Conditions: Usher Syndrome Retinitis Pigmentosa
Keywords: Usher Syndrome Retinitis Pigmentosa Usher Syndrome associated Retinitis Pigmentosa
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
To evaluate the safety and tolerability of ascending doses of subretinal injections of SAR421869 in participants with Usher syndrome type 1B.

To evaluate for possible biological activity of SAR421869.

Detailed description:
Following screening procedures, the gene transfer agent were injected once only under the retina by an opthalmic surgeon under anesthesia. Participants then had regular follow-up visits where general health examinations, blood tests and ophthalmic examinations including best corrected visual acuity, slit lamp examination, intraocular pressure, fundoscopy, autofluorescence, optical coherence tomography, perimetry and electroretinogram were undertaken.

At the end of the study, the participants were invited to enter in an open-label safety study for long-term follow-up visits (at least once every six months) including ophthalmological examinations and recording of adverse events (AEs) were continued for 5 years; then the Investigator followed the participants by telephone for a subsequent 10 years at a minimum interval of once a year to monitor delayed AEs.

Arms:
arm 1: Starting dose of SAR421869 given through one subretinal injection. arm 2: Escalating dose of SAR421869 given through one subretinal injection. arm 3: Escalating dose of SAR421869 given through one subretinal injection. arm 4: Maximum tolerated dose (MTD) of SAR421869 given through one subretinal injection. arm 5: MTD of SAR421869 given through one subretinal injection.

Interventions: intervention 1: SAR421869
Intervention descriptions: intervention 1: Formulation: Sterile suspension for intraocular injection, 100 microliters (μL) aliquots in 0.3 milliliter (mL) type I borosilicate glass 'V' vials with a butyl stopper and aluminum crimp seal.

Route of administration: subretinal injection

Protocol document:
Prot_000.pdf: 
Property of the Sanofi Group - strictly confidential
Page 1
Amended Clinical Trial Protocol 08
US1/001/10 - Study TDU13600
IND number: 14846
EudraCT number: 2012-002574-31 - NCT number: NCT01505062
A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR421869, 
Administered to Patients with Retinitis Pigmentosa Associated with Usher 
Syndrome Type 1B
In France:
Sanofi-Aventis Recherche & Développement
1 avenue Pierre Brossolette
91380 Chilly-Mazarin (France)
In the US:
Sanofi US Services Inc.
55 Corporate Drive
Bridgewater, NJ 08807 (US)
MEDICAL MONITOR
This confidential document is the property of Sanofi Group. No unpublished information contained herein may be disclosed without 
the prior written approval of Sanofi Group.
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NAMES AND ADDRESSES OF
COORDINATING 
INVESTIGATOR
Name:
Address:
Tel:
Fax:
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE
Name:
Address:
Tel:
Fax:
E-mail:
SPONSOR
Company:
Address:
sanofi-aventis R&D
1 Avenue Pierre Brossolette
91380 Chilly-Mazarin
France
OTHER EMERGENCY 
TELEPHONE NUMBERS
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DOCUMENT HISTORY
Document
Country-
specificity if 
applicable
Date, version
Amended Protocol 8
07 August 2018, Version 1 (electronic 3.0)
Amended Protocol 7
23 September 2015, Version 7 (electronic 2.0)
Amendment 7
23 September 2015, Version 1 (electronic 1.0)
Amended Protocol 6
22 April 2015, Version 6
Amendment 6
22 April 2015, Version 1
Amended Protocol 5
14 April 2014, Version 5 (electronic 1.0)
Amendment 5
14 April 2014, Version 1
Amended Protocol 4
14 April 2014, Version 4 (electronic 2.0)
Amendment 4
22 January 2014, Version 1 (electronic 1.0)
Amended Protocol 3
31 January 2013, Version 3
Amendment 3
31 January 2013, Version 1 
Amended Protocol 2
31 August 2012, Version 2 
Amendment 2
31 August 2012, Version 1 
Amended Protocol 1
20 October 2011, Version 1
Amendment 1
20 October 2011, Version 1 
Original Protocol
23 August 2011, Version 1 (electronic 1.0)
Amended Protocol 8 07 August 2018
This amended protocol is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
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OVERALL RATIONALE FOR THE AMENDMENT
Summary of main changes:

Additional 6 patients added to Part A (dose finding) to test additional dose levels
Rationale: Due to variability observed in previous batch strength, patients in Cohort 3 have 
received different doses when calculated by measured strength. While strength remained 
within specification, one patient has received 0.33x106 TU/eye dose, while the two 
following patients (treated with a new batch) received 2.4x106 TU/eye dose. Following 
DSMB review additional safety data in Part A was requested. Next two dose levels based 
on dilution from the measured batch strength will be investigated. This will provide 
additional safety information and improve dose selection for Parts B and C. 

Adding mention of a diluent for IMP 
Rationale: dilution is needed to administer above mentioned additional dose levels.

Inclusion criteria modified to better define target population
Rationale: Following new natural history data and DSMB recommendations, BCVA 
lowest threshold and minimal EZ zone area is added in order to select patients with some 
residual photoreceptor zone and some visual function, who could benefit more from 
treatment. ERG is removed from inclusion criteria since it does not appear to provide 
additional benefit for selection of the target population.

Prophylactic glucocorticoid schedule added as mandatory after surgery and IMP injection
Rationale: anti-inflammatory regimen is added to decrease the risk of intraocular 
inflammation following the subretinal injection procedure. This modification is agreed 
with DSMB following two cases of uveitis classified as serious adverse events following 
subretinal injection of lentiviral vectors (one case in this study, the other with another 
project using the same lentiviral vector technology). The DSMB, in agreement with study 
Investigators, reviewed the cases and recommended the modification of the protocol with 
regard to glucocorticoids in order to reduce the occurrence of post-operative ocular 
inflammation. 

Additional list of ophthalmic AESIs added for better safety.
Rationale: additional list of ophthalmic AESIs will permit early reception of these safety 
events in sponsor’s safety database, with more detailed data reported. This will ensure 
earlier monitoring for potential safety signals.  

Simplifying retinotomy description
Rationale: this will allow better adaptation of retinotomy and IMP injection to individual 
patients, with respect to lesion size and target retinal areas.

Correction of baseline definition:
Rationale: definition of baseline was provided to use the data most close to the treatment 
for more precise evaluation of treatment-emergent safety events and efficacy signals
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Other minor changes are also implemented to facilitate operational conduct, clarify or eliminate 
inconsistencies.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
Whole document
UshStat / UshStat® replaced with SAR421869
UshStat® was previous name.
DOCUMENT HISTORY
Added, including a table and the sentence 
stating the amendment is substantial.
Template applied.
OVERALL RATIONALE FOR THE 
AMENDMENT
Added, for Amendment 8.
Template applied.
Section 17 APPENDICES
Appendix E added: History of protocol 
amendments. Summary of rationales for 
previous amendments moved to Appendix E 
(were at the beginning, before table of contents).
Template applied.
Section 1 SYNOPSIS + Section 6.2 
SECONDARY ENDPOINTS + 
Section 9.3.3 Screening Clinical and 
Laboratory/Diagnostic Measurements 
Day -28 + Section 9.3.4 Baseline Clinical 
Laboratory/Diagnostic Measurements 
Day -1 + Section 9.3.7 Follow-up 
Procedures
Section 9.3.11.2 Contrast sensitivity
Section 17 APPENDICES
Section 9.3.11.11 Visual Function 
Questionnaire (VFQ-25)
Secondary (Biological Activity) Endpoints:
- ‘Contrast sensitivity’ added
- ‘CVAQC (when possible)’ added to endpoint 
‘Visual function questionnaire VFQ 25’.
Additional section (refer to Appendix D).
Appendix D added: Low-Contrast Sloan Letter 
Chart Testing.
Details on CVAQC added.
For better biological activity evaluation.
Section 1 SYNOPSIS (Study design, 
Study dosing schedule, and Study 
population) + Section 7 STUDY DESIGN
+ Section 8 STUDY POPULATION
Number of patients in cohorts of Part A and 
Part B; dose by measured strength added for 
Part A; number of patients to complete the 
study.
Additional patients to test additional dose levels 
based on dilution from the measured batch 
strength; to provide additional safety 
information and improve dose selection for 
Parts B and C.
Section 2 STUDY SCHEDULE
Section 3 STUDY DIAGRAM
Additional table for Cohorts 3b, 3c, 4, and 5.
Diagram changed.
Clarification and consistency.
Section 4.4 SAR421869 DRUG 
DEVELOPMENT
Section 9.2.4 SAR421869 preparation
Section 10 STUDY MATERIALS
10.1 SAR421869; 10.1.1 Packaging and 
Labelling; 10.1.2 Storage and Disposition 
of Study Medications
Diluent added in components, specification on 
dilution.
One sentence deleted.
Specifications added.
For dilution (measured batch strength).
Details provided in Pharmacy manual.
For dilution.
Section 1 SYNOPSIS (Study design, 
Study dosing schedule)
Section 4.12 RATIONALE FOR DOSING 
INTERVALS
Section 4.14 RATIONALE FOR 
INCLUSION OF CHILDREN AND 
ADOLESCENTS
Precision of age of pediatric patients in Part C.
Number of patients of Cohort 4 (Part B) -
Precision of age of pediatric patients in Part C.
Number of patients of Cohort 4 (Part B).
Clarification.
Section 6 ENDPOINTS (1st paragraph)
Specification on baseline (before surgery).
Definition of baseline to use the data most 
close to the treatment for more precise 
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Section # and Name
Description of Change
Brief Rationale
evaluation of safety and efficacy.
Section 1 SYNOPSIS + Section 8.2 
ENTRY CRITERIA
Entry criteria: 2 inclusion criteria added for all 
cohorts; specific inclusion criteria added for 
Cohorts 3b and 3c (Part A), Cohort 4 (Part B), 
and Cohort 5 (Part C).
Specific inclusion criteria to better define target 
population (to select patients with some 
residual photoreceptor zone and some visual 
function; ERG removed from inclusion criteria).
Section 9.2.2 Intraocular injection + 
Section 9.2.3 Positioning the subretinal 
bleb
Details on retinotomy provided in study manuals.
Better adaptation of retinotomy and IMP 
injection.
Section 9.2.2 Intraocular injection + 
Section 9.3.13 Postsurgical 
ophthalmological adverse events
Specifications on prophylactic glucocorticoid 
schedule added, wording of anti-inflammatory 
protocol adapted.
Modification with regard to glucocorticoids in 
order to reduce the occurrence of postoperative 
ocular inflammation.
Section 9.3.5 Re-screening
Additional section.
To facilitate operational conduct.
Section 9.3.11.1 Best-Corrected Early 
Treatment Diabetic Retinopathy Study 
(ETDRS) Visual Acuity
Addition of ETDRS testing as back-up of EVA 
(electronic visual acuity) testing.
To facilitate operational conduct.
Section 11.5 ADVERSE EVENTS OF 
SPECIAL INTEREST + Table ‘Summary 
of adverse event reporting instructions’ in 
Section 11.6 GENERAL GUIDELINES 
FOR REPORTING ADVERSE EVENTS
AESIs added.
Additional list of ophthalmic AESIs added for 
better safety.
Section 13 DATA MANAGEMENT AND 
STATISTICAL ANALYSES
13.4 SAFETY ENDPOINTS 
13.4.1 Adverse events
Addition of a specific grouping for ocular 
inflammatory events.
For better safety evaluation.
Section 13 DATA MANAGEMENT AND 
STATISTICAL ANALYSES 
13.6 OTHER MEASURES 
13.6.2 Withdrawals
One sentence deleted.
Consistency.
Section 1 SYNOPSIS + Section 13.7 
INTERIM ANALYSIS STATISTICAL 
ANALYSES SPECIFIC TO THE DSMB 
MEETINGS
Specifications on interim analyses.
Clarification.
Throughout
Minor editorial and document formatting 
revisions.
Minor, therefore have not been summarized.
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TABLE OF CONTENTS
TABLE OF CONTENTS..................................................................................................................................7
LIST OF ABBREVIATIONS..........................................................................................................................12
INVESTIGATOR STATEMENT ....................................................................................................................14
1
SYNOPSIS.....................................................................................................................................15
2
STUDY SCHEDULE ......................................................................................................................21
2.1
FOR COHORTS 1-3A....................................................................................................................21
2.2
FOR COHORTS 3B, 3C, 4, 5 ........................................................................................................23
3
STUDY DIAGRAM.........................................................................................................................25
4
INTRODUCTION AND RATIONALE.............................................................................................26
4.1
CLINICAL PATHOLOGY ...............................................................................................................27
4.2
DIAGNOSIS AND MONITORING OF USHER SYNDROME TYPE 1B ........................................28
4.3
PHARMACOLOGICAL TREATMENT............................................................................................29
4.4
SAR421869 DRUG DEVELOPMENT............................................................................................30
4.5
SUMMARY OF PROOF OF PRINCIPLE NONCLINICAL STUDIES.............................................31
4.6
RATIONALE FOR STUDY.............................................................................................................32
4.7
RATIONALE FOR SAR421869......................................................................................................32
4.8
RATIONALE FOR INJECTION INTO THE EYE............................................................................33
4.9
RATIONALE FOR PROPOSED SUBRETINAL INJECTION SITE................................................33
4.10
RATIONALE FOR UNILATERAL ADMINISTRATION...................................................................34
4.11
RATIONALE FOR THE CLINICAL DOSE .....................................................................................34
4.12
RATIONALE FOR DOSING INTERVALS......................................................................................35
4.13
RATIONALE FOR TARGET PATIENT POPULATION..................................................................36
4.14
RATIONALE FOR INCLUSION OF CHILDREN AND ADOLESCENTS .......................................38
5
OBJECTIVES ................................................................................................................................40
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5.1
PRIMARY OBJECTIVE..................................................................................................................40
5.2
SECONDARY OBJECTIVE ...........................................................................................................40
6
ENDPOINTS ..................................................................................................................................41
6.1
PRIMARY ENDPOINT ...................................................................................................................41
6.2
SECONDARY ENDPOINTS ..........................................................................................................41
7
STUDY DESIGN ............................................................................................................................43
8
STUDY POPULATION ..................................................................................................................45
8.1
PATIENT RECRUITMENT.............................................................................................................45
8.2
ENTRY CRITERIA .........................................................................................................................45
8.3
WITHDRAWAL CRITERIA.............................................................................................................49
8.4
STUDY STOPPING CRITERIA .....................................................................................................50
8.5
DOSE-LIMITING TOXICITIES .......................................................................................................50
9
TREATMENT PLAN AND METHODS ..........................................................................................51
9.1
ALLOCATION OF TREATMENTS.................................................................................................51
9.2
STUDY MEDICATION ADMINISTRATION ...................................................................................51
9.2.1
Hospitalization................................................................................................................................51
9.2.2
Intraocular Injection........................................................................................................................51
9.2.3
Positioning of the Subretinal Bleb..................................................................................................53
9.2.4
SAR421869 Preparation ................................................................................................................53
9.2.5
SAR421869 Administration............................................................................................................53
9.2.6
Post-Surgical Monitoring................................................................................................................54
9.2.7
Concurrent Treatments ..................................................................................................................54
9.2.8
Study Conduct Specific to Children and Adolescents....................................................................54
9.3
SPECIFIC PROCEDURES ............................................................................................................55
9.3.1
Screening/Baseline Procedures.....................................................................................................55
9.3.2
Screening Clinical and Laboratory/Diagnostic Measurements ......................................................56
9.3.3
Screening Clinical and Laboratory/Diagnostic Measurements Day -28 ........................................56
9.3.4
Baseline Clinical Laboratory/Diagnostic Measurements Day -1....................................................57
9.3.5
Re-screening..................................................................................................................................58
9.3.6
Surgery...........................................................................................................................................58
9.3.7
Follow-up Procedures ....................................................................................................................58
9.3.7.1
Follow-up Day 1 Clinical and Laboratory/Diagnostic Measurements ............................................58
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9.3.7.2
Follow-up Week 1, 2, 4, 12, 24 and 48 Clinical and Laboratory/Diagnostic Measurements .........59
9.3.8
Samples for PCR ...........................................................................................................................60
9.3.9
Samples for Immunology ...............................................................................................................60
9.3.10
Future Use of Samples ..................................................................................................................60
9.3.11
Ophthalmological Assessments.....................................................................................................60
9.3.11.1 Best-Corrected Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity..................61
9.3.11.2 Contrast sensitivity.........................................................................................................................61
9.3.11.3 Slit-Lamp Examination ...................................................................................................................61
9.3.11.4 Fundoscopy....................................................................................................................................61
9.3.11.5 Intraocular Pressure Measurement................................................................................................61
9.3.11.6 Optical Coherence Tomography....................................................................................................61
9.3.11.7 Fundus Photography......................................................................................................................62
9.3.11.8 Electroretinogram...........................................................................................................................62
9.3.11.9 Perimetry........................................................................................................................................63
9.3.11.10Autofluorescence Imaging .............................................................................................................63
9.3.11.11Visual Function Questionnaire (VFQ-25).......................................................................................64
9.3.12
Medication, Adverse Event and Concomitant Medication Review ................................................64
9.3.13
Post-surgical ophthalmological adverse events.............................................................................64
9.3.14
Clinical Laboratory Tests ...............................................................................................................65
9.4
FLEXIBILITY OF ASSESSMENT DATA CAPTURE .....................................................................66
10
STUDY MATERIALS.....................................................................................................................67
10.1
SAR421869....................................................................................................................................67
10.1.1
Packaging and Labelling................................................................................................................67
10.1.2
Storage and Disposition of Study Medications ..............................................................................68
10.1.3
Precautions/Overdose ...................................................................................................................68
10.2
OTHER STUDY SUPPLIES...........................................................................................................68
11
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY REPORTING.......................69
11.1
ADVERSE EVENT DEFINITION ...................................................................................................69
11.2
RELATIONSHIP OF AN ADVERSE EVENT TO THE STUDY DRUG/PROTOCOL 
PROCEDURE ................................................................................................................................69
11.3
SEVERITY OF AN ADVERSE EVENT..........................................................................................70
11.4
SERIOUS ADVERSE EVENT DEFINITION ..................................................................................70
11.5
ADVERSE EVENTS OF SPECIAL INTEREST .............................................................................71
11.6
GENERAL GUIDELINES FOR REPORTING ADVERSE EVENTS ..............................................73
11.6.1
Instructions for reporting serious adverse events ..........................................................................73
11.6.2
Guidelines for reporting adverse events of special interest...........................................................74
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11.6.3
Guidelines for management of specific laboratory abnormalities ..................................................74
11.7
OBLIGATIONS OF THE SPONSOR .............................................................................................75
11.8
WITHDRAWALS DUE TO ADVERSE EVENTS............................................................................75
11.9
POST-MORTEM ............................................................................................................................76
12
DATA SAFETY MONITORING BOARD .......................................................................................77
12.1
ROLE .............................................................................................................................................77
12.2
RESPONSIBILITIES ......................................................................................................................77
12.3
ANNUAL SAFETY REPORTS.......................................................................................................77
13
DATA MANAGEMENT AND STATISTICAL ANALYSES............................................................78
13.1
SAMPLE SIZE ESTIMATES ..........................................................................................................78
13.2
STATISTICAL ANALYSES ............................................................................................................78
13.3
INTERIM ANALYSIS......................................................................................................................78
13.4
SAFETY ENDPOINTS ...................................................................................................................78
13.4.1
Adverse Events..............................................................................................................................78
13.4.2
Ophthalmological Safety Endpoints...............................................................................................79
13.4.3
Secondary Endpoints.....................................................................................................................79
13.4.4
Immunology Endpoint ....................................................................................................................79
13.4.5
Laboratory Parameters ..................................................................................................................79
13.4.6
Other Safety Parameters ...............................................................................................................79
13.4.7
Concomitant Medication ................................................................................................................79
13.5
BIODISTRIBUTION ENDPOINT....................................................................................................80
13.6
OTHER MEASURES .....................................................................................................................80
13.6.1
Patient Characteristics ...................................................................................................................80
13.6.2
Withdrawals....................................................................................................................................80
13.6.3
Deaths............................................................................................................................................80
13.7
INTERIM ANALYSIS STATISTICAL ANALYSES SPECIFIC TO THE DSMB MEETINGS ..........80
13.8
CASE REPORT FORMS AND DATA COLLECTION....................................................................81
13.9
DOUBLE-BLIND CODES...............................................................................................................81
13.10
CRITERIA FOR TERMINATION OF THE TRIAL ..........................................................................81
14
ETHICAL CONSIDERATIONS......................................................................................................82
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14.1
PATIENT INFORMATION LEAFLETS AND INFORMED CONSENT FORMS.............................82
14.2
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD REVIEW...........................................82
15
REGULATORY REQUIREMENTS AND SPONSOR/INVESTIGATOR OBLIGATIONS .............84
15.1
STUDY INITIATION .......................................................................................................................84
15.2
MONITORING................................................................................................................................84
15.3
DOCUMENTATION AND RECORD KEEPING.............................................................................85
15.4
CLINICAL STUDY REPORT..........................................................................................................85
15.5
TERMINATION OF THE STUDY...................................................................................................85
15.6
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
REQUIREMENTS ..........................................................................................................................86
15.7
PUBLICATION AND COMMUNICATION ......................................................................................86
15.8
PROTOCOL AMENDMENTS ........................................................................................................86
16
REFERENCES...............................................................................................................................87
17
APPENDICES................................................................................................................................91
APPENDIX A
OCULAR INFLAMMATION GRADING................................................................................92
APPENDIX B
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI ..................................94
APPENDIX C
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES   BY SANOFI....................................................................................................99
APPENDIX D
LOW-CONTRAST SLOAN LETTER CHART TESTING...................................................104
APPENDIX E
HISTORY OF PROTOCOL AMENDMENTS.....................................................................107
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LIST OF ABBREVIATIONS
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
AMD:
age related macular degeneration
AST:
aspartate aminotransferase
BCVA:
best-corrected visual acuity
BP:
blood pressure
BUN:
blood urea nitrogen
cDNA:
complimentary deoxyribonucleic acid
CFR:
code of federal regulations
CHOL:
cholesterol
CPK:
creatinine phosphokinase
CRF:
case report form
CRO:
contract research organization
CS:
clinically significant
CVAQC:
cardiff visual ability questionnaire for children
DSMB:
data safety monitoring board
EC:
Ethics Committee
ECG:
electrocardiogram
EIAV:
equine immune anemia virus
ERG:
electroretinogram
EVA:
electronic visual acuity
EZ:
ellipsoid zone
FAF:
fundus autofluorescence
FDA:
U.S Food and Drug Administration
FIM:
first in man
GATE:
german adapting thresholding estimation
GCP:
good clinical practice
GGT:
gamma glutamic transpeptidase
GLP:
good laboratory practice
HCT:
hematocrit
HGB:
hemoglobin
HIV:
human immunodeficiency virus
HR:
heart rate
ICH:
International Conference on Harmonization
IMP:
Investigational Medicinal Product
IOP:
intraocular pressure
IRB:
International Review Board
ISCEV:
International Society for Clinical Electrophysiology of Vision
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LDH:
lactate dehydrogenase
MCH:
mean corpus hemoglobin
MCV:
mean corpus volume
MTD:
maximum tolerated dose
MYO7A:
myosin 7a gene
NCS:
not clinically significant
NEI:
national eye institute
NHP:
non human primate
OCT:
optical coherence tomography
OXB:
oxford biomedica ltd
PCR:
polymerase chain reaction
PI:
principal investigator
PT:
prothrombin time
PTT:
partial prothrombin time
RBC:
red blood cells
RDW:
red cell distribution width
RP:
retinitis pigmentosa
RPE:
retinal pigment epithelium
RPE-65:
retinal pigment epithelium protein - 65
SAE:
serious adverse event
SD-OCT:
spectral domain OCT
SITA:
swedish interactive thresholding algorithm
SKP:
semi-automated kinetic perimetry
SUSAR:
suspected unexpected serious adverse reaction
TBIL:
total bilirubin
TP:
total protein
TU:
transducing unit
USA:
United States of America
USH1B:
usher syndrome type 1b
VFQ-25:
visual function questionnaire -25
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INVESTIGATOR STATEMENT
I am aware of my responsibilities as an investigator under the guidelines of ICH-Good Clinical 
Practice, The Declaration of Helsinki, the Code of Federal Regulations, Title 21, the applicable 
regulations of the study site and the study protocol and I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control who will be 
involved in the study, ensuring they have access to the study protocol and any amendments and 
are aware of their obligations.
I, the undersigned, have read and agree with protocol number US1/001/10 - TDU13600.
Signed
Name 
Date
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1
SYNOPSIS
Official Title
A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected SAR421869, Administered to 
Patients with Retinitis Pigmentosa Associated with Usher Syndrome Type 1B
Clinical Phase
I/IIa
Study Objectives
Primary Objectives
To evaluate the safety and tolerability of ascending doses of subretinal injections of SAR421869 in 
patients with Usher syndrome Type 1B.
Secondary Objective
To evaluate for possible biological activity of SAR421869.
Study Endpoints
Primary Safety Endpoints
The incidence of adverse events over a 12-month period following a single intraocular dose of 
SAR421869.
Clinically important changes from baseline in the following safety assessments.

Best-corrected visual acuity (BCVA).

Slit-lamp examination.

Indirect ophthalmoscopy.

Fundus photography.

Intraocular Pressure (IOP).

Optical Coherence Tomography (OCT).

Laboratory parameters.

Vital signs.

Concomitant medications.

Physical examinations.
Secondary (Biological 
Activity) Endpoints
To determine a delay in retinal degeneration following subretinal injection of SAR421869, through 
changes in function relative to the untreated contralateral eye utilizing the following retinal 
analytical techniques:

Best-corrected visual acuity (BCVA).

Contrast sensitivity.

Indirect ophthalmoscopy.

Visual function questionnaire VFQ-25 / CVAQC (when possible).

Full dilated slit-lamp examination.

Fundus photography - Pan-retinal photomontage.

Visual field testing: Semi-automated Kinetic Perimetry (SKP) and Full-Field German 
Adaptive Thresholding Estimation (GATE) Static Perimetry, and microperimetry.

Autofluorescence.

Electroretinogram (ERG).

Optical coherence tomography (OCT).
Other Endpoints

SAR421869 distribution in the blood and urine assessed by polymerase chain reaction 
(PCR).

Humoral antibody response to SAR421869 administration.

Hematology, biochemistry, urinalysis and other laboratory data will be measured at 
various time points throughout the study.
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Study Design
This is a Phase I/IIa open label dose escalation study of subretinally injected SAR421869 in patients with retinitis pigmentosa (RP)
associated with Usher Syndrome Type 1B. In this study at least three doses of SAR421869 will be evaluated over five patient 
cohorts. The study is separated into a dose escalation phase, Part A, followed by a two part dose extension phase at the maximum 
tolerated dose, Parts B and C.
Part A will evaluate at least 3 ascending dose levels of SAR421869, in 300 L of vehicle. A total of at least 15 patients ≥18 years of 
age will be entered: 3 patients in Cohorts 1 and 2 and at least 9 patients in Cohort 3. An interval of 21 days between dosing the first 
and subsequent patients will be observed in Cohorts 1-3 in order to assess the safety. If DSMB requires additional patients – total 
up to 24 may be included in Part A.
After dosing the last patient in each of the first three cohorts, the patients will be followed for 28 days to ensure there are no 
dose-limiting toxicities. If after a minimum interval of 28 days from dosing the last patient of the previous cohort, the safety and 
tolerability is considered satisfactory by the DSMB, then patients in the next cohort will be dosed.
If the safety and tolerability of SAR421869 is considered satisfactory by the DSMB in Part A of the study, the study will proceed to 
Part B.
In Part B (Cohort 4), 6 patients ≥18 years of age will be treated at the maximum tolerated dose (MTD) determined from Part A, to 
further characterize the risk: benefit profile of SAR421869. These patients will be enrolled in parallel.
Part C (Cohort 5) provides the opportunity to extend the study to include pediatric patients 6-17 years of age treated at the MTD. 
Prior to the inclusion of pediatric patients, the DSMB will review all safety data including the data from Part B, three months after all 
6 patients in cohort 4 have been dosed. An interim report including all available safety data, preliminary efficacy data and the 
recommendations from the DSMB will be submitted to the regulatory authorities and institutional review boards/ethics committees 
for review, before up to 6 patients 6-17 years will be included in Part C of the study (Cohort 5).
All patients will be followed for 48 weeks. After this period they will enter an open-label safety study for long-term follow-up. Patients 
will attend visits at a minimum interval of one visit every 6 months for assessments that will include ophthalmological examinations 
and recording of adverse events for 240 weeks (5 years).
In addition, the investigator will conduct visits/contact the patient by telephone for a subsequent 10 years at a minimum interval of 
once a year to monitor delayed adverse events.
In the event that a patient dies during the study then consent for post-mortem will be sought from the patient’s family. In the event 
of development of an infection that is classified as an important medical event, particularly any opportunistic infection or onset of an 
autoimmune condition, effort will be made to collect data regarding the infectious agent and the outcome of the relevant 
investigations to characterize the autoimmune disease.
Study Dosing Schedule
Part A
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector total dose per eye
Volume
  by target 
strength
(TU/eye )*
by measured 
strength
(TU/eye )**
1
≥18
3
1.4x105
2.1x104
300 µL
2
≥18
3
4.7x105
1.1x105
300 µL
3a
≥18
1
1.4x106
0.33x106
300 µL
3a
≥18
2 
1.4x106
2.4x106
300 µL
3b
≥18
3 
-
0.33x106
300 µL
3c
≥18
3
-
1.4x106
300 µL
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Part B
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector total dose per eye
Volume
4
≥18
Up to 6
MTD
300 µL
Part C
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector total dose per eye
Volume
5
      6-17
Up to 6
MTD
300 µL
Note: * dose as calculated from target product strength; ** dose as calculated from dilution (as applicable) of measured strength
Study Population
All patients must have a clinical and molecular diagnosis of RP caused by MYO7A mutations.
The results of the gene mutation analysis will be collected in the study database provided that written results are made available to 
the site, and participants (patients and/or the patient’s parent[s]/legal guardian[s]) would give consent to record the results. Twenty 
seven to 36 patients will complete the study. The protocol accommodates the possibility of several screen failures due to the 
rigorous inclusion and exclusion criteria. It is anticipated that up to three additional patients may need to be enrolled during the 
study to replace those who fail to complete the first six months of follow-up appointments.
Entry Criteria
Main Inclusion Criteria
For the purpose of this study 1 month is equivalent to 28 days.
Patients must meet ALL of the following criteria to be considered for enrolment into this study.

Signed and dated written informed consent must be obtained from the patient (or assent in the case of minors from their 
legal guardian/representative), in accordance with the local regulations.

Clinical and molecular diagnosis of Retinitis Pigmentosa associated with Usher syndrome Type 1B, caused by at least 
one pathogenic MYO7A mutation on both alleles, confirmed by direct sequencing and co-segregation analysis within the 
patient’s family.

Patients must have suitable verbal, auditory and/or tactile sign language communication (in the opinion of the 
investigator) as to allow written informed consent to be obtained.

Females of childbearing potential must have a negative urine pregnancy test at screening and at baseline, and agree to 
use an effective form of contraception such as the contraceptive pill or intra uterine device for at least three months 
following SAR421869 administration, or be surgically sterile or postmenopausal, with the last menstrual period being over 
two years prior to enrolment.

Males of reproductive potential must agree with their partner to use two forms of contraception, including one barrier 
method for at least three months following SAR421869 administration if their partner is of childbearing capacity, or must 
be surgically sterile.

Patients enrolled in France must be affiliated to or benefit from a social security regimen. 

Patients must agree to not donate blood, organs, tissues or cells for at least three months following SAR421869 
administration.
Part A
Specific Inclusion Criteria Cohorts 1, 2 and 3a

≥18 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye equating to a horizontal visual field 
diameter of ≤20 degrees, measured through the center of the visual field grid. The visual field constriction will be 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 08
07-Aug-2018
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Version number: 1
Property of the Sanofi Group - strictly confidential
Page 18
measured by Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed by centralized 
independent assessment of the SKP data.

No detectable rod-derived amplitudes on the full field electroretinogram performed to ISCEV standards.
Specific Inclusion Criteria Cohorts 3b and 3c

≥18 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye equating to a horizontal visual field 
diameter of ≤20 degrees, measured through the center of the visual field grid. The visual field constriction will be 
measured by Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed by centralized 
independent assessment of the SKP data.

Patients with a baseline BCVA >20/200 in both eyes.

Patients with subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm (in any dimension on OCT 
evaluation).

All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform 
required study procedures as judged and confirmed by the study Investigator.
Part B
Specific Inclusion Criteria Cohort 4

≥18 years of age

Concentric constriction of kinetic visual field centrally in the worse seeing-eye equating to a horizontal visual field 
diameter of ≤20 degrees, measured through the center of the visual field grid. The visual field constriction will be 
measured by Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed by centralized 
independent assessment of the SKP data.

Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from normal sensitivity volume (decibel-
steradian) on full-field GATE Static Perimetry using the size V (1.7°) test target. The percentage reduction in normal 
sensitivity volume will be confirmed by centralized independent assessment of the data.

Patients with a baseline in both eyes BCVA >20/200.

Patients with subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm (in any dimension on OCT 
evaluation).

All eligible patients must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform 
required study procedures as judged and confirmed by the study Investigator.
Part C
Specific Inclusion Criteria Cohort 5

6-17 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye equating to a horizontal visual field 
diameter of ≤20 degrees, measured through the center of the visual field grid. The visual field constriction will be 
measured by Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed by centralized 
independent assessment of the SKP data.

Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from normal sensitivity volume (decibel-
steradian) on full-field GATE Static Perimetry using the size V (1.7°) test target. The percentage reduction in normal 
sensitivity volume will be confirmed by centralized independent assessment of the data.

Patients with a baseline BCVA >20/200.

Patients with subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm (in any dimension on OCT 
evaluation).

All eligible patients must demonstrate an ability to understand, reasonably well cooperate to perform required study 
procedures as judged and confirmed by the study Investigator.
Exclusion Criteria
ANY one of the following will exclude patients from being enrolled into the study:

Presence of significant ocular abnormalities in the study eye that in the opinion of the investigator would preclude the 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 08
07-Aug-2018
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planned surgery, effective safety follow-up, or interfere with the interpretation of study endpoints (eg, glaucoma, corneal 
or significant lens opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization).

Any pre-existing factor or past history of eye disease in children that may predispose to an increased risk of surgical 
complications in the study eye (eg, trauma, previous surgery, uveitis, congenital, developmental or structural 
abnormalities).

Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter 
ocular function (eg, malignancies, diabetes, juvenile rheumatoid arthritis or sickle-cell disease).

Any ocular surgery including laser and cataract surgery with intraocular lens implantation, aphakia or prior vitrectomy, in 
the study eye within 6 months of screening.

Any contraindication to pupil dilatation in either eye.

Treatment with intravitreal, subtenon, or periocular steroid within 4 months of the screening visit.

Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study (eg, fluorescein, 
dilation drops), or medications planned for use during the peri-operative period, particularly topical, injected or systemic 
corticosteroids.

Life-threatening illness.

Alcohol or other substance abuse.

Laboratory test abnormalities or abnormalities in electrocardiogram or chest X-ray that, in the opinion of the principal 
investigator, are clinically significant and would make the patient unsuitable for participation in the study.

Intercurrent illness or infection 28 days prior to SAR421869 administration.

Contraindications to use of anesthesia (local or general, as appropriate).

Concurrent anti-retroviral therapy that would inactivate the investigational agent.

Pre-menopausal or non-surgically sterile women who are unwilling to use an effective form of contraception such as the 
contraceptive pill or intrauterine device.

Pregnant or breastfeeding women.

Males or females who do not agree to use barrier contraception as specified in the inclusion criteria.

History of any investigational agent within 28 days prior to SAR421869 administration.

Participation in a prior gene transfer therapy study.

Enrolment in any other clinical study, for any condition, including those relating to Usher syndrome Type 1B, throughout 
the duration of the SAR421869 study.

Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks 
prior to surgery.

Long term treatment with systemic corticosteroids within 28 days prior to the screening visit or ongoing systemic 
corticosteroid treatment at screening or on Day -1.

Current treatment with immunosuppressant therapies.

A history of malignancy within a five year period or have had a positive cancer screening test within a one year period of 
the screening visit.

Past medical history of HIV, or hepatitis A, B or C.

Inability to comply with the study protocol.
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Amended Clinical Trial Protocol 08
07-Aug-2018
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Statistical Analysis
This is an exploratory study, the primary objective of which is to evaluate safety and estimation of biological activity effects. No 
formal sample size calculation has been performed.
Due to a small number of patients enrolled in this study, the data will be analyzed by descriptive statistics and exploratory figures. A 
statistical analysis plan will be finalized prior to database lock. It is envisaged that analyses will be performed on all available data. 
BCVA and perimetry measurements are subject to broad intra-individual variability. The baseline value used for statistical analysis 
of these measures will be an average of all values obtained before surgery.
Interim Analysis
No formal interim analysis is planned in this study. A review of data will be conducted on all available safety data and any available 
preliminary efficacy/activity data up to the 3-month time point for Cohort 4 patients. This review, consisting of descriptive statistics 
and exploratory figures will be used to provide data to the regulatory authorities and IRB/ethics committees before pediatric patients 
are enrolled in Cohort 5. Formal statistical tests will not be performed as part of this analysis.
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2
STUDY SCHEDULE 
2.1
FOR COHORTS 1-3A
Pre-SAR421869
Days
Weeks
-28
-1
0
Day 1
1
2
4
12
24
36
48k
Surgery
Visit Windows
+10 days
-7 days
N/A
N/A
±3 days
±3 days
±3 days
±14 days
±14 days
±14 days
±14 days
SAR421869 administration
X
Entry Criteria
X
Informed consent/assent
X
Medical history
X
Concomitant medication 
X
X
X
X
X
X
X
X
X
X
X
Anesthesia assessment
X
Height
X
Weight
X
Vital signs c
X
X
X
X
X
X
X
X
X
X
X
ECG
X o
Chest X-ray
X o
Physical examination
X
X
Ophthalmological examination
BCVA a
X
X
X
X
X
X
X
X
X
X
Slit lamp examination
X
X
X
X
X
X
X
X
X
X
Intraocular pressure
X
X
X
X
X
X
X
X
X
X
Fundoscopy
X
X
X
X
X
X
X
X
X
X
Autofluorescence
X
X
X
X
X
OCT p
X
X
X
X
X
X
X
X
X
X
Perimetry  (SKP, GATE, microperimetry)a
X m
X n
X
X
X
X
X
X
Fundus photography b
X
X
X
X
X
X
X
X
Multifocal and full Field ERG
X
X
X
VFQ-25
X o
X o
Hematologyd
X
X o
X o
X o
X o
X o
Chemistry panele
X
X o
X o
X o
X o
X o
Kidney functionf
X
X o
X o
X o
X o
Liver functiong
X
X o
X o
X o
X o
X o
Coagulationh
X
X o
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Amended Clinical Trial Protocol 08
07-Aug-2018
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Pre-SAR421869
Days
Weeks
-28
-1
0
Day 1
1
2
4
12
24
36
48k
Surgery
Visit Windows
+10 days
-7 days
N/A
N/A
±3 days
±3 days
±3 days
±14 days
±14 days
±14 days
±14 days
Urinalysisi
X
X o
X o
X o
X o
X o
Blood for PCR
X
X j
X
X
X
X
X
X
X
X
Blood for Immunology
X o
X
X
X
X q
X q
Urine for PCR
X
X j
X
X
X
X
X
X
X
X
Urine pregnancy test
X o
X o,l
X o
X o
X o
X o
X o
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Notes:
a.
BCVA, Semi-automated Kinetic Perimetry (SKP), full field German Adaptive Thresholding Estimation (GATE) static perimetry and microperimetry will be performed 3 times during screening period; once at the 
screening visit (Day -28) and on two occasions at baseline (Day -1).
b.
A photomontage will be taken at the screening visit and Week 48 only.
c.
Vital signs: blood pressure (BP, lying down), heart rate (HR) and temperature taken and recorded before SAR421869 administration. Following surgery vital signs will be measured every 30 minutes for one hour. 
Vital signs will be obtained on all subsequent follow-up visits.
d.
Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), red cell distribution width 
(RDW), platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils.
e.
Chemistry panel: serum electrolytes (phosphorus, calcium, sodium, chloride, bicarbonate and potassium), fasting blood glucose (only at screening), creatine phosphokinase (CPK), lactate dehydrogenase (LDH)
f.
Kidney function: Creatinine, blood urea nitrogen (BUN) and uric acid.
g.
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (AP), total protein (TP), albumin, gamma glutamic transpeptidase (γGT, GGT), 
cholesterol (CHOL) (only at screening).
h.
Coagulation: prothrombin time (PT), partial thromboplastin time (PTT) at screening and baseline only.
i.
Urinalysis: Microscopic urinalysis for protein, blood, ketones.
j.
Blood and where possible urine sample 60 minutes after surgery.
k.
Week 48 or early termination procedures.
l.
Visit window does not apply to urine pregnancy test; must be negative on Day -1.
m.
Semi-automated Kinetic Perimetry conducted at screening visits Day -28 may be repeated prior to Day -1 if requested by the centralized independent assessor. 
n.
Semi-automated Kinetic Perimetry will be conducted twice at baseline (Day -1)
o.
In subjects of <18 years only investigations may be omitted unless considered clinically indicated.
p.
Infra-red fundus montage to be performed at each visit.
q.
Only in patients with a positive antibody response at Week 24.
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2.2
FOR COHORTS 3B, 3C, 4, 5
Pre SAR421869
Days
Weeks
-28 
(screening 
visit)
-1 (baseline 
visit)
0
Day 1
1
2
4
12
24
48
Surgery
Visit Windows
+10 days
-7 days
N/A
N/A
±3 days
±3 days
±3 days
±14 days
±14 days
±14 days
SAR421869 administration
X
Entry Criteria
X
X ***
Informed consent/assent
X
Medical history
X
Concomitant medication 
X
X
X
X
X
X
X
X
X
X
Anesthesia assessment
X
X ***
Height
X
Weight
X
X ***
Vital signs c
X
X
X
X
X
X
X
X
X
X
ECG
X o
X ***
Chest X-ray
X o
X ***
Physical examination
X
X ***
X
BCVA a
X
X
X
X
X
X
X
X
X
Contrast sensitivity (before dilatation)
X
X
X
X
X
Slit lamp examination
X
X
X
X
X
X
X
X
X
Intraocular pressure
X
X
X
X
X
X
X
X
X
Fundoscopy
X
X
X
X
X
X
X
X
X
Autofluorescence
X
X
X
X
X
OCT p
X
X
X
X
X
X
X
X
X
Perimetry  (SKP, GATE, microperimetry)a
X m
X n
X
X
X
X
X
Fundus photography b
X
X
X
X
X
X
X
Intraoperative video-recording
(intra-operative OCT, where available)
X
Multifocal and full Field ERG
X
X
VFQ-25/ CVAQC (when possible)*
X o *
X o
Hematologyd
X
X o **
X o
X o
X o
X o
Chemistry paneld
X
X o **
X o
X o
X o
X o
Kidney functionf
X
X o **
X o
X o
X o
Liver functiong
X
X o **
X o
X o
X o
X o
Coagulationh
X
X o **
Urinalysisi
X
X o
X o
X o
X o
X o
Blood for PCR
X
X j
X
X
X
X
X
X
X
(electronic 
 
 
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Amended Clinical Trial Protocol 08
07-Aug-2018
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Page 24
Pre SAR421869
Days
Weeks
-28 
(screening 
visit)
-1 (baseline 
visit)
0
Day 1
1
2
4
12
24
48
Surgery
Visit Windows
+10 days
-7 days
N/A
N/A
±3 days
±3 days
±3 days
±14 days
±14 days
±14 days
Blood for Immunology
X o
X
X
X
Xq
Urine for PCR
X
X j
X
X
X
X
X
X
X
Urine pregnancy test
X o
X o,l
X o
X§
Xo
Xo
Adverse events
X
X
X
X
X
X
X
X
X
X
Notes:
a
BCVA, Semi-automated Kinetic Perimetry (SKP), full field German Adaptive Thresholding Estimation (GATE) static perimetry and microperimetry will be performed 3 times during screening period; once at the 
screening visit (Day -28) and on two occasions at baseline (Day -1).
b
A photomontage will be taken at the screening visit and Week 48 only.
c
Vital signs: blood pressure (BP, lying down), heart rate (HR) and temperature taken and recorded before SAR421869 administration. Following surgery vital signs will be measured every 30 minutes for one hour. 
Vital signs will be obtained on all subsequent follow-up visits.
d
Hematology: white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCH), red cell 
distribution width (RDW), platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils.
e
Chemistry panel: serum electrolytes (phosphorus, calcium, sodium, chloride, bicarbonate and potassium), fasting blood glucose (only at screening), creatine phosphokinase (CPK), lactate dehydrogenase (LDH).
f
Kidney function: Creatinine, blood urea nitrogen (BUN) and uric acid.
g
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), alkaline phosphatase (ALP), total protein (TP), albumin, gamma glutamic transpeptidase (γGT, GGT), 
cholesterol (CHOL) (only at screening).
h
Coagulation: prothrombin time (PT), partial thromboplastin time (PTT) at screening and baseline only.
i
Urinalysis: Microscopic urinalysis for protein, blood, ketones.
j
Blood and where possible urine sample 60 minutes after surgery.
k
Week 48 or early termination procedures.
l
Visit window does not apply to urine pregnancy test; must be negative on Day -1.
m Semi-automated Kinetic Perimetry conducted at screening visits Day -28 may be repeated prior to Day -1 if requested by the centralized independent assessor. 
n
Semi-automated Kinetic Perimetry will be conducted twice at baseline (Day -1).
o
In subjects of <18 years only investigations may be omitted unless considered clinically indicated.
p
Infra-red fundus montage to be performed at each visit.
q
Only in patients with a positive antibody response at Week 24
* - VFQ-25 for adults ≥18 years/CVAQC for children <18 years.
**- To be repeated just in case of re-screening, if previous screening was earlier, than 38 days before surgery.
***- anesthesia assessment and physical examination will be repeated if outside 28 days or Day -1 window. Weight, ECG, chest X-ray and additional physical examination may be repeated by request of 
anesthesiologist atrescreening.
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3
STUDY DIAGRAM
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4
INTRODUCTION AND RATIONALE
Usher syndrome is characterized by sensorineural hearing loss and retinitis pigmentosa (RP). 
It accounts for the majority of the deaf-blindness population and between 8-33% of 
individuals with RP (1). The disease is named after the British ophthalmologist Charles 
Usher, who examined the pathology and transmission of the illness in 1914 on the basis of 
69 cases (2). The prevalence of Usher syndrome ranges from 3.6 to 6.2 per 100,000 in the 
US and European populations (3, 4, 5, 6, 7).
Usher syndrome is inherited in an autosomal recessive pattern and is classified into subtypes 
called Usher 1, 2 and 3 in order of decreasing severity of deafness. Usher 1 and 2 are the more 
common forms. People with Usher 1 syndrome are congenitally profoundly deaf and have 
vestibular dysfunction as well as prepubertal onset of retinitis pigmentosa leading to 
blindness. Babies with Usher syndrome Type 1 are usually slow to develop motor skills such 
as walking.
Usher syndrome Type 1B which accounts for 30-50% of Usher syndrome Type 1 (prevalence 
of ~1 per 100,000 people in the population [3, 4, 5]) is caused by a mutation in the 
gene coding for the unconventional myosin (motor) protein (MYO7A [8]). Myosin VIIa is 
expressed in the hair cells of the cochlea in the ear and the retinal pigment epithelial and 
photoreceptor cells of the retina, two tissues known to be affected in Usher syndrome 
Type 1B patients (9, 10). In addition, myosin VIIa is also expressed in the olfactory 
epithelium, brain, choroid plexus, intestine, liver, kidney, adrenal gland, testis, and 
lymphocytes (11). In the ear, myosin VIIa plays a role in the development and maintenance of 
inner ear structures such as hair cells (stereocilia) which transmit sound and motion signals to 
the brain. Loss of normal myosin VIIa function leads to disorganized development of the hair 
cell structure causing congenital profound deafness and vestibular dysfunction. While the 
molecular basis of retinal degeneration in Usher syndrome Type 1B patients is not completely 
understood, loss of normal myosin VIIa function leads to photoreceptor degeneration from the 
outer periphery to the macula.
The earliest symptom associated with RP in Usher syndrome Type 1B patients is most 
commonly night blindness; this is considered a hallmark of the disease and can become 
apparent from the age of about 10 years. For example, patients might report difficulties with 
tasks at night or in dark places, such as trouble walking in dimly lit rooms, difficulties seeing 
in low light, at dusk, or in foggy conditions. Peripheral vision is gradually lost in the first 
instance leading to a restriction of the visual field (tunnel vision), which then generally 
progresses to complete blindness. They may also report a prolonged period of time needed to 
adapt from light to dark. Peripheral vision loss is often asymptomatic; however some patients 
notice a reduction in visual acuity and report it as tunnel vision. Although the therapeutic 
window for Usher syndrome Type 1B is large in terms of the retinal pathology, with sight 
gradually being lost from birth (diagnosis from about 10 years), the earlier the correct 
MYO7A gene can be delivered, the greater the potential for preventing further peripheral and 
central vision loss.
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SAR421869 (previously named UshStat) is an EIAV-based lentiviral vector product aimed at 
introducing the normal MYO7A cDNA which codes for the relatively large functional myosin 
VIIa protein (2215 amino acids) into the photoreceptors and RPE cells, thereby restoring 
normal cellular function in both cell types and attenuating vision loss associated with Usher 
syndrome Type 1B. Due to the relatively large size of the MYO7A cDNA, it is expected that 
lentiviral vectors which can accommodate larger inserts (~8-9 kb) will be well suited for 
effective gene delivery to treat Usher syndrome Type 1B.
SAR421869 will be dosed on one occasion subretinally to patients who have been genotyped 
for this syndrome and in whom there is residual vision.
4.1
CLINICAL PATHOLOGY
Usher syndrome is a rare genetic disorder which is responsible for a significant proportion of 
deaf-blindness. Usher syndrome is inherited in an autosomal recessive pattern and is classified 
into subtypes called Usher syndrome Type 1, Type 2 and Type 3 (USH1, USH2 and USH3) in 
order of decreasing severity of deafness. USH1 and USH2 are the more common forms.
People with USH1 are usually born deaf and often have difficulties in maintaining their 
balance owing to problems in the vestibular system. Babies with USH1 are usually slow to 
develop motor skills such as walking.
By contrast, people with USH2 typically have mild to severe non-progressive hearing loss 
from birth and normal vestibular response (1). USH3 is similar to USH2, except the onset is 
later (12), hearing loss is progressive and vestibular function deteriorates (1). While 
differences in auditory and vestibular function are the main features used to distinguish 
between different types of Usher syndrome, retinitis pigmentosa (RP) is present in all three 
types (12).
These subtypes have been designated on the basis of the mutated gene that causes them, 
although they cannot be differentiated on a clinical basis (12). Thirty to fifty percent of USH1 
patients are affected by Usher syndrome Type 1B (USH1B) (13). USH1B is caused by 
mutations in the unconventional myosin VIIa gene (MYO7A), which is one of the five genes 
identified among the 7 loci known in Usher syndrome Type 1 (12). This gene codes for the 
unconventional myosin (motor) protein (myosin VIIa), which is present in a variety of tissues. 
Myosin VIIa displays a critical function in the ear and eye, where the myosin plays a role in 
the development and maintenance of inner ear structures such as hair cells (stereocilia), which 
transmit sound and motion signals to the brain. Alterations in this gene can cause an inability 
to maintain balance (vestibular dysfunction) and hearing loss. Loss of normal myosin VIIa 
function in the eye leads to photoreceptor degeneration from the outer periphery to the 
macula.
In the eye, mutant myosin VIIa results in defective motility of both phagosomes and 
melanosomes, suggesting that myosin VIIa plays a role in the intracellular transport of these 
organelles. The phagosomes result from phagocytosis of the photoreceptor outer segment tips 
(14) as part of the renewal of the photoreceptor disk membranes, a critical process for the 
viability of photoreceptor cells (15).
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The role of the melanosomes in the RPE cells is not fully understood, but may involve light 
absorption, a possible contribution to phagosome digestion, and protection against lipid 
peroxidation and the formation of cytotoxic oxiranes from resultant ingestion of photoreceptor 
outer segment phospholipids (16).
Over 90% of the ocular myosin VIIa protein is found in RPE cells of normal retinas. 
Mutations that affect the normal function of these genes can result in RP and vision loss. The 
therapeutic window for Usher syndrome Type 1B is potentially large in terms of the retina, 
with sight gradually being lost from birth (diagnosed at approximately 10 years) to beyond 
40 years of age, although the earlier the delivery of the correct MYO7A gene can be 
performed, the greater the potential for preventing further vision loss (4, 12).
4.2
DIAGNOSIS AND MONITORING OF USHER SYNDROME TYPE 1B
The earliest symptom in Usher’s Retinitis Pigmentosa (RP) is most commonly night blindness 
and this is considered a hallmark of the disease. Patients might report difficulties with tasks at 
night or in dark places, such as trouble walking in dim lit rooms, difficulties seeing in low 
light, at dusk, or in foggy conditions. They may also report a prolonged period of time needed 
to adapt from light to dark. Peripheral vision loss is often asymptomatic; however, some 
patients notice this vision loss and report it as tunnel vision.
On examination, Snellen visual acuity can vary from 20/20 to light perception, but it is 
usually preserved until late in the disease. While the retina can appear unaffected in early
stages of the disease, typical key findings include mid-peripheral retinal hyperpigmentation, 
optic nerve pallor, atrophy of the RPE in the mid periphery of the retina and retinal arteriolar 
attenuation.
The electroretinogram (ERG) is the most critical diagnostic test for RP because it provides an 
objective measure of rod and cone function across the retina and is sensitive to even mild 
photoreceptor impairment.
The full field ERG in RP typically shows a marked reduction of both rod and cone signals, 
although rod loss generally predominates. ‘a’ and ‘b’ waves are reduced since the primary site 
of disease is at the photoreceptors or RPE. The ERG is usually abnormal by early childhood, 
and is characterized by severe and selective loss of rod function occurring with varying 
degrees of cone abnormality.
Progressive loss of peripheral vision is a major symptom along with visual acuity changes; 
therefore, perimetry is the most useful measure for ongoing follow-up care of patients with 
RP. Goldmann (kinetic) perimetry is recommended, as it can more easily detect progressive 
visual field changes. Mid-peripheral scotomas develop early in RP. These visual field defects 
can join together to form a ring scotoma. Patients can go on to develop constricted visual 
fields or tunnel vision. Some patients progress to legal blindness with their peripheral vision 
limited to less than 20°, while their central vision remains intact (17, 18, 19). The term “legal 
blindness” is defined by the US federal statute as a central visual acuity of 20/200 or less in 
the better seeing-eye with the use of a correcting lens (20). An eye which also has a limitation 
in the fields of vision such as the widest diameter of the visual field subtends an angle no 
greater than 20 degrees shall also be considered as having a central visual acuity of 20/200 or 
less, even if the eye has an actual visual acuity of 20/20.  Hence, a visual field less than 20° is 
also defined as legally blind.
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In this study, in addition to routine ophthalmic examinations, a number of modalities will be 
used to monitor safety and any signs of bioactivity. Each technology has value in identifying 
disease severity and monitoring progression, but as each has intrinsic limitations others can 
complement, ERG to detect the electrophysiology of the retina, fundus autofluorescence 
(FAF) and optical coherence tomography (OCT) will visualize lipofuscin accumulation and 
cross-sectional retinal structure,  respectively, and perimetry to assess visual fields.
Regular measurements combining these techniques throughout the study will ensure the 
treated eye is effectively monitored for safety and may detect any early signs of bioactivity in 
this patient population.
4.3
PHARMACOLOGICAL TREATMENT
There are currently no approved treatment options for RP associated with Usher syndrome 
Type 1B gene defect. Early diagnosis of the condition is seen as a key factor, since the earlier 
it is diagnosed, the sooner a child can begin special educational training programs to manage 
the loss of hearing and vision, such as orientation and mobility training, and learning sign 
language and Braille. In conjunction with the effects of congenital deafness and vestibular 
dysfunction, a patient’s vision will inevitably deteriorate in time until he or she is blind. This 
means that RP associated with Usher syndrome Type 1B gene defect has a progressively 
debilitating effect on a patient’s life from birth.
For RP associated with Usher syndrome Type 1B, there are no therapies that stop disease 
progression or restore lost visual function. Therapeutic approaches are restricted to slowing 
down the degenerative process by sunlight protection, treating complications (cataract and 
macular edema), and helping patients to cope with the social and psychological impact of 
blindness (21).
Gene Transfer
SAR421869 is a gene therapy product designed to introduce the corrective MYO7A gene to 
photoreceptors and supporting RPE cells, thereby attenuating the deterioration in vision 
caused by RP associated with Usher syndrome Type 1B. SAR421869 is a non-replicating, 
recombinant lentiviral vector derived from the genome of the non-primate lentivirus ‘Equine 
Infectious Anemia Virus’ (EIAV).
The EIAV vector contains only 10% (861 nucleotides) of the wild type EIAV genome. There 
are no functional viral proteins or viral coding regions in the recombinant EIAV vector, thus
ensuring that no viral sequences are expressed in the recipient patient.
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4.4
SAR421869 DRUG DEVELOPMENT
SAR421869
The SAR421869 product and 
 is
are both presented as a frozen liquid formulation that must be stored at ≤-70°C.
The product is shown in Table 1.
A target strength of 4.7x106 TU/mL will be produced which corresponds to undiluted material
from the manufacturing process. Additional lower dosage strengths will be prepared from this 
material by dilution.
Table 1 - Components of the Medicinal Product
Product description
Quantity
Function
Reference to 
Standards
Active Substance:
SAR421869
≥6.0x105 to <1.5x107 TU/mL
Target strength:4.7x106 TU/mL
Active
 
Once SAR421869 is completely thawed, the appearance is a “turbid or clear colorless 
suspension free from particulates”. Upon thawing of 
the 
appearance is a clear colorless solution, having no visible particulates. More detail 
information is provided in the study pharmacy manual.
Mechanism of Action
The protein encoded by the SAR421869 vector is the unmutated form of human myosin VIIa. 
Myosin VIIa protein has been localized to connecting cilium in photoreceptors and the apical 
processes of the RPE. Myosin VIIa protein is always co-localized with cilia, which indicates a 
role in maintaining axonemal structures or function. A defect in axonemal transport of 
rhodopsin has been suggested as a cause of RP. Consequently, mutations that affect the 
MYO7A gene can result in RP and vision loss. SAR421869 is a lentiviral vector product 
aimed at introducing normal MYO7A cDNA which codes for the relatively large functional 
myosin VIIa protein (2215 amino acids) in the RPE cells and photoreceptors, thereby
restoring normal cellular function in both cell types and attenuating vision loss associated 
with Usher syndrome Type 1B.
Lentiviral vectors are advantageous for gene therapy applications for several reasons: they 
deliver genes stably and permanently into the genome of transduced cells in vivo, they are 
capable of transducing non-dividing cells and can carry large expression cassettes (22).
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4.5
SUMMARY OF PROOF OF PRINCIPLE NONCLINICAL STUDIES
Full details of the non-clinical studies performed with SAR421869 can be found in the 
Investigator Brochure.
Pharmacology Studies
Shaker1 mice provide the only currently available in vivo model of Usher syndrome Type 1B. 
These mice lack a functional myosin VIIa protein, are deaf and have vestibular dysfunction. 
Exposing shaker1 mice to similar light intensities to those experienced by a typical Usher 
syndrome Type 1B patient leads to photoreceptor rod degeneration over a 6- to 12-month 
period. Other retinal abnormalities in the shaker1 mouse include accumulation of opsin in the 
cilium and translocation defects in alpha transducin across the cilium. In the RPE the motility 
of both phagosomes and melanosomes are also defective. Pharmacology studies following 
subretinal administration of EIAV lentiviral vector (SAR421869) coding the normal human 
MYO7A gene has demonstrated:

SAR421869 vector shows expression of myosin VIIa protein in the photoreceptors of 
shaker1 mice, a genetic model of Usher syndrome Type 1B.

SAR421869 vector restored apical melanosome localization in RPE cells of 
shaker1 mice.

SAR421869 vector reduced opsin levels in the connecting cilia of photoreceptors in 
shaker1 mice to levels seen in wild type mice.

SAR421869 vector restored the light sensitivity of photoreceptors in shaker1 mice to 
mediate alpha-transducin translocation from the outer segments to the inner segments 
in response to light exposure.
Pharmacokinetic Studies
The investigations into the pharmacokinetic profile of SAR421869 have focused on what cell 
types are transduced by the vector following subretinal injection, the profile of the target 
therapeutic proteins and whether the product escapes from the ocular compartment, the target 
organ.
Since there are no MYO7A knockout models in rabbits and NHPs, EIAV-based lentiviral 
vectors similar to SAR421869 expressing reporter genes coding for either β-galactosidase 
(LacZ) or green fluorescent protein (GFP), were used to identify retinal cell types that are 
transduced by the vector. Following subretinal delivery of the EIAV lentiviral vector, gene 
delivery and expression was most evident in rod and cone photoreceptors and Retinal Pigment 
Epithelial (RPE) cells in mice, rabbits and three different NHP species; namely Cynomolgus 
macaques, baboons and Rhesus macaques.
The biodistribution of SAR421869 in the Rhesus macaque was shown to be confined to the 
ocular compartment following subretinal dosing. Extensive biodistribution and vector 
shedding studies with similar EIAV ocular products (RetinoStat® and SAR422459) in rabbits 
and Rhesus macaques also demonstrated that vector DNA was primarily located in the
retina/choroid and sclera, and absent in all non-ocular tissue by the end of the study.
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Toxicology Studies
Non-clinical GLP toxicology studies have been performed to assess acute and long-term 
effects of SAR421869 in the Rhesus macaque. Single subretinal injections of SAR421869 at a 
dose level of 9.08x105 TU/eye into the right eye followed by a 3-month (92-day) observation 
period resulted in ocular findings of anterior chamber inflammation/anterior uveitis with 
concomitant transient decreases in IOP, vitreal opacities, retinal opacities, retinal edema/haze 
and retinal vessel congestion. No signs of toxicity were noted at the level of the retina and 
most changes were to be expected with the subretinal dosing procedure. All noteworthy 
ocular findings resolved during the 3-month observation period, with the exception of
vitreous/retinal opacities and pigment changes in the retina/choroid. The results of this study 
are consistent with a transient and dose-related inflammation response that has been seen with 
other EIAV-based lentiviral vector products when dosed subretinally in the eyes of Rhesus 
macaques in GLP regulatory safety studies. Overall, the studies demonstrate no significant 
findings and provide safety data for the proposed clinical dose levels.
4.6
RATIONALE FOR STUDY
This is a Phase I/IIa, first in man, dose escalation study with a one-year follow-up duration, 
designed to assess whether SAR421869 is safe, well tolerated and efficacious in patients with 
moderate to severe RP associated with Usher syndrome Type 1B.
Evaluation of a safe and effective dose of SAR421869 in this study will enable optimum dose 
identification and further characterization of the safety profile in the target population in 
Phase II/III efficacy studies.
4.7
RATIONALE FOR SAR421869 
Usher syndrome Type 1B is a severely debilitating disease resulting in significant hearing loss 
at birth and progressive blindness. There are no treatments currently available and none in 
development.
The underlying cause of the retinal pathology of Usher syndrome Type 1B is mutations in the 
unconventional myosin VIIa gene (MYO7A). It is believed that by replacing the mutated gene
in the RPE, with the corrected gene using SAR421869, that this deficiency will be corrected, 
and that the treatment of RP associated with Usher syndrome Type 1B with SAR421869 will 
result in a substantial alteration of the pathophysiology of the disease leading to attenuation of 
the deterioration in vision which is associated with the syndrome.
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4.8
RATIONALE FOR INJECTION INTO THE EYE
The eye is a suitable target organ for gene therapy due to the following:

The eye is easily accessible to the surgeon compared to other organs, both in terms of 
administering the treatment and in terms of evaluating the effect.

The treatment approach is designed to correct the underlying genetic abnormality. 
Administration of SAR421869 directly into the eye provides a convenient means of
delivering the normal MYO7A cDNA and so is able to restore retinal transport 
function resulting in a longer duration of effect, or permanent restoration of myosin 
VIIa protein function. 

The eye is easily accessible to safety monitoring using multiple methodologies.
4.9
RATIONALE FOR PROPOSED SUBRETINAL INJECTION SITE
In patients with RP, there exists a transition zone between normal and abnormal retina that 
can be defined readily on spectral domain OCT. The reduction in visual sensitivity in the 
transitional zone correlates well with the progressive increase in retinal degeneration, and 
particularly a decrease in outer nuclear layer (ONL) thickness. This zone contains normal and 
degenerating photoreceptors with both normal and abnormal sensitivity, and thus is a good 
candidate region for localized gene therapy, and to perform the retinotomy and SAR421869
bleb placement in Usher Syndrome 1B patients.
The transition zone is detectable in very early disease with the least severely affected 
definable region beginning at about 3 mm from the center of the fovea and extending 
outward, with the most severe region beyond about 8-9 mm from fixation. In more advanced 
stages, the first transition region begins about 2 mm or less from the fovea and the rest of the 
regions of transition are collapsed such that abnormally thinned outer nuclear layer (ONL) 
occurs by 2 to 4 mm eccentricity and the region of greatest abnormality of outer retinal layer 
(that of extensive retinal remodeling with profound loss or absence of photoreceptors as well 
as absence of sensitivity), would be reached within 5 mm or less distance from the fovea (23).
In Part A of the study patients will have a visual field in the worse seeing-eye that subtends 
≤20 degrees on the retina. This visual field is equivalent to 3-6 mm from the center of the 
fovea and in the center of the transition zone of these patients. Subretinal injection in this 
region will be widely separated from the fovea, thus minimizing any risk to central visual 
acuity, but will also be in a region of the transition zone that may improve in function and 
where SAR421869 may give benefit.
In Parts B and C of the study patients will have much less restricted visual fields and the 
transitional zone will be wider (approximately 3-9 mm around the fovea) ensuring the risk to 
central visual acuity is further minimized by performing the subretinal injection even more 
distant from the fovea, but still maintaining the possibility to show benefit of SAR421869.
In addition, the placement of the retinotomy site and subretinal injection nasal to the optic 
disc will minimize the risk to foveal retinal function. The optic disc and superior and inferior 
nerve fiber layers extending from the disc will form an anatomical buffer between the 
injection site and the fovea, further minimizing the possibility of foveal extension and thus 
risk to central vision.
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4.10
RATIONALE FOR UNILATERAL ADMINISTRATION
In this study the contralateral non-administered eye will act as the control (ie, intra patient 
control) as well as the untreated areas of the study eye. The more severely affected of the two 
eyes will be injected. This is done with the intention of minimizing risk to the less affected 
eye and thus reducing risk to the patient’s remaining vision.
4.11
RATIONALE FOR THE CLINICAL DOSE
The rationale for the clinical dose is based on the number of transducing units delivered per 
eye in a fixed volume of formulation buffer. Using ocular allometric scaling and information 
from the published literature (Table 2), it was anticipated that a volume of 100 µL of 
SAR421869 could be safely subretinally dosed to NHPs without the need for vitrectomy 
(which is technically difficult in these species). Therefore, a total volume of 100 µL was used 
to deliver SAR421869 subretinally in the NHP GLP combined toxicology/biodistribution
study. Absorption and retinal re-attachment was complete by 1-2 weeks following subretinal 
administration in NHP and there were no observed long term morphological changes to the 
retinal structures examined at 12 week post dosing. The relative difference in ocular volume 
between NHP and human is around 3-fold, therefore a total volume of up to 300 µL will be 
delivered subretinally in this FIM study following a vitrectomy using standard ophthalmic 
surgical approaches.
The dose selection for the FIM study was based on the maximum tolerated dose (MTD) used 
in the NHP GLP combined toxicology/biodistribution studies. The MTD is defined as 
reversible inflammation that resolves to grade 1+ aqueous cell and flare scores within 2 weeks 
of dosing with no chronic degraded view of the fundus, sustained perivascular sheathing, or 
white exudates over the optic disc and fovea at 2 weeks. In addition, there should be no 
elevation in intraocular pressure over the observation period or general wellbeing of the 
animals. The MTD in the NHP was determined to be around 9.08x105 TU/eye. Based on the 
average 3-fold ocular allometric scaling of ocular volume between NHP and the human eye 
the expected MTD in man is 2.72x106 TU/eye. 
The first dose in man is equivalent to 1.4x105 TU/eye, the second dose equivalent to 
4.7x105 TU/eye and the highest dose planned will be undiluted SAR421869 which is 
equivalent to 1.4x106 TU/eye. All three of these dose levels are below the MTD in the NHP. 
Escalation to the next dose level only occurs following the review of the safety data on the 
preceding dose cohort by an independent safety data monitoring board, (DSMB), who advise 
on the progress of the SAR421869 development program.
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Table 2 - Allometric scaling of approximate ocular volumes and safe subretinal injection 
volumes
Species
Approximate 
axial ocular 
diameter (cm)
Approximate 
orbital volume 
(cm3)
Relative ocular 
volume as 
compared to 
mouse
Safe maximal 
subretinal 
volume (μL)
Allometric 
scale-up 
based on size 
relative to 
mouse safe 
volumes
Mouse
0.34 (24)
0.16 (25)
-
2
-
Rat
0.64 (26)
1.1
7
10
5
Rabbit
1.5 (27)-1.6 (28)
5 (29)- 14.1
88
100 (30)
50
Macaque 
1.7 (31)
20.6
129
100 (32)–150 (33)
50-75
Human
2.4 (34)
57.9
362
1000 (35),(36)
500
4.12
RATIONALE FOR DOSING INTERVALS
A single unilateral dose of SAR421869 will be administered to each study patient who
completes screening. Patients with advanced RP will be included in Cohorts 1, 2 and 3. 
Cohort 4 (MTD adults) and Cohort 5 (MTD including pediatric patients) will include patients 
with less advanced RP. In the non-clinical studies bleb resolution, vector clearance and gene 
expression have all occurred within two weeks post administration. Therefore, allowing 
21 days between dosing individual patients (Cohorts 1-3) and 28 days between patient cohorts 
(Cohorts 1-4), will permit adequate time to assess short-term safety, including ocular 
inflammation and post-operative complications prior to dose escalation or the inclusion of 
adult patients with less advanced disease.
Thus, prior to dose escalation there will be up to 4 month safety data on the first patient, up to 
three months on the second and up to one month safety data on the third patient in the 
preceding cohort. These data will permit assessment of the short-term safety profile during the 
dose escalation part of the study. In addition, the long-term safety data (approximately 
12-14 months) from patients with advanced disease dosed in the first three cohorts of the 
study will be available at the time of treating the final, less severely affected patient groups 
(Cohorts 4 and 5).
Prior to the inclusion of pediatric patients ≥6 years of age (Cohort 5), the DSMB will review 
all safety data, including data from Parts A and B, three months after all 6 patients in Cohort 4 
have been dosed. An interim report including all available safety data, preliminary efficacy 
data and the recommendations from the DSMB will be submitted to the regulatory authorities 
and institutional review boards/ethics committees for review, before patients 6-17 years of age 
can be enrolled into Part C of the study.
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4.13
RATIONALE FOR TARGET PATIENT POPULATION
The patient population in the study will all have genetically confirmed RP due to Usher 
syndrome Type 1B and be selected using clinical, psychophysical and electrophysiological 
criteria. Molecular genetic diagnosis of RP associated with Usher syndrome Type 1B will be 
confirmed by direct sequencing and co-segregation analysis within the patient’s family caused 
by at least one pathogenic mutation on each of the MYO7A alleles. It is well established, that 
as a clinical entity Usher syndrome Type 1B may be caused by a spectrum of mutations in 
MYO7A. However different mutations do not have any significant influence on the clinical 
presentation and no statistically significant difference in visual function (34).
In the USA the federal definition of blindness is a reduction in central visual acuity to 20/200 
or less in the better eye with the use of a correcting lens. However, an eye that has limitation 
of visual fields such that the widest diameter of the visual field subtends an angle no greater 
than 20 degrees is considered legally blind, the equivalent to a central visual acuity of 
20/200 or less (37, 38).
Although RP is cited as a disease that causes legal blindness, studies have shown that less 
than 0.5% of patients have lost all vision in both eyes (39). However, more recent data has 
shown that, of patients with Usher syndrome Type 1, 38% have a visual acuity of 20/40 in at 
least 1 eye and 38% a visual acuity of 20/200 or worse in both eyes (15). This disparity is due 
to RP being a disease of the peripheral retina with the reduction in vision, at least in the early 
stages of disease, being due to visual field restriction rather than deterioration of central visual 
acuity.
Grover et al. evaluated the distribution of visual field loss using kinetic perimetry and 
classified the Usher Type 1 patients into one of 5 distinct phenotypes on the basis of field 
defects (40).
Phenotype 1:
Normal
Phenotype 2:
Presence of partial or complete ring scotoma, the latter either completely or 
incompletely extending into the periphery
Phenotype 3:
Concentric central field loss with a remaining peripheral island less than one 
half of the field circumference
Phenotype 4:
Marked concentric loss (≤10 degrees)
Phenotype 5:
No visual field – blind.
Usher syndrome Type 1B is a disease of the peripheral retina, with foveal sparing at least in 
the early stages of the disease. Sparing of the central vision means that visual acuity can be 
preserved until relatively late in the disease, with the probability of a patient being classified 
as legally blind due to impairment of visual acuity of 25% at 52 years, 60% at 61 years and 
75% at 71 years. Furthermore, in some of these cases the reduction in central retinal 
sensitivity is due to local lesions, such as RPE defects or the sequellae of chronic cystoid 
macular edema, that are not directly related to the underlying molecular defect in the Usher 
disease process or by dense cataract, which is associated with Usher syndrome Type 1 in the 
advanced stages.
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Concentric visual field loss which makes a major contribution to the reduction in retinal 
sensitivity and the underlying marked abnormality of retinal electrophysiology can be 
detected early in the disease using perimetry and ERG, respectively. Loss in peripheral visual 
fields thus makes a major contribution to the prevalence of legal blindness in the Usher 
syndrome Type 1 population. Loss of peripheral field sensitivity occurs earlier in the disease 
and progresses more rapidly with a probability of 25% at 42 years, 50% at 52 years and 
75% at 56 years.
Generally the visual field reduction becomes substantial in the second and third decades of 
life. Taking the classification of Grover et al., and relating it to the temporal progression of 
the disease, it has been possible to distinguish three phases in the pathogenesis of Usher 
syndrome Type 1. In addition to increasing severity, phases 1, 2, and 3 also show a tendency 
for age dependence occurring between 1-20 years, 20-50 years and after 50 years of age, 
respectively (41).
Phase 1:
Characterized by a pathological ERG, but no major visual field losses. Visual 
acuity can be normal.
Phase 2:
Increased loss of peripheral vision and some visual acuity loss.
Phase 3:
Major loss in visual acuity and severe visual field restriction.
The progression to legal blindness is thus significantly age-dependent and it is estimated that 
the prevalence of legal blindness in the Usher syndrome Type 1B population is between 
12-17%. However, due to the relationship between disease progression and age, the relative 
contribution of peripheral visual field restriction to overall reduction in retinal sensitivity and 
progression to legal blindness, is greater in the early phases than that of central visual acuity 
loss. The outcome of this disparity is that patients can be classified as legally blind on the 
basis of markedly reduced peripheral vision but retain a good degree of central visual acuity.
In the current study the patient population selected in Part A (Cohorts 1-3) have a specific 
peripheral visual field restriction (≤20 degrees) set for the worse seeing-eye. It is expected 
that the patient peripheral visual field will also be severely constricted in the better eye, but 
the study does not require any specific criteria in the better eye. The Part A patient population 
may therefore not be legally blind, as defined by the US federal statute, based on the status of 
the better seeing-eye. They will broadly fall into field phenotypes 4-5, or phase 3 of disease 
progression.
Patients to be enrolled in Parts B and C (Cohorts 4 and 5) of the current study will broadly fall 
into Phase 2 or Phenotype 3 of the classification.
In patients with Usher syndrome Type 1B, regions of structurally and functionally normal 
retina are definable along-side areas of severe laminopathy and visual loss. Visual loss in 
Usher syndrome type 1 is predictably related to a decline in retinal outer nuclear layer 
thickness (ONL) caused by photoreceptor damage and loss, with a resulting gliotic response.
Full-field Static Perimetry has been extensively used to evaluate visual field loss. It is 
accurate and reproducible and has the advantage of detecting retinal sensitivity and thus the 
degree of retinal damage in any one region. Furthermore, sensitivity measured by static 
perimetry has been shown to correlate with morphological changes observed using SD OCT 
in the transitional zone in Usher syndrome Type 1 (42).
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In this study full-field GATE Static Perimetry will be used to help identify the patient 
populations and during follow-up for safety monitoring as well as detection of any signs of 
bioactivity. GATE is a new, fast, full thresholding algorithm which is considerably faster than 
the 4-2-1 strategy, yet gives comparable results (43).
In Part A of the study, patients will be required to have severe visual field constriction 
(evaluated by SKP). Patients will broadly be expected to have visual field loss in the worse 
seeing-eye that is equivalent to ≥50% reduction from normal sensitivity volume on full-field 
GATE Static Perimetry.
In Parts B and C of the study patients will have less advanced disease. Due to early foveal 
sparing in Usher syndrome type 1B, patients will not be selected on central visual acuity 
(since this will be near minimally affected), but instead on the restriction in visual fields. 
Patients in these groups will have some visual field loss. To reflect this, the criterion of a 
visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from normal 
sensitivity volume on full-field GATE Static Perimetry has been selected.
These parameters are consistent with the clinical and morphological findings that can be 
expected to be observed in the advanced population selected for Part A of the study, and less 
severe patients to be included in Parts B and C.
4.14
RATIONALE FOR INCLUSION OF CHILDREN AND ADOLESCENTS
The opportunity for intervention is potentially large in terms of the retina in Usher syndrome 
Type 1B, with sight gradually being lost from birth to beyond 40 years of age. Once the 
neural retina has degenerated it is very unlikely that any function can be restored with current 
therapies. Therefore, the earlier the delivery of a normal MYO7A gene can be performed, the 
greater the potential for preventing further deterioration of visual function (2, 10).
From 6 years of age the human eye is fully developed, thus inclusion of children from 6 years 
of age will allow evaluation of SAR421869 in this important population without the need to 
change dose, volume, method or technical difficulty of administration. Appropriate measures 
will be implemented to minimize any pain or discomfort associated with study procedures in 
children, including SAR421869 administration under general anesthesia and where necessary
in-patient hospitalization for post-operative management.
In a recent study in Leber Congenital Amaurosis patients aged 8 years and older have been 
included. This study evaluated subretinally injected adeno-associated virus vector expressing 
the RPE-65 gene, the greatest benefit in terms of improvement in vision was seen in the 
younger patients. This therapy is now being studied in patients of 3 years and older to further 
evaluate the population and define the optimal time for intervention in the natural history of 
the disease to maximize benefit (www.clinicaltrials.gov Trial Identifiers NCT00749957 and 
NCT00999609). Given that Usher syndrome Type 1B is also an incurable inherited retinal 
degeneration disease starting from a young age, it was considered appropriate to enroll 
patients <18 years of age since SAR421869 may also demonstrate greater benefit in this 
younger population. However, the initial evaluation of the safety of SAR421869 will be in 
adults.
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Prior to the inclusion of children/adolescents into the study, the DSMB will review all safety 
data, including data from Part B, three months after all 6 patients in Cohort 4 have been 
dosed. An interim report including all available safety data, preliminary efficacy data and the
recommendations from the DSMB will be submitted to the regulatory authorities and 
institutional review boards/ethics committees for review, before children/adolescents can be 
enrolled.
Patient Informed Consent for Adults and Children
People with Usher 1 syndrome are congenitally profoundly deaf and have vestibular 
dysfunction as well as prepubertal onset of retinitis pigmentosa leading to blindness. The 
subject will be required to have at least one effective form of communication in order to 
obtain and provide informed consent or assent to participate in the study.  This can be verbal, 
auditory, written and or tactile communication. Tactile signing is a common means of 
communication used by people with both a sight and hearing impairment and is based on a 
standard system of Deaf Manual Signs.  No specific method of tactile sign language is 
prescribed in this protocol.  The tactile sign language often used by people who first lose their 
hearing and later their sight is hand-over-hand signing where the receiver’s hands are placed 
lightly upon the back of the hands of the signer to read the signs through touch and 
movement. The sign language used in hand-over-hand signing is often a slightly modified 
version of the local Sign Language.  Several other versions of tactile sign language exist such 
as Tracking, Tactile Fingerspelling and Braille signing.
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5
OBJECTIVES
5.1
PRIMARY OBJECTIVE
To evaluate the safety and tolerability of ascending doses of subretinal injections of 
SAR421869 in patients with Usher syndrome Type 1B.
5.2
SECONDARY OBJECTIVE
To evaluate for possible biological activity of SAR421869.
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6
ENDPOINTS
All patients enrolled into this study will be followed for one year. For all endpoints with 
repeated measures, the primary time point will be considered the 12-month visit unless 
otherwise specified. BCVA and perimetry measurements are subject to broad intra-individual 
variability therefore the baseline value used for these measures will be an average of all the 
values obtained before surgery. For all other endpoints - last available measures before 
surgery will be considered as baseline value.
6.1
PRIMARY ENDPOINT
The incidence of adverse events over a 12-month period following a single intraocular dose of
SAR421869.
Clinically important changes from baseline (Day -28) in the following safety assessments:

Best-corrected visual acuity (BCVA).

Slit lamp examination.

Indirect ophthalmoscopy.

Fundus photography.

Intraocular pressure (IOP).

Optical coherence tomography (OCT).

Laboratory parameters.

Vital signs.

Concomitant medications.

Physical examinations.
6.2
SECONDARY ENDPOINTS
The primary time points will be considered the 6- and 12-month visits.
To determine a delay in retinal degeneration following subretinal injection of SAR421869 
through changes in function relative to the untreated contralateral eye utilizing the following 
retinal analytical techniques:

Best-corrected visual acuity (BCVA).

Contrast sensitivity.

Indirect ophthalmoscopy.

Visual function questionnaire VFQ-25/ CVAQC (when possible).

Full dilated slit-lamp examination.

Fundus photography – Panretinal photomontage.
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
Visual field testing: Semi-automated Kinetic Perimetry (SKP) and Full-Field German
Adaptive Thresholdings Estimation (GATE) Static Perimetry, and microperimetry.

Autofluorescence.

Electroretinogram (ERG).

Optical coherence tomography (OCT).
Adverse Events
The number and severity of any adverse events associated with SAR421869 administration 
will be assessed at each time point.
Immunology Endpoint
Humoral antibody response to SAR421869 administration.
Clinical Laboratory Tests
Hematology, biochemistry, urinalysis and other laboratory data will be measured at various 
time points throughout the study. Values will be flagged as High or Low if outside the 
laboratory normal range. Out of range values will be assessed as clinically significant (CS) or 
not clinically significant (NCS) by the investigator. CS out of range values will be recorded as 
adverse events. Blood for immunology and blood for PCR will also be taken at multiple time 
points throughout the study, as will urine samples for biodistribution assessment. 
Biodistribution Endpoint
SAR421869 distribution in blood and urine will be assessed by polymerase chain reaction 
(PCR).
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7
STUDY DESIGN
This is a Phase I/IIa, open-label, dose escalation study of subretinally injected SAR421869 in 
patients with Usher’s RP. In this study at least three doses of SAR421869 will be evaluated 
over five patient cohorts stratified by disease severity and age. The study is separated into a 
dose escalation phase, Part A followed by a two part dose extension phase at the maximum 
tolerated dose, Parts B and C.
An independent data safety monitoring board (DSMB) will be convened to monitor safety and 
will meet regularly either at face-to-face meetings or by teleconference once the first patient 
has been enrolled. Based on accrual of the data, the committee will comprehensively review 
the safety and tolerability of the treatment for each individual patient, and make decisions 
regarding dose escalation, study continuance and recommended amendments to the protocol.
Part A will evaluate at least 3 ascending dose levels of SAR421869, in 300 L of vehicle. 
A total of at least 15 patients (≥18 years of age) will be entered: 3 patients in Cohort 1 and 
2 and at least 9 patients in Cohort 3. An interval of 21 days between dosing the first and 
subsequent patient will be observed in Cohorts 1-3 in order to assess safety. The DSMB will 
recommend whether to dose escalate following review of the data one month after all three 
patients have been dosed in each cohort in Part A. If DSMB requires additional patients –
total up to 24 may be included in Part A.
If the safety and tolerability of SAR421869 is considered satisfactory by the DSMB in Part A 
and to further characterize the risk: benefit profile of SAR421869, the study will proceed to 
Part B, where 6 patients ≥18 years of age with less severe disease (Cohort 4) may be treated at 
the maximum tolerated dose determined from Part A, these patients may be enrolled in
parallel.
The DSMB will review all safety data including the data from Parts A and B three months 
after all patients in Cohort 4 have been dosed. An interim report including all available safety 
data and preliminary efficacy data will be submitted to the regulatory authorities and 
institutional review boards/ethics committees for review, before up to 6 patients 6-17 years of 
age can be enrolled in Part C of the study (Cohort 5). Patients enrolled into Part C will be 
treated at the MTD determined from Part A of the study and further characterized in Part B of 
the study.
It is anticipated that up to three additional patients may need to be enrolled during the study to
replace those who fail to complete the first six months of follow-up appointments.
All patients will be followed for 48 weeks. After this period they will enter an open-label 
safety study for long-term follow-up. Patients will attend visits at a minimum interval of one 
visit every six months for assessments that will include ophthalmological examinations and 
recording of adverse events for 240 weeks (5 years).
In addition, the investigator will conduct visits/contact the patient by telephone for a 
subsequent 10 years at a minimum interval of once a year to monitor delayed adverse events. 
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The long-term follow-up of patients in the current study will be described in a separate 
protocol.
In the event that a patient dies during the study then consent for a post-mortem will be sought 
from the patient’s family. In the event of development of an infection that is classified as an 
important medical event, particularly any opportunistic infection or onset of an autoimmune 
condition, effort will be made to collect data regarding the infectious agent and the outcome 
of the relevant investigations to characterize the autoimmune disease.
Table 3 - Study Design and Dosing Schedule
Part A
Cohort
Age (yr)
Number of patients
Subretinal Injection
Vector total dose per eye
by target strength 
(TU/eye )
by measured 
strength 
(TU/eye )**
Volume
1
≥18
3
1.4x105
2.1x104
300 µL
2
≥18
3
4.7x105
1.1x105
300 µL
3a
≥18
1
1.4x106
0.33x106
300 µL
3a
≥18
2
1.4x106
2.4x106
300 µL
3b
≥18
3
-
0.33x106
300 µL
3c
≥18
3
-
1.4x106
300 µL
Part B
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector total dose per eye
Volume
4
≥18
Up to 6
MTD
300 µL
Part C
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector total dose per eye
Volume
5
6-17
Up to 6
MTD
300 µL
Note:  * dose as calculated from target product strength; 
** dose as calculated from dilution (as applicable) of measured strength
Alternative Treatment following SAR421869 Administration
The re-administration of SAR421869 has not currently been assessed in nonclinical studies.
To safeguard patients, SAR421869 will not be available to those who have previously 
received SAR421869 until and unless appropriate nonclinical data are available. Repeat 
administration will not be permitted to any patient without prior approval of relevant national 
regulatory authorities, ethics committees (ECs) and institutional review boards (IRBs), and
even then it would be the subject of a separate formal clinical research protocol.
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8
STUDY POPULATION
All patients must have a clinical and molecular diagnosis of RP caused by MYO7A 
mutations.
The results of the gene mutation analysis will be collected in the study database provided that 
written results are made available to the site, and participants (patients and/or the patient’s 
parent[s]/legal guardian[s]) would give consent to record the results.
Twenty seven to 36 patients will complete the study. The protocol accommodates the 
possibility of several screen failures due to the rigorous inclusion and exclusion criteria.
Patients with differing disease severity and/or ages will be recruited, as defined by entry 
criteria.
8.1
PATIENT RECRUITMENT
Patients will be recruited from the hospitals’ Usher syndrome Type 1B patient population 
following IEC/IRB and regulatory approval.
This is a multicenter study with sites in the USA and EU. The selected sites have extensive 
experience in ophthalmic surgery, intraocular injections and handling of gene therapy 
products.
8.2
ENTRY CRITERIA
Main Inclusion Criteria
For the purposes of this study 1 month is equivalent to 28 days.
Patients must meet ALL of the following criteria to be considered for enrolment into this 
study.
1. Signed and dated written informed consent must be obtained from the patient (or 
assent in the case of minors from their legal guardian/representative), in accordance 
with the local regulations.
2. Clinical and molecular diagnosis of Retinitis Pigmentosa associated with Usher 
syndrome Type 1B, caused by at least one pathogenic MYO7A mutation on both 
alleles, confirmed by direct sequencing and co-segregation analysis within the 
patient’s family.
3. Patients must have suitable verbal/auditory and/or tactile sign language 
communication (in the opinion of the investigator) as to allow written informed 
consent to be obtained.
4. Females of childbearing potential must have a negative pregnancy test at screening
and at baseline, and agree to use an effective form of contraception such as the 
contraceptive pill or intra uterine device for at least three months following 
SAR421869 administration, or be surgically sterile or postmenopausal, with the last 
menstrual period being over two years prior to enrolment.
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5. Males of reproductive potential must agree with their partner to use two forms of 
contraception, including one barrier method for at least three months following 
SAR421869 administration if their partner is of childbearing capacity, or must be 
surgically sterile.
6. Patients enrolled in France must be affiliated to or benefit from a social security 
regimen. 
7. Patients must agree to not donate blood, organs, tissues or cells for at least three 
months following SAR421869 administration.
Part A
Specific Inclusion Criteria Cohorts 1, 2 and 3a

≥18 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye
equating to a horizontal visual field diameter of ≤20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by Semi-
automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed 
by centralized independent assessment of the SKP data.

No detectable rod-derived amplitudes on the full field electroretinogram performed to 
ISCEV standards.
Specific Inclusion Criteria Cohort 3 subgroups 3b and 3c

≥18 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye to 
≤20 degrees measured through the center of the visual field grid. The visual field 
constriction will be measured by Semi-automated Kinetic Perimetry (SKP) and the 
degrees of constriction will be confirmed by centralized independent assessment of the 
SKP data.

Baseline BCVA >20/200 in both eyes.

Subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm in any 
dimension. This will be confirmed by centralized independent assessment of the OCT.

Ability to understand, willingness to cooperate and ability to reliably perform required 
study procedures as judged and confirmed by the study Investigator.
Part B
Specific Inclusion Criteria Cohort 4

≥18 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye
equating to a horizontal visual field diameter of ≤20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by 
Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be 
confirmed by centralized independent assessment of the SKP data.
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
Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from 
normal sensitivity volume (decibel-steradian) on full-field GATE Static 
Perimetry using the size V (1.7°) test target. The percentage reduction in normal 
sensitivity volume will be confirmed by centralized independent assessment of the 
data.

Screening BCVA >20/200.

Subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm in any 
dimension. This will be confirmed by centralized independent assessment of the OCT.

ability to understand, willingness to cooperate and ability to reliably perform required 
study procedures as judged and confirmed by the study Investigator.
Part C
Specific Inclusion Criteria Cohort 5

6-17 years of age.

Concentric constriction of kinetic visual field centrally in the worse seeing-eye
equating to a horizontal visual field diameter of ≤20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by Semi-
automated Kinetic Perimetry (SKP) and the degrees of constriction will be confirmed 
by centralized independent assessment of the SKP data.

Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from 
normal sensitivity volume (decibel-steradian) on full-field GATE Static Perimetry 
using the size V (1.7°) test target. The percentage reduction in normal sensitivity 
volume will be confirmed by centralized independent assessment of the data.

Screening BCVA >20/200.

subfoveal Retinal Pigment Epithelium (RPE) intact and Ellipsoid zone ≥1mm in any 
dimension. This will be confirmed by centralized independent assessment of the OCT.

ability to understand, reasonably well cooperate to perform required study procedures 
as judged and confirmed by the study Investigator. 
Exclusion Criteria
ANY one of the following will exclude patients from being enrolled into the study:
1. Presence of significant ocular abnormalities in the study eye that in the opinion of the 
investigator would preclude the planned surgery, effective safety follow-up, or interfere 
with the interpretation of study endpoints (eg, glaucoma, corneal or significant lens 
opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization).
2. Any pre-existing factor or past history of eye disease in children that may predispose to 
an increased risk of surgical complications in the study eye (eg, trauma, previous surgery, 
uveitis, congenital, developmental or structural abnormalities).
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3. Concomitant systemic diseases including those in which the disease itself, or the 
treatment for the disease, can alter ocular function (eg, malignancies, diabetes, juvenile 
rheumatoid arthritis or sickle cell disease).
4. Any ocular surgery including laser and cataract surgery with intraocular lens 
implantation, aphakia or prior vitrectomy, in the study eye within 6 months of screening.
5. Any contraindication to pupil dilatation in either eye.
6. Treatment with intravitreal, subtenon, or periocular steroid within 4 months of the 
screening visit.
7. Any known allergy to any component of the delivery vehicle or diagnostic agents used 
during the study (eg, fluorescein, dilation drops), or medications planned for use during 
the peri-operative period, particularly topical, injected or systemic corticosteroids.
8. Life-threatening illness.
9. Alcohol or other substance abuse.
10. Laboratory test abnormalities or abnormalities in electrocardiogram or chest X-ray, that 
in the opinion of the principal investigator, are clinically significant and would make the 
patient unsuitable for participation in the study
11. Intercurrent illness or infection 28 days prior to SAR421869 administration.
12. Contraindications to use of anesthesia (local or general, as appropriate).
13. Concurrent anti-retroviral therapy that would inactivate the investigational agent.
14. Pre-menopausal or non-surgically sterile women who are unwilling to use an effective 
form of contraception such as the contraceptive pill or intrauterine device.
15. Pregnant or breastfeeding women.
16. Males or females who do not agree to use barrier contraception as specified in the 
inclusion criteria.
17. History of any investigational agent within 28 days prior to SAR421869 administration.
18. Participation in a prior gene transfer therapy study.
19. Enrolment in any other clinical study, for any condition, including those relating to Usher 
syndrome Type 1B, throughout the duration of the SAR421869 study.
20. Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation
therapy within the four weeks prior to surgery.
21. Long-term treatment with systemic corticosteroids within 28 days prior to the screening 
visit or ongoing systemic corticosteroid treatment at screening or on Day -1.
22. Current treatment with immunosuppressant therapies.
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23. A history of malignancy within a five year period or have had a positive cancer screening 
test within a one year period of the screening visit.
24. Past medical history of HIV, or hepatitis A, B or C.
25. Inability to comply with the study protocol.
8.3
WITHDRAWAL CRITERIA
Once SAR421869 has been administered it cannot be removed, therefore patients are unable
to withdraw from the study treatment. However, an individual may withdraw consent from 
any study related procedures at any time throughout the study and this will not affect the 
standard of care they receive.
Individual patients may also be withdrawn under the following circumstances:

The patient experiences a serious or severe adverse event that prevents him/her from 
continuing.

The patient incurs a significant protocol violation. Withdrawal will be judged by the 
Investigator and the Medical Monitor on a case by case basis.

The patient requests early discontinuation.

Request of the Sponsor.

Investigator’s request (eg, if the Investigator considers that the patient’s health is 
compromised by remaining in the study or the patient is not sufficiently co-operative).

The patient is lost to follow-up. (All attempts will be made to locate patients lost to 
follow-up).
Any patient that is withdrawn early from the study will be encouraged to consent to an open-
label, long-term follow-up study. If the patient withdraws or is withdrawn from the study, the 
Week 48 procedures should be completed if possible.
The long-term safety follow-up will be described in a separate protocol which will be 
submitted to regulatory agencies and Institutional Review Boards/Independent Ethics 
Committees for approval.
The open-label, follow-up study has been designed to capture the essential safety data 
pertinent to gene therapy follow-up, as well as key efficacy assessments, whilst providing the 
patient with a degree of flexibility for minimizing inconvenience. The long-term follow-up 
protocol will also permit patients to receive alternative treatment during their participation 
while allowing for safety follow-up.
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8.4
STUDY STOPPING CRITERIA
The following are considered stopping criteria:

Prolonged anterior chamber inflammation and/or prolonged posterior chamber 
inflammation continuing without signs of resolution 28 days after SAR421869 
administration.
Criteria for suspending enrolment or further study conduct are defined in the DSMB charter 
and all events will be reviewed by the DSMB.
In the event of early study termination all patients who have been dosed with SAR421869 
will continue to be followed up as per protocol.
8.5
DOSE-LIMITING TOXICITIES
Dosing will stop if a dose-limiting toxicity is encountered in a dosing cohort. Events that 
constitute a dose-limiting toxicity will be defined in the DSMB charter. Dose-limiting 
toxicities will include:

Severe or persistent ocular inflammation.

Other significant ocular toxicity (eg, large retinal detachment, evidence of direct 
toxicity).

Other systemic toxicities (eg, acute allergic reaction).

Any safety issue that has been identified that adversely changes the benefit/risk 
balance to study participants.
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9
TREATMENT PLAN AND METHODS
9.1
ALLOCATION OF TREATMENTS
Dose Escalation Part A
Patients will be allocated to treatment in the order in which they are enrolled into the study.
Dose escalation or progression to the next patient cohort will be based on safety in the three 
patients of the previous cohort, including events such as the presence and severity of 
manifested clinical signs and symptoms, laboratory tests including clinical chemistry, 
hematology, urinalysis and antibodies. The DSMB will thoroughly review and discuss the 
results from the previous cohort before proceeding with any subsequent dose escalation. All 
patients in the previous cohort must be observed for a minimum of 28 days before additional 
participants receive drug at the next dose level.
Dose Extension (MTD) Parts B and C
The Maximum Tolerated Dose to be used in Parts B and C (Cohorts 4 and 5) of the study will 
be determined from the dose escalation phase (Part A). Cohort 4 will include only adult 
patients (≥18 years or older) with less advanced RP, while Cohort 5 will provide the 
opportunity to include pediatric patients 6-17 years of age. Before pediatric patients can be
enrolled into the study, the DSMB will review all safety data including the data from Part B, 
three months after all patients in Cohort 4 have been dosed. An interim report including all 
available safety data and preliminary efficacy data will be submitted to the regulatory 
authorities and institutional review boards/ethics committees for review prior to the enrolment 
of pediatric patients.
9.2
STUDY MEDICATION ADMINISTRATION
9.2.1
Hospitalization
Hospitalization is not required but may be necessary for convenience of some patients. 
Patients will not take anything by mouth for a minimum of 8 hours prior to surgery.
9.2.2
Intraocular Injection
After informed consent is completed, patients will have baseline assessments and eligibility
will be confirmed. Eligible patients will be scheduled for surgery, which will be performed
under anesthesia. The study eye will be the eye that in the opinion of the investigator, in 
consultation with the patient, is the worse seeing eye. In order to select the worse eye the 
investigator will review the patient historic and Day -1 visual acuity and visual field data and 
also consider which eye is dominant and any preferences shown by the patient. The study eye 
will be marked prior to entering the operating room and once in the operating room the study 
eye will be reconfirmed.
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Surgery will be performed under general anesthesia or waking sedation at the surgeon’s 
discretion, with additional periocular/retrobulbar injections according to surgeon and 
anesthesiologist preferences. Surgery will be performed under sterile conditions in accordance 
with hospital operating room protocols.
A standard 20- or 23-gauge 3 port pars plana vitrectomy will be performed. If achievable, a 
posterior vitreous detachment will be induced and the posterior hyaloid will be removed from 
the posterior retinal surface at least to include the anticipated retinotomy site.
The posterior retina will be examined and the appropriate site for subretinal injection will be 
identified. Additional details on retinotomy will be provided in study manuals. The final 
positioning of the retinotomy and subretinal bleb will be determined by the surgeon.
The retina will be approached with a needle loaded with SAR421869. A 
hydraulically-induced retinotomy will be created and a subretinal bleb created. If the surgeon 
determines that the bleb is not forming in the correct position, he/she can choose to stop 
infusing and create another retinotomy. This can be done up to twice until the full volume has 
been delivered.
At the discretion of the surgeon an air-fluid exchange may be undertaken.
Following the administration of SAR421869, the fundus will be examined by indirect
ophthalmoscopy and scleral depression to look for peripheral retinal tears. If there are any 
peripheral retinal tears, they will be treated with cryopexy and a fluid-air exchange will be 
done. The vitreous cavity may be filled with the appropriate tamponade at the discretion of 
the surgeon.
The eye will be patched and the patient will be taken to the post-operative observation area.
For each patient, the following protocol required anti-inflammatory regimen including 
antibiotics and corticosteroid medications must be administered to reduce the possibility of 
clinically significant intraocular inflammation after subretinal injection procedure.

Immediately following the completion of the subretinal injection procedure 
administer:
-
In Children: one dose of intravenous methylprednisolone 1 mg/kg for patients 
≥50 kg or 0.5 mg/kg for patients <50 kg. Maximum corticosteroid dose not to 
exceed 80 mg for children <16 years.
-
In Adults: one dose of intravenous methylprednisolone 1 mg/kg.
-
At the discretion of the surgeon, a subconjunctival injection of corticosteroids 
(eg, Dexamethasone 5 to 10 mg) and/or a subconjunctival injection of antibiotics 
may be given.

Starting (post-operative) Day 1 administer/initiate:
-
In Children: oral prednisone 1 mg/kg/day for patients ≥ 50 kg or 0.5 mg/kg/day 
for patients <50 kg daily for 5 days, then reduce dose to 0.5 mg/kg/day for patients 
≥50 kg or 0.25 mg/kg/day for patients <50 kg daily for 5 days, then reduce dose by 
10 mg daily until the corticosteroid taper is complete. Maximum corticosteroid 
dose not to exceed 80 mg for children <16 years.
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-
In Adults: oral prednisone 1 mg/kg/day for 5 days, then reduce dose to 
0.5 mg/kg/day for 5 days, then reduce dose by 10 mg daily until the corticosteroid 
taper is complete.
-
Topical broad-spectrum antibiotic (eg, ofloxacin, ciprofloxacin, moxifloxacin, 
trimethoprim-polymyxin B or similar) QID for 7-10 days. 
-
Topical prednisolone acetate 1% (or similar) 4 times a day (QID) for 7-10 days, 
then three times a day (TID) for 7-10 days, then two times a day (BID) for 
7-10 days, then once daily (QD) for 7-10 days. (Note: The frequency of the topical 
corticosteroid drops and the timing for the start of the taper may be adjusted as 
needed in response to the patient’s manifestation of post-operative inflammation 
with the goal of resolving the post-operative ocular inflammatory response within 
28 days after the surgical procedure).
-
A topical steroid ointment (eg, sterdex, tobradex or similar) may also be given at 
bedtime (qhs) for 7-10 days at the discretion of the surgeon.
Intraocular inflammation worsening during the course of treatment with the protocol defined 
anti-inflammatory regimen (see Section 9.3.12 Medication, Adverse Event and Concomitant 
Medication Review) or persisting or occurring after the completion of the above protocol 
defined anti-inflammatory regimen must be recorded as a post-surgical adverse event.
For the management of intraocular inflammation persisting or occurring after the completion 
of the above post-surgical anti-inflammatory regimen or worsening during the course of the 
regimen see Section 9.3.12 Specific Procedures - Medication, Adverse Event and 
Concomitant Medication Review
9.2.3
Positioning of the Subretinal Bleb
The placement of the retinotomy site and subretinal injection will be detailed in study 
manuals.
9.2.4
SAR421869 Preparation
SAR421869 will be provided in 100 µL aliquots in 0.3 mL Type I borosilicate glass ‘V’ vials 
with a butyl stopper and aluminum crimp seal. Each vial of SAR421869 will be issued in a 
white plastic tamper proof container secured in packaging. The vial and plastic 
tamper-evident container will be labelled appropriately.
Further details of the preparation of SAR421869 for administration are provided in the study 
pharmacy manual.
9.2.5
SAR421869 Administration
All disposable surgical supplies; including gloves, masks, gowns, dressings and swabs used
during the surgical procedure will be destroyed by incineration according to hospital policy at 
the end of the operation. The first dressings removed from the patient’s wounds following 
surgery will also be disposed of by incineration.
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9.2.6
Post-Surgical Monitoring
Vital signs will be documented 30 and 60 minutes after the end of surgery. After 60 minutes, 
if the patient is feeling well and able to tolerate food and drink, he/she will be discharged. 
Before discharge, blood and urine samples will be obtained for PCR assay for viral particles.
9.2.7
Concurrent Treatments
Concurrent treatments for any concurrent diseases are permitted in this protocol and will be 
recorded in the CRF.
9.2.8
Study Conduct Specific to Children and Adolescents
It is important to note that children and adolescents will not be enrolled in the current study 
unless data from adult patients treated with SAR421869 demonstrate that the risk is justified
by an anticipated benefit to the patients.
The process of informed assent of children/ adolescents and the consent of their parents, 
guardians or other legal representatives will ensure that all parties understand the unique risks 
associated with gene therapy as well as the specific risks associated with ocular gene therapy. 
Moreover, the process will ensure that all parties understand the risks of participating in early 
clinical research where the safety and efficacy of a therapy may not have been fully 
established. The management of children and adolescents will be approached on an individual 
patient basis within the constraints of the protocol and the necessary procedures and 
monitoring to ensure safety. The patient and parents/legal guardians will be fully informed 
and consulted at all stages of the research and concerning all decisions regarding the 
management of the individual during subsequent follow-up.
Signed and dated written informed consent must be obtained from the patient (or assent in the 
case of minors from their legal guardian/representative), in accordance with the local 
regulations.
As in adults, the following procedures will be followed when including children and 
adolescents in the protocol:

To ensure effective monitoring of both vector and product, biodistribution and 
immunology samples will be collected at the same intervals as in adult patients.

Children and adolescents will enter the open label long-term follow-up protocol 
designed to monitor the long-term safety of patients treated with SAR421869.
Appropriate measures will be implemented to minimize any pain or discomfort associated 
with study procedures in children, including administering SAR421869 under general 
anesthesia if necessary, and where appropriate providing in-patient hospitalization for 
postoperative management.

The administration of SAR421869 to children of less than 12 years will be under
general anesthesia with neuromuscular paralysis and controlled ventilation.

Postoperative nausea and vomiting will be managed proactively through prophylactic 
use of anti-emetics. 
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
Perioperative analgesia will be administered (eg, subtenon lidocaine block), at the time 
of surgery and oral post-operative analgesia will be available to minimize any 
discomfort.

The surgeons and anesthesiologists will be experienced in pediatric ocular surgery and 
anesthesia.

The ophthalmic monitoring procedures included in this protocol are non- invasive and 
as such involve minimal discomfort to the patient. Pupil dilatation is necessary for 
effective examination and this can result in some sensitivity to light. In general, these 
examinations are well tolerated and in this vulnerable group any discomfort will be 
kept to a minimum.

Particularly for the younger age patients, hospitalization may be necessary for some 
procedures, which would normally be managed in an out-patient setting for adults. 
Accommodation and logistic assistance will be provided to family members/care 
givers to ensure they can be close to children in the event of hospitalization.

Routine phlebotomy for safety laboratory blood samples will be kept to a minimum. 
All routine safety bloods will be taken at screening. However, subsequent hematology 
and chemistry evaluations will be as clinically indicated and at the discretion of the 
investigator. Blood draws will be performed by personnel adequately trained and 
knowledgeable in phlebotomy techniques in pediatric patients.

Chest X-ray and ECG will not be required at screening unless considered clinically 
indicated by the investigator or anesthesiologist (non-compulsory investigations in 
children are indicated in Section 3).
9.3
SPECIFIC PROCEDURES
It is important to note that children and adolescents will not be enrolled in the current study 
unless data from adult patients treated with SAR421869 demonstrate that the risk is justified 
by an anticipated benefit to the patients.
9.3.1
Screening/Baseline Procedures
A screening log must be maintained for all patients screened for entry to the study with 
reasons for screen failure/not entering the study documented.
Patient screening will take place in the 28 days prior to SAR421869 administration.
During screening, height, weight, sex, reproductive status, inclusion/exclusion criteria, 
clinical symptoms of Usher syndrome Type 1B, medical history, treatment history, ECG, 
chest X-ray and anesthesia assessment (as appropriate) will be recorded.
Details of the screening procedures are detailed in the study schedule in Section 2.
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9.3.2
Screening Clinical and Laboratory/Diagnostic Measurements
SKP (study part A) or full-field GATE Static Perimetry (study Parts B&C) data from 
Day -28 will be reviewed by a centralized independent assessor to evaluate patient study 
eligibility, with regards to the visual field of the worse seeing-eye. If in the assessor’s opinion 
the Day -28 results are borderline in regards to the patients eligibility status then the test may 
be repeated, the retest will be conducted prior to Day -1.
A pan-retinal photomontage retinal photographic image will be taken at screening to 
document the whole retina prior to the beginning of the study.
Details of the screening procedures are detailed in the study schedule in Section 2.
Following the completion of SAR421869 administration to the first three patients in the trial 
(Cohort 1, dose level 1) the fourth patient (Cohort 2, dose level 2) may commence screening 
prior to a decision being reached by the investigator, the Sponsor and independent data 
monitoring committee to increase the dose of SAR421869. Similarly, screening by 
anticipation may be initiated for all subsequent cohorts. 
9.3.3
Screening Clinical and Laboratory/Diagnostic Measurements Day -28
The following assessments are required 28 (visit window +10 days) days prior to 
administration of SAR421869.

Entry criteria.

Informed consent/assent.

Medical history.

Anesthesia assessment.

Height.

Weight.

Vital signs.

ECG (not unless clinically indicated in <18 years old).

Chest X-ray (not unless clinically indicated in <18 years old).

Physical examination.

Ophthalmological examination:
-
BCVA (procedure to be performed up to three times in total at screening, once at 
this visit),
-
Contrast sensitivity,
-
Slit-lamp examination,
-
Intraocular pressure (IOP),
-
Fundoscopy,
-
Autofluorescence,
-
ERG (multifocal and full field),
-
OCT including an infra-red imaging montage,
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Semi-automated Kinetic Perimetry (SKP) full-field German Adaptive 
Thresholding Estimation (GATE) Static Perimetry and Microperimetry 
(procedures to be performed up to three times in total during screening, at least
once at this visit),
-
Fundus photography – including a photomontage.

Clinical laboratory samples.

Urinalysis.

Pregnancy test (not unless clinically indicated in <18 years old).

Blood for PCR.

Urine for PCR.

Adverse events.

Concomitant medications.
9.3.4
Baseline Clinical Laboratory/Diagnostic Measurements Day -1
The following assessments must either be completed on Day -1 or in the preceding 7 days 
with the exception of the urine pregnancy test that must be negative on Day -1 (not unless 
clinically indicated in <18 years old).

Vital signs.

Ophthalmological examination:
-
BCVA (procedure to be performed up to three times at screening, twice at this 
visit),
-
Contrast sensitivity,
-
Slit-lamp examination,
-
Intraocular pressure (IOP),
-
Fundoscopy,
-
OCT including an infra-red imaging montage,
-
SKP, full-field GATE static perimetry and microperimetry (procedures to be 
performed at least twice and up to three times during screening),
-
VFQ25 questionnaire / CVAQC (when possible).

Clinical laboratory samples (not unless clinically indicated in <18 years old).

Urinalysis (not unless clinically indicated in <18 years old).

Pregnancy test (not unless clinically indicated in <18 years old).

Blood for immunology.

Adverse events.

Concomitant medications.
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9.3.5
Re-screening
Re-screening will be allowed once within 90 day period from initial informed consent, in case 
patient was eligible by all inclusion – exclusion criteria, but was not treated. All eligibility 
criteria need to be reviewed. Patient will undergo a baseline visit (if was not done) or repeat it 
within a 7 days period before surgery.
Additional (standard) examinations/ tests can be needed during such visit: 

Laboratory tests of hematology, chemistry panel, kidney function, liver function and
coagulation will be repeated if done earlier than 38 days before surgery, or – by a 
request of anesthesiologist. 

Anesthesia assessment and physical examination will be repeated if outside of the 
Day -28 to Day -1 window before surgery. Weight, ECG, chest X-ray and additional 
physical examination may be repeated by a request of anesthesiologist.
9.3.6
Surgery
The following assessments are performed on the day of surgery:

Fundus photography will be performed in the operating room during surgery. This will 
be post bleb placement and will record the position of the bleb relative to the retinal 
anatomy.

Where available, the following assessments will be performed:
-
Surgery video-recording,
-
and/or intra-operative OCT.

Vital signs 30 and 60 minutes after surgery

Blood and where possible urine for PCR 60 minutes after surgery.

Adverse events.

Concomitant medications.
9.3.7
Follow-up Procedures
Patient follow-up visits are outlined in the study schedule in Section 2.
9.3.7.1
Follow-up Day 1 Clinical and Laboratory/Diagnostic Measurements

Vital signs

Ophthalmological examination:
-
BCVA,
-
Slit-lamp examination,
-
Intraocular pressure (IOP),
-
Fundoscopy,
-
OCT including an infra-red imaging montage,
-
Fundus photography.
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
Clinical laboratory samples (except coagulation and kidney function ([not unless 
clinically indicated in <18 years old]).

Blood for PCR.

Urine for PCR.

Urinalysis (not unless clinically indicated in <18 years old).

Adverse events.

Concomitant medications.
9.3.7.2
Follow-up Week 1, 2, 4, 12, 24 and 48 Clinical and Laboratory/Diagnostic 
Measurements

Vital signs.

Physical examination (Week 48 only).

Ophthalmological examination:
-
BCVA,
-
Contrast sensitivity (Weeks 12, 24, 36 and 48 only),
-
Slit-lamp examination,
-
Intraocular pressure (IOP),
-
Fundoscopy,
-
Autofluorescence (Weeks 4, 12, 24 and 48 only),
-
OCT including an infra-red imaging montage,
-
SKP, full-field GATE static perimetry and Microperimetry (Weeks 2, 4, 12, 24, 36 
and 48 only),
-
Fundus photography (Weeks 2, 4, 24, 36 and 48 only),
-
Fundus photomontage (Week 48 only),
-
ERG (Weeks 24 and 48 only),
-
VFQ25 questionnaire (Week 48 only) / CVAQC (when possible, 48 week only).

Clinical Laboratory Samples (except coagulation, at Weeks 4, 24 and 48 only, not in 
<18 years old unless clinically indicated).

Urinalysis (Weeks 4, 24 and 48 only), (not unless clinically indicated in <18 years 
old).

Pregnancy test (Weeks 4, 12, 24, 36 and 48 only), (not unless clinically indicated in 
<18 years old).

Blood for PCR.

Urine for PCR.

Blood for Immunology (For all the patients at Weeks 4, 12, and 24 only).  In patients 
with positive antibody response at Week 24, additional immunology blood testing will 
be performed at Week 36 and/or Week 48 to document the antibody response kinetic 
until the value returns to baseline in these patients (the need for sample collection 
beyond Week 48 (if needed) would be collected in the long term safety study. 

Adverse events.

Concomitant medications.
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9.3.8
Samples for PCR
Blood and Urine samples for PCR are required to be taken at screening and at follow-up visits 
post administration of SAR421869; 60 minutes after surgery, Day 1, Weeks 1, 2, 4, 12, 24, 36
and 48.
The processing of the blood samples for PCR analysis will be performed at the designated 
hospital by a person designated by the PI. The samples will be labelled with the patient 
number, date of collection and visit number. They will then be stored in the freezer at ≤-70°C 
prior to shipment to the Sponsor designated company. The shipment of samples will be on dry 
ice. The Sponsor clinical project manager or designee will be notified at least 24 hours in 
advance of any shipment.
Urine and blood samples will be analyzed using PCR to assess the presence of vector RNA 
and/or DNA.
9.3.9
Samples for Immunology
Samples for immunology are required to be taken at baseline (Day -1) and at the following 
follow-up visits post administration of SAR421869: Weeks 4, 12, and 24.
The processing of the blood samples for immunology analysis will be performed at the 
designated hospital by a person designated by the PI. The samples will be labelled with the 
patient number, date of collection and visit number. They will then be stored in the freezer at 
≤-70°C prior to shipment to the Sponsor designated company. The shipment of samples will 
be on dry ice. The Sponsor clinical project manager or designee will be notified at least 
24 hours in advance of any shipment.
Blood samples collected for immunology will be analyzed by the Sponsor designated 
company using Western blot analysis or ELISA.
9.3.10 Future Use of Samples
For subjects who have consented to it, the samples that are unused or left over after testing
may be used for other research purposes (excluding genetic analysis) related to
ophthalmology. 
Your sample(s) will be transferred to a Sanofi site (or subcontractor site). Your sample(s) will 
be handled and stored at a secure site specialized for such investigations under the 
responsibility of the sponsor up to 15 years after completion of the final report of the main 
clinical. Thereafter, all samples will be destroyed.
9.3.11 Ophthalmological Assessments
Ophthalmological assessments will be carried out by certified individuals at the study site. As 
far as possible, for each patient, assessments will be performed by the same individual at each 
visit. Technical details of all ophthalmological assessments will be provided in the 
investigator site file. All findings will be documented in the source documentation and the 
appropriate CRF.
Studies have shown that a number of imaging modalities provide a sensitive method of 
monitoring disease progression and response in retinal dystrophies.
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9.3.11.1 Best-Corrected Early Treatment Diabetic Retinopathy Study (ETDRS) Visual 
Acuity
A BCVA examination will be performed using the EVA (electronic visual acuity) testing 
system according to the recommended protocol. Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart testing will be used as a back-up in case the EVA is not functioning or 
available. In such cases the same method used to record BCVA at the screening visit for a 
given patient should be used throughout the study.
9.3.11.2 Contrast sensitivity
A contrast sensitivity assessment will be performed using the Sloan Low Contrast Letter 
acuity chart. In low vision patients, functional vision, eg, the ability to recognize faces and 
read moderate size print and the orientation and mobility capacities were better correlated to 
contrast sensitivity levels than visual acuity measurements (23, 44). The 100%, 2.5%, and 
1.25% contrast level Sloan Low Contrast Acuity charts will be used for testing. For detailed 
instructions see Appendix D.
Contrast sensitivity is not to be measured using both eyes.
9.3.11.3 Slit-Lamp Examination
Slit-lamp examination will be performed using the investigator’s standard procedure. 
This procedure will be the same for all subjects examined. Observations will be made to 
indicate the absence or presence of findings for ocular adnexa, anterior and posterior 
segments. Intraocular inflammation will be graded using a standard scale.
9.3.11.4 Fundoscopy
Dilated funduscopic examination will be performed according to the investigator’s standard 
practice. Investigators will specifically document the presence or absence of retinal 
detachment, retinal tears or holes, subretinal hemorrhage, exudation, fluid or fibrosis. 
Additional observations will also be documented.
9.3.11.5 Intraocular Pressure Measurement
Applanation tonometry will be used for IOP measurements.
9.3.11.6 Optical Coherence Tomography
Optical coherence tomography (OCT) is a non-invasive technique that provides high 
resolution axial images of the retina. A low coherence infrared source is used to image the 
retina and a portion of coherent backscattered light is detected using an optical interferometer.
Depth and intensity information can be captured digitally to visualize the structural 
morphology of the intraretinal layers. Spectral domain OCT (SD-OCT) is the most advanced 
method available and provides high resolution, rapid scanning, high repeatability and the 
capacity for transverse scans and the 3-dimentional mapping of single retinal layers. Macular 
thickness, subretinal fluid, and other architectural OCT features provide useful information on 
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the transverse and axial location of retinal lesions. Optical coherence tomography (OCT) will 
be performed using the Spectralis  SD-OCT imaging system (Heidelberg Engineering) to 
evaluate the cross-sectional anatomy of the macula and document areas of retinal atrophy.  
The Spectralis system will also be used to collect infra-red images for the infrared imaging
montage.
9.3.11.7 Fundus Photography
Fundus photography remains an invaluable tool to record the characteristics of the retina at 
any one stage of the disease and is used in combination with other imaging modalities 
(eg, auto fluorescence) to accurately map the appearance of the atrophy. A suitable fundus 
camera, (Zeiss FF4 series and the Topcon TRC-50EX or similar) will be used to document the 
retinal anatomy. At screening a seven field retinal photomontage will be taken to document 
the whole retina and standard photographs at subsequent visits (at the 35°setting to document 
the appearances of the macula and posterior pole) with specific emphasis on recording the 
treated area of the retina.
9.3.11.8 Electroretinogram
Full field electroretinography (ERG) measures the electrical responses of various cell types in 
the retina, including the photoreceptors, inner retinal cells bipolar and amacrine cells, and the 
ganglion cells. It is a non-invasive technique in which electrodes are placed on the cornea and
the skin near the eye. During a recording, the patient's eyes are exposed to standardized 
stimuli and the resulting ERG signal is displayed showing the time course of the signal's 
amplitude. The ERG is composed of electrical potentials contributed by different cell types 
within the retina, and the stimulus conditions (flash or pattern stimulus, whether a background 
light is present, and the colors of the stimulus and background) can elicit stronger response 
from certain components.
If a dim flash ERG is performed on a dark-adapted eye (scotopic), the response is primarily 
from the rod system and flash ERGs performed on a light-adapted eye (photopic) will reflect 
the activity of the cone system. In response to sufficiently bright flashes, the ERG will contain 
an ‘a-wave’ (initial negative deflection) followed by a ‘b wave’ (positive deflection). The 
leading edge of the a-wave is produced by the photoreceptors, while the remainder of the 
wave is produced by a mixture of cells including photoreceptor inner segments, bipolar, 
amacrine, and Mueller cells.
A full field electroretinogram will be conducted using the standard procedure according to the 
ERG Standardization Committee of the International Society for Clinical Electrophysiology 
of Vision (ISCEV). Stimulus protocols for both scotopic and photopic function will be 
performed.
Multifocal electroretinography will be performed using the VERIS multifocal ERG according 
to the manufacturer’s protocol.
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9.3.11.9 Perimetry
Semi-automated Kinetic Perimetry (SKP) and Full-field German Adapative Thresholding 
Estimation (GATE) Static Perimetry are non- invasive, psychophysical tests that can rapidly 
and accurately assess the visual fields and create a detailed map of the retina documenting 
scotoma and the level of retinal function at specific regions. Compared to manual Goldmann 
kinetic perimetry, Semi-automated Kinetic Perimetry (SKP) allows greater standardization, 
control, and documentation of how the testing is performed, and minimizes the variability 
normally observed when different perimetrists test the same patient.
Full-field Static Perimetry assesses the sensitivity of the entire field of vision through 
estimation of thresholds at specific loci determined by the number of test locations and the 
pattern of the grid. The Swedish Interactive Thresholding Algorithm (SITA) fast strategy for 
static perimetry was initially optimized specifically for glaucoma, however, a new fast 
strategy, GATE, has been shown to be appropriate for retinal disease. Using the GATE 
strategy and radially-oriented, centrally condensed grids that extend from 56° nasally to 
80° temporally, the entire full field is captured. The centrally condensed grid captures detail 
of sensitivity boundaries and gradients within the central portion of the field and, thus, can 
more precisely define remaining visual field in advanced disease. The differential luminance 
sensitivities are exported digitally for computation and modelling to create a “Hill of Vision”, 
from which volumetric estimates of retinal function can be measured for the entire Hill of 
Vision or any subregion therein.
Perimetry (both Semi-automated Kinetic Perimetry (SKP) and Full-field GATE Static 
perimetry) will be performed using the Haag Streit Octopus 900 perimeter. 
Microperimetry will also be performed on the MP1. The MP1 provides a quantitative 
assessment of fixation by tracking fundus movements while the patient looks steadily at the 
fixation target. The MP1 can also accurately map a scotoma by delineating the absolute or 
relative non-seeing areas within the visual field. This is accomplished by projecting a light 
stimulus onto the patient’s retina until it becomes visible to the patient. With the MP1 it is 
possible to monitor the evolution of a disease and the exact changes it effects on a patient’s 
vision over the long term, because follow-up examinations are automatically performed in 
previously examined areas.
9.3.11.10
Autofluorescence Imaging
Autofluorescence imaging of the retina will be performed to document the distribution of 
lipofuscin and degenerative geography using the Spectralis system (Heidelberg Engineering). 
Fundus autofluorescence (FAF) is a non- invasive imaging technique to visualize lipofuscin, 
particularly in the parafoveal area. Abnormally increased FAF suggests RPE dysfunction, 
while decrease FAF indicates RPE atrophy and photoreceptor death (38). Images are acquired 
using a confocal laser ophthalmoscope system effectively gathering light from a single focal 
plane and eliminating AF from sources anterior to the retina (39).
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9.3.11.11
Visual Function Questionnaire (VFQ-25)
An individual's own perception of vision-related quality of life is perhaps one of the most 
meaningful measures of that individual's visual function level. The National Eye Institute 
(NEI) Visual Functioning Questionnaire (VFQ-25) was developed to measure vision-specific 
health-related quality of life.
The VFQ-25 assesses difficulty with near vision activities, difficulty with distance vision 
activities, limitations in social functioning due to vision, role limitations due to vision, 
dependency on others due to vision, mental health symptoms due to vision, future 
expectations for vision, driving difficulties, pain and discomfort in or around the eyes, 
limitations with peripheral vision and color vision. The VFQ-25 questionnaire was developed 
from patient focus groups representing a diverse set of visual conditions, the intention being 
to develop a scale that can be generalized to all patients with vision deficits, regardless of 
cause. Across the range of developmental conditions (cataract, glaucoma, AMD, and diabetic 
retinopathy), as well as other conditions as diverse as corneal diseases and vascular occlusions 
of the retina, NEI-VFQ scores vary in the expected direction with differences in visual 
performance and disease state.
The Cardiff Visual Ability Questionnaire for Children (CVAQC) will be administered to 
children aged 6 to <18 years old. This PRO instrument measures the self-perceived visual 
ability in visually impaired children and young people aged 6 to 17 years. The 25-item Cardiff 
Visual Ability Questionnaire for Children (CVAQC) is a short, psychometrically robust and a 
selfreported instrument that works to form a unidimensional scale for the assessment of the 
visual ability in children and young people with a visual impairment. A list of 121 items was 
generated from 13 focus groups with children and young people with and without a visual 
impairment. A long 89-item questionnaire was piloted with 45 visually impaired children and 
young people using face-to-face interviews. Rasch analysis was used to analyze the response 
category function and to facilitate item removal ensuring a valid unidimensional scale. The 
validity and reliability of the short questionnaire were assessed on a group of 109 visually 
impaired children (58.7% boys; median age 13 years) using Rasch analysis and intraclass 
correlation coefficient (ICC). The final 25-item questionnaire has good validity and reliability 
as demonstrated by a person separation index of 2.28 and reliability coefficient of 0.84. The 
items are well targeted to the subjects with a mean difference of -0.40 logit between item and 
person means, and an ICC of 0.89 demonstrates good temporal stability (45).
9.3.12 Medication, Adverse Event and Concomitant Medication Review
Review of concomitant medication and adverse events will be conducted by a physician at all 
visits and be recorded in the electronic CRF and reported as required.
9.3.13 Post-surgical ophthalmological adverse events
Patients who develop post-surgical complications such as ocular inflammation and raised IOP
should be treated according to local standard of care procedures.
Intraocular inflammation worsening during the course of treatment with the protocol defined 
anti-inflammatory regimen (see Section 9.2.2 Intraocular Injection) or persisting or occurring 
after the completion of the protocol defined anti-inflammatory regimen must be recorded as a 
post-surgical ophthalmological adverse event.
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In this setting the treatment and follow-up of the patient will be at the discretion of the 
investigator, guided by the severity and longevity of the inflammation, in an effort to 
minimize the risk of loss of visual function as a result of the ongoing inflammatory process. 
In the situation where the intraocular inflammation is clinically worsening the presence of an 
intraocular infection should be excluded.
Treatment with high dose, oral corticosteroids (1 mg/kg/day for patients ≥50 kg; 
0.5 mg/kg/day for patients <50 kg; maximum dose not to exceed 80 mg/day for children 
<16 years) is recommended for any patient manifesting worsening intraocular inflammation 
(eg, ≥2+ for anterior chamber cells, ≥2 vitreous haze and/or cells, the presence of vitreous 
snowballs or retinal vasculitis). In such cases, the oral corticosteroids should be continued 
until the ocular inflammation is resolved and then tapered as appropriate.
Raised IOP greater than 30 mmHg must be recorded as a post-surgical adverse event and may 
be treated with IOP lowering drops with the patient reviewed within a week. If the IOP 
remains greater than 25 mmHg another pressure lowering drop will be added and the patient 
reviewed again within a week. This sequence will be repeated until the IOP remains below 
25 mmHg. For increases in IOP occurring while the patient is receiving topical steroids per 
the recommended protocol defined anti-inflammatory regimen, consideration may be given to 
reducing the frequency of the topical steroids if the intraocular inflammation is controlled.
9.3.14 Clinical Laboratory Tests
Clinical laboratory safety tests will be performed in a clinical laboratory. Urine pregnancy 
tests may be performed at the site using a licensed test (dipstick).
The following clinical laboratory tests will be performed.
Serum Chemistry
Calcium
Lactate dehydrogenase (LDH)
Chloride
Creatine Phosphokinase (CPK)
Phosphorous
Blood urea nitrogen (BUN)
Bicarbonate
Uric acid
Potassium
Creatinine
Sodium
Total bilirubin
Aspartate aminotransferase (AST)
Glucose
Alanine aminotransferase (ALT)
Albumin
Alkaline phosphatase (ALP)
Total protein
Gamma glutamic transpeptidase (GGT)
Cholesterol
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Hematology
White blood cell (WBC) count with differential
Hematocrit
Red blood cell (RBC) count
Hemoglobin
Neutrophils 
Platelet count
Lymphocytes 
Monocytes 
Mean corpuscular hemoglobin concentration (MCHC)
Eosinophils 
Mean corpuscular volume (MCV)
Basophils
Red Cell Distribution Width (RDW)
Urinalysis
Color
Glucose
Appearance
Ketones
Specific gravity
Blood
pH
Bilirubin
Protein
Microscopy including WBC/high power field (HPF), RBC/HPF
Pregnancy Test (females of childbearing potential only)
Urine human chorionic gonadotropin (hCG)
Other Safety Tests

Coagulation parameters: prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen
9.4
FLEXIBILITY OF ASSESSMENT DATA CAPTURE
A certain degree of flexibility is required for capturing the data at the various time points 
throughout the study primarily as not all tests can be carried out on the same day due to 
investigator availability and time. In addition, if a patient is not well enough to undertake a 
certain test on a given day it may need to be postponed. The following time windows for 
carrying out the tests are shown below. If tests are performed outside of this, then a protocol 
deviation form must be completed explaining the reason for the delay in the test or if the 
assessment has not been done.

Screening (Day -28) tests may be performed at any time up to 37 days prior to Day -1.

Day -1 (baseline) tests must be performed in the preceding 7 days or on the day of the
scheduled visit, with the exception of the urine pregnancy test that must be negative 
on Day -1 (not unless clinically indicated in <18 years old).

Day 0 tests must be performed on the day of the scheduled visit.

Weeks 1, 2 and 4 tests may be performed ±3 days of the scheduled visit.

Follow-up visits for Weeks 12, 24, 36 and 48 may be performed ±14 days of the 
scheduled visit.
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10
STUDY MATERIALS
10.1
SAR421869
SAR421869 will be supplied by the Sponsor. All patients will be injected with subretinal 
SAR421869 under general anesthesia or waking sedation at the surgeon’s discretion, with 
additional periocular/retrobulbar injections according to surgeon and anesthesiologist 
preferences.
Adequate vials of SAR421869 will be supplied per patient, depending on dose level.
For certain doses a dilution will be performed by qualified personnel of the site. 
 will be supplied for this purpose.
Details of SAR421869 and 
 and their proper handling will be provided in a 
pharmacy manual available at the clinical site.
All healthcare staff handling SAR421869 must wear an apron, gloves, mask and protective
goggles. All materials contaminated with SAR421869 eg, syringes, swabs, bandages, must be 
destroyed by incineration in accordance with hospital policy on genetically modified 
materials. Certificates of Destruction must be completed and copies maintained in the study 
trial file. Healthcare staff who are pregnant, or suspect that they are, must not administer or 
handle SAR421869.
10.1.1 Packaging and Labelling
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements.
SAR421869 will be provided in 100 µL aliquots in 0.3 mL Type I borosilicate glass ‘V’ vials 
with a butyl stopper and aluminum crimp seal. Each vial of SAR421869 will be issued in a 
white plastic tamper evident container secured in packaging. The vial and plastic tamper-
evident container will be labelled appropriately.
 will be provided in 2R Type I borosilicate glass vials with a 
FluroTec® bromobutyl rubber stopper and aluminum crimp seal. Each vial of 
will be packaged and labelled appropriately.
Investigators and pharmacists should note that the clinical trial supplies may only be used for 
the clinical trial for which they are indicated. They must not be employed for any other trial, 
whether of SAR421869 or not, or for any other clinical or nonclinical use.
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10.1.2 Storage and Disposition of Study Medications
SAR421869 and 
 are frozen liquid formulation, stored at ≤-70°C, in aliquots of 
0.1 mL. SAR421869 must be stored in a locked ≤-70°C freezer in the hospital pharmacy. It
must be stored in such a way that it cannot be mixed up or confused with other medications, 
be they clinical trial supplies or medicines for routine clinical use. The locked ≤-70°C freezer 
must be monitored daily and any deviations in temperature above -70°C reported to the 
Sponsor via the study coordinator within 72 hours, or prior to clinical use.
Dispensing will be documented by completing a log with the date of dispensing and the 
patient details. Used and unused vials should be returned to the hospital pharmacy (or in 
accordance with local standard operating procedures) and stored in labeled biohazard bags 
prior to reconciliation by the trial monitor. Where local procedures require immediate 
destruction of used and unused vials, the process will be witnessed, signed and documented 
on a destruction log.
At each visit, the clinical trial monitor will review the drug-dispensing log and reconcile it 
with the unused vials/destruction log.
10.1.3 Precautions/Overdose
There is no known method of vector removal from the eye should an error occur during 
SAR421869 administration.
10.2
OTHER STUDY SUPPLIES
Electronic case report forms will be used in this study (see Data Collection section below). 
The Principal Investigator and Co-Investigators must keep all study supplies and 
documentation in a secure place.
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11
OBLIGATIONS OF THE INVESTIGATOR REGARDING SAFETY 
REPORTING
11.1
ADVERSE EVENT DEFINITION
An adverse event (AE) is any untoward medical occurrence in a patient that develops or 
worsens in severity during the conduct of a clinical study of a pharmaceutical product and 
does not necessarily have a causal relationship to the investigational product. This can, 
therefore, be any unfavorable and unintended physical sign, symptom, or laboratory 
parameter that develops or worsens in severity during the course of the study, whether or not 
considered related to the investigational product.
All AEs must be described in the appropriate section of the CRF and their seriousness and 
putative relationship (causality) to the study medication and/or protocol procedures noted. 
Adverse events are recorded following signature of the informed consent; this is to ensure that 
any adverse events associated with the screening procedures are captured.
11.2
RELATIONSHIP OF AN ADVERSE EVENT TO THE STUDY DRUG/PROTOCOL 
PROCEDURE
The Investigators are required to provide an assessment of relationship of AEs and SAEs to 
the investigational product.
An event will be considered “not related” to use of the investigational product if any of the 
following tests are met:

An unreasonable temporal relationship between administration of the investigational 
product and the onset of the event (eg, the event occurred either before, or too long 
after, administration of the investigational product for it to be considered 
product-related).

A causal relationship between the investigational product and the event is biologically 
implausible (eg, death as a passenger in an automobile accident).

A clearly more likely alternative explanation for the event is present (eg, typical 
adverse reaction to a concomitant drug and/or typical disease related event).
Individual AE/SAE reports will be considered “related” to use of the investigational product if 
the “not related” criteria are not met.
“Associated with the use of the drug” means that there is a reasonable possibility that the 
event may have been caused by the product under investigation (ie, there are facts, evidence, 
or arguments to suggest possible causation).
An event not meeting any of the above definitions for “not related” will be considered 
“related” to the investigational product.
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11.3
SEVERITY OF AN ADVERSE EVENT
For each AE, the severity must be recorded as one of the following:

Mild: Discomfort noticed but does not interfere with the patient’s daily routines (an 
annoyance).

Moderate: Some impairment of function, not hazardous to health (uncomfortable or 
embarrassing).

Severe: Significant impairment of function, hazardous to health (incapacitating).
11.4
SERIOUS ADVERSE EVENT DEFINITION
Adverse events are classified as either serious or non-serious.
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death, or

Is life-threatening, or
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization, or

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.

Is a medically important event.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may
jeopardize the patient or may require medical or surgical intervention (ie, specific 
measures or corrective treatment) to prevent one of the other outcomes listed in the 
definition above.
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive:

Intensive treatment in an emergency room or at home for:
-
Allergic bronchospasm,
-
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.), 
-
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.).

Development of drug dependence or drug abuse.
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
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x 
ULN.

Suicide attempt or any event suggestive of suicidality.

Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling).

Bullous cutaneous eruptions.

Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the investigators in oncology studies).

Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing 
specifically the effect of a study drug on these diseases).

Suspected transmission of an infectious agent: if  any suspected transmission of an 
infectious agent via a medicinal product (eg, product contamination).
Elective Surgeries
For the purpose of this protocol, the following conventions will apply for SAE reporting of 
elective surgery:

A pre-scheduled elective procedure or a routinely scheduled treatment is not to be 
considered an SAE, even if the subject is hospitalized, provided the site stipulates that:
-
The condition requiring the pre-scheduled elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress between 
the subject’s consent to participate in the clinical study and the time of the 
procedure or treatment,
-
The pre-scheduled elective procedure or routinely scheduled treatment is the sole 
reason for admission and intervention,
-
Any untoward medical event occurring during the pre-scheduled elective 
procedure or routinely scheduled treatment should be recorded as an AE or SAE.
11.5
ADVERSE EVENTS OF SPECIAL INTEREST
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring 
and rapid communication by the Investigator to the Sponsor may be appropriate. Such events 
may require further investigation in order to characterize and understand them. 
Adverse events of special interest may be added or removed during a study by protocol 
amendment. Reporting guidelines for AESIs are provided 
in Section 11.6.2

Acute hypersensitivity/ anaphylaxis

Pregnancy:
-
Pregnancy of a female subject entered in a study and treated with SAR421869,
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-
Pregnancy occurring in a female partner of a male subject within 3 months of male 
subject’s treatment of with SAR421869,
-
The pregnancy will be qualified as an SAE only if it fulfills one of the seriousness 
criteria (see Section 11.4),
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.

Symptomatic overdose (serious or non-serious) with IMP:
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least 30% 
the intended dose or if the dose is administered in less than half the recommended 
duration of administration. 
Of note, asymptomatic overdose has to be reported as a standard AE.

Increase in alanine transaminase (ALT) (see the “Increase in ALT” flow diagram in 
Appendix C of the protocol). 

Other project specific AESIs: 
-
Infection, particularly any opportunistic infection,
-
Immunological reactions (eg, new incidence or exacerbation of rheumatologic or 
other autoimmune disorder),
-
New incidence or exacerbation/recurrence of a hematological disorder.

Ocular AESIs:
-
AEs that cause a decrease in VA of >15 ETDRS letters or > +0.3 Log MAR 
(compared with baseline or the last assessment of VA at the last visit) lasting 
>1 week or 2 successive visits.
-
AEs that require surgical intervention (eg, conventional surgery, vitreous tap or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy 
with gas) to prevent permanent loss of sight.
-
AEs associated with severe intraocular inflammation (ie, >2 step increase in 
anterior chamber cells and flare or a >2 step increase in VH, as described in 
Appendix A).
-
AEs that, in the opinion of the Investigator, may require medical intervention to 
prevent permanent loss of sight.
In the event that a patient enrolled in the study experiences any of the above, blood samples 
for PCR and/or immunological analysis will be taken to rule out involvement of IMP.
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11.6
GENERAL GUIDELINES FOR REPORTING ADVERSE EVENTS

All AEs, regardless of seriousness or relationship to IMP, spanning from the signature 
of the informed consent form until the end of the study as defined by the protocol for 
that patient, are to be recorded on the corresponding page(s) or screen(s) of the CRF.

Whenever possible, diagnosis or single syndrome should be reported instead of 
symptoms. The investigator should specify the date of onset, intensity, action taken 
with respect to IMP, corrective treatment/therapy given, additional investigations 
performed, outcome, and his/her opinion as to whether there is a reasonable possibility 
that the AE was caused by the IMP or by the study procedure(s). 

The investigator should take appropriate measures to follow all AEs until clinical 
recovery is complete and laboratory results have returned to normal, or until 
progression has been stabilized, or until death, in order to ensure the safety of the 
patients. This may imply that observations will continue beyond the last planned visit 
per protocol, and that additional investigations may be requested by the monitoring 
team up to as noticed by the Sponsor. Patients who experience an ongoing SAE or an 
AESI, at the pre-specified study end-date, should be followed until resolution, 
stabilization, or death and related data will be collected. The duration of post-study 
follow-up and reporting of AEs will be until recovery.

When treatment is prematurely discontinued, the patient’s observations will continue 
until the end of the study as defined by the protocol for that patient.
11.6.1 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately:

ENTER (within 24 hours) the information related to the SAE in the appropriate 
screens of the e-CRF; the system will automatically send a notification to the 
monitoring team after approval of the investigator within the e-CRF or after a standard 
delay.

SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and 
the dates on which these examinations were performed, to the representative of the 
monitoring team whose name, fax number, and email address appear on the clinical 
trial protocol. Care should be taken to ensure that the patient's identity is protected and 
the patient's identifiers in the clinical trial are properly mentioned on any copy of a 
source document provided to the Sponsor. For laboratory results, include the 
laboratory normal ranges.

All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc.) should be sent when available (by fax or e-mail) to
the monitoring team. In addition, every effort should be made to further document any 
SAE that is fatal or life threatening within a week (7 days) of the initial notification.

A back-up plan (using a paper CRF process) is available and should be used when the 
e CRF system does not work.
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Any SAE brought to the attention of the investigator at any time after the end of the study for 
the patient and considered by him/her to be caused by the IMP with a reasonable possibility, 
should be reported to the monitoring team.
11.6.2 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE
notification guidelines described in Section 11.6.1, even if not fulfilling a seriousness 
criterion, using the corresponding pages of the CRF (to be sent) or screens in the e CRF.
Instructions for AE reporting are summarized in Table 4.
11.6.3 Guidelines for management of specific laboratory abnormalities
Decision trees for the management of certain laboratory abnormalities by the Sponsor are 
provided in Appendix C.
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 

Neutropenia.

Thrombocytopenia.

Acute renal insufficiency.

Suspicion of rhabdomyolysis.
Table 4 - Summary of adverse event reporting instructions
Event category
Reporting 
timeframe
Specific events in this 
category
Case Report Form 
completion
AE 
form
Safety 
Comple-
mentary Form
Other 
specific 
forms
Adverse Event (non-
SAE, non-AESI)
Routine
Any AE that is not SAE or AESI
Yes
No
No
Serious Adverse 
Event (non-AESI or 
AESI)
Expedited (within 
24 hours)
Any AE meeting seriousness criterion 
per Section 11.4
Yes
Yes
No
Adverse Event of 
Special Interest
Expedited (within 
24 hours)
Acute hypersensitivity/ anaphylaxis
Yes
Yes
No
Pregnancy
Yes
Yes
Yes
Symptomatic overdose
Yes
Yes
No
ALT≥3 ULN (if baseline ALT<ULN) and 
ALT≥2 x baseline (if baseline ALT≥ULN)
Yes
Yes
Yes
Any opportunistic infection
Yes
Yes
No 
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Event category
Reporting 
timeframe
Specific events in this 
category
Case Report Form 
completion
AE 
form
Safety 
Comple-
mentary Form
Other 
specific 
forms
Immunological reactions (eg, new 
incidence or exacerbation of 
rheumatologic or other autoimmune 
disorder)
Yes
Yes
No 
New incidence or 
exacerbation/recurrence of a 
hematological disorder
Yes
Yes
No
Ocular AESIs
Yes
Yes
Yes
11.7
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:

All SAEs that are both unexpected and at least reasonably related to the IMP 
(SUSAR), to the regulatory authorities, IECs/IRBs as appropriate and to the 
Investigators.   

All SAEs that are expected and at least reasonably related to the IMPs to the 
regulatory authorities, according to local regulations.
In this study, some AEs are considered related to the underlying condition and thus will not 
be considered unexpected [please refer to the IB].
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected.
The Sponsor will report all safety observations made during the conduct of the trial in the 
clinical study report.
11.8
WITHDRAWALS DUE TO ADVERSE EVENTS
Once SAR421869 has been administered it cannot be removed from the eye. A patient may
withdraw consent from follow-up monitoring only. If an AE occurs the patient will be 
followed up until the AE is resolved or has stabilized. As the primary endpoint of this study is 
safety and tolerability the patient will continue to be monitored.
Withdrawal from the study and reason for withdrawal must be documented in the CRF.
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11.9
POST-MORTEM
To obtain vital information about the safety of gene therapy, subjects will be informed that at 
the time of death, no matter what the cause, permission for a post-mortem will be requested of 
their families. Autopsies can yield important information that may enable a better 
understanding of the long-term safety of gene therapy products. In addition to the standard 
autopsy, samples of major organs will be taken along with biopsy samples from any 
malignancy associated with the patient’s death. PCR and/or immunological analysis will be 
undertaken by the laboratory designed by the sponsor to rule out involvement of the 
Investigational Product.
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12
DATA SAFETY MONITORING BOARD
12.1
ROLE
An independent Data Safety Monitoring Board (DSMB) will be formed to undertake an 
ongoing review of data from the study. The primary role of the DSMB is to ensure the 
protection and safety of patients participating in the study. The DSMB will review the general 
progress and conduct of the study and assist in resolving any issues that may arise. The 
composition and responsibilities, together with the agreed schedule for reviewing data will be 
detailed in a guidance document (DSMB Charter) approved and signed by all members of the 
committee. The members of this committee will include appropriately qualified medical, and 
if needed statistical personnel.
12.2
RESPONSIBILITIES

Monitor and review safety data of patients participating in the study and advice on 
study termination as appropriate.

Recommend whether to dose escalate after the first three patients in each cohort have 
been dosed.

Recommend the termination of the study if unforeseen safety issues occur which alter 
the risk assessment of the trial.

Provide advice on any other matters as deemed necessary for the safe conduct of the 
trial.
Detailed responsibilities of the DSMB are provided in the DSMB charter.
12.3
ANNUAL SAFETY REPORTS
The Sponsor will make provision for a harmonized International Birth date for SAR421869.
This date will serve as a data lock point from which all annual safety reports will be 
generated. This will be the date of the first regulatory authority protocol approval.
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13
DATA MANAGEMENT AND STATISTICAL ANALYSES
13.1
SAMPLE SIZE ESTIMATES
This is an exploratory study the primary objective of which is to evaluate safety and 
estimation of biological activity effects. No formal sample size calculation has been 
performed.
13.2
STATISTICAL ANALYSES
Due to the small number of patients enrolled in this study, the data will be analyzed by 
descriptive statistics and exploratory figures. A statistical analysis plan will be finalized prior 
to database lock. It is envisaged that analyses will be performed on all available data.
13.3
INTERIM ANALYSIS
An interim analysis will be conducted on all available safety data and any available 
preliminary efficacy data up to the 3 month time point for Cohort 4 patients. The interim 
analysis, consisting of descriptive statistics and exploratory figures will be used to provide 
data to the regulatory authorities and IRB/ethics committees before pediatric patients are 
enrolled in Cohort 5. Formal statistical tests will not be performed as part of the interim 
analysis.
13.4
SAFETY ENDPOINTS
13.4.1 Adverse Events
The number and percentage of patients with treatment emergent adverse events (ie, started or 
increased in severity after the patient received study treatment and includes abnormal lab 
results, ECGs etc.) will be summarized . The adverse events recorded prior to SAR421869 
administration will not be summarized and will be separated from the adverse events that are 
recorded post SAR421869 administration in the final listings.
An overall summary will include the number and percentage of patients with:

A fatal AE (death).

At least one serious AE.

At least one severe AE.

At least one related AE.

Without any AEs.
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
An additional table will show the number and percentage of patients with treatment 
emergent adverse events broken down by System Organ Class, High Level Term and 
Preferred Term. Related AEs will be summarized separately.

Specific grouping will be done for ocular events that are inflammatory in nature. 
13.4.2 Ophthalmological Safety Endpoints
Changes in other safety endpoints will be summarized at each visit; in addition, where 
appropriate, individual profile plots and mean plot of changes in the variable against time will 
be presented. The primary time points will be considered the 48-week (12-month) visit; the 
individual change at this time point only will plotted against dose received.
13.4.3 Secondary Endpoints
Secondary endpoints will be summarized at each visit; in addition, where appropriate, 
individual profile plots and mean plot of changes in the variable against time will be 
presented. The primary time points will be considered the 24-week (6-month) and 48-week 
(12-month) visit; the individual change at this time point only will plotted against dose 
received.
13.4.4 Immunology Endpoint
The number and percentage of patients with antibody response to SAR421869 administration
at all time-points will be tabulated.
13.4.5 Laboratory Parameters
Hematology, biochemistry and other laboratory data will be listed at each time point by 
treatment cohort and, for appropriate values, will be flagged as ‘High’ or ‘Low’ if outside the 
laboratory normal range.
An additional listing will be provided for those patients who have laboratory values that are 
abnormal and considered to be clinically significant. Laboratory values that become abnormal 
will also be recorded as an adverse event.
13.4.6 Other Safety Parameters
All other safety parameters (vital signs, physical examination, ECG) will be listed by patient, 
treatment assignment, and cohort. New abnormalities will be recorded and summarized under 
adverse events.
13.4.7 Concomitant Medication
Concomitant medication will be listed by patient, treatment assignment, and study visit.
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13.5
BIODISTRIBUTION ENDPOINT

The number and percentage of patients with SAR421869 detected in the blood by 
urine by polymerase chain reaction (PCR) at all time-points will be tabulated.
13.6
OTHER MEASURES
13.6.1 Patient Characteristics
Patient demographic (height, weight, sex, reproductive status) data will be summarized by 
treatment cohort.
The number of patients meeting each inclusion/exclusion criteria will be tabulated. Medical 
history, treatment history, chest X-ray and anesthesia assessment will be listed.
13.6.2 Withdrawals
The number (%) of patients who withdraw from the study over time, along with their reasons 
for withdrawal, will be tabulated.
13.6.3 Deaths
All deaths occurring during the study and its follow-up period will be listed and included in 
the adverse events summary.
13.7
INTERIM ANALYSIS STATISTICAL ANALYSES SPECIFIC TO THE DSMB
MEETINGS
Below described data will serve as IA (as mentioned in Section 13.3) and will be submitted 
for DSMB review of Cohort 4. Similar outputs can be used for additional DSMB review, as 
agreed.
As a minimum the following individual data and mean data will be plotted against time
following surgery:

Adverse events and concomitant medications will be listed.

Laboratory results.

Humoral antibody response and vector distribution data.

BCVA.

IOP.

Slit-lamp examination and fundoscopy data.
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13.8
CASE REPORT FORMS AND DATA COLLECTION
Data must be transcribed from the patient’s notes and entered onto the eCRF completely, 
legibly and in a timely fashion by the PI or his designees. The PI or designees will ensure that 
all CRFs are readable. The PI will also verify that all the data contained on these forms are 
accurate and will sign a form for each patient after the last study visit to document this 
approval.
Case report forms and copies of anonymized supporting documentation such as ECG 
recordings, fluorescein scans, X-rays etc. necessary to support regulatory submissions and 
reports will be provided to, and will remain the property of the Sponsor, and must be available 
for review and retrieval by the Sponsor or Contract research organization (CRO) staff at any 
time. The Investigator (or his designee) is requested to enter data promptly into the eCRF in 
order to facilitate review, monitoring, and correction of CRFs in a timely fashion.
Any subsequent alterations to the source documents must be made by striking out the 
previous entry with a single line and by writing the new value next to it. All such changes 
must be initialed and dated by the PI (or his designee). Whiting or scribbling out of errors is 
not acceptable.
When the monitor reviews the eCRFs certain queries may arise. These will be tracked and 
documented in the eCRF along with the resolution. Copies of these query resolution forms 
will be kept in both the Investigators’ and the Sponsor’s archive.
The PI will retain a copy of all eCRFs and other study related documents in a secure but 
accessible place.
13.9
DOUBLE-BLIND CODES
Double-blind codes are not required.
13.10 CRITERIA FOR TERMINATION OF THE TRIAL
The study may be terminated at any time at the request of the regulatory authorities, the 
IRB/EC or a PI. The study may be terminated at any time by the Sponsor on the basis of any 
safety concern, inadequate enrolment or developments in a related study or program which 
would challenge the clinical and ethical justification for continued enrolment.
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14
ETHICAL CONSIDERATIONS
14.1
PATIENT INFORMATION LEAFLETS AND INFORMED CONSENT FORMS
All patients invited to participate in a clinical trial are entitled to make their decision based on 
the maximum amount of information available at the time. In order to make that choice, they 
will be given a written document expressed in clear concise lay language in their native 
tongue to read. The document will previously have been approved by the relevant ethics 
committees and may be updated as new important information becomes available that may 
affect a patient’s willingness to participate or continue in the trial.
This document will inform potential patients about the nature of the indication and the drug, 
its efficacy and safety profile in animals and man, the human experience to date and the route 
of administration. It will also outline the numbers of patients in the trial and the steps of the 
protocol as they will apply to the individual, including number of visits, venipunctures and 
other invasive procedures and types of measurements to be performed so that the individual 
has a clear picture of the risks, inconveniences and benefits that may accrue from the trial. 
Participants (both male and female) must understand the need for reliable contraception if 
appropriate.
The individual must be made aware that he/she may refuse to join the trial or may withdraw at 
any time without prejudicing further medical care and is covered by the Sponsor clinical trial 
insurance in the event of a mishap. A contact with who suspected trial related injuries may be 
discussed will also be detailed. Individuals must also know that their personal hospital records 
may be reviewed in confidence by the Sponsor (or CRO) staff, Regulatory Authorities and 
ethics committees from time to time, and that personal information about them will be held on 
a confidential database. Conditions for ensuring the security and confidentiality of the 
database should be explained.
Consent must be recorded in writing after the patient has had adequate time to reflect on the 
information and to ask further questions if need be. The consent form must be signed and 
dated by the patient and then countersigned by the Investigator or delegate. A copy of the 
signed consent form may need to be presented to each of the various hospital departments 
participating in the study.
14.2
ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD REVIEW
Prior approval must also be obtained by the relevant EC/IRB of the local hospital. The 
EC/IRB will conform to the standards of ICH E6 and/or the Code of Federal Regulations 
(CFR), specifically 21 CFR Part 56. The EC/IRB will be provided with copies of the protocol, 
any amendments, patient information and consent forms for review. Independent ethics 
committee approval must always be recorded in writing. The approval documents should 
clearly identify the protocol by title and an EC/IRB identifying number, identify the 
committee members present when the approval was granted, and list any required 
amendments with the reasons for them. If a protocol is refused approval, the reasons will be 
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given in writing. Amendments and refusals will be notified to all other committees 
considering the study and refusals will be notified to relevant Regulatory Authorities. The 
EC/IRB will review ongoing studies at appropriate intervals.
The study will not begin and study supplies will not be shipped to the site until written 
approval is received by the Sponsor. The EC/IRB will also provide a list of its members, their 
affiliations and its written procedures if requested by the Sponsor as part of the pre-study 
documentation. The EC/IRB must keep records of all its procedures and decisions for at least 
three years after completion of the trial and make them available on request to representatives 
of regulatory authorities.
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15
REGULATORY REQUIREMENTS AND 
SPONSOR/INVESTIGATOR OBLIGATIONS 
This study will be conducted in accordance with the GCP Guidelines as issued by the 
International Conference on Harmonisation (ICH 135/95, 1996), the Declaration of Helsinki 
and the Code of Federal Regulations Title 21 (Appendix B). These documents will be 
provided in the site study file. To ensure compliance with the guidelines, the study will be 
audited by third parties including independent auditors and possibly Regulatory Authorities. 
The Investigators agree, by written consent to this protocol, to co-operate fully with 
compliance checks by allowing access to all documentation by authorized individuals. 
The study may not begin and clinical trial supplies will not be shipped until the Sponsor 
receives relevant regulatory and EC/IRB written approvals.
15.1
STUDY INITIATION
It is essential that all personnel concerned with the trial understand their duties and 
responsibilities fully. In order to facilitate this process, site initiation visits will be conducted 
by the Sponsor or designee prior to first patient recruitment and after EC/IRB approval has 
been obtained. It is expected that all personnel involved will attend this meeting and will 
familiarize themselves with the protocol, the CRF and the principles of GCP which will be 
implemented during the trial.
15.2
MONITORING
The purposes of clinical trial monitoring are to verify that the rights and wellbeing of human 
patients are protected, that reported trial data are accurate, complete and verifiable from 
source documents and that the conduct of the study is in accordance with current GCP and 
regulatory requirements. In order to assist with the collection in a timely fashion of accurate, 
verified data which are in accordance with the protocol, monitors will visit the study sites 
regularly. They will audit source documents and compare them with data contained in the 
CRF. If inconsistencies occur, these queries will be answered by the investigator. The 
monitors will also check patient accrual, drug dispensing logs, temperature monitoring logs 
and other equipment as necessary, lists of persons to whom clinical trial related activities have 
been delegated and relevant communications with family physicians. They will also visit 
associated laboratories to ensure their continuing compliance with the protocol and with GCP 
and deal with any problems arising in the course of the study. The investigators and others 
involved in the study must make adequate time available to be present at these visits.
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15.3
DOCUMENTATION AND RECORD KEEPING
Essential records must be retained by the trial sites for at least five years after the last 
approval in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region OR at least two years have elapsed since the formal
discontinuation of clinical development of the investigational product.
No records may be destroyed or moved without the Sponsor’s written permission. The
Sponsor will archive and retain all documents pertaining to the study for the lifetime of the 
product under investigation and final study reports will be kept for a further five years.
15.4
CLINICAL STUDY REPORT
This clinical study will be summarized by the sponsor (or designated CRO) and a final 
audited report must be retained on file. This report will include discussions of the study 
objectives, methodology, findings, and conclusions. The PIs will be asked to review and 
comment on the draft report and will be required to sign the final version. In a multicenter
study, other investigators will be provided with a copy of the final report for their 
information. This report must be archived with all other study related documents.
15.5
TERMINATION OF THE STUDY
The study may be terminated at any time at the request of the regulatory authorities, the 
Institutional Review Board/Independent Ethics Committee or a PI. The study may be 
terminated at any time by the Sponsor on the basis of any safety concern, inadequate 
enrolment or developments in a related study or program which would challenge the clinical 
and ethical justification for continued enrolment.
The study may be terminated prematurely by an investigator by giving 30 days written notice. 
The Sponsor retains the right to terminate the study immediately upon written notice. If a 
clinical study is terminated early for whatever reason, the investigator will return all samples 
and supplies, to the Sponsor and will notify the EC/IRB. Whichever party terminates the 
study will provide a written statement as to the reason for the termination. The Sponsor (or 
CRO) will notify Regulatory Authorities as appropriate of premature terminations.
At the end of a clinical study, investigators must return to the Sponsor (or CRO) all unused 
clinical trial supplies and loaned equipment unless other arrangements have been made.
Study completion is defined as the date when the final patient has completed his/her final visit 
for the study.
All patients enrolled to the current study will be encouraged to enter a long-term follow-up 
study performed under a separate protocol, in which they will be followed intensively for 
5 years and then for a maximum of 10 years.
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15.6
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
REQUIREMENTS
The Sponsor will purchase and maintain no fault compensation for clinical trial insurance 
sufficient to meet local regulatory requirements. In the event of a proven study drug-induced 
injury, proof of guilt or negligence will not be required. Settlements will be decided by 
arbitration and the decision of the arbitrator will be final.
15.7
PUBLICATION AND COMMUNICATION
The Sponsor actively encourages publication of clinical trial data in reputable peer reviewed 
journals. Authorship will be discussed and agreed in advance.
In this context, no submission for publication and/or written and/or oral disclosure regarding 
the Study shall be made by the Investigator without prior written consent of the Sponsor. 
Therefore, the Investigator agrees to:

Submit the draft of any proposed publication and communication to the Sponsor at 
least sixty (60) days prior to submission for publication communication.

Submit the draft of any proposed abstract to the Sponsor at least thirty (30) days prior 
to submission for publication.
As the Study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, publication of the results of the Study shall be made only as part of a 
publication of the results obtained by all sites performing the Protocol.
15.8
PROTOCOL AMENDMENTS
All items in this protocol must be followed exactly. If any deviations occur, they must be 
documented and explained. If an amendment is required, this will be enacted through a formal 
documented protocol amendment procedure and must receive approval from all 
Health Authorities and Committees, as required. The approved amendment will be distributed 
to all protocol recipients with instructions to append them to the protocol (or a revised 
protocol will be issued).
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16
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congenital amaurosis. Human Gene Therapy. 2005,17:845-58.
36. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al.  Effect 
of gene therapy on visual function in Leber’s congenital amaurosis. N. Engl. J. Med. 
2008,358:2231-9.
37. Disability Evaluation Under Social Security. 2.00 Special Senses And Speech – Adult. 2. 
Definition of statuatory blindness. 
<http://www.ssa.gov/disability/professionals/bluebook/2.00-SpecialSensesandSpeech-
Adult.htm>
38. von Rückmann A, Fitzke FW, Bird AC.  In Vivo Fundus Autofluorescence in Macular 
Dystrophies. Arch Ophthalmol. 2010,115(5):609-15.
39. Sharp PF, Manivannan A, Xu H, Forrester JV.  The scanning laser ophthalmoscope--a 
review of its role in bioscience and medicine. Phys. Med. Biol. 2004,49:1085.
40. Grover S, Fishman GA, Anderson RJ, Alexander KR, Derlacki DJ. Rate of visual fields 
loss in retinitis pigmentosa. Ophthalmology. 1997, 104:460-5.
41. Sadeghi AM, Eriksson K, Kimberling WJ, Sjöström A, Möller C.  Longterm visual 
prognosis in Usher syndrome Types 1 and 2. Acta Ophthalmol Scand. 2006, 84:537-44.
42. Jacobson SG, Aleman TS, Sumaroka A, Cideciyan AV, Roman AJ, Windsor EA et.al.  
Disease boundaries in the retina of patients with Usher Syndrome caused by MYO7A 
gene mutations. Inv Ophthalmol & Vis Sci. 2009,50(4);1886-93.
43. Schiefer U, Pascual JP, Edmunds B, Feudner E, Hoffmann EM, Johnson CA, et.al. 
Comparison of the new perimetric GATE strategy with conventional full-threshold and 
SITA standard strategies. Investigative ophthalmology & visual science. 2009,50(1):488-
94.
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44. Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, et al. 
Contrast letter acuity as a visual component for the Multiple Sclerosis Functinal 
Composite. Neurology. 2003. 25;61(10):1367-73.
45. Khadka J, Ryan B, Margrain TH, Court H, Woodhouse JM. Development of the 25-item 
Cardiff Visual Ability Questionnaire for Children (CVAQC). British Journal of 
Ophthalmology. 2010;94(6):730-5.
46. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical 
data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509-16.
47. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardisation of vitreal 
inflammatory activity in intermediate and posterior uveitis. Ophthalmol. 1985; 92:467-71.
48. Youssef PN, Sheibani N, Albert DM. Retinal Light Toxicity. Eye. 2011,25:1-14.
49. Morgan JI, Hunter JJ, Masella B, Wolfe R, Gray DC, Merigan WH, et al. Light-Induced 
Retinal Changes Observed with High-Resolution Autofluorescence Imaging of the Retinal 
Pigment Epithelium Invest Ophthalmol Vis Sci. 2008,49(8):3715-29.
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17
APPENDICES
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Appendix A
   Ocular Inflammation grading
Slit-lamp examination will be performed throughout the study to monitor for ocular 
inflammation. In addition, BCVA, other clinical examination and the results of other 
investigations such as FA may also assist in the evaluation.
The objective assessment of inflammation will comprise separate assessment of the anterior 
segment, vitreous and fundus. Active inflammation only will be assessed and any signs of 
previous inflammation (eg, premacular fibrosis, healed old choroidoretinal scars will not be 
included in the evaluation of the severity score.)
Prelimbal injection will be noted as present or absent, no attempt will be made to assign a 
severity score. Anterior chamber findings will be graded according to cell numbers and the 
intensity of flare using the widest slit beam and luminescence of the slit lamp (Pigmented 
cells and red blood cells will not be counted). See Table 1.
Table 1 - Slit-Lamp Examination Grading of Anterior Chamber Cells and Flare
Grade
Cells / field (Field size is 1mm x1mm)
0
<1 cells/field
0.5+
1-5
1+
6-15
2+
16-25
3+
26-50
4+
>50
Grade
Description of flare
0
None
1+
Faint
2+
Moderate (iris and lens detail clear)
3+
Marked (iris and lens detail hazy)
4+
Intense (fibrin or plastic aqueous)
(The standardization of uveitis nomenclature [SUN] working group. J Ophthalmol 2005;140:509-516) (46)
Vitreous haze, if present is the most reliable sign of intraocular inflammation and the main 
indicator of response to treatment. Vitreous haze is can be determined using fundoscopy 
(indirect ophthalmoscopy). The scoring system is given in Table 2 but it is important to note 
that the grading system is subjective only and media, corneal or lens opacities may 
significantly influence the score.
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Table 2 - Grading of Vitreous Haze
Grade
Description
Clinical findings
0
nil
none
1
minimal
posterior pole clearly visible
2
mild
posterior pole detail slightly hazy
3
moderate
posterior pole detail very hazy
4
marked
posterior pole detail barely visible
5
severe
fundal detail not visible
(Neussenblatt RB, Palestine AG, Chan CC et al. Standardisation of vitreal inflammatory activity in intermediate and posterior 
uveitis. Ophthalmol 1985; 92:467-471) (47)
Inflammation will be assessed by slit-lamp examination and fundoscopy at all study visits. 
The inflammation grading data will be reported and monitored by the DSMB.
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Appendix B
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
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on 
paragraph 29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added)
59th WMA General Assembly, Seoul, October 2008
A. INTRODUCTION
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data.
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs.
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles.
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty.
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my patient will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act in the patient's best interest when providing 
medical care."
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research.
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6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests.
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality.
8. In medical practice and in medical research, most interventions involve risks and 
burdens.
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence.
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration.
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects.
12. 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 adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected.
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment.
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits.
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15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee.
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent.
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research.
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals 
or communities affected by the condition under investigation.
19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject.
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results.
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects.
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees.
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity.
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24. In medical research involving competent human subjects, 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, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject's freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed.
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee.
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship.
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended 
to promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden.
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject's dissent 
should be respected.
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative.
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30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects.
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances:

The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or

Where for compelling and scientifically sound methodological reasons the use of 
placebo is necessary to determine the efficacy or safety of an intervention and the 
patients who receive placebo or no treatment will not be subject to any risk of serious 
or irreversible harm. Extreme care must be taken to avoid abuse of this option.
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits.
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship.
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available.
22.10.2008
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Appendix C
General Guidance for the follow-up of laboratory abnormalities   
by Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
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INCREASE IN ALT
ALT 3 ULN (if baseline ALT <ULN) 
Or, ALT 2 times the baseline value 
(if baseline ALT ULN)
ALT 5 ULN
(if baseline ALT < ULN)
Or, ALT 3 times the baseline 
value
(If baseline ALT ULN)
ALT > 5 ULN
(if baseline ALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ULN)
Total bilirubin 2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOW the instructions #1 to 7 listed in the box below. 
1. INVESTIGATE THE CLINICAL CONTEXT in the previous 72 hours, specifically for malaise with or without 
loss of consciousness, dizziness, and/or hypotension and/or episode of arrhythmia; rule out muscular injury
2. PERFORM the following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubin and Prothrombin Time / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, and 
depending on the clinical context, check for recent infections, eg, EBV, Herpes viruses and toxoplasma 
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDER auto-antibodies: anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
4. CONSIDER consultation with hepatologist
5. CONSIDER patient hospitalization if INR>2 (or PT<50%) and/or central nervous system disturbances suggesting 
hepatic encephalopathy
6. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal product is discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
7. COLLECT/STORE one sample following handling procedures described in PK sections (for studies with PK 
sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of investigational medicinal product).
COMPLETE the 
specific CRF form for 
“ALT increase” 
And INFORM the 
Monitoring Team 
within 24 hours
Monitor LFTs 
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
NOTE: ALT ≥3 ULN (IF BASELINE ALT < ULN) OR ALT ≥2 TIMES THE BASELINE VALUE (IF BASELINE ALT ≥
ULN) SHOULD BE NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM. IN ADDITION, IF ALT < 3
ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED WITHIN 24 HOURS TO THE
MONITORING TEAM
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
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Appendix D
Low-Contrast Sloan Letter Chart Testing
The following are instructions for testing patients using the front illuminated Low-Contrast
Sloan Letter Charts (LCSLC; Precision Vision, LaSalle, IL). A standardized script with 
instructions to be read to the patient by the examiner is included below. The examiner should 
read through the following instructions and practice testing prior to examining study patients.
Preparation and Set-Up:
1. Set room lighting level to 80-100 cd/m2 (equivalent is about 80-100 foot-candles). 
This level illumination may be achieved in a bright exam room/hallway with 
fluorescent lighting. Having exact lighting is less important than using the same 
room/area for each patient/testing session.
2. Place the charts at 2 meters distance from the patient’s eyes. An artist’s easel or 
similar device may be used, or use a ledge, stand, or chair to prop the charts 
perpendicular to the floor. Use a pre-measured string or tape to measure the distance 
from the patient’s eyes (bridge of nose) to the testing charts at the beginning of each 
testing session (each patient).
3. The 100%, 2.5%, and 1.25% contrast level charts will be used for testing.
4. Patients should wear their usual distance correction for testing (glasses or contact 
lenses that are used for driving, etc.). The same glasses or contact lenses (same 
prescription) should be used for each testing session throughout the study.
5. Patients should be asked to read the charts with each eye independently. The eye that 
is not being tested should be covered with an opaque device.
Vision Testing
1. Instruct patient to read slowly, letters only, left to right, starting at the top of the chart.
2. Instruct the patient that they are not allowed to re-read any line.
3. The patient is allowed to correct a “mis-speak” of a single letter only if he/she does so 
before reading the next letter---instruct the patient of this.
4. During the chart reading, PUSH (encourage) the patient until he/she cannot read any 
letters after being told to guess.
5. The patient must guess at each letter, even if he/she cannot easily read it, until he/she 
cannot or does not correctly identify any of the 5 letters on a particular line.
6. Stopping Rule: Once the patient cannot or does not correctly identify any of the 
5 letters on a line after attempting it, STOP. Go on to the next chart.
7. Test all 3 charts in the same order (100%, 2.5%, 1.25%) for each patient.
8. Scoring the test: During testing, circle all letters read correctly on the data forms for 
each chart for each eye. Put an “X” through each incorrectly identified letter; leave 
unattempted letters unmarked.
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9. Fill in the number of letters correct at the end of each line of 5 letters. Record the total 
number of letters correct for each chart at the bottom of the column. 
10. If a patient is unable to identify any of the letters correctly on the first line of any of 
the 3 charts, please indicate this at the top of the data collection form.
Script For Testing to be Read to Patient:
These instructions should be read to the patient once he/she is comfortably seated in front of 
the charts at 2 meters distance (see above for instructions on Preparation and Set-Up):
1. I am going to show you 3 different eye charts with letters on them. The letters will 
become increasingly lighter for each chart.
2. For each chart, please begin at the very top of the chart and read each letter slowly, 
from left to right on each line.
3. If you mis-speak on a letter or feel you have identified it incorrectly, you may correct 
your response only before you read the next letter.
4. You are not allowed to re-read an entire line.
5. Please try not to lean forward in the chair while reading the letters.
After the first chart (100% chart) has been uncovered, say:
1. You may begin reading the letters.
2. Please start at the top of the chart. 
For each chart, allow the patient to continue reading letters until he/she either:
1) Does not identify any of the 5 letters on any given line correctly - say:
You may stop. We will go on to the next chart now.
OR
2) States that they are unable to read any more letters - point to the line which is next for the 
patient to attempt (use the yellow-tipped pointer only) and say:
Can you read any of the letters on this line?
a) If patient responds no - say: Please guess if you can.
If patient responds that they cannot - say:
You may stop. We will go on to the next chart now.
b) If patient responds yes or begins reading, then continue to record responses until the patient 
cannot or does not correctly identify any of the 5 letters on a given line.
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Stopping Rule: For each chart, once the patient cannot or does not identify any of the 5 
letters correctly on a given line, say: You may stop. We will go on to the next chart now.
Please use the yellow-tipped pointer only to point to the charts (pens and fingers may leave 
marks). The examiner may point to the chart when requested by the patient to indicate the line 
that they are attempting/should attempt next.
Repeat the above procedure for each of the 3 charts (100%, 2.5%, and 1.25% in that order) 
with each eye independently.
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Appendix E
History of protocol amendments
Protocol Amendment 7 dated September 23, 2015
Justification for change
In Section 1 Synopsis and in Section 7.2 Entry Criteria.
The sentence “Affiliated with the French social security healthcare system (French patients 
only)” in the Synopsis Main Inclusion Criteria and Section 7.2 which was added as part of 
Protocol Amendment 2 has now been removed in Protocol Amendment 7 to ensure that there 
were no country specific restrictions to patient enrolment in this global, multicentre, 
multinational study.
Justification for change
In Section 8.2 Study Medication Administration and in Section 8.9 Specific Procedures
Based on the DSMB recommendation, a common perioperative medication regimen was
developed and aligned with the study investigators and surgeons for the use of perioperative 
anti-inflammatory agents.
Protocol Amendment 6 dated April 22, 2015
Justification
There were errors in the versioning of protocol amendments (two versions of amendment 4: 
OXB Amendment 4 dated Jan. 22, 2014; Sanofi Amendment 4 dated April 14, 2014 and 
Sanofi Amendment 5 dated April 14, 2014 that occurred during the transfer of sponsorship 
from Oxford Biomedica to Sanofi (Note: Transfer of Sponsorship from Oxford Biomedica to 
Sanofi occurred on June 12, 2014). Therefore, protocol amendment 6 has been prepared to 
rectify the above versioning errors, as an administrative remediation. Additionally, the 
inclusion criteria applying to Cohorts 3, 4 and 5 have been revised to clarify the target 
populations.  On March 13 2015, following evaluation of all safety data to date, the DSMB 
endorsed the beginning of Cohort 3, endorsed the recommendation to include patients with no 
detectable rod-derived amplitudes on the full field ERG and for the preparation of 
Amendment 6 to correct all afore mentioned versioning errors.
Justification for change
The following text has been modified to reflect the need to enroll in subsequent study cohorts 
patients with adequately advanced disease to minimize the risk of vision impairment while 
maintaining the likelihood that the remaining photoreceptors would have sufficient residual 
function to produce the normal MYO7A gene following transduction.  While adequately 
addressing a potential safety concern, the requirement to enroll only patients with no 
detectable rod-cone derived amplitudes or evidence of severe rod-cone dysfunction on the full 
field electroretinogram in the study may limit the likelihood to observe early signals of 
biological activity, the secondary objective of the study, due to the advanced stage of disease 
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in the enrolled population.   Following consultation with experts, the following update to the 
ERG inclusion criterion for the remaining cohorts to be enrolled was proposed: no detectable 
rod-derived amplitudes on full field electroretinogram performed to ISCEV standards. This 
revised criterion would characterize Usher Type 1B patients with advanced retinitis 
pigmentosa who would also exhibit some evidence of cone dysfunction but does not require 
that the cone function be so severe that the likelihood of observing a biological effect is 
reduced.  The revised ERG criterion was discussed with the DSMB who has reviewed all 
available safety data to date in patients treated subretinally with this EIAV lentiviral vector 
(as UshStat® for Usher Syndrome Type 1B and as StarGen for Stargardt’s disease) with no 
safety concerns.  The DSMB endorsed the beginning of Cohort 3 and endorsed the 
recommendation to include patients with no detectable rod-derived amplitudes on the full 
field ERG.
Amended text
1. Synopsis - Main Inclusion Criteria - Part B&C, 7. Study Population & 7.2 Entry Criteria –
Part B&C

No detectable rod derived amplitudes on the full field electroretinogram performed 
to ISCEV standards.
Justification for change
Inclusion criteria added to clarify that patients enrolled in Cohorts 4 and 5 will not meet the 
definition of legal blindness as determined by visual field constriction.
Added Text
1. Synopsis - Main Inclusion Criteria- Part B & C, 7. Study Population & 7.2 Entry Criteria –
Part B&C

Concentric constriction of kinetic visual field centrally in the worse seeing-eye 
equating to a horizontal visual field diameter of >20 degrees, measured through 
the center of the visual field grid. The visual field constriction will be measured by 
Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be 
confirmed by centralized independent assessment of the SKP data.
Justification for change
The following text was added to exclude breast feeding women from the study.
Added Text
1. Synopsis – Exclusion Criteria & 7.2 Entry Criteria - Exclusion Criteria

Pregnant or breastfeeding women.
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Justification for change
Criterion #23 pertaining to mentally or physically disabled patients has been deleted. 
Compliance with GCP precludes the need for this exclusion criterion.
Deleted Text
1. Synopsis – Exclusion Criteria & 7.2 Entry Criteria - Exclusion Criteria

Any physical or mental disability that, in the opinion of the investigator will 
impair the ability of the patient to provide informed consent/assent or effective 
safety assessments as specified by the protocol.
Justification for change
The following text was added to include collection of the results of the MYO7A gene 
mutation documenting patient eligibility for the study.
Added Text
1.Synopsis – Study Population and 7. Study Population

The results of the gene mutation analysis will be collected in the study database 
provided that written results are made available to the site, and participants 
(patients and/or the patient’s parent[s]/legal guardian[s]) would give consent to 
record the results.
Justification for change
The inclusion criteria for study Part A and Part B/C differ in terms of severity of disease. The 
text was amended to clarify that the efficacy data for part A will be analyzed separately.
Amended Text
1.Synopsis - Statistical Analysis  & 12.2 Statistical Analysis

Note: In addition, analysis of the data from Part A will be provided separately.
Justification for change
Appendix C was deleted since there will be multiple local labs with the addition of new sites 
in the USA and EU. 
Deleted Text 
ToC, 1. Synopsis – Exclusion Criteria, 7.2 Entry Criteria - Exclusion Criteria, & 16 
Appendices

Appendix C – Clinical Laboratory Tests.
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Justification for change
The following text was updated to revise the time-points for immunology testing and include 
the possibility of additional immunology blood testing in the event of a positive antibody 
response. In all patients, immunology blood testing will be performed at -1 day, Week 4, 12, 
24 to assess a baseline and the antibody response kinetic and possibly to identify the peak.  In 
patients with positive antibody response at Week 24, additional immunology blood testing 
will be performed at Week 36 and/or Week 48 to document the antibody response kinetic 
until the value returns to baseline in these patients (the need for sample collection beyond 
Week 48, if needed, would be collected in the long term safety study. 
Added Text
2. Study Schedule 

Blood for Immunology : Day -1, Weeks 4, 12, 24, 36 and 48.
8.9 Specific Procedures

Blood for Immunology : Weeks 4, 12, 24, 36 and 48.
Deleted Text
2. Study Schedule 

Footnote for  “Weeks 48i”.

Blood for Immunology - Week 2.
8.9 Specific Procedures

Blood for Immunology - Week 2.
Justification for change
The following text was amended to clarify the requirement to have at least one effective form 
of communication in order to obtain and provide informed consent or assent to participate in 
the study.
Amended Text 
3.14. Rationale for Inclusion of Children and Adolescents – Patient Informed Consent for 
Adults and Children

People with Usher 1 syndrome are congenitally profoundly deaf and have 
vestibular dysfunction as well as prepubertal onset of retinitis pigmentosa leading 
to blindness.  The subject will be required to have at least one effective form of 
communication in order to obtain and provide informed consent or assent to 
participate in the study.  This can be verbal, auditory, written and or tactile 
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communication. Tactile signing is a common means of communication used by 
people with both a sight and hearing impairment and is based on a standard system 
of Deaf Manual Signs.  No specific method of tactile sign language is prescribed 
in this protocol.  The tactile sign language often used by people who first lose their 
hearing and later their sight is hand-over-hand signing where the receiver’s hands 
are placed lightly upon the back of the hands of the signer to read the signs 
through touch and movement. The sign language used in hand-over-hand signing 
is often a slightly modified version of the local Sign Language.  Several other 
versions of tactile sign language exist such as Tracking, Tactile Fingerspelling and 
Braille signing.
Deleted Text in Section 3.14 Rationale for Inclusion of Children and Adolescents–
Patient Informed Consent for Adults and Children

Given that Usher syndrome Type 1B patients are also usually hearing-impaired, it 
will be a prerequisite that all patients have at least one form of effective 
communication to enable informed consent. Communication can be verbal, 
auditory or with the use of tactile sign language. Effective communication will be 
essential for the consent process and for patient enrolment in the study, since 
effective measurement of the ophthalmological evaluations requires both patient 
understanding of the procedure and their active participation. Effective 
communication is essential to ensure the ophthalmic investigations are conducted 
to the highest standard to detect signals of safety and benefit.
Justification for change:
Given the progression of RP in these patients we expect that it may be necessary to follow up 
these patients for more than 1 year to assess efficacy and currently, there are no approved 
therapies in RP.  Also, the statement would likely conflict with exclusion criteria #19. 
Deleted Text
6. Study Design

If UshStat® demonstrates no clinical efficacy in any of the patients after one year 
following administration then the patients may be offered alternative therapies. 
Justification for change
The following text has been updated to include additional European sites.
Amended Text
7.1 Patient Recruitment

This is a multicenter study with sites in the USA and EU.
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Justification for change
The following text has been modified to clarify the process for obtaining the informed consent 
(ICF).
Amended Text
8.8 Study Conduct Specific to Children and Adolescents

Signed and dated written informed consent must be obtained from the patient (or 
assent in the case of minors from their legal guardian/representative), in 
accordance with the local regulations.
Justification for change
Text amended to clarify study personnel performing blood draws in pediatric patients are 
adequately trained.
Amended text:
8.8 STUDY CONDUCT SPECIFIC TO CHILDREN AND ADOLESCENTS

Blood draws will be performed by personnel adequately trained and 
knowledgeable in phlebotomy techniques in pediatric patients.
Justification for change
The following statement was added to clarify that the sample(s) collected may be used for 
other research purposes and will be stored for up to 15 years.
Added Text:
8.9 Specific Procedures

Future Use of Samples.
For subjects who have consented to it, the samples that are unused or left over after 
testing may be used for other research purposes (excluding genetic analysis) related to 
ophthalmology.
Your sample(s) will be transferred to a Sanofi site (or subcontractor site). Your sample(s) will 
be handled and stored at a secure site specialized for such investigations under the 
responsibility of the sponsor up to 15 years after completion of the final report of the main 
clinical. Thereafter, all samples will be destroyed.
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Justification for change
To explore further the treatment effect (safety and biological activity) at the bleb level, video 
of the surgery and/or intra-operative OCT will be collected, where available, in order to 
define as precisely as possible the area of the bleb and consequently, the zone of cell 
transduction.  For the patients already enrolled, if a video of the surgery was obtained the 
patient will be asked to consent to allow the video to be collected and used for analysis.
Added Text 
8.9 Specific Procedures

Where available, the following assessments will be performed:
-
Surgery video-recording,
-
And/or intra-operative OCT.
Justification for change
Statement added to clarify content of the labeling in accordance with local requirements.
Amended Text
9.1.1 Packaging and Labelling

Packaging is in accordance with the administration schedule. The content of the 
labeling is in accordance with the local regulatory specifications and requirements.
Other Administrative Updates
The Protocol has been reviewed and updated to correct grammatical and administrative errors.
Protocol Amendment 5 dated April 14, 2014
Note: Amendment 5 was never submitted to the health authorities during the 
sponsorship transfer however, the amendment was submitted and approved by the local 
IRBs/ECs in the USA and France. The following text below captures all of the 
administrative and content changes pertaining to Sanofi amendment 4 dated 
April 14, 2014 that were incorporated into the protocol amendment 5.
Justification
On June 12, 2014, the study sponsorship will be transferred from Oxford BioMedica Ltd. to 
Sanofi. Therefore the protocol is updated to reflect this change of sponsorship.
Amended text
The header is modified to change the sponsor name, to add the compound code (SAR422459), 
and the study code (TDU13583), as per the new sponsor coding rules.
The cover page is updated with the new sponsor related information.
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Core text: Oxford BioMedica or OXB has been replaced by “the Sponsor” where appropriate.
Corrections of a wording mistake
In Table 3 in Section 7 and the same table in protocol synopsis, Vector Concentration has 
been replaced by Vector total dose per eye.
Changes in AESI and SAE process:
Section 11 has been amended to align the protocol with the Sanofi protocol standards as 
regards to the definition and reporting of adverse events, adverse events of special interest and 
pre-specified lab abnormalities. 
Decision trees for standard pre-specified lab abnormalities data ie, neutropenia, 
thrombocytopenia, acute renal failure, suspicion of rhabdomyolysis and ALT increase have 
been added in appendices. Criteria for Potentially Clinically Significant Abnormalities for 
Studies in Children have been added in appendices.
Other Administrative Updates
The protocol has also been reviewed and updated to correct grammatical and administrative 
errors and harmonize formatting and spelling to US English.
New Sponsor reference numbers have been added.
The names of the PIs in the cover page have been deleted as per new sponsor rules. A page is 
added to specify the name of the coordinating investigator, the monitoring team’s 
representative, the new sponsor, and other emergency telephone numbers.
OXB Sponsor signature page has been deleted following the change of Sponsor. As per new 
Sponsor rules, no Sponsor signature page will be included in the protocol.
The publication policy (Section 15.7) has been updated, in order to harmonize the text across 
all the protocols initially generated by Oxford BioMedica Ltd.
Appendix C (Clinical laboratory tests) has been updated to be consistent with the UshStat®
US1/002/13 – LTS13619 study.
Protocol Amendment 4 dated January 22, 2014
Justification for Amendment 4 changes
The protocol has been amended in response to recommendations from the Agence Nationale 
de Sécurité du Médicament (ANSM) and Comités de Protection des Personnes (CPP).
Justification for change
The following text has been updated as patients in France will be asked to consent to a post-
mortem as part of the study informed consent process.
Amended text
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2.5 & 7 Study Design 
In the event that a patient dies during the study then consent for post-mortem will be sought 
from the patient’s family, unless the patient has already documented their decision with 
regards to a post-mortem. The consent of the family is intended to correspond to the patient’s 
wishes with regards to a post-mortem.
11.8 Post-mortem
To obtain vital information about the safety of gene therapy, patients will be informed that at 
the time of death, no matter what the cause, permission for a post-mortem will be requested of 
their families, unless the patient has already documented their wishes with regards to a 
post-mortem. 
Justification for change
The following text has been amended to clarify that consent and assent will be obtained in 
accordance with country specific regulations.
Amended text
2.7.1 & 8.2.1 Main inclusion criteria
1. Signed and dated written informed consent must be obtained from the patient (or in the case 
of minors from their legal guardian/representative), in accordance with the country specific 
regulations.
9.8 Study Conduct Specific to Children and Adolescents
Children and adolescents will be asked to assent to the study in accordance with country 
specific regulations and ICH GCP guidelines.
Justification for change
The following text has been amended to clarify that written communication is a suitable form 
of communication for the study.  
Amended text
2.7.1 & 8.2.1 Main inclusion criteria
Patients must have suitable verbal, auditory, written and/or tactile sign language 
communication skills (in the opinion of the investigator) as to allow written informed consent 
to be obtained.
4.15 Patient informed consent
Communication can be verbal, auditory, written or with the use of tactile sign language.  
Justification for change
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The following text has been updated to include both rod and cone dysfunction in the inclusion 
criteria
Amended Text
2.7.1. Main Inclusion Criteria, 8. Study Population & 8.2.1 Inclusion Criteria

No detectable rod-cone derived amplitudes on the full field electroretinogram 
performed to ISCEV standards.
Justification for change
The following text was added to exclude breast feeding women from the study.
Additional Text
2.7.2 & 8.2.2 Exclusion Criteria
15.
Pregnant or breastfeeding women.
Justification for change
The following text has been amended to clarify the exclusion criteria relating to alcohol and 
substance abuse.
Amended Text
2.7.2 & 8.2.2 Exclusion Criteria
9. A history or state of dependence or addiction to alcohol or drugs.
Justification for change
Criterion #23 has been deleted as it was felt that it could be classed as discriminatory to 
mentally or physically disabled patients. Compliance with GCP and exclusion 
criterion 24 preclude the need for this exclusion criterion.
Deleted Text
2.7.2 & 8.2.2 Main exclusion criteria
Any physical or mental disability that, in the opinion of the investigator will impair the ability 
of the patient to provide informed consent/assent or effective safety assessments as specified 
by the protocol.
Justification for change
The inclusion criteria for study Part A and Part B/C differ in terms of severity of disease.  The 
text was amended to clarify that the efficacy data for part A will be analysed separately.
Amended Text
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2.8 & 13.2 Statistical Analysis
It is envisaged that analyses will be performed on all available data and in addition analysis of 
Part A data will be provided separately.
Justification for change
The following text was added to clarify the study definition of tactile communication.
Additional Text
4.13. Rationale for Target Patient Population 
People with Usher 1 syndrome are congenitally profoundly deaf and have vestibular 
dysfunction as well as prepubertal onset of retinitis pigmentosa leading to blindness.  The 
subject will be required to have at least one effective form of communication in order to 
provide informed consent and participate in the study.  This can be verbal, auditory, written 
and or tactile communication. Tactile signing is a common means of communication used by 
people with both a sight and hearing impairment and is based on a standard system of Deaf 
Manual Signs.  No specific method of tactile sign language is prescribed in this protocol.  The 
tactile sign language often used by people who first lose their hearing and later their sight is 
hand-over-hand signing where the receiver’s hands are placed lightly upon the back of the 
hands of the signer to read the signs through touch and movement. The sign language used in 
hand-over-hand signing is often a slightly modified version of the local Sign Language.  
Several other versions of tactile sign language exist such as Tracking, Tactile Fingerspelling 
and Braille signing.  
Justification for change
The following text was amended to ensure that the blood volume drawn from paediatric 
patients is appropriate for their body weight.
Amended Text
9.8 Study Conduct Specific to Children and Adolescents
Blood draws will be performed by a dedicated paediatric phlebotomy service, in order to 
ensure that the volume of blood drawn from paediatric patients is appropriate for their body 
weight.
Justification for change
The following text was deleted as study specific exceptions to Annex 13 have been granted by 
ANSM.  Detailed information on packaging and labelling is not required in a clinical 
protocol.
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Deleted Text
10.1.1 Packaging and Labelling 
Packaging and labelling will be in accordance with the Directive 2003/94/EC Good 
Manufacturing Practice (GMP) Annex 13 and The Code of Federal Regulations, specifically 
21CFR Part 211. 
Other Administrative Updates:
The Protocol has also been reviewed to update study personnel details and correct 
grammatical and administrative errors.  
Protocol Amendment 3 dated January 31, 2013
Justification for change
To ensure consistency across sites a centralised independent assessor will evaluate patients 
-28 day visual field data to confirm eligibility (the method of assessing visual field eligibility, 
Semi-automated Kinetic Perimetry (SKP) for Part A of the study, and full-field GATE static 
perimetry for Parts B and C, has not been altered). If the patient’s visual field restriction at 
Day -28 is ambiguous then the assessor may request a repeat of the same test prior to Day -1. 
The independent reviewer’s assessment of the results from the retest will determine the 
patient’s eligibility for inclusion in the study. The requirement for the retest to be conducted 
prior to Day -1 is to allow early confirmation of patient’s eligibility and prevent ineligible 
patients from undergoing further unnecessary study procedures.
References to the patients legal blindness as defined by the US federal statute have been 
removed from the eligibility criteria, as for a patient to be classed as legally blind in the USA 
on visual field criteria they must have a maximum visual field of ≤20 degree in the better eye. 
For this protocol the visual field criteria is set for the worse seeing-eye only.
Amended or Additional Text
2.7.1 & 8.2.1 Entry Criteria
Concentric constriction of kinetic visual field centrally in the worse seeing-eye equating to a 
horizontal visual field diameter of ≤20 degrees, measured through the center of the visual 
field grid. The visual field constriction will be measured by Semi-automated Kinetic 
Perimetry (SKP) and the degrees of constriction will be confirmed by centralized 
independent assessment of the SKP data.
Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from normal 
sensitivity volume (decibel-steradian) on full-field GATE Static Perimetry using the size 
V (1.7°) test target. The percentage reduction in normal sensitivity volume will be 
confirmed by centralized independent assessment of the data.
3. Study schedule
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m
BCVA, full field static perimetry and microperimetry will be performed 3 times during 
screening period; once at the screening visit (Day -28) and on two occasions at baseline 
(Day -1).
k.
Semi-automated Kinetic Perimetry conducted at screening visits Day -28 may be 
repeated prior to Day -1 if requested by the centralized independent assessor.
l.
Semi-automated Kinetic Perimetry will be conducted twice at baseline (Day -1).
4.9 Rationale for Proposed Subretinal Injection Site
In Part A of the study patients will have a visual field in the worse seeing-eye that subtends 
≤20 degrees on the retina.
4.13 Rationale for Target Patient Population
In the current study the patient population selected in Part A (Cohorts 1-3) has a specific 
peripheral visual field restriction (≤20 degrees) set for the worse seeing-eye. It is expected 
that the patient’s peripheral visual field will also be severely constricted in the best seeing-
eye, but the study does not require any specific criteria in the better eye. The Part A patient 
population may therefore not be legally blind, as defined by the US federal statute. They will 
broadly fall into field phenotypes 4-5, or phase 3 of disease progression.
8. STUDY POPULATION
Concentric constriction of kinetic visual field centrally in the worse seeing-eye to ≤20 
degrees.
9.9.2 Screening Clinical and Laboratory/Diagnostic Measurements
SKP (study Part A) or full-field GATE Static Perimetry (study Parts B and C) data from 
Day -28 will be reviewed by a centralized independent assessor to evaluate patient study 
eligibility, with regards to the visual field of the worse seeing-eye. If in the assessor’s opinion 
the Day -28 results are borderline in regards to the patient’s eligibility status then the test may 
be repeated, the retest will be conducted prior to Day -1.
9.9.3 Screening Clinical and Laboratory/Diagnostic Measurements Day -28
Microperimetry and Static Perimetry (procedure to be performed up to three times in 
total at screening, once at this visit)
Semi-automated Kinetic Perimetry (to be conducted once at this visit, may be repeated 
prior to Day -1 if requested by independent assessor)
Justification for change
The following section was deleted as it was not factually correct, BCVA measurements do no 
impact patient eligibility in this study. In addition amendment 3 changes the perimetry 
reading used to assess eligibility to be those conducted prior to Day -1.
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Deleted Text
9.9.2 Screening Clinical and Laboratory/Diagnostic Measurements
BCVA and perimetry will be performed on three occasions during the screening period, (once 
at Day -28 and twice at Day -1). These measures are subject to broad intra-individual 
variability thus to ensure eligibility of the patient an average value in each case will be used.
Justification for change
This section was amended to clarify the perimetry evaluations utilized in the target patient 
population. 
Amended or Additional Text
4.13 Rationale for Target Patient Population
In this study full-field GATE Static Perimetry will be used to identify the patient populations 
and during follow-up for safety monitoring as well as detection of any signs of bioactivity. 
GATE is a new, fast, full thresholding algorithm which is considerably faster than the 
4-2-1 strategy, yet gives comparable results44.
In Part A of the study, patients will be required to have severe visual field constriction 
(evaluated by SKP). Patients will broadly be expected to have visual field loss in the worse 
seeing-eye that is equivalent to ≥50% reduction from normal sensitivity volume on full-field 
GATE Static Perimetry.
Justification for change
The following paragraph was added to clarify which of the screening BCVA and perimetry 
exam results will be used to calculate the baseline value.
Additional Text
2 Synopsis & 6 Endpoints
BCVA and perimetry measurements are subject to broad intra-individual variability. The 
baseline value used for statistical analysis of these measures will be an average of all values 
obtained during the screening period.
Justification for change
To ensure consistency across sites when identifying the treatment eye, details of the 
parameters that will be used to identify the “worse seeing-eye” have been added.
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Amended or Additional Text
9.2.2 Intraocular Injection 
The study eye will be the eye that in the opinion of the investigator, in consultation with the 
patient, is the worse seing eye. In order to select the worse eye the investigator will review the 
patient historic and Day -28 visual acuity and visual field data and also consider which eye is 
dominant and any preferences shown by the patient.
Justification for change
This section has been amended to clarify the visit window for each study visit.
Amended or Additional Text
9.9.14 Flexibility of Assessment Data Capture

Screening/baseline (Day -28) tests may be performed at any time up to 37 days prior 
to Day -1.

Day -1 tests must be performed in the preceding 7 days or on the day of the scheduled 
visit, with the exception of the urine pregnancy test that must be negative on Day -1 
(not unless clinically indicated in <18 years old).

Day 0 tests must be performed on the day of the scheduled visit.
Justification for change
The DSMB recommended the addition of the following section.
Additional Text
11.6 Adverse Events of Special Interest
AEs of special interest include the following:

Recurrent malignancy.

New malignancy.

Infection, particularly any opportunistic infection.

Immunological reactions (eg, new incidence or exacerbation of rheumatologic or other 
autoimmune disorder).

New incidence or exacerbation of a neurological disorder.

New incidence or exacerbation/recurrence of haematological disorder (eg, aenemia).

Other adverse events (eg, inflammation, ischemia, cardiovascular event.
In the event that a patient enrolled in the study experiences any of the above, blood samples 
for PCR and/or Immunological analysis will be taken to rule out involvement of 
Investigational Product.
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Justification for change
The AE severity terms were updated to replace references to the impact of AEs on study 
participation, with references to the impact of AEs on patient general wellbeing. It was felt 
that this better reflected the actual severity of the AEs.
Amended Text
11.3 Severity of an Adverse Event
For each AE, the severity must be recorded as one of the following:
MILD:
Discomfort noticed but does not interfere with the patient’s daily routines 
(An annoyance)
MODERATE:
Some impairment of function, not hazardous to health (Uncomfortable or 
embarrassing)
SEVERE: 
Significant impairment of function, hazardous to health (Incapacitating
Justification for change
The following section was amended to clarify the safety follow-up that will be undertaken if a 
patient dies or suffers an opportunistic infection which participating in the study.
Additional Text
2.5 Synopsis & 7 Study design
In the event that a patient dies during the study then consent for post-mortem will be sought 
from the patient’s family. In the event of development of an infection that is classified as an 
important medical event, particularly any opportunistic infection or onset of an autoimmune 
condition, effort will be made to collect data regarding the infectious agent and the outcome 
of the relevant investigations to characterize the autoimmune disease.
Justification for change
The following text was amended to clarify that as part of the long-term safety follow-up 
study, patients will only be contacted by telephone if they are unable to attend study visits.
Amended Text
2 Synopsis & 7 Study Design
In addition, the investigator will conduct visits/contact the patient by telephone for a 
subsequent 10 years at a minimum interval of once a year to monitor delayed adverse events.
Justification for change
The male and female normal lab ranges had been documented incorrectly.
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Amended Text
APPENDIX C
Haematocrit
Adult
F - <30 or >55
M - <35 or >60
F- 36 - 46
M- 41- 53
%
Justification for change
Addition of information on post-mortem requirements for the study.
Additional Text
11.8 Post-mortem
To obtain vital information about the safety of gene therapy, subjects will be informed that at 
the time of death, no matter what the cause, permission for a post-mortem will be requested of 
their families. Autopsies can yield important information that may enable a better 
understanding of the long-term safety of gene therapy products. In addition to the standard 
autopsy, samples of major organs will be taken along with biopsy samples from any 
malignancy associated with the patient’s death. PCR and/or Immunological analysis will be 
undertaken by OXB to rule out involvement of the Investigational Product.
Other Administrative Updates
The Protocol has been reviewed and updated to correct grammatical and administrative errors.
Protocol Amendment 2 dated August 31, 2012
Justification for changes
Due to the addition of a study site in France a requirement for French patients to be affiliated 
with the French social security system has been added to the inclusion criteria. References to 
the “Food and Drug administration (FDA)” have been changed to “regulatory authority” 
throughout the protocol in order to be inclusive of the French regulatory authority.
The study specific EudraCT number has also been added.
Amended or Additional Text
Title Page
EudraCT number: 2012-002574-31
Section 2.7.1 Synopsis Main Inclusion Criteria
6. Affiliated with the French social security healthcare system (French patients only).
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Section 8.1 Patient Recruitment
This study is multicentre with sites in the U.S.A, and France. The selected sites have 
extensive experience in ophthalmic surgery, intraocular injections and handling of gene 
therapy products.
Section 8.2.1 Main Inclusion Criteria
6. Affiliated with the French social security healthcare system (French patients only)
Justification for changes
The following paragraph has been amended to clarify that the study will comply with ICH 
GCP and any local pharmacovigilance regulatory reporting requirements.
Amended or Additional Text
Section 11.6. Reporting a Serious Adverse Event
OXB’s pharmacovigilance provider will report all suspected unexpected serious adverse 
reactions (SUSARs) to the Regulatory Authorities in accordance with ICH GCP, and any 
local pharmacovigilance regulatory reporting requirements, after the investigator or any agent 
acting on behalf of the sponsor, or the sponsor being notified of the SUSAR.
Justification for changes
The following paragraph has been amended to clarify that routine safety bloods in children 
and adolescents will only be done if clinically indicated and at the discretion of the 
investigator.
Amended or Additional Text
Section 9.8 Study conduct specific to children and adolescents
Routine phlebotomy for safety laboratory blood samples will be kept to a minimum. All 
routine safety bloods will be taken at screening. However, subsequent hematology and 
chemistry evaluations will be as clinically indicated and at the discretion of the investigator.
Other Administrative Updates
The Protocol has been reviewed and updated to correct grammatical and administrative errors.
Protocol Amendment 1 dated October 20, 2011
Justification for changes
The study design and dosing intervals have been amended in response to review by the Food 
and Drug Administration (FDA). Part B of the study will consist of patients’ ≥18years old 
(Cohort 4) with less severe disease, that will be treated at the maximum tolerated dose from 
Part A. The DSMB will review all data from Parts A and B and an interim report including all 
available safety data, preliminary efficacy data and the recommendations from the DSMB will 
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be submitted to the regulatory authorities and institutional review boards for review before up 
to 6 patients ≥6 years or older will be included in Part C of the study (Cohort 5).
The Principal Investigator has recommended that the autofluorescence images and colour 
fundus photography time points are reduced in the early post-operative period, as patients find 
them difficult to tolerate and the images do not provide accurate data so soon after the 
surgical procedure. A reduction in autofluorescence imaging and colour fundus photographs 
also reduces the light exposure that may have a detrimental effect on the retina (48). As an 
infra-red light source is barely visible to the human eye, is more comfortable for the patient 
and presents no concerns about retinal light toxicity, a small montage using infra-red imaging 
will be included as part of the OCT imaging to provide comparable information to the 
previously specified autofluorescence imaging time points (49). An additional fundus 
montage will also be included at Week 48.
Since full field and multifocal Electroretinogram (ERG) assessment forms part of the 
inclusion criteria to determine patient eligibility during the 28-day screening period, the ERG 
time point has been moved from baseline (Day -1) to the screening visit (Day -28).
Macular edema was included in the exclusion criteria in error. It is not a contraindication to 
surgery, is often observed on spectral domain OCT in a number of patients with Usher types 
1B, and an improvement following treatment would be considered a benefit.
The results of microperimetry will be transitorily affected by retinal elevation in the region of 
the bleb during the early post-operative period, therefore it is not a good primary safety 
assessment during this phase. Once the transient effect of the elevated bleb is resolved the 
microperimetry testing could be considered a secondary biological endpoint.
Amended or Additional Text
The protocol has been updated throughout to include the changes to the patient population for 
Part B and the addition of Part C.
Section 4.12 Rationale for dosing Intervals
Prior to the inclusion of paediatric patients ≥6 years of age (Cohort 5), the DSMB will review 
all safety data, including data from Parts A and B, three months after all 3 patients in  
Cohort 4 have been dosed. An interim report including all available safety data, preliminary 
efficacy data and the recommendations from the DSMB will be submitted to the regulatory 
authorities and institutional review boards/ethics committees for review, before patients 
≥6 years of age or older can be enrolled into Part C of the study.
Section 4.13 Rationale for Target Patient Population
Patients to be enrolled in Parts B and C (Cohorts 4 and 5) of the current study will broadly fall 
into phase 2 or phenotype 3 of the classification.
Sections 6.2 and 2.4 Secondary Endpoints Visual field testing: (Semi-automated Kinetic 
(SKP) and Full-Field GATE Static Perimetry), and microperimetry.
Section 7.0 and 2.5 Study Design
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The DSMB will recommend whether to dose escalate following review of the data one month 
after all three patients have been dosed in each cohort in Part A.
If the safety and tolerability of UshStat® is considered satisfactory by the DSMB in Part A 
and to further characterize the risk: benefit profile of UshStat®, the study will proceed to Part 
B, where 3 patients ≥18 years of age with less severe disease, (Cohort 4) may be treated at the 
maximum tolerated dose determined from Part A, these patients may be enrolled in parallel.
The DSMB will review all safety data including the data from Parts A and B three months 
after all 3 patients in Cohort 4 have been dosed. An interim report including all available 
safety data and preliminary efficacy data will be submitted to the regulatory authorities and 
institutional review boards/ethics committees for review and consideration, before up to 
6 patients ≥6 years of age or older can be enrolled in Part C of the study (Cohort 5). Patients 
enrolled into Part C will be treated at the MTD determined from Part A of the study and 
further characterised in Part B of the study.
All patients will be followed for 48 weeks. After this period they will enter an open-label 
safety study for long-term follow-up visits. Patients will attend visits at a minimum interval of 
one visit every six months, for assessments that will include ophthalmological examinations 
and recording of adverse events for 240 weeks (5 years).
Part C
Cohort
Age (yr)
Subretinal Injection
Number of patients
Vector concentration
Volume
5
≥6
6
MTD
300 µL
Section 8 Study Population
Three populations of patients with differing disease severity and/or ages will be recruited:
Part C
Patient population to be included in Cohort 5
(a)
Patients ≥6 years of age.
(b)
Clinical and molecular diagnosis of Retinitis Pigmentosa caused by MYO7A 
mutations.
(c)
Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from 
normal sensitivity.
(d)
Electroretinographic evidence of severe rod-cone dystrophy.
Section 8.2.1 and 2.7 Inclusion Criteria
Specific Inclusion Criteria Cohort 4

≥18 years of age
Part C
Specific Inclusion Criteria Cohort 5
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
≥6 years of age

Visual field loss in the worse seeing-eye that is equivalent to ≥30% reduction from 
normal sensitivity volume (decibel-steradian) on full-field GATE Static Perimetry 
using the size V (1.7°) test target.

Evidence of severe rod-cone dysfunction on full-field electroretinogram performed to 
ISCEV standards.
Section 9.1.2 Dose Extension (MTD) Parts B and C
The Maximum Tolerated Dose to be used in Parts B and C (Cohorts 4 and 5) of the study will 
be determined from the dose escalation phase (Part A). Cohort 4 will include only adult 
patients (≥18 years or older) with less advanced RP, while Cohort 5 will provide the 
opportunity to include paediatric patients ≥6 years of age. Before paediatric patients can be 
enrolled into the study, the DSMB will review all safety data including the data from Part B, 
three months after all 3 patients in Cohort 4 have been dosed. An interim report including all 
available safety data and preliminary efficacy data will be submitted to the FDA and 
institutional review boards/ethics committees for review prior to the enrollment of paediatric 
patients.
Section 8.2.2 and 2.7.2 Exclusion Criteria
Presence of significant ocular abnormalities in the study eye that in the opinion of the 
Investigator would preclude the planned surgery, effective safety follow-up, or interfere with 
the interpretation of study endpoints (eg, glaucoma, corneal or significant lens opacities, 
pre-existing uveitis, intraocular infection, choroidal neovascularization).
Section 9.9 Study Procedures and 3. Study Schedule
Autofluorescence has been removed from the visit schedule at Screen Day -1, Day 1, 
Weeks 1, 2 and 36.
Fundus photography has been removed from the visit schedule at Screen Day -1, Week 1 and 
12.
Autofluorescence will be performed at Weeks 4, 12, 24 and 48.
Fundus photography will be performed at Weeks 2, 4, 24, 36 and 48.
Full field and multifocal Electroretinogram (ERG) assessment during the 28 day screening 
period has been moved from baseline (Day -1) to the screening (Day -28) visit.
An infra-red fundus montage using infra-red imaging will be performed as part of every OCT
procedure.
Section 13.3 Interim Analysis
An interim analysis will be conducted on all available safety data and any available 
preliminary efficacy data up to the 3 month time point for Cohort 4 patients. The interim 
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analysis, consisting of descriptive statistics and exploratory figures will be used to provide 
data to the FDA and IRB/ethics committees before paediatric patients are enrolled in 
Cohort 5. Formal statistical tests will not be performed as part of the interim analysis.
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TDU13600 16.1.1 Amended Protocol 08
Clinical Approval
09-Aug-2018 09:54 GMT+0200
Clinical Approval
09-Aug-2018 12:40 GMT+0200

SAP_001.pdf: 
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UshStat (SAR421869) TDU13600 Study SAP 
July 22, 2016 
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TABLE OF CONTENTS 
1.0 
INTRODUCTION ............................................................................................................... 1 
2.0 
STUDY OBJECTIVES ........................................................................................................ 1 
2.1 
Primary Objective ................................................................................................................................. 1 
2.2 
Secondary Objective ............................................................................................................................. 1 
3.0 
STUDY DESIGN ................................................................................................................ 1 
3.1 
Study Stopping Criteria ........................................................................................................................ 4 
3.2 
Dose Limiting Toxicities ...................................................................................................................... 4 
4.0 
TARGETED STUDY POPULATION .................................................................................... 4 
4.1 
Inclusion Criteria .................................................................................................................................. 4 
4.1.1 
Main Inclusion Criteria .................................................................................................................. 4 
4.1.2 
Specific Inclusion Criteria for Cohorts 1, 2 and 3 ......................................................................... 5 
4.1.3 
Specific Inclusion Criteria for Cohort 4 ......................................................................................... 5 
4.1.4 
Specific Inclusion Criteria for Cohort 5 ......................................................................................... 6 
4.2 
Exclusion Criteria ................................................................................................................................. 6 
5.0 
ENDPOINTS ..................................................................................................................... 8 
5.1 
Primary Endpoints ................................................................................................................................ 8 
5.2 
Secondary Endpoints ............................................................................................................................ 8 
5.3 
Other Endpoints .................................................................................................................................... 9 
5.3.1 
Immunology Endpoint ................................................................................................................... 9 
5.3.2 
Clinical Laboratory Tests ............................................................................................................... 9 
5.3.3 
Biodistribution Endpoint ................................................................................................................ 9 
6.0 
GENERAL STATISTICAL CONSIDERATIONS ................................................................... 9 
6.1 
Sample Size .......................................................................................................................................... 9 
6.2 
Primary Data Set ................................................................................................................................... 9 
6.3 
Handling Data Irregularities ............................................................................................................... 10 
6.4 
Interim Analyses ................................................................................................................................. 10 
6.5 
Analyses Specific to DSMB Reports .................................................................................................. 10 
6.6 
Software to be used for Analyses ....................................................................................................... 10 
7.0 
STATISTICAL ANALYSES .............................................................................................. 11 
7.1 
Patient Flow and Compliance ............................................................................................................. 11 
7.2 
Baseline Characteristics ...................................................................................................................... 11 
7.3 
Primary Endpoint ................................................................................................................................ 12 
7.3.1 
Adverse Events .............................................................................................................................12 
7.3.2 
Best-Corrected Visual Acuity (BCVA) ........................................................................................13 
7.3.3 
Ocular Inflammation .....................................................................................................................13 
7.3.4 
Intraocular Pressure (IOP) ............................................................................................................13 
7.3.5 
Optical Coherence Tomography (OCT) .......................................................................................13 
7.3.6 
Laboratory Parameters ..................................................................................................................14 
7.3.7 
Vital Signs ....................................................................................................................................14 
7.3.8 
Concomitant Medications .............................................................................................................14 
7.3.9 
Physical Examinations ..................................................................................................................15 
7.4 
Secondary Endpoints .......................................................................................................................... 15 
7.4.1 
Full-field Kinetic and Static Perimetry .........................................................................................15 
7.4.2 
Electroretinogram (ERG) ..............................................................................................................15 
7.4.3 
Visual Function Questionnaire (VFQ-25) .....................................................................................16 
7.4.4 
Supplementary Reading Center Data ............................................................................................16 
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TABLE OF CONTENTS (CONTINUED) 
 
 
7.5 
Other Endpoints .................................................................................................................................. 16 
7.5.1 
Immunology ..................................................................................................................................16 
7.5.2 
Biodistribution Endpoint ...............................................................................................................16 
7.6 
Safety Analysis ................................................................................................................................... 16 
7.6.1 
Determination of Maximum Tolerated Dose (MTD) ....................................................................16 
8.0 
A LIST OF PROPOSED TABLES/FIGURES ...................................................................... 17 
8.1 
Patient Flow and Compliance ............................................................................................................. 18 
8.2 
Baseline Characteristics ...................................................................................................................... 21 
8.3 
Primary Outcome Analyses ................................................................................................................ 25 
8.3.1 
Adverse Events .............................................................................................................................25 
8.3.2 
BCVA, Ocular Inflammation and IOP ..........................................................................................32 
8.3.3 
Laboratory Parameters ..................................................................................................................37 
8.3.4 
OCT ..............................................................................................................................................37 
8.3.5 
Vital Signs ....................................................................................................................................38 
8.4 
Secondary Outcome Analyses ............................................................................................................ 38 
8.4.1 
Full-field Kinetic and Static Perimetry .........................................................................................38 
8.4.2 
ERG ..............................................................................................................................................39 
8.4.3 
VFQ-25 .........................................................................................................................................44 
8.5 
Other Endpoints .................................................................................................................................. 44 
8.5.1 
Immunology ..................................................................................................................................44 
8.5.2 
Biodistribution Endpoint ...............................................................................................................45 
9.0 
PATIENT PROFILES ....................................................................................................... 45 
9.1 
Baseline Characteristics ...................................................................................................................... 45 
 
 
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1.0 
INTRODUCTION 
This statistical analysis plan provides details of the proposed statistical analyses for the 
clinical trial entitled “A Phase I/IIa Dose Escalation Safety Study of Subretinally Injected 
UshStat, Administered to Patients with Retinitis Pigmentosa Associated with Usher 
Syndrome Type 1B.” Study number TDU13600. This document contains a review of the 
study objectives and design, general statistical considerations, comprehensive statistical 
analysis methods for efficacy and safety endpoints, and a list of proposed tables and graphs. 
Any deviation from this statistical analysis plan will be described in the final study report, as 
appropriate. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the safety and tolerability of ascending doses of subretinal injections of UshStat 
in patients with Usher syndrome type 1B. 
2.2 
Secondary Objective 
To evaluate possible biological activity of UshStat. 
3.0 
STUDY DESIGN 
This is a Phase I/IIa open-label dose escalation study of subretinally injected UshStat in 
patients with Usher’s retinitis pigmentosa (RP). All patients will be followed for 48 weeks. 
After 48 weeks, patients will enter an open-label safety study, and long-term follow-up visits, 
including ophthalmological examinations and recording of Adverse Events (AEs), will 
continue for 240 weeks (five years). For a subsequent 10 years, delayed AEs will also be 
monitored. Details of the assessments and analysis methods for this long-term follow-up 
study will be discussed in a separate SAP. 
 
A projected total of up to 18 patients will be enrolled in this study, consisting of five dose 
cohorts. The study is separated into a dose escalation phase, Part A (Cohorts 1, 2 and 3), 
followed by two dose extension phases at the maximum tolerated dose (MTD), Parts B 
(Cohort 4) and C (Cohort 5). Part A will evaluate three ascending dose levels of UshStat in 
300 µL of vehicle. Up to nine patients will be enrolled in Part A, three patients per dose 
cohort. All patients enrolled in Part A must be at least 18 years of age, have clinical and 
molecular diagnosis of RP associated with Usher syndrome type 1B caused by MYO7A 
mutation(s), exhibit concentric constriction of kinetic visual field centrally in the worse 
seeing eye to ≤20 degrees confirmed by visual field measurement by Semi-automated Kinetic 
Perimety (SKP), and have no detectable rod-derived amplitudes on full-field 
electroretinogram (ERG).  
 
 
 
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In Part A of the study, a minimum interval of 21 days between the dosing of the first and 
subsequent patients in each cohort and a minimum interval of 28 days between cohorts has 
been selected in order for the DSMB to assess any acute toxicity, post-operative 
complications and the safety profile at each dose level of UshStat. The DSMB will be 
responsible for determining whether to proceed enrolling the next cohort of patients. Based 
on accrual of the data, the DSMB will comprehensively review the safety and tolerability of 
UshStat and make the decisions regarding dose escalation, study continuance, and 
recommended amendments to the protocol. If after a minimum interval of 28 days from the 
dosing of the third patient in a given cohort, the safety and tolerability is considered 
satisfactory by the DSMB, then the next cohort of three patients will be enrolled. The 
maximum tolerated dose (MTD) will be defined as the highest dose level that has an 
acceptable safety and tolerability and positive benefit/risk profile in the opinion of the 
DSMB. 
 
If the safety and tolerability is considered satisfactory by the Data Safety and Monitoring 
Board (DSMB), regulatory authorities and institutional review boards (IRB) / independent 
ethics committees (EC) in Part A of the study, then the study will proceed to Part B that may 
enroll a maximum of three patients in parallel.  
 
Patients enrolled in Part B must be at least 18 years old, have RP associated with Usher 
syndrome type 1B caused by MYO7A mutation(s), exhibit concentric constriction of kinetic 
visual field centrally in the worse seeing eye equating to a horizontal visual field diameter of 
>20 degrees confirmed by visual field measurement by Semi-automated Kinetic Perimetry 
(SKP), exhibit visual field loss in the worse seeing eye that is equivalent to at least 30% 
reduction from normal sensitivity volume (decibel-steradians) on full-field German Adaptive 
Thresholding Estimation (GATE) Static Perimetry using the size V test target, and have no 
detectable rod-derived amplitudes on full field ERG. 
 
Part C provides the opportunity to extend the study to include pediatric patients at least  
six years of age. Prior to inclusion of pediatric patients, the DSMB will review all safety data 
three months after all three patients in Cohort 4 have been dosed. An interim report including 
all available safety data, preliminary efficacy/activity data and the recommendations from the 
DSMB will be submitted to regulatory agencies and institutional review boards/ethics 
committee for review before patients of at least six years of age will be included in Part C of 
the study (Cohort 5).  
 
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The UshStat doses to be studied are: 
 
 
Subretinal Injection 
Part A 
 
Cohort 
Age 
Number of 
patients 
Vector total dose per eye 
Volume 
 
1 
≥18 
3 
1.4 x 105 TU 
300µL 
 
2 
≥18 
3 
4.7 x 105 TU 
300µL 
 
3 
≥18 
3 
1.4 x 106 TU 
300µL 
Part B 
 
4 
≥18 
3 
MTD 
300µL 
Part C 
 
5 
≥6 
Up to 6 
MTD 
300µL 
 
The initial UshStat dose to be studied will be 1.4 × 105 transducing units (TU), in 300 L of 
vehicle. Dose levels will increase to a maximum of 1.4 × 106 TU. The MTD will be defined 
as the highest dose level that has an acceptable safety and tolerability and positive 
benefit/risk profile in the opinion of the DSMB. 
 
Patients will be allocated to active treatment (UshStat), in the order in which they are 
enrolled into the study. A minimum of 21 days must be allowed between dosing of the first 
and subsequent patients in any cohort, and a minimum of 28 days must be allowed between 
the final patient of one cohort and the first patient of the subsequent cohort. Three patients 
(with 21 days of follow-up between the first and subsequent patients) will be initially 
enrolled into the first cohort and receive the lowest dose of study drug  
(1.4 × 105 TU). If the DSMB agrees safety and tolerability are acceptable for this group of 
patients at the lowest dose (after a minimum of 28 days), then three more patients will be 
enrolled into the second cohort, receiving the next dose of UshStat (4.7 × 105 TU). Patients in 
Cohort 3 will receive a dose of 1.4 × 106 TU of investigational medicinal product (IMP), in 
accordance with the procedures outlined in the preceding paragraph. 
 
Following determination of the MTD and review of the Part A study data by the DSMB and 
the appropriate regulatory authorities (IRB/EC), three patients will be enrolled in parallel at 
the MTD in Part B (Cohort 4). Finally, the DSMB will review all safety data three months 
after all three patients in Cohort 4 have been dosed, and regulatory agencies and IRB/EC will 
review an interim report including all available safety data, preliminary efficacy/activity data 
and the recommendations from the DSMB. Patients of at least six years of age will be 
included in Part C of the study (Cohort 5).  
 
 
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3.1 
Study Stopping Criteria 
The following are considered stopping criteria: 
 Prolonged anterior chamber inflammation and/or prolonged posterior chamber 
inflammation continuing without signs of resolution 28 days after UshStat 
administration. 
Criteria for suspending enrolment or further study conduct are defined in the DSMB Charter 
and all events will be reviewed by the DSMB. In the event of early study termination, all 
patients who have been dosed with UshStat will continue to be followed-up as per protocol. 
In addition, the study enrolment may be terminated at any time at the request of the Food and 
Drug Administration (FDA), the IRB/EC, the primary investigator (PI), or Sponsor. 
3.2 
Dose Limiting Toxicities 
Dosing will stop if a dose-limiting toxicity is encountered in a dosing cohort. Events that 
constitute a dose-limiting toxicity are defined by the DSMB Charter. Dose-limiting toxicities 
include: 
 Severe or persistent ocular inflammation; 
 Other significant ocular toxicity (e.g., large retinal detachment, evidence of direct 
toxicity); 
 Other systemic toxicities (e.g., acute allergic reaction); 
 Any safety issue that has been identified that adversely changes the benefit/risk 
balance to study participants. 
4.0 
TARGETED STUDY POPULATION 
Patients will be recruited from the hospitals’ Usher syndrome type 1B patient population 
following IEC/IRB and regulatory approval. Up to 18 patients of either sex with Usher 
syndrome type 1B will be enrolled. This is a multicenter study with sites in the USA and EU. 
The selected sites have extensive experience in ophthalmic surgery, intraocular injections and 
handling of gene therapy products. 
4.1 
Inclusion Criteria 
4.1.1 Main Inclusion Criteria 
Patients must meet ALL of the following criteria to be considered for enrolment into this 
study. 
1. Signed and dated written informed consent must be obtained from the patient  
(or assent in the case of minors from their legal guardian/representative), in 
accordance with the local regulations. 
2. Clinical and molecular diagnosis of RP associated with Usher syndrome type 1B, 
caused by at least one pathogenic MYO7A mutation on both alleles, confirmed by 
direct sequencing and co-segregation analysis within the patient’s family. 
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3. Patients must have suitable verbal/auditory and/or tactile sign language 
communication (in the opinion of the investigator) as to allow written informed 
consent to be obtained. 
4. Females of childbearing potential must have a negative urine pregnancy test at 
screening and at baseline, and agree to use an effective form of contraception such 
as the contraceptive pill or intra uterine device for at least three months following 
UshStat administration, or be surgically sterile or postmenopausal, with the last 
menstrual period being over two years prior to enrollment. 
5. Males of reproductive potential must agree with their partner to use two forms of 
contraception, including one barrier method for at least three months following 
UshStat administration if their partner is of childbearing capacity, or must be 
surgically sterile. 
 
Partners of study patients should use barrier contraception for at least three months after 
UshStat administration. 
4.1.2 Specific Inclusion Criteria for Cohorts 1, 2 and 3  
 ≥18 years of age; 
 Concentric constriction of kinetic visual field centrally in the worse seeing eye 
equating to a horizontal visual field diameter of ≤20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by  
Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be 
confirmed by centralized independent assessment of the SKP data; 
 No detectable rod-derived amplitudes on the full field electroretinogram performed to 
ISCEV standards. 
4.1.3 Specific Inclusion Criteria for Cohort 4  
 ≥18 years of age; 
 Concentric constriction of kinetic visual field centrally in the worse seeing eye 
equating to a horizontal visual field diameter of >20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by  
Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be 
confirmed by centralized independent assessment of the SKP data; 
 Visual field loss in the worse seeing eye that is equivalent to ≥30% reduction from 
normal sensitivity volume (decibel-steradian) on full-field GATE Static Perimetry 
using the size V (1.7°) test target. The percentage reduction in normal sensitivity 
volume will be confirmed by centralized independent assessment of the data; 
 No detectable rod-derived amplitudes on the full field electroretinogram performed to 
ISCEV standards. 
 
 
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4.1.4 Specific Inclusion Criteria for Cohort 5  
 ≥6 years of age; 
 Concentric constriction of kinetic visual field centrally in the worse seeing eye 
equating to a horizontal visual field diameter of >20 degrees, measured through the 
center of the visual field grid. The visual field constriction will be measured by  
Semi-automated Kinetic Perimetry (SKP) and the degrees of constriction will be 
confirmed by centralized independent assessment of the SKP data; 
 Visual field loss in the worse seeing eye that is equivalent to ≥30% reduction from 
normal sensitivity volume (decibel-steradian) on full-field GATE Static Perimetry 
using the size V (1.7°) test target. The percentage reduction in normal sensitivity 
volume will be confirmed by centralized independent assessment of the data; 
 No detectable rod-derived amplitudes on the full field electroretinogram performed to 
ISCEV standards. 
4.2 
Exclusion Criteria 
ANY one of the following criteria will exclude patients from being enrolled into the study: 
1. 
Presence of significant ocular abnormalities in the study eye that in the opinion of the 
investigator would preclude the planned surgery, effective safety follow-up, or 
interfere with the interpretation of study endpoints (e.g. glaucoma, corneal or 
significant lens opacities, pre-existing uveitis, intraocular infection, choroidal 
neovascularization). 
2. 
Any pre-existing factor or past history of eye disease in children that may predispose 
to an increased risk of surgical complications in the study eye (e.g. trauma, previous 
surgery, uveitis, congenital, developmental or structural abnormalities). 
3. 
Concomitant systemic diseases including those in which the disease itself, or the 
treatment for the disease, can alter ocular function (e.g. malignancies, diabetes, 
juvenile rheumatoid arthritis or sickle-cell disease). 
4. 
Any ocular surgery including laser and cataract surgery with intraocular lens 
implantation, aphakia or prior vitrectomy, in the study eye within six months of 
screening. 
5. 
Any contraindication to pupil dilation in either eye. 
6. 
Treatment with intravitreal, subtenon, or periocular steroid within four months of the 
screening visit. 
7. 
Any known allergy to any component of the delivery vehicle or diagnostic agents 
used during the study (e.g. fluorescein, dilation drops), or medications planned for use 
during the peri-operative period, particularly topical, injected or systemic 
corticosteroids. 
8. 
Life-threatening illness. 
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9. 
Alcohol or other substance abuse. 
10. Laboratory test abnormalities or abnormalities in electrocardiogram or chest X-ray, 
that in the opinion of the principal investigator, are clinically significant and would 
make the patient unsuitable for participation in the study. 
11. Intercurrent illness or infection 28 days prior to UshStat administration. 
12. Contraindications to use of anesthesia (local or general, as appropriate). 
13. Concurrent anti-retroviral therapy that would inactivate the investigational agent. 
14. Pre-menopausal or non-surgically sterile women who are unwilling to use an 
effective form of contraception such as the contraceptive pill or intrauterine device. 
15. Pregnant or breastfeeding women. 
16. Males or females who do not agree to use barrier contraception as specified in the 
inclusion criteria. 
17. History of any investigational agent within 28 days prior to UshStat administration. 
18. Participation in a prior gene transfer therapy study. 
19. Enrolment in any other clinical study, for any condition, including those relating to 
Usher syndrome type 1B, throughout the duration of the UshStat study. 
20. Current or anticipated treatment with anticoagulant therapy or the use of 
anticoagulation therapy within the four weeks prior to surgery. 
21. Long-term treatment with systemic corticosteroids within 28 days prior to the 
screening visit or ongoing systemic corticosteroid treatment at screening or on  
Day -1. 
22. Current treatment with immunosuppressant therapies. 
23. A history of malignancy within a five year period or have had a positive cancer 
screening test within a one year period of the screening visit. 
24. Past medical history of HIV, or hepatitis A, B or C. 
25. Inability to comply with the study protocol. 
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5.0 
ENDPOINTS  
5.1 
Primary Endpoints 
The primary objective of this study is evaluation of safety and tolerability of ascending doses 
of UshStat in patients with Usher syndrome type 1B. Safety and tolerability of the IMP will 
be evaluated using the following endpoints: 
 The incidence of AEs over a 12-month period following a single intraocular dose of 
UshStat. 
 Clinically important changes from baseline (Day -28) in the following safety 
assessments: 
o Best-corrected visual acuity (BCVA) 
o Slit-lamp examination  
o Indirect ophthalmoscopy  
o Fundus photography  
o Intraocular pressure (IOP) 
o Ocular coherence tomography (OCT) 
o Laboratory parameters 
o Vital signs 
o Concomitant medications 
o Physical examinations 
For all primary endpoints with repeated measures, the primary time point will be considered 
the Week 48 (12-month) visit unless otherwise specified. BCVA and perimetry 
measurements are subject to broad intra-individual variability therefore the baseline value 
used for these measures will be an average of all the values obtained during the screening 
period.  
5.2 
Secondary Endpoints 
The secondary objective is to evaluate UshStat for possible biological activity. An attempt 
will be made to determine a delay in retinal degeneration following subretinal injection of 
UshStat, through changes in function relative to the untreated contralateral eye using the 
following retinal analytical techniques: 
 BCVA 
 Indirect ophthalmoscopy 
 Visual function questionnaire (VFQ-25) 
 Full dilated slit-lamp examination 
 Fundus photography – photomontage 
 Visual field testing: Semi-automated Kinetic Perimetry (SKP), Full-Field GATE 
Static Perimetry, and microperimetry 
 Autofluorescence  
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 Electroretinogram (ERG) 
 OCT 
 
The primary time points for secondary endpoints will be considered the Week 24 (6-month) 
and Week 48 (12-month) visits. 
5.3 
Other Endpoints 
5.3.1 Immunology Endpoint 
Humoral antibody response to UshStat administration. 
5.3.2 Clinical Laboratory Tests 
Hematology, biochemistry, urinalysis and other laboratory data will be measured at various 
time points throughout the study. Values will be flagged as High or Low if outside the 
laboratory normal range. Out-of-range values will be assessed as clinically significant (CS) 
or not clinically significant (NCS) by the investigator. CS out-of-range values will be 
recorded as adverse events. Blood for immunology and blood for PCR will also be taken at 
multiple time points throughout the study, as will urine samples for biodistribution 
assessment. 
5.3.3 Biodistribution Endpoint 
UshStat distribution in blood and urine will be assessed by polymerase chain reaction (PCR). 
6.0 
GENERAL STATISTICAL CONSIDERATIONS 
6.1 
Sample Size 
This is an exploratory study for which the primary objective is to evaluate safety through 
adverse events and clinically meaningful impacts on vision endpoints. No formal sample size 
calculation has been performed. A total of 18 patients will be enrolled in five cohorts. The 
first three cohorts will consist of three patients each, and three and six patients will be 
enrolled in the fourth and fifth cohorts, respectively, at the MTD. 
6.2 
Primary Data Set 
The primary data set to be used to prepare the final analysis and DSMB reports will include 
data from all eligible patients, regardless of adherence to the protocol. However, since 
patients receive only a single treatment, adherence to the protocol will only be affected if 
patients drop out of the study, are lost to follow-up or if patients are seen outside of the visit 
windows as defined in the study protocol. If a patient withdraws from the study, the Week 48 
procedures will be completed where possible.  
 
 
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6.3 
Handling Data Irregularities 
Data which are missing could impact conclusions drawn from even a small number of 
patients, and therefore presentations (tabular and graphical) will include an indication of 
missing values and, where possible, explanations will be provided. All data collected will be 
reported in DSMB reports. There will be no replacement of missing data and no data will be 
removed. Data from experimental procedures, or procedures in which individuals are unable 
to provide reliable results (e.g., poor fixation perimetry), may be presented separately, 
footnoted, or otherwise indicated in the report. 
6.4 
Interim Analyses 
The DSMB will review accumulating data and evaluate safety of the study prior to escalation 
to the next dose cohort. No formal interim analyses will be performed prior to dose 
escalation, but the following section provides analyses that are specific to DSMB reports.  
 
Following completion of Part B of the study, an interim review of data will be conducted on 
all available safety data and any available preliminary efficacy/activity data up to the three-
month time point for patients in the first four cohorts. This review, consisting of descriptive 
statistics and exploratory figures will be used to provide data to the FDA and IRB/ethics 
committees before pediatric patients are enrolled in Cohort 5. Formal statistical tests will not 
be performed as part of the analysis. 
6.5 
Analyses Specific to DSMB Reports 
At a minimum, the DSMB will be provided with the following accumulating data prior to 
making decisions regarding dose escalation: 
 Adverse events and concomitant medications 
 Laboratory results 
 Humoral antibody response and vector distribution data 
 BCVA 
 IOP 
 Slit lamp examination and fundoscopy data 
 
Note that additional endpoint data may be provided in DSMB reports when available or at 
the request of the DSMB. Thus, Sections 7 and 8 describe analyses and tables/plots 
(respectively) that will be presented upon final analyses, and at a minimum, those relevant to 
the above endpoints will be provided in DSMB reports.  
6.6 
Software to be used for Analyses 
Data analyses will be conducted using SAS version 9.2 or higher. Some graphs may be 
generated in R version 3.2.1 or higher. 
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7.0 
STATISTICAL ANALYSES 
In this Phase I/IIa study, statistical analyses will be primarily descriptive and include  
patient-level reports referred to herein as patient profiles. Although UshStat is applied to only 
the study eye, where available, ophthalmic results for both the study and fellow eyes will be 
reported and clearly identified as “study” or “fellow.” Comparisons between the study and 
fellow eyes could be biased as the two eyes were not randomized to determine which eye 
received Investigational Product. The following sections describe data presentations which 
will be available for review prior to proceeding to each cohort and/or at the end of the study. 
Some variables (primarily ophthalmic variables) may be combined with others in patient 
profiles. Refer to Sections 8 and 9 for sample reports. 
 
Data will be summarized using graphical, tabular and/or listing presentations. In addition to 
patient profiles, continuous-scaled variables will be summarized by mean and standard 
deviation and/or median and range while categorical variables will be summarized in 
frequency tables. Percentages given in the summary tables will be rounded and therefore may 
not always add up to exactly 100 percent. 
 
The primary analysis time point will be 48 weeks following administration of UshStat, but all 
results contributing to the primary and secondary endpoints and assessments of safety at all 
study visits will be presented. 
7.1 
Patient Flow and Compliance 
The number of patients screened for eligibility will be reported in a figure, along with the 
number deemed ineligible at the Screening (Day -28) visit. The reasons for ineligibility will 
be provided in footnotes.  
 
A summary of patients’ compliance to the follow-up schedule and study procedures will also 
be tabulated. The number (%) of patients completing and withdrawing from the study over 
time along with reasons for withdrawal, including death, by cohort will be presented in 
tabular format.  
7.2 
Baseline Characteristics 
Baseline demographic and patient characteristics, including height, weight, vital signs, 
reproductive status, medical history, ocular history, chest X-ray, physical examination 
findings, ECG, ophthalmic examination findings (including IOP and visual acuity), imaging 
parameters and laboratory values, obtained from tests given at Screening (Day -28) and 
Baseline (Day -1) visits will be summarized.  
 
 
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7.3 
Primary Endpoint 
The primary endpoint is composed of several endpoints related to safety, each of which will 
be presented at the patient and eye level (refer to Sections 8 and 9). Primary analysis for 
these endpoints, except adverse events, will compare change from Day -28 to Week 48. 
Graphical presentation of cohort summaries will also be presented as described, and 
clinically important changes from Baseline (Day -28) to Week 48 will be indicated and 
summarized. 
7.3.1 Adverse Events 
AEs will be coded using MedDRA® (last version available at time of database lock). All 
reported events for all patients with cohort, event description, event date, resolution date, 
severity, outcome, relatedness, SAE indication, duration, High Level Term (HLT), System 
Organ Class (SOC), and Preferred Term (PT) will be listed. Specifically, AEs prior to 
treatment, treatment emergent adverse events (TEAEs), (i.e., started or increased in severity 
after the patient receives IMP, including abnormal lab results, ECG, etc.) and TEAEs of 
special interest will be listed separately. An overall summary table of TEAEs will also be 
provided that includes the number and percentage of TEAEs and patients with at least one 
TEAE in each dose cohort with:  
 A fatal AE (death) 
 At least one serious AE 
 At least one severe AE 
 At least one AE related to IMP  
 At least one TEAE related to procedure 
 Without any AEs 
 
In addition, tables will present both the number and percentage of TEAEs and patients with 
TEAEs by SOC, HLT, PT, severity and cohort. Adverse events of special interest (AESI), 
detailed in the protocol, will be summarized by SOC, HLT, PT, severity and cohort. AESIs 
will be indicated, where appropriate in the patient profile listing of AEs. AEs related to the 
IMP and serious adverse events (SAEs) will be indicated in the AE listing and described in 
detail in the body of the report. Specific grouping will be done for events inflammatory in 
nature in the eye. Summary tables will be presented both with the inflammatory events 
grouped and without the events grouped. All events with the following preferred terms will 
be considered inflammatory in nature in the eye: 
 
 Anterior chamber cell 
 Anterior chamber inflammation 
 Choroidal effusion 
 Conjunctivitis 
 Eye inflammation 
 Eye discharge 
 Keratitis 
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 Macular oedema 
 Subretinal fluid 
 Uveitis 
 Vitreous floaters 
7.3.2 Best-Corrected Visual Acuity (BCVA) 
BCVA (Early Treatment Diabetic Retinopathy Study [ETDRS] letters read) will be listed by 
visit and eye. BCVA for all patients’ study eye and fellow eye will be presented graphically 
by visit and cohort. Mean changes in BCVA by visit and cohort will be summarized in a 
table and graph by cohort and visit. 
7.3.3 Ocular Inflammation 
The grading system of ocular inflammation can be found in Appendix A of the study 
protocol. The inflammatory grades will be treated as ordinal variables and plotted by patient 
over time. Scores for ocular inflammation, including anterior chamber cells, flare (slit lamp 
examination) and vitreous cells, haze (indirect ophthalmoscopy) and macular edema, will be 
listed by eye and shown graphically similar to the other ophthalmic endpoints. Summary 
counts for the number of ‘step-up’ and ‘step-down’ changes in the inflammation scale in the 
study eye may be tabulated by cohort and visit. Clinically important changes (i.e., ≥ 2 step 
change) as observed in slit lamp examination and/or indirect ophthalmoscopy at any point 
from Day -28 to Week 48 will be indicated and listed where appropriate.  
7.3.4 Intraocular Pressure (IOP) 
The IOP for each visit will be measured using applanation tonometry. IOP will be listed by 
visit and eye. IOP for all patients’ study eye and fellow eye will be presented graphically by 
visit and cohort. Mean changes in IOP by visit and cohort will be summarized in a table and 
graph by cohort and visit. 
 
Clinically important changes and the number of individuals with IOP ≥ 25, ≥ 30, and ≥ 35 
mmHg at any point from Day -28 to Week 48 will be tabulated by cohort and visit. 
7.3.5 Optical Coherence Tomography (OCT) 
Central macular thickness, subretinal fluid, macular volume and other architectural features 
will be measured by OCT. Individual values of macular thickness (in the central sub-field) 
and macular volume will be listed and illustrated graphically similar to the other ophthalmic 
endpoints. Macular thickness and volume will be listed by visit and eye. Macular thickness 
and volume for all patients’ study eye and fellow eye will be presented graphically by visit 
and cohort. Mean changes in macular thickness and volume by visit and cohort will be 
summarized in a table and graph by cohort and visit. 
 
 
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7.3.6 Laboratory Parameters 
Clinical laboratory results, including hematology (WBC, RBC, hemoglobin, hematocrit, 
mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, 
platelets, neutrophils, lymphocytes, monocytes, eosinophils and basophils), blood chemistry 
(phosphorus, calcium, sodium, chloride, bicarbonate, potassium, fasting blood glucose, 
creatine phosphokinase, lactate dehydrogenase), kidney and liver function tests ( creatinine, 
blood urea nitrogen, uric acid, alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, alkaline phosphatase, total protein, albumin, gamma glutamic 
transpeptidase, cholesterol), coagulation (prothrombin time and partial thromboplastin time) 
urinalysis (color, appearance, specific gravity, pH, protein, glucose, ketones, blood, bilirubin, 
microscopy), and urine pregnancy test (for females of childbearing age) will be listed for 
each patient and visit in the patient profiles. Individual lab values will be flagged as ‘High’ or 
‘Low’ if outside the clinical site’s normal ranges. A summary of the number of patients with 
abnormal and/or clinically significant laboratory values will be provided. The following 
laboratory values and thresholds will be highlighted to indicate their clinical significance for 
major functions: 
 
 WBC above 2ULN (upper limit of normal) 
 Neutropenia < 1500 
 Platelets < 100,000 
 Creatinine > 1.5ULN 
 ALT ≥ 3ULN 
 AST ≥ 3ULN 
 Total bilirubin ≥ 2 ULN 
 
The lab values will be graded by site physicians, and clinically significant abnormal lab 
values will also be recorded as AEs.  
7.3.7 Vital Signs 
Vital signs will be summarized and also listed by cohort and visit. In addition, patients’ vital 
signs at each study visit will be listed with other examination results in a patient profile. Any 
abnormalities or clinically significant changes in patients’ vital signs will be indicated.  
7.3.8 Concomitant Medications 
Concomitant medications including the WHO drug coding will be listed by patient, cohort 
and study visit.  
 
 
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7.3.9 Physical Examinations 
Physical examinations will be conducted at Day -28 and Week 48 visits. System abnormality 
frequencies and percentages (including head/ear-nose-throat, respiratory, gastrointestinal, 
cardiovascular, musculoskeletal, neurologic, endocrine/metabolic, lymphatic/hematologic, 
dermatologic, psychological and genitourinary) will be tabulated by cohort at each time 
point. Clinically significant changes, occurring if an assessment was normal at Day -28 but is 
abnormal at Week 48, in physical examination assessments from Day -28 to Week 48 will be 
indicated. 
7.4 
Secondary Endpoints 
The secondary endpoints include changes in the study eye from Day -28 to Weeks 24 and 48 
in function relative to the untreated, contralateral eye in several visual function measures. 
The primary endpoints of BCVA, ocular inflammation and OCT will also serve as secondary 
endpoint measures. Analysis of these parameters will be conducted as outlined in Sections 
7.3.2, 7.3.3 and 7.3.5, respectively. 
7.4.1 Full-field Kinetic and Static Perimetry  
Full-field kinetic and static perimetry will be used to document scotoma and the level of 
retinal function for each patient, and clinically significant changes from Day -28 will be 
highlighted. Perimetry will be performed three times during the screening period (once at 
Day -28 and twice at Day -1) and the mean of the reported perimetry values will be used to 
determine baseline perimetry measurements.  
 
Individual and mean change in total volume loss in visual field as well as total volume of full 
hill of vision will be plotted (dB steradians) over time. Values in each eye will be listed by 
patient, cohort and visit.  
 
Semi-automated kinetic perimetry (SKP) will be used to estimate total area (degrees2) of 
visual field sensitivity for different stimulus intensity levels (I4e, III4e and V4e isopters). 
Individual and mean change in total areas will be plotted against time. Values in each eye 
will be listed by patient, cohort and visit. 
7.4.2 Electroretinogram (ERG) 
Full-field ERG responses include 30 Hz flicker; photopic single flash a- and b-waves; 
scotopic cone-rod flash a- and b-waves; and scotopic rod, dim white light b-wave. 
Amplitudes and implicit times will be presented in tabular format and graphically by patient 
and cohort for study eye and fellow eye as appropriate. Mean changes from baseline will also 
be summarized. Clinically significant changes, defined as a decrease in ERG amplitude of 
greater than 50%, from Day -28 ERG data will be indicated and listed where appropriate.  
 
Peak amplitudes (nV/deg2) and latency (ms) values for multifocal ERG (mfERG) responses 
at Day -28 will be tabulated for each of six concentric rings in the visual field by patient and 
eye. The concentric ring minimum and maximum are collected separately. The minimum and 
maximum are summed together to obtain the peak amplitude (nV/deg2). To examine change 
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in mfERG responses in the central visual field across visits, the mean changes from Day -28 
across the peak amplitudes and latencies of inner rings (Rings 1-3) will be tabulated and 
plotted against time by cohort, patient and eye. In addition, mean changes across the peak 
amplitude and latencies of outer rings (Rings 4-6) will also be tabulated and plotted by 
cohort, patient and eye against time. 
7.4.3 Visual Function Questionnaire (VFQ-25) 
All VFQ-25 responses will be re-coded to a scale of 0 to 100 following the scoring rules 
provided by the questionnaire. The mean of all re-coded scores will determine the score for 
each patient, which will range from 0 to 100. The scores for the 12 VFQ-25 sub-scales will 
also be provided, if appropriate. Change in the VFQ-25 responses from Day -1 to Week 48 
will be tabulated by patient and cohort and 95% confidence limits and/or ranges will be 
provided. Meaningful changes from Day -1 will be highlighted where appropriate.  
7.4.4 Supplementary Reading Center Data 
Fundus photography photomontage, fundus autofluorescence (FAF), and microperimety data 
will all be analyzed separately by Translational Clinical Trials Center (TCTC) at Casey Eye 
Institute, the Central Reading Center at the end of the study. These exploratory measures will 
not be summarized for DSMB meetings. 
7.5 
Other Endpoints 
7.5.1 Immunology 
The number and percentage of patients with antibody responses to any UshStat component at 
all relevant time points will be tabulated by dose cohort. 
7.5.2 Biodistribution Endpoint 
The number and percentage of patients with UshStat detected in the blood and urine by PCR 
at all relevant time points will be tabulated by cohort (See Section 2 of protocol for specific 
visits). These data may not be available for review between cohorts but will be reported when 
available. 
7.6 
Safety Analysis 
The primary, secondary and additional outcomes described in the preceding sections pertain 
mostly to assessing patient safety. The only additional safety assessment will be the 
determination of the MTD. 
7.6.1 Determination of Maximum Tolerated Dose (MTD) 
The MTD will be defined as the highest dose level that has an acceptable safety and 
tolerability and positive benefit/risk profile in the opinion of the DSMB.   
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8.0 
A LIST OF PROPOSED TABLES/FIGURES 
This section contains a list of proposed tables and figures that will be presented in analysis of 
study data, but not all figures and tables will be included in DSMB reports. At a minimum, 
figures and tables from Sections 8.1 through 8.4.2 will be included in DSMB reports, but 
additional figures and tables from remaining sections will be included when possible. 
 
 
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8.1 
Patient Flow and Compliance 
Table 1A will summarize patient compliance with the follow-up schedule. Visits occurring past the protocol required date will be 
indicated where appropriate. Those that have not yet been completed, but remain within the allowed window (See Section 2 of the 
study protocol) will be highlighted in green. 
 
 
Table 1A: Screening and Surgery Dates and Visit Completion by Cohort 
 
Patient 
ID 
Cohort 
Study Eye 
Screen1 
Date 
Screen2 
Date 
Surgery 
Date 
Day1 
Date 
Week1 
Date 
Week2 
Date 
Week4 
Date 
Week12 
Date 
Week24 
Date 
Week36 
Date 
Week48 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1B graphically displays screened patients, patients deemed ineligible at Pre-dose Visit 1 and Pre-dose Visit 2, as well as the 
reasons for ineligibility. It also reflects eligible patients and those being treated at Day 0. 
 
 
 
 
Screened at Pre-dose Visit 1 
(N=) 
Determined to be ineligible at 
Pre-dose Visit 1 
(N=) 
Reasons: 
 
Eligible at Pre-dose Visit 2 and  
received IMP at Day 0  
(N=) 
Determined to be ineligible at 
Pre-dose Visit 2 
(N=) 
Reasons: 
Eligible at Pre-dose Visit 1 
and screened at Pre-dose Visit 2 
(N=) 
 
 
Eligible at Week 48 and did not enroll 
in LTS13619 
(N=) 
Reasons: 
Eligible at Week 48 and enrolled 
into LTS13619  
(N=) 
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Table 1C will list the overall numbers and percentages of patients completing and withdrawing from the study, and these values 
will also be stratified by cohort. Reasons for withdrawal, including death will be provided where applicable. 
 
 
Table 1C: Study Follow-up Completion and Withdrawal (including deaths) 
 
 
Cohort 
Completed 
N (%) 
Withdrawals 
N (%) 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
Total 
 
 
 
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8.2 
Baseline Characteristics 
Table 2A will summarize Baseline demographic information for all patients and stratify the information by cohort. 
 
Table 2A: Demographics Summary by Cohort 
 
 
 
Enrolled 
Patients 
(N=X) 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Cohort 3 
(N=X) 
Cohort 4 
(N=X) 
Cohort 5 
(N=X) 
AGE (years) 
Median (Range) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
GENDER 
Female 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Male 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
RACE 
American Indian or Alaskan 
Native 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Asian 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Black or African American 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Native Hawaiian or other 
Pacific Islander 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Other 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
White 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
ETHNICITY 
Hispanic or Latino 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Not Hispanic or Latino 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
HEIGHT (cm) Median (Range) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
WEIGHT (kg) Median (Range) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
X (X-X) 
 
 
 
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Table 2B will list demographic information by patient. 
 
Table 2B: Detailed Demographic Listing by Cohort 
 
 
Cohort 
Patient 
ID 
Age 
Gender 
Race 
Ethnicity 
Height 
(cm) 
Weight 
(kg) 
 
 
 
 
 
 
 
 
 
 
Table 2C will give a summary of individual patient medical history. Further detailed table(s) may be provided where appropriate. 
 
Table 2C: General Medical History by Patient 
 
Patient 
ID 
Exam 
Date 
Cardio- 
vascular 
Hematology/ 
Oncology 
Psych- 
iatric 
Gastro- 
intestinal 
Neurologic 
Endocrine 
Nephrologic 
Resp- 
iratory 
Autoimmune 
Musculo- 
skeletal 
Allergies 
Non-Ocular 
Surgery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2D will summarize Baseline physical examination parameters for all patients by cohort. Individual patient profiles will also 
include physical examination information, laboratory values, vital signs, etc. at Baseline as well as during follow-up. See Section 9 
for patient profile examples. 
 
Table 2D: Baseline Physical Examination Parameters by Cohort 
 
 
All Eligible 
Patients 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Cardiovascular Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Dermatologic Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Endocrine/Metabolic Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
GI Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Genitourinary Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Head/ENT Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Lymphatic/Hematologic Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Musculoskeletal Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Neurologic Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
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All Eligible 
Patients 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Psychologic Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Respiratory Assessments 
Normal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
Abnormal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
 
Table 2E will give a summary of individual patient reproductive status. 
 
Table 2E: Reproductive Status by Patient 
 
Patient 
ID 
Hysterectomy 
Vasectomy 
Tubal 
ligation 
Postmenopausal 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient profiles will provide notable ocular history at baseline for each patient in tabular format. Please refer to Section 9 for 
examples of patient profiles.  
 
 
 
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8.3 
Primary Outcome Analyses 
8.3.1 Adverse Events 
Table 3A lists the total and percentage of patients (overall and by cohort) experiencing no TEAE, any severe or serious TEAEs, a 
TEAE resulting in death and any TEAE related to IMP or the procedure. Tables 3B to 3I will include the MedDRA version used for 
grading as a footnote. All of the AEs presented will be graded using the same MedDRA version. Tables 3B and 3C summarize 
TEAEs and patients with at least one TEAE by MedDRA SOC, HLT, PT, severity and cohort and Table 3D summarizes treatment 
emergent AESIs by MedDRA SOC, HLT, PT, severity and cohort. 
 
Table 3A: Number and Percentage of TEAEs and Patients Experiencing TEAEs or No Events by Type of Event and Cohort 
 
 
Patients 
Events 
 
All 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
All 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
Cohort 5 
Type of Event 
Fatal 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
No Events 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Related to IMP 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Related to Procedure 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Serious 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Severe 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
 
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Table 3B: Number of TEAEs by MedDRA SOC, HLT, PT, Severity and Cohort (Event-based Counts) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SYSTEM 
ORGAN CLASS 
(SOC) 
HIGH LEVEL 
TERM (HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3C: Number of Patients Experiencing TEAEs by MedDRA SOC, HLT, PT, Severity and Cohort  
(Patient-based Counts) 
(Note that if more than one event in each category is reported for a single patient, the most recent event of maximum severity is counted.) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild Moderate Mild Moderate 
Severe 
Mild Moderate Mild Moderate 
Severe 
SYSTEM ORGAN 
CLASS (SOC) 
HIGH LEVEL TERM 
(HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3D: Number of TEAEs of Special Interest by MedDRA SOC, HLT, PT, Severity and Cohort  
(Event-based Counts) 
 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild Moderate Mild Moderate 
Severe 
Mild Moderate Mild Moderate 
Severe 
SYSTEM 
ORGAN 
CLASS (SOC) 
HIGH LEVEL 
TERM (HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All\ 
 
 
 
 
 
 
 
 
 
 
 
 
Tables 3E and 3F summarize TEAEs and patients with at least one TEAE by MedDRA SOC, HLT, PT, severity and cohort, with 
all inflammatory events grouped into a single PT.  
Table 3E: Number of TEAEs by MedDRA SOC, HLT, PT, Severity and Cohort with Inflammatory Events Grouped 
(Event-based Counts) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SYSTEM 
ORGAN CLASS 
(SOC) 
HIGH LEVEL 
TERM (HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
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COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3F: Number of Patients Experiencing TEAEs by MedDRA SOC, HLT, PT, Severity and Cohort with Inflammatory 
Events Grouped (Patient-based Counts) 
(Note that if more than one event in each category is reported for a single patient, the most recent event of maximum severity is counted.) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild Moderate Mild Moderate 
Severe 
Mild Moderate Mild Moderate 
Severe 
SYSTEM ORGAN 
CLASS (SOC) 
HIGH LEVEL TERM 
(HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
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Tables 3G and 3H summarize patients with at least one TEAE related to IMP and procedure, respectively, by MedDRA SOC, HLT, 
PT, severity and cohort. 
Table 3G: Number of TEAEs Related to IMP by MedDRA SOC, HLT, PT, Severity and Cohort (Patient-based Counts) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SYSTEM 
ORGAN CLASS 
(SOC) 
HIGH LEVEL 
TERM (HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3H: Number of TEAEs Related to Procedure by MedDRA SOC, HLT, PT, Severity and Cohort 
(Patient-based Counts) 
 
 
COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SYSTEM 
ORGAN CLASS 
(SOC) 
HIGH LEVEL 
TERM (HLT) 
PREFERRED 
TERM (PT) 
 
 
 
 
 
 
 
 
 
 
 
SOC1 
HLT1 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
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COHORT 
All Cohorts 
1 
2 
3 
4 
Mild Mild 
Moderate 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Mild Moderate 
Severe 
SOC2 
HLT1 
 
 
 
 
 
 
 
 
 
 
 
 
PT1 
 
 
PT2 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tables 3I and 3J list AEs prior to treatment and TEAEs by patient and cohort, respectively. Table 3K lists all adverse events of 
special interest (AESI). 
 
Table 3I: Listing of Adverse Events Prior to Treatment by Patient and Cohort 
 
  
 
 
MedDRA Classification 
Cohort 
Patient 
ID 
Enroll 
Date 
AE 
Description 
Event 
Date 
Severity 
of Event 
Outcome 
Duration 
(Days) 
System 
Organ 
Class 
High 
Level 
Term 
Preferred Term 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Table 3J: Listing of TEAEs by Patient and Cohort 
 
 
 
 
Relatedness 
MedDRA Classification 
Cohort 
Patient 
ID 
Surgery 
Date 
AE 
Description 
Event 
Date 
Outcome 
Duration 
(Days) 
Severity 
of Event 
Relation to 
Investigational 
Medicinal 
Product 
Relation 
to 
Surgery 
System 
Organ 
Class 
High 
Level 
Term 
Preferred 
Term 
 
 
 
 
  
 
 
 
 
 
 
 
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Relatedness 
MedDRA Classification 
Cohort 
Patient 
ID 
Surgery 
Date 
AE 
Description 
Event 
Date 
Outcome 
Duration 
(Days) 
Severity 
of Event 
Relation to 
Investigational 
Medicinal 
Product 
Relation 
to 
Surgery 
System 
Organ 
Class 
High 
Level 
Term 
Preferred 
Term 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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Table 3K: Listing of Treatment Emergent Adverse Events of Special Interest by Patient and Cohort 
 
 
 
 
Relatedness 
MedDRA Classification 
Cohort 
Patient 
ID 
Surgery 
Date 
AE 
Description 
Event 
Date 
Outcome 
Duration 
(Days) 
Severity 
of Event 
Relation to 
Investigational 
Medicinal 
Product 
Relation 
to 
Surgery 
System 
Organ 
Class 
High 
Level 
Term 
Preferred 
Term 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
8.3.2 BCVA, Ocular Inflammation and IOP 
Table 3L lists the primary outcomes of BCVA, ocular inflammation and IOP for the study and fellow eyes by patient and visit, 
Tables 3M and 3N summarize mean changes in BCVA and IOP, respectively, by cohort and visit for the study and fellow eyes and 
Table 3O summarizes the number and percentage of individuals with elevated (≥ 25, ≥ 30 and ≥ 35 mmHg) IOP in the study eye. 
Changes in ophthalmic inflammation by dose group, visit and eye will also be summarized in Table 3P. Ophthalmic outcome data 
will be displayed graphically in plots similar to Figures 3Q and 3R. Tables and plots will be given for the study eye as well as for 
the fellow eye, and labeled appropriately. 
 
Table 3L: Ophthalmic Outcome Listing for Study Eye and Fellow Eye by Patient and Visit 
 
 
 
IOP 
BCVA 
Anterior 
Cells 
Anterior 
Flare 
Vitreous 
Cells 
Vitreous 
Haze 
Macular 
Edema 
Patient 
ID 
Visit 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3M: Mean Changes from Pre-surgical BCVA by Cohort and Visit 
 
 
Study Eye 
Fellow Eye 
N 
Mean 
Std 
Min 
Max 
N 
Mean 
Std 
Min 
Max 
Cohort 
Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3N: Mean Changes from Pre-surgical IOP by Cohort and Visit 
 
 
Study Eye 
Fellow Eye 
N 
Mean 
Std 
Min 
Max 
N 
Mean 
Std 
Min 
Max 
Cohort 
Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3O: Patients Experiencing Elevated IOP in the Study Eye Following Treatment by Cohort 
 
 
IOP >= 25 mmHg 
IOP >= 30 mmHg 
IOP >= 35 mmHg 
No 
Yes 
No 
Yes 
No 
Yes 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Cohort 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
All 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 3P: Changes in Ophthalmic Inflammation in the Study Eye by Cohort and Visit 
 
 
 
Anterior Chamber 
Cells 
Anterior Chamber 
Flare 
Vitreous Cells 
Vitreous Haze 
No 
Change 
Half-Step 
Increase 
No 
Change 
1-Step 
Increase 
Half-Step 
Decrease 
No 
Change 
Half-Step 
Increase 
2-Step 
Decrease 
1-Step 
Decrease 
No 
Change 
Half-Step 
Increase 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
N 
% 
Cohort 
Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 3Q: Ophthalmic Outcomes Over Time (Days from Surgery) by Patient 
 
 
 
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Mean changes from Baseline (Day -28) will be plotted for ophthalmic outcomes versus dose 
cohort in a plot similar to Figure 3R.  
 
Figure 3R: Mean Change in Ophthalmic Outcome from Baseline by Dose Cohort 
 
 
 
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8.3.3 Laboratory Parameters 
Laboratory parameters will be listed for each patient in the patient profiles indicating lab 
values above or below the clinical site’s normal ranges. Table 3S lists the patients that had 
abnormal and/or clinically significant lab values.  
 
Table 3S: Listing of Patients with Abnormal and/or Clinically Significant Labs 1 
 
Site 
Patient 
ID 
Age Gender 
Weight 
(kg) 
Visit 
Category 
Lab 
Value 
Normal Limits 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Lab values that are in bold are clinically significant. 
 
Table 3T summarizes mean changes from Baseline for each continuous laboratory parameter. 
 
Table 3T: Mean Change in Continuous Laboratory Parameters by Cohort and Visit 
 
 
Quartiles 
95% CI 
Lab Category 
Lab Name 
Cohort 
Visit 
N 
Mean 
Std 
25% 
50% 
75% 
Lower 
Upper 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.4 OCT 
Table 3U lists OCT data by patient. This information will also be included in patient profiles. 
See Section 9 for patient profile examples. Figures similar to 3Q and 3R may also be used to 
summarize continuous OCT endpoint variables. 
 
Table 3U: OCT Listing by Patient and Visit 
 
 
Central 
Macular 
Thickness 
Macular 
Volume 
Increase in 
Cystoid Macualr 
Edema 
Unfavorable 
Change in 
Subretinal Fluid 
 
Comments 
Patient 
ID 
Visit 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
OCT 
Data 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.3.5 Vital Signs 
Table 3V summarizes median vital signs by cohort and visit. A listing of vital signs by visit will be provided in each patient’s 
profile report (see Section 9). Clinically significant changes or abnormalities will be noted. 
 
Table 3V: Vital Signs 
 
 
Temperature Median (Min, Max) 
 
Blood Pressure Median (Min, Max) 
 
Cohort 
Visit 
Degrees 
Fahrenheit 
Degrees 
Celsius 
Respiration Median 
(Min, Max) 
Systolic 
Diastolic 
Pulse 
Median (Min, Max) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Secondary Outcome Analyses 
8.4.1 Full-field Kinetic and Static Perimetry  
Individual and mean static perimetry data will be presented similarly to other ophthalmic outcome data as in Figures 3L and 3M. 
Individual scotoma as measured by kinetic perimetry may be represented graphically where appropriate in a patient profile. Tables 
4A and 4B list static (GATE) and kinetic (SKP) data, respectively, by cohort, patient and visit for both study and fellow eyes.  
 
Table 4A: Static (GATE) Perimetry Data by Patient 
 
 
Cohort 
 
Patient 
ID 
 
Visit 
Volume of Full Field                                        Hill of Vision                             
(Decibel Steradians) 
111pt grid- Volume of Full Field Hill of Vision (Decibel 
Steradians) 
Study 
Fellow 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 4B: Kinetic (SKP) Perimetry Data by Patient 
 
 
Cohort 
 
Patient 
ID 
 
Visit 
I4E Isopter Area 
(Squared Degrees) 
III4E Isopter Area 
(Squared Degrees) 
V4E Isopter Area 
(Squared Degrees) 
VI4E Isopter Area 
(Squared Degrees) 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
 
 
  
 
 
 
 
 
 
 
 
8.4.2 ERG 
Table 4C lists full field ERG response amplitudes (microvolts) and implicit times (ms) parameters by patient and visit for the study 
eye. Fellow eye data will be summarized similarly. The a- and b- wave amplitudes and implicit times may be represented 
graphically, similar to Figure 4D by patient and cohort as appropriate. Mean change in full field ERG will also be summarized. 
Clinically significant changes from Day -28 in ERG data will be indicated and listed where appropriate.  
 
 
Table 4C: Full Field ERG Response (Study Eye) Amplitude and Implicit Time Data by Cohort, Patient and Visit 
 
 
 
 
30 Hz Flicker 
Photopic Single Flash  
(a-wave) 
Photopic Single Flash 
(b-wave) 
Scotopic  
Cone-Rod  
(a-wave) 
Scotopic  
Cone-Rod  
(b-wave) 
Scotopic Rod  
(dim, b-wave) 
 
Cohort 
Patient 
ID 
Visit 
Amplitude 
Implicit 
Time 
Amplitude 
Implicit 
Time 
Amplitude 
Implicit 
Time 
Amplitude 
Implicit 
Time 
Amplitude 
Implicit 
Time 
Amplitude 
Implicit 
Time 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 4D: Full Field ERG Data Over Time 
 
 
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Tables 4E, 4F and 4G list the mean peak amplitude and latencies for each patient at Day -28 for each ring, mean changes in these 
values for the central (Rings 1-3) visual field and mean changes for the peripheral (Rings 4-6) visual field, respectively. Figures 4H 
and 4I illustrate the change in peak and latency values for the central and peripheral visual fields, respectively, against time for each 
patient.   
 
Table 4E: Mean Peak Amplitudes and Latencies at Baseline (mfERG) by Cohort and Patient 
 
 
 
Ring 1 
Ring 2 
Ring 3 
Ring 4 
Ring 5 
Ring 6 
Cohort 
Patient 
ID 
Study 
Eye 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4F: Central Field (Rings 1-3) Summary mfERG Data by Cohort and Patient 
 
 
 
Mean Central 
Field 
(Baseline) 
Mean Change 
(Week 24) 
Mean Change 
(Week 48) 
Cohort 
Patient 
ID 
Study 
Eye 
OD 
OS 
OD 
OS 
OD 
OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4G: Peripheral Field (Rings 4-6) Summary mfERG Data by Cohort and Patient 
 
 
 
Mean Peripheral 
Field 
(Baseline) 
Mean Change 
(Week 24) 
Mean Change 
(Week 48) 
Cohort 
Patient 
ID 
Study 
Eye 
OD 
OS 
OD 
OS 
OD 
OS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Figure 4H: Change in Central Field (Rings 1-3) mfERG Response Over Time 
 
 
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Figure 4I: Change in Peripheral Field (Rings 4-6) mfERG Response Over Time 
 
 
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8.4.3 VFQ-25 
At the end of the study, mean change in VFQ-25 scores will be tabulated by cohort (Table 4J) and may be summarized using plots similar to those 
in Figures 3L and 3M. Please refer to Section 8.3.2 for these plots. 
 
Table 4J: Change in VFQ-25 by Cohort 
 
Cohort 
Mean (SD) Change VFQ-25 
95% Confidence Limits 
 
 
 
 
8.5 
Other Endpoints 
Summary reports from the immunological and biodistribution endpoint data will be provided. Tables similar to those seen in the following sections 
may also be provided to supplement these reports.  
8.5.1 Immunology 
 
Table 5A: Detailed Listing of Immunologic Results by Cohort and Patient 
 
Cohort 
Patient ID 
Immunological Report Date 
Visit 
ELISA Assay Results (RU) 
Positive/ Negative ELISA 
Response 
Western Blot Required 
Positive/Negative Western 
Blot Result 
Baseline 
Post-Admin 
 
 
 
 
 
 
 
 
 
 
 
 
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8.5.2 Biodistribution Endpoint 
 
Table 5B: Detailed Listing of PCR by Cohort, Patient and Specimen 
(result includes the actual quantitative result or one of ND (negative), NQ < LLOQ (not quantifiable, < lower level of quantitation),  
or a shaded box indicating that the result was not available.) 
 
Cohort 
Patient 
ID 
Specimen 
Screening 
Day 0 
Day 1 
Week 1 
Week 2 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
  
Plasma 
 
 
 
 
 
 
 
 
 
 
 
 
Buffy coat 
 
 
 
 
 
 
 
 
 
 
 
 
Urine 
 
 
 
 
 
 
 
 
 
 
  
9.0 
PATIENT PROFILES 
An overall summary will be provided for each patient so that safety may be evaluated by case. The following sections contain a list of proposed 
tables and plots summarizing data from TDU13600 and LTS13619 that are included in each patient profile.   
9.1 
Baseline Characteristics 
DEMOGRAPHY 
Patient 
ID 
Cohort 
Date of 
birth 
Age Gender Race 
Ethnicity 
Study 
Eye 
Screening 
Date 
Surgery 
Date 
Terminati
on Date 
Mutation 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
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OCULAR MEDICAL HISTORY 
Condition 
Study 
Eye 
Diagnosis 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
MEDICAL HISTORY 
Disease/Disorder 
Date of 
Diagnosis 
Ongoing 
 
 
 
COMMENTS: 
 
 
PRIMARY ENDPOINTS (ADVERSE EVENTS) 
AE Description 
Start Date 
(Study Day) 
End Date 
Ongoing 
Outcome Severity AESI SAE 
Related to 
Surgery 
Related to 
Investigation 
Medicinal 
Product 
System 
Organ 
Class 
Preferred Term 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
COMMENTS: 
 
 
STUDY EYE EXAMINATION (ABNORMALITIES) 
Visit 
Macular 
Edema 
Abnormal 
Optic 
Nerve 
Retinal 
Detachment 
Intraretinal 
Hemorrhage 
Subretinal 
Hemorrhage 
Subretinal 
Fibrosis 
Other 
Specify 
Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
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IMMUNOLOGY 
Visit 
ELISA Assay 
Result-Baseline 
ELISA 
Assay 
Result-Post 
Admin 
Positive/Negative 
ELISA Response 
Western 
Blot 
Required 
Positive/Negative 
Western Blot 
Result 
 
 
  
 
 
 
 
  
 
 
 
 
BIODISTRIBUTION 
Specimen 
Screening 
Day 0 
Day 1 
Week 1 
Week 2 
Week 4 
Week 12 
Week 24 
Week 36 
Week 48 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
IOP, BCVA, OCULAR INFLAMMATION1 
 
BCVA 
IOP 
Anterior Cells 
Anterior Flare 
Vitreous Cells 
Vitreous Haze 
Macular 
Edema 
Visit 
Visit Date 
Study Fellow Study Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
1The SC1 BCVA is not presented in the table because the SC2 BCVA is an average of the SC1 and SC2 BCVA values. 
 
 
OCT 
 
Central 
Macular 
Thickness 
Macular 
Volume 
Evidence of 
Treatment 
Efficacy 
Increase inCystoid 
MacularEdema 
Unfavorable 
Changein 
SubretinalFluid 
Reported AE 
 
Visit Study Fellow Study Fellow Study Fellow 
Study 
Fellow 
Study 
Fellow 
Study Fellow 
OCT 
Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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OCT 
 
Central 
Macular 
Thickness 
Macular 
Volume 
Evidence of 
Treatment 
Efficacy 
Increase inCystoid 
MacularEdema 
Unfavorable 
Changein 
SubretinalFluid 
Reported AE 
 
Visit Study Fellow Study Fellow Study Fellow 
Study 
Fellow 
Study 
Fellow 
Study Fellow 
OCT 
Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
 
PERIMETRY 
 
Static (GATE) Perimetry 
Kinetic (SKP) Perimetry 
 
Volume of Full 
Field 
Hill of Vision 
(Decibel 
Steradians) 
111 pt grid-
Volume of Full 
Field Hill of 
Vision (Decibel 
Steradians) 
I4E Isopter 
Area (Squared 
Degrees) 
III4E Isopter 
Area (Squared 
Degrees) 
V4E Isopter 
Area (Squared 
Degrees) 
VI4E Isopter 
Area (Squared 
Degrees) 
Visit Study Fellow 
Study 
Fellow Study Fellow Study Fellow Study Fellow Study Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
FULL-FIELD ERG RESPONSE 
 
Light 
adapted 3.0 
flicker ERG 
Light 
adapted 3.0 
ERG a-wave 
Light 
adapted 3.0 
ERG b-
wave 
Dark 
adapted 3.0 
ERG a-wave 
Dark 
adapted 3.0 
ERG b-
wave 
Dark 
adapted 
0.01 ERG b-
wave 
 
Visit Amp 
Imp 
Time Amp 
Imp 
Time Amp 
Imp 
Time Amp 
Imp 
Time Amp 
Imp 
Time Amp 
Imp 
Time 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
MEAN PEAK AMPLITUDES AND LATENCIES AT BASELINE (mfERG) 
 
Amplitude (nV/deg2) - max+min 
Latency (ms) 
 
 
Ring 1 
Ring 2 
Ring 3 
Ring 4 
Ring 5 
Ring 6 
Comments 
Visit 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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MEAN PEAK AMPLITUDES AND LATENCIES AT BASELINE (mfERG) 
 
Amplitude (nV/deg2) - max+min 
Latency (ms) 
 
 
Ring 1 
Ring 2 
Ring 3 
Ring 4 
Ring 5 
Ring 6 
Comments 
Visit 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
COMMENTS 
 
 
 
SUMMARY CLINICAL OBSERVATIONS 
 
 
 
OVERALL CONCLUSIONS 
 
 
 
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Visual Acuity 
 
 
 
Intraocular Pressure (IOP) 
 
 
 
 
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ADMINISTRATION OF INVESTIGATIONAL PRODUCT 
Surgery 
Date 
Full Dose 
Administered 
Fluid-air 
Exchange 
Performed 
Air 
Bubble 
Removed 
Procedure 
Resulted 
in 
Retinal 
Tear 
Complication(s) 
During 
Surgery 
  
 
 
 
 
COMMENTS: 
 
 
 
ECG 
CHEST X-RAY 
Visit Abnormal CS Specify Abnormal CS Specify 
 
 
 
 
 
 
 
COMMENTS: 
 
 
VITAL SIGNS 
 
Blood Pressure 
 
Visit 
Temperature 
(°F) 
Respiratory 
Rate (/min) 
Systolic Diastolic 
Pulse 
(/min) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
PHYSICAL EXAM 
 
Cardiovascular 
Dermatologic 
Endocrine/Metabolic 
Gastrointestinal 
Genitourinary 
Head/ENT 
Visit Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline 
Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
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PHYSICAL EXAM 
 
Lymphatic/Hematologic 
Musculoskeletal 
Neurologic 
Psychologic 
Respiratory 
Visit Abnormalities 
Change 
from 
Baseline 
Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline Abnormalities 
Change 
from 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
LENS ASSESSMENT 
 
Natural Lens 
Nuclear Score 
Cortical Score 
PCS Score 
Visit 
Visit Date 
Study Fellow Study Fellow Study Fellow Study Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
 
FUNDUS PHOTOS TDU Study 
 
Treatment 
Efficacy 
Increased 
Inflammation 
Hemmorhage 
Reported AE 
Retinal 
Detachment 
Comments 
Visit Study Fellow 
Study 
Fellow 
Study 
Fellow 
Study Fellow Study Fellow 
Study 
Fellow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
 
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NOTE: For Laboratory Listings, Yellow Indicates Outside of Site's Normal Laboratory Reference Range 
 
 
 
HEMATOLOGY2,3 
Visit 
WBC 
(109/L) 
RBC 
(1012/L) 
Haemoglobin 
(g/L) 
Haematocrit 
MCV 
(fL) 
MCH 
(pg/cell) RDW 
Platelets 
(109/L) 
Neutrophils 
Neutrophils 
Total 
(109/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
HEMATOLOGY2,3 
Lymphocytes Monocytes Eosinophils Basophils 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
2Neutrophil totals were not collected until September 2014 
3RDW-CV values were converted from RDW-SD values 
 
 
COAGULATION 
CHEMISTRY 
Visit 
PT 
(seconds) 
PTT 
(seconds) 
Phosophorus 
(mmol/L) 
Calcium 
(mmol/L) 
Sodium 
(mEq/L) 
Chloride 
(mEq/L) 
Bicarbonate 
(mEq/L) 
Potassium 
(mEq/L) 
Fasting 
Blood 
Glucose 
(mmol/L) 
Blood 
Glucose 
(mmol/L) 
Creatinine 
kinase 
(umol/L) 
Lactate 
Dehydrogenase 
(U/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
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KIDNEY AND LIVER FUNCTION 
 
Kidney Function 
Liver Function 
Visit 
Creatinine 
(umol/L) 
BUN 
(mmol/L) 
Uric 
Acid 
(umol/L) 
ALT 
(U/L) 
AST 
(U/L) 
Total 
Bilirubin 
(umol/L) 
Alkaline 
Phosphatase 
(U/L) 
Total 
Protein 
(g/L) 
Albumin 
(g/L) 
GGT 
(U/L) 
Cholesterol 
(mmol/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
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URINALYSIS 
Visit 
Protein 
(Negative) 
Blood 
(Negative) 
Ketones 
(Negative) 
Urine 
Pregnancy 
Test 
(Negative) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMMENTS: 
 
 
CONCOMITANT MEDICATIONS 
Start 
Date 
Action 
Date 
Action 
Medication 
Name 
Indication 
Route 
Dose 
Units 
Schedule 
Result 
of AE 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
COMMENTS: 
 
 
 
 
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SAR421869 TDU13600
COORDINATING CENTER
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TOC FOR ALL TLFS FOR TDU13600 
•
Table 1A: Screening and Surgery Dates and Visit Completion by Cohort
•
Figure 1B: Patient Flow Diagram
•
Table 1C: Study Follow-up Completion and Withdrawal (including deaths)
•
Table 2A: Demographics Summary by Cohort
•
Listing 2B: Detailed Demographic Listing by Cohort
•
Listing 2C: General Medical History by Patient
•
Listing 2D: Study Eye Ocular History by Patient
•
Listing 2E: Fellow Eye Ocular History by Patient
•
Table 2F: Baseline Physical Examination Parameters by Cohort
•
Table 2G: Reproductive Status by Patient
•
Listing 2H: Detailed Surgery Listing by Patient
•
Table 3A: Number and Percentage of Patients Experiencing TEAEs or No Events by Type of
Event and Cohort
•
Table 3B: Number of Patients Experiencing TEAEs by MedDRA SOC, HLGT, HLT, PT, and
Cohort
•
Table 3C: Number of Patients with TEAEs of Special Interest by MedDRA SOC, HLGT, HLT,
PT, and Cohort
•
Table 3D: Number of Patients with SAEs by MedDRA SOC, HLGT, HLT, PT, and Cohort
•
Table 3E: Number of Patients Experiencing Inflammatory TEAEs by MedDRA SOC, HLGT,
HLT, PT, and Cohort
•
Table 3F: Number of Patients with TEAEs Related to IMP by MedDRA SOC, HLGT, HLT,
PT, and Cohort
•
Table 3G: Number of Patients with TEAEs Related to Procedure by MedDRA SOC, HLGT,
HLT, PT, and Cohort
•
Table 3H: Listing of Adverse Events Prior to Treatment by Patient and Cohort
•
Table 3I: Listing of TEAEs by Patient and Cohort
•
Table 3J: Listing of Treatment Emergent Adverse Events of Special Interest by Patient and
Cohort
•
Table 3K: Listing of Treatment Emergent Serious Adverse Events by Patient and Cohort
•
Listing 3L: Ophthalmic Outcome Listing for Study Eye and Fellow Eye by Patient and Visit
•
Table 3M: Mean Changes from Pre-surgical BCVA by Cohort and Visit
•
Table 3N: Mean Changes from Pre-surgical IOP by Cohort and Visit
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• Table 3O: Patients Experiencing BCVA Change in the Study Eye at Week 48 Following 
Treatment by Cohort 
• Table 3P: Patients Experiencing Elevated IOP in the Study Eye at Week 48 Following 
Treatment by Cohort 
• Tables 3Q-3S: Changes in Ophthalmic Inflammation in the Study Eye by Cohort and Visit 
• Figures 3T-3V: BCVA in Study and Fellow Eyes by Patient in Cohort X 
• Figures 3W-3Y: IOP in Study and Fellow Eyes by Patient in Cohort X 
• Figure 3Z: Mean Changes in BCVA in the Study Eye over Time by Cohort 
• Figure 3AA: Mean Changes in IOP in the Study Eye over Time by Cohort 
• Listing 3BB: Listing of Patients with Abnormal and/or Clinically Significant Labs 
• Listing CC: Abnormal Physical Examination Listing by Patient 
• Table 3DD: Mean Change in Continuous Laboratory Parameters by Cohort and Visit 
• Listing 3EE: OCT Listing by Patient and Visit 
• Figures 3FF-3HH: Central Retinal Thickness (OCT) for Study and Fellow Eyes in Cohort X 
• Figures 3II-3KK: Macular Volume (OCT) for Study and Fellow Eyes in Cohort X 
• Table 3LL: Change from Baseline in Vital Signs by Cohort and Visit 
• Listing 4A: Static (GATE) Perimetry Data by Patient 
• Figures 4B-4D: Volume of Full Field Hill of Vision Measured by Static (GATE) Perimetry by 
Patient in Cohort X 
• Figures 4E-4G: 111pt grid-Volume of Full Field Hill of Vision Measured by Static (GATE) 
Perimetry by Patient in Cohort X 
• Listing 4H: Kinetic (SKP) Perimetry Data by Patient 
• Figures 4I-4K: SKP Data in Study Eyes by Patient in Cohort X 
• Listing 4L: Full Field ERG Response (Study Eye) Amplitude and Implicit Time Data by 
Cohort, Patient and Visit 
• Table 4M: Mean Peak Amplitudes and Latencies at Baseline (mfERG) by Cohort and Patient 
• Table 4N: Central Field (Rings 1-3) Summary mfERG Data by Cohort and Patient 
• Table 4O: Peripheral Field (Rings 4-6) Summary mfERG Data by Cohort and Patient 
• Listing 5A: Detailed Listing of Immunologic Results from Blood Samples by Cohort and 
Patient 
• Listing 5B: Biodistribution Endpoint Data 
 
 
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COORDINATING CENTER 
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CC • 401 N. Washington St., Suite 700 • Rockville, MD 20850 • Tel: 301-251-1161 • Fax: 800-230-6742 
Confidential  
ADVERSE EVENT TABLE SHELL FOR TDU13600 
 
PRIMARY SYSTEM ORGAN CLASS 
 
HLGT: High Level Group Term 
 
 
HLT: High Level Term 
 
 
 
Preferred Term n(%) 
Cohort 1 
(1.4 x 105 TU) 
(N=3) 
Cohort 2 
(4.7 x 105 TU) 
(N=3) 
Cohort 3 
(1.4 x 106 TU) 
(N=3) 
All 
Cohorts 
(N=9) 
Any Class 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
SOC1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
HLGT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
HLT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
 
PT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
SOC2 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
HLGT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
HLT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
 
PT1 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
HLT2 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
 
PT2 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
HLGT2 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
HLT3 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
 
 
 
PT3 
X (X%) 
X (X%) 
X (X%) 
X (X%) 
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