Conditions: Corneal Persistent Epithelial Defect
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 35
Healthy volunteers: no

Brief summary:
This study will enroll participants with a non-infected, corneal persistent epithelial defect (PED) resulting from an ocular chemical and/or thermal ocular injury which is non-responsive or refractory to current standard of care for at least 14 days. It will assess the efficacy and safety of Nexagon® (lufepirsen) plus standard of care versus NEXAGON-vehicle (placebo) plus standard of care. The recovery of the corneal epithelium will be the primary outcome measure, defined as a cornea that re-epithelializes by Day 28 of treatment and remains re-epithelialized for at least a further 28 days.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Nexagon® (lufepirsen) High Dose Concentration intervention 2: Nexagon® (lufepirsen) Low Dose Concentration intervention 3: Vehicle intervention 4: Open-label Nexagon® (lufepirsen)
Intervention descriptions: intervention 1: Nexagon® (lufepirsen) is administered topically in the affected eye three (3) times over 28 days. intervention 2: Nexagon® (lufepirsen) is administered topically in the affected eye three (3) times over 28 days. intervention 3: Vehicle is administered topically in the affected eye three (3) times over 28 days. intervention 4: Open-label Nexagon® (lufepirsen) for participants who do not heal (re-epithelialize) at the end of the 28-day treatment phase.

Protocol document:
Prot_000.pdf: 
Amber Ophthalmics, Inc. 
CONFIDENTIAL - Not for disclosure or publication 
Protocol:  NEX-PED-005 
EXPEDE Protocol 
Version 6, 19 April 2022 
Page 1 of 77 
Protocol Title: 
A Phase 2, randomized, prospective, double-masked, vehicle-
controlled study to assess the efficacy and safety of Nexagon®
(NEXAGON) applied topically in subjects with corneal persistent 
epithelial defects (PED) resulting from severe ocular chemical and/or 
thermal injuries. 
Protocol Abbreviation: NEXAGON for the treatment of corneal PEDs following SEVERE 
ocular chemical and/or thermal injuries (EXPEDE) 
Protocol Number: 
NEX-PED-005 
Version: 
6 
Compound: 
Nexagon® (NEXAGON) 
Comparator: 
Nexagon® vehicle (Vehicle) 
Effective Date: 
19April 2022 
Sponsor: 
Amber Ophthalmics, Inc. 
6020 Cornerstone Court West 
Suite 100  
San Diego, CA 92121  
USA 


Amber Ophthalmics, Inc. 
CONFIDENTIAL - Not for disclosure or publication 
Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 2 of 77 
STUDY DESCRIPTION 
This is a Phase 2 randomized, prospective, double-masked, vehicle-controlled, multi-center study to 
evaluate the efficacy and safety of two topical ocular dose concentrations of NEXAGON as a treatment 
for non-healing corneal persistent epithelial defects (PEDs) resulting from severe chemical and/or thermal 
ocular injuries. 
The primary efficacy endpoint for this study will be corneal epithelial recovery, defined as a cornea 
that re-epithelializes 
 and remains re-epithelialized for at 
 after 
initial re-epithelialization was first recorded. 
 
 
 
Safety will be determined by the incidence of Treatment Emergent Adverse Events during the course of 
the study. 
Potentially eligible subjects will be those who present with a clinically non-infected PED resulting from 
a severe chemical and/or thermal injury.  Clinical signs of the ocular injury include de-epithelialization, 
conjunctival inflammation (hyperemia), limbal ischemia and corneal edema refractory to standard of care.  
Prior to enrollment, the PED must have been present for a minimum of 14 days, 
 
 and in the opinion of the Investigator, 
 
Eligibility of a subject will be confirmed if they meet all of the inclusion criteria and have no exclusion 
criteria. 
On Day 1 of the Treatment Period, subjects will be randomly assigned 
 to receive either 
NEXAGON 
 or NEXAGON 
 or Vehicle 0% applied to their study eye in addition to 
continuing on the prescribed standard of care (SOC) regimen.  SOC will remain unchanged for the duration 
of the study treatment, 
 
 IP will be re-applied 
.  If re-epithelialization has not 
occurred 
 subjects will receive another application of the masked investigational product.  If re-
epithelialization occurs 
 during the masked Treatment Period, subjects will enter a 
Post-
healing Follow-up Period to assess durability of the corneal epithelium.  If, however, by 
 of the 
masked Treatment Period, re-epithelialization has still not occurr d, all subjects irrespective of the 
investigational product assignment at randomization will be eligible to receive
 
 
 If corneal 
re-epithelialization healing is still not achieved, these subjects will exit the study.  If re-epithelization 
occurs, subjects will enter a 
Post-healing Follow-up Period to assess durability of the corneal 
epithelium. 
At the time of study enrollment, the size of the PED will be measured following staining of the cornea with 
fluorescein dye using a slit lamp biomicroscope 
 
No ocular drops or ointments, prescribed as part of the 
standard of care regimen, will be permitted for 
 application of investigational product.  
Investigational product will be applied 
 
 the study eye.  
 
 
 


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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 3 of 77 
Study visits during the 
 Treatment Period will include assessment of re-epithelialization, 
measurement of the size of the PED, visual acuity, ocular symptoms, adverse events and use of concomitant 
medications. 
At the time of re-epithelialization.
, the subject 
will enter a Post-healing Follow-up Period where durability of the corneal epithelium will be assessed 
 
after initial healing.  The subject will then exit the study. 
If, after initial epithelialization, the epithelium breaks down within the 
 Post-healing Follow-up 
Period the subject will exit and receive 
 salvage dose applications of NEXAGON 
within 
the open-label section of the study.  If re-epithelialization occurs by 
, a final assessment of 
the epithelium will be performed 
 later to determine durability. 
 
 


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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 4 of 77 
REVISION CHRONOLOGY 
Version 
Number 
Version Date 
Summary of Revisions 
Version 1 
 
 
Version 2 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
Version 3 
 
 
 
 
 
 
 
 


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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 5 of 77 
Version 
Number 
Version Date 
Summary of Revisions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   


Amber Ophthalmics, Inc. 
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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 6 of 77 
Version 
Number 
Version Date 
Summary of Revisions 
 
 
Version 4 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
Version 5 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 7 of 77 
Version 
Number 
Version Date 
Summary of Revisions 
Version 6 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 8 of 77 
INVESTIGATOR SIGNATURE PAGE 
 
 
I confirm agreement to maintain the protocol in confidence and to conduct the study in compliance 
with the protocol, good clinical practice and all applicable regulations. 
 
 
 
_______________________________ 
 
______________________ 
__________________ 
Investigator Printed Name 
 
 
         Signature  
      Date (dd/mmm/yyyy) 
 
 
 
 
 


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Protocol:  NEX-PED-005 
EXPEDE Protocol 
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SPONSOR SIGNATORY/SIGNATORIES 
_____________________ 
 
    Date (dd/mmm/yyyy) 
 
 
19Apr2022


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Protocol:  NEX-PED-005 
EXPEDE Protocol 
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SPONSOR INFORMATION 
AMBER OPHTHALMICS, INC. (“AMBER”) 
Amber Office: 
Medical Monitor: 
Sponsor Contacts: 
 
 
 
 
 
 
 
 
 
 
  
 
Regulatory Agency Identifying Number(s): 
 
 


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Protocol:  NEX-PED-005 
EXPEDE Protocol 
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LIST OF ABBREVIATIONS 
< 
Less than 
> 
Greater than 
≤ 
Less or equal to 
≥ 
Greater or equal to 
% 
Percent or percentage 
AE 
Adverse event 
ALT 
Alanine transaminase 
Amber 
Amber Ophthalmics, Inc. 
AMT 
Amniotic membrane transplant 
API 
Active pharmaceutical ingredient 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
 
 
BCVA 
Best Corrected Visual Acuity 
oC 
Degrees Celsius 
CF 
Counting Fingers 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CODA001 
Active pharmaceutical ingredient 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CV 
Curriculum vitae 
ECG 
Electrocardiogram 
e.g.
Latin, exempli gratia (for example) 
et al. 
Latin, et alii (and others) 
etc. 
Latin, et cetera (and other similar things) 
ETDRS 
Early treatment diabetic retinopathy study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FUP 
Follow-up 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HbA1c 
Hemoglobin A1c 
HM 
Hand movements 
HSV 
Herpes simplex virus 
HZV 
Herpes zoster virus 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ID 
Identification 


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Protocol:  NEX-PED-005 
EXPEDE Protocol 
Version 6, 19 April 2022 
Page 12 of 77 
i.e.
Latin, id est (that is) 
IEC 
Independent ethics committee 
IP 
Investigational product 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
kg 
Kilogram(s) 
LAR 
Legally authorized representative 
LOCF 
Last observation carried forward 
µg 
Microgram(s) 
µL 
Microliter(s) 
mg 
Milligram(s) 
mL 
Milliliter(s) 
mm 
Millimeter(s) 
mmHg 
Millimeter of mercury 
MP 
Megapixel 
mRNA 
Messenger ribonucleic acid 
NEXAGON (Nexagon®) 
Formulation with active pharmaceutical ingredient 
NOEL 
On observed effect level 
NPL 
No perception of light 
P or p 
Probability 
PED 
Corneal persistent epithelial defects 
pH 
Potential of hydrogen 
PL 
Perception of light 
PP 
Per protocol population 
PRK 
Photorefractive keratectomy 
PT 
Preferred term 
® 
Registered trademark 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SMO 
Site management organization 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
UCVA 
Uncorrected visual acuity 
U.S./USA
United States/United States of America 
VA 
Visual acuity 
Vehicle 
Nexagon® vehicle 
WMA 
World Medical Association 


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Protocol:  NEX-PED-005 
EXPEDE Protocol 
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TABLE OF CONTENTS
STUDY DESCRIPTION .................................................................................................................... 2 
REVISION CHRONOLOGY ............................................................................................................ 4 
INVESTIGATOR SIGNATURE PAGE ............................................................................................ 8 
SPONSOR SIGNATORY/SIGNATORIES ....................................................................................... 9 
SPONSOR INFORMATION ........................................................................................................... 10 
LIST OF ABBREVIATIONS .......................................................................................................... 11 
PROTOCOL SYNOPSIS ................................................................................................................. 16 
1.
INTRODUCTION................................................................................................................... 28
1.1. 
Background ...................................................................................................................................................... 28 
1.2. 
Nexagon® ........................................................................................................................................................ 28 
1.2.1. 
Toxicology ................................................................................................................................................. 30 
1.2.2. 
Effects in Humans – Clinical Summary ..................................................................................................... 31 
1.3. 
Study Rationale ................................................................................................................................................ 32 
1.4. 
Dose Concentration, Administration and Regimen Rationale .......................................................................... 32 
1.4.1. 
Dose Concentration Selection .................................................................................................................... 33 
1.4.2. 
Dose Administration and Regimen ............................................................................................................ 34 
2.
STUDY OBJECTIVES ........................................................................................................... 35 
3.
STUDY ENDPOINTS ............................................................................................................ 35 
4.
INVESTIGATIONAL PLAN ................................................................................................. 35 
4.1. 
Study Description ............................................................................................................................................. 35 
4.1.1. 
Study Visit Windows ................................................................................................................................. 37 
5.
STUDY POPULATION ......................................................................................................... 38 
5.1. 
Number of Subjects and Centers ...................................................................................................................... 38 
5.2. 
Inclusion Criteria .............................................................................................................................................. 38 
5.3. 
Exclusion Criteria............................................................................................................................................. 38 
5.4. 
Other Eligibility Criteria Considerations .......................................................................................................... 39 
5.5. 
Prior and Concomitant Medications ................................................................................................................. 39 
5.5.1. 
Standard of Care - Topical Ocular Concomitant Medications ................................................................... 39 
5.5.2. 
Prohibited Medications .............................................................................................................................. 40 
6.
STUDY ASSESSMENTS AND PROCEDURES .................................................................. 41 
6.1. 
Informed Consent ............................................................................................................................................. 41 
6.2. 
Demography ..................................................................................................................................................... 41 
6.3. 
Urine Pregnancy Test ....................................................................................................................................... 41 
6.4. 
Clinical Laboratory Tests ................................................................................................................................. 41 
6.5. 
Medical History and Concomitant Medication ................................................................................................. 42 
6.6. 
 
6.7. 
Ocular Assessments following Randomization ................................................................................................ 43 
6.7.1. 
Ocular Symptoms Questionnaire ............................................................................................................... 43 
6.7.2. 
Ocular Pain Measurement Rating Scales ................................................................................................... 43 
6.7.3. 
Ocular Injury - Physician Assessment ........................................................................................................ 44 
6.7.4. 
Slit Lamp Examination .............................................................................................................................. 44 
6.7.5. 
Measuring the Epithelial Defect and Photography Assessments ................................................................ 44 
6.7.6. 
Visual Acuity ............................................................................................................................................. 45 
6.7.7. 
Ophthalmoscopy ........................................................................................................................................ 45 
6.7.8. 
Intraocular Pressure.................................................................................................................................... 45 
7.
INVESTIGATIONAL PRODUCT ......................................................................................... 46 
7.1. 
Description of the Investigational Product ....................................................................................................... 46 
7.2. 
Dosage..............................................................................................................................................................
 


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7.3. 
Packaging and Labeling ................................................................................................................................... 46 
7.4. 
Investigational Product Storage, Handling and Administration ....................................................................... 47 
7.4.1. 
Investigational Product Storage ................................................................................................................. 47 
7.4.2. 
Investigational Product Dispensing – Masked Study Kits ......................................................................... 47 
7.4.3. 
Investigational Product Dispensing – Open-Label Ancillary Cartons ........................................................ 48 
7.4.4. 
Investigational Product Administration ...................................................................................................... 48 
7.5. 
Product Accountability ..................................................................................................................................... 49 
7.6. 
Assigning the Subject Identifier (Subject ID) .................................................................................................. 50 
7.7. 
Treatment Assignment ..................................................................................................................................... 50 
7.8. 
Unmasking ....................................................................................................................................................... 50 
8.
SUBJECT COMPLETION AND WITHDRAWAL ............................................................... 51 
8.1. 
Subject Completion  ......................................................................................................................................... 51 
8.1.1. 
Subject Premature Withdrawal from Study ................................................................................................ 51 
8.2. 
Eligibility Assessment (Screening) Failures ..................................................................................................... 52 
9.
ADVERSE EVENT DEFINITIONS ...................................................................................... 52 
9.1. 
Definition of an AE .......................................................................................................................................... 52 
9.1.1. 
Treatment Emergent Adverse Event (TEAE) ............................................................................................. 52 
9.2. 
Definition of a SAE .......................................................................................................................................... 53 
9.2.1. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs ......................... 53 
9.3. 
Assigning Causality ......................................................................................................................................... 53 
9.4. 
Reporting of SAEs to the Sponsor ................................................................................................................... 54 
10.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ......................................... 55 
10.1. 
Study Design Considerations ........................................................................................................................... 55 
10.1.1. 
Primary Hypotheses ................................................................................................................................... 55 
10.1.2. 
Sample Size Assumptions .......................................................................................................................... 55 
10.2. 
Data Analysis Considerations .......................................................................................................................... 55 
10.2.1. 
Analysis Populations .................................................................................................................................. 55 
10.2.2. 
General Considerations .............................................................................................................................. 56 
10.2.3. 
Interim Analysis ......................................................................................................................................... 56 
10.2.4. 
Multiplicity Adjustment ............................................................................................................................. 57 
10.2.5. 
Baseline Characteristics ............................................................................................................................. 57 
10.2.6. 
Subject Disposition .................................................................................................................................... 57 
10.2.7. 
Efficacy Analyses ...................................................................................................................................... 57 
10.2.8. 
Safety Analyses .......................................................................................................................................... 59 
11.
STUDY CONDUCT CONSIDERATIONS ............................................................................ 59 
11.1. 
Institutional Review Board / Independent Ethics Committee (IRB/IEC) ......................................................... 59 
11.2. 
Ethical Conduct of the Study............................................................................................................................ 59 
11.3. 
Informed Consent ............................................................................................................................................. 60 
11.4. 
Study Discontinuation ...................................................................................................................................... 60 
11.5. 
Premature Termination or Suspension of a Trial .............................................................................................. 60 
11.6. 
Study Initiation ................................................................................................................................................. 61 
11.7. 
Protocol Deviations .......................................................................................................................................... 62 
11.8. 
Case Report Forms ........................................................................................................................................... 62 
11.9. 
Records Retention ............................................................................................................................................ 62 
11.10. Data Handling .................................................................................................................................................. 62 
11.11. Study Monitoring and Compliance .................................................................................................................. 63 
11.12. Use of Information and Publications ................................................................................................................ 63 
11.13. Protocol Amendments ...................................................................................................................................... 64 
APPENDIX 1: 
 .................................... 65 
APPENDIX 2: 
 ....................................................... 66 
APPENDIX 3: 
 ....................................................... 67 
APPENDIX 4: 
.............................................................. 68 
APPENDIX 5: BIOMICROSCOPY/SLIT LAMP EXAMINATION FOR OCULAR SIGNS ..... 69 


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APPENDIX 6: MEASURING THE EPITHELIAL DEFECT........................................................ 72 
APPENDIX 7: SLIT LAMP DIGITAL PHOTOGRAPHY OF THE EPITHELIAL DEFECT ..... 73 
APPENDIX 8: 
 ............................................. 74 
APPENDIX 9: 
  
 
 
REFERENCES  ................................................................................................................................ 76 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments........................................................................................ 24 
 
LIST OF FIGURES 
Figure 1: 
Dose Regimen ............................................................................................................. 23 
Figure 2: 
Study Flow Diagram - Visit Schedule and Dosing Days ............................................ 27 
 


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PROTOCOL SYNOPSIS 
Title 
A Phase 2, randomized, prospective, double-masked, vehicle-controlled 
study to assess the efficacy and safety of Nexagon® (NEXAGON) applied 
topically in subjects with corneal persistent epithelial defects (PED) 
resulting from severe ocular chemical and/or thermal injuries.  
Study Population 
This protocol will enroll up to a maximum of 
subjects.  A total of 
 
subjects are required to complete this study. 
All eligible subjects will present with a non-infected, corneal PED as a 
result of a chemical and/or thermal ocular injury which is refractory to 
current standard of care for at least 14 days.  
Study Objective 
The objective of this protocol is to assess the efficacy and safety of two 
topical ocular dose concentrations of NEXAGON as treatment of non-
healing corneal PEDs resulting from severe chemical and/or thermal ocular 
injuries. 
Endpoints 
Primary Endpoint: 
• 
Corneal epithelial recovery, defined as a cornea that re-epithelializes 
by 
 of treatment and remains re-epithelialized for at least  
 after initial re-epithelialization was first recorded, as 
assessed by the Investigator. 
Secondary Endpoints: 
 
 
 
  
 
 
 
 
 
Exploratory Endpoints: 
 
 
 
 
  
 
 
 
 
 
 
Safety: 
• 
Incidence of Treatment Emergent Adverse Events.  


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Study 
Periods/Duration 
The study will comprise a 
 Treatment Period and a Post-healing 
Follow-up Period of 
 both of which are double-masked.   
Once determined to be eligible, subjects will be randomized to receive 
either NEXAGON 
or NEXAGON 
or Vehicle in a 
 ratio 
respectively.  Investigational product will be applied
 
 
 during the Treatment Period: 
 
 
 
 
 
 
However, if by 
 of the Treatment Period the cornea has not fully re-
epithelialized, irrespective of the investigational product assignment at 
randomization, subjects will enter the open-label section of the study and 
will receive 
 applications of NEXAGON 
 
  NEXAGON 
 will 
be applied 
 
  Subjects receiving 
salvage therapy will be followed from the first salvage dose application to 
determine if re-epithelialization occurs 
. 
For each subject, the 
 masked Treatment Period will end when 
EITHER, corneal re-epithelialization is 
 recorded following up to a 
maximum of 
 applications of investigational product OR 
subjects enter the open-label section of the study as a result of an unhealed 
PED 
. 
Those subjects who achieve re-epithelialization will immediately begin the 
Post-Healing Follow-up Period.  No further investigational product 
will be applied.  The aim of the post epithelialization follow-up period is to 
assess the durability of the epithelium.   
For those subjects that achieve re-epithelialization but epithelialization is 
NOT sustained during the 
Post-healing Follow-up Period, the subject 
will become eligible to receive the salvage dose(s) of NEXAGON 
 and 
enter the open-label section of the study 
  If re-
epithelialization is not achieved 
 
 a second dose of NEXAGON 
 will be applied.  If re-
epithelialization occurs 
, a final assessment of the 
epithelium durability will be performed 
.   
Subjects will also exit the study if re-epithelialization is not achieved 
 
 in the open-label section of the study.  
The MAXIMUM duration for study participation for a subject is 
  
 
 
 
 
 
  


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Refer to Table 1: Schedule of Assessments for details of the visit schedule 
and the procedures to be conducted at each study visit.  
Investigational 
Product 
Administration for 
Randomized 
Subjects 
Each investigational product dose application
 
 
 
  
No topical ocular standard of care treatment will be permitted 
 
before or 
 following investigational product administration. 
 
 
  
Three treatment arms will be evaluated in this study.  Randomization will 
be in a 
 ratio: 
• GROUP A – NEXAGON
 
• GROUP B – NEXAGON
 
• GROUP C – Vehicle 
There will be a single application of investigational product 
 
.  A potential additional application of investigational product will be 
scheduled 
 if re-epithelialization has not occurred.   
If re-epithelialization of the study eye has still not occurred at the end of the 
 masked Treatment Period, or following initial re-epithelialization 
durability is not maintained, subjects will receive 
 salvage dose 
applications of - NEXAGON
 in the open-label section of the study   
Study Description 
Potentially eligible subjects will be those who present with a clinically non-
infected PED as a result of a severe chemical and/or thermal injury 
refractory to standard of care.  Clinical signs of the ocular injury include 
de-epithelialization, conjunctival inflammation (hyperemia), limbal 
ischemia and corneal edema.  
Before the entry of a subject can be considered, the PED must have been 
present for at least 14 days,
 
 
 
 
 
 
  
Subject consent to participate in the study must be obtained by the Principal 
Investigator or suitably qualified designee before any protocol-specific 
procedures are undertaken.  Eligibility assessments and baseline 
evaluations will be performe
 
 
 
  
 
 


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The first investigational product application will occur following 
randomization 
 
 
 
 
  The eye will then be covered with a double 
eye pad and taped shut for approximately
.   
 
 
 
Each subject will attend twice-weekly assessment visits until corneal 
re-epithelialization occurs.  
If re-epithelialization of the defect has NOT occurred by 
 of the 
masked Treatment Period, another single application of masked 
investigational product will be administered. 
If corneal re-epithelialization has NOT occurred by 
 of the 
masked Treatment Period, subjects will receive 
salvage dose 
applications of NEXAGON 
in the open-label section of the study.  
 
 
 If re-epithelialization has not occurred 
 
 the subject will exit the study.   
Once re-epithelialization has occurred, 
 
, the subject will enter the Post-healing 
Follow-up Period 
 
 
  Subjects will be assessed 
 following initial re-epithelialization to confirm durability of 
the epithelium.  The subject will then exit the study having completed all 
visits. 
If, after initial epithelialization, the epithelium breaks down within the 
 Post-healing Follow-up Period, the subject will receive 
 
salvage dose applications of NEXAGON 
, in the 
open-label section of the study.     
If a re-epithelialized cornea develops 
, these subjects 
will also be followed for 
 to assess durability of healing 
 
. 
Refer to Figure 2: Study Flow Diagram 
 
 


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At each study visit following randomization until the end of the Treatment 
Period, the subject will undergo assessments as detailed in Table 1:  
Schedule of Assessments.  Assessments will include
 
 
 
 
 The occurrence 
of any Treatment Emergent Adverse Events will also be assessed at each 
study visit, and up to 
 following the final application of 
investigational product.   
Standard of Care 
during the 
Treatment Period 
and the Open-label 
section of the study  
During the Treatment Period and the open-label section of the study, 
EXCEPT for 
 before and the 
period after investigational 
product administration, the subjects will continue to receive the standard of 
care regimen prescribed to them by the Investigator at the study site. 
Details of the medications administered, doses and dosing regimens 
must be recorded in the source documentation and case report form.  
 
 
 
 
Systemic standard of care will not be defined by the protocol but by the 
Investigator’s or study site routine practice.  However, systemic 
medications and regimen for the treatment of the PED should remain 
unchanged for the duration of the study, until re-epithelialization or study 
exit.  
NOTE: Use of topical anesthetic drops will ONLY be permitted for 
ophthalmic assessments conducted at each study visit.   
Inclusion/Exclusion 
Criteria  
INCLUSION CRITERIA 
A subject will be eligible for inclusion in this study only if ALL of the 
following criteria apply: 
1. 
Male and female of any age. 
2. 
Clinically non-infected, corneal persistent epithelial defect (PED) as a 
result of a severe chemical and/or thermal ocular injury in one or both 
eyes.  
3. 
 
 
4. 
 
5. 
Providing written informed consent and ability to comply with the visit 
and dosing schedule. 


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NOTES: 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
EXCLUSION CRITERIA 
A subject will not be eligible for inclusion in this study if ANY of the 
following exclusion criteria apply: 
1. 
  
2. 
Have active clinically significant ocular infection. 
3. 
Subjects with corneal perforation or impending corneal perforation.  
4. 
Subjects with any other past or present ophthalmic disease or medical 
condition that, in the Investigator’s opinion, may affect the safety of 
the subject or the outcome of the study.  
5. 
Treatment with systemic corticosteroids 
 
 
 
 
 
 
 
 
6. 
Subjects with severe lid abnormalities as a result of the injury 
contributory to the persistence of the epithelial defect such as inability 
to close the lids.  
7. 
Subjects with a history of severe ocular conditions contributory to the 
persistence of an epithelial defect prior to the injury. 
8. 
Female subjects of childbearing potential who are pregnant, nursing, 
planning a pregnancy or not using an adequate and medically 
acceptable form of birth control.  An adult woman is considered to be 
of childbearing potential unless she is a) post-menopausal (defined as 
at least 12 months of amenorrhea), b) surgically sterilized and at least  
3 months post-surgical, or c) using a hormonal contraceptive, intra-


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uterine device, diaphragm with spermicide, or condom with 
spermicide for the duration of the study. 
9. 
Subjects who have participated in an interventional clinical trial within 
30 days prior to Day 1.  
 


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Figure 1: 
 
 
 
 
    


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TABLE 1: 
 


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Figure 2: 
 
 
 


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1. 
INTRODUCTION  
1.1. 
Background 
Chemical and thermal injuries to the eye constitute a medical emergency (Spector and Fernandez, 2008) 
and can result in significant damage to the ocular surface and the anterior segment.  Permanent 
unilateral or bilateral visual impairment may result (Spector and Fernandez, 2008).   
An intact corneal epithelium is crucial for maintaining the integrity and functioning of the eye.  Damage to 
the ocular surface results in impaired vision, pain and discomfort and leaves the eye susceptible to infection.  
After significant injuries, the full restoration of the cornea may never occur despite current standard of 
care (Farjo, 2004).  In these cases of severe injury, failure of the epithelium to heal may result in blindness 
or loss of the eye.  A key factor inhibiting the healing response and exacerbating tissue damage is excessive 
inflammation as seen with severe chemical and thermal injuries to the eye.  The mainstay of treatment for 
a damaged corneal epithelium is to optimize the health of and protect the denuded cornea from further 
trauma in an effort to promote epithelial healing.  However, not all patients will respond to standard 
treatment regimens leading to a defect in the corneal epithelium that may not heal and persists (Vajpayee 
et al., 2003). 
These ocular wounds known as persistent corneal epithelial defects (PED) can be defined as a loss of 
the integrity of the corneal surface, caused by injury or disease, which does not heal within the normal 
timeframe, but persists for weeks or even months (McCulley et al., 1993).  Subjects whose defect fails 
to heal with standard treatment can experience severe pain, foreign body sensation, tearing, blepharospasm, 
decreased visual acuity and photophobia (Oskouee et al., 2007).  A novel therapeutic agent designed to 
reduce the cycle of inflammation, regenerate the microvasculature and blood flow, and promote epithelial 
healing could benefit those patient’s refractory to standard of care.  
Current treatments for PEDs that result from chemical and thermal injuries include corticosteroids, 
collagenase inhibitors, ascorbate, epidermal growth factors, autologous serum, amniotic membranes, 
tear supplements, therapeutic contact lenses and tarsorrhaphy.  However, there is no treatment that can 
consistently improve outcomes in PED and relieve the associated severe disability experienced 
(Oskouee et al., 2007; Saw et al.,2007; Gordon et al., 1995; Williams et al., 1999).  
1.2. 
Nexagon® 
Nexagon® (NEXAGON) is a topical oligonucleotide 
 which is a 
selective inhibitor of connexin43 (Cx43) overexpression. NEXAGON is being developed for the 
treatment of chemical or thermal injury to the cornea resulting in a PED which is non-responsive to 
standard of care.  
Overexpression of Cx43 leads to the assembly and recycling of the inflammasome pathway of 
inflammation resulting in ischemia and a non-responsive PED due to lack of microvascular blood 
supply at the limbus. NEXAGON has been shown to promote epithelial regeneration by breaking the cycle 
of inflammation, re-establishing microvasculature and blood flow, thereby promoting regeneration of the 
epithelium.  
The active pharmaceutical ingredient (API) of NEXAGON is CODA001, which is an unmodified 
oligonucleotide molecule. 
 
 
 
 
 
  


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When applied directly to a wound by way of the NEXAGON formulation, CODA001 functions by 
hybridizing to connexin43 mRNA to temporarily inhibit local expression of connexin43 which results 
in temporary inhibition of hemichannel formation.  The transient down-regulation of connexin43 results 
in a break of the inflammasome cycle and inflammatory cytokine levels which have been shown to 
inhibit wound healing (Kim et al., 2016; McCarty and Percival, 2013; Singer and Clark, 1999).  
Breaking the inflammasome cycle enables restoration of vascular integrity and tissue perfusion, and 
with respect to the ocular surface, it will restore limbal perfusion essential for corneal healing (Ormonde 
et al., 2012).  
Down-regulation of connexin43 expression by CODA001 has been shown to promote healing in a 
number of preclinical in vivo animal and ex vivo tissue models, including skin lesions, and burns (Qiu 
et al., 2003; Coutinho et al., 2003; Grupcheva et al., 2012).   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
In the clinical setting, NEXAGON was shown to reduce inflammation and restore limbal perfusion to 
promote re-epithelialization in a number of patients treated in a compassionate use protocol following 
severe ocular chemical and/or thermal injuries resulted in PEDS refractory to standard therapies 
(Ormonde et al, 2012). 
 
 


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1.2.1. 
Toxicology  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 


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All of these studies were conducted with small to very large multiples of clinical doses (with respect to 
the CODA001 dose level), and no toxicity was observed in any of the studies based on extensive 
evaluations of potential local and systemic effects.   
1.2.2. 
Effects in Humans – Clinical Summary 
The safety, tolerability and clinical effects of topical administration of NEXAGON have been 
investigated in four Phase 1 studies (one ocular and three dermal) and three dermal Phase 2 studies in 
venous leg ulcer and diabetic foot ulcer patients.   
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
  
Human clinical experience with NEXAGON to date has indicated that NEXAGON has an excellent 
safety profile and is well tolerated.  The only adverse events reported as being possibly related to 
NEXAGON were transient sensations of stinging/tingling/burning when administered to chronic 
venous ulcers (3 patients in total).  No other possibly related or related adverse events or serious adverse 
events have been reported to date in any of the clinical studies and the 12 compassionate use patients.  
Details of the ocular clinical studies and the isolated compassionate use for ocular applications are 
described in more detail in the latest edition of the Investigator’s Brochure for NEXAGON® – Ocular 
Administration. 


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1.3. 
Study Rationale 
There are a range of primary ocular surface disorders that can cause a defect of the corneal epithelium such 
as chemical injuries, thermal injuries, neurotrophic keratitis, keratoconjunctivitis sicca, cicatricial 
pemphigoid, Stevens-Johnson syndrome, or toxic epidermal necrolysis (Letko et al., 2001).   
The purpose of this study is to investigate the effect of NEXAGON in treating wounds to the eye that have 
been caused by severe chemical and/or thermal injuries and which have remained unhealed 
 
despite conventional medical and surgical standard of care treatment over that period.   
NEXAGON, which is a topical gel 
, has 
 
 
 
 
 
As detailed in Section 1.2.2, Effect in Humans – Clinical Summary, encouraging clinical results have been 
shown in eight patients treated with NEXAGON on a compassionate use basis.  Each patient had a PED 
as a result of chemical and/or thermal injuries and re-epithelialization of the cornea could not be achieved 
by standard of care alone.  Details of all eight patients are provided in the latest edition of the Investigator’s 
Brochure for NEXAGON - Ocular Administration 
 
   
The rationale for this current study is to determine, under a formal clinical protocol, whether NEXAGON 
is an effective treatment modality for PEDs that have developed as a result of severe chemical and/or 
thermal injuries, and which are non-responsive 
Two dose 
concentrations of NEXAGON will be assessed against a Vehicle control.  
1.4. 
Dose Concentration, Administration and Regimen Rationale 
NEXAGON is formulated with two components, namely the active pharmaceutical ingredient (API), 
called CODA001 which is an unmodified 
oligonucleotide 
 
 
NEXAGON 
 have been selected as the two dose 
concentrations to be used in this study.  The comparator will be the Vehicle 
 
.  
The primary endpoint will be corneal epithelial recovery, 
 
 
Previous dosing experiences of NEXAGON in ocular indications are as follows: 
• 
Study NEX-OCU-001:  A Phase 1, dose-rising safety study in 26 participants which assessed 
the safety of 
 of
 
of NEXAGON applied to the de-epithelialized eye following photo-refractive keratectomy.  
There were no side effects or dose-limiting toxicities attributable to any dose of NEXAGON 
in any of these subjects in this study.  Therefore, all four dose concentrations were safe and 
tolerated when applied to a wounded human eye.    
• 
Study NTX-OCI-001:  A Phase 2 randomized, prospective, double-masked, vehicle-
controlled study to evaluate the safety and efficacy of topical NEXAGON in subjects with 
ocular surface chemical burns.  Subjects were randomized to either NEXAGON (
 


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the 
equivalent volume of NEXAGON Vehicle.  Investigational product was given on 
 
 in addition to the subjects receiving standard of care.  Clinical doses of 
 
 was 
chosen largely based on the previous Phase 1 study and the anticipated effect of standard of 
care on NEXAGON application.  No overt toxicity was seen in NEX-OCU-001 
 
 or in the animal toxicology studies up to 32 mg/mL 
(3.2%) per eye.  The study was closed due to slow enrollment after a total of 34 of 66 subjects 
were recruited, analysis of the data indicated that further investigation of the effects of 
NEXAGON in patients with severe ocular burns that are more difficult to heal was warranted 
in a subsequent trial.  
• 
Ocular Compassionate Use Cases:  Eight patients with a PED resulting from chemical or 
thermal injuries have been treated with NEXAGON on a compassionate use basis as 
re-epithelialization of the cornea could not be achieved by standard of care.  The dose 
concentrations used in the compassionate use settings have included 
 
 and whilst some subjects had 
, others 
required 
 applications to achieve re-epithelialization.  Total doses 
administered ranged from 
 to 8.2 mg (refer to the latest edition of the Investigator’s 
Brochure for Nexagon® – Ocular Administration). 
For the first 6 compassionate use cases, NEXAGON was applied by being extruded from a syringe 
.  However, following Protocol NTX-OCI-001, 
the two most recent compassionate use patients received NEXAGON on 
 
  Re-epithelization was achieved in both these 
later subjects, although the most recent case also underwent bilateral AMT and further applications 
of NEXAGON to achieve healing. 
• 
Toxicology:  
 
 
 
 
 
1.4.1. 
Dose Concentration Selection 
Whilst prior ocular use in the compassionate use setting has demonstrated positive activity with dose 
concentrations 
 higher dose concentrations have also yielded 
encouraging results, especially in subjects with very severe ocular injuries.  Due to the nature of these 
severe ocular injuries, it is expected that the increased inflammation and increased tearing in the eye 
will give a combined dilution effect on the applied topical drug.   
 
 
  
 
  
The lower dose concentration of NEXAGON 
 provides continuity 
 
 used to treat 8 subjects under a compassionate use situation.  Efficacy by 
way of re-epithelialization and preservation of the eyes, was demonstrated in this series of subjects after 
the PEDs were deemed refractory to standard of care.  However, until now the dose concentration of 


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 has yet to be evaluated formally in a randomized, double-masked, controlled clinical trial 
setting. 
Similarly, a higher dose concentration of NEXAGON 
 has also been selected for 
this study.  This is because the severity of ocular injuries to be included in the study are associated with 
increased inflammation and increased tearing. 
 
 
 This dose is substantially lower than the dosing 
administered in toxicology study GLP-2017-0024, where multiple repeat applications of NEXAGON 
 were applied over 
 to mechanically wounded and non-wounded rabbit eyes.  Study GLP-
2017-0024 did not show any signs of toxicity, nor impede corneal re-epithelialization between 
wounding days. 
1.4.2. 
Dose Administration and Regimen 
A single dose administration of investigational product – either NEXAGON 
 or 
Vehicle – 
 
 
 
 
 
.  
 
 
  
The dosing schedule for this study 
 
 
  
After randomization, investigational product will be administered 
 
 
 
 
 
 
  
For Protocol NEX-PED-005, the lowest dose concentration of NEXAGON 
will equate to a 
total daily dose of 
 per application.  This dose lies within the 
therapeutic window used for previous compassionate use patients and overlaps previous clinical 
experience.
 
The compassionate use series of patients indicated that 
 may 
sometimes be required to attain re-epithelialization in the most severe or resistant cases.  Therefore, if 
re-epithelialization has not occurred by 
 another investigational product application will be 
permitted.  This dosing schedule is based on compassionate use experience and with the expectation 
that initial healing will likely begin immediately following the 
 doses.  
 
 
 
  
However, if by 
 corneal re-epithelialization has still not occurred, those subjects will receive 
 
 salvage dose applications of NEXAGON 
, irrespective of the 
investigational product assignment at randomization.  The rationale for receiving 
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to enable all unhealed subjects enrolled into the study - particularly those randomized to Vehicle - the 
opportunity of receiving application(s) of investigational product at the highest dose concentration of 
NEXAGON available.   
2. 
STUDY OBJECTIVES 
The objective of this study is to assess the efficacy and safety of two topical ocular dose concentrations of 
NEXAGON as a treatment for non-healing corneal PEDs resulting from severe chemical and/or thermal 
ocular injuries. 
3. 
STUDY ENDPOINTS 
Primary Endpoint 
• 
Corneal epithelial recovery, defined as a cornea that re-epithelializes by 
 of treatment and 
remains re-epithelialized for at 
 after initial re-epithelialization was first recorded, as 
assessed by the Investigator. 
Secondary Endpoints 
 
  
 
 
 
 
Exploratory Endpoints 
 
 
 
 
 
  
 
 
 
 
 
 
 
Safety 
• 
Incidence of Treatment Emergent Adverse Events.  
4. 
INVESTIGATIONAL PLAN  
4.1. 
Study Description 
The purpose of this Phase 2 protocol is to evaluate the efficacy and safety of two topical ocular dose 
concentrations of NEXAGON in subjects with corneal PEDs arising from severe chemical and/or thermal 
injuries which are non-responsive to current standard of care.  
Enrollment for this study will continue until 
 complete the study.  Up to a maximum 
 
 in total will be randomized.  The study is double-masked, and neither the 
Investigator, subject, nor Sponsor/CRO personnel involved in the day to day protocol activities will know 
which treatment group has been allocated.  Subjects will be randomized to either Group A (NEXAGON 
), Group B (NEXAGON 
) or Group C (Vehicle).   


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Potentially eligible subjects will be those who present with a clinically non-infected persistent epithelial 
defect as a result of a severe chemical and/or thermal injury refractory to standard of care. Clinical signs of 
the ocular injury include de-epithelialization, conjunctival inflammation (hyperemia), limbal ischemia and 
corneal edema.  
Before entry of a subject into this protocol can be considered, the PED must have been present for a 
minimum of 14 days, 
 
 
  
As detailed in the study entry criteria, for subjects presenting with bilateral ocular surface damage, only 
one eye will be eligible to be the ‘study eye’
 
If the Investigator has any doubts about the eligibility of a subject, he/she will be advised to contact the 
study Sponsor/Medical Monitor to discuss the case further to determine whether the subject is eligible to 
participate in this protocol. 
All subjects who are considered for study inclusion will first have the study explained to them in full.  If 
they are willing to participate, written informed consent will be obtained before any study-related 
procedures are performed.  ONLY subjects that meet all of the inclusion criteria and have no exclusion 
criteria will be eligible for randomization to double-masked investigational product.   
 
 
  No topical 
ocular drops or ointments are permitted within 
 prior to investigational product application or 
after. 
The study will comprise of 2 periods: 
• 
masked Treatment Period, where investigational product will be applied 
 
.  Each subject will attend 
 
assessment visits until corneal re-epithelialization occurs.  If by 
 re-epithelization has not 
occurred, the subject will enter the open-label section of the study and receive
 salvage 
dose applications of NEXAGON 
 
 
• 
Post-healing Follow-up Period, which will commence as soon as re-epithelization occurs in the 
Treatment Period in order to assess durability of the healed cornea 
 later; the masking 
will remain during this period.   
For all subjects, the first investigational product application will occur following randomization on  
 
 
 
 
 
 
 
  
Refer to Section 7 and the Pharmacy Manual for instructions on investigational product administration.   
During the Treatment Period, masked investigational product will initially be administered 
 
 


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If re-epithelialization of the defect has NOT occurred by 
 another single application of masked 
investigational product will be administered.   
If re-epithelialization occurs 
 during the masked Treatment Period, subjects will enter a 
 
Follow-up Period to assess durability of the corneal epithelium. 
However, if by 
 of the masked Treatment Period, the cornea has still not fully re-epithelialized, then 
subjects will receive a salvage treatment dose of NEXAGON 
 
 If re-epithelialization has not been achieved after 
 
 a second salvage dose of NEXAGON 
  Final assessment of 
healing for these subjects will be conducted on 
   
If re-epithelialization has not occurred by 
 the subject will exit the study.   
Once re-epithelialization has occurred, 
, the 
subject will enter the Post-healing Follow-up Period and 
 
 
.  Subjects will be assessed again 
 following initial re-epithelialization 
to confirm durability of the epithelium.  The subject will then exit the study having completed all visits. 
If the healed epithelium is not sustained within the Post-healing Follow-up Period, the subject will exit and 
receive the salvage dose(s) as part of the open-label section of the study.  If a re-epithelialized cornea 
develops following the salvage dose application(s), these subjects will also be followed for 
 to 
assess durability of healing. 
 
 
 
  
At each study visit, following randomization until the end of the study, the subject will undergo assessments 
as detailed in Table 1 (Schedule of Assessments).  Assessments will be performed by a designee at the 
study site who is masked to the allocated investigational product 
 
 
 
 The occurrence of any Treatment Emergent Adverse Events will also be assessed 
at each study visit, and up to 
 following the final application of investigational product.   
Please refer to Table 1 (Schedule of Assessments) and to Section 6 for full details of study 
assessments and procedures required at each visit.  Figure 2 (Study Flow Diagram) shows the 
schedule of visits and dosing days. 
4.1.1. 
Study Visit Windows 
Subject’s visit dates can be booked within the windows detailed in Table 1: Schedule of Assessments.  
Ensure that when determining the visit dates that these are done with reference to the Day 1 visit date 
of the Treatment Period and not the subject’s previous visit.  Visits that are not able to be completed 
within the windows specified in this protocol must be recorded as protocol deviations. 
Note: Day 1 corresponds to the day of randomization, Day 0 is not utilized in this study design. 


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5. 
STUDY POPULATION 
5.1. 
Number of Subjects and Centers 
A total of 
 are required to complete this study.  To allow for discontinuations, up to a 
maximum 
 with PED resulting from a severe chemical and/or thermal injury will be 
randomized.  The study will be conducted at
  
5.2. 
Inclusion Criteria 
A subject will be eligible for inclusion in this study only if ALL of the following criteria apply: 
1. 
Male and female of any age. 
2. 
Clinically non-infected, corneal persistent epithelial defect (PED) as a result of a severe chemical 
and/or thermal ocular injury in one or both eyes.  
3. 
 
 
4. 
 
5. 
Providing written informed consent and ability to comply with the visit and dosing schedule. 
NOTES: 
 
 
  
 
 
 
 
 
 
 
 
 
 
5.3. 
Exclusion Criteria 
A subject will not be eligible for inclusion in this study if ANY of the following exclusion criteria 
apply: 
1. 
  
2. 
Have active clinically significant ocular infection. 
3. 
Subjects with corneal perforation or impending corneal perforation.  
4. 
Subjects with any other past or present ophthalmic disease or medical condition that, in the 
Investigator’s opinion, may affect the safety of the subject or the outcome of the study.  
5. 
Treatment with systemic corticosteroids
 
 
 
 
 


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6. 
Subjects with severe lid abnormalities as a result of the injury contributory to the persistence of 
the epithelial defect such as inability to close the lids.  
7. 
Subjects with a history of severe ocular conditions contributory to the persistence of an epithelial 
defect prior to the injury. 
8. 
Female subjects of childbearing potential who are pregnant, nursing, planning a pregnancy or not 
using an adequate and medically acceptable form of birth control.  An adult woman is considered 
to be of childbearing potential unless she is a) post-menopausal (defined as at least 12 months of 
amenorrhea), b) surgically sterilized and at least 3 months post-surgical, or c) using a hormonal 
contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide for the 
duration of the study. 
9. 
Subjects who have participated in an interventional clinical trial within 30 days prior to Day 1.  
5.4. 
Other Eligibility Criteria Considerations 
To assess any potential impact on subject eligibility with regards to safety, the Investigator must refer 
to the latest edition of the Investigator’s Brochure for NEXAGON – Ocular Administration, for detailed 
information regarding warnings, precautions, contraindications, adverse events and other significant 
data pertaining to the investigational product being used in this study. 
5.5. 
Prior and Concomitant Medications 
All medical and surgical treatments/procedures for the PED since the original chemical and/or thermal 
injury should be recorded and transcribed into the CRF.   
A record will be kept of all medication administered, surgical procedures undertaken and supplements 
used by subjects since the time of injury and PRIOR to study enrollment.   
Similarly, over the course of the study FOLLOWING enrollment, a record will be kept of all 
concomitant medication administered, procedures undertaken and supplements used by subject until 
study exit will also be recorded.  Subjects must be questioned at each study visit concerning any new 
medications or changes in current medications including over-the-counter medication.  
For each medication taken or procedure performed, the following information will be collected: 
• 
Medications generic name/procedure name 
• 
Eye that was treated, if applicable 
• 
Indication for the medication/procedure 
• 
Dose, route and frequency of administration of medication 
• 
Date started medication/date of procedure 
• 
Date stopped medication 
5.5.1. 
Standard of Care - Topical Ocular Concomitant Medications 
Over the course of the study, from baseline assessments through to study completion, subjects will 
continue to receive the standard of care regimen prescribed to them by their Investigator.  The standard 
of care should remain unchanged until re-epithelialization or study exit if re-epithelialization is not 
achieved. Details will be recorded on the prior and concomitant medication case report form.  
  


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The only exception will be on study days where IP is to be administered.  On these days, it is important 
for the Investigator or delegate to advise the subject 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patching: Is only required as indicated post application of the investigational product. 
 
   
 
 
   
Therapy considered necessary to a subject’s welfare may be given at the discretion of the Investigator 
but prior to application this should first be discussed with the Medical Monitor or Sponsor 
representative.   
Systemic standard of care will not be defined by the protocol but by the Investigator’s or study site 
routine practice.  However, systemic medications and regimen for the treatment of the PED should 
remain unchanged for the duration of the study, until re-epithelialization or study exit.  Details must be 
recorded in the source documents and the CRF. 
5.5.2. 
Prohibited Medications 
Medications to be avoided over the course of the study are: 
•
 
 
 


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• 
 
 
 
6. 
STUDY ASSESSMENTS AND PROCEDURES 
6.1. 
Informed Consent  
Written informed consent will be obtained for this study by the Principal Investigator or suitably 
qualified designee from all subjects before any protocol-specific procedure can be performed.   
This study will be conducted in accordance with the provisions of the Declaration of Helsinki.  
In obtaining and documenting informed consent, the Investigator must comply with applicable 
regulatory requirements and must adhere to Good Clinical Practice (GCP).  The Investigator must fully 
inform subjects of all pertinent aspects of the study.  Before informed consent may be obtained, the 
Investigator, or a person designated by the Investigator, must provide the subject ample time and 
opportunity to inquire about details of the study and to decide whether or not to participate in the trial.  
All questions about the trial must be answered to the satisfaction of the subject.  Prior to the subject’s 
participation in the trial, the written informed consent must be signed and personally dated by the 
subject and by the person who conducted the informed consent discussion.  For additional information, 
please refer to Section 11.3. 
6.2. 
Demography 
PRIOR to Day 1 when eligibility is being assessed, the following will be collected on the CRF: 
• 
Gender 
• 
Ethnicity 
• 
Race, and  
• 
Date of birth 
6.3. 
Urine Pregnancy Test 
Urine pregnancy tests will be performed on all female subjects of childbearing potential immediately 
PRIOR to randomization on Day 1 BEFORE application of investigational product.  The test must be 
confirmed as negative before randomization.  Another final pregnancy test will be performed when 
the subject re-epithelizes or when the subject exits the study due to non-healing of the PED or another 
reason. 
In the event of pregnancy, the subject will be withdrawn from the study and the pregnancy will be 
followed up to term for safety evaluation.   
6.4. 
Clinical Laboratory Tests 
Routine blood laboratory tests will be performed BEFORE application of investigational product.  
Baseline blood samples may be done during the Eligibility Assessments OR prior to randomization on 
Day 1.   
These baseline laboratory results will serve as a record for subjects on study entry, enable comparison 
with results on study exit post treatment (whether healing occurred or not) and enable Investigators to 


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make an informed assessment of any adverse events or serious adverse events, that may occur during 
the study.  
NO specific laboratory results (other than a positive pregnancy test) will be used to exclude a subject 
from entry or continued participation in the study, unless in the Investigator’s opinion the results 
indicate the subject has a concurrent condition that may affect the safety of the subject or potentially 
the outcome of the study (Exclusion Criteria 5). 
The same blood tests will be repeated when the subject completes the Treatment Period of the study.  
Refer to Table 1 - Schedule of Assessments.  A sample of up to 
 will be collected 
at each timepoint and the sample prepared as detailed in the Laboratory Manual.  
The tests to be performed are as follows: 
• 
 
 
• 
 
 
6.5. 
Medical History and Concomitant Medication 
A medical history, including details of any ongoing medical conditions, will be recorded PRIOR to Day 
1 and before eligibility is confirmed.  Aside from being used to determine subject eligibility, this 
information will permit the Investigator to record the nature, duration and severity of any ongoing 
baseline medical conditions prior to randomization and receiving investigational product treatment.  All 
medications that are used during a subject’s participation in the study must be recorded in the 
source documents and transcribed onto the CRF.   
6.6. 
Ocular History and Eligibility Assessments Prior to Day 1 and Prior 
to Randomization Day 1 
A detailed ocular examination and history will be conducted PRIOR to the Day 1 visit and assessed 
against the inclusion and exclusion criteria of this protocol.  For subjects with a bilateral ocular injury, 
both eyes should be assessed. 
Specific information regarding the etiology and prior history of the PED must be recorded as follows: 
• 
Cause of the defect; 
• 
Date when the defect first appeared (regarded as the first day of injury); 
• 
Medications and/or surgical procedures that have been used to treat the PED, including non-
prescription therapies, since injury;  
• 
Measurements of the defect to enable assessment of epithelial defect responsiveness to standard 
of care;  
• 
Classification of the lesion using the Dua grading scale as detailed in Appendix 1.  
Other assessments will include: 
• 
Ocular symptoms questionnaire – to record severity of symptoms  
• 
Ocular Injury - Physician Assessment  
• 
Visual acuity  
• 
Biomicroscopy  


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• 
PED assessment including digital photography  
• 
Ophthalmoscopy 
On Day 1, prior to randomization, the following assessments will include: 
• 
Ocular symptoms questionnaire  
• 
Ocular Injury - Physician Assessment  
• 
Visual acuity  
• 
 
• 
PED assessment including digital photography 
Refer to Table 1 - Schedule of Assessments for assessments prior to and on Day 1.   
 
 
 
6.7. 
Ocular Assessments following Randomization  
Once eligibility is confirmed the following assessments will be conducted at all further study visits, 
unless otherwise specified.  If investigational product is to be administered at a study visit, the ocular 
assessments MUST be conducted PRIOR to investigational product application.  In addition, the Ocular 
Symptoms Questionnaire and Ocular Pain Measurement Rating Scale which both involve subject 
responses should be conducted before other ocular assessment are conducted by the Investigator or 
delegate.  
 
 
6.7.1. 
Ocular Symptoms Questionnaire 
The Investigator will query the subject for the severity of the ocular symptoms in the study eye as 
indicated in Appendix 2.  This questionnaire should be conducted before other ocular assessments are 
performed by the Investigator or delegate. 
 
6.7.2. 
Ocular Pain Measurement Rating Scales 
 
 
 
This rating scale should be conducted before other ocular assessments are performed by the Investigator 
or delegate. Refer to Appendix 3 for details. 
 


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6.7.3. 
Ocular Injury - Physician Assessment 
The Investigator will assess the injury in the study eye at 
 
 
  Refer to Appendix 8 for the assessment scale and criteria. 
 
6.7.4. 
Slit Lamp Examination 
Slit lamp biomicroscopy (without pupil dilation) will be performed during the study on both the study 
eye treated with investigational product and fellow eye.  Observations for the slit lamp biomicroscopy 
will be graded as detailed in Appendix 5. 
6.7.5. 
Measuring the Epithelial Defect and Photography Assessments 
The epithelial defect size will be recorded to assess eligibility PRIOR to Day 1 and randomization on 
Day 1 then at all following visits, as indicated in Table 1: Schedule of Assessments.  The cornea will 
be stained with fluorescein prior to measurement. 
The size of the PED will be measured: 
 
 
 
 
 
 
 
 
 
 
To ensure the corneal epithelium remains undisturbed after randomization, 
 
  Assessment and measurement of the defect size will be done 
 
 using fluorescein.  
 
 
 
One drop of lubricant can be used to moisten a fluorescein strip, shaken once, then touched to either 
the tear film or the inferior fornix. After two to three blinks, photographs can be taken. 
 
 
 
 
 
 Extreme care must be taken to avoid physical disruption of the healing epithelium. 
 
 
  
 
 


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photographs may be taken 
, i.e., focused and with the entire 
defect in view, are achieved. Refer to Appendix 6 and Appendix 7 for details. 
A separate User’s Manual will provide additional instructions on the slit lamp photography to those site 
personnel responsible for taking the digital images and measuring the PED.  All users must also have 
training on the instructions prior to undertaking any photographs for this study. 
 
6.7.6. 
Visual Acuity 
Visual acuity is to be performed in the same manner at each scheduled assessment.  Refer to 
Appendix 4.  
 
  
 
  
 
 
6.7.7. 
Ophthalmoscopy 
If possible, an ophthalmoscopic assessment –
 
 
will be performed with the eye dilated when re-epithelialization 
occurs or when the subject exits the Treatment Period with an unhealed PED.   
 
 
6.7.8. 
Intraocular Pressure 
Intraocular pressure (IOP) will be assessed in both the study eye and fellow eye only on the days shown 
in Table 1: Schedule of Assessments.  
 
 
  
 
  
 
A final IOP measurement will be taken when the subject exits the study.   
The method used to measure IOP, whilst not standardized across study sites, MUST be kept the same 
for each individual subject within a study site.  
 
 


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7. 
INVESTIGATIONAL PRODUCT 
7.1. 
Description of the Investigational Product 
The investigational product used in the study will be NEXAGON® 
 
(NEXAGON) formulated at
 and Vehicle 
0.0 mg/mL (0%).   
NEXAGON is a
 gel for topical ophthalmic application.  The investigational product 
is formulated with sterile, 
 
 
 
  
 
   
 
 All vials are identical in appearance and the vial labels will not 
identify the contents, i.e., the treatment allocated to a subject will be masked to both the site and other 
personnel working on this study.  Vials will be labeled with codes and it will not be possible to know 
what the contents of the vials are, unless there is a medical emergency requiring unmasking (refer to 
Section 7.8). 
7.2. 
Dosage  
Each investigational product and Vehicle dose application to the study eye will comprise of 
 
 
 
No topical ocular drops or ointment standard of care treatment will be permitted 
 
 following investigational product administration. 
Investigational product will be applied on
 
 
 
  
 
 
 
7.3. 
Packaging and Labeling 
The contents of the investigational product label will be in accordance with all applicable regulatory 
requirements.  Each Investigator will be supplied with sufficient supplies to conduct the trial.  
Additional study kits treatment packs will be supplied as needed to the site. 


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The investigational product will be provided to the site packaged in tamper-evident masked study kits.  
Investigational product is double-masked with neither the Investigator or subject knowing which 
treatment arm has been allocated.  
 
  The labels on the primary and 
secondary containers will not identify the contents.  
 
 
 Refer to Section 7.7 Treatment Assignment for further details. 
 
 
 
 
 
7.4. 
Investigational Product Storage, Handling and Administration 
Investigational product will be dispatched to a site only after receipt of required documents in 
accordance with all regulatory requirements and Amber procedures. 
Only subjects enrolled in the study may receive investigational product, in accordance with all 
regulatory requirements.  Investigational product must be dispensed or administered according to 
procedures described herein.   
7.4.1. 
Investigational Product Storage 
Investigational product study kits should be maintained 
  
 and must be stored in a secure area, with access limited to the Investigator and 
authorized site staff. 
Each site will be dispatched a pre-determined supply of investigational product study kits and ancillary 
cartons.  Additional study kits and ancillary cartons of investigational product will be supplied as 
needed.  
7.4.2. 
Investigational Product Dispensing – Masked Study Kits 
Three treatment groups will be evaluated in this study
 
• 
GROUP A – 
 
• 
GROUP B – 
 
• 
GROUP C – Vehicle (0%) 
Only authorized site staff will be able to dispense and supply investigational product to the study 
subject.  No special safety requirements are required prior to handling the investigational product. 
The designee will remove the assigned study kit - the lowest Kit Number in their inventory - from the 
refrigerator and write the Subject Identifier (ID) on the outer study kit label.  The designee must also 
confirm that the tamper-evident label which seals the study kit is still intact.  If the tamper-evident label 
is voided in any way the kit should be set-aside in the secure storage area and not used.  The Study 


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Monitor should be contacted and a replacement study kit can be organized through the nominated 
unmasked study statistician. 
An intact study kit will be opened on Day 1 of the study, the day of randomization.  The designee 
should remove the vial labelled Day 1 and 
 
 and to ensure 
that there is no visible damage to the container.  If the investigational product container appears to be 
compromised, it should not be used, but instead returned 
 
 
  
Once checked and confirmed as being in a good condition, the appropriate vial
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
7.4.3. 
Investigational Product Dispensing – Open-Label Ancillary Cartons 
For subjects requiring a 
 
  
 
 
 
 
 
 
 
 
7.4.4. 
Investigational Product Administration 
No topical ocular drops or ointments standard of care treatment should be applied 
 
investigational product administration. 
When the subject is due to receive investigational product, the vial should be
 
 
 


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Further details on presentation, storage, administration and accountability will be provided in the study 
Pharmacy Manual.  
7.5. 
Product Accountability 
The Investigator is responsible for investigational product accountability, reconciliation and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or designated 
staff must maintain investigational product accountability records throughout the course of the study.  
The responsible person(s) will document the amount of investigational product received from and 
returned to Amber, the amount administered to subjects, and the amounts destroyed at the site.  


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7.6. 
Assigning the Subject Identifier (Subject ID)  
Upon signing the informed consent form, each subject will be allocated a unique Subject ID, consisting 
of a 3-digit study site number and then a 3-digit sequential number corresponding to the order in which 
subjects are screened at that site, e.g., 001, 002, 003, etc.  
The unique Subject ID assigned will be retained by that subject for the duration of their participation 
in the study.  
7.7. 
Treatment Assignment 
Subjects will be assigned to one 
 treatment arms in accordance with the randomization 
schedule.  
 
 
 
 
 
 
 
 
  
 
7.8. 
Unmasking 
The Investigator may unmask a subject’s treatment assignment only in the case of an emergency when 
knowledge of the investigational product is essential for the clinical management or welfare of the 
subject. 
 
 
 
 
 
 
 
If a drug-related serious adverse event (SAE; as defined in Section 9.2: “Definition of an SAE”) is 
reported, the Medical Monitor may unmask the treatment assignment for the individual subject.  If an 
expedited regulatory report to one or more regulatory agencies is required, the report will identify the 
subject’s treatment assignment.  When applicable, a copy of the regulatory report may be sent to the 
Investigator in accordance with relevant regulations, Sponsor policy or both.  


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8. 
SUBJECT COMPLETION AND WITHDRAWAL 
8.1. 
Subject Completion  
In order to be considered a study completer, subjects must meet the following TWO criteria: 
1. Complete the masked Treatment Period until either of the following 
a. Re-epithelialization 
b. Completion of 
  
2. Enter and complete the 
 Post-healing Follow-up Phase (following re-epithelialization 
during 
Double Masked Treatment Phase or re-epithelialization during open-label 
section of the study*). 
 
 
 
8.1.1. 
Subject Premature Withdrawal from Study 
A subject who is administered investigational product, but who does not complete the study, as defined 
in Section 8.1, has prematurely discontinued.  Prematurely discontinued subjects will not be replaced.   
A subject may voluntarily discontinue participation in this study at any time.  The Investigator may 
also, at his/her discretion, discontinue the subject from participating in this study at any time for 
safety reasons.   
In addition, subjects WILL be withdrawn from the study, in consultation with the Medical 
Monitor and the Investigator, if any of the following criteria are met: 
• 
A subject is significantly non-compliant with the requirements of the protocol. 
• 
A subject becomes pregnant (NOTE: the pregnancy will be followed up to term for safety 
follow-up.  Relevant safety information collected after the study has completed will be 
reported as supplemental information). 
 
 
• 
Sponsor discontinues the study. 
Premature withdrawal from the study MAY occur if: 
• 
A subject is treated with a prohibited medication.  This decision will be made by the Medical 
Monitor in conjunction with the Investigator as to whether premature withdrawal is 
warranted. 
• 
The condition of the study eye worsens in the opinion of the Investigator and alternative 
rescue treatment is required. 
Subjects who meet the criteria for premature withdrawal, during the Treatment Period will have the 
/ Exit Visit performed. 
Subjects who meet the criteria for premature withdrawal, during the Post-healing Follow-up 
Period will complete all the ophthalmic assessments of the visit where the premature withdrawal 
criterion was identified, if possible.   


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All subjects who exit the study prematurely will have a safety follow-up visit (unscheduled visit) or 
telephone call scheduled 30 days after their last application of investigational product to assess any 
AEs/SAEs.  
If a subject is prematurely discontinued from participation in the study for any reason, the 
Investigator must make every effort to locate and perform all evaluations specified above.   
Any clinically significant adverse events or clinically significant unfavorable changes in the laboratory 
tests observed during the discontinuation visit will necessitate that the subject be followed or referred 
for treatment until satisfactory resolution occurs.  
In the event that a subject is prematurely discontinued from the study at any time due to an adverse 
event (AE) (as defined in Section 9.1) or SAE (as defined in Section 9.2), the procedures stated in 
Section 9 must be followed.  
8.2. 
Eligibility Assessment (Screening) Failures 
A subject who has at least one study procedure performed (in addition to signing a consent form) and 
is assigned a Subject ID, but is not randomized, is classified as having failed study entry and deemed a 
Screen Failure.  Subject ID, demography and reason for screen failure will be recorded  in the electronic 
CRF. 
9. 
ADVERSE EVENT DEFINITIONS 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an adverse event (AE) or serious adverse event (SAE), as provided in this protocol.  During 
the study when there is a safety evaluation, the Investigator or site staff will be responsible for detecting, 
documenting and reporting AEs and SAEs as detailed in this section of the protocol. Country specific 
safety reporting requirements are detailed further in the Safety Management Plan for the protocol.  
9.1. 
Definition of an AE 
An AE is any untoward medical occurrence in a subject or clinical investigation subject administered 
a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational product whether 
or not related to the investigational product. 
AEs will be recorded from the time of first application of the investigational product and until the final 
visit.   
9.1.1. 
Treatment Emergent Adverse Event (TEAE) 
Treatment emergent AEs (TEAEs), those that occur after the first dose of study medication, are 
undesirable events not present prior to investigational product treatment, or an already present event 
that worsens either in intensity or frequency following treatment. 


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9.2. 
Definition of a SAE 
An SAE (experience) or reaction is any untoward medical occurrence that at any dose: 
a. Results in death. 
b. Is life-threatening and/or sight threatening. 
NOTE:  The term "life-threatening" or “sight threatening” in the definition of "serious" refers 
to an event in which the subject was at risk of death or loss of vision at the time of the 
event; it does not refer to an event which hypothetically might have caused death or 
loss of vision if it were more severe. 
c. Requires in subject hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
d. Results in persistent or significant disability/incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza and accidental trauma, which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption.  
e. Is a congenital anomaly/birth defect. 
Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalizations, or the development of drug dependency or drug abuse.  
9.2.1. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as AEs and SAEs 
Clinically significant abnormal laboratory findings or other abnormal assessments that are present at 
baseline and significantly worsen following the start of the study will be reported as AEs and SAEs.   
The Investigator will exercise his/her medical and scientific judgment in deciding whether an abnormal 
laboratory finding or other abnormal assessment is clinically significant.  
9.3. 
Assigning Causality 
The Principal Investigator or medically qualified Sub-investigator, listed on the FDA Form 1572, must 
make a determination of the relationship of the AE or SAE to the investigational product using the 
following categories: 


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Definitely related:  This category applies to those AEs that the Investigator feels are incontrovertibly 
related to the IP.  An AE may be assigned an attribution of definitely related if or when it meets all of 
the following criteria: (1) it follows a reasonable temporal sequence from administration of the IP; (2) 
it could not be reasonably explained by the known characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the subject; and (3) it follows 
a known response pattern to treatment with IP. 
Probably related:  This category applies to those AEs which, after careful medical consideration at 
the time they are evaluated, are felt with a high degree of certainty to be related to the IP.  An adverse 
event may be considered probable if or when (must meet at least three of the four criteria):  (1) it follows 
a reasonable temporal sequence from application of the IP; (2) it could not readily have been produced 
by subject’s clinical state, environmental or toxic factors, or other therapies administered to the subject; 
(3) it disappears or ameliorates upon discontinuation of the IP; or (4) it follows a known response 
pattern to treatment with IP. 
Possibly related:  This category applies to those AEs which, after evaluation are judged unlikely to be 
related to the IP, but this cannot be ruled out with certainty.  An adverse event may be considered 
possible if or when (must meet at least two of the four criteria):  (1) it follows a reasonable temporal 
sequence from application of IP; (2) it could not readily have been produced by subject’s clinical state, 
environmental or toxic factors, or other therapies administered to the subject; (3) disappears or is 
decreased upon discontinuation of the IP; or (4) it follows a known response pattern to treatment with 
IP.  
Unlikely to be related:  In general, this category can be considered applicable to those adverse events 
which, after careful medical consideration at the time they are evaluated, are judged likely to be 
unrelated to the IP.  An adverse event may be considered unlikely if or when (must meet at least two 
of the four criteria):  (1) it does not follow a reasonable temporal sequence from application of IP; (2) 
it could not readily have been produced by subject’s clinical state, environmental or toxic factors, or 
other therapies administered to the subject; (3) disappears or is decreased upon removal of the IP; or 
(4) it does not follow a known response pattern to treatment with IP.  
Unrelated:  This category applies to those adverse events which, after careful consideration at the time 
they are evaluated, are clearly and incontrovertibly due to extraneous causes (disease, environment, 
etc.) and determined with certainty to have no relationship to the study IP.  
This causality assessment must be signed and dated by the person making the evaluation in source 
documents.  
9.4. 
Reporting of SAEs to the Sponsor  
SAEs will be reported promptly to the Sponsor (or delegate), as described in the following table, once 
the Investigator determines that the event meets the protocol definition of an SAE. 
Type of SAE 
Initial SAE Reports 
Follow-up Information on a Previously 
Reported SAE 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
Within 24 hours 
from first 
becoming aware 
SAE data 
collection 
documents 
24 hours 
Updated SAE data 
collection 
documents 


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10. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The following section is to describe the planned analyses and reporting for this study. It includes a 
description of the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. Further details and the including the specific statistical methods that 
will be used are included in the NEX-PED-005 Statistical Analysis Plan (SAP).  The statistical analysis 
methods presented in the SAP will supersede the statistical analysis methods described below. 
10.1. 
Study Design Considerations 
10.1.1. Primary Hypotheses 
 
 
 
 
 
 
 
 
 
 
10.1.2. Sample Size Assumptions 
 
 
 
   
 
 
 
10.2. 
Data Analysis Considerations  
10.2.1. Analysis Populations 
 
 
 
 
 
 
 
 
 
 
 


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10.2.2. General Considerations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
10.2.3. Interim Analysis 
A staged interim analysis (IA) will be performed 
 
 
 
 
 
 
 


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Further details of each stage of the IA are described in NEX-PED-005 Statistical Analysis Plan.  
10.2.4. Multiplicity Adjustment 
 
 
 
 
 
 
  
 
10.2.5. Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, or disease status will be summarized and 
listed.  Medical history, ocular history, and etiology of the PED will also be summarized and listed. 
10.2.6. Subject Disposition 
Subject enrollment, inclusion in analysis populations, and study completion/withdrawal from the study 
for the main study as well as the open-label section of the study will be summarized and listed. 
10.2.7. Efficacy Analyses 
The primary efficacy outcome will be the comparison of each dose of NEXAGON to Vehicle for: 
• 
The proportion of subjects with corneal epithelial recovery, defined as a cornea that 
re-epithelializes by 
 of treatment and remains re-epithelialized for at 
 
after initial re-epithelialization was first recorded (during the masked treatment portion of the 
study). 
The secondary efficacy outcomes will be the comparison of each dose of NEXAGON to Vehicle for: 
 
 
 
 
 
 
 
 
The exploratory efficacy outcomes will be the comparison of each dose of NEXAGON to Vehicle for: 


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using an analysis of covariance model incorporating all three treatment groups and baseline as a 
 
 
 
 
 
 
10.2.8. Safety Analyses 
Verbatim descriptions of adverse events (AEs) will be mapped to MedDRA terms and be presented in 
a data listing.  Treatment emergent AEs (TEAEs), those that occur after the first dose of study 
medication, will be summarized by treatment group using frequency and percent for each system organ 
class (SOC) and preferred term (PT) within each SOC.  Similar summaries will be presented for: related 
TEAEs, TEAEs by maximum severity, serious TEAEs, and TEAEs leading to test article 
discontinuation. 
Slit lamp biomicroscopy and ophthalmoscopy measures will be summarized 
 
 
Clinical laboratory results will be summarized
 
 
 
 
Summaries of safety measures during the open-label section of the study will be completed similarly, 
for those subjects entering into the open-label salvage.  
11. 
STUDY CONDUCT CONSIDERATIONS 
11.1. 
Institutional Review Board / Independent Ethics Committee 
(IRB/IEC) 
The Principal Investigator agrees to provide the IRB/IEC with all appropriate material, including the 
Investigator’s brochure and the subject Information Sheet and Consent Form.  The trial will not be 
initiated until appropriate IRB/IEC approval (as per GCP Essential Documents 8.2.7) of the protocol 
and the informed consent document have been obtained in writing by the Investigator, and copies have 
been received by Amber.  Appropriate reports including an annual update/report on the progress of the 
study by the Principal Investigator will be submitted to the IRB/IEC and Amber, in accordance with 
applicable regulatory requirements and in agreement with policy established by Amber. 
11.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki (see References). 


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11.3. 
Informed Consent 
Properly executed written informed consent, in compliance with the International Conference on 
Harmonization, and other regulatory requirements (as relevant), shall be obtained from each subject 
before the subject is entered into the trial or before any unusual or non-routine procedure is performed.  
Attention will be directed to the basic elements of disclosure that are required for incorporation into the 
informed consent under GCP 4.8 and/or U.S. Federal Regulations for Protection of Human Subjects 
(21 CFR 50.25[a]), as applicable.  Additional elements of informed consent, if appropriate, must be 
included in the document (21 CFR 50.25[b]). 
Sample informed consent documents will be provided to each site.  Amber or a representative will 
review the site informed consent document for inclusion of all required elements prior to submission 
to the IRB/IEC.  Revisions to the approved informed consent must also be reviewed and approved by 
Amber prior to submission to the IRB/IEC.  The final IRB/IEC-approved document must be provided 
to Amber for regulatory purposes. 
The informed consent document must be signed by each subject/legally authorized representative 
(LAR) before his or her participation in the study.  A copy of the signed and dated Informed Consent 
Form and the Subject Information Sheet must be provided to the subject.  If new information related to 
the study arises, subjects will be asked to sign a revised informed consent document.  If applicable, it 
will be provided in a certified translation of the local language.  Signed consent forms must remain in 
each subject’s medical record and must be available for verification by Study Monitors at any time. 
The approved Informed Consent Form will be filed at site. 
11.4. 
Study Discontinuation 
Amber has the right to terminate or suspend this study at any time.  Reasons for terminating the study 
may include but are not limited to the following: 
• 
The incidence or severity of adverse events in this or other studies that indicates a potential 
health hazard to subjects; 
• 
Subject enrollment is unsatisfactory; 
• 
Data recording is repeatedly inaccurate or incomplete, i.e., persistent non-compliance with 
GCP; 
• 
Large numbers of prematurely discontinued subjects; 
• 
Significant protocol violations (i.e., violation of eligibility criteria, dosing errors, and/or 
missing data for study endpoint analysis). 
Compliance with the following is mandatory: GCP 5.21 (Sponsor: Premature Termination or 
Suspension of a Trial and GCP 4.12 Investigator: Premature Termination or Suspension of a Trial). 
11.5. 
Premature Termination or Suspension of a Trial 
If a trial is prematurely terminated or suspended, Amber must promptly inform the 
Investigator/institution and the regulatory authority(s) of the termination or suspension and the 
reason(s) for the termination or suspension.  The IRB/IEC must also be informed promptly and provided 
the reason(s) for the termination or suspension by Amber or by the Investigator/institution, as specified 
by the applicable regulatory requirement(s). 
If the study is prematurely terminated or suspended for any reason, the Investigator/institution must 
promptly inform the trial subjects, must assure appropriate therapy and follow-up for the subjects, and, 


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Version 6, 19 April 2022 
 
Page 61 of 77 
where required by the applicable regulatory requirement(s), must inform the regulatory authority(s).  In 
addition: 
• 
If the Investigator terminates or suspends a trial without prior agreement of Amber, the 
Investigator must inform the institution where applicable, and the Investigator/institution 
must promptly inform Amber and the IRB/IEC and must provide Amber and the IRB/IEC a 
detailed written explanation of the termination or suspension. 
• 
If Amber terminates or suspends a trial (see GCP 5.21), the Investigator must promptly 
inform the institution where applicable and the Investigator/institution must promptly inform 
the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or 
suspension. 
• 
If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial (see GCP 3.1.2 
and 3.3.9), the Investigator must inform the institution where applicable, and the 
Investigator/institution must promptly notify Amber and provide Amber with a detailed 
written explanation of the termination or suspension. 
The following data and materials are required by Amber before a study can be considered to be 
complete or terminated: 
All essential documents as detailed in GCP Section 8, including the following: 
• 
Laboratory findings, clinical data and all special test results from screening through the end 
of the study (including the follow-up period) for all enrolled subjects. 
• 
CRF/Records used in this study.  Records (including correction forms) for all enrolled 
subjects will be properly completed by appropriate study personnel and signed and dated by 
the Investigator as required. 
• 
Completed investigational product accountability records, investigational product inventory 
log, and inventory of returned clinical material forms. 
• 
Return of all unused investigational product to Amber, unless an alternate disposal method is 
agreed upon at study initiation by Amber and investigational site(s). 
• 
Copies of protocol amendments and IRB/IEC approval/notification, if appropriate. 
• 
A summary of the study prepared by the Principal Investigator (IRB/IEC summary closure 
letter is acceptable).  
11.6. 
Study Initiation 
Investigator(s) must complete all regulatory documentation as required by local and national 
regulations.   
Essential documents required for authorization of supply of the investigational product: 
The following documentation must be received by the Amber staff before investigational product is 
supplied to the site [GCP 5.14.2]:  
• 
Investigator's current CV or Investigator biography with the following details as a minimum:   
o Completed in English  
o The Investigator's name and address  
o Study location address (if different from above)  
o Qualification details  


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o Current position(s)  
o Previous professional experience  
• 
All required signatures from site personnel on final approved protocol and any amendment(s).  
• 
IEC/IRB written and dated favorable opinion/approval of the following [GCP 3.3.6]:  
o Protocol  
o Informed consent documents  
o Any other information required by the IEC/IRB for favorable opinion/approval  
• 
Regulatory approval and importation license (where applicable). 
• 
Investigator/Institution agreements [GCP 5.1.4]. 
• 
Financial agreements (these may be included in Investigator/Institution Agreement).  
• 
Completed and signed Investigator and Sub-investigators' financial disclosure form in 
compliance with the Food and Drug Administration (FDA) Financial Disclosure Rule. 
• 
FDA form 1572.  
Please refer to GCP Section 8 for full details of essential documents required for the conduct of a 
clinical trial. 
11.7. 
Protocol Deviations  
A deviation from the protocol when no amendment has been submitted and approved would be regarded 
as a protocol violation.  All protocol violations must be documented and reported to Amber.   
11.8. 
Case Report Forms 
Study data will be recorded on electronic Case Report Forms.  When electronic CRFs are used, 
corrections to data will be made according to 21 CFR Part 11, Electronic Records; Electronic 
Signatures. 
11.9. 
Records Retention 
The Investigator will maintain all research records, reports, and case history reports for a period of two 
years after regulatory approval of the investigational product.  If no application is filed or if the 
application is not approved, records must be maintained for two years after all investigations have been 
completed, terminated or discontinued and the FDA has been notified.  
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements of if needed by Amber (as per GCP 5.5.11). 
It is the policy of Amber that the study data must be verifiable with the source data, which necessitates 
access to all original recordings, laboratory reports, and subjects’ records.  The Investigator must 
therefore agree to allow access to subjects’ records, and source data must be made available for all 
study data.  The subjects (or their legal representatives) must also allow access to their medical records.  
Subjects will be informed of the importance of increased record access and permission granted by 
signature on the informed consent document prior to enrollment. 
11.10. Data Handling 
Clinical data will be recorded in a computer format for subsequent statistical analyses.  Data files will 
be stored on electronic media with a final master data file kept by Amber or their authorized 


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representative after descriptive and statistical analyses and reports have been generated and are 
complete.  Data from these forms will be entered into a computerized database, validated, coded using 
specific dictionaries, and quality-assured.  Following the resolution of data questions and queries, a 
random audit may be performed. 
11.11. Study Monitoring and Compliance 
All aspects of the study will be carefully monitored by Amber or authorized representatives of Amber, 
according to GCP and standard operating procedures for compliance with applicable government 
regulations.  Access to all records, both during the trial and after trial completion, must be made 
available to Amber at any time for review and audit to ensure the integrity of the data.  
Every attempt must be made to follow the protocol and to obtain and record all data requested for each 
subject at the specified times.  However, ethical reasons may warrant the failure to obtain and record 
certain data or to record data at the times specified.  If data are not recorded per protocol, the reasons 
must be clearly documented on the CRF/records. 
11.12. Use of Information and Publications 
It is understood by the Investigator that the information generated in this study will be used by Amber 
in connection with the development of the product and therefore may be disclosed to government 
agencies in various countries.  To allow for the use of information derived from the study, it is 
understood that the Investigator is obliged to provide Amber with complete test results, all study data, 
and access to all study records and images, de-identified to protect subject confidentiality.  
Amber recognizes the importance of communicating medical study data and therefore encourages their 
publication in reputable scientific journals and at seminars or conferences.  Any results of medical 
investigations with Amber products and/or publication/lecture/manuscripts based thereon will be 
exchanged and discussed by the Investigator and Amber representative(s) 30 days before submission 
for publication or presentation.  Due regard shall be given to Amber legitimate interests, e.g., 
manuscript authorship, obtaining optimal patent protection, coordinating and maintaining the 
proprietary nature of submissions to health authorities, coordinating with other ongoing studies in the 
same field and protecting confidential data and information.  Amber shall be furnished with a copy of 
any proposed publication.  Comments will be rendered without undue delay and not later than 14 days 
after requested.    
Results from Investigations will not be made available to any third party by the investigating team 
outside the publication procedure, as outlined previously.  Amber will not quote from publications by 
Investigators in its scientific information and/or promotional material without full acknowledgment of 
the source (i.e., author and reference). 


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11.13. Protocol Amendments 
Only Amber may modify the protocol.  Protocol amendments will only be made after consultation and 
agreement between Amber and the Investigator(s).  Amendments must be approved by all applicable 
national and local committees including, but not limited to, the FDA or the Drugs Controller General 
of India before implementation.  The only exception is when an Investigator considers that a subject 
may be harmed and immediate action is necessary.  Under these circumstances, approval by the 
chairman of the IRB/IEC or an authorized designee must be sought as soon as is practicable.  The 
Investigator must inform Amber and the full IRB/IEC no later than 5 working days after the emergency 
occurs.  Protocol-specified safety reporting requirements must be adhered to independent of any other 
variables.  All amendments that have an impact on subject risk or the study objectives or that require 
revision of the informed consent document must be approved by the IRB/IEC before implementation.  
Administrative changes to the protocol and/or changes that do not impact subject safety, risk, or comfort 
may be implemented prior to IRB/IEC approval if local institutional policy permits. 
 
 


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APPENDIX 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 2: 
  
Determine the severity and frequency of each symptom in the study eye (if bilateral injury, also the 
fellow eye) by questioning the subject with regard to the following:   
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 


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APPENDIX 3: 
 
At each scheduled visit, the Visual Analogue Scale, below, will be completed by the subject to rate 
the intensity of the pain being experienced by the subject in the study eye (if bilateral injury, also the 
fellow eye) at that moment in time.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 4: VISUAL ACUITY AND REFRACTION 
Visual acuity is to be performed in the same manner at each visit.  Visual acuity will be assessed using 
the Snellen Chart.  The test distance and illumination for the chart must be kept constant 
throughout the study.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


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APPENDIX 5: BIOMICROSCOPY/SLIT LAMP EXAMINATION FOR 
OCULAR SIGNS 
Slit lamp biomicroscopy (without pupil dilation) will be performed during the study on both the study 
eye treated with investigational product and the fellow eye.  Observations for the slit lamp 
biomicroscopy will be graded as below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page 71 of 77 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 


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APPENDIX 6: MEASURING THE EPITHELIAL DEFECT  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 7: SLIT LAMP DIGITAL PHOTOGRAPHY OF THE 
EPITHELIAL DEFECT 
Digital photographs will be taken of the corneal PED during the slit lamp examination.  A separate 
User’s Manual will provide additional detailed instructions on the slit lamp photography to those site 
personnel responsible for taking the digital images.  All users must also have training on the instructions 
prior to undertaking any photographs for this study. 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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Version 6, 19 April 2022 
 
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APPENDIX 8: OCULAR INJURY – PHYSICIAN ASSESSMENT 
The Investigator will assess the study eye (if bilateral injury, also the fellow eye) against the following 
criteria ONLY at the following visits:  
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
 
 
 
 
 
  
  
  
 
  
 
 
 


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APPENDIX 9: 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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Version 6, 19 April 2022 
 
Page 76 of 77 
REFERENCES 
Brookmeyer, R. and Crowley, J. A confidence interval for the median survival time. 
Biometrics 1982; 38:29-41. 
Coutinho P, Qiu C, Frank S, Tamber K, Becker D. Dynamic changes in connexin expression 
correlate with key events in the wound-healing process. Cell Biol Int 2003;27(7):525-541. 
Dua HS, King AJ and Joseph A (2001) A new classification of ocular surface burns. The 
British journal of ophthalmology 85:1379-1383. 
Farjo AA SH. Corneal Epithelium. In Yanoff M, Duker JS, editors. Ophthalmology. 
2004:413-20. 
Gordon JF, Johnson P, Musch DC. Topical fibronectin ophthalmic solution in the treatment 
of persistent defects of the corneal epithelium. Chiron Vision Fibronectin Study Group. 
Am J Ophthalmol 1995;119(3):281-7. 
Grupcheva CN Laux WT, Rupenthal ID, McGhee J, McGhee CNJ, Green CR. Improved 
corneal wound healing through modulation of gap junction communication using 
Connexin43-specific antisense oligodeoxynucleotides. Investigative Ophthalmology and 
Visual Science 2012;53:1130-1138. 
Kim Y, Davidson JO, Gunn KC, Phillips AR, Green CR, Gunn AJ (2016) Role of 
Hemichannels in CNS Inflammation and the Inflammasome Pathway. Adv Protein 
Chem Struct Biol 2016;104:1-37. Epub 2015 Dec 31. Review. PMID:27038371 
Laux-Fenton WT, Chang C, McGhee CN, Grupcheva CN, Becker DL, Green CR. 
Modulation of connexins for corneal tissue remodelling and engineering. 2004. 
Letko E, Stechschulte SU, Kenyon KR, Sadeq N, Romero TR, Samson CM, et al. Amniotic 
membrane inlay and overlay grafting for corneal epithelial defects and stromal ulcers. 
Arch Ophthalmol 2001;119(5):659-63. 
McCarty SM, Percival SL. Proteases and Delayed Wound Healing. Adv Wound Care (New Rochelle) 
2013;2(8):438-447. 
McCulley JP, Horowitz B, Husseini ZM, Horowitz M. Topical fibronectin therapy of 
persistent corneal epithelial defects. Fibronectin Study Group. Trans Am Ophthalmol 
Soc 1993;91:367-86; discussion 386-90. 
Mukerji N, Vajpayee RB, Sharma N. Technique of area measurement of epithelial defects. 
Cornea 2003;22(6):549-51. 
Ormonde S, Chou CY, Goold L, Petsoglou C, Al-Taie R, Sherwin T, McGhee CN, Green 
CR. Regulation of connexin43 gap junction protein triggers vascular recovery and 
healing in human ocular persistent epithelial defect wounds. J Membr Biol 
2012;245(7):381-388. 
Oskouee SJ, Amuzadeh J, Rajabi MT. Bandage contact lens and topical indomethacin for 
treating persistent corneal epithelial defects after vitreoretinal surgery. Cornea 
2007;26(10):1178-81. 
Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, et al. Targeting connexin43 
expression accelerates the rate of wound repair. Curr Biol 2003;13(19):1697-703. 


Amber Ophthalmics, Inc. 
CONFIDENTIAL - Not for disclosure or publication 
Protocol:  NEX-PED-005 
 
EXPEDE Protocol 
Version 6, 19 April 2022 
 
Page 77 of 77 
Saw VP, Minassian D, Dart JK, Ramsay A, Henderson H, Poniatowski S, et al. Amniotic 
membrane transplantation for ocular disease: a review of the first 233 cases from the UK 
user group. Br J Ophthalmol 2007;91(8):1042-7. 
Singer AJ, Clark RAF. Cutaneous Wound Healing. N Engl J Med 1999;341:738-746. 
Spector J, Fernandez WG. Chemical, thermal, and biological ocular exposures. Emerg Med 
Clin North Am 2008;26(1):125-36, vii. 
Vajpayee RB, Mukerji N, Tandon R, Sharma N, Pandey RM, Biswas NR, et al. Evaluation of 
umbilical cord serum therapy for persistent corneal epithelial defects. Br J Ophthalmol 
2003;87(11):1312-6. 
Williams PB, Crouch ER, Jr., Crouch ER, Mazaheri M. Topical aminocaproic acid facilitates 
reepithelialization of persistent epithelial defects. Curr Eye Res 1999;18(2):150-7. 
World Medical Association (WMA) Declaration of Helsinki – Ethical Principles for Medical 
Research Involving Human Subjects, 64th WMA General Assembly, Fortaleza, Brazil, 
October 2013. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 2, randomized, prospective, double-masked, vehicle-
controlled study to assess the efficacy and safety of Nexagon®
(NEXAGON) applied topically in subjects with corneal persistent 
epithelial defects (PED) resulting from severe ocular chemical and/or 
thermal injuries.
Sponsor: 
Protocol Number:
NEX-PED-005
Author: 
Date:
10FEB2022
Version: 
1.0


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A Phase
2, randomized, prospective, double-masked, vehicle-
controlled study to assess the efficacy and safety of Nexagon® 
(NEXAGON) applied topically in subjects with corneal persistent 
epithelial defects (PED) resulting from severe ocular chemical and/or 
thermal injuries.
Protocol Number:
NEX-PED-005
SAP Version: 
1.0
SAP Date:  
10FEB2022
Statistical Analysis Plan Approval (Approval pg. 1 of 2)
Prepared by:
__________________________
_____________
Date
Reviewed by:
__________________________
_____________
             
Date
	




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Statistical Analysis Plan Approval (Approval pg. 2 of 2)
Approved by: __________________________
_____________
Date
Approved by: __________________________
_____________
Date
	



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Table of Contents
Table of Contents.................................................................................................................................4 
List of Abbreviations.............................................................................................................................7 
1. 
Introduction...............................................................................................................................9 
2. 
Study Objectives ......................................................................................................................9 
2.1 Primary Endpoint......................................................................................................................9 
2.2 Secondary Endpoints ...............................................................................................................9 
2.3 Exploratory Endpoints ..............................................................................................................9 
2.4 Safety Variables .....................................................................................................................10 
2.5 Statistical Hypotheses............................................................................................................10 
3. 
Study Design and Procedures ...............................................................................................11 
3.1 General Study Design ............................................................................................................11 
3.2 Study Visit Windowing............................................................................................................13 
3.3 Dose Regimen, Study Flow Diagram, and Schedule of Visits and Assessments .................17 
4. 
Study Treatments...................................................................................................................23 
4.1 Method of Assigning Subjects to Treatment Groups .............................................................23 
4.2 Masking and Unmasking........................................................................................................23 
5. 
Sample Size and Power Considerations................................................................................23 
6. 
Data Preparation ....................................................................................................................24 
6.1 Input Data...............................................................................................................................24 
6.2 Output Data............................................................................................................................24 
7. 
Analysis Populations ..............................................................................................................25 
 
 
 
 
 
 
 
 
 
 
 
 
8. 
General Statistical Considerations.........................................................................................26 
8.1 Unit of Analysis.......................................................................................................................26 
8.2 Missing or Inconclusive Data Handling ..................................................................................26 
8.3 Definition of Baseline and Final On-Treatment Visit ..............................................................27 
8.4 Data Analysis Conventions ....................................................................................................28 
8.5 Adjustments for Multiplicity.....................................................................................................28 
9. 
Disposition of Subjects...........................................................................................................29 
10. 
Demographic and Pretreatment Variables.............................................................................30 
10.1 Demographic Variables..........................................................................................................30 


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10.2 Pretreatment Variables ..........................................................................................................30 
11. 
Medical History and Concomitant Medications......................................................................31 
11.1 Medical History.......................................................................................................................31 
11.2 PED History............................................................................................................................31 
11.3 Prior and Concomitant Medications .......................................................................................31 
11.4 Concomitant Procedures........................................................................................................32 
12. 
Treatment Exposure...............................................................................................................32 
13. 
Efficacy Analyses – Masked Portion of Study........................................................................32 
13.1 Primary Efficacy Outcome Analysis .......................................................................................32 
13.1.1 
Sensitivity Analyses....................................................................................................34 
13.2 Secondary Efficacy Outcome Analyses .................................................................................34 
13.2.1 
Time to Corneal Epithelial Recovery..........................................................................35 
13.2.2 
Visual Acuity...............................................................................................................35 
13.2.3 
Number of Treatment Doses......................................................................................36 
14. 
Exploratory Analyses .............................................................................................................36 
14.1 Change from Baseline in PED Area.......................................................................................37 
14.2 Corneal Re-epithelialization ...................................................................................................37 
14.3 Change from Baseline in Ocular Symptoms..........................................................................37 
 
 
 
 
14.4 Open-Label Analyses for Subjects Receiving Salvage Dose ................................................39 
14.5 Intra-Subject Corneal Re-epithelialization in Fellow Eye of Subjects with Bilateral Injuries..40 
15. 
Safety Analyses .....................................................................................................................40 
15.1 Adverse Events ......................................................................................................................40 
 
15.3 Slit Lamp Examination ...........................................................................................................43 
15.4 PED Assessment Including Digital Photography ...................................................................44 
15.5 Ophthalmoscopy ....................................................................................................................44 
15.6 Intraocular Pressure...............................................................................................................45 
15.7 Clinical Laboratory Data.........................................................................................................45 
16. 
Interim Analyses.....................................................................................................................46 
16.1 IA Stage 1...............................................................................................................................46 
16.2 IA Stage 2...............................................................................................................................48 
17. 
Changes from Protocol-Stated Analyses ...............................................................................50 
18. 
References.............................................................................................................................50 
19. 
Revision History .....................................................................................................................50 
20. 
Tables for Final Analysis ........................................................................................................50 


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21. 
Tables for Interim Analyses....................................................................................................54 
22. 
Data Listings ..........................................................................................................................57 
23. 
Figures ...................................................................................................................................59 


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List of Abbreviations
ADaM
Analysis Data Model
AE
Adverse Event
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
BCVA
Best Corrected Visual Acuity
CF
Counting Fingers
CI
Confidence Interval
COVID-19
Coronavirus (COVID-19) pandemic
CP
Conditional Power
CRA
Clinical Research Associate
CRO
Contract Research Organization
CS
Clinically Significant
DTA
Data Transfer Agreement
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOS
End of Study
ETDRS
Early Treatment Diabetic Retinopathy Study
FAS
Full Analysis Set
FAS-IA
Full Analysis Set for the IA
FUP
Follow-up
HM
Hand Movements
IAP1
Interim Analysis Primary Endpoint 1
IAP2
Interim Analysis Primary Endpoint 2
IAS1
Interim Analysis Secondary Endpoint 1
IAS2
Interim Analysis Secondary Endpoint 2
ICH
International Conference on Harmonisation
IOP
Intraocular Pressure
LOCF
Last Observation Carried Forward
logMAR
Logarithm of the Minimum Angle of Resolution
LS
Lease Squares
IP
Investigational Product
MedDRA
Medical Dictionary for Regulatory Activities
NCS
Not Clinically Significant
NPL
No Perception of Light
OL
Open-Label
PCI
Potentially Clinically Important
PDF
Portable Document Format
PED
Persistent Epithelial Defect
PL
Perception of Light
PP
Per Protocol
PT
Preferred Term
re-epi
re-epithelialization


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RTF
Rich Text Format
SaaS
Software-as-a-Service
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDC
Statistics & Data Corporation
SDTM
Study Data Tabulation Model
SOC
System Organ Class
SOP
Standard Operating Procedure
TEAE
Treatment-Emergent Adverse Event
VA
Visual Acuity
WHODrug
World Health Organization Drug Dictionary


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1.
Introduction
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol NEX-PED-005,
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for 
Industry: Structure and Content of Clinical Study Reports.
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that 
will be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol, and any changes to the protocol stated analyses 
will be detailed in Section 17. If additional analyses are required to supplement the planned analyses 
described in this SAP, they may be completed and will be identified in the clinical study report.
2.
Study Objectives
The objective of this study is to assess the efficacy and safety of two topical ocular dose concentrations 
of Nexagon® (NEXAGON) as a treatment for non-healing corneal persistent epithelial defects (PEDs)
resulting from severe chemical and/or thermal ocular injuries.
2.1
Primary Endpoint
The primary efficacy endpoint is corneal epithelial recovery, defined as a cornea that 
re-epithelializes by 
 of treatment and remains re-epithelialized for 
 after 
initial re-epithelialization was first recorded, as assessed by the Investigator.
2.2
Secondary Endpoints
2.3
Exploratory Endpoints


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x
2.4
Safety Variables
The safety variables include the incidence of treatment-emergent adverse events (TEAEs).
2.5
Statistical Hypotheses
The null and alternative hypotheses, based on the primary endpoint, are as follows:
x
 


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3. Study Design and Procedures
3.1
General Study Design
This phase 2 multi-center trial is a randomized, prospective, double-masked, vehicle-controlled 
study to assess the efficacy and safety of NEXAGON applied topically in subjects with corneal 
PED resulting from severe ocular chemical and/or thermal injuries.
A subject’s participation is to start with screening (Eligibility Assessment Visit) to determine 
eligibility for enrollment into the study prior to Day 1. If the subject is considered eligible for the 
study, the subject will be randomized to receive either NEXAGON 
 or NEXAGON 
 
or Vehicle
, respectively on Day 1.
For all subjects, the first investigational product application will occur following randomization 
   
 with investigational product (NEXAGON 
 or NEXAGON 


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or Vehicle) 
.  Following investigational product application, 
The study will comprise of 2 periods, a Treatment Period and Post-healing Follow-up Period:
Treatment Period (Masked):
During the Treatment Period, masked investigational product will be administered on 
 
-
If re-epithelialization of the defect has NOT occurred 
another single application 
of masked investigational product will be administered 
  
-
If re-epithelialization occurs at any time during the masked Treatment Period, subjects will 
enter a 
Post-healing Follow-up Period to assess durability of the corneal 
epithelium.
-
Post-healing Follow-up Period (Masked)
During the 
Post-healing Follow-up Period subjects will be assessed 
following initial re-epithelialization to confirm durability of the epithelium.  
-
If the healed epithelium is sustained within the Post-healing Follow Period (durable), the 
subject will then exit the study having completed all visits. 
-
Open-Label Section
In the open-label section of the study subjects will receive a salvage dose of NEXAGON 
.
-
If re-epithelialization has not been achieved 
 dose of 
NEXAGON 
 will be applied 
  A final assessment of healing for 
these subjects will be conducted 
  
-
 
 
 
 
 
 
 
 
 


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-
If re-epithelialization has not occurred
, the subject will exit the study.  
The maximum duration for study participation for a subject 
 
 
 
At each study visit, following randomization until the end of the study, the subject will undergo 
assessments as detailed in Table 2 (Schedule of Assessments).  Assessments will be performed 
by a designee at the study site who is masked to the allocated investigational product and include 
  The occurrence of any 
Treatment Emergent Adverse Events will also be assessed at each study visit, and up to 
following the final application of investigational product.  
3.2
Study Visit Windowing 
Study day will be referred to in all tables and listings. Table 1a shows the planned study visits and 
the acceptable visit window for each visit for subjects who are in the study for the maximum 
duration. Table 1b shows the planned study visits and acceptable visit window by study period.
Visits that are not able to be completed within the windows specified in the protocol must be 
recorded as protocol deviations.
Note: Day 1 corresponds to the day of randomization, there is no Day 0.


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Table 1a. Study Visit Windows


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Table 1b. Study Visit Windows 


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3.3
Dose Regimen, Study Flow Diagram, and Schedule of Visits and Assessments
The dosing regimen is provided in Figure 1, the study flow diagram (visit schedule and dosing 
days) is provided in Figure 2 and the schedule of visits and assessments is provided in Table 2.


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Figure 2. Study Flow Diagram –


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Table 2. Schedule of Visits and Assessments


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4. Study Treatments
4.1
Method of Assigning Subjects to Treatment Groups
A subject who meets all the inclusion criteria and none of the exclusion criteria is eligible for 
randomization 
 Subjects are to be randomized to one of three treatment group:
x
GROUP A – NEXAGON 
x
GROUP B – NEXAGON 
x
GROUP C – Vehicle (0%)
A statistician not directly involved in the analysis of the study results will prepare the randomization 
schedule using block randomization to maintain balance between treatment groups. 
Randomization is to be done 
When a subject is confirmed to be eligible for randomization 
 treatment assignment for 
that subject will be determined by
4.2
Masking and Unmasking
All subjects, investigators, and study personnel involved with the conduct of the study will be 
masked with regard to treatment assignments.
The Investigator may unmask a subject’s treatment assignment only in the case of an emergency 
when knowledge of the investigational product is essential for the clinical management or welfare 
of the subject. 
If a drug-related serious adverse event (SAE) is reported, the Medical Monitor may unmask the 
treatment assignment for the individual subject. 
5.
Sample Size and Power Considerations
Assuming the true rate of corneal epithelialization in each of the NEXAGON arms of 
Assuming a discontinuation rate 
 Enrollment will continue until 


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6.
Data Preparation
6.1
Input Data
Electronic case report forms (eCRFs) will be developed 
Data from source documents will be entered into the eCRF by site personnel.
The electronic clinical study database will be 
 
After data are entered into the clinical study database, electronic edit checks and data review will 
be performed. All data validation specifications and procedures are detailed in the 
When the database has been declared to be complete and 
accurate, the database will be locked. Any changes to the database after data have been locked 
can only be made with the approval of 
All analyses outlined in this document will be carried out after the following have occurred:
x
All data 
 requirements are met according 
 
 
 
 
 
 
 
 
 
 
 
x
Protocol deviations have been identified and status defined (major/minor deviations).
x
Analysis populations have been determined.
x
Randomized treatment codes have been unmasked.
In addition, the laboratory data,
will be included in the 
statistical analysis.
6.2
Output Data
Data from the electronic clinical study database and external data will be transferred to 
and incorporated into standard formats following the Study Data Tabulation Model 
(SDTM). Data will then be mapped to analysis datasets using the Analysis Data Model (ADaM).
Both SDTM- and ADaM-formatted data will be used to create the subject listings, while all tables 
and figures will be based on the ADaM-formatted data.
SDTM will follow the 
 and will be implemented using the SDTM 
Implementation Guide 
and the SDTM Controlled Terminology 
ADaM data will follow the ADaM 
model and will be implemented using the ADaM 
Implementation Guide
and the ADAM Controlled terminology
. Both SDTM 
and ADaM will be validated 
 Any discrepancies in the validation 
will be noted in reviewer’s guides accompanying the final data transfers.


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Define.xml will be created for SDTM and ADaM 
7. Analysis Populations


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8.
General Statistical Considerations
8.1
Unit of Analysis
The study eye will be defined as 
8.2
Missing or Inconclusive Data Handling
 
 
 
 
 
 
 
 
 
 
 


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8.3
Definition of Baseline and Final On-Treatment Visit
Baseline will be defined as the last measurement prior to the first dose of study medication. 
Change from baseline will be calculated as follow-up visit value minus baseline value.
The final on-treatment visit is defined as the day of initial corneal re-epithelialization, treatment 
or day of discontinuation during treatment.


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8.4
Data Analysis Conventions
All data analysis will be performed by 
after the study is completed and the database has 
been locked and released for unmasking. Statistical programming and analyses will be performed 
using 
Output will be provided in rich text format (RTF) for tables and 
portable document format (PDF) for tables, listings, and figures using landscape orientation. All 
study data will be listed by subject, treatment, and visit (as applicable) based on all randomized 
subjects unless otherwise specified.
Summaries for continuous and ordinal variables will include the number of observations (n), 
arithmetic mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima 
will be reported with the same precision as the raw values; means and medians will be presented 
to one additional decimal place than reported in the raw values. Standard deviations will be 
presented to two additional decimal places than reported in the raw values. Summaries for discrete 
variables will include counts and percentages. All percentages will be rounded to one decimal 
place (i.e., XX.X%). Differences between active treatment groups and placebo will be calculated 
as active minus placebo and change from baseline will be calculated as follow-up visit minus
baseline.
Unless otherwise specified, summaries will be presented by treatment group and, where 
appropriate, visit. Listings will be sorted by treatment group, subject number, visit/time point, and 
parameter as applicable.
8.5
Adjustments for Multiplicity


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9.
Disposition of Subjects
Subject enrollment, inclusion in analysis populations, and study completion/withdrawal from the study 
for the main study as well as the open-label section of the study will be summarized and listed in terms 
of the numbers and percentages of subjects who were randomized, completed the study, and 
discontinued from the study. Subjects who are not discontinued from the study will be considered study 
completers. Disposition will be summarized by treatment group and for all subjects.
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment group for all subjects who discontinued the 
study. The reasons for study discontinuation that will be summarized include AE, lost to follow-up, 
physician decision, protocol violation, screen failure, study terminated by sponsor, withdrawal by 
subject, and other. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects.
 
 


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10. Demographic and Pretreatment Variables
10.1
Demographic Variables
The demographic variables collected in this study include age, gender at birth, race, and ethnicity.
Demographic variables will be summarized for all randomized subjects 
A subject listing that includes all demographic variables will be provided.
10.2
Pretreatment Variables
Baseline disease characteristics will be summarized separately for all randomized subjects 
   
Summaries will be presented for the study eye. For subjects with a bilateral ocular injury, the 
assessments detailed above will also be listed for the fellow eye (in addition to the study eye).


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11. Medical History and Concomitant Medications
11.1
Medical History
General ocular history, and non-ocular medical history will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA)
 Medical history, including details of any ongoing 
medical conditions, will be recorded prior to Day 1 and before eligibility is confirmed.
SOCs will be listed in alphabetical order and PTs within an SOC will be listed in order of 
descending frequency across all subjects.
Listings of medical history will be generated separately for both ocular data and non-ocular data.
11.2
PED History
A detailed ocular examination and history will be conducted prior to the Day 1 visit and assessed 
against the inclusion and exclusion criteria of the protocol.
11.3
Prior and Concomitant Medications


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Prior and concomitant medications will be listed for all randomized subjects. 
 
 
 
 
 
11.4
Concomitant Procedures
Concomitant procedures will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) 
and summarized by SOC and PT. 
Concomitant procedures will be listed using all randomized 
12.
Treatment Exposure
Treatment exposure will be defined in two ways, as the extent of treatment exposure and the 
number of treatment doses. The number of treatment doses is the number of actual applications 
of NEXAGON or Vehicle.
13.
Efficacy Analyses – Masked Portion of Study
13.1
Primary Efficacy Outcome Analysis
The primary efficacy outcome will be the comparison of each dose of NEXAGON to Vehicle for 
the proportion of subjects with corneal epithelial recovery, defined as a cornea that re-epithelializes 
of treatment and remains re-epithelialized 
 after initial re-epithelialization 
was first recorded (during the masked treatment portion of the study and assessed by the 


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Investigator). Subjects who discontinue the study early, or who have missing data resulting in the 
inability to conclude corneal epithelial recovery, will be considered as not having corneal epithelial 
recovery (missing data imputed as failure).
The number and proportion of subjects with corneal epithelial recovery will be summarized by 
treatment group and tested between treatment groups 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 


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13.1.1
Sensitivity Analyses
13.2
Secondary Efficacy Outcome Analyses
The secondary efficacy outcomes will be analyzed using the 
 with reference to the masked 
treatment period. 


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The following secondary efficacy endpoints,
13.2.1
 
 


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14. Exploratory Analyses
The exploratory efficacy outcomes will be 


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x
Primary, secondary, and exploratory endpoints will also be assessed (as applicable) for 
the open-label section of the study.
x
14.1


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14.4
 


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15. Safety Analyses
All safety analyses will be conducted using the safety population. Summaries of safety measures 
during the masked treatment and follow-up periods 
 will be 
completed similarly.
15.1
Adverse Events
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and that does not necessarily have
a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporarily associated with 
the use of an investigational product whether or not related to the investigational product. AEs will 
be recorded from the time of first application of the investigational product and until the final visit.
Treatment-emergent adverse events (TEAEs), defined as AEs that occur after the first dose of 
study medication, are undesirable events not present prior to investigational product treatment, or 
an already present event that worsens either in intensity or frequency following treatment.


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Serious Adverse Events (SAE) any untoward medical occurrence that at any dose results in death,
is life-threatening and/or sight threatening, results in persistent or significant disability/incapacity, 
is a congenital anomaly/birth defect. SAEs are undesirable events (experiences) or reaction not 
present prior to investigational product treatment, or an already present event that worsens in 
magnitude to be classified as an SAE, either in intensity or frequency following treatment.
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the subject. The assessment of severity 
is made irrespective of relationship to study drug or seriousness of the event and should be 
evaluated according to the following scale:
x
Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with 
the subject’s daily activities.
x
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere 
with the subject’s daily activities.
x
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities.
The relationship of each AE or SAE to the study drug should be determined by the Investigator 
using these explanations: definitely related, probably related, possibly related, unlikely to be 
related, and unrelated. Only definitely, probably, and possibly related  TEAEs will be considered 
as treatment-related TEAEs. For TEAEs prior to rescue medication use, only those TEAEs with 
an onset date prior to the date that rescue medications were first used will be included.
Clinically significant abnormal laboratory findings or other abnormal assessments that are present 
at baseline and significantly worsen following the start of the study will be reported as AEs and 
SAEs. The Investigator will exercise his/her medical and scientific judgment in deciding whether 
an abnormal laboratory finding or other abnormal assessment is clinically significant.
Verbatim descriptions of AEs will be mapped to MedDRA
 terms and presented in a 
data listing. Adverse events recorded in the eCRF which began prior to treatment will not be 
included in the summary tables but will be included in the AE data listings. All AEs, SAEs, and 
TEAEs will be presented separately in subject data listings. The TEAEs leading to study treatment 
discontinuation will also be listed separately.
An overall summary will be presented that includes the number of events and the number and 
percentage of subjects who experienced at least one TEAE, by treatment group and over all 
subjects. This summary will also include breakdowns of TEAEs further categorized as ocular 
(study eye and, for subjects with bilateral injury, fellow eye separately) or non-ocular, treatment-
related TEAEs, TE-SAEs, TEAEs leading to treatment withdrawal, TEAEs leading to death,
TEAEs by maximal severity, and TEAEs by relationship to study drug.


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Treatment-emergent adverse events (TEAEs), those that occur after the first dose of study 
medication, will be summarized by treatment group using frequency and percentages for each 
SOC and PT within each SOC. Similar summaries will be presented for treatment related TEAEs, 
TEAEs by maximum severity, serious TEAEs, and TEAEs leading to test article discontinuation.
Separate summaries of TEAEs will be provided showing the number and percentage of subjects
who experienced at least one TEAE by treatment group and over all subjects. Non-ocular TEAEs 
will be summarized using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT. Ocular TEAEs will be similarly summarized at the subject
level for study and fellow eyes separately. If a subject reports the same PT multiple times within 
the same SOC, that PT will only be reported once within that SOC. As with the PT, if a subject
reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summary, SOCs will be listed in ascending alphabetical order; PTs will be listed in order of 
descending frequency for all subjects within each SOC.
The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC and 
PT within each SOC by treatment group. Summaries of TEAEs by maximal severity, strongest 
relationship to study drug, and strongest relationship to study drug and maximal severity will be 
presented for ocular AEs and non-ocular AEs separately. To count the number of subjects with 
any TEAEs, if a subject has multiple TEAEs coded to the same PT within the same SOC, the 
subject will be counted once under the maximum severity. TEAEs that led to test article
discontinuation, defied as drug interruption or drug withdrawal as response to the AE, treatment 
related TEAEs, and TE-SAEs will also be summarized by SOC and PT.
15.2


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15.3
Slit Lamp Examination
A slit lamp examination will be performed at each visit. 


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15.4
PED Assessment
The epithelial defect size will be assessed prior to Day 1 and randomization on Day 1 then at each 
follow-up visit.
15.5


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15.7
Clinical Laboratory Data
No specific laboratory results (other than a positive pregnancy test) will be used to exclude a 
subject from entry or continued participation in the study, unless in the Investigator’s opinion the 
results indicate the subject has a concurrent condition that may affect the safety of the subject or 
potentially the outcome of the study.


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The same blood tests will be repeated when the subject completes the Treatment Period of the 
study. Refer to Table 2 (Schedule of Assessments).
Laboratory data will be presented in data listings. Clinical laboratory results will be summarized 
using continuous summaries, including continuous change from baseline. Qualitative laboratory 
values will be summarized with discrete statistics, including frequency and percent of subjects with 
normal, abnormal, high, and low values and using shift tables from baseline. A listing of potentially 
clinically important (PCI) laboratory findings will also be presented, where PCI is defined as any 
laboratory results that are abnormal, high or low.
16.


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16.2


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18.
References
1.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics.
1982;38:29-41.
2.
Chan, I. S. F., and Zhang, Z. (1999). “Test-Based Exact Confidence Intervals for the Difference 
of Two Binomial Proportions.” Biometrics 55:1202–1209.
19.
Revision History
Documentation of revision to the SAP will commence after approval of the final version 1.0.
20.
Tables for Final Analysis
Tables that will be included in the topline delivery are shown in boldface font.


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Table Number
Title
Population
14.1.1
Subject Disposition
All Randomized Subjects
14.1.2.1.1
Demographic Characteristics
All Randomized Subjects
14.1.3.1
Ocular Medical History
Safety Population
14.2.1.1
Corneal Epithelial Recovery
Full Analysis Set


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14.2.2.1
Time to Corneal Epithelial Recovery
Full Analysis Set


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14.3.1
Overall Summary of TEAEs by Treatment 
Group
Safety Population
14.3.2.1
Ocular TEAEs by System Organ Class and 
Preferred Term (Study Eye)
Safety Population
14.3.6
TEAEs That Led to Premature Test Article 
Discontinuation
Safety Population


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14.3.7
Treatment-Related TEAEs
Safety Population
14.3.8
Treatment-Emergent Serious Adverse Events
Safety Population
14.3.9.1
Ocular Injury Questionnaire - Physician 
Assessment
Safety Population
14.3.9.3
PED Measurements 
Safety Population
14.3.9.6
Exposure to Study Drug
Safety Population
14.3.10.1.1
Clinical Laboratory Measures - Hematology
Safety Population
14.3.10.1.2
Clinical Laboratory Measures – Shift in 
Hematology
Safety Population
14.3.10.2.1
Clinical Laboratory Measures - Chemistry
Safety Population
14.3.10.2.2
Clinical Laboratory Measures – Shift in 
Chemistry
Safety Population
21. Tables for Interim Analyses
Tables that will be included in Interim Analysis Stage I are shown in boldface font. 


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Table Number
Title
Population
1


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22. Data Listings
Listing 
Number
Title
Population
16.1.7
Randomization Schedule
All Randomized Subjects
16.2.1.1
Subject Disposition
All Randomized Subjects


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16.2.2.1
Protocol Deviations
All Randomized Subjects
16.2.4.1
Demographics
All Randomized Subjects
16.2.4.2.1
Ocular Medical History
All Randomized Subjects
16.2.4.2.2
Non-Ocular Medical History
All Randomized Subjects
16.2.4.3
PED History
All Randomized Subjects
16.2.4.4
Ocular Prior and Concomitant Medications
All Randomized Subjects
16.2.4.5
Non-Ocular Prior and Concomitant 
Medications
All Randomized Subjects
16.2.4.6
Concomitant Procedures
All Randomized Subjects
16.2.5
Investigational Product Administration
All Randomized Subjects
16.2.7.1
All Adverse Events
All Screened Subjects
16.2.7.2.1
Treatment-Emergent Adverse Events
All Screened Subjects
16.2.7.2.2
Treatment-Emergent Adverse Events 
Leading to Test Article Discontinuation
All Screened Subjects
16.2.7.2.3
Treatment-Related Treatment-Emergent 
Adverse Events 
All Screened Subjects
16.2.7.3
Serious Adverse Events
All Screened Subjects
16.2.8.1.1
Clinical Laboratory Measurements –
Hematology
All Randomized Subjects


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16.2.8.2.1
Clinical Laboratory Measurements –
Chemistry
All Randomized Subjects
23.
Figures
Figure 
Number
Title
Population