
6 ±30 minutes 
7 Via intravitreal injection with fellow-eye sham procedure. 
8 Before and after pupil dilation. 
9 Obtained only if necessary for grading ocular inflammation. 
10 Ocular AEs commencing at Visit 3 or Visit 4 will be followed in a focused manner by the unmasked 
study team at subsequent visits until resolution or the determination that no further clinical evolution will 
occur. 
 
 
 

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5 POPULATION 
The study population will include subjects with LHON due to the G11778A ND4 mutation 
with loss of vision in at least one eye for ≤180 days in duration. 
5.1 
Number of Subjects 
It is planned that approximately 40 subjects will be screened in order to randomize 36 into 
the study at 7 sites (one each in France, Germany, Italy, and the United Kingdom and 3 in 
the United States).  
5.2 
Selection for the Study 
5.2.1 
Selection Criteria 
Subjects must meet all the following criteria at the Screening Visit (Visit 1) in order to be 
included into the study. 
1. Age 15 years or older. 
2. Onset of vision loss based on medically documented history or subject testimony, in at 
least one eye for ≤180 days in duration and if both eyes are affected the duration of 
vision loss in both eyes must be ≤180 days in duration. 
3. Each eye of the subject maintaining visual ability to allow at least for counting of the 
examiner’s fingers at any distance. 
4. Female subjects (if of childbearing potential) must agree to use effective methods of 
birth control up to 6 months after IVT injection and male subjects must agree to use 
condoms for up to 6 months after IVT injection. 
5. Ability to obtain adequate pupillary dilation to permit thorough ocular examination and 
testing. 
6. Signed written informed consent. 
5.2.2 
Non-Selection Criteria 
Subjects who meet at least one of the following criteria at the Screening Visit (Visit 1) will 
not be included into the study. 
1. Any known allergy or hypersensitivity to GS010 or its constituents. 
2. Contraindication to IVT injection. 
3. IVT drug delivery to either eye within 30 days prior to the Screening Visit (Visit 1). 
4. Previous vitrectomy in either eye. 
5. Narrow angle in either eye contra-indicating pupillary dilation. 
6. Presence of disorders of the ocular media, such as the cornea and lens, which may 
interfere with visual acuity and other ocular assessments during the study period. 
7. Vision disorders, other than LHON, involving visual disability or with the potential to 
cause further vision loss during the trial period. 
8. Causes of optic neuropathy other than LHON and glaucoma. 

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9. Subjects with known mutations of other genes involved in pathological retinal or optic 
nerve conditions. 
10. Presence of ocular or systemic disease, other than LHON and well-controlled 
glaucoma, whose pathology or associated treatments might affect the retina or the optic 
nerve. 
11. History of amblyopia associated with a Snellen visual acuity equivalent of worse than 
20/80 (equivalent to 6/24 at 6 meters, decimal acuity 0.25, LogMAR +0.6) in the 
affected eye. 
12. Presence of ocular conditions, which in the opinion of the Investigator will prevent 
good quality SD-OCT imaging from being obtained. 
13. Presence, in either eye, of uncontrolled glaucoma, defined as an IOP greater than 25 
mmHg, despite maximal medical therapy with IOP-lowering agents. 
14. Active ocular inflammation or history of idiopathic or autoimmune-associated uveitis. 
15. Subjects participating in another clinical trial and receiving an IMP within 90 days prior 
to the Screening Visit (Visit 1). 
16. Previous treatment with an ocular gene therapy product. 
17. Subjects who have undergone ocular surgery of clinical relevance (per Investigator 
opinion) within 90 days preceding the Screening Visit (Visit 1). 
18. Female Subjects who are or who intend to breast feed during the trial period. 
5.3 
Inclusion Criteria 
Subjects included in the study must satisfy all the following criteria at the Inclusion Visit 
(Visit 2). 
1. Documented results of genotyping showing the presence of the G11778A mutation in 
the ND4 gene and the absence of the other primary LHON-associated mutations (ND1 
or ND6) in the subject’s mitochondrial DNA. 
2. Review of all selection criteria to ensure continued compliance. For Selection 
Criterion 2, the vision loss duration should only be calculated based on the Visit 1 date. 
3. Have a negative test for infection with human immunodeficiency virus (HIV). 
4. Have a negative pregnancy test for women of childbearing potential (a woman who is 
two years post-menopausal or surgically sterile is not considered to be of childbearing 
potential). 
5.4 
Exclusion criteria 
Subjects who meet at least one of the following criteria at the Inclusion Visit (Visit 2) will 
not be included in the study. 
1. Any non-selection criteria which may have appeared after the screening visit. 
2. Subjects taking idebenone who have not completely discontinued the idebenone at least 
7 days prior to Visit 2. If the subject has not discontinued idebenone at least 7 days 
prior to Visit 2, the visit may be delayed until the 7-day period is complete. 
3. Presence, at the time of study inclusion, of infectious conjunctivitis, keratitis, scleritis 
or endophthalmitis in either eye. 

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4. Presence of systemic illness, including alcohol and drug abuse (except nicotine), or 
medically significant abnormal laboratory values that are deemed by the Investigator 
to preclude the subject’s safe participation in the study. 
5. Presence of illness or disease that, in the opinion of the Investigator, include symptoms 
and/or the associated treatments that can alter visual function, for instance cancers or 
pathology of the central nervous system. 
6. Any medical or psychological condition that, in the opinion of the Investigator, may 
compromise the safe participation of the subject in the study or would preclude 
compliance with the study protocol or ability of the subject to successfully complete 
the study. 
7. Subjects unable or unwilling to comply with the protocol requirements. 
5.5 
Deviation from Inclusion/Exclusion Criteria 
No protocol deviation related to study inclusion or exclusion criteria, conduct of the trial, 
subject management, or subject assessment will be allowed prospectively. 

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6 STUDY CONDUCT 
6.1 
Study Procedures by Time Point 
6.1.1 
Visit 1 – Screening Visit 
The following procedures will be conducted at the Screening Visit (Visit 1), 28 to 2 days 
before the Treatment Visit (Visit 3): 
• Informed consent read, understood, and signed. If the subject is unable to read the 
informed consent document, presence of an impartial witness is required to confirm 
that the contents of the document were explained to the subject. The impartial witness 
must sign the informed consent form (ICF). The subject must always be asked to sign 
or mark the ICF regardless of their vision ability. 
• Assess subject eligibility for the study with regard to selection and non-selection 
criteria. If the subject fails to meet any of these criteria, the subject will not be selected 
for study participation and no further assessments will be conducted. 
• Collection of subject demographics (gender, date of birth), relevant medical and 
surgical history, and relevant prior medications. 
 
 
 
 
 
 
 
 
• Blood draw for serum pregnancy test for women of childbearing potential. Testing will 
be conducted at the central laboratory unless it is determined that the results will not be 
received from the central laboratory in time for Visit 2, in which case a local laboratory 
may be used. The results of this test must be available and documented at Visit 2. 
• Blood draw for genotyping to confirm the presence of the G11778A mutation in the 
mitochondrial ND4 gene. All subjects will be required to have a blood sample taken 
for genotyping analysis by the central study laboratory. Subjects with previously 
documented G11778A ND4 mitochondrial mutation can proceed to visit 2 without the 
results of the central laboratory genotyping. Subjects without previously documented 
G11778A ND4 mitochondrial mutation will be required to have the results of the 
central laboratory genotyping available for Visit 2. 
 
 
 
 
 
 
 
• Blood draw for serum HIV testing. Testing will be conducted at the central laboratory 
unless it is determined that the results will not be received from the central laboratory 
in time for Visit 2, in which case a local laboratory may be used. The results of this test 
must be available and documented at Visit 2. 

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• Refraction for best corrected visual acuity (BCVA) performed prior to pupil dilation. 
• 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• HVF 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photography after pupil dilation.  
• Recording of concomitant medications, including supplements. 
• Recording of AEs and SAEs. 
6.1.2 
Visit 2 – Inclusion Visit 
The following procedures will be conducted at the Inclusion Visit (Visit 2), the day before 
IMP administration: 
• Assess subject eligibility for the study with regard to inclusion and exclusion criteria. 
If the subject fails to meet any of these criteria, the subject will be excluded and no 
further assessments will be conducted. 
 
 
 
 
 
• Review of laboratory results to confirm subject’s eligibility. 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• HVF 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
 
 
 
 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
• Recording of AEs and SAEs. 

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6.1.3 
Visit 3 - Treatment Visit 
The following procedures will be conducted at the IMP Administration Visit on Day 0 
(Visit 3). All Visit 3 procedures will be performed by the unmasked study team. A 
schedule of events for the unmasked site team is in Section 4.2. 
The following procedures will be performed 60-120 minutes prior to IMP administration: 
 
 
 
 
• Administration of IOP lowering agent. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
• Recording of AEs and SAEs. 
After these procedures are complete, pupil dilation, local anti-sepsis, topical anesthesia, 
GS010 administration, and sham procedures will be performed per the IVT and Sham 
Procedure Guide.   
Following IVT injection, the following procedures will be conducted: 
 
 
 
 
 
 
• Recording of any new AEs and SAEs.  
• Recording of any new changes or additions to concomitant medications and any new 
changes in concomitant medication dose or regimen, including supplements, after IVT 
injection. 
6.1.4 
Follow-up Visits 
6.1.4.1 
Visit 4 – Day 1 
The following procedures will be conducted on Day 1 (Visit 4), the day following IMP 
administration. All Visit 4 procedures will be performed by the unmasked study team. A 
schedule of events for the unmasked site team is in Section 4.2. 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. This assessment will be 
for safety purposes only and will not be analyzed as efficacy data. 

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• HVF 30-2 testing performed prior to pupil dilation. This assessment will be for safety 
purposes only and will not be analyzed as efficacy data. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. This 
assessment will be for safety purposes only and will not be analyzed as efficacy data. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. This 
assessment will be for safety purposes only and will not be analyzed as efficacy data. 
• Color fundus photos if necessary for grading ocular inflammation.  
• Collection of AEs and SAEs.  
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.2 
Visit 5 – Week 2 
The following procedures will be conducted at Week 2 (Visit 5, ±2 days) following IMP 
administration: 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.3 
Visit 6 – Week 4 
The following procedures will be conducted at Week 4 (Visit 6, ±3 days) following IMP 
administration: 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 

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• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.4 
Visit 7 – Week 8 
The following procedures will be conducted at Week 8 (Visit 7, ±6 days) following IMP 
administration: 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.5 
Visit 8 – Week 12 
The following procedures will be conducted at Week 12 (Visit 8, ±9 days) following IMP 
administration: 
 
 
 
 
  
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 

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• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.6 
Visit 9 – Week 24 
The following procedures will be conducted at Week 24 (Visit 9, ±17 days) following IMP 
administration: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation.  
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.7 
Visit 10 – Week 48 
The following procedures will be conducted at Week 48 (Visit 10, ±30 days) following 
IMP administration: 
 
 
 
 
 
 
 
 

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• Refraction for BCVA performed prior to pupil dilation. 
• 
 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.1.4.8 
Visit 11 – Week 72 
The following procedures will be conducted at Week 72 (Visit 11, ±30 days) following 
IMP administration: 
 
 
 
 
 
 
 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
• 
 
• 
 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 

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6.1.4.9 
Visit 12 – Week 96 (or End of Study Visit) 
The following procedures will be conducted at Week 96 (Visit 12, ±30 days, or end of 
study visit) following IMP administration: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Refraction for BCVA performed prior to pupil dilation. 
•
 
 
. 
• ETDRS visual acuity testing performed prior to pupil dilation. 
• Humphrey Visual Field 30-2 testing performed prior to pupil dilation. 
• SD-OCT performed after pupil dilation. 
• Pelli-Robson contrast sensitivity testing performed prior to pupil dilation. 
• Farnsworth-Munsell 100 Hue color vision test performed prior to pupil dilation. 
• Color fundus photos if necessary for grading ocular inflammation. 
• Recording of AEs and SAEs. 
• Recording of any changes and additions to concomitant medications and any changes 
in concomitant medication dose or regimen, including supplements. 
6.2 
Premature Discontinuation 
Subjects who discontinue participation in the study prematurely (i.e. prior to Visit 12) will 
complete an end-of-study visit including all procedures listed for Visit 12. 
A subject will be withdrawn from the study under any of the following circumstances: 
• Subject’s request at any time for any reason. 
• Physician’s determination that subject’s further participation in the protocol is not in 
the subject’s best interest. 
• The Sponsor’s decision. 
• Health Authorities’ decision. 
For any discontinuation, the Investigator will obtain all the required details and document 
the date of and the reason for the discontinuation in the case report form (CRF). If possible, 
Week 48 ETDRS visual acuity should be obtained. 

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If the reason for withdrawing from the study is an AE, the specific event will be recorded 
in the CRF. 
6.3 
Unscheduled Visits 
Unscheduled visits may be performed anytime during the study to assess or follow up 
adverse events, at the subject’s request, or at the request of the investigator. The date and 
reason for the unscheduled visit should be recorded in the source documentation. 
If unscheduled visits occur, the Investigator must record the following in the subject’s 
source document and CRF: 
• Any AEs. 
• Reason for unscheduled visit. 
• Recording of any changes or additions to concomitant medications dose or regimen. 
• Any clinical assessments, vision and non-vision related, deemed appropriate for the 
clinical care of the subject. 
Unscheduled visits should not alter the timing of the routine study schedule. 
6.4 
Additional Care of Subjects 
Subjects who complete the study through Visit 12 (96 weeks of follow-up) will be offered 
participation in a long-term safety and efficacy study as detailed in a separate protocol that 
will be initiated for further evaluation of the safety and efficacy durability. The long term 
safety study will be conducted according to current regulatory authority recommendation. 

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7 DESCRIPTION OF STUDY PROCEDURES 
7.1 
Informed Consent 
Prior to entering the study, the Investigator will explain to each subject (and the subject’s 
parent/legal guardian if the subject is under the legal age of consent) the nature of the study, 
its purpose, procedures, expected duration, alternative therapies available, and the benefits 
and risks involved in study participation. 
If the subject is of the legal age of consent, they will be given the Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC)-approved ICF to review and the 
opportunity to ask questions. The subject will be informed of their right to withdraw from 
the study at any time without prejudice. The subject should be able to answer simple 
questions about the study after the ICF has been reviewed and explained. After this 
explanation and before any study-specific procedures have been performed, the subject 
will voluntarily sign and date the ICF to indicate the desire to participate in the study. If 
the subject is unable to read the informed consent document, presence of an impartial 
witness is required to confirm the contents of the document were explained to the subject. 
The impartial witness must sign the ICF. The subject must always be asked to sign or mark 
the form regardless of their vision. The Investigator will also sign and date the ICF. The 
time (hour and minute) the consent is signed must also be recorded by the subject or legal 
guardian and the person providing consent to the subject. Prior to participation in the study, 
the subject will receive a copy of the signed and dated consent form along with an 
emergency card with contact information for the Investigator and clinical facility staff in 
the event of a medical emergency during the trial. 
If the subject is under the legal age of consent, the potential subject’s parent or legal 
guardian will be given IRB/IEC-approved ICF to review and the subject will be given an 
IRB/IEC-approved pediatric assent form. Both the subject and the parent/legal guardian 
will be given the opportunity to ask questions. Both the subject and their parent/legal 
guardian will be informed of the subject’s right to withdraw from the study at any time 
without prejudice. The subject and their parent/legal guardian should be able to answer 
simple questions about the study after the ICF and assent form have been reviewed and 
explained. After this explanation and before any study-specific procedures have been 
performed, the parent/legal guardian will voluntarily sign and date the ICF to indicate their 
informed consent for the subject to participate in the study. The subject will sign and date 
the pediatric assent form to indicate their desire to participate in the study. The Investigator 
will also sign and date the ICF and assent form. The time (hour and minute) the consent 
and assent are signed must also be recorded by the subject (on the assent form), the 
parent/legal guardian (on the ICF), and the person providing consent/assent (on both 
forms). Prior to participation in the study, the subject’s parent/legal guardian will receive 
copies of the signed and dated consent and assent forms along with an emergency card with 
contact information for the Investigator and clinical facility staff in the event of a medical 
emergency during the trial. 

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7.2 
Demographics and Other Clinical Evaluations 
7.2.1 
Demographics, Medical History, and Prior Medications 
After subjects have signed an ICF for the purpose of this study, each subject’s 
comprehensive medical history will be recorded, including medical and demographic 
information (according to national data collection regulations). All prior medications 
including prescription and non-prescription medications and preparations and health and/or 
dietary supplements taken by the subject within the previous 30 days will also be recorded. 
In addition, hospitalizations in the past 3 months and the reason for admission 
(medical/surgical/psychiatric/other) in the past 3 months will also be recorded. 
7.2.2 
Pregnancy Testing 
Blood samples for serum pregnancy testing will be collected at the Screening Visit (Visit 
1) for women of childbearing potential. Testing will be conducted at the central laboratory 
unless it is determined that the results will not be received from the central laboratory in 
time for Visit 2, in which case a local laboratory may be used. The results of this test must 
be available and documented at Visit 2. Samples will be handled according to a 
standardized procedure. This procedure will be provided to the Investigator centers prior 
to study start. Subjects with positive pregnancy tests will be excluded from study 
participation.  
7.2.3 
Virology 
Blood samples for HIV testing will be collected at the Screening Visit (Visit 1). Testing 
will be conducted at the central laboratory unless it is determined that the results will not 
be received from the central laboratory in time for Visit 2, in which case a local laboratory 
may be used. The results of this test must be available and documented at Visit 2. Samples 
will be handled according to a standardized procedure. This procedure will be provided to 
the Investigator centers prior to study start. Subjects with positive tests for HIV will be 
excluded from study participation.   
7.2.4 
ND4 (G11778A) Genotyping 
All subjects will be required to have a blood sample taken at Visit 1 for genotyping analysis 
by the central study laboratory. Subjects with previously documented G11778A ND4 
mitochondrial mutation can proceed to visit 2 without the results of the central laboratory 
genotyping. Subjects without previously documented G11778A ND4 mitochondrial 
mutation will be required to have the results of the central laboratory genotyping available 
for Visit 2. Samples will be handled according to a standardized procedure. The testing 
will be analyzed by the central laboratory. This procedure will be provided to the 
Investigator centers prior to study start. The presence of the G11778A ND4 mitochondrial 
DNA mutation must be documented at Visit 2 (Inclusion Visit). 

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7.3 
Ophthalmic Evaluations 
Detailed descriptions of all the ophthalmic evaluations will be detailed in the Ophthalmic 
Evaluations Manual. A central reading center will be used in quality control and analysis 
as detailed per evaluation in the Ophthalmic Evaluations Manual.  
7.3.1 
Visual Acuity 
Enrolled subjects will include those able to read letters on the ETDRS chart (“on-chart” 
subjects) and those unable to read letters on the ETDRS chart but able to count fingers of 
the examiner at a given distance (“off-chart” subjects). On-chart subjects will have visual 
acuity measured with the ETDRS chart and an ETDRS score will be calculated. On-chart 
subjects will also have a Snellen acuity obtainable from the number of lines read on the 
ETDRS chart.  
Off-chart subjects included in the study must maintain the visual ability to allow them to 
count fingers of the examiner as per the selection criteria. Off-chart subjects will not have 
an ETDRS score or a Snellen acuity obtainable from the ETDRS chart. Snellen acuity will 
be obtained utilizing the measured distance at which the subject was able to count the 
fingers of the examiner and a standardized formula available at (Karanjia 2014): 
http://www.countfingers.com/ 
The Snellen acuities of on-chart and off-chart subjects will be converted to LogMAR for 
statistical analysis. Snellen acuities will be transformed to LogMAR using the standard 
formula available at: 
http://www.myvisiontest.com/logmar.php 
Additionally, 1 ETDRS line is considered equivalent to 0.1 LogMAR. 
The visual testing at Visit 4 will be conducted for safety purposes and will not be analyzed 
as efficacy data (see Section 7.6.3). 
7.3.2 
Refraction for Best Corrected Visual Acuity 
BCVA is defined as the best visual acuity that can be achieved by a subject with vision 
correction (e.g. glasses or contact lenses). Refraction testing for BCVA will be conducted 
at the Screening Visit (Visit 1) and Inclusion Visit (Visit 2) and at each follow up study 
visit at which visual acuity testing is conducted. 
7.3.3 
Spectral Domain Optical Coherence Tomography 
SD-OCT will be obtained with the Spectralis® OCT (Heidelberg Engineering). Parameters 
will be obtained for the optic nerve (retinal nerve fiber layer) and posterior pole per 
standard protocols included in the Spectralis software. A central reading center will 
perform quality control, analysis and interpretation of all SD-OCT data. 

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7.3.4 
Visual Field Assessment 
Standardized automated visual fields will be obtained with an HVF Analyzer II (Carl Zeiss 
Meditec Inc.) using the 30-2 SITA Fast strategy, Stimulus III White to measure MD in 
decibels of sensitivity. A central reading center will perform quality control, analysis and 
interpretation of all HVF results. 
7.3.5 
Contrast Sensitivity 
Assessment of the effect of IMP on contrast sensitivity will be measured with the Pelli-
Robson chart. 
7.3.6 
Color Vision 
Assessment of the effect of GS010 on color vision will be assessed using a Farnsworth-
Munsell 100 Hue color vision test. 
7.3.7 
Color Fundus Photos 
Color fundus photos will be obtained at Visit 1 to establish a baseline. Color fundus photos 
will be obtained at Visit 4 through Visit 12 as necessary when required for grading of 
vitreous inflammation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

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7.5 
Clinical Laboratory Tests 
For any test abnormality deemed clinically significant, an AE should be recorded (unless 
the result was considered erroneous) and repeat analysis will be performed until resolution 
or until the Investigator determines that resolution of the laboratory abnormality is not 
expected. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 

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7.5.5 
Laboratory Results Review 
 
 
 
 
 
 
 
It is the Investigator’s responsibility to review the results of all laboratory tests as they 
become available. This review will be documented by the Investigator’s dated signature on 
the laboratory report. For each abnormal laboratory test result, the Investigator needs to 
ascertain if this is a clinically significant abnormal change from baseline for that individual 
subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.7 
Protocol Deviations 
Any protocol deviation related to the conduct of the trial, subject management, or subject 
assessment will be discussed with the Investigator on a case by case basis and documented. 
Protocol deviations will not be approved prospectively. 

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8 STUDY DRUG MANAGEMENT 
8.1 
Description of GS010 
AAV is a small parvovirus that infects humans and other primate species. The vector used 
in this study is a recombinant form of the serotype 2 of the AAV2 vector, rAAV2/2, 
encoding the human ND4 gene under the control of the cytomegalovirus immediate early 
promoter in an intron-containing expression cassette (beta globin intron, HBB2), flanked 
by the viral inverted terminal repeats. The construct includes the cis-acting elements of the 
human COX10 mRNA (mitochondrial targeting sequence 5’ of the complementary DNA 
[cDNA], and the 3’untranslated region at the 3’ end of the cDNA) ensuring the efficient 
mRNA targeting to mitochondria and delivery of the corresponding protein.  
8.1.1 
Formulation  
GS010 (rAAV2/2-ND4) drug product is a sterile suspension of purified viral vector 
formulated in balanced salt solution (BSS) plus 0.001% Pluronic F68®. It is filled in vials 
and stored frozen at ≤ -70°C ready for intended medical use. Details on the preparation of 
GS010 IMP for administration to subjects are described in the Pharmacy Manual. 
8.1.2 
Storage 
IMP is stored at ≤-70°C in a freezer under the supervision of the study pharmacist or the 
Investigator. The IMP vials will be dispensed only with the written authorization of the 
Investigator or his/her delegate that has been specifically designated to this study. After 
reconstitution (see Section 8.3), the IMP may be stored for up to 12 hours at 2 to 8oC before 
injection. 
GS010 IMP must be kept in a locked and restricted access storage facility. 
8.2 
Packaging and Labeling 
GS010 IMP is individually packaged. The primary label on the vial as well as secondary 
container labeling is in the country-specific language for each site. The labels are compliant 
with local regulatory requirements. The primary and secondary packaging together comply 
with the labeling requirements.  
Packaging of IMP will be compliant with the International Air Transport Association 
(IATA) regulation for genetically modified organisms.  
GS010 IMP will be shipped on dry ice (with 1 probe for temperature monitoring during 
transport). 
8.3 
Dose and Administration 
GS010 IMP reconstitution will be performed at the site pharmacy according to the 
reconstitution protocol described in the Pharmacy Manual. Reconstitution kits will be 

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supplied by the Sponsor. The Pharmacy Guide and the Guide for Intra-Vitreal Injection of 
GS010 (rAAV2/2-ND4) and Sham Procedures will describe all details for preparation and 
proper handling of GS010 IMP. 
GS010 IMP will be administered on Day 0 (Visit 3) via a single IVT injection in one eye 
of each subject. The dose of GS010 to be administered is 9E10 vg/eye. The injection will 
be performed in the vitreous humor under local anesthesia. The volume of the injected 
formulation is 90 μL. 
Sham IVT injection will be performed on the fellow eye (i.e. the one not randomized to 
receive GS010). Sham procedures will be performed by applying pressure to the eye at the 
location of a typical procedure using the blunt end of a syringe without needle. 
IVT injection and sham procedures, including pre- and post-procedure steps, will be 
performed according to the Guide for Intra-Vitreal Injection of GS010 (rAAV2/2-ND4) 
and Sham Procedures. 
8.4 
Dispensing and Accountability 
GS010 IMP will only be dispensed, according to Investigator’s prescription, to eligible 
subjects who meet all selection and inclusion criteria and according to the treatment 
scheme.  
GS010 IMP will be tracked during the handling process from prescription to destruction 
(through dispensation, reconstitution, administration and decontamination). 
The Investigator or, depending on center organization, the Pharmacist or the person 
responsible for study medication management will keep an IMP accountability log 
detailing the dates, batch number and quantity dispensed for each subject.  
Accountability records will be verified by the study monitor during site visits. All used and 
unused GS010 IMP vials will be recorded.  
At the end of the study, all unused GS010 IMP vials will be destroyed at the investigation 
center following internal procedures for genetically modified organisms (GMOs). A copy 
of the certificate of destruction should be made available to the sponsor. 
GS010 IMP accountability is ultimately the responsibility of the Investigators. This 
responsibility however may be delegated to the Hospital Pharmacists. This delegation will 
be documented in the Site Trial Master file. 
8.5 
Prior and Concomitant Therapy 
Prior therapy is defined as prescription and non-prescription medications and preparations, 
including health and/or dietary supplements taken within 30 days prior to signing the 
informed consent, but discontinued prior to signing informed consent. Concomitant 
therapy is defined as prescription and non-prescription medications and preparations, 

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health and/or dietary supplements other than GS010 IMP that the subject receives during 
the course of the study (i.e. any time after the signing of informed consent). This includes 
any medication started prior to signing informed consent and continued after signing. 
Idebenone must be completely discontinued for at least 7 days prior to Visit 2 and is 
prohibited throughout the study. If idebenone has not been discontinued at least 7 days 
prior to Visit 2 and if the study protocol timeframe between the visits is respected, Visit 2 
may be delayed until the 7-day period is complete. 
8.6 
Method of Assigning Treatment 
The right eye of each subject will be randomly allocated to receive either GS010 or sham 
treatment in a 1:1 allocation ratio. The fellow (left) eye will receive the treatment not 
allocated to the right eye. Therefore, each subject will receive GS010 in one eye and sham 
treatment in the fellow eye. Prior to randomization, each subject’s better- and worse-seeing 
eye will be determined. Efron’s minimization method will be used in the randomization 
process to balance as much as possible the two treatment groups (GS010 and sham) in the 
better-seeing eyes. 
To enroll a subject (Visit 1), the Investigator will call an interactive response system (IRS) 
and provide brief details about the subject to be enrolled. Each subject will receive a subject 
number assigned at screening, which will serve as the subject identifier throughout the 
study. The subject number will be required in all communication between the Investigator 
(or designee) and the IRS regarding a particular subject. Subject numbers will be tracked 
via the IRS. 
To randomize a subject (Visit 2), the masked Investigator (or designee) will call the IRS 
and provide brief details about the subject to be randomized. Eligible subjects will be 
randomized in a 1:1 ratio (right/left eye), taking into account the Efron’s minimization 
method, using the IRS. 
The IRS User Guide will describe the steps of the randomization process from the subject’s 
screening up to before IVT injection. 
An algorithm with a testing hierarchy will be employed prior to randomization to determine 
the better- and worse-seeing eye of each subject, as follows: 
1. ETDRS visual acuity score for subjects able to read the ETDRS chart. The eye with the 
higher ETDRS score is the better-seeing eye. For subjects who cannot read the ETDRS 
chart (“off chart” subjects) a standard study procedure will be used to determine visual 
acuity based on counting fingers at a given distance. The eye with the best visual acuity 
based on this method is the better-seeing eye. If one eye of a subject is able to read 
letters on the ETDRS chart and one eye cannot, the eye able to read the ETDRS chart 
is the better-seeing eye. 
2. SD-OCT parameters (to be used if there is no inter-eye difference based on Criterion 
1): 

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i. 
The initial SD-OCT parameter will be the total volume of the RGC layer of the 
macula. The better-seeing eye will have the greater volume and quadrant 
thickness, unless there is macula edema. A difference of ≥5% is considered 
significant to determine greater volume. 
ii. 
The second SD-OCT parameter (to be used if there is no inter-eye difference in 
criteria 2i) will be the combined volume of the RGC layer of the inner and outer 
nasal quadrants of the macula. The better-seeing eye will be the eye with greater 
volume. A difference of ≥5% is considered significant to determine greater 
volume. 
3. Contrast sensitivity measured with the Pelli-Robson chart (to be used if there is no 
inter-eye difference in criteria 1 or 2). The eye with the best Log CS (contrast 
sensitivity) score is the better-seeing eye. 
8.7 
Masking 
Masking will be accomplished with sham injection. Sham IVT injection will be performed 
by applying pressure to the eye at the location of a typical procedure using the blunt end of 
a syringe without a needle. Thus treatment allocation will be double-masked. The subject 
will remain masked at all times during the study. An unmasked team at the site will perform 
all procedures at Visit 3 and Visit 4 and focused follow up of ocular AEs commencing at 
Visits 3 and 4 until resolution of the AE or the determination that no further clinical 
evolution is expected. The unmasked team includes the injecting investigator(s), allied 
medical 
professionals 
who 
assist 
with 
IVT 
injection 
and 
ophthalmic 
technicians/optometrists who perform vision testing at Visit 4. The unmasked team will 
enter eye-related AEs identified at Visits 3 and 4 into the CRF in a masked way. A masked 
team at the site will conduct all other study procedures. A schedule of events for the 
unmasked site team is in Section 4.2. 
Unmasked individual pharmacovigilance CRO personnel may know the treatment 
allocation of a given subject. No Sponsor or CRO personnel in charge of the conduct of 
the study (e.g. CRA, data manager, study manager etc.) will have access to treatment 
information. 
8.8 
Procedure for Unmasking 
The treated/untreated eye information (GS010-treated eye versus sham-treated eye) should 
not be unmasked unless knowledge of the subject’s eye treatment is required for the 
subject’s clinical care and safety. The Investigator/clinical masked team will be provided 
with instructions to allow them to unmask the treatment via IRS. In the unlikely event that 
knowledge of the eye treatment assignment is necessary in order to care for a subject, the 
Investigator may decide to unmask the treatment allocation for safety reasons. If the eye 
treatment is unmasked, the Sponsor and the assigned Clinical Research Associate (CRA) 
must be notified within 24 hours. Documentation of unmasking should be recorded in the 
subject’s medical record with the reason for unmasking, the date and time of the 
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9 ADVERSE EVENTS 
The condition of the subject will be monitored throughout the study. Overall incidence of 
AEs and SAEs will be evaluated for the study as a whole. 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
related to the medicinal (investigational) product. Any event or laboratory abnormality that 
leads to a medical intervention, including withdrawal of IMP or significant additional 
concomitant therapy, will be considered an AE. Worsening of visual acuity determined by 
the Investigator to be due to progression of LHON will not be considered an AE. 
AEs should be volunteered by the subject, be observed from examination of the subject at 
a clinic visit, or be from observations of clinically significant laboratory values or special 
examination abnormal values. AEs will not be solicited by the use of a specific list of 
anticipated events. 
All AEs are to be assessed and recorded in a timely manner. Each AE is to be documented 
with reference to severity, date of occurrence, duration, treatment, and outcome. 
Furthermore, each AE is to be classified as being serious or non-serious. In addition, the 
Investigator must assess whether the AE is drug-related or not. Changes in severity of AEs 
and resolution dates should be documented as separate events. 
AEs will be captured from the first study-related procedure through to the completion of 
the protocol-defined safety follow-up as defined in Section 9.5 and Section 10.3.  
Surgical procedures, planned before enrolment of the subject in the study, are not 
considered AEs if the condition was known before study inclusion. In this case the medical 
condition should be reported in the subject’s medical history.  
Intermittent AEs will not be reported as multiple AEs. The definition of an intermittent AE 
is “a recurring event with the same severity, frequency, and causality.” 
Clinically relevant abnormal findings observed during vital signs measurements or 
physical examinations will be reported as AEs. 
9.1 
Reporting and Documentation of Adverse Events 
9.1.1 
Reporting 
At each visit, any AE directly observed or mentioned by the subject will be reported by the 
Investigator or designee on the page “Adverse Events” of the CRF (also called the “AE 
page”). The unmasked team will report AEs commencing at Visits 3 and 4 and the masked 
team will document AEs commencing at all other visits. The unmasked team will enter 

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eye-related AEs identified at Visits 3 and 4 into the CRF in a masked way and will perform 
focused follow up at subsequent visits of ocular AEs commencing at Visit 3 and Visit 4 
until AE resolution or the determination that no further clinical evolution will occur. The 
following items must be documented:  
Nature of the event with self-explanatory and concise medical terminology (indicate a 
diagnosis or syndrome instead of symptoms). 
Date of onset and date of resolution (i.e. actual dates when the event starts and is resolved 
rather than dates when the Investigator is informed). 
• Severity. 
• Relationship to IMP. 
• Relationship to study procedure. 
• Outcome. 
• Seriousness.  
• Action taken regarding the IMP. 
• Any action taken regarding the event, whether by the Investigator, the subject (as 
reported by the subject), or by another physician (as reported by the subject or in the 
subject’s medical record).  
AEs requiring therapy must be treated with recognized standards of medical care to protect 
the health and well-being of the subject. Any treatment given will be reported on the page 
"Concomitant medication" of the CRF.  
9.1.1.1 
Assessment of Severity 
The severity of the clinical AE is graded according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. The CTCAE scale will be provided to the 
Investigators.  
Should an event be missing in one of the scales, the following 3 point scale is used:  
• Mild: Discomfort noticed, but no disruption of normal daily activity.  
• Moderate: Discomfort sufficient to affect normal daily activity.  
• Severe: Inability to work or perform normal daily activity.  
The correspondence between the two scales is as follows: 
CTCAE 
3-Point Scale 
1 
Mild 
2 
Moderate 
3/4/5 
Severe 
 

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9.1.1.2 
Relationship to IMP and/or Procedures 
The relationship of each AE to IMP and/or study procedures will be evaluated as follows:  
• Unrelated: There is evidence of relationship to a cause other than the IMP/procedure. 
Does not meet criteria listed under unlikely, possible or probable.  
• Unlikely: Does not follow a reasonable temporal sequence from administration. Is most 
likely produced by the subject's clinical state or by environmental factors or other 
therapies administered.  
• Possible: Follows a reasonable temporal sequence from administration. Is not likely 
produced by the subject's clinical state or by environmental factors or other therapies 
administered.  
• Probable: Follows a reasonable temporal sequence from administration. Clear-cut 
temporal association with IMP. 
9.1.1.3 
Outcome 
The outcome of each AE will be rated as follows:  
• Recovered. 
• Not recovered. 
• Recovered with sequelae. 
• Fatal. This outcome is to be used only for the event leading to death. The outcome of 
all other events at the time of the death must be reported. The outcome of ongoing ones 
is reported as "not recovered". 
• Unknown.  
• Worsening. This outcome is used when an AE worsens. The new status of the event is 
documented as another AE on the AE page in the CRF. 
9.1.2 
Documentation  
AEs will be reported in the source document with at least the nature, the start date and the 
treatment (if applicable) of the event.  
9.2 
Ocular Inflammation 
Specific assessment and documentation of ocular inflammation will be required. Ocular 
inflammation is an expected event based on preclinical NHP studies of GS010 and Phase 
I evaluation of GS010 in GS-LHON-CLIN-01. Specific, standardized schemes for 
assessing anatomic location, severity and clinical evolution will be employed. Specific 
scales will be used for anterior uveitis (anterior chamber) and intermediate uveitis 
(vitreous).  
The Standardization of Uveitis Nomenclature (SUN) Working Group provided 
standardized methods for (1) anatomic classification of uveitis; (2) grading scheme for 
anterior chamber cells; (3) grading scheme for anterior chamber flare; and (4) activity of 

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uveitis terminology (for clinical evolution) (Jabs 2005). Investigators will grade cases of 
ocular inflammation according to these scales. These scales are provided in Table 1, 
Table 2, Table 3, Table 4, and Table 5 below. 
 
Table 1 
Anatomic Classification of Uveitis (SUN Working Group) 
Type 
Primary Site of Inflammationa 
Includes 
Anterior uveitis 
Anterior chamber 
Iritis 
Iridocyclitis 
Anterior cyclitis 
Intermediate uveitis 
Vitreous 
Pars planitis 
Posterior cyclitis 
Hyalitis 
Posterior uveitis 
Retina or choroid 
Focal, multifocal, or diffuse 
choroiditis 
Chorioretinitis 
Retinochoroiditis 
Retinitis 
Neuroretinitis 
 
Panuveitis 
Anterior chamber, vitreous, and 
retina or choroid 
 
SUN = Standardization of Uveitis Nomenclature 
a As determined clinically. Adapted from the International Uveitis Study group anatomic classification. 
 
 
Table 2 
Grading Scheme for Anterior Chamber Cells (SUN Working 
Group) 
Grade 
Cells in Fluida 
0 
<1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
SUN = Standardization of Uveitis Nomenclature 
a Field size is a 1 mm by 1 mm slit beam. 
 

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Table 3 
Grading Scheme for Anterior Chamber Flare (SUN Working 
Group) 
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
SUN = Standardization of Uveitis Nomenclature 
 
 
Table 4 
Activity of Uveitis Terminology (SUN Working Group) 
Term 
Definition 
Inactive 
Grade 0 cellsa 
Worsening Activity 
Two step increase in level of inflammation (e.g., anterior chamber 
cells, vitreous haze) or increase from Grade 3+ to Grade 4+. 
Improved Activity 
Two step decrease in level of inflammation (e.g., anterior chamber 
cells, vitreous haze) or decrease to Grade 0. 
Remission 
Inactive disease for ≥ 3months after discontinuing treatments for eye 
disease 
SUN = Standardization of Uveitis Nomenclature 
a Applies to anterior chamber inflammation. 
 
Grading of vitreous cells will be performed based on the slit lamp examination utilizing a 
1 mm by 1 mm slit lamp beam and the same grading scheme utilized for anterior chamber 
cells (Table 2). 
Grading of vitreous haze will be performed in a standardized fashion by the central 
ophthalmology reading center, based on color fundus photos of the posterior pole. Baseline 
color fundus photos will be obtained at Visit 1 for all subjects. Color fundus photos will be 
obtained at subsequent visits when needed for grading of vitreous inflammation. The 
National Institutes of Health grading system (Nussenblatt 1985) will be used to grade the 
vitreous haze on the fundus photo. Table 5 and photos will serve as the basis for vitreous 
haze grading: 

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Table 5 
National Institutes of Health Grading System for Vitreous 
Haze 
Grade 
Amount of Vitreous Flare/Haze 
0 
No flare 
0.5+ 
Trace 
1+ 
Clear optic disc and vessels, hazy nerve fiber layer 
2+ 
Hazy optic disk and vessels 
3+ 
Optic disc visible 
4+ 
Optic disc not visible 
Quality Unsatisfactory 
Photo quality inadequate for vitreous inflammation grading 
Not Performed 
Photograph not performed 
 
 
9.3 
Clinical Laboratory Changes 
A laboratory abnormality is reported as an AE if it is out of range, considered by the 
Investigator as clinically significant (i.e. with clinical manifestations or requiring treatment 
or clinical management) and confirmed by a repeat measurement (if relevant). Worsening 
of laboratory parameters from pre-drug administration state will be considered on the same 
basis. 
9.4 
Concomitant Medication Assessments 
The Investigator or designee will record any concomitant therapies given for the treatment 
of AEs on the concomitant medication page of the subject’s source document and CRF. 
During the study, any medication taken by the subject is to be reported by the subject and 
noted on the subject’s source document and CRF. Any changes in concomitant therapy 
during the study will be documented, including cessation of therapy, initiation of therapy, 
and dose changes. 

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9.5 
Adverse Event Follow-up 
AEs occurring during the course of the study must be followed until resolution or the last 
visit planned by the protocol. AEs not resolved by the last visit planned by the protocol 
will be listed in the CRF as continuing/not resolved. 
Subjects who experience the onset of an AE thought to be related to IMP after their final 
visit (Visit 12 or the end of study visit) will be followed up until the resolution of the AE 
or for 30 days after the AE occurs, whichever comes first. AEs not resolved after 30 days 
will be listed in the CRF as continuing/not resolved. SAEs thought to be related to IMP 
occurring after the final visit (Visit 12 or the end of study visit) must be reported as 
described in Section 10.3. 
9.6 
Pregnancy 
If a female subject or the partner of a male subject believes she is pregnant (e.g., missed 
period, self-administered pregnancy test) the subject will be instructed to return to the 
clinical unit within 48 hours to undergo a serum pregnancy test. All confirmed pregnancies 
that occur within this study will be followed until resolution (i.e., termination [voluntary 
or spontaneous] or birth).  
If the pregnancy is confirmed before the subject receives IMP, the subject will be excluded 
from study participation and will not receive IMP. 
Pregnancy (without associated unexpected or adverse sequelae) is not a reportable AE but 
must be reported to the Sponsor within 24 hours of the Investigator or study staff first 
becoming aware of the subject’s condition. 

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10 SERIOUS ADVERSE EVENTS 
10.1 Definition of Serious Adverse Event 
A SAE is any AE that meets any of the following criteria: 
• Results in Death. 
• Is Life-threatening. 
• Requires Inpatient hospitalization or prolongation of existing hospitalization. 
• Results in Persistent or significant disability/incapacity. 
• Is a Congenital anomaly/birth defect in the offspring of a subject who received IMP. 
Other important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are: 
• Intensive treatment in an emergency room or at home for allergic bronchospasm. 
• Blood dyscrasias. 
• Convulsions that do not result in inpatient hospitalization. 
10.2 Definition of Terms 
Life threatening: An AE is life threatening if the subject was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death. For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life threatening even 
though drug induced hepatitis can be fatal. 
Hospitalization: AEs requiring hospitalization should be considered SAEs. Hospitalization 
for elective surgery for a pre-existing condition that has not worsened or hospitalization 
for routine clinical procedures that are not the result of an AE need not be considered AEs 
or SAEs. If anything untoward is reported during the procedure, that occurrence must be 
reported as an AE, either 'serious' or 'non-serious' according to the usual criteria. 
In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician's office or outpatient setting. When 
in doubt as to whether 'hospitalization' occurred or was necessary, the AE should be 
considered serious. 
Disability/incapacitating: An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the subject's ability to carry out normal life 
functions. 

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10.3 Reporting Serious Adverse Events 
Any SAE occurring during the course of a study, i.e. between signature of the ICF and the 
end-of-study visit, irrespective of the treatment received by the subject MUST be reported 
to the Sponsor or their representative. The Investigator must complete and fax a "Serious 
Adverse Event Form" to the Sponsor or their designee within 24 HOURS of occurrence or 
knowledge of the event.  
An Investigator’s delegate may complete the SAE form; however, the Principal 
Investigator or delegate physician must sign it. The form can be sent to the Sponsor or their 
designee with the delegate's signature if the Principal Investigator/delegate physician’s 
signature cannot be obtained within one working day. The Principal Investigator/delegate 
physician’s signature must be obtained as soon as possible, as must his/her evaluation of 
the relationship to the IMP. The signed form must be faxed to the Sponsor or their designee 
immediately.  
The SAE form must be completed in English.  
10.3.1 
Follow-up 
If follow-up information is not available at the time of the event, this information must be 
forwarded to the Sponsor or their designee within one day of knowledge. The Sponsor or 
their designee may request information as needed.  
10.3.2 
Post-Study Serious Adverse Events 
Any SAE occurring after the end of study visit and that is considered by the Investigator 
to be possibly or probably related to the IMP must be reported to the Sponsor or their 
designee as described above.  
If the end of study visit is performed less than 28 days after IVT injection, ALL SAEs 
occurring between the end of study visit until 28 days after IVT injection will be reported 
to the Sponsor or their designee, regardless of their relationship to the IMP.  
10.3.3 
Notification to Regulatory Authorities/Gene Therapy 
Bodies/IRBs/IECs 
The Sponsor or their designee is responsible for notifying serious and unexpected AEs to 
Health Authorities and to IRBs/IECs in accordance with local law.  
Gene Therapy Bodies will be informed as locally required.  
10.3.4 
Information to Investigator  
When an SAE has been reported to Health Authorities, the Sponsor or their designee will 
inform all other Investigators working in this study as well as those working with GS010 
in other studies in accordance with local laws and regulations. 

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10.3.5 
Documentation  
All SAEs will be reported on the AE pages of the CRF using the same information as 
documented on the SAE form and in source documents. Copies of SAE forms will be filed 
in the Investigator Site File along with copies of any correspondence with the IRB/IEC. 
The Investigator Site File will also include copies of notification letters and/or faxes of 
forms sent to Health Authorities and Gene Therapy Bodies if appropriate. 

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11 QUALITY CONTROL AND ASSURANCE 
11.1 Quality Control 
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified Investigators and appropriate study centers, review of protocol procedures with 
the Investigators and associated personnel before the study, and periodic monitoring visits 
by the Sponsor or their designee. Written instructions will be provided for study drug 
preparation and dosing, and collection, preparation, and shipment of blood samples. 
Guidelines for CRF completion will be provided and reviewed with study personnel before 
the start of the study. The Sponsor (or designee) will review CRFs for accuracy and 
completeness during on-site monitoring visits and after transmission to the Sponsor (or 
designee). Any discrepancies will be resolved with the Investigator or suitably qualified 
designee, as appropriate.  
11.2 Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines.  
In accordance with the standards defined in Sponsor SOPs and applicable regulatory 
requirements, clinical studies sponsored by the Sponsor are subject to Sponsor Quality 
Audits at the study sites, which will be conducted by personnel from an appropriate unit. 
Site visit audits will be made periodically by the Sponsor’s (or the CRO’s) qualified 
compliance auditing team, which is an independent function from the study conduct team. 
Audits will include, but are not limited to, review of drug supply, presence of required 
documents, the informed consent process, and comparison of CRFs with source 
documents. The Investigator agrees to participate with audits conducted at a reasonable 
time in a reasonable manner. Full consultation with the Investigator will be made prior to 
and during such an audit, which will be conducted according to the Quality Assurance Unit 
SOPs. In addition, this study is subject to audit by regulatory authorities. If such a 
regulatory inspection occurs, the Investigator agrees to allow the regulatory inspector direct 
access to all relevant study documents. The Investigator should contact the Sponsor 
immediately if this occurs and must fully cooperate with the inspection conducted at a 
reasonable time in a reasonable manner. 

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12 STATISTICS 
12.1 General Considerations 
A statistical analysis plan (SAP) will be prepared after the protocol is approved and before 
database lock occurs. The SAP will provide further details regarding the endpoints, data 
handling rules, and the statistical methodology to be used to address all study objectives. 
The SAP will also include formats for the summary and analysis tables, listings, and 
graphical displays. 
GS-LHON-CLIN-03A (RESCUE) will include subjects affected for 180 days or less. 
Evidence indicates that improvement due to gene transfer therapy may be greatest at earlier 
stages of disease. This trial randomizes the right eye of each subject to receive GS010 or 
sham treatment in a 1:1 ratio and also uses the Efron’s minimization method to balance as 
best as possible the treatment allocation to better- and worse-seeing eyes, as described in 
Section 8.6 for secondary analysis. 
Data for quantitative variables will be presented by arithmetic mean (for other continuous 
variables), standard deviation (SD) median, first quartile (Q1), third quartile (Q3), 
minimum and maximum. Data for binary variables (responder analysis) will be presented 
by using counts and percentages. Least square (LS) means, 95% confidence interval and 
P-values will be reported derived from models and statistical tests. 
12.2 Sample Size 
Sample size calculation is based on the primary endpoint (LogMAR) and on the paired 
comparison of treated and sham eye. There is no published data regarding the within 
subject variance and the sample size calculation through paired comparison will therefore 
be very speculative for two reasons. The first reason is the within subject correlation 
between right and left eye and the second reason is the absence of information on the within 
and between subject variance of the LogMAR. Usually the within subject correlation is 
positive and the use of a null correlation is conservative. The absence of information on 
the LogMAR requires a second rough approximation of the mean and variance of LogMAR 
because the mean of ETDRS (Lam et al. 2014) is highly correlated to the variance of 
ETDRS (R² = 0.839 for the log-log relationship). This correlation is in favor of the use of 
the LogMAR to stabilize the variance but the transformation from ETDRS mean and 
variance to LogMAR mean and variance requires additional assumptions.  Starting with a 
mean 23.4 and a standard deviation of 28.3 (Lam et al. 2014) and a difference of 20 letters 
on average between treated and sham eye, using the relationship between the log mean and 
the log variance obtained with Lam et al. (2014) results (log variance = 1.743 log mean + 
0.48, R² = 0.839) and assuming a perfect lognormal distribution of ETDRS, the difference 
in means of the lognormal distributions is 0.65 (3.32 - 2.67) and the pooled standard 
deviation of the log distributions is 0.914. Assuming no correlation between both eyes, the 
within subject standard deviation is (2x0.914²)0.5 = 1.29. The standardized difference in 
means is therefore 0.65/1.29 = 0.504 rounded to 0.50. The sample size required to get a 
power of 85% is exactly 36 subjects. 

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12.3  Analysis Populations 
12.3.1 
Intent-to-Treat Population 
The intent-to-treat population will consist of all subjects who are randomized and receive 
study treatment (GS010 or sham treatment). This population will be the population for the 
primary efficacy analysis. 
12.3.2 
Safety Population 
The safety population is defined as those subjects who received IMP. This population will 
be used as the population for all safety analyses. 
12.4 Statistical Methods 
12.4.1 
Primary Analysis and Associated Planned Analyses 
The primary analysis will be performed on the ITT subject population, which consists of 
all randomized and treated subjects. The change from baseline to Week 48 in the LogMAR 
acuity will be the primary response. The ETDRS score will not be directly used because 
there is a clear relationship between the mean and variance and according to Taylor's power 
law (log SD² = 1.743 log mean + 0.48, R² = 0.839) the best transformation is the logarithm 
(slope close to 2 and ease of interpretation of the difference in means of log). Because 
LogMAR is a logarithmic scale and is well known by ophthalmologists, this scale is 
retained as the primary one. The change from baseline of the treated eye will be compared 
to the change from baseline of the sham eye using a mixed model including the subject, 
the treatment and the baseline as covariates.  
The center will not be included in the analysis as the number of subjects recruited per site 
will be very small. The difference in the mean change from baseline to Week 48 between 
the two treatment groups and associated 95% confidence interval will be reported. 
Alternative non parametric analysis (signed Wilcoxon test) will be performed as a 
sensitivity analysis to decrease the influence of possible outliers.  
The treatment effect reflects well the effect on the better- and worse-seeing eye if no 
marked interaction between the eye status (better- versus worse-seeing) and treatment 
exists. To verify this hypothesis, a model including the subject as a random factor, the 
treatment as a fixed factor as well as the eye status (better- or worse-seeing) and the 
interaction between eye status and treatment will be fitted. If the P-value of the interaction 
test is below 0.15 a potential interaction is detected. In that case the better-seeing eye 
treated with GS010 will be compared to the better-seeing eye treated with sham and the 
worse-seeing eye treated with GS010 will be compared the worse-seeing eye treated with 
sham in an ANCOVA model  including the LogMAR at baseline and the treatment. The 
study is then powered (1-β = 0.8) to detect a difference of approximately 30 letters between 
the two treatments. 

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A meta-analysis combining study GS-LHON-CLIN-03A (RESCUE) and study 
GS-LHON-CLIN-03B (REVERSE) is planned to verify whether the treatment effect at 
Week 48 as well as at Week 96 is dependent upon the time from onset of disease. If the 
treatment effect does not depend upon the eye status, a model using the change from 
baseline as the response, the subject as a random factor, the treatment as a fixed factor, the 
time from the onset of disease as a covariate and the interaction between the treatment and 
the time from the onset will be fitted. If the treatment effect is not the same in the better- 
and worse-seeing eye, a model will be fitted for the better-seeing eye and another model 
will be fitted for the worse-seeing eye. The subject factor will not be included in the model, 
but the LogMAR at baseline, the treatment, and the time from onset of disease will be 
included. 
The generalizability of the treatment effect across countries will be addressed in the meta-
analysis because the number of subjects per country could be sufficient to detect major 
heterogeneity. 
12.4.2 
Secondary Analysis 
The treatment estimate at Week 96 will be based on the same statistical approach as the 
primary endpoint analysis. Another analysis will compare time course of the response up 
to Week 96 using the mixed model procedure. The responder analyses at both Week 48 
and Week 96 will be based on a McNemar test for paired samples. To verify whether the 
treatment effect is dependent upon the better-seeing eye or the worse-seeing eye at study 
entry, a test of homogeneity of subgroups (better-seeing or worse-seeing eye treated) 
effects in stratified paired binary data (Zhao 2014) will be performed. 
Like the primary endpoint, a meta-analysis will be performed combining both studies (GS-
LHON-CLIN-03A (RESCUE) and study GS-LHON-CLIN-03B (REVERSE). A 
conditional logistic model will be used to assess the effect of better- and worse-seeing eye 
at study entry and the effect of time from onset of disease and the effect of treatment. 
12.4.3 
Analysis of Vision-Related Secondary Endpoints 
SD-OCT will be presented by summary statistics for continuous data. Visual field data 
generated from HVF analyzer II, Goldmann applanation tonometry, color vision, and 
contrast sensitivity data will be summarized between the two treatments by using 
descriptive statistics. 
 
 
 
 
12.4.5 
Analysis of Safety 
Incidence and severity of all treatment and non-treatment emergent local and systemic AEs 
and SAEs will be presented by system organ class and preferred term. Summary descriptive 

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statistics will be presented for all continuous variables. The visual testing at Visit 4 will be 
conducted for safety purposes and will not be analyzed as efficacy data (see Section 7.6.3). 
All AEs will be coded using the most up-to-date version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Only AEs occurring after administration of IMP will be 
included in the safety analysis. 
The incidence of AEs (number and percent of subjects reporting the AE at least once during 
the study) will be summarized by body system and preferred term for all AEs, by the 
Investigator’s attribution of relationship to study drug and by severity. The details will be 
included in the statistical analysis plan. 
12.4.5.1 
Laboratory Data 
At each visit where clinical laboratory assessments are conducted, summary statistics for 
the absolute laboratory value and the changes from baseline will be presented. Statistical 
testing will be performed at the Visit 12/end of study visit. Shift tables will be presented to 
compare the shifts between the baseline and post-baseline visits. Clinically significant 
abnormal lab values for different parameters will be summarized. 
 
 
 
 
12.4.5.3 
Other Variables Related to Safety 
  
 
 
 
 
 
 
Concomitant medication verbatim terms on CRFs will be mapped to Anatomical 
Therapeutic Chemical Level 4 categories and Drug Reference Names using the World 
Health Organization (WHO) dictionary (Version December 1, 2006). Incidence (number 
and percent of subjects reporting the medication at least once during the study) will be 
summarized for all concomitant medications. 
12.4.6 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (gender, age, weight, height) will be summarized 
using descriptive statistics. Qualitative variables (gender) will be summarized using 
frequencies while quantitative variables (age, weight) will be summarized using mean, SD, 
median, Q1, Q3, minimum, and maximum. 

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12.5 Interim Analysis 
No interim efficacy analyses are planned. 
12.6 Timing of Primary Analysis 
Primary endpoint analysis will be performed as soon as the last subject completes the Week 
48 assessment and data are cleaned. At that point, all subjects will be recruited and followed 
for at least 48 weeks except in case of premature withdrawal. Many subjects will have 
reached Week 96 but not all of them. The study will be formally unmasked for the efficacy 
analysis at Week 48 to allow an early registration if results meet the expectations. The 
study will still continue up to scheduled end (Week 96). Although the study will have been 
unmasked for the study statistician, every effort (see Appendix V in Section 20.5) will be 
invested to maintain the masking of subjects and personnel in charge of the conduct of the 
study including study managers, data managers, CRAs, investigators (except international 
coordinating investigators per Appendix V in Section 20.5). After the completion of the 
study, only the analyses related to the Week 96 endpoints will be performed (see Appendix 
V in Section 20.5). 
12.7 Handling of Missing Data 
In case of missing data at Week 48, the following rules will be applied in the first 
imputation method: 
Rule 1: If the LogMAR is available at the previous and the following visits then the imputed 
value at Week 48 will be a linear interpolation of LogMAR. 
Rule 2: If there is no following visit due to drop out then the relative change (RCi) from 
visit Vi to visit Vi+1 will be calculated at each visit from the baseline to the visit preceding 
Week 48 in the group treated with a sham. The last available visit (Vi) with data (Xi) will 
be used as the starting time point. The imputed score at Vi+1 for each eye will be equal to 
Xi+1 = Xi * RCi. The imputed score at the next missing visit Vi+2 will be equal to Xi+2 = 
Xi+1*RCi+1, and so on up to Week 48 visit. The RCi will be the same for the treated and 
sham eyes. 
With the first method of imputation the between eye difference at Week 48 will be 
proportional to the between eye difference at the time of withdrawal because the same RCi 
coefficients are used for both eyes. 
The second imputation method leading to an additional sensitivity analysis will apply the 
same Rule 1 but Rule 2 will be based on the evolution of the difference between treated 
and sham eye. RCi is then the relative change from visit i to visit i+1 of the difference 
between treated and sham eye in all subjects attending visit i and i + 1. The sensitivity 
analysis will be a one sample t-test performed on the difference between treated and sham 
eyes at Week 48. This method assumes that the evolution of drop-out is similar in terms of 
between eye differences to that of subjects who were followed-up.  

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The third imputation method will apply the same Rule 1 but for Rule 2 the last available 
data will be carried forward for the sham eye and the worst available value (either sham or 
treated eye) will be carried forward for the treated eye. This should be the most 
conservative imputation method. 

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13 ETHICS AND RESPONSIBILITIES 
13.1 Good Clinical Practice 
The current study will comply with the International Conference on Harmonisation (ICH), 
Good Clinical Practice (GCP), and applicable regulatory requirements. 
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the protocol, current ICH GCP guidelines, and applicable regulatory and 
country-specific requirements. GCP is an international ethical and scientific quality 
standard for designing, conducting, recording, and reporting studies that involve the 
participation of human subjects. Compliance with this standard provides the public 
assurance that the rights, safety, and well-being of study subjects are protected, consistent 
with the principles that originated in the Declaration of Helsinki and that the clinical study 
data are credible. 
13.2 Data and Safety Monitoring Board 
An independent DSMB will be constituted and responsible for periodically reviewing study 
data to assure the continued safe conduct of the study. The DSMB will meet to review the 
data at least every 6 months. Operational and logistical details will be provided in a separate 
DSMB charter. 
13.3 Institutional Review Board/Independent Ethics Committee 
The local IRB/IEC to whom an Investigator is responsible has primary responsibility over 
any clinical trial performed at that location. The protocol will be reviewed by an 
independent and appropriately constituted IRB/IEC. Study enrolment and protocol-related 
procedures, which do not form part of the subject’s normal clinical treatment, will not be 
performed until the IRB/IEC of record has provided written approval of the protocol or a 
modification thereof. The IRB/IEC must be constituted and operate in accordance with the 
principles and requirements of ICH GCP. 
Study drug can only be supplied to the Investigator after documentation of all ethical and 
legal requirements for starting the study have been received by the Sponsor. This 
documentation must also include an IRB/IEC membership list that contains members’ 
occupations. If the IRB/IEC will not disclose the names of the committee members, the 
IRB/IEC Federal-wide Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/IEC should mention the study title, study code, study site (or 
region or area of jurisdiction, as applicable), and any other documents reviewed. It must 
mention the date on which the decision was made and must be officially signed by a 
committee member. 
13.4 Informed Consent 
Prior to the subject incurring the first study-related procedure, the Investigator or 
designated individual will explain to each subject and parent/legal guardian (if applicable), 

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the nature of the study, its purpose, procedures, expected duration, alternative therapies 
available, and the benefits and risks involved in study participation. All informed consent 
documents, pediatric assent documents, and other documents used in the conduct of the 
study will have been approved by an IRB/IEC. For adults who are unable to consent for 
themselves (e.g., subject has a mental incapacity) consent can be obtained from the 
subject’s legal representative prior to the recruitment of that subject into the trial. If the 
subject is unable to understand the ICF or assent form due to language barrier and the ICF 
and assent form are not available in the subject’s language, the subject should not be 
enrolled in the study. Subjects and parents/legal guardians (if applicable) will be given 
consent documents and pediatric subjects will be given assent documents to review and 
will have the opportunity to ask questions. Subjects and parents/legal guardians (if 
applicable) will be informed of the subject’s right to withdraw from the study at any time 
without prejudice. The potential subject and parent/legal guardian (if applicable) should be 
able to answer simple questions about the study after the ICF and assent form (as 
applicable) have been reviewed and explained.  
After this explanation and before any study-specific procedures have been performed, the 
subject or parent/legal guardian (if applicable) will voluntarily sign and date the ICF to 
indicate desire to participate in the study or their informed consent for the pediatric 
subject’s participation. Subjects under the legal age of consent will voluntarily sign the 
pediatric assent form to indicate desire to participate in the study. The Investigator will also 
sign and date the ICF and assent form. The time (hour and minute) the consent is signed 
must also be recorded by the subject or parent/legal guardian (on the ICF), the pediatric 
subject (if applicable on the pediatric assent form), and the person obtaining consent (on 
both forms as applicable). 
If the subject is of the legal age of consent but is unable to read the informed consent 
document, presence of an impartial witness is required to confirm the contents of the 
document were explained to the subject. The impartial witness must sign the ICF. The 
subject must always be asked to sign or mark the form regardless of their vision.  
Prior to participation in the study, the subject (if of the legal age of consent) or parent/legal 
guardian (if the subject is under the legal age of consent) will receive copies of the signed 
and dated ICF and signed and dated assent form (if applicable) along with an emergency 
card with contact information for the Investigator and site staff in the event of a medical 
emergency during the study. 
13.5 Case Report Forms and Study Records Management 
The Investigator is responsible for the quality of the data recorded in the CRFs. The data 
recorded should be a complete and accurate account of the subject’s record collected during 
the study. Study data are not to be gathered directly onto the CRF but must be gathered 
onto primary source documents at the clinical site. Completion of source documents will 
precede the completion of the CRF. Source documents may be electronic, hard copy, or a 
combination of both. Source documents are defined as the results of original observations 
and activities of a clinical investigation. Source documents will include, but are not limited 

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to, progress notes, electronic data, screening logs, and recorded data from automated 
instruments. All source documents pertaining to this study will be maintained by the 
Investigators and made available for direct inspection by the authorized study personnel 
outlined in the ICF. The CRF will be considered the source document for individual CRF 
elements such as study-specific scales if those data are collected directly onto a CRF. 
Data collection will be completed according to the guidelines provided by the Sponsor or 
its designee in writing. All required data are to be recorded using the CRFs and source 
documents for every subject that signed an informed consent. Site staff will be trained on 
the CRF completion guidelines and requirements for source documentation. 
Completed CRFs will be reviewed by the study monitor in line with CRF review guidelines 
for the study to ensure completeness and consistency. The Sponsor or its designee will 
review every subject’s CRF with source data verification for at least all critical data points. 
The source data verification plan for this study will define the level of source data 
verification required for non-critical data points. Screen failure CRF and source documents 
require only source data verification for critical data points such as informed consent, AEs, 
reason for termination, and inclusion/exclusion. Any discrepancies found during the CRF 
review will be clarified by the Investigator or designated individual. This includes CRF 
reviews at the site by the Sponsor or its designee, or during quality assurance review of the 
data.  
An explanation must be documented for any missing data. Any changes to information in 
the study progress notes and other source documents will be initialed and dated on the day 
the change is made by a site staff member authorized to make the change. Changes will be 
made by striking a single line through erroneous data (so as not to obliterate the original 
data), and clearly entering the correct data (e.g., wrong data right data). If the reason for 
the change is not apparent, a brief explanation for the change will be written in the source 
documentation by the clinician. 
The Investigator must sign and date a declaration attesting to his/her responsibility for the 
quality of all data recorded, and that the data represents a complete and accurate record of 
each subject’s participation in the study.  
All CRF entries, corrections, and alterations must be made by the Investigator or designated 
individual. The Investigator or designated individual must adjust the CRF (if applicable) 
and complete the query. 
13.6 Access to Source Documentation 
The Investigator must agree to complete a subject identification and enrolment log to 
permit easy identification of each subject during and after the study. This document will 
be reviewed by the Sponsor site contact for completeness. The subject identification and 
enrolment log will be treated as confidential and will be filed by the Investigator in the 
Investigator Site File. To ensure subject confidentiality, no copy will be made. All reports 
and communications relating to the study will identify subjects by initials and assigned 

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number only. The Investigator must also complete a subject-screening log, which reports 
on all subjects who were seen to determine eligibility for inclusion in the study. 
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; 
explanation of the study and date of informed consent; dates of visits; results of safety and 
efficacy parameters as required by the protocol; record of all AEs; concomitant 
medications; study drug administered; date of study completion or early discontinuation, 
and reason for early discontinuation if applicable. 
13.7 Study Files and Record Retention 
All documents pertaining to the study, including all versions of the approved study 
protocol, copy of the informed consent document and Health Insurance Portability and 
Accountability Act documents, completed CRFs, source documents (subject records, 
hospital records, laboratory records, drug accountability records, etc.), and other study-
related documents will be retained in the permanent archives of the study site. 
The Investigator must therefore notify and obtain approval in writing from the Sponsor 
prior to destruction of any study records or provide an opportunity for the Sponsor to collect 
such records. If the Investigator withdraws from the study (e.g., relocation, retirement) all 
study-related records should be transferred, in a written agreement with the Sponsor, to a 
mutually agreed upon designee within a Sponsor-specified timeframe. 
13.8 Data Generation and Analysis 
13.8.1 
Data Collection and Data Management 
Study specific data that has been outlined in the protocol will be entered into the clinical 
database by individual(s) designated by the Investigator. Data is verified electronically 
using a series of on-line programmed edit checks that have been created by the Clinical 
Data Manager and programmed by the Clinical Data Programmer or Designee. Data 
discrepancies will be brought to the attention of the clinical team and investigated by the 
CRA and site staff. CRAs will review and verify all data collected in the CRF against 
source documentation during scheduled monitoring visits. The CRA will work closely with 
the site staff to address any discrepancies which have been found so that proper resolutions 
can be made and documented in the clinical database. An audit trail within the system will 
track all changes made to the data. 
13.8.2 
Database Quality Assurance 
The clinical database will be reviewed and checked for omissions, apparent errors, and 
values requiring further clarification using computerized and manual procedures. Data 
queries requiring clarification will be generated and addressed by the investigational site. 
Only authorized personnel will make corrections to the clinical database, and all 
corrections will be documented in an audit trail. 

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13.9 Financial Disclosure 
The disclosure of any financial interests from each Investigator or sub-Investigator, 
including financial interests of the spouse and each dependent child of the Investigator who 
is directly involved in the treatment or evaluation of research subjects that could affect the 
reliability of data submitted to regulatory authorities is required for this study. The 
collection of this financial interest information at the start of the study, and at the 
completion of the study and 1 year following study completion, is required by the FDA 
when submitting a marketing application and is in line with the GCP requirement to 
consider any potential conflicts of interest. 

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14 AUDITING AND MONITORING 
In accordance with applicable regulations, GCP, and Sponsor procedures, the clinical 
monitor(s) will periodically contact the site, including conducting on-site visits at intervals 
agreed upon by the Investigator and documented in the Clinical Monitoring Plan and the 
Site Initiation Visit Report.  
The clinical monitor(s) will contact the site prior to the start of the study to discuss the 
protocol and data collection procedures with site personnel. In accordance with applicable 
regulations and GCP guidelines, the Investigator shall make available for direct access all 
study-related records upon request of the Sponsor, the Sponsor’s agents, clinical 
monitor(s), auditors, and/or IRB/IEC. The Sponsor’s monitors will visit the site during the 
study in addition to maintaining frequent telephone and written communication. The 
extent, nature, and frequency of on-site visits will be based on such considerations as the 
study objectives and/or endpoints, the purpose of the study, study design complexity, and 
enrollment rate.  
The Investigator must allow the clinical monitor(s) direct access to all relevant documents 
and to allocate his/her time and the time of his/her staff to the clinical monitor(s) to discuss 
findings and any relevant issues. 

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15 AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, 
may be made only by the Sponsor or their designee. A protocol change intended to 
eliminate an apparent immediate hazard to subjects may be implemented immediately, 
provided the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The 
written amendment must be submitted to the IRB/IEC and the Investigator must await 
approval before implementing the changes. The Sponsor or their designee will submit 
protocol amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the IRB/IEC, the Investigator, and/or the Sponsor, the amendment to 
the protocol substantially changes the study design and/or increases the potential risk to 
the subject and/or has an impact on the subject's involvement as a study participant, the 
currently approved written ICF will require similar modification. In such cases, informed 
consent will be renewed for subjects enrolled in the study before continued participation. 

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16 STUDY REPORT AND PUBLICATIONS 
A clinical study report will be prepared following completion of the study. The report will 
be a record of the total study conduct and will be subject to Sponsor approval and 
restrictions on distribution/disclosure.  
The study data will be owned by the Sponsor. Publication of any and all data will be at the 
discretion of the Sponsor. The Investigator will not disseminate, present, or publish any of 
the study data without the prior written approval of the Sponsor to do so. 

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17 STUDY DISCONTINUATION  
Upon completion of the study, study closeout activities must be conducted by the Sponsor 
or their designee in conjunction with the Investigator, as appropriate. 
In addition, the Sponsor reserves the right to temporarily suspend or prematurely 
discontinue this study at any time and for any reason. If such action is taken, the Sponsor 
will discuss this with the Investigator (including the reason[s] for taking such action) at 
that time. The Sponsor will also inform the regulatory authorities of the suspension or 
termination of the study and the reason(s) for the action. If required by applicable 
regulations, the Investigator must inform the IRB/IEC promptly and provide the reason(s) 
for the suspension or termination. If the study is prematurely discontinued, all study data 
and study drug remaining on site must be returned to the Sponsor or its designee. 

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18 CONFIDENTIALITY 
All subject-identifying documentation generated in this study must be considered 
confidential and must not be disclosed to any persons not directly concerned with the study 
without written permission from the subject. However, authorized regulatory officials and 
Sponsor personnel (or their representatives) will be allowed full access to inspect and copy 
the records. All subject bodily fluids, and/or other materials collected shall be used solely 
in accordance with this protocol and the informed consent signed by the subject, unless 
otherwise agreed to in writing by the Sponsor. 
Each subject will be identified by initials and an assigned subject number when reporting 
study information to any entity outside of the study center. Data containing subject 
identification will not be removed from the study center without subject identifiers having 
been redacted. 
 

 
 

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20.2 APPENDIX II – Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly 
Helsinki, Finland, June 1964 
And amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
And the: 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects. Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people. The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 
The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my subject will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the subject's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the subject." 
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects. 

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In medical research on human subjects, considerations related to the well being of the 
human subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease. Even the best-proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights. Some research populations are vulnerable and need 
special protection. The particular needs of the economically and medically disadvantaged 
must be recognized. Special attention is also required for those who cannot give or refuse 
consent for themselves, for those who may be subject to giving consent under duress, for 
those who will not benefit personally from the research and for those for whom the 
research is combined with care. 
Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 
Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
Investigator, the Sponsor or any other kind of undue influence. This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any SAEs. The researcher should also submit to the committee, for 

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review, information regarding funding, Sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.  
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. The 
responsibility for the human subject must always rest with a subject of the research, even 
though the subject has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed. Physicians should cease any investigation if the risks are found 
to outweigh the potential benefits or if there is conclusive proof of positive and beneficial 
results. 
Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject. This is especially 
important when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 
The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the subject’s information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 

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When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the Investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the Investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee. The protocol should state that consent to remain in 
the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
Both authors and publishers have ethical obligations. In publication of the results of 
research, the Investigators are obliged to preserve the accuracy of the results. Negative as 
well as positive results should be published or otherwise publicly available. Sources of 
funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the subjects who are research subjects. 
The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 

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At the conclusion of the study, every subject entered into the study should be assured of 
access to the best-proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research. The refusal of a subject to participate in a study must never interfere with the 
subject-physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the subject, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician’s judgment it offers hope of saving life, re-establishing 
health or alleviating suffering. Where possible, these measures should be made the object 
of research, designed to evaluate their safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, published. The other relevant guidelines of 
this Declaration should be followed. 

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20.5 APPENDIX V – Masking of the Treated Eye and Performance of the 
Primary Analysis 
The following measures will be applied to keep the integrity of the database: 
• The first masked review of data will be performed as late as possible, once all SAS 
programs are validated for study GS-LHON-CLIN-03A. 
• Data will be cleaned and frozen up to and including the Week 48 visit. 
• The cut-off date for the cleaning of subject visits will be recorded.   
• A snapshot of the cleaned data base will be kept for statistical purposes and for possible 
inspection. The date of the snapshot will be recorded. 
• A procedure will be written to trace data modification after the freeze of the database. 
Modifications will be listed in an appendix. 
• The listing per subject of frozen visits (at least up to Week 48) will be provided and the 
status "ongoing" will be provided for unfrozen visits. 
• A table will indicate the number of subjects with frozen data at each visit (for example 
36/36 subjects at Week 48, 28/36 subjects at Week 72 and 23/36 subjects at Week 96).  
• The masked team in charge of the collection and verification of data will remain 
masked up until the last visit (Week 96) of the last subject.  
• For International coordinating investigators who review the Week 48 study report all 
efforts will be made to maintain their making regarding the individual subject results. 
• Statistical results will be disclosed as late as possible. Date of disclosure will be 
recorded and a second snapshot of the data base will be done at that time. 
• Review of listings of individual data will be restricted to very few people (e.g. for 
pharmacovigilance for safety data). 
• The final masked review (Week 96) will exclude people who had access to unmasked 
individual subject data.  
• No amendment of the SAP will be possible after the break of the randomization code. 
Any addition will be considered a posteriori/ad-hoc analyses.