Clinical trial NCT04485546
Conditions: Neurotrophic Keratitis
Keywords: Stage 1 Neurotrophic Keratitis Corneal Disease Ocular Disease
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2020-09-09; Completion date: 2022-03-30
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is to evaluate the safety and efficacy of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution in patients with Stage 1 neurotrophic keratitis (NK).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: cenegermin-bkbj
Intervention descriptions: intervention 1: Cenegermin-bkbj ophthalmic solution administered as one drop in affected eye(s) every 2 hours 6 times daily for 8 weeks

Protocol documents:
Prot_002.pdf: 
 
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CLINICAL STUDY PROTOCOL 
 
Title: 
An 8-week, multicenter, open label, prospective study with 
24 weeks of follow-up to evaluate safety and efficacy of 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution in patients with Stage 1 Neurotrophic 
Keratitis (NK) 
 
Short Title:  
DEFENDO 
 
Study Number: 
NGF0120  
 
 
EudraCT Number/IND: 
115892 
 
Study Product: 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution 
 
Phase of the study: 
IV 
 
 
Protocol Version - Date: 
Version No.0.4–FINAL 04May 2021 
 
Amendment 2 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé US. It is understood that the information will not be used, 
divulged, or published without prior written consent of Dompé US., except to the extent such 
disclosure is required by applicable laws and regulations. 
 
 
 
 
 
 
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Dompé Drug Safety 
 
  
 
 
 
  
 
 
 
  
 
 
Dompé Quality  
 
 
 
  
 
 
 
 
Clinical Research Organization 
 
 
 
 
 
 
 
 
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Table of Contents 
1. 
STUDY SYNOPSIS .............................................................................................. 10 
2. 
SCHEDULE OF EVALUATIONS ...................................................................... 21 
2.1. 
BACKGROUND INFORMATION ....................................................................... 21 
2.2. 
RELEVANT NON-CLINICAL PHARMACOLOGY ........................................... 22 
2.3. 
A SUMMARY OF CLINICAL DATA .................................................................. 23 
2.4. 
STUDY RATIONALE ........................................................................................... 24 
2.4.1. 
Alternative treatments ............................................................................................. 24 
2.4.2. 
Description of the Study product ............................................................................ 24 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ................. 25 
3.1. 
STUDY OBJECTIVES ........................................................................................... 25 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE ........................................................ 25 
3.3. 
OVERALL STUDY DESIGN ................................................................................ 26 
3.3.1. 
Rationale for Selection of dose, and treatment schedule in the study ..................... 29 
4. 
SELECTION OF STUDY POPULATION ........................................................ 31 
ADULT MALES AND FEMALES WITH STAGE 1 NK (AS DEFINED IN THE INCLUSION 
CRITERIA) WILL BE INCLUDED. A TOTAL OF 35 PATIENTS WILL BE 
ENROLLED. .......................................................................................................... 31 
4.1. 
INCLUSION CRITERIA ....................................................................................... 31 
4.2. 
EXCLUSION CRITERIA ...................................................................................... 32 
4.3. 
SELECTION OF STUDY EYE ............................................................................. 33 
4.4. 
ASSIGNMENT OF SUBJECT NUMBER ............................................................. 33 
5. 
STUDY PRODUCT .............................................................................................. 34 
5.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE 
STUDY PRODUCT ............................................................................................... 34 
5.1.1. 
Presentation of Study Product ................................................................................. 34 
 
 
 
 
5.1.4. 
Description of Study Product .................................................................................. 35 
5.2. 
DOSE, ROUTE AND SCHEDULE OF PRODUCT ADMINISTRATION .......... 36 
5.3. 
ACCOUNTABILITY OF THE STUDY PRODUCT ............................................ 37 
5.3.1. 
Prior and concomitant medications ......................................................................... 37 
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6. 
STUDY PROCEDURE AND ASSESSMENTS ................................................. 39 
6.1. 
STUDY VISITS AND EXAMINATIONS AND TREATMENT VISITS ............ 39 
6.1.1. 
Visit 1 (Day -14):  SCREENING............................................................................ 39 
6.1.2. 
Visit 2 (Day 0 ± 2 days):  BASELINE ................................................................... 40 
6.1.3. 
Visit 3 (Day 14/Week 2 - 2 days) STUDY PRODUCT PICK-UP VISIT .............. 42 
6.1.4. 
Visit 4 (Day 28/Week 4 -2 days):  TREATMENT VISIT ...................................... 42 
6.1.5. 
Visit 5 (Day 42/Week 6 - 2 days):  STUDY PRODUCT PICK-UP VISIT ............ 43 
6.1.6. 
Visit 6 (Day 56/Week 8 - 4 days):  END OF TREATMENT OR PREMATURE 
DISCONTINUATION VISIT ................................................................................ 44 
6.1.7. 
Visit 7 (Day 224/Week 32 ±7 days):  FOLLOW-UP/FINAL STUDY VISIT ....... 45 
6.2. 
EARLY WITHDRAWAL FROM STUDY ............................................................ 46 
6.3. 
END OF STUDY .................................................................................................... 47 
7. 
ENDPOINTS ......................................................................................................... 48 
7.1. 
STUDY ENDPOINTS ............................................................................................ 48 
7.1.1. 
Efficacy endpoints .................................................................................................. 48 
7.1.2. 
Exploratory Efficacy Endpoints .............................................................................. 48 
7.1.3. 
Safety endpoints ...................................................................................................... 48 
8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION . 49 
8.1. 
DEFINITIONS........................................................................................................ 49 
8.2. 
MONITORING FOR ADVERSE EVENTS .......................................................... 52 
8.3. 
RECORDING ......................................................................................................... 53 
8.3.1. 
Follow-Up of patients with Adverse Events ........................................................... 53 
8.3.2. 
Relationship of AEs to the Study Product .............................................................. 54 
8.3.3. 
Severity of AEs ....................................................................................................... 54 
8.4. 
SERIOUS ADVERSE EVENT REPORTING ....................................................... 55 
8.4.1. 
Reporting Procedure for Investigators to Lexitas Pharma Services, Inc. And Dompé 
Drug Safety ............................................................................................................. 55 
8.4.2. 
Conditions that should not be reported as serious adverse events .......................... 56 
8.4.3. 
Reporting Procedure to IRB/IEC and to Regulatory Authorities ........................... 56 
8.4.4. 
Periodical Reporting to Regulatory Authorities ..................................................... 57 
8.5. 
EXPOSURE TO STUDY PRODUCT DURING PREGNANCY .......................... 58 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ............ 58 
8.7. 
OVERDOSE ........................................................................................................... 58 
8.8. 
UNMASKING ........................................................................................................ 59 
9. 
STATISTICS ......................................................................................................... 60 
9.1. 
SAMPLE SIZE ....................................................................................................... 60 
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9.2. 
PATIENT POPULATION ...................................................................................... 60 
9.3. 
STATISTICAL METHODOLOGY ....................................................................... 60 
9.3.1. 
Demographic and baseline characteristics .............................................................. 60 
9.3.2. 
Analysis of efficacy variables ................................................................................. 60 
9.3.3. 
Analysis of safety variables .................................................................................... 61 
9.3.4. 
Missing data (mandatory) ....................................................................................... 61 
9.3.5. 
Changes to the statistical plan ................................................................................. 61 
10. 
ETHICAL CONSIDERATIONS ......................................................................... 62 
10.1 REGULATORY BODY APPROVAL................................................................................ 62 
10.2 INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE . 62 
10.3 ETHICAL CONDUCT OF THE STUDY .......................................................................... 62 
10.4 PATIENT INFORMATION AND CONSENT .................................................................. 62 
10.5 CONFIDENTIALITY ......................................................................................................... 62 
10.6 COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 63 
11 
DATA HANDLING AND RECORD KEEPING ............................................... 64 
11.1 CASE REPORT FORMS .................................................................................................... 64 
11.2 DATA MANAGEMENT .................................................................................................... 64 
12 
STUDY MANAGEMENT .................................................................................... 65 
12.1 MONITORING AND QUALITY ASSURANCE .............................................................. 65 
12.2 ACCESS TO RECORDS .................................................................................................... 65 
12.3 AUDIT AND INSPECTION ............................................................................................... 65 
12.4 PROTOCOL AMENDMENTS ........................................................................................... 65 
12.5 DISCONTINUATION OF THE STUDY ........................................................................... 65 
12.6 PUBLICATIONS ................................................................................................................ 66 
13 
REFERENCES...................................................................................................... 67 
14 
APPENDICES ....................................................................................................... 68 
14.1 APPENDIX 1-SPONSOR APPROVAL PAGE ................................................................. 69 
14.2 APPENDIX 2 -INVESTIGATOR’S SIGNATURE PAGE ................................................ 70 
14.3 APPENDIX 3-OXERVATE™ PACKAGE INSERT ......................................................... 71 
14.4 APPENDIX 4-FLUORESCEIN STAINING NEI / INDUSTRY WORKSHOP SCALE 
AND MACKIE CLASSIFICATION ...................................................................... 74 
 
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TABLE OF TABLES 
Table 1 Dosing Schedule ............................................................................................................. 27 
 
Table 3 Medications and Procedures ........................................................................................... 38 
 
TABLE OF FIGURES 
Figure 1 Study Schematic............................................................................................................ 29 
 
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List of Abbreviations and Definitions of Terms 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AMT 
Amniotic Membrane Transfer 
AT 
Artificial Tears 
BCDVA 
Best Corrected Distance Visual Acuity 
BLA 
Biologics License Agreement 
°C 
Degrees Celsius 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DHHS 
Department of Health and Human Services 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
e-CRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
°F 
Degrees Fahrenheit 
FCS 
Fluorescein Corneal Staining 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GVHD 
Graft Versus Host Disease 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDEEL 
Impact of Dry Eye on Everyday Life 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LNGFR 
Low-Affinity Nerve Growth Factor Receptor 
Log MAR 
Logarithm of the Minimum Angle of Resolution 
mg/ml 
Milligrams per millilitre 
MGD 
Meibomian Gland Disease 
ml 
millilitre 
mNGF 
Murine Nerve Growth Factor 
MOP 
Manual of Procedures 
NEI 
National Eye Institute 
NGF 
Nerve Growth Factor 
NGF0212 
(REPARO) 
Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of 
Recombinant Human Nerve Growth Factor for 
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Neurotrophic Keratitis (REPARO) 
NGF0214 
(US Trial) 
Topical Recombinant Human Nerve Growth Factor (Cenegermin) for 
Neurotrophic Keratopathy Multicenter Randomized Vehicle-Controlled 
Pivotal Trial 
NK 
Neurotrophic Keratitis/Keratopathy 
OCP 
Ocular Cicatricial Pemphigoid 
OCT 
Optical Coherence Tomography 
PED 
Persistent Epithelial Defect 
PID 
Patient Identification`` 
PI 
Principal Investigator 
PK 
Punctate keratitis 
rhNGF 
Recombinant Human Nerve Growth Factor 
SAE 
Serious Adverse Event 
SLE 
Slit Lamp Examination 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SPK 
Superficial punctate keratitis/keratopathy  
TEAE 
Treat-Emergent Adverse Events 
TFBUT 
Tear Film Break Up Time 
μl 
Microliter 
μg/ml 
Microgram per millilitre 
 
 
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1. 
STUDY SYNOPSIS  
 
CLINICAL STUDY SYNOPSIS:  
Study Number  
NGF0120 
Title of Study  
An 8-week, multicenter, open label, prospective study with 
24 weeks of follow-up to evaluate safety and efficacy of 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution in patients with Stage 1 Neurotrophic 
Keratitis (NK) 
 
Short Title 
DEFENDO 
EudraCT N°/IND  
115892 
 
Study Centers (Country)  
Approximately 5 US study centers 
Development Phase  
IV 
Objectives  
Primary Objective 
The primary objective of this study is to evaluate the safety 
and efficacy of OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution administered 6 
times daily for 8 weeks on the ocular surface, visual function 
and quality of life in patients with Stage 1 NK.   
 
Secondary Objective 
The secondary objective is to evaluate patients who heal at 
week eight and remain healed (as defined in section 3.3) 
throughout the follow-up period. In addition, the study aims 
to evaluate the percentage of subjects that achieve an 
improvement in corneal sensitivity as measured by the 
Cochet-Bonnet aesthesiometer at 4 and 8 weeks, and by the 
last visit week 32. 
 
Exploratory Objectives 
The exploratory objectives are to evaluate the change from 
baseline to weeks 4 & 8 in Schirmer I and the Tear Film 
Break-Up Time (TFBUT).  
 
Additional Objectives (site specific) 
The additional objectives are to evaluate the change from 
baseline at week 8 and week 24 in confocal microscopy and 
anterior segment Optical Coherence Tomography (OCT). 
 
 
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Study Design and 
Methodology  
This clinical study will be a multi-center, open label, 
prospective study of 8 weeks of treatment with 24 weeks of 
follow-up to evaluate the safety and efficacy of 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution administered as one drop in the 
affected eye(s), 6 times per day at 2-hour intervals, for eight 
weeks in patients with Stage 1 Neurotrophic Keratitis (NK).  
The study is divided into four phases as follows: 
1. Screening Visit (Day -14):  Procedures for inclusion 
will be performed at both Visit 1 (Screening) and 
Visit 2 (Baseline).  Commercially available artificial 
tears (AT) provided by the sponsor will be permitted 
during the Screening period as needed up to four 
times a day. 
2. Washout period (from day minus 14 to day 0):   14 
days with no further treatment except commercially 
available preservative-free artificial tears provided by 
the sponsor (Note:  Xiidra™ and Restasis™ use is 
disallowed for 14 days prior to Visit 2.)  Artificial 
tears (AT) provided by the sponsor will be permitted 
up to four times a day and will be tracked via daily 
diary during washout period. 
3. Treatment: 
a. Treatment (weeks 1-8): eligible patients 
will start OXERVATE™ 0.002% (20 
mcg/mL) cenegermin-bkbj ophthalmic 
solution administered as one drop in the 
affected eye(s), 6 times per day at 2-hour 
intervals, for eight weeks. During the 
treatment period, only study product will be 
permitted for topical ocular treatment. 
Commercially available preservative free 
artificial tears (AT) provided by Sponsor are 
not allowed during the treatment period 
except as rescue therapy.   
4. Follow up (weeks 9-32):   For the 24 weeks post 
treatment: 
a. For patients completely healed, no treatment 
is allowed except for commercially available 
AT provided by the Sponsor, administration 
frequency is at the physician’s discretion 
during follow-up based on patients need for 
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lubrication. The use of artificial tears will be 
tracked via a daily dosing diary. 
b. For patients not completely healed and who 
don’t meet criteria for premature 
discontinuation, will also be followed up but 
any topical treatment is allowed at the 
discretion of the physician. All treatments 
will be tracked as concomitant medications. 
No surgical procedures are permitted during 
the follow-up (i.e. sutured Amniotic 
Membrane Transfer (AMT), sutured 
tarsorrhaphy). Permitted items include 
topical medications and suture less AMT. 
 
The study will be a total of 34 weeks in duration: a screening 
period of 2 weeks, followed by 8 weeks of treatment and a 
24-week follow-up period. At the end of the screening period 
(at Visit 2), patients meeting the entry criteria for this study 
will be assigned to treatment with OXERVATE™ 0.002% 
(20 mcg/mL) cenegermin-bkbj ophthalmic solution 
which will be known as Study Product beginning the morning 
following Visit 2.  
Following the completion of the treatment period, patients 
will be followed up for an additional 24 weeks (for patients 
healed and non-healed [and not meeting discontinuation 
criteria] at Week 8) and will be evaluated at the end of the 
follow-up period. At the investigator’s discretion, the subject 
may be seen for an Unscheduled Visit to evaluate for safety. 
Patients who prematurely discontinue for whatever reason 
will not be followed post discontinuation and should have 
Visit 6 assessments completed. 
 
At Visit 1, eligible patients will be instructed to discontinue 
all topical ophthalmic medications and will only be allowed 
to use commercially available preservative-free artificial tears 
provided by the sponsor to be used up to four times per day 
during the screening period. At the conclusion of the Baseline 
Visit (Visit 2) eligible patients will be dispensed a 2-week 
supply of Study Product from the onsite freezer in a sealed 
bag and will be instructed to self-administer the Study 
Product one drop six times a day starting on the day after 
Day 0/ Visit 2 through Week 8 of the controlled treatment 
period.   
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A two week supply of study product will additionally be 
dispensed to the patients during the treatment period at Visits 
3, 4 and 5/Weeks 2, 4 and 6.  
Starting from Visit 2, only the study product will be allowed.  
Preservative free AT provided by the sponsor will not be used 
during the study product treatment period. After the 8 weeks 
of study product treatment, and during the follow up period, 
AT should be used only if strictly needed. The use of AT will 
be tracked in the daily dosing diary. 
At Visit 6 (End of Treatment), patients will be assessed for 
corneal healing. 
 
Rescue Therapy: Commercially available preservative free 
artificial tears (AT) provided by Sponsor are not allowed 
during the treatment period. Per the investigators discretion 
if the patient requires rescue therapy during the 8-week 
treatment period then they can receive artificial tears 
provided by the sponsor up to four times per day. The 
frequency of rescue therapy must be documented in the 
patient's diary. 
 
Completely healed patients at week 8 are defined by SPK 
as Grade ≤1 in the central qualifying zone via FCS (per NEI 
scale) and no persistent staining in the non-qualifying zones 
(excluding the superior zone) defined as the absence of 
pathological staining via corneal photography .  Patients who 
are completely healed at Week 8 will be followed for an 
additional 24 weeks during the follow-up period.  During the 
24-week follow-up period (Weeks 9-32) the patients will be 
followed without any Study Product, however, preservative-
free AT (provided by the study sponsor) may be used and 
documented on the daily diary.   If warranted for patient 
safety, the Investigator may elect to see the subject at an 
Unscheduled Visit(s) to evaluate the patient.  
 
Patients who are not completely healed at week 8 defined 
by SPK as Grade 2 via FCS in the central qualifying zone 
AND who do not meet the criteria for premature 
discontinuation, will also be followed for an additional 24 
weeks during the follow-up period.  During the 24-week 
follow-up period (Weeks 9-32) the patients will be followed 
and may be treated at the physician’s discretion (retreatment 
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with OXERVATE™ 0.002% (20 mcg/mL) cenegermin-
bkbj ophthalmic solution is not permitted). Any 
concomitant treatment must be documented on concomitant 
medication log.   If warranted for patient safety, the 
Investigator may elect to see the subject at an Unscheduled 
Visit(s) to evaluate the patient. 
 
Patients who meet the definition of Deterioration or No 
Improvement in the study eye at week 8 and during the 
follow up period, will be discontinued from the study and 
treated as appropriate at the discretion of the investigator.   
Deterioration or No Improvement is defined by any of the 
following:   
 
In the Study Eye, the FCS is unchanged 
(Grade=3) from baseline in the qualifying NEI 
zone. 
 
At the PIs discretion in the study eye if any of the 
non-qualifying zones progress from baseline. 
 
decrease in BCDVA by >10 ETDRS letters from 
baseline. 
 
progression in staining to a lesion/PED or corneal 
melting or perforation. 
 
onset of infection (viral, fungal, bacterial) 
 
Require an ocular surgical procedure, including 
the need for a corneal transplant.  
Note: If there is a deterioration in the non-study eye, the 
Investigator may discontinue treatment in that eye and 
initiate alternative treatment at their discretion in the non-
study eye but continue following the study eye per protocol. 
 
All patients will attend the following clinic visits in the 
following sequence:   
 
Screening (Visit 1/Day -14) 
 
Baseline and First Study Product Pick-Up (Visit 
2/Day 0) 
 
Product Pick-Up (Visit 3/Week 2) 
 
Treatment Assessment and Study Product Pick-Up 
(Visit 4/Week 4) 
 
Product Pick-Up (Visit 5/Week 6)  
 
End of 8-week Treatment (Visit 6/Week 8) 
 
Follow-Up and Final Study Visit (Visit 7/Week 32)   
 
 
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Study Visits 
Number of Patients  
35 evaluable patients (those patients completing 8 weeks of 
Oxervate™) 
Diagnosis and Main Criteria 
for Inclusion/Exclusion  
Inclusion Criteria: 
To be eligible for inclusion into this study, each patient must 
fulfil the following inclusion criteria:  
1. Male or female aged ≥ 18 years.   
2. Patients with Stage 1 NK defined by the Mackie 
criteria (Appendix 4)  
3. Patients with Stage 1 NK characterized by all the 
following:  
a. superficial punctate keratopathy (SPK) as 
shown by fluorescein corneal staining (FCS) 
equal to a grade 3 within the central zone 
using the National Eye Institute (NEI) scale 
(Appendix 4).  
AND 
b. evidence of decreased corneal sensitivity (≤ 4 
cm using the Cochet-Bonnet aesthesiometer) 
in the central qualifying zone. 
4. No improvement in NEI zone score between the 
Screening Visit (Visit 1) and Treatment Visit (Visit 
2) for the qualifying zone determined at Visit 2. 
5. Have a best corrected distance visual acuity 
(BCDVA), using corrective lenses if necessary, in the 
study eye of at least +1.0 Log MAR (Snellen 
<20/200) if the clinician attributes the vision loss to 
the epithelium and the loss is not related to the 
macula in the affected eye(s).  
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6. The same eye (eligible eye/study eye) fulfills all the 
above criteria on the day of Screening (Visit 1) and 
again on Visit 2. 
7. Patients with punctal occlusion or punctal plugs 
inserted prior to the study are eligible for enrollment 
provided that the punctal occlusion is maintained 
during the study period. If a punctal plug falls out 
during the study, it must be reinserted within 7 days.   
8. Patients who are at high risk of progression or have a 
history of Stage 2 or Stage 3 NK per the Mackie 
classification. 
9. Patients who have only one functional eye can be 
included if they meet all the criteria above and per 
the investigator’s discretion are proper candidates to 
designate the one functional eye as the study eye.  
10. Only patients who satisfy all Informed Consent 
requirements may be included in the study. The 
subject and/or his/her legal representative has read, 
signed, and dated the IRB approved Informed 
Consent document before any study-related 
procedures are performed. 
11. Patients must have the ability and willingness to 
comply with study procedures. 
 
 
Exclusion Criteria: 
1. In the opinion of the Investigator, there is evidence of 
an active ocular infection (bacterial, viral, protozoal) 
in either eye. 
2. Use of non-diagnostic (e.g., topical drops used for 
clinical testing/evaluations) medications that can 
induce corneal toxicity between Visit 1 and Visit 2. 
3. In the opinion of the investigator, have current or 
history of conditions that may confound the study 
data including but not limited to Ocular Cicatricial 
Pemphigoid (OCP), Graft Versus Host Disease 
(GVHD), neuromyelitis optica, uncontrolled dry eye, 
and Steven Johnson’s syndrome.  
4. History of severe systemic allergy or severe ocular 
allergy (including seasonal conjunctivitis expected 
during the subject’s participation in the trial) or 
chronic conjunctivitis and/or keratitis other than dry 
eye disease. 
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5. Intraocular inflammation defined as Tyndall score 
>0. 
6. Patients with severe vision loss with no potential for 
visual improvement in the study eye, in the opinion 
of the investigator, or if the subject is deemed legally 
blind.  
7. Patients with active severe blepharitis and/or severe 
meibomian gland disease who in the opinion of the 
investigator will require routine treatment during the 
study or have required routine treatment within 2 
weeks of the study treatment visit (Visit 2).  (This 
includes the use of doxycycline within 2 weeks prior 
to the treatment visit (Visit 2) for active MGD.) 
8. History of any ocular surgery (including eyelid 
surgery and cataract surgery) within the three months 
before study treatment (Visit 2) and for Lasik or 
refractive surgical procedures within 3 months before 
study treatment (Visit 2). (An exception to the 
preceding statement is allowed if, in the opinion of 
the investigator, the ocular surgery is deemed the 
cause of the NK.)  
9. Ocular surgery or elective ocular surgery expected 
during participation in the trial. 
10. Prior surgical procedure(s) for the treatment of NK 
including but not limited to tarsorrhaphy, 
conjunctival flap, the exception is for amniotic 
membrane transplantation. Enrollment of patients 
previously treated with amniotic membrane 
transplantation is allowed two weeks after the 
membrane has fully disappeared within the area with 
removal of any sutures or two weeks from removal of 
the Prokera ring before study treatment visit (Visit 2). 
11. Treatment with Botox (botulinum toxin) injections in 
the study eye, used to induce pharmacologic 
blepharoptosis within 60 days prior study treatment 
visit (Visit 2).  
12. Anticipated need to use therapeutic contact lenses or 
contact lens wear for refractive correction during the 
study treatment period in the Study Eye. 
13. Patients with unstable medical condition that may 
confound the study data in the opinion of the 
investigator including but not limited to diabetes, 
thyroid disease, autoimmune disease, Parkinson’s 
disease, and Multiple Sclerosis. Stable conditions 
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managed with oral or injectable medications can be 
included, if per the investigator’s discretion the 
patient is not anticipated to have flare ups that could 
affect the ocular surface.   
14. Patients with eyelid abnormality that may alter eyelid 
function including but not limited to Blepharospasm, 
Cerebrovascular accident, entropion, ectropion, 
floppy lid syndrome. 
15. Use of glaucoma drops within 14 days prior to study 
treatment visit (Visit 2) and for the duration of the 
study. Patients can use oral Diamox during the study 
to control IOP.    
16. Pregnant or lactating at study entry or who are 
planning a pregnancy. 
17. Premenopausal female not using a medically 
acceptable form of birth control (abstinence, oral 
contraception, intrauterine device, surgically 
sterilized). 
18. History of drug addiction or alcohol abuse 
documented within the past 5 years. 
19. Participation in a clinical trial with a new active 
substance 14 days prior to study treatment visit (Visit 
2). Per the investigator’s evaluation that the 
participation in another clinical trial for an ocular 
surface product does not have residual effects on the 
ocular surface beyond 14 days prior to treatment that 
could confound the data by having an effect on 
staining. 
20. Participation in another clinical trial study at the 
same time as the present study. 
21. Participation in a Neurotrophic Keratitis study during 
the past 60 days prior to study treatment visit (Visit 
2). 
22. Are an employee of the site that is directly involved 
in the management, administration, or support of this 
study or be an immediate family member of the 
same. 
23. Prior failure with treatment for Stage 1, 2 or 3 NK 
with OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution. Failure 
defined as non-responder or lack of efficacy. 
 
 
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Study Product, Dosage and 
Mode of Administration  
 
OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution: in a 
multiple-dose vial 
 
6 times/day 
 
Topical Drop 
 
 
 
Duration of Treatment  
8 weeks 
Reference product, Dosage 
and Mode of Administration  
NA 
Efficacy Endpoints 
1. Percentage of patients who experience epithelial 
healing at 4 and 8 weeks. (Epithelial healing is 
defined as Grade 1 or absence of staining (Grade 0) 
in a previously qualifying zone.) 
2. Percentage of patients who remain healed (as defined 
in #1 above) throughout the follow-up period. 
3. Schirmer I change from baseline to weeks 4 & 8 
4. TFBUT change from baseline to weeks 4 & 8 
5. Percentage of patients that achieve an improvement 
in corneal sensitivity in the NEI zone used to qualify 
in the study eye as measured by the Cochet-Bonnet 
aesthesiometer at 4 and 8 weeks, and at the last visit 
(week 32). 
6. Mean change in BCDVA from baseline to Week 8. 
7. Percentage of patients that achieve a 15- letter gain in 
BCDVA at 4 and 8 weeks. 
8. Quality of life questionnaires change from baseline at 
week 8 and week 32 
a. 
IDEEL 
b. 
EQ-5D-5L. 
 
Exploratory Efficacy 
Endpoints  
1. Frequency of preservative free artificial tears use (n° 
drops/day) during the follow up period.  
At selected sites:   
The following may be evaluated as part of a post-hoc 
analysis: 
2. Change from baseline structural nerve regeneration 
(density, length, nerve density, tortuosity) per 
confocal microscopy.   
3. Change from baseline in epithelial thickness per 
anterior segment OCT. 
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Safety Measures  
Adverse Event Monitoring 
Statistical Methods 
Subject Characteristics and Disposition: For categorical 
variables, frequencies and percentages will be presented. 
Continuous variables will be summarized using descriptive 
statistics (n, mean, median, standard deviation, minimum, and 
maximum). 
Baseline demographic and background variables will be 
summarized. The number of patients who enroll in the study 
and the number and percentage of patients who complete the 
study will be presented. The frequency and percentage of 
patients who withdraw or discontinue from the study, along 
with the reason for withdrawal or discontinuation, will also be 
summarized. 
Analysis of efficacy variables:  Analyses for responder 
outcomes will include percentage of response and exact 95% 
confidence intervals. Analyses of change from baseline and 
continuous outcomes will include mean and associated 
asymptotic 95% confidence intervals.  No formal hypothesis 
test will be conducted. 
Analysis of safety variables: Adverse events (AEs) will be 
coded by preferred term and system organ class using the latest 
version of the Medical Dictionary for Regulatory Activities 
and will be summarized overall. AEs will also be summarized 
by severity and relationship to study drug. Serious AEs and 
AEs leading to discontinuation of study drug will also be 
summarized. 
 
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2. 
SCHEDULE OF EVALUATIONS 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
Day 
(-14) 
Day 0 
(±2) 
Day 14 
(-2) 
Day 28 
(-2) 
Day 42 
(-2) 
Day 56 
(-4) 
Day 224 
(±7) 
 
Week -2 
 
Week 2 
Week 4 
Week 6 
Week 8 
Week 32 
Procedures 
Screening 
Baseline 
Product 
Pick-Up 
Treatment 
Follow-Up 
Product 
Pick-Up 
End of 
Treatme
nt  
Follow-up/ 
End of 
Study 
ICF/HIPAA 
X 
 
 
 
 
 
 
Demographics, Systemic 
and Ocular Medical 
History 
X 
 
 
 
 
 
 
Collect date of Stage 1 
NK initial diagnosis 
X 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
X 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
IDEEL 
 
X 
 
X 
 
X 
X 
EQ-5D-5L 
 
X 
 
X 
 
X 
X 
BCDVA 
X 
X 
 
X 
 
X 
X 
External Ocular 
Examination 
X 
X 
 
X 
 
X 
X 
Slit Lamp Examination 
X 
X 
 
X 
 
X 
X 
Corneal Photography 
Without Fluorescein 
X 
X 
 
X 
 
X 
X 
TFBUT 
 
X 
 
X 
 
X 
X 
FCS (NEI Scale) 
X 
X 
 
X 
 
X 
X 
Corneal Photography 
with  Fluorescein  
X 
X 
 
X 
 
X 
X 
Corneal Sensitivity 
Testing 
X 
X 
 
X 
 
X 
X 
Schirmer Test (w/o 
Anesthesia) 
 
X 
 
X 
 
X 
X 
IOP 
X 
X 
 
 
 
X 
X 
Anterior Segment OCT 
(selected sites) 
 
X 
 
 
 
X 
X 
Confocal microscopy 
(selected sites) 
 
X 
 
 
 
 
X 
X 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Assigned to Treatment 
 
X 
 
 
 
 
 
Product Dispensation 
 
X 
X 
X 
X 
 
 
Collect Used/Unused 
Study Product 
 
 
X 
X 
X 
X 
 
AT Dispensation 
X 
- 
 
 
 
X 
 
Dispense Daily Dosing 
Diary 
X 
X 
X 
X 
X 
X 
 
Evaluate Daily Dosing 
Diary 
 
  
X 
X 
X 
X 
 
Evaluate AT Use- in 
patient daily diary 
 
X 
 
 
 
 
X 
2.1. 
BACKGROUND INFORMATION 
Neurotrophic keratitis (NK), also known as neurotrophic keratopathy, is a rare degenerative corneal 
disease caused by an impairment of corneal nerve innervation leading to a decrease or absence in 
corneal sensation. The cornea is an avascular tissue that is provided with the richest innervation of all 
body tissues via the trigeminal nerve. Corneal hypoesthesia or anesthesia and decreased reflex tearing 


 
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resulting from impaired corneal innervation can lead to a corneal epitheliopathy with a subsequent 
breakdown of the corneal epithelium, leading to potential visual impairment. Abnormal corneal 
sensation and epithelial defects with a poor tendency for spontaneous healing are the primary clinical 
manifestations of NK, which increase the risk for corneal complications associated with vision loss such 
as a persistent epithelial defect (PED), ulceration, melting, perforation and infectious keratitis.  
Neurotrophic keratitis has been divided into three stages according to the Mackie classification scheme 
and treatment recommendations are based on the severity of the corneal involvement.[1]  
 
Based on the Mackie scale, Stage 1 NK is defined by the presence of an epithelial dystrophy or punctate 
keratopathy accompanied by corneal hypoesthesia. Stage 1 NK requires discontinuation of all topical 
medications and the administration of preservative-free artificial tears. While some Stage 1 NK patients 
may heal many do progress to Stage 2 NK. Based on the Mackie scale, Stage 2 NK is defined by the 
presence of a persistent epithelial defect (PED). The goal of treatment in Stage 2 is to avoid progression 
of the disease to a corneal ulcer. The same therapeutic approaches as in Stage 1 are used in patients with 
stage 2 often accompanied by the addition of patching or therapeutic contact lenses and the use of 
prophylactic antibiotics to prevent the risk of corneal infection. Based on the Mackie scale, Stage 3 NK 
is defined by the presence of a corneal ulcer, which may progress to corneal melting and perforation. 
When a corneal ulcer develops, therapy is aimed at promoting corneal healing and preventing corneal 
melting or perforation. Surgical procedures at this stage (tarsorrhaphy, flap procedures and amniotic 
membrane transplantation) can preserve or restore ocular integrity but at the expense of cosmetic 
appearance and visual function.[2, 3] As of today, the only FDA approved pharmacologic therapy for the 
treatment of NK is OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution, a 
recombinant human nerve growth factor (rhNGF).[4, 5]   
 
Nerve growth factor (NGF) is a polypeptide essential for the survival and growth of sympathetic and 
sensory neurons, and for differentiation of neurons in the central nervous system. It binds with at least 
two classes of receptors: high-affinity tropomyosin receptor kinase A (TrkA), a transmembrane tyrosine 
kinase, and low-affinity NGF receptor (LNGFR), also known as p75 neurotrophin receptor (p75NTR).[6, 
7]  
 
NGF and its receptors TrkA and p75 are expressed in the anterior segment of the eye (iris, ciliary body, 
lens, cornea, and conjunctiva), and NGF is released in the aqueous humor. Several pieces of 
experimental evidence suggest that NGF affects all tissues of the anterior ocular segments, playing a 
crucial role in the physiopathology of several anterior ocular segment diseases.[8, 9] 
 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution is a recombinant human 
nerve growth factor approved by the FDA in August 2018 and it is indicated for the treatment of 
neurotrophic keratitis.  Relevant pre-clinical, toxicological and clinical data are summarized below and 
can be found in the Package Insert (Appendix 3).[4] 
2.2. 
RELEVANT NON-CLINICAL PHARMACOLOGY 
Both in vitro and in vivo data illustrate the biological activity of NGF in terms of neuronal growth and 
differentiation, as well as in prevention of apoptosis of retinal ganglion cells. Cultured corneal/limbal 


 
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cells of rabbit respond well to the proliferation stimulus induced by adding rhNGF or mNGF to the 
culture media.[10-12] 
 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution, a recombinant human nerve 
growth factor, is the first FDA-approved pharmacologic treatment that targets the root pathogenesis of 
neurotrophic keratitis.[4] 
 
Cenegermin-bkbj, the active ingredient of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution, is structurally identical to the human nerve growth factor (NGF) protein made in 
ocular tissues. 
 
NGF is an endogenous protein involved in the differentiation and maintenance of neurons, which acts 
through specific high-affinity (i.e., TrkA) and low-affinity (i.e., p75NTR) nerve growth factor receptors 
in the anterior segment of the eye to support corneal innervation and integrity. Endogenous NGF is 
believed to support corneal integrity through 3 mechanisms; corneal innervation, cell proliferation and 
tear secretion (shown in preclinical models).[1, 2, 8, 13] 
 
2.3. 
A SUMMARY OF CLINICAL DATA  
The safety and efficacy of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution, 
was studied in a total of 151 patients with neurotrophic keratitis in two, eight-week, randomized 
controlled multi-center, double-masked studies. In the first study conducted in Europe NGF0212 
(REPARO), patients were randomized into three different groups. One group received OXERVATE™ 
0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution, a second group received 10µg/mL 
cenegermin, and the third group received vehicle.[14] In the second study conducted in the US NGF0214, 
patients were randomized into two groups. One group was treated with OXERVATE™ 0.002% (20 
mcg/mL) cenegermin-bkbj ophthalmic solution the other group was treated with vehicle.[15] All eye 
drops in both studies were given six times daily at 2-hour intervals in the affected eye(s) for eight 
weeks. In the first study, only patients with the disease in one eye were enrolled, while in the second 
study, patients with the disease in both eyes were treated in both eyes (bilaterally), the worse eye was 
considered the study eye for efficacy evaluations. Complete corneal healing (defined as absence of 
staining of the corneal lesion and no persistent staining in the rest of the cornea at eight weeks) was 
demonstrated in 72 percent of patients treated with OXERVATE™ 0.002% (20 mcg/mL) cenegermin-
bkbj ophthalmic solution compared to 33.3 percent of patients (p<0.001) treated with vehicle in the 
REPARO trial. For the US trial NGF0214, 65.2 percent of patients treated with OXERVATE™ 0.002% 
(20 mcg/mL) cenegermin-bkbj ophthalmic solution compared to 16.7 percent of patients treated with 
vehicle had complete corneal healing at week 8.[14, 15] 
 
The data from the two studies were enclosed into the biologics license application (BLA) and the FDA 
granted the approval for OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution for 
the treatment of all stages of NK.[4]  


 
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2.4. 
STUDY RATIONALE 
This clinical trial has been designed to demonstrate the efficacy and safety of OXERVATE™ 0.002% 
(20 mcg/mL) cenegermin-bkbj ophthalmic solution given 6 times a day at 2-hour intervals for 8 weeks 
in patients with Stage 1 NK. Efficacy will be assessed as epithelial healing of Stage 1 NK as measured 
by corneal fluorescein staining.  Further, the study will evaluate the preservation of effect measured by 
the percentage of treated patients who remain healed at the 32 week follow up.   
2.4.1. 
Alternative treatments 
The only FDA approved product for treatment of NK is OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution.  Alternative non-surgical treatment options may include 
therapeutic soft contact lenses, suture-less amniotic membrane, or tarsorrhaphy. 
2.4.2. 
Description of the Study product 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution: in a multiple-dose vial. 


 
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3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES   
Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of OXERVATE™ 0.002% (20 
mcg/mL) cenegermin-bkbj ophthalmic solution administered 6 times daily for 8 weeks on the ocular 
surface, visual function and quality of life in patients with Stage 1 NK.   
Secondary Objective 
The secondary objective is to evaluate patients who heal at week eight and remain healed (as defined in 
section 3.3) throughout the follow-up period. In addition, the study aims to evaluate the percentage of 
subjects that achieve an improvement in corneal sensitivity as measured by the Cochet-Bonnet 
aesthesiometer at 4 and 8 weeks, and by the last visit week 32. 
Exploratory Objectives 
The exploratory objectives are to evaluate change from baseline to weeks 4 & 8 in Schirmer I and the 
Tear Film Break-Up Time (TFBUT) change from baseline to weeks 4 & 8. 
Additional Objectives (site specific) 
Analysis to evaluate the change from baseline at week 8 and week 24 in confocal microscopy and 
anterior segment OCT. 
 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE 
This study will be performed at approximately 5 study centers located in the United States. At each 
study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is 
conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local 
regulations.  
The PI at each study center will be responsible for the management of the study, which will consist of 
maintaining the study file and the patient records, corresponding with the IRB/IEC, completing the case 
report forms (CRFs) and reporting SAEs (or other important AEs as specified in section 8.0) within 24 
hours of initial awareness.  
The PI is responsible for supervising any individual or party to whom the investigator delegates trial 
related duties and functions conducted at the trial site. If the investigator/institution retains the services 
of any individual or party to perform trial-related duties and functions, the investigator/institution 
should ensure this individual or party is qualified to perform those trial-related duties and functions and 
should implement procedures to ensure the integrity of the trial-related duties and functions performed 
and any data generated. 


 
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3.3. 
OVERALL STUDY DESIGN  
This clinical study will be a multi-center, open label, prospective study of 8 weeks of treatment with 24 
weeks of follow-up to evaluate the safety and efficacy of OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution administered as one drop in the affected eye(s), 6 times per day at 
2-hour intervals, for eight weeks in patients with Stage 1 Neurotrophic Keratitis (NK).  
The study is divided into four phases as follows: 
5. Screening Visit (Day -14):  Procedures for inclusion will be performed at both Visit 1 
(Screening) and Visit 2 (Baseline).  Commercially available artificial tears (AT) provided by the 
sponsor will be permitted during the Screening period as needed up to four times a day. 
6. Washout period (from day minus 14 to day 0):   14 days with no further treatment except 
commercially available preservative-free artificial tears provided by the sponsor. (Note:  Xiidra™ 
and Restasis™ use is disallowed for 14 days prior to Visit 2.)  Artificial tears (AT) provided by 
the sponsor will be permitted up to four times a day and will be tracked via daily diary during 
washout period. 
7. Treatment: 
a. Treatment (weeks 1-8): eligible patients will start OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution administered as one drop in the affected eye(s), 6 
times per day at 2-hour intervals, for eight weeks. During the treatment period, only 
study product will be permitted for topical ocular treatment. Commercially available 
preservative free artificial tears (AT) provided by Sponsor are not allowed during the 
treatment period.   
8. Follow up (weeks 9-32):   For the 24 weeks post treatment: 
a. For patients completely healed, no treatment is allowed except for commercially 
available AT provided by the Sponsor, administered at the physician’s discretion. The 
use of artificial tears will be tracked via a daily dosing diary. 
b. For patients not completely healed and who don’t meet criteria for premature 
discontinuation, will also be followed up but any treatment is allowed at the discretion of 
the physician. All treatment will be tracked as concomitant medications. 
 
Rescue Therapy: Commercially available preservative free artificial tears (AT) provided by 
Sponsor are not allowed during the treatment period. Per the investigator’s discretion if the 
patient requires rescue therapy during the 8-week treatment period then they can receive 
artificial tears provided by the sponsor for up to four times per day. The frequency of rescue 
therapy must be documented in the patient's diary. 
 
 
The study will be a total of 34 weeks in duration: a screening period of 2 weeks, followed by 8 weeks of 
treatment and a 24-week follow-up period. At the end of the screening period (at Visit 2), patients 
meeting the entry criteria for this study will be assigned to treatment with OXERVATE™ 0.002% (20 


 
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mcg/mL) cenegermin-bkbj ophthalmic solution which will be known as Study Product beginning the 
morning following Visit 2.  
Following the completion of the treatment period, patients will be followed up for an additional 24 
weeks (for patients healed and non-healed [and not meeting d/c criteria] at Week 8) and will be 
evaluated at the end of the follow-up period. At the investigator’s discretion, the subject may be seen for 
an Unscheduled Visit to evaluate for safety. Patients who prematurely discontinue for whatever reason 
will not be followed post discontinuation and should have Visit 6 assessments completed. 
At Visit 1, eligible patients will be instructed to discontinue all topical ophthalmic medications and will 
only be allowed to use commercially available preservative free tears provided by the sponsor to be 
used up to four times per day during the screening period. At the conclusion of the Baseline Visit (Visit 
2) eligible patients will be dispensed a 2-week supply of Study Product from the onsite freezer in a 
sealed bag and will be instructed to self-administer the Study Product one drop six times a day starting 
on the day after Day 0/ Visit 2 through Week 8 of the controlled treatment period according to the 
dosing schedule shown in Table 1 (Dosing Schedule).  
Table 1 Dosing Schedule 
TREATMENT  
TREATMENT DOSING SCHEDULE* 
OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution 
 
Morning (8 AM) 
Mid-morning (10 AM) 
Noon (12 PM) 
Early afternoon (2 PM) 
Mid afternoon (4 PM) 
Late afternoon (6 PM) 
* The above is an example.  The timing of instillation can be adjusted if a patient’s awakening 
and/or bedtime differs throughout the 8 weeks. The patient should try and keep the daily dosing 
schedule as consistent as possible by trying to schedule sleep and wake times. A daily dosing diary will 
be maintained by the subject to track compliance for each dose of study product. 
A two week supply of study product will additionally be dispensed to the patients during the treatment 
period at Visits 3, 4 and 5/Weeks 2, 4 and 6.  
Starting from Visit 2, only the study product will be allowed.  Preservative free AT provided by the 
sponsor will not be used during the study product treatment period. After the 8 weeks of Study Product 
treatment, and during the follow up period, AT should be used only if strictly needed.  The use of AT 
will be tracked in the daily dosing diary. 
 


 
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At Visit 6 (End of Treatment), patients will be assessed for corneal healing. 
 
Completely healed patients at week 8 are defined by SPK as Grade ≤1 in the central qualifying 
zone via FCS (per NEI scale) and no persistent staining in the non-qualifying zones (excluding the 
superior zone) defined as the absence of pathological staining via corneal photography.  Patients who are 
completely healed at Week 8 will be followed for an additional 24 weeks during the follow-up period.  
During the 24-week follow-up period (Weeks 9-32) the patients will be followed without any Study 
Product, however, preservative-free AT (provided by the study sponsor) may be used documented on the 
daily diary. If warranted for patient safety, the Investigator may elect to see the subject at an Unscheduled 
Visit(s) to evaluate the patient.  
Patients who are not completely healed at week 8 are defined by SPK as Grade 2 via FCS in 
the central qualifying zone AND who do not meet the criteria for premature discontinuation, will also 
be followed for an additional 24 weeks during the follow-up period. During the 24 week follow-up period 
(Weeks 9-32) the patients will be followed may be treated at the physician’s discretion (retreatment with 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution is not permitted). Any 
concomitant treatment must be documented on concomitant medication log.  If warranted for patient 
safety, the Investigator may elect to see the subject at an Unscheduled Visit(s) to evaluate the patient. 
Patients who meet the definition of Deterioration or No Improvement in the study eye at 
week 8 and during the follow up period, will be discontinued from the study and treated as appropriate 
at the discretion of the investigator.   
 
Deterioration or No Improvement is defined by any of the following:   
 In the Study Eye, the FCS is unchanged (Grade=3) from baseline in the qualifying NEI zone. 
 At the PIs discretion, in the study eye there is a progression from baseline in the non-qualifying 
zones 
 decrease in BCDVA by >10 ETDRS letters from baseline. 
 progression in staining to a PED or corneal melting or perforation 
 onset of infection 
 Require an ocular surgical procedure, including the need for a corneal transplant. 
Note: If there is a deterioration in the non-study eye, the Investigator may discontinue treatment in that 
eye and initiate alternative treatment at their discretion in the non-study eye, but continue following the 
study eye per protocol. 
All patients will attend the following clinic visits in the following sequence:   
 Screening (Visit 1/Day -14) 
 Baseline and First Study Product Pick-Up (Visit 2/Day 0) 
 Product Pick-Up (Visit 3/Week 2) 
 Treatment Assessment and Study Product Pick-Up (Visit 4/Week 4) 
 Product Pick-Up (Visit 5/Week 6)  
 End of 8-week Treatment (Visit 6/Week 8) 
 Follow-Up and Final Study Visit (Visit 7/Week 32).   


 
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The trial structure for subjects is shown in Figure 1 
 
 
Figure 1 Study Schematic 
 
 
Any subject who meets the definition of experiencing a deterioration in the study eye, will be 
discontinued from the study, and followed per the Investigator’s discretion.   
 
If there is a deterioration in the non-study eye, the Investigator may discontinue treatment in that eye 
and initiate alternative treatment at their discretion in the non-study eye, but continue following the 
study eye per protocol. 
3.3.1. 
Rationale for Selection of dose, and treatment schedule in the study 
The dose proposed in this study, OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic 
solution (one drop in each eye six times daily for 8 weeks), was tested in the previous NK studies 
(NGF0212 and NGF0214).   
The 20 μg/ml concentration of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic 
solution is well sustained by the current manufacturing process and is the commercial formulation 
currently approved and available in the USA.  
The dose and route of administration of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution selected in this study is based on the approved marketed concentration as an eye 
drop approved for the treatment of NK.   


 
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Given the nature of the disease, an eight week treatment period at 6 doses/day is considered sufficient 
time to produce a reversal of PED in a Stage 2 and Stage 3 (more severe) NK patient population and 
reaches the maximal response in terms of efficacy as seen in up to 72% (REPARO) of patients who had 
complete corneal healing defined as absence of staining of the corneal lesion and no persistent staining 
in the rest of the cornea after 8 weeks of treatment.   An established safety profile exists with cenegermin 
20 µg /mL having been evaluated in six prior clinical trials.  Additionally, toxicology and data showed 
cenegermin to be well tolerated in animal models with no systemic or ocular toxicity. 
Patients with tolerability issues or worsening of symptoms may be discontinued at any time during the 
study. 


 
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4. 
SELECTION OF STUDY POPULATION 
Adult males and females with Stage 1 NK (as defined in the inclusion criteria) will be included. A total 
of 35 evaluable patients (those patients completing 8 weeks of Oxervate™)  are planned to be enrolled. 
4.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria:  
1. Male or female aged ≥ 18 years.   
2. Patients with Stage 1 NK defined by the Mackie criteria (Appendix 4)  
3. Patients with Stage 1 NK characterized by all the following:  
a. superficial punctate keratopathy (SPK) as shown by fluorescein corneal staining (FCS) 
equal to a grade 3 within the central zone using the National Eye Institute (NEI) scale 
(Appendix 4).  
AND 
b. evidence of decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet 
aesthesiometer) in the central qualifying zone of staining. 
4. No improvement in NEI zone score between the Screening Visit (Visit 1) and Treatment Visit 
(Visit 2) for the qualifying zone determined at Visit 2. 
5. Have a best corrected distance visual acuity (BCDVA), using corrective lenses if necessary, in the 
study eye, of at least +1.0 Log MAR (Snellen <20/200 ) if the clinician attributes the vision loss 
to the epithelium and the loss is not related to the macula in the affected eye(s).  
6. The same eye (eligible eye/study eye) fulfills all the above criteria on the day of Screening (Visit 
1) and again on Visit 2. 
7. Patients with punctal occlusion or punctal plugs inserted prior to the study are eligible for 
enrollment provided that the punctal occlusion is maintained during the study period. If a punctal 
plug falls out during the study, it must be reinserted within 7 days.   
8. Patients who are at high risk of progression or have a history of Stage 2 or Stage 3 NK per the 
Mackie classification. 
9. Patients who have only one functional eye can be included if they meet all the criteria above and 
per the investigator’s discretion are proper candidates to designate the one functional eye as the 
study eye.  
10. Only patients who satisfy all Informed Consent requirements may be included in the study. The 
subject and/or his/her legal representative has read, signed, and dated the IRB approved Informed 
Consent document before any study-related procedures are performed. 
11. Patients must have the ability and willingness to comply with study procedures. 
 


 
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4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study. 
1. In the opinion of the Investigator, there is evidence of an active ocular infection (bacterial, viral, 
protozoal) in either eye. 
2. Use of non-diagnostic (e.g., topical drops used for clinical testing/evaluations) medications that 
can induce corneal toxicity between Visit 1 and Visit 2. 
3. In the opinion of the investigator, have current or history of conditions that may confound the 
study data including but not limited to Ocular Cicatricial Pemphigoid (OCP), Graft Versus Host 
Disease (GVHD), neuromyelitis optica, uncontrolled dry eye, and Steven Johnson’s syndrome.  
4. History of severe systemic allergy or severe ocular allergy (including seasonal conjunctivitis 
expected during the subject’s participation in the trial) or chronic conjunctivitis and/or keratitis 
other than dry eye disease. 
5. Intraocular inflammation defined as Tyndall score >0. 
6. Patients with severe vision loss with no potential for visual improvement in the study eye in the 
opinion of the investigator, or if the subject is deemed legally blind.  
7. Patients with active severe blepharitis and/or severe meibomian gland disease who in the opinion 
of the investigator will require routine treatment during the study or have required routine 
treatment within 2 weeks of the study treatment visit (Visit 2).  (This includes the use of 
doxycycline within 2 weeks prior to the treatment visit (Visit 2) for active MGD.) 
8. History of any ocular surgery (including eyelid surgery and cataract surgery) within the three 
months before study treatment (Visit 2) and for Lasik or refractive surgical procedures within 3 
months before study treatment (Visit 2). (An exception to the preceding statement is allowed if, 
in the opinion of the investigator, the ocular surgery is deemed the cause of the NK).  
9. Ocular surgery or elective ocular surgery expected during participation in the trial. 
10. Prior surgical procedure(s) for the treatment of NK including but not limited to tarsorrhaphy, 
conjunctival flap, the exception is for amniotic membrane transplantation. Enrollment of patients 
previously treated with amniotic membrane transplantation is allowed two weeks after the 
membrane has fully disappeared within the area with removal of any sutures or two weeks from 
removal of the Prokera ring before study treatment visit (Visit 2). 
11. Treatment with Botox (botulinum toxin) injections in the study eye, used to induce pharmacologic 
blepharoptosis within 60 days prior study treatment visit (Visit 2).  
12. Anticipated need to use therapeutic contact lenses or contact lens wear for refractive correction 
during the study treatment period in the Study Eye. 
13. Patients with unstable medical condition that may confound the study data in the opinion of the 
investigator including but not limited to diabetes, thyroid disease, autoimmune disease, 
Parkinson’s disease, and Multiple Sclerosis. Stable conditions managed with oral or injectable 
medications can be included, if per the investigators discretion the patient is not anticipated to 
have flare ups that could affect the ocular surface.   
14. Patients with eyelid abnormality that may alter eyelid function including but not limited to 
Blepharospasm, Cerebrovascular accident, entropion, ectropion, floppy lid syndrome. 


 
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15. Use of glaucoma drops within 14 days prior to study treatment visit (Visit 2) and for the duration 
of the study. Patients can use oral Diamox during the study to control IOP.    
16. Pregnant or lactating at study entry or who are planning a pregnancy. 
17. Premenopausal female not using a medically acceptable form of birth control (abstinence, oral 
contraception, intrauterine device, surgically sterilized). 
18. History of drug addiction or alcohol abuse documented within the past 5 years. 
19. Participation in a clinical trial with a new active substance 14 days prior to study treatment visit 
(Visit 2). Per the investigator’s evaluation that the participation in another clinical trial for an 
ocular surface product does not have residual effects on the ocular surface beyond 14 days prior 
to treatment that could confound the data by having an effect on staining. 
20. Participation in another clinical trial study at the same time as the present study. 
21. Participation in a Neurotrophic Keratitis study during the past 60 days prior to study treatment 
visit (Visit 2). 
22. Are an employee of the site that is directly involved in the management, administration, or 
support of this study or be an immediate family member of the same. 
 
23. Prior failure with treatment for Stage 1, 2 or 3 NK with OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution.  Failure defined as non-responder or lack of efficacy. 
4.3. 
SELECTION OF STUDY EYE 
The study eye is the eye at Visit 2 having Grade 3 FCS per the NEI scale in the central zone and a 
decreased corneal sensitivity (≤ 4 cm using the Cochet-Bonnet aesthesiometer) in the central zone at 
both Visit 1 and Visit 2.  If both eyes have a qualifying central zone meeting FCS and corneal 
sensitivity requirements at both Visit 1 and Visit 2, the right eye will be selected as study eye.   
Note:  If both eyes meet the FCS and corneal sensitivity requirements in the central zone, the subject 
will be treated bilaterally. If only one eye qualifies, but the contralateral eye has FCS in the central zone 
≥2 on NEI scale and the Investigator feels that both eyes would benefit from treatment (i.e. the 
qualifying eye is abnormal, but does not meet criteria for study) both eyes may be treated with study 
product.  Data will be collected and recorded in the eCRF for both eyes throughout the study. 
If there is only one qualifying eye/one study eye, only one eye will be treated; however, both eyes will 
be evaluated, and data will be collected for both eyes.  
4.4. 
ASSIGNMENT OF SUBJECT NUMBER 
Each patient who is screened to participate in this study will be assigned a unique 6-digit PID number 
(e.g. 001101) consisting of a 3-digit study center number followed by the 3-digit screening number 
assigned sequentially by each study center.  


 
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5. 
STUDY PRODUCT 
5.1. 
PRESENTATION, STORAGE, PACKAGING AND LABELING OF THE STUDY PRODUCT 
5.1.1. 
Presentation of Study Product 
The Study Product will be provided as the commercially available OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution.  The patient will receive 1 or 2 biweekly cartons sufficient for 
two weeks of dosing at Visit 2, Visit 3, Visit 4, and Visit 5.  The patients will be provided with enough 
pipettes and adaptors to be used for the administration of the Study Product. The subject will receive a 
total of 56 (or 112 for bilateral treatment) OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj 
ophthalmic solution vials over the 8-week duration of the study product treatment, 1 OXERVATE™ 
0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution vial to be used per day. The patient will 
pick up Study Product from the Investigator’s office and bring back used vial for reconciliation at the 
subsequent study visit. 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
   


 
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5.1.4. 
Description of Study Product 
Study Product is OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution.  
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution is a sterile perservative-free 
ophthamic solution containing 0.002% (20 mcg/mL) of rhNFG drug substance.   
 
Each vial contains 1.0 ml of solution.   
 
 
 


 
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Commercially available artificial tears will be supplied to patients in the study by the sponsor. Study 
sponsor will provide SYSTANE® Preservative-Free Original Lubricant Eye Drops to be used up to four 
times per day as needed during the screening period, and as needed for rescue therapy and during the 
follow-up period. 
 
5.2. 
DOSE, ROUTE AND SCHEDULE OF PRODUCT ADMINISTRATION 
Both OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution (study product) and 
SYSTANE Original® (to be used for the screening and follow-up periods only) are to be used in this 
study and are for topical ocular usage only.  
 
The Study Product will be dosed one drop (35 µl- .70 μg of cenegermin-bkbj/drop) 6 times a day in the 
affected eye(s) for 8 weeks of treatment. The timing of instillation should be adjusted if a patient’s 
awakening and/or bedtime differs based on the suggestion above in Table 1 Dosing Schedule. An 
example of Dosing Instructions is also provided in the Manual of Procedures (MOP).   
 
Instructions for First Dose:  
Patients will be instructed to self-administer the study product one drop in the affected eye(s) six times a 
day at 2 hour intervals starting on the day after Visit 2 (Day 0-Baseline and First Study product Pick 
Up) of the treatment period. On Day 1, the patient will start the first dose following Table 1 Dosing 
Schedule. The patient should not start therapy on the same day as Day 0/Visit 2. 
 
On the day of Visit 3/Week 2 (For Study Product Pick-Up), the Study Product dosed is to be instilled in 
the clinic by the patient at approximately 2 hours intervals according to their established daily schedule 
for self-administration of the study product at home and the Study Product should be taken from the kit 
which is dispensed at the visit. This to ensure the patient does not miss a dose during the drop off and 
pick up day.  
 
Systane Original® (commercially available preservative free artificial tears provided by sponsor) will be 
used only as strictly needed during the Screening and Follow up periods. The use of Systane Original®  
will be clearly documented in the patient’s study dosing diary and in the eCRF.  
 


 
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5.3. 
ACCOUNTABILITY OF THE STUDY PRODUCT 
Upon receipt, the study staff designated by the Investigator will inventory the clinical study products, and 
complete and sign the Receipt of Study Product documentation. A copy of the form will be maintained in 
the Investigator’s records and the original will be provided to Lexitas. 
 
The designated study staff must keep a complete and accurate accounting of all Study Product used via a 
Dispensing Log. In no case will the Study Product be used in any unauthorized situation. 
 
At Visits 3, 4, 5 and 6, patients will return the used or unused study boxes/vials to the clinic in the original 
carton. 
All Study Product returned by patients should be inventoried same day of return. Inventory will take place 
at Visits 3, 4, 5 and 6.   These records will be made available to the study monitor for the purpose of 
accounting for all study products. The study monitor will account for all Study Products. The investigator 
will maintain all used and unused vials after inventory for the duration of the clinical trial. Upon 
completion of the trial all used and unused vials will be packaged for return to Dompé once the study 
monitor has concluded no data from patient inventory reconciliation is missing. Once the study is 
concluded and all records are reviewed for accuracy the CRO will give the PI permission to package and 
return all vials to Dompé. Return instructions will be provided to investigators. 
 
It is the Investigator’s responsibility to ensure the reconciliation of study medications at the conclusion 
of the study. Any discrepancies and/or deficiencies in study drug accountability must be recorded along 
with an explanation in the appropriate accountability log.  
 
Study Product which has been dispensed to a patient and returned unused will not be re-dispensed to a 
different patient.  
 
Unused Study Product must not be discarded or used for any purpose other than the present study. Any 
remaining Study Product at the end of the trial will be disposed of as determined by Dompé. 
 
5.3.1. 
Prior and concomitant medications 
As a general rule, no ophthalmic medication other than Study Product and concomitant Study Product 
(Systane® -artificial tears provided by Sponsor) will be given to the patient from the screening day until 
all the final study evaluations have been completed. Systane®, provided by the Sponsor, may be used 
during screening and the follow up only.  
 
All medications (including over-the-counter drugs, systemic medications, herbal products, vitamins, and 
antacids) should be documented at screening and also taken within 14 days of study treatment Visit 2 
and throughout the study will be clearly documented on the Concomitant Medications eCRF page. 
 
Medication entries should be specific to product name (if a combination drug product) and spelled 
correctly. The dose, unit, frequency, route of administration, start date, discontinuation date, and 
indication should also be recorded. For medications administered only one time, the frequency column 
may reflect "once." 


 
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Table 3 Medications and Procedures 
Minimum Washout Period 
Prior to Treatment (Visit 
2)  
Have had incisional ocular surface surgery (e.g., LASIK, refractive, 
pterygium removal). 
90 days  
Ocular surgery (including eyelid surgery or cataract surgery) 
90 days 
Botox (botulinum toxin) injections in the study eye. 
60 days 
Any Investigational Product for NK 
60 days 
Any Investigational Product applied to the ocular surface if per the 
investigators discretion the investigational product does not have 
residual effects on the ocular surface that can confound the data 
14 days 
Topical ocular or systemic antibiotics for the treatment of an ocular 
condition 
14 days 
Topical cyclosporine (all doses and formulations) 
14 days 
Lifitegrast 
14 days 
Glaucoma topical medications (Use of Diamox orally during the 
study is acceptable)-Investigator should ensure stable IOP before/by 
Visit 2 
14 days 
Topical ocular corticosteroids, ocular non-steroidal anti-
inflammatory drugs (NSAIDs), and topical dermatologic 
corticosteroids on the face within 14 days prior to Visit 2 and during 
study participation 
14 days 
Topical ocular antihistamine and/or mast cell stabilizers within 14 
days prior to Visit 2. Have used topical ocular vasoconstrictors for 
the purpose of eye whitening within 14 days prior to Visit 2 
(phenylephrine used to dilate the eyes is allowed). 
14 days 
Treatments for blepharitis MGD including but not limited to thermal 
pulsation (Lipiflow), debridement of lid margin (BlephEx), thermal 
application (MeiBoFlo, Tear Care), meibomian gland probing or 
doxycycline. 
14 days 
All topical ophthalmic gels, ointments or drops that can induce 
corneal toxicity (diagnostic medications used for clinical 
testing/evaluations are acceptable). 
14 days  
Enrollment of patients previously treated with amniotic membrane 
transplantation is allowed two weeks after the membrane has fully 
disappeared within the area with removal of any sutures or two 
weeks from removal of the Prokera ring before study treatment visit 
(Visit 2). 
14 days 
 


 
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6. 
STUDY PROCEDURE AND ASSESSMENTS 
For the detailed description of all the clinical examinations listed below refer to the Manual of 
Procedures (MOP).   See the Schedule of Evaluations in Section 2.0 for the list of procedures by visit in 
the recommended order. The descriptions of the procedures to be performed at each visit are provided 
below.  If possible, the same investigator should perform the assessments for one subject.  
6.1. 
STUDY VISITS AND EXAMINATIONS AND TREATMENT VISITS 
6.1.1. 
Visit 1 (Day -14):  SCREENING 
Site staff will conduct the following screening assessments in the order outlined below. (Note: 
Procedures that are not required to be conducted in a specific order will be noted with an *) 
 
1. Informed Consent/HIPAA:   Explain the purpose and nature of the study, and have the subject 
or legally authorized representative read, sign, and date the IRB approved informed consent 
document. Provide a photocopy of the signed document to the subject and place the original 
signed document in the subject chart. 
2. *Demographics, Ocular and Medical History, Previous and Concomitant Ocular and 
Systemic Medications and Conditions:  Document demographic information and medical 
history, including herbal therapies, vitamins, and all over the counter as well as prescription 
topical and systemic medications. Document etiology of NK and all concomitant ocular diseases 
and systemic conditions. Patients IOP should be measured at screening and if conversion to oral 
Diamox is initiated, patient should be deemed to have a stable IOP by Visit 2. 
3. *Pregnancy Test:  Perform a urine pregnancy test on any female of childbearing potential and 
record the results. If a pregnancy test is not required, indicate as not applicable in the eCRF.   
4. *Adverse Events: Begin monitoring of AE’s. 
5. Ophthalmic Examinations:  The following examination/procedures will be performed on 
BOTH EYES and in order unless otherwise specified.  (The grading scale and detailed 
description of the examinations/procedures are described in the MOP): 
a. Best-Corrected Distance Visual Acuity (BCDVA) Vision must be measured at each 
visit using ETDRS visual acuity chart at 4 meters (13 feet).  BCDVA testing should 
precede the administration of any eye drops to dilate or anesthetize the eye, or any 
examination requiring contact with the eye.  If vision is corrected, the same 
correction should be used throughout the BCDVA testing.  
b. External Ocular Examination Assess the motility of the extraocular muscles and the 
appearance and function of the eyelids before the instillation of any dilating or 
anesthetic eye drops. 


 
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c. Slit Lamp Examination (SLE):  SLE will assess eyelids, lashes, conjunctiva, cornea, 
lens, iris, and anterior chamber. The slit lamp examination must be performed 
before the instillation of any dilating or anesthetic eye drops or the fluorescein 
agent. 
d. Corneal Photo Without Fluorescein: Photos of the cornea of both eyes (Visit 1) and 
the treated eye(s) (Visit 2, Visit 4, Visit 6, and Visit 7) will be taken after slit lamp 
examination and before the instillation of fluorescein agent by a slit lamp camera 
focusing on the epithelial defect and using white, diffuse (homogenous) frontal 
illumination. 
e. Instill Fluorescein 
f. Corneal Fluorescein Staining:  Following the instillation of fluorescein in the 
qualifying eye(s) grade (density) of the SPK will be determined using the NEI 
(National Eye Institute [NEI]/Industry Workshop 0-15) scale.   
g. Corneal Photo with Fluorescein:  As soon as possible after completing the Corneal 
Fluorescein Staining, a corneal photo of both eyes (Visit 1) and the treated eye(s) 
(Visit 2, Visit 4, Visit 6, and Visit 7) using cobalt blue illumination will be taken to 
document the observed corneal findings. 
h. Corneal Sensitivity:  Corneal Sensitivity will be measured using a Cochet Bonnet 
aesthesiometer before the instillation of any dilating or anesthetic eye drops.  
Corneal sensitivity will be assessed in the qualifying NEI zones of each eye.  
Nonqualifying zones (excluding superior) may be tested if the qualifying NEI zone 
does not meet the corneal sensitivity inclusion.  
i. IOP 
6. Inclusion/Exclusion Criteria Screen the subject for protocol inclusion/exclusion criteria as 
per Sections 4.1 and 4.2. 
7. Dispense Systane Original®:  Instruct patient to use only as strictly needed and up to 4 times 
per day during screening period; additionally, instruct the patient to return Systane®  bottle (s) at 
Visit 2 
8. *Dispense Study dosing diary (for Systane use) 
6.1.2. 
Visit 2 (Day 0 ± 2 days):  BASELINE  
Patients will enter the single-arm open-label phase of the study if they continue to meet eligibility 
criteria at Visit 2/Baseline. 
 
1. IDEEL (Impact of Dry Eye on Everyday Life):  This questionnaire will be assessed by the 
patient using a self-administered format. This questionnaire is designed to assess health-related 


 
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quality of life in patients with visual impairments by representing the patient perspective on the 
impact of vision problems on functioning. 
 
2. EQ-5D-5L:  This self-administered questionnaire will be completed by the patient before any 
ophthalmic examination is performed at a given study visit. The EQ-5D is a standardized measure 
of health status developed by the EuroQol Group in order to provide a simple, generic measure of 
health for clinical and economic appraisal. 
3. *Concomitant Ocular and Systemic Medications Update:  Record any change from 
Screening/Visit 1 in concurrent ocular or non-ocular medications including information on all 
concomitant and previous medications used within the past 14 days before Visit 2. 
4. *Record AE’s 
5. *Pregnancy Test:  Perform a urine pregnancy test on any female of childbearing potential and 
record the results. If a pregnancy test is not required, indicate as not applicable in the eCRF.   
6. Ophthalmic Examinations: following examination/procedures will be performed on BOTH 
EYES unless otherwise specified: 
a. BCDVA  
b. External Ocular Examination  
c. Slit Lamp Examination    
d. Corneal Photo Without Fluorescein 
e. Instill Fluorescein 
f. Tear Film Break-Up Time (TFBUT) 
g. Corneal Fluorescein Staining:  Using NEI scale (0 to 3 is used for each of the five 
areas per cornea).  
h. Corneal Photo with Fluorescein 
i. Wait 10 minutes before performing Schirmer Test 
j. Corneal Sensitivity 
k. Schirmer Test Without Anesthesia (Schirmer I)   
l. IOP  
m. Anterior Segment OCT (selected sites) 


 
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n. Confocal microscopy (selected sites) 
7. Inclusion/Exclusion:  Patients must continue to meet the Screening/Enrollment Criteria.  
At the end of the Baseline Visit (Day 0), it will be determined if the subject qualifies for 
continued participation and treatment in the study.   
8. Study Product Dispensing:  Eligible patients will be supplied with a biweekly kit of Study 
product sufficient for 2 weeks of treatment per visit. 
9. *Dispense Daily Study Dosing Diary 
10. Collect used/unused AT and collect/review AT dosing diary 
11. *Instructions to Subject:  Instruct the subject to initiate dosing the study eye or bilaterally (if 
applicable) the following day and to return to the clinic for Visit 3/Week 2 Visit in 2 weeks (14 
days).  Further instruct the subject to return to the clinic with the Daily Study Dosing Diary and 
all the empty used/unused daily kit of Study product in the original carton box. Also, remind 
subject that Systane®, nor any other topical ocular medications), are allowed during study 
product treatment period. 
6.1.3. 
Visit 3 (Day 14/Week 2 - 2 days) STUDY PRODUCT PICK-UP VISIT 
1. *Concomitant Ocular and Systemic Medications Update 
2. *Record AE’s 
3. *Collect Used/Unused Study Product, Daily Dosing Diary, and Inventory 
4. *Study Product Dispensing:  Patients will be supplied with a biweekly kit of Study product 
sufficient for 2 weeks of treatment. 
5. *Dispense Daily Study Dosing Diary 
6.1.4. 
Visit 4 (Day 28/Week 4 -2 days):  TREATMENT VISIT 
1. IDEEL  
2. EQ-5D-5L 
3. *Concomitant Ocular and Systemic Medications Update 
4. *Record AE’s 
5. Ophthalmic Examinations: The following examinations/procedures will be performed on 
BOTH EYES unless otherwise specified: 
a. BCDVA  


 
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b. External Ocular Examination  
c. Slit Lamp Examination    
d. Corneal Photo Without Fluorescein  
e. Instill Fluorescein 
f. TFBUT 
g. Corneal Fluorescein Staining  
h. Corneal Photo with Fluorescein 
i. Wait 10 minutes before performing Schirmer Test 
j. Corneal Sensitivity 
k. Schirmer Test Without Anesthesia (Schirmer I) 
6. *Collect used Study product and Daily Study Dosing Diary 
7. *Study Product Dispensing:  Patients will be supplied with a new biweekly kit of Study 
product sufficient for 2 weeks of treatment. 
8. *Dispense Daily Study Dosing Diary 
9. Instructions to Patient:  Instruct the patient to return to the clinic for Visit 5/Week 6 Study 
product Pick-Up visit in two weeks. Further instruct the patient to return to the clinic with the 
Daily Study Dosing Diary and all the empty used/unused daily kit of Study Product in original 
carton box. 
6.1.5. 
Visit 5 (Day 42/Week 6 - 2 days):  STUDY PRODUCT PICK-UP VISIT  
1. * Concomitant Ocular and Systemic Medications Update 
2. *Record AE’s 
3. *Collect Used/Unused Study Product, Daily Study Dosing Diary, and Inventory 
4. *Study Product Dispensing:  Patients will be supplied with a biweekly kits of Study product 
sufficient for 2 weeks of treatment. 
5. *Dispense Daily Study Dosing Diary 
6. *Instructions to Subject:  Instruct the patient to return to the clinic for Visit 6/Week 8 End of 
Treatment visit in two weeks.  Further instruct the patient to return to the clinic with the Daily 
Study Dosing Diary and all the empty used/unused daily kit of Study Product in the original 


 
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carton. Patients should be instructed to try and complete therapy before last treatment 
appointment, so at time of end of treatment evaluation the patient should have completed the 
six times a day dosing on Day 56/Week 8 for Visit 6. This will require PIs and their staff to try 
and schedule the last visit at the end of the day, so the patient has sufficient time to complete 6 
doses on the day of Visit 6. 
6.1.6. 
Visit 6 (Day 56/Week 8 - 4 days):  END OF TREATMENT OR PREMATURE 
DISCONTINUATION VISIT 
1. IDEEL  
2. EQ-5D-5L 
3. *Pregnancy Test for women of childbearing potential: Perform a urine pregnancy test and 
record the results. 
4. *Concomitant Ocular and Systemic Medications Update 
5. *Record AE’s 
6. Ophthalmic Examinations: The following examination/procedures will be performed on 
BOTH EYES unless otherwise specified: 
a. BCDVA  
b. External Ocular Examination  
c. Slit Lamp Examination    
d. Corneal Photo Without Fluorescein  
e. Instill Fluorescein 
f. TFBUT 
g. Corneal Fluorescein Staining  
h. Corneal Photo with Fluorescein 
i. Wait 10 minutes before performing Schirmer Test 
j. Corneal Sensitivity 
k. Schirmer Test Without Anesthesia (Schirmer I) 
l. IOP  
m. Anterior Segment OCT (selected sites) 


 
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n. Confocal Microscopy (selected sites) 
7. Collect used Study Product and Subject Dosing Diary 
8. Dispense Daily Study Dosing Diary 
9.  Dispense Systane® 
6.1.7. 
Visit 7 (Day 224/Week 32 ±7 days):  FOLLOW-UP/FINAL STUDY VISIT 
1. IDEEL  
2. EQ-5D-5L 
3. *Concomitant Ocular and Systemic Medications Update 
4. *Record AE’s 
5. Ophthalmic Examinations. The following examination/procedures will be performed on 
BOTH EYES unless otherwise specified: 
a. BCDVA  
b. External Ocular Examination  
c. Slit Lamp Examination    
d. Corneal Photo Without Fluorescein  
e. Instill Fluorescein 
f. TFBUT 
g. Corneal Fluorescein Staining  
h. Corneal Photo with Fluorescein 
i. Wait 10 minutes before performing Schirmer Test 
j. Corneal Sensitivity 
k. Schirmer Test Without Anesthesia (Schirmer I) 
l. IOP 
m. Anterior Segment OCT (selected sites) 
n. Confocal Microscopy (selected sites)  


 
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6. *Collect Daily Study Dosing Diary 
7. Patient will be discharged from the study 
6.2. 
EARLY WITHDRAWAL FROM STUDY 
A premature discontinuation will occur when a patient who signed the ICF ceases participation in the 
study, regardless of circumstances, before the completion of the study protocol procedures. Patients can 
be prematurely discontinued from the study for one of the following reasons:  
 Progression from Stage 1 to Stage 2 or Stage 3 NK, or corneal melting/perforation  
 At the PI discretion patient is considered to be a non-responder (no improvement from baseline). 
 In the qualifying/Study Eye, the FCS is unchanged (Grade=3) from baseline after 8 weeks of 
treatment in the qualifying NEI zone or there is an increase in FCS ≥1 within a non-qualifying 
NEI zone in the same eye. 
 Decrease in BCDVA by >10 ETDRS letters 
 Onset of infection (bacterial or viral) 
 Protocol violation, including lack of compliance defined as <80% of doses taken based on diary 
documentation between treatment clinic visits. 
 Withdrawal of consent  
 Lost to follow-up during the treatment period (Every effort must be made to contact the patient; 
a registered letter must be sent)  
 Study terminated by the Sponsor  
 Other reasons, such as administrative reasons or pregnancy  
 Development of AE or unacceptable toxicity per the investigator’s discretion, precluding further 
therapy with the study drug. 
 
 Severe protocol violations, such as an incorrect treatment administration, or a concomitant use of 
not permitted medications. Before removal, these cases should first be discussed with Dompé. 
The reasons for premature discontinuation from the study will be reflected on the Study Termination 
Record of the CRF. For patients who prematurely discontinue, Visit 6 procedures will be completed, and 
these patients will be considered off study and will no longer be followed. 


 
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For patients that discontinue prematurely, the investigator should refer patients for further treatment as 
appropriate.  
Replacement Procedures  
Patients in this study who prematurely discontinue before completion of 8 weeks of treatment with 
Oxervate™ will be replaced. Patients prematurely discontinuing during follow up treatment will not be 
replaced.  
6.3. 
END OF STUDY 
For this trial, the End of Study is defined as the date of the last visit of the last subject. 


 
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7. 
ENDPOINTS 
7.1. 
STUDY ENDPOINTS 
7.1.1. 
Efficacy endpoints 
1. Percentage of patients who experience epithelial healing at 4 and 8 weeks. (Epithelial healing is 
defined as Grade 1 or absence of staining (Grade 0) in a previously qualifying zone.) 
2. Percentage of patients who remain healed (as defined in #1 above) throughout the follow-up 
period. 
3. Schirmer I change from baseline to weeks 4 & 8 
4. TFBUT change from baseline to weeks 4 & 8 
5. Percentage of patients that achieve an improvement in corneal sensitivity in the NEI zone used 
to qualify in the study eye as measured by the Cochet-Bonnet aesthesiometer at 4 and 8 weeks, 
and at the last visit (week 32). 
6. Quality of life questionnaires change from baseline at week 8 and week 32 
7. IDEEL 
8. EQ-5D-5L 
9. Mean change in BCDVA from baseline to Week 8. 
10. Percentage of patients that achieve a 15- letter gain in BCDVA at 4 and 8 weeks. 
7.1.2. 
Exploratory Efficacy Endpoints 
1. Frequency of preservative free artificial tears use (n° drops/day) during the follow up period.  
At selected sites:   
The following may be evaluated as part of a post-hoc analysis: 
2. Change from baseline structural nerve regeneration (density, length, nerve density, tortuosity) 
per confocal microscopy.   
3. Change from baseline in epithelial thickness per anterior segment OCT. 
7.1.3. 
Safety endpoints 
1. Adverse Events (AEs) and Treatment-emergent adverse events (TEAEs), assessed throughout 
the study 


 
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8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
8.1. 
DEFINITIONS  
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
pharmaceutical product, whether or not considered related to the Study Product.  
This definition includes an exacerbation of preexisting medical conditions or events, historical conditions 
not present prior to study treatment, which reappear following study treatment, intercurrent illnesses, 
hypersensitivity reactions, drug-drug or drug-food interactions, medication errors, overdose (both 
intentional or unintentional), drug misuse/abuse, false positive laboratory test, or the significant 
worsening of the disease under investigation.   
 
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as an adverse experience which is reasonably likely to 
have been caused by the drug.  An adverse reaction, in contrast to an adverse event, is characterized by 
the fact that a causal relationship between a pharmaceutical product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant factors, including 
pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases, and relevant history. 
Adverse drug reactions may arise from use of the Study Product within or outside the terms of the 
marketing authorization or from occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse, and medication errors, occupational 
exposure. 
The Investigator carefully assesses relationship between event and Study drug using the information 
below. 
Arguments that may suggest a reasonable causal relationship could be: 
• The event is consistent with the known pharmacology of the drug 
• The event is known to be caused by or attributed to the drug 
• A plausible time to onset of the event relative to the time of drug exposure 
•  Evidence that the event is reproducible when the drug is re-introduced 
• No medically sound alternative etiologies that could explain the event (e.g. pre-existing or 
concomitant diseases, or co-medications) 
• The event is typically drug-related and infrequent in the general population not exposed to the 
drug 
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller effect size 
if dose is diminished) 
Arguments that may suggest that there is no reasonable possibility of a causal relationship could be: 


 
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• No plausible time to onset of the event relative to the time of drug exposure is evident (e.g. pre-
treatment cases, diagnosis of cancer or chronic disease within days/weeks of drug administration; 
an allergic reaction weeks after discontinuation of the drug concerned) 
• Continuation of the event despite the withdrawal of the medication, considering the 
pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this criterion may 
not be applicable to events whose time course is prolonged despite removing the original trigger. 
• Additional arguments amongst those stated before, like alternative explanation (e.g. situations 
where other drugs or underlying diseases appear to provide a more likely explanation for the 
observed event than the drug concerned) 
• Disappearance of the event even though the study drug treatment continues or remains 
unchanged. 
 
Adverse events are to be considered unrelated if the relationship to the study drug as described in the table 
in section [8.3.2]  is none or unlikely; whereas any AE reported in the study having a possible, probable 
or highly probable relationship to study drug will be considered as an ADR. [For the purposes of safety 
reporting, “reasonable possibility” means there are facts (evidence) or arguments to suggest a causal 
relationship between the drug and the adverse event.] 
Adverse Event of Special Interest (AESI) 
The term AESI relates to any specific AE that has been identified at the project level as being of particular 
concern for prospective safety monitoring and safety assessment within the study, e.g. the potential for 
AEs based on knowledge from other compounds in the same class.  
In the present study, the following sight-threatening events will follow into the definition of AESI and 
will be considered equivalent to a SAE and will be reported following the procedures described below for 
the reporting of a SAE: 
 
 Adverse Events that caused a decrease in visual acuity of >30 ETDRS letters or > +0.6 LogMAR 
(compared with the last assessment of visual acuity at the last visit) lasting >1 hour. 
 Adverse Events that caused a decrease in visual acuity to the level of Light Perception or worse 
lasting >1 hour. 
 Adverse Events that required surgical intervention (e.g., conventional surgery, vitreous tap or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to prevent 
permanent loss of sight. 
 Adverse Events associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis). 
 Adverse Events that, in the opinion of the investigator, required medical intervention to prevent 
permanent loss of sight. 
 


 
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Serious Adverse Event 
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that at any dose: 
 results in death, 
 is life-threatening (i.e. the patient was at risk of death at the time of the event. It does not refer to an 
event which hypothetically might have caused death if it were more severe), 
 requires inpatient hospitalization or prolongation of existing hospitalization, 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency 
ward for observation and/or treatment (usually involving an overnight stay) that would not have been 
appropriate in the physician's office or an out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred, the event 
should be considered serious. 
 results in persistent or significant disability/incapacity, 
NOTE: This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., 
sprained ankle) which may interfere or prevent everyday life functions, but do not constitute a 
substantial disruption. 
 is a congenital anomaly/birth defect, 
 is medically significant or important medical condition, i.e. an important medical event that based 
upon appropriate medical judgment, may jeopardize the patient, and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
An important medical condition is an event that may not result in death, be life-threatening, or require 
hospitalization but may be considered a SAE when, based upon appropriate medical judgment, it 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in patient hospitalization, or the development of drug dependency or drug abuse. 
Pre-planned hospitalization or hospitalization for routine treatment or monitoring of the studied 
indication, not associated with any deterioration in condition are not considered to be SAEs.   
These events must be recorded in the AE page of the CRF where a variable will be ticked to indicate that 
they are not SAEs.  
Death shall always be reported as SAE. Cause of death shall always be specified when known. 


 
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Any preplanned surgery or procedure should be clearly documented in the site source documents by the 
medically qualified Investigator at the time of the patient’s entry into the study. If it has not been 
documented at the time of the patient’s entry into the study, then it should be documented as a serious 
adverse event and reported to Dompé. 
Dompé considers cancer and abortion (spontaneous or non-spontaneous) as serious adverse events, as 
well as any suspected transmission via a medicinal product of an infectious agent is considered a serious 
adverse reaction. 
 
Unexpected Adverse Events  
An AE or ADR is considered unexpected if it is not listed in the package insert. An event is unexpected 
also when it is not listed at the specificity or severity that has been observed and listed in the package 
insert. 
The determination of expectedness shall be made based on the package insert. It is the responsibility of 
the Sponsor to assess whether an AE is expected or unexpected. 
Suspected serious unexpected adverse reaction 
A suspected serious unexpected adverse reaction (SUSAR) is defined as an adverse reaction that is 
both unexpected (not consistent with the applicable product information) and meets the definition of a 
Serious Adverse Reaction. 
8.2. 
MONITORING FOR ADVERSE EVENTS  
At each visit following study informed consent form signature, after the subject has had the opportunity 
to spontaneously mention any problems, the Investigator or appropriate designee should inquire about 
AEs by asking the standard questions:  
• “Have you had any health problems since your last study visit?”  
• “Have there been any changes in the medicines you take since your last study visit?”  
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result of 
an untoward (unfavorable and unintended) change in a subject’s medical health. Anticipated day-to-day 
fluctuations of preexisting conditions that do not represent a clinically significant exacerbation or 
worsening need not be reported as AEs. Changes in any protocol-specific [ocular or] systemic parameter 
evaluated during the study are to be reviewed by the Investigator. In addition, the subject’s responses to 
any questionnaire utilized during the study are to be reviewed by the Investigator. Any untoward 
(unfavorable and unintended) change in a protocol-specific parameter or questionnaire response that is 
clinically relevant is to be reported as an AE. These clinically relevant changes will be reported regardless 
of causality. 


 
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8.3. 
RECORDING 
AEs will be collected and recorded for any untoward event that occurs in a patient from the time he or 
she signs the ICF for the trial until 24 weeks after the last dose of Study Product. Thus, any untoward 
medical occurrences or unfavorable and unintended signs, symptoms, or diseases that occur in the 
pretreatment, treatment, or post treatment period are to be considered AEs and/or SAEs, and consequently 
recorded and reported as such. Should a non-serious AE become serious, the Investigator will then follow 
the same reporting procedures as for SAEs. 
Each AE will be described by:  
• 
Its duration (start and stop dates)  
• 
Severity  
• 
Its relationship to the study drug; (suspected/unsuspected) 
• 
Action(s) taken 
• 
Outcome 
Medical conditions/diseases, or cancer related signs/symptoms present before starting study treatment 
shall be documented in the medical history section of the CRF; these conditions are considered AEs only 
if they increase either in frequency or severity once informed consent has been signed.  
8.3.1. 
Follow-Up of patients with Adverse Events 
The Investigator is responsible for adequate and safe medical care of patients during the trial and for 
ensuring that appropriate medical care and relevant follow-up procedures are maintained after the trial. 
All AEs should be followed-up to determine outcome of the reaction. The Investigator should follow up 
the event until resolution or stabilization of the condition. It is the Investigator's responsibility to assure 
that the patients experiencing AEs receive definite treatment for any AE, if required. 
If subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to the 
Sponsor as soon as it becomes available. In addition, a letter from the Investigator that summarizes the 
events related to the case as well as results of any relevant laboratory tests also may be requested. Further, 
depending upon the nature of the SAE, Dompé may request copies of applicable segments of the patient’s 
medical records. In case of death, a copy of the autopsy report, if performed, should also be provided. 
The Investigator shall inform the Sponsor with an appropriate written communication, whenever he/she 
becomes aware of new available information regarding the SAE once the condition is resolved or 
stabilized and when no more information about the event is expected. Additional information received 
after the initial SAE has been reported to the Sponsor should be reported as follow-up information 
following the same procedure and timeline as the initial SAE.  


 
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For pharmacovigilance purposes, all SAEs should be followed-up to clarify as completely as possible 
their nature and/or causality and until all queries have been resolved. All SAEs will be followed up until 
the events resolve or the events or sequelae stabilize, or it is unlikely that any additional information can 
be obtained after demonstration of due diligence with follow-up efforts (i.e. subject or Investigator is 
unable to provide additional information, or the subject is lost to follow up), unless subject has withdrawn 
his/her consent. 
8.3.2. 
Relationship of AEs to the Study Product 
The Investigator will assess the possible relationship between the AE and the investigational medication, 
according to the criteria in Table below: 
Relationship of the Adverse Event to the Study Product 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the Study Product, e.g. patient is 
a passenger in a road traffic accident.  
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test 
abnormality with temporal relationship to drug administration which makes 
a causal relationship improbable and in which other drugs, chemicals or 
underlying disease provide more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s 
condition or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Study Product 
and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of l Study Product 
and, if applicable, re-appears upon repeat exposure 
 
8.3.3. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below. For each 
episode, the highest severity grade attained should be reported. 


 
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Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to 
work or to do usual activities [unacceptable]) 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators to Lexitas Pharma Services, Inc. And Dompé 
Drug Safety 
The Investigator must report all SAEs, regardless of presumed causal relationship, to Lexitas Pharma 
Services, Inc. Pharmacovigilance and to Dompé Drug Safety, by e-mail (preferred) or fax within 24 hours 
of learning of the event.  
SAE reporting should be sent to:  
SAE Email address: DompeSafety@lexitas.com  
Dompé Drug Safety: USDrugSafety@dompe.com 
Dompé Drug Safety: +1 (347) -294-3328  
In case of failure of/lack of access to email, or fax, the event should be reported using the SAE hotline 
telephone number: 844-237-6724. 
If an SAE is reported via telephone, the telephone report should be followed by a written report using a 
reporting method described above (i.e., completion of paper form). 
The investigator should also report information on SAEs that continue after patient has completed his/her 
participation in the study (whether study completion or withdrawal) unless patient has withdrawn his/her 
consent. 
Information on SAEs will be recorded on the SAE form approved by the Sponsor. Additional follow-up 
information (e.g., test results, autopsy, and discharge summary) may be requested to supplement the SAE 
report form and can be attached as de-identified records. Follow-up reports (as many as required) should 
be completed and e-mailed/faxed following the same procedure and timeline above, marking the SAE 
form as “follow up Number XX”.   
Whenever more than one SAE is observed, the Investigator should identify which is the primary serious 
adverse event, i.e. the most relevant one. In any case, the Investigator is requested to record his/her opinion 
about the relatedness of the observed event(s) with the investigational medication. 


 
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In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually 
need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of a 
SAE occurring to a patient after that patient has ended his/her participation in the study (whether study 
completion or withdrawal), the SAE should be reported by the Investigator to the Dompé/Lexitas 
Pharmacovigilance. Such “post-study cases” should be regarded for expedited reporting purposes as 
though they were study reports. Therefore, a causality assessment and determination of expectedness are 
needed for a decision on whether expedited reporting is required.  
 
8.4.2. 
Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be SAE, 
and shall not be reported as such, but only need to be recorded in the CRF: 
 Hospitalizations planned before entry into the clinical study which is part of the normal treatment 
or monitoring of the studied indication and not associated with any deterioration in condition.  
 Hospitalization for routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition. 
 Hospitalization for treatments, which was elective or pre-planned, for a pre-existing condition that 
is unrelated to the indication under study and did not worsen. 
 Hospitalization for general care not associated with any deterioration in condition.  
 Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
SAEs given above and not resulting in hospital admission.  
In addition, the following situation shall not be considered SAE: 
 
 Trial end points 
 Abnormal lab values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
 
8.4.3. 
Reporting Procedure to IRB/IEC and to Regulatory Authorities 
SUSAR shall be reported to the Regulatory Authority (FDA and non-US concerned Authority as 
applicable) by Dompé as soon as possible and in no event later than: 
 
(a) seven calendar days after becoming aware of the information if the event is fatal or life threatening; 
to be followed by any relevant information within eight days. 
 
(b) fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 


 
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Lexitas Pharma Services, Inc shall follow up on safety information and shall report any relevant updated 
findings as soon as available. 
If the results of an investigation show that an adverse drug reaction not initially determined to be 
reportable is reclassified as reportable, Dompé shall report such reaction in a written safety report as soon 
as possible, but in no event later than 7/15 calendar days after the determination is made. 
In addition, each IRB/IEC/Regulatory Authority and Investigator will receive appropriate periodic safety 
updates as per applicable local requirements and regulations.   
In addition to reporting the SAE to Dompé and Lexitas, the Investigator must also comply with the 
requirements related to the reporting of SAEs to the local IRB which approved the study. The 
requirements of IRBs vary from one IRB to another; however, as a minimum requirement, the 
Investigators must promptly report all suspected unexpected serious adverse reactions (SUSAR) to their 
IRB.  
In line with provisions set forth in 21CFR312, Dompé shall notify all participating Investigators in an 
IND safety report of any suspected adverse reaction that is both serious and unexpected and of potential 
serious risks, from clinical trials or any other source, as soon as possible, but in no case later than:  
 seven calendar days after becoming aware of the information if the event is fatal or life threatening; 
to be followed by any relevant information within eight days.  
 fifteen calendar days after becoming aware of the information if the event is serious but neither fatal 
nor life threatening. 
The Investigators in turn shall notify their local IRB. 
Copies of all correspondence relating to reporting of any SUSARs to the local IRB should be 
maintained in the Investigator’s Files. 
Dompé shall also notify FDA in an IND safety report of potential serious risks, from clinical trials or 
any other source, as soon as possible after Dompé determines that the information qualifies for 
reporting, shall notify of: 
- any suspected adverse reaction that is both serious and unexpected. Dompé must report an adverse 
event as a suspected adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event. 
- findings from other studies that suggest a significant risk in humans exposed to the drug. Such a 
finding would result in a safety-related change in the overall conduct of the clinical investigation. 
- findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug 
- increased rate of occurrence of serious suspected adverse reactions. 
8.4.4. 
Periodical Reporting to Regulatory Authorities  
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety Update 
Report – DSUR) to relevant Regulatory Authorities. 


 
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8.5. 
EXPOSURE TO STUDY PRODUCT DURING PREGNANCY 
Women of childbearing potential are not excluded from the study if adequate birth control methods are 
being utilized. Women of childbearing potential are defined as all women physiologically capable of 
becoming pregnant. Adequate birth control methods are summarized in the protocol’s exclusion criteria. 
Prior to enrolment in the clinical trial, female patients of childbearing potential and their partners must be 
advised of the importance of avoiding pregnancy during the entire course of the study treatment and for 
the 30 days after the study treatment period ends and of the potential risks associated with an unintentional 
pregnancy. During the trial, female patients are to be instructed to contact the Investigator immediately if 
they suspect they might be pregnant. In the same way, male patients who become aware that the partner 
might be pregnant, are to be instructed to contact the Investigator immediately. 
The Investigator must report every pregnancy on a Pregnancy Report Form as soon as possible (within 
24 hours of learning of the pregnancy) to the same contacts specified in Section 8.4.1., even if no AE has 
occurred, and follow it to term. If, however, the pregnancy is associated with an SAE (e.g., if the mother 
is hospitalized for dehydration), in addition to the pregnancy report form, a separate SAE report form 
must be filed as described in Section 8.4.1. with the appropriate serious criterion (e.g., hospitalization) 
indicated on the SAE report form.  
Any pregnancy leads to the immediate exclusion from the trial. Miscarriage, stillbirth, and any 
malformation/disease must be reported as a SAE. 
The pregnant woman (patient or partner) should be followed for pregnancy outcome through delivery or 
termination of the pregnancy. In any pregnancy that progresses to term, the infant should be followed 
until 6 months after birth and any congenital abnormalities/birth defects in the infant should be reported 
as an SAE.  
 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned 
in the CRF, and the patient must be followed up until the resolution of the AE or as instructed by the 
medical monitor. 
8.7. 
OVERDOSE 
Cases of overdose (accidental or intentional) should be reported in the eDC.  Any overdose which results 
in a serious adverse event is to be reported to Dompé and Lexitas Pharmacovigilance and Dompé Medical 
Expert, following the same procedure for SAE, within 24 hours from the Investigator’s knowledge of its 
occurrence. This includes reports related to drug intake through different routes (e.g. ingestion) or with 
suicidal intentions and consequent drug overdose. 
An overdose of OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution is defined as the 
administration of 50% or more additional drops on any given treatment day. 
 
The Investigator shall provide information about symptoms, corrective treatment, and outcome of 
overdose. The Medical Expert should be contacted to discuss corrective treatment, if necessary. 


 
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8.8. 
UNMASKING 
This is a single-arm open-label trial with no provisions for masking Study Product. 


 
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9. 
STATISTICS 
A general description of the statistical methods used to analyze the efficacy and safety data is outlined 
below.  Specific details will be provided in the Statistical Analysis Plan (SAP). 
9.1. 
SAMPLE SIZE 
A sample size of 35 evaluable patients (patients completing 8 weeks of Oxervate™) will achieve a lower 
limit of 95% confidence interval equal to 40% and 54% when the percentage of subjects who experience 
epithelial healing is 58% (at 4-week) and 72% (at 8-week), respectively. 
The sample size calculation was based on previous trial calculations from NGF0212 (REPARO) and 
NGF0214 (US trial) that showed statistical superiority in complete healing after 8 weeks of treatment 
with cenegermin, 72% and 65.5% respectively. Assumption for this target, has been proportion of patients 
achieving complete healing of staining (grade 1 or less on NEI scale) by week 8.  
9.2. 
PATIENT POPULATION 
Screened Population  
The Screened Population will consist of all patients who attended Screening, signed the ICF, and were 
assigned a PID number.  
Analysis Sets 
Full Analysis Set: consist of all patients who receive at least one dose of study drug. 
 
Full Treated Set: consist of all patients who receive all 8 weeks of treatment. 
 
9.3. 
STATISTICAL METHODOLOGY 
9.3.1. 
Demographic and baseline characteristics 
Subject Characteristics and Disposition 
For categorical variables, frequencies and percentages will be presented. Continuous variables will be 
summarized using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). 
Baseline demographic and background variables will be summarized. The number of patients who enroll 
in the study and the number and percentage of patients who complete the study will be presented. The 
frequency and percentage of patients who withdraw or discontinue from the study, along with the reason 
for withdrawal or discontinuation, will also be summarized. 
9.3.2. 
Analysis of efficacy variables 
Analyses for responder outcomes will include percentage of response and exact 95% confidence intervals. 
Analyses of change from baseline and continuous outcomes will include mean and associated asymptotic 
95% confidence intervals.  No formal hypothesis test will be conducted. 


 
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9.3.3. 
Analysis of safety variables 
Adverse events will be coded by preferred term and system organ class using the latest version of the 
Medical Dictionary for Regulatory Activities and will be summarized overall. Adverse events will also 
be summarized by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation 
of study drug will also be summarized. 
9.3.4. 
Missing data (mandatory) 
The percentage of missing data at each visit will be reported to assess possible causes of dropout.  Details 
for missing data imputation will be described in the SAP. 
9.3.5. 
Changes to the statistical plan 
Any deviations from the original statistical plan will be described in the Clinical Study Report. 
 


 
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10. 
ETHICAL CONSIDERATIONS 
10.1 REGULATORY BODY APPROVAL 
Dompé or the CRO or other consultant appointed by Dompé will obtain the necessary approval from the 
Competent Authorities, as needed, prior to initiation of the study. 
The study will not be started until written approval from the relevant Competent Authorities (or no 
objection within the timeframe set by the local regulation, as applicable) has been received by Dompé. 
 
10.2 INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE  
United States  
Approval by the Institutional Review Board (IRB) before the start of the study will be the responsibility 
of the Principal Investigator (PI). A copy of the approval letter will be supplied to the sponsor, along with 
a roster of IRB members or the US Department of Health and Human Services (DHHS) general assurance 
number. During the course of the study, the PI will provide timely and accurate reports to the IRB on the 
progress of the study, at intervals not exceeding 1 year (or as appropriate), and will notify the IRB of 
serious adverse events (SAEs) or other significant safety findings. The study protocol, informed consent 
form (ICF), information sheet advertisements, and amendments (if any) will be approved by the IRBs at 
the study centers in conformance with Code of Federal Regulations (CFR), Title 21, Part 56.  
10.3 ETHICAL CONDUCT OF THE STUDY  
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, October 2013) and ICH Harmonised Tripartite Guideline for Good Clinical 
Practice (ICH-GCP) and any local regulations. 
 
10.4 PATIENT INFORMATION AND CONSENT  
Patients, after being explained the study, will give voluntary and written informed consent before 
participating in any study-related procedures.  
The informed consent statement contains all the elements of informed consent contains all the core 
elements and mandatory statements as defined in the CFR. Signed copies of the ICF and the HIPAA form 
(if not included as part of the ICF) will be given to the patient, and both documents will be placed in the 
PI’s study files. A unique patient identification (PID) number will be assigned according to Section 4.4 
of the protocol at the time the patient signs the ICF.  
10.5 CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. An agreement 
for disclosure will be obtained in writing by the patient and will be included in the ICF. Patient’s data 
collected during the study will be handled in accordance with applicable data protection laws and 
regulations.  


 
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On the CRFs and Daily Study Dosing Diaries, patients will be identified ONLY by the assigned patient 
number. If patient names are included on copies of documents submitted to Lexitas Pharma Services, Inc., 
the names will be obliterated or masked, and the assigned patient number added to the document. 
10.6 COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance contract according to 
national laws for patients/Investigators/Institutions participating in the clinical trial.   
 
In case of questions about medical care, cost for medical care or insurance, patients can talk to their 
Investigator. Contact details will be given in the Patient Informed Consent Document. 
 
 


 
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11 DATA HANDLING AND RECORD KEEPING  
11.1 CASE REPORT FORMS 
All data relating to the study will be recorded on CRFs to be provided by the Lexitas, through the EDC 
system. The PI is responsible for verifying that all data entries in the CRFs are accurate and correct. The 
PI must sign the completed CRF before its submission to the sponsor.  
11.2 DATA MANAGEMENT  
Data collection will involve the use of an EDC system, to which only authorized personnel will have 
access. In addition to periodic monitoring occurring within the system by Dompé/Lexitas Monitors, 
programmatic edit checks will be used to review the data for completeness, logic, and adherence to study 
protocol. As a result of this monitoring and these checks, queries may be electronically issued to the 
study centers and electronically closed by those study centers. The identifying information (assigned 
username, date, and time) for both the originator of the query (if created during the monitoring process) 
and the originator of the data change (if applicable), as well as the PI’s approval of all changes performed 
on his or her patients’ data, will be collected.  
All data collected in the context of this study will be stored and evaluated per regulatory requirements 
and applicable guidelines for electronic records. Also, data will be stored and evaluated in such a way as 
to guarantee patient confidentiality in accordance with the legal stipulations applying to confidentiality 
of data. Study records (e.g., copies of CRFs, regulatory documents) will be retained at the study center, 
along with adequate source documentation, according to FDA and ICH requirements. All study records 
must be available for audit by Dompé; its authorized representatives; and Regulatory Inspection by 
Regulatory Authority.  
The investigator/institution should maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial patients. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should 
be traceable, should not obscure the original entry, and should be explained if necessary, via an audit 
trail. 
 


 
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12 STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013) and ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (ICH-GCP) and any local regulations. 
12.1 MONITORING AND QUALITY ASSURANCE 
During the course of the trial a clinical research associate (CRA) will make routine site visits to review 
protocol compliance, assess Study Product and Study concomitant product accountability, and ensure the 
trial is being conducted according to the pertinent regulatory requirements. The review of the patients’ 
medical records will be performed in a manner that adequately maintains subject confidentiality. Further 
details of the trial monitoring (including medical monitoring) will be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, Clinical Research Organization (CRO) Drug Safety and 
quality assurance, sponsor and or its designees may carry out on-site inspections and/or audits which may 
include source data checks. Therefore, direct access to the original source data will be required for 
inspections and/or audits. All inspections and audits will be carried out with consideration to data 
protection as well as subject confidentiality to the extent that local, state, and federal laws apply. 
12.2 ACCESS TO RECORDS 
The Investigator will allow designated Dompé representatives, including staff from the appointed CRO, 
and regulatory/ethics bodies to have direct access to the source documents to verify the data reported in 
the CRFs. Source documents are the originals of any documents used by the Investigator or 
hospital/institution that allow verification of the existence of the patient and substantiate the integrity of 
the data collected during the trial. 
12.3 AUDIT AND INSPECTION 
The study site may be audited by Dompé or inspected by a regulatory agency on one or more occasions 
The Investigator may be informed in advance of such a visit.  
12.4 PROTOCOL AMENDMENTS 
Any amendment to this protocol will be provided to the PI in writing by Dompé. No protocol amendment 
may be implemented (with the exceptions noted below) before it has been approved by the IRB/IEC and 
the signature page, signed by the PI, has been received by Dompé. If the protocol is amended to eliminate 
or reduce the risk to patients, the amendment may be implemented before IRB/IEC review and approval. 
However, the IRB/EC must be informed in writing of such an amendment, and approval must be obtained 
within reasonable time limits. Deviating from the protocol is permitted only if necessary for the safety or 
clinical management of the patients and must immediately be reported to Dompé US. 
12.5 DISCONTINUATION OF THE STUDY 
Dompé reserves the right to terminate the study in its entirety or at a specific study center at any time on 
the basis of new information regarding safety or efficacy, or if study progress is unsatisfactory, or for 
other valid administrative reasons. 


 
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12.6 PUBLICATIONS 
All data generated in this study will be the property of Dompé. Publication of the results by the PI will be 
subject to mutual agreement between the PI and Dompé US. Data either complete or preliminary cannot 
be published by PI without permission from Dompé. 


 
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13 REFERENCES 
 
1. Mastropasqua, L., et al. Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of 
Corneal Nerves. J Cell Physiol 2017; 232(4):717-724. 
2. Sacchetti, M. and A. Lambiase. Diagnosis and management of neurotrophic keratitis. Clin 
Ophthalmol 2014; 8:571-9. 
3. Versura, P., et al. Neurotrophic keratitis: current challenges and future prospects. Eye Brain 
2018; 10:37-45. 
4. OXERVATE™ (cenegermin-bkbj) ophthalmic solution 0.002% (20 mcg/mL) [US package 
insert]. Dompé U.S. Inc. 2018; Available from: Accessed  
5. Di Zazzo, A., et al. Neurotrophic keratopathy: Pros and cons of current treatments. Ocul Surf 
2019. 
6. Levi-Montalcini, R. The nerve growth factor 35 years later. Science 1987; 237(4819):1154-62. 
7. Sofroniew, M.V., C.L. Howe, and W.C. Mobley. Nerve growth factor signaling, 
neuroprotection, and neural repair. Annu Rev Neurosci 2001; 24:1217-81. 
8. Müller, L.J., et al. Corneal nerves: structure, contents and function. Experimental Eye Research 
2003; 76(5):521-542. 
9. Lambiase, A., et al. Clinical applications of NGF in ocular diseases. Arch Ital Biol 2011; 
149(2):283-92. 
10. Lambiase, A., et al. Nerve growth factor (NGF) reduces and NGF antibody exacerbates retinal 
damage induced in rabbit by experimental ocular hypertension. Graefes Arch Clin Exp 
Ophthalmol 1997; 235(12):780-5. 
11. Sacchetti, M., A. Bruscolini, and A. Lambiase. Cenegermin for the treatment of neurotrophic 
keratitis. Drugs Today (Barc) 2017; 53(11):585-595. 
12. Lambiase, A., et al. Nerve growth factor promotes corneal healing: structural, biochemical, and 
molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 2000; 41(5):1063-9. 
13. Muzi S, C.V., Sornelli F, et al. Nerve Growth Factor in the Developing and Adult Lacrimal 
Glands of Rat With and Without Inherited Retinitis Pigmentosa. Cornea 2010(29):1163-1168. 
14. Bonini, S., et al. Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of 
Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis. Ophthalmology 2018; 
125(9):1332-1343. 
15. Pflugfelder, S.C., et al. Topical Recombinant Human Nerve Growth Factor (Cenegermin) for 
Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial. 
Ophthalmology 2019. 
 


 
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14 APPENDICES 
 
 






 
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14.3 APPENDIX 3- OXERVATE™ 0.002% (20 MCG/ML) CENEGERMIN-BKBJ OPHTHALMIC 
SOLUTION PACKAGE INSERT 
 
PATIENT INFORMATION 
OXERVATE (ox'-er-vayt) 
(cenegermin-bkbj) 
ophthalmic solution, 
for topical ophthalmic use 
What is OXERVATE? 
OXERVATE is a prescription eye drop solution used to treat a condition called neurotrophic keratitis. 
OXERVATE is safe and effective in children two years of age and older. 
Before you use OXERVATE, tell your doctor about all of your medical conditions, including if 
you: 
 have an infection in your eye. If you get an eye infection while using OXERVATE, talk your doctor 
right away. 
 are using any other eye drops. 
 wear contact lenses. 
 are pregnant or plan to become pregnant. It is not known if OXERVATE will harm your unborn baby. 
 are breastfeeding or plan to breastfeed. It is not known if OXERVATE passes into your breast milk. 
Talk to your doctor about the best way to feed your baby if you use OXERVATE. 
Tell your doctor about all the medicines you take, including prescription and over-the counter 
medicines, vitamins, and herbal supplements. 
How should I use OXERVATE? 
 See the complete Instructions for Use at the end of this Patient Information leaflet for detailed 
instructions about the right way to use OXERVATE.
 Use OXERVATE exactly as your doctor tells you.
 Use 1 drop of OXERVATE in the affected eye or both eyes if needed, 6 times each day, about 2 
hours apart starting in the morning. Continue your treatment for 8 weeks.
 If you use any other eye drops, wait at least 15 minutes before or after using OXERVATE. This 
will help to avoid one eye drop diluting the other eye drop.
 If you also use an eye ointment or gel or an eye drop that is thick, use OXERVATE first, and then 
wait at least 15 minutes before using the other eye ointment, gel, or drops.
 If you wear contact lenses in your affected eye or both eyes remove them before using OXERVATE 
and wait 15 minutes after using OXERVATE before reinserting them.
 If you miss a dose of OXERVATE, take your next dose at your scheduled time. Do not take an extra 
dose to make up for a missed dose.
 Do not use other eye medicines without talking to your doctor.
 Talk to your doctor first before you stop using OXERVATE.
 If you have any questions about how to use OXERVATE, ask your doctor or pharmacist.
What should I avoid while using OXERVATE? 
Your vision may be blurred for a short time after using OXERVATE. If this happens, wait until your 
vision clears before you drive or use machines. 
What are the possible side effects of OXERVATE? 
The most common side effect of OXERVATE is eye pain, enlarged blood vessels in the white of the 
eyes (ocular hyperemia), swelling (inflammation) of the eye, and increase of tears (increased 
lacrimation). 
Tell your doctor if you have any side effects that bother you. These are not all the possible side effects 
of OXERVATE. Call your doctor for medical advice about side effects. You may report side effects to 
FDA at 1-800-FDA-1088. 


 
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General information about the safe and effective use of OXERVATE. 
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information 
leaflet. Do not use OXERVATE for a condition for which it was not prescribed. Do not give 
OXERVATE to other people, even if they have the same symptoms you have. It may harm them. 


 
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You can ask your pharmacist or doctor for information about OXERVATE that is written for health 
professional. 
What are the ingredients in OXERVATE? 
Active ingredient: cenegermin-bkbj 
Inactive ingredients: disodium hydrogen phosphate anhydrous, hydroxypropylmethyl cellulose, 
L-methionine, mannitol, polyethylene glycol 6000, sodium dihydrogen phosphate dihydrate, trehalose 
dihydrate, Water for Injection, USP, and hydrochloric acid and/or sodium hydroxide to adjust pH. 
Manufactured by: 
Dompé farmaceutici S.p.A. 
Via Campo di Pile 
67100 L’Aquila, Italy 
U.S. License No. 2074 
Manufactured for: Dompé U.S. Inc. 
One Marina Park Drive - Ste. 1410, Boston, MA 02210 
For more information, go to www.oxervate.com or call 1-833-366-7387. 
This Patient Information has been approved by the U.S. Food and Drug Administration 
Revised or Issued: October 2019 
 
DocuSign Envelope ID: 748C4B97-61BD-4B17-A30C-883AA45B1F20


 
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14.4 APPENDIX 4-FLUORESCEIN STAINING NEI / INDUSTRY WORKSHOP SCALE AND 
MACKIE CLASSIFICATION 
 
The 5 areas of the cornea will be scored by the investigator according to the following scoring 
system and the total score will also be calculated. NOTE: The TBUT and the FCS may be 
performed right eye then left eye or staggered with the TBUT for the left eye being done 
during the waiting period before completing the FCS for the right eye. 
https://www.aao.org/image/neiindustry-grading-system 
 
Area Key: 1=Central, 2=Superior, 3=Temporal, 4=Nasal,5=Inferior 
 
DocuSign Envelope ID: 748C4B97-61BD-4B17-A30C-883AA45B1F20


 
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DocuSign Envelope ID: 748C4B97-61BD-4B17-A30C-883AA45B1F20

SAP_003.pdf: 




 
 
Statistical Analysis Plan 
 
     Protocol: NGF0120 
   
Confidential  
Final Version 1.0, 2021-05-20 
 
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AMEMDMENT HISTORY ..................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 6 
1 INTRODUCTION ............................................................................................. 7 
1.1 Study Objectives ..................................................................................................... 7 
1.2 Study Design .......................................................................................................... 7 
1.3 Criteria for Evaluations Defined in Protocol ............................................................. 9 
1.3.1 
Demographics and Background Characteristics ................................................................. 9 
1.3.2 
Treatment of Subjects ......................................................................................................... 9 
1.3.3 
Efficacy Assessments ........................................................................................................ 10 
1.3.4 
Safety Assessments .......................................................................................................... 11 
1.4 Study Data ............................................................................................................ 12 
2 GENERAL ANALYSIS DEFINITIONS .......................................................... 12 
2.1 Study Eye ............................................................................................................. 12 
2.2 Treatment Group .................................................................................................. 13 
2.3 Study Period, Visit, and Day ................................................................................. 13 
2.4 Definition of Baseline ............................................................................................ 13 
2.5 Out of Window and Unscheduled Visits ................................................................ 13 
2.6 Analysis Populations ............................................................................................. 13 
2.6.1 
Screened Population ......................................................................................................... 13 
2.6.2 
Enrolled Population ........................................................................................................... 13 
2.6.3 
Full Analysis Set ................................................................................................................ 13 
2.6.4 
Full Treated Set ................................................................................................................. 14 
2.7 Unit of Analysis ..................................................................................................... 14 
2.8 Definition of Subgroups ......................................................................................... 14 
2.9 Descriptive Summaries ......................................................................................... 14 
2.10 Type 1 Error Control for Multiple Tests.................................................................. 14 
2.11 Handling of Missing Data ...................................................................................... 14 
3 SUBJECT INFORMATION ............................................................................ 15 
3.1 Disposition Information ......................................................................................... 15 
3.2 Study Visits ........................................................................................................... 15 
3.3 Demographics Characteristics .............................................................................. 16 
3.4 Medical and Ocular History and Surgical Procedures ........................................... 16 
3.5 Pregnancy Status ................................................................................................. 16 
3.6 Protocol Deviations ............................................................................................... 16 
4 TREATMENTS AND MEDICATIONS ........................................................... 16 
4.1 Prior Medications .................................................................................................. 16 
4.2 Concomitant Medications ...................................................................................... 16 
4.3 Use of Artificial Tears ............................................................................................ 17 
4.4 Extent of Exposure to Study Product .................................................................... 17 
4.5 Treatment Compliance of Study Product............................................................... 17 
5 ANALYSIS OF EFFICACY ............................................................................ 17 
5.1 Primary Efficacy Variable ...................................................................................... 17 
5.2 Secondary Efficacy Variables ............................................................................... 18 
5.3 Exploratory Efficacy Variables .............................................................................. 26 
5.4 Methods of Efficacy Analysis ................................................................................ 26 
6 ANALYSIS OF SAFETY ............................................................................... 27 


 
 
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6.1 Adverse Events ..................................................................................................... 27 
6.2 Intraocular Pressure.............................................................................................. 28 
6.3 Slit Lamp Examination .......................................................................................... 28 
6.4 External Ocular Examination ................................................................................. 28 
7 DETERMINATION OF SAMPLE SIZE .......................................................... 28 
8 PLANNED INTERIM ANALYSIS................................................................... 28 
9 CHANGES FROM PROTOCOL .................................................................... 28 
10 REFERENCES ............................................................................................ 29 
Appendix 1: Schedule of Evaluations (from Protocol) .................................. 30 
Appendix 2 Shells for Tables, Listing, and Figures ....................................... 31 
 


 
 
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AMEMDMENT HISTORY 
None 


 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
Adverse event 
AT 
Artificial tears 
BCDVA 
Best-corrected distance visual acuity 
CSR 
Clinical study report 
eCRF 
Electronic case report form 
ENRL 
Enrolled Population 
FAS 
Full Analysis Set 
FCS 
Fluorescein Corneal Staining 
FTS 
Full Treated Set 
ICF 
Informed consent form 
IDEEL 
Impact of Dry Eye on Everyday Life 
IOP 
Intraocular Pressure 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEI 
National Eye Institute 
NK 
Neurotrophic Keratitis 
OCT 
Optical Coherence Tomography 
OD 
Right eye 
OS 
Left eye 
OU 
Both eyes 
PED 
Persistent Epithelial Defect 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAF 
Safety Population 
SAP 
Statistical analysis plan 
SCRN 
Screened Population 
SD 
Standard deviation 
SOC 
System Organ Class 
SPK 
Superficial punctate keratitis/keratopathy 
TEAE 
Treatment-emergent AEs 
TFBUT 
Tear film break-up time 
TFLs 
Tables, Figures, and Listings 
WHO-DD 
World Health Organization-Drug Dictionary 
 


 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the final statistical analysis for 
subject information, safety data, and efficacy data to be performed for the study 
entitled “An 8-week, multicenter, open label, prospective study with 24 weeks of 
follow-up to evaluate safety and efficacy of OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution in patients with Stage 1 Neurotrophic 
Keratitis (NK)” (Version No.0.4–FINAL 04May2021). Mock shells are also 
produced as a separate working document to facilitate programming of Tables, 
Figures, and Listings (TFLs) according to finalized SAP. The SAP is to be 
interpreted in conjunction with the protocol, and supersedes the statistical 
considerations identified in the protocol. If the final clinical study report (CSR) 
contains changes to any planned statistical analyses, the justification for any 
such differences will be fully documented in the CSR. 
1.1 Study Objectives 
The primary objective of this study is to evaluate the safety and efficacy of 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution 
administered 6 times daily for 8 weeks on the ocular surface, visual function and 
quality of life in patients with Stage 1 NK. 
The secondary objective is to evaluate patients who heal at week eight and 
remain healed throughout the follow-up period. In addition, the study aims to 
evaluate the percentage of subjects that achieve an improvement in corneal 
sensitivity as measured by the Cochet-Bonnet aesthesiometer at 4 and 8 weeks, 
and by the last visit at week 32. 
The exploratory objectives are to evaluate the change from baseline to weeks 4 
& 8 in Schirmer I and the Tear Film Break-Up Time (TFBUT). 
The additional objectives (site-specific) are to evaluate the change from baseline 
at week 8 and week 24 in confocal microscopy and anterior segment Optical 
Coherence Tomography (OCT). 
1.2 Study Design 
This clinical study will be a multi-center, open label, prospective study of 8 weeks 
of treatment with 24 weeks of follow-up to evaluate the safety and efficacy of 
OXERVATE™ 0.002% (20 mcg/mL) cenegermin-bkbj ophthalmic solution 
administered as one drop in the affected eye(s), 6 times per day at 2-hour 
intervals, for eight weeks in patients with Stage 1 NK. The study population will 
comprise of both female and male subjects. A total of 35 evaluable subjects 
(those patients completing 8 weeks of Oxervate™) aged ≥ 18 years will be 
enrolled in approximately 5 sites within the United States. 
All patients will attend the following clinic visits in the following sequence: 
• Screening (Visit 1/Day -14) 
• Baseline and First Study Product Pick-Up (Visit 2/Day 0) 


 
 
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• Product Pick-Up (Visit 3/Week 2) 
• Treatment Assessment and Study Product Pick-Up (Visit 4/Week 4) 
• Product Pick-Up (Visit 5/Week 6) 
• End of 8-week Treatment (Visit 6/Week 8) 
• Follow-Up and Final Study Visit (Visit 7/Week 32) 
The trial structure for subjects is shown in Figure 1. 
 
The study will be a total of 34 weeks in duration: a screening (washout) period of 
2 weeks, followed by 8 weeks of treatment and a 24-week follow-up period. At 
the end of the screening period (at Visit 2), patients meeting the entry criteria for 
this study will be assigned to treatment with OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution which will be known as Study Product 
beginning the morning following Visit 2. On Day 0 (baseline visit-Visit 2) and at 
Visit 3, Visit 4, and Visit 5, the study personnel will give to the Subject the b-
weekly kit containing 2 weeks of the study product and delivery kits. 
Following the completion of the treatment period, patients will be followed up for 
an additional 24 weeks (for patients healed and non-healed [and not meeting 
discontinuation criteria] at Week 8) and will be evaluated at the end of the follow-
up period. At the investigator’s discretion, the subject may be seen for an 
Unscheduled Visit to evaluate for safety. Patients who prematurely discontinue 
for whatever reason will not be followed post discontinuation and should have 
Visit 6 assessments completed. 
Ocular assessments should be conducted by the same assessor throughout a 
subject’s participation period to reduce observer variability. All efficacy 


 
 
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assessments will be carried out consistently either in the morning or the 
afternoon (preferred time window is ±2 hours) throughout all study visits to 
minimize intra-subject diurnal variability. The detailed schedule of evaluations is 
included in the Appendix 1. 
1.3 Criteria for Evaluations Defined in Protocol 
1.3.1 Demographics and Background Characteristics 
Demographic information including date of birth, gender, ethnicity, race, as well 
as iris color and date of informed consent will be recorded.  
Medical history and ocular medical history will be documented and recorded at 
screening. 
1.3.2 Treatment of Subjects 
1.3.2.1 Concomitant Medications 
All medications (including over-the-counter drugs, systemic medications, herbal 
products, vitamins, and antacids) should be documented at screening. 
Additionally, all medications taken within 14 days of study treatment Visit 2 and 
throughout the study will be clearly documented on the Concomitant Medications 
eCRF page. Medication entries should be specific to product name (if a 
combination drug product) and spelled correctly. The dose, unit, frequency, route 
of administration, start date, discontinuation date, and indication should also be 
recorded. For medications administered only one time, the frequency column 
may reflect "once". 
All medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD).  
1.3.2.2 Rescue Therapy 
Commercially available preservative free artificial tears (AT) provided by Sponsor 
are not allowed during the treatment period. Per the investigators discretion if the 
patient requires rescue therapy during the 8-week treatment period then they can 
receive artificial tears provided by the sponsor up to four times per day. The 
frequency of rescue therapy must be documented in the patient's diary.  
During the 24 weeks post treatment, for patients completely healed, no treatment 
is allowed except for commercially available AT provided by the Sponsor, 
administered at the physician’s discretion. The use of AT will be tracked via a 
daily dosing diary. Patients not completely healed and who don’t meet criteria for 
premature discontinuation will also be followed up but any treatment is allowed at 
the discretion of the physician, with the exception of additional Oxervate™. 
1.3.2.3 Study Drug Administration 
The subject will receive a total of 56 OXERVATE™ 0.002% (20 mcg/mL) 
cenegermin-bkbj ophthalmic solution vials per treated eye over the 8-week 
duration of the study product treatment, 1 OXERVATE™ 0.002% (20 mcg/mL) 


 
 
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cenegermin-bkbj ophthalmic solution vial to be used per day. The patient will pick 
up Study Product from the Investigator’s office and bring back used vials for 
reconciliation at the subsequent study visit. Patients will be instructed to self-
administer the study product one drop in the affected eye(s) six times a day at 2 
hour intervals starting on the day after Visit 2 (Day 0-Baseline and First Study 
product Pick Up) of the treatment period. On Day 1, the patient will start the first 
dose. The patient should not start therapy on the same day as Day 0/Visit 2. The 
Study Product will be dosed one drop (- 0.70 μg/35 μl of cenegermin-bkbj 
0.002% solution) 6 times a day at 2-hour intervals in the affected eye(s) for 8 
weeks of treatment. 
1.3.2.4 Study Drug Compliance  
On Day 0 (baseline visit-Visit 2) and at Visit 3, Visit 4, and Visit 5, the study 
personnel will give to the Subject the biweekly kit containing two weeks of the 
study product and delivery kits. At Visits 3, 4, 5 and 6, patients will return the 
used or unused study boxes/vials to the clinic in the original carton. All Study 
Product returned by patients should be inventoried same day of return. Inventory 
will take place at Visits 3, 4, 5 and 6. Any discrepancies and/or deficiencies in 
study drug accountability must be recorded along with an explanation in the 
appropriate accountability log. 
1.3.3 Efficacy Assessments 
1.3.3.1 Fluorescein corneal staining  
Following the instillation of fluorescein in the qualifying eye(s) grade (density) of 
the SPK will be determined at Visit 1, 2, 4, 6, 7 using the NEI (National Eye 
Institute [NEI]/Industry Workshop 0-15) scale of 0 to 3 for each of the five areas: 
Zone 1 Central, Zone 2 Superior, Zone 3 Temporal, Zone 4 Nasal, and Zone 5 
Inferior.  
Epithelial healing, defined as Grade 1 or absence of staining (Grade 0) in a 
previously qualifying zone, will be determined by the investigators and recorded 
on eCRF at Visit 4, 6, and 7.  
1.3.3.2 Corneal Sensitivity Testing 
Corneal Sensitivity will be measured (in cm) using a Cochet Bonnet 
aesthesiometer at Visit 1, 2, 4, 6, 7 
1.3.3.3 Best Corrected Distance Visual Acuity (BCDVA) 
The logarithm of the minimal angle of resolution (logMAR) visual acuity score 
(ranged from -0.3 to 1) and Snellen score (ranged from 20/10 – 20/200) will be 
recorded at Visit 1, 2, 4, 6, 7. 
1.3.3.4 Tear Film Break-Up Time (TFBUT) 
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1.3.3.5 Schirmer Test (w/o Anesthesia) 
Unanesthetized Schirmer’s test measures the amount of wetting (mm) at Visit 2, 
4, 6, 7. 
1.3.3.6 Impact of Dry Eye on Everyday Life (IDEEL) 
This 57-item questionnaire assesses dry eye impact at Visit 2, 4, 6, 7, and 
constitutes following 3 modules:  
• Dry eye Quality of Life (27 questions) comprising three sections: “Daily 
activities”,  “Feelings”  and “Work”. 
• Dry eye Treatment satisfaction & Bother (10 questions) comprising two 
sections: “Treatment – In general” and “Treatment- Eye drop”. 
• Dry eye Symptom bother (20 questions). 
1.3.3.7 EQ-5D-5L 
The EQ-5D-5L is a standardized measure of health status developed by the 
EuroQol Group in order to provide a simple, generic measure of health for clinical 
and economic appraisal (Herdman et. al. 2011). This self-administered 
questionnaire consists of five dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) in a scale of 1 (no problems) to 5 
(extreme problems) with high score favoring worse as well as the health today 
score in a scale of 0 (the worst health you can imagine) to 100 (the best health 
you can imagine) at Visit 2, 4, 6, 7. 
1.3.3.8 Anterior Segment Optical Coherence Tomography (OCT) (selected sites) 
Anterior segment OCT will be performed at selected sites at Visit 2, 6, 7 to 
assess epithelial thickness (uM) of central, superior, temporal, nasal, and inferior 
zones; Stromal Thickness (μM) in the NEI Central Zone, presence/absence of 
Epithelial surface irregularities, Persistent Epithelial Defect (PED), Scarring of 
Stroma, Stromal Thinning, Descemet's Membrane Folds, and Corneal Ulceration  
1.3.3.9 Confocal microscopy (selected sites) 
Confocal microscopy will be performed at selected sites at Visit 2, 6, 7. Structural 
nerve regeneration (density, length, nerve density, tortuosity) will be assessed by 
a reading center to be determined. 
1.3.4 Safety Assessments 
1.3.4.1 Adverse events  
Adverse events (AEs) will be collected and recorded for any untoward event that 
occurs in a patient from the time he or she signs the ICF for the trial until 24 
weeks after the last dose of Study Product. Thus, any untoward medical 
occurrences or unfavorable and unintended signs, symptoms, or diseases that 
occur in the pretreatment, treatment, or post treatment period are to be 
considered AEs and/or SAEs, and consequently recorded and reported as such. 
Should a non-serious AE become serious, the Investigator will then follow the 
same reporting procedures as for SAEs. Each AE will be recorded for duration 


 
 
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(start and stop dates), severity, relationship to the study drug, action(s) taken, 
outcome. 
1.3.4.2 Intraocular Pressure 
Intraocular Pressure (IOP) measurements (mmHg) will be performed by 
Goldmann applanation tonometry with a single measurement at visit 1, 2, 6, 7.  
1.3.4.3 Slit Lamp Examination 
Slit Lamp Examination will be performed to assess lashes, eyelids, conjunctiva, 
cornea, lens, sclera, iris, and anterior chamber at visit 1, 2, 4, 6, 7 based on 
following categories: Normal, Abnormal Non-Clinically Significant, Abnormal 
Clinically Significant.  
1.3.4.4 External Ocular Examination 
The motility of the extraocular muscles and the appearance and function of the 
eyelids will be assessed at Visit 1, 2, 4, 6, 7, and recorded as: Normal, Abnormal 
Non-Clinically Significant, Abnormal Clinically Significant. 
 
1.4 Study Data 
The study data to be analyzed include all clinical data captured by eCRF, as well 
as external data per data transfer agreements. The eCRF database will be 
locked for the final analyses.  
2 
GENERAL ANALYSIS DEFINITIONS 
All analysis dataset preparations and statistical analyses will be performed using 
SAS® version 9.4 (SAS/STAT 15.1) or higher. Listings for CSR Appendix 16.2 will 
include, as a minimum, all the subject data points to be used for analyses. Data 
listings will be provided for all subjects with data available. 
2.1 Study Eye 
Based on the protocol, the study eye is the eye at Visit 2 having Grade 3 FCS 
per the NEI scale in the central zone and a decreased corneal sensitivity (≤ 4 
cm using the Cochet-Bonnet aesthesiometer) in the central zone at both Visit 1 
and Visit 2. If both eyes have a qualifying central zone meeting FCS and corneal 
sensitivity requirements at both Visit 1 and Visit 2, the right eye will be selected 
as study eye. If both eyes meet the FCS and corneal sensitivity requirements in 
the central zone, the subject will be treated bilaterally. If only one eye qualifies, 
but the contralateral eye has FCS in the central zone ≥2 on NEI scale and the 
Investigator feels that both eyes would benefit from treatment (i.e. the qualifying 
eye is abnormal, but does not meet criteria for study) both eyes may be treated 
with study product. Data will be collected and recorded in the eCRF for both eyes 
throughout the study. If there is only one qualifying eye/one study eye, only one 
eye will be treated; however, both eyes will be evaluated, and data will be 
collected for both eyes. 


 
 
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2.2 Treatment Group 
All the analyses will be conducted based on a single treatment group, which is 
labelled as “cenegermin-bkbj 0.002%”.  
2.3 Study Period, Visit, and Day  
The overall study consists of initial Screening, a 14-day Washout Period, an 8-
week Treatment Period, and a 24-week Follow-up Period.  
A reference date refers to the date of the first study product administration. All 
safety and efficacy assessments at all visits will be assigned a day relative to this 
date. The relative day will be defined as: visit date – reference date + 1 for visits 
on or after the reference date, and visit date – reference date for visits before the 
reference date.  
2.4 Definition of Baseline 
In general, the baseline is defined as the last assessment before the first study 
product administration unless specifically stated otherwise. Ocular 
measurements will use the most recent measurement for each eye. 
2.5 Out of Window and Unscheduled Visits 
All scheduled assessments after first administration of randomized study product 
will be used. The protocol defined windows for scheduled visits will not be used 
in the analyses by visit.  Data will be assigned to the scheduled visit closer in 
time to the scheduled visit. Unscheduled visit data will only be used in an 
analysis if there is no other available data closer in time to a scheduled visit. Post 
first dose unscheduled assessments will be taken into account for worst-case 
determination as applicable. All unscheduled visit data will be included in data 
listings. 
2.6 Analysis Populations 
A summary table of number (%) of patients in each analysis population/set will be 
provided.   
2.6.1 Screened Population 
The Screened Population will consist of all patients who attended Screening, 
signed the informed consent form, and were assigned a patient identification 
number.  
2.6.2 Enrolled Population 
The Enrolled Population (ENRL) will consist of all patients who signed the 
informed consent form and attended Visit 2.  
2.6.3 Full Analysis Set 
The full analysis set (FAS) will include all enrolled patients who received at least 
one dose of study drug.  The FAS will be used also for safety analyses.  


 
 
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2.6.4 Full Treated Set 
The full treated set (FTS) will include all enrolled patients who received treatment 
of study drug through Visit 6.  
2.7 Unit of Analysis 
In general, the unit of analysis will be study eye (affected eye) for eye-level 
summary, and subject for subject-level summary. Data for both eyes will be 
presented in the data listings. 
2.8 Definition of Subgroups 
No subgroup analyses are planned. 
2.9 Descriptive Summaries 
Summary statistics and statistical analyses will generally be performed only for 
subjects included in the relevant analysis population. For the calculation of 
summary statistics and statistical analysis, unrounded data will be used. For 
endpoints that are continuous in nature: number of observations, mean, median, 
minimum and maximum, and standard deviation (SD) values will be presented as 
descriptive statistics summary for both observed values and change from 
baseline values at each scheduled visit if applicable. For endpoints that are 
categorical in nature: frequency counts and percentages will be presented as 
descriptive statistics summary at each scheduled visit if applicable.  
The number of decimal places to display for calculated data will be determined 
by the original scale of the data. Means and medians will be reported with one (1) 
additional decimal place. Standard deviation will be reported with two (2) 
additional decimal places. Minimum and maximum will be reported with the same 
number of significant digits as the method of capture.  
2.10 Type 1 Error Control for Multiple Tests 
Not applicable. This is an exploratory, hypothesis generating study. All efficacy 
analyses are considered exploratory. 
2.11 Handling of Missing Data 
The primary efficacy analysis will be based on observed cases (i.e. no missing 
data imputation). Sensitivity analyses will be performed using various missing 
data imputation approaches as described in Section 5.1. 
All analyses unless specified will be conducted on an as observed case basis, 
that is, no further imputation of missing data will be carried out unless expressly 
stated otherwise. 
Imputation for Missing Concomitant Medication and AE Start and Stop 
Days: 
Missing and/or incomplete dates for concomitant medications and AEs will be 
imputed for calculating Start/Onset Day and Stop Day only. The Start/Onset Day 


 
 
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and Stop Day may be used for calculating prior or concomitant medications or 
calculating treatment emergent AEs. Missing and/or incomplete dates will be 
imputed in a manner that assumes the worst case scenario (i.e. Start/Onset as 
close as possible to the First Study Treatment Administration and stopped such 
that it assumed to have lasted for the longest possible duration, taking into 
account that the Start/Onset date should not be after the Stop date). 
Imputation for missing Stop Date: 
• For a completely missing stop year (regardless of day or month) the 
medication/AE will be assumed to be ongoing. 
• For a missing stop month (and a medication/AE that is not ‘Ongoing’) the 
medication/AE will be assumed to have ended the last available month of 
that year. 
• For a missing stop day (and a medication/AE that is not ‘Ongoing’) the 
medication/AE will be assumed to have ended on the last day of the 
month if the month is available. 
Imputation for missing Start/Onset Date: 
• For a completely missing Start/Onset date (day, month and year), the 
Start Day of medication/AE will be considered pre-treatment (i.e. prior) if 
the stop date or partial stop date concludes the medication/AE was 
stopped before the first administration of the study product. In all other 
instances (i.e. inconclusive stop date or Ongoing medication/AE) the Start 
Day of medication/AE will be assumed to have started at the date of the 
first administration of the study product (i.e. assumed to be concomitant or 
treatment emergent as is applicable). 
• For a missing start/onset month the medication/AE will be assumed to 
have started in January of that year, or at the date of first administration of 
the study product if the start/onset year was the same as the year of first 
administration of the study product. 
• For a missing start/onset day the medication/AE will be assumed to have 
started on the first day of the month, or at the date of first administration of 
the study product and the year was the same as the Randomization month 
and year. 
 
3 
SUBJECT INFORMATION 
In general, all subject information will be summarized for the FAS Population, 
unless stated otherwise. 
3.1 Disposition Information  
Summaries will be provided for number and percentage of completed or 
discontinued study with the reasons of discontinuation as collected on eCRF. 
3.2 Study Visits 


 
 
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The number and percentage of subjects completing each scheduled visit will be 
tabulated.  
3.3 Demographics Characteristics  
Descriptive statistics or frequency tabulation will be provided for age, gender, 
race, and ethnicity. 
3.4 Medical and Ocular History and Surgical Procedures 
A summary table will be prepared for the medical history/surgical procedure data, 
and one for ocular history/surgical procedure data. Conditions will be categorized 
according to MedDRA-coded terms. This table will indicate the number and 
percentage of subjects who presented with previous history overall and by 
system organ class (SOC) and preferred term (PT).  SOC will be sorted 
alphabetically and PT within each SOC will be sorted by overall descending order 
of frequency. 
The initial diagnosis of neurotrophic keratitis/keratopathy will be included in a 
listing. 
3.5 Pregnancy Status 
The data for urine pregnancy testing will be presented in a listing, for female 
subjects with childbearing potential only.  
3.6 Protocol Deviations  
All reported protocol deviations and determined exclusions from any analysis 
population(s) will be documented and included in the CSR. All reported protocol 
deviations and inclusion or exclusion exceptions will be included in a listing.   
4 
TREATMENTS AND MEDICATIONS 
In general, all treatment parameters will be summarized for the Full Analysis Set, 
unless stated otherwise. All reported medications will be coded using World 
Health Organization-Drug Dictionary (WHO-DD). For summary of medications, 
the coded generic medication name (Preferred Term) will be sorted by overall 
descending order of frequency.  
4.1 Prior Medications 
Prior medications are medications that discontinued prior to receiving the first 
administration of the study product at Day 1 based on imputed stop day. 
Summary tables will be prepared for the reported use of all prior medications by 
generic name and location (ocular vs non-ocular).  
4.2 Concomitant Medications 
Concomitant medications include all medications that a subject used during the 
study on or after the first administration of the study product at Day 1. Summary 
tables will be prepared for the reported use of all concomitant medications by 


 
 
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generic name and location (ocular vs non-ocular), and further classified as On 
Treatment Period (medications started between the day of first administration of 
the study product and the day of last administration of the study product), and On 
Follow-up Period (medications started after the day of last administration of the 
study product). 
4.3 Use of Artificial Tears 
Use of artificial tears during the washout period is calculated as days on the use 
of artificial tears, defined as one plus the difference in days between date of last 
instillation of artificial tears and the date of first instillation of artificial tears during 
the washout period. Use of artificial tears will be summarized by descriptive 
statistics.  
4.4 Extent of Exposure to Study Product 
Extent of exposure to study product is calculated as days on therapy, defined as 
one plus the difference in days between date of last instillation of study 
medication and the date of first instillation of study medication. For subjects for 
whom the date of last dose is unknown, extent of exposure will be calculated 
based on the date of last contact.  Extent of exposure to study product will be 
summarized using descriptive statistics.  
4.5 Treatment Compliance of Study Product 
The overall treatment compliance of study product in the treatment period is 
calculated as: 100 × The total number of doses / (The total number of days of 
exposure to study product × 6), where the total number of doses is summed from 
numbers of daily doses recorded on the Study Product Diary. Overall compliance 
in the treatment period is categorized as <80%, 80-120%, >120%. 
5 
ANALYSIS OF EFFICACY 
5.1 Primary Efficacy Variable 
The primary efficacy variable is the achievement of epithelial healing at Visit 
6/Week 8, which is defined as Grade 1 or absence of staining (Grade 0) in the 
central qualifying zone of study eye via FCS (per NEI scale).  The primary 
efficacy variable will be summarized as a binary goal attainment variable 
(Yes/No).  
The primary analysis will be based on observed cases (i.e. no missing data 
imputation). As a sensitivity analysis, the last post baseline observation prior to 
Week 8 will be carried forward for imputing missing data at Week 8. In addition 
the worst post baseline observation prior to Week 8 will be carried forward for 
imputing missing data at Week 8 and patients who took any rescue medication 
prior to Week 8 will be considered as a treatment failure (not epithelial healed) at 
Week 8. 


 
 
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All summaries and analyses for the primary efficacy variable will be presented for 
both FAS and FTS populations. 
5.2 Secondary Efficacy Variables 
All the analyses of secondary efficacy variables will be performed based on the 
observed cases in the FAS population. No missing data imputation will be 
considered. 
• Percentage of patients who experienced epithelial healing at 4 weeks 
The patients who experienced epithelial healing at Visit 4/Week 4 will be 
determined for study eye similarly as the primary efficacy variable. It will be 
summarized as a binary goal attainment variable (Yes/No). 
• Percentage of patients who achieved epithelial healing at Week 8 and 
remained healed throughout the follow-up period 
The patients who achieved epithelial healing at Week 8 and remained healed 
throughout the follow-up period will be determined for study eye at Visit 7/Week 
32 similarly as the primary efficacy variable. It will be summarized as a binary 
goal attainment variable (Yes/No) based on the subset of patients who achieved 
epithelial healing at Week 8, as well as based on the FTS. 
• Percentage of patients who experienced complete healing at Week 4 and 8 
The patients who experienced complete healing at Week 4 and 8 will be 
determined for study eye by the investigator and recorded on eCRF. The 
complete healing is defined as Grade ≤ 1 in the central qualifying zone of study 
eye via FCS (per NEI scale) and no persistent staining in the non-qualifying 
zones (excluding the superior zone) defined as the absence (Grade 0) of 
pathological staining via corneal photography. It will be summarized as a binary 
goal attainment variable (Yes/No). 
• Percentage of patients who achieved complete healing at Week 8 and 
remained completely healed throughout the follow-up period 
The patients who achieved complete healing at Week 8 and remained healed 
throughout the follow-up period will be determined for study eye at Visit 7/Week 
32 by the investigator and recorded on eCRF. It will be summarized as a binary 
goal attainment variable (Yes/No) based on the subset of patients who achieved 
complete healing at Week 8, as well as based on the FTS. 
• Mean change in corneal sensitivity from baseline at 4, 8, and 32 weeks  
The corneal sensitivity (cm) in the NEI zone of the study eye as measured by the 
Cochet-Bonnet aesthesiometer will be summarized as a continuous variable. 
• Percentage of patients that achieve an improvement in corneal sensitivity at 
4, 8, and 32 weeks  


 
 
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The improvement in corneal sensitivity, defined as change from baseline > 0 (cm) 
of the study eye, will be summarized as a binary goal attainment variable 
(Yes/No). 
• Schirmer I change from baseline to weeks 4, 8, and week 32 
The Schirmer tear test result (mm) in the study eye will be summarized as a 
continuous variable. 
• TFBUT change from baseline to weeks 4, 8, and week 32 
The average TFBUT result (sec) of two repeat measurements in the study eye 
will be summarized as a continuous variable. 
• Mean change in BCDVA from baseline to Week 4, 8, and week 32 
The logMAR visual acuity score in the study eye will be summarized as a 
continuous variable. 
• Percentage of patients that achieve a 15-letter gain in BCDVA at 4 and 8 
weeks. 
The patients that achieve a 15-letter gain in BCDVA at 4 and 8 weeks will be 
determined based on Week 4 or 8 logMAR – Baseline logMAR  ≤ -0.3. It will be 
analyzed using a binary goal attainment variable (Yes/No).  
• IDEEL change from baseline at week 4, 8, and week 32 
Subscores will be derived for the following modules, and will be calculated only if 
at least 50% of the items of the dimension are completed; otherwise, the scores 
are missing.  
Module 1: 
 
Dry eye impact on daily life (27 questions) comprising 3 QoL domains: 1.a “Daily 
activities limitations”, 1.b “Emotional well being” and 1.c “Work limitations”. 26 
questions will be considered as part of one of these 3 domains. Question 22 will 
not be considered part of a domain. 
 
1.a: Daily Activities 
Daily activities section 
Used in 
calculation of 
domain 
score? 
1. Doing close work in the morning or afternoon (such as 
crossword puzzles, reading, looking at a computer, and/or  
sewing)  
Yes 
2. Doing close work in the evening or at night  
Yes 
3. Driving 
Yes 


 
 
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Response for questions 1 to 9 
Original 
response code 
Item score 
I did not do this activity for reasons other than 
my dry eyes 
1 
5 
None of the time 
2 
5 
A little of the time 
3 
4 
Some of the time 
4 
3 
Most of the time 
5 
2 
All of the time 
6 
1 
I can no longer do this activity due to my 
dry eyes 
7 
0 
 
The response option “I did not do this activity for reasons other than my dry eyes” 
has a response coded 1 but a scored item value of 5. The original response code 
is the value to be used for data-entry. The item score is used during the 
computation of the Daily Activity Limitations Scale Score. Higher item scores are 
intended to reflect better quality of life (i.e. less limitations on daily activities). 
Only the first 6 questions are included in the Daily activity Limitations scale score. 
Questions 7, 8 and 9 are excluded. If 50% (3) or fewer of the 6 questions used in 
calculating Daily Activity Limitations score have missing item score, then the 
scale score is calculated by multiplying the mean of the non missing item score 
by 20. If 4 or more of the 6 item scores are missing then the scale score is not 
calculated and should be set at missing. Multiplying by 20 transforms the scale 
score to a 0 to 100 scale, with 0 reflecting the greatest degree of limitations on 
daily activities measurable by the scale and 100 reflecting the greatest freedom 
from limitations on daily activities. 
 
1.b Feelings 
Feelings 
Used in 
calculation of 
domain score? 
10. Irritability  
Yes 
4. Being around and/or using scented products (such as 
cologne or hairspray)  
Yes 
 
 
5. Working on a computer 
Yes 
6. Going somewhere where there is tobacco smoke or being 
around someone who smokes  
Yes 
7. Wearing contact lenses  
 
No 
8. Wearing make-up near or on my eyes  
 
No 
9. Flying on an airplane  
No 
 


 
 
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Feelings 
Used in 
calculation of 
domain score? 
 
11. Impatience  
 
Yes 
12. Feeling sad  
 
Yes 
 
 
13. Worry that my dry eyes will get worse  
 
Yes 
14. Feeling annoyed  
 
Yes 
15. Feeling like my eyes do not look nice  
 
Yes 
 
 
16. Feeling like I have to make adjustments to my life  
 
Yes 
17. Feeling different from other people because of my dry 
eyes  
Yes 
18. Feeling like I am always aware of my eyes  
 
Yes 
19. Feeling older than I really am  
 
Yes 
20. Feeling like people look at me and think I am fine when 
I'm not  
Yes 
21. Feeling like there is nothing I can do for my dry eyes  
 
No 
 
 
Response for questions 10 to 21 
Original 
response 
code 
Item score 
None of the time 
1 
4 
A little of the time 
2 
3 
Some of the time 
3 
2 
Most of the time 
4 
1 
All of the time 
5 
0 
 
11 questions are included in the Emotional Well-Being score. Question 21 
(IDLEMO12) is excluded from calculation. If 50% (5) or fewer of the 11 questions 
used in the calculation of Emotional Well-Being score have missing item score, 
then the scale score is calculated by multiplying the mean of the non missing 
item scores by 25. If 6 or more of the 11 item scores are missing then the scale 
score is not calculated and should be set at missing. Multiplying by 25 transforms 


 
 
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the scale score to a 0 to 100 scale, with 0 reflecting the worst level of emotional 
well-being measurable by the scale and 100 reflecting the best. 
 
1.c Work 
Work 
Used in 
calculation of 
domain score? 
22. Are you currently working?  
 
- 
23. Feeling distracted  
 
Yes 
24. Feeling like I couldn't concentrate  
 
Yes 
25. Having to take a break from work  
 
Yes 
26. Having to change the way I work (such as the way I 
read, look at a computer, or work outside)  
Yes 
27. Having to change my work environment (such as 
how close I am to an air conditioning or heating vent)  
Yes 
 
Response for question 22 
Original response 
code 
Item score 
Yes 
1 
1 
No 
2 
0 
 
Response for 
questions 23 to 27  
Original 
response 
code 
Item score 
If Response for 
question 22=0 
Item score 
If Response for 
question 22=1 
None of the time 
1 
Missing 
4 
A little of the time 
2 
Missing 
3 
Some of the time 
3 
Missing 
2 
Most of the time 
4 
Missing 
1 
All of the time 
5 
Missing 
0 
 
5 questions are included in the Work Limitations domain. If 50% (2) or fewer of 
the 5 questions used in the calculation of the Work Limitations score have 
missing item scores, then the scale score is calculated by multiplying the mean of 
the non missing item scores by 25. If 3 or more of the 5 item scores are missing 
then the scale score is not calculated and should be set to missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting 
the greatest degree of limitation at work measurable by the scale and 100 
reflecting the least limitation at work. 
 
Module 2:  
 


 
 
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Dry eye Treatment satisfaction & Bother module (10 questions) comprising 2 
QoL domains: 2.a “Treatment satisfaction / Happiness” and 2.b “Treatment-
related bother”. 
 
2.a Treatment  - In general  
 
Treatment in General 
Used in 
calculation of 
domain score? 
1. OVER THE LAST TWO WEEKS, how often did you use 
treatment for your dry eyes?  
- 
2. I was happy with how quickly my treatments worked  
Yes 
3. I was happy with how long the effects of my 
treatments lasted  
Yes 
4. The treatments I used completely eliminated my dry 
eye symptoms  
Yes 
5. The treatments I used relieved most of my dry eye 
symptoms  
Yes 
6. I was bothered by how often I had to use dry eye  
treatments  
Yes 
 
Response for question 1 
Original 
response 
code 
Item score 
 
None of the time 
1 
0 
A little of the time 
2 
1 
Some of the time 
3 
2 
Most of the time 
4 
3 
All of the time 
5 
4 
 
Response for questions 
2 to 5 
Original 
response 
code 
Item score 
If Response for 
question 1 = 0 
Item score 
If Response for 
question 1 > 0 or 
missing 
None of the time 
1 
Missing 
0 
A little of the time 
2 
Missing 
1 
Some of the time 
3 
Missing 
2 
Most of the time 
4 
Missing 
3 
All of the time 
5 
Missing 
4 
Response for question 6  
 
 
 
None of the time 
1 
Missing 
4 
A little of the time 
2 
Missing 
3 
Some of the time 
3 
Missing 
2 
Most of the time 
4 
Missing 
1 


 
 
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All of the time 
5 
Missing 
0 
 
5 questions are included in the Treatment Satisfaction/Happiness scale score.  
If 50% (2) or fewer of the 5 questions used in the calculation of Treatment 
Satisfaction/Happiness score have missing item score, then the scale score is 
calculated by multiplying the mean of the non missing item score by 25. If 3 or 
more of the 5 item scores are missing then the scale score is not calculated and 
should be missing. Multiplying by 25 transform the scale score to a 0 to 100 
scale, with 0 reflecting the lowest level of satisfaction/happiness with treatment 
measurable by the scale and 100 reflecting the highest level of 
satisfaction/happiness with treatment. 
 
2.b Treatment- Eye Drops 
 
Treatment- Eye Drops 
Used in 
calculation of 
domain score? 
7. Do you ever use eye drops to treat your dry eyes?  
- 
8. I was bothered by blurriness shortly after using my eye 
drops  
Yes 
9. I was embarrassed when I had to use my eye drops  
Yes 
10. I felt like I could not go anywhere without my eye drops  
Yes 
 
Response for question 7  
Original response 
code 
Item score 
 
Yes 
1 
1 
No 
2 
0 
 
Response for question 
8 to 10 
Original 
response 
code 
Item score 
If Response for 
question 1 = 0 
Item score 
If Response for 
question 1 > 0 
None of the time 
1 
Missing 
4 
A little of the time 
2 
Missing 
3 
Some of the time 
3 
Missing 
2 
Most of the time 
4 
Missing 
1 
All of the time 
5 
Missing 
0 
 
3 questions are included in the Treatment-Related Bother scale score. If 50% (1) 
or fewer of the 3 questions used in the calculation of Treatment-Related Bother 
scale score have missing item scores, then the scale score is calculated by 
multiplying the mean of the non missing item score by 25. If 2 or more of the 3 
item scores are missing then the scale score is not calculated and should be set 
at missing. Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 
0 reflecting the greatest degree of treatment related bother measurable by the 
scale and 100 reflecting the lowest degree of treatment-related bother. 


 
 
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Module 3:  
 
Dry eye Symptom bother (20 questions) comprising a unique domain. 
 
Symptom Bother 
Used in 
calculation of 
domain score? 
1.OVER THE LAST TWO WEEKS, how often did you 
experience dry eye symptoms?  
Yes 
2. Eyes that felt gritty or sandy  
Yes 
3. Felt like I needed to close my eyes even though I was not 
tired  
Yes 
4. Burning or stinging eyes  
Yes 
5. Tired eyes  
Yes 
6. Blurry vision  
Yes 
7. Itchy eyes  
Yes 
8. Irritated eyes  
Yes 
9. Eyes that felt like they had been scratched by something  
Yes 
10. Eye dryness  
Yes 
11. Mucus in, around, or coming out of my eyes  
Yes 
12. Puffy or swollen eyes  
Yes 
13. Eye redness  
Yes 
14. Aching or sore eyes  
Yes 
15. Felt like something was in my eye  
Yes 
16. Frequent and/or rapid blinking  
Yes 
17. Difficulty blinking because of little or no moisture in my eyes  
Yes 
18. Sensitivity to light, glare, and/or wind  
Yes 
19. Sensitivity to recirculated air (such as air conditioning and 
heat)  
Yes 
20. Headaches associated with dry eye symptoms  
Yes 
 
Response for question 1 
Original response 
code 
Item score 
None of the time 
1 
0 
A little of the time 
2 
1 
Some of the time 
3 
2 
Most of the time 
4 
3 
All of the time 
5 
4 
 
Response for questions 2 to 20 
Original 
response code 
Item score 
I did not have this symptom / Not applicable 
6 
0 
Not at all 
7 
1 


 
 
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Slightly 
8 
2 
Moderately 
9 
3 
Very much 
10 
4 
 
All questions are included in the Symptom Bother scale score. If 50% (10) or 
fewer of the 20 questions used in the calculation of Symptom Bother scale score 
have missing item scores, then the scale score is calculated by multiplying the 
mean of the non missing item score by 25. If 11 or more of the 20 item scores 
are missing then the scale score is not calculated and should be set at missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting 
the greatest degree of treatment related bother measurable by the scale and 100 
reflecting the lowest degree of treatment-related bother. 
Change from baseline of above-defined subscores will be summarized as a 
continuous variable at each visit, and mean changes from baseline of all the 
subscores will be graphically presented (e.g. radar plot) for each visit.  
• EQ-5D-5L change from baseline at week 4, 8, and week 32 
Change from baseline of each dimension score and overall score of health today 
will be summarized as a continuous variable at each visit, and mean changes 
from baseline of all the dimension scores will be graphically presented (e.g. radar 
plot) for each visit. 
5.3 Exploratory Efficacy Variables 
All exploratory efficacy analyses will be performed based on the observed cases 
in the FAS population. 
• Frequency of preservative free artificial tears use (drops/day) during the 
follow up period 
The number of doses of artificial tears used by patients during the follow-up 
period will be based on the number of used vials recorded in the artificial tears 
accountability log, and will be summarized as a continuous variable.  
• Change from baseline structural nerve regeneration per confocal microscopy 
The confocal microscopy images will be examined by an external reading center 
to be determined, and will be summarized as a continuous variable.  
• Change from baseline in epithelial thickness per anterior segment OCT 
Exploratory analysis of anterior segment OCT data will be and will be 
summarized as a continuous variable. 
5.4 Methods of Efficacy Analysis 
Descriptive statistics of the observed and change from baseline of each 
continuous efficacy endpoint described above will be tabulated by visit where that 
endpoint is assessed. Where appropriate, the asymptotic 95% confidence 
intervals of mean change from baseline will be presented. 


 
 
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Analyses for responder/categorical endpoints such as percentage of patients 
who experience epithelial healing at 4 and 8 weeks, and percentage of patients 
who remain healed throughout the follow-up period will include percentage of 
response, and associated exact (Clopper-Pearson) 95% confidence intervals 
where appropriate. 
All efficacy results will be tabulated based on both FAS and FTS as appropriate.  
6 
ANALYSIS OF SAFETY  
All safety parameters will be summarized based on the FAS Population. 
6.1 Adverse Events 
Adverse events data is collected from the time that informed consent was given, 
for the duration of the trial on the ‘Adverse Events’ eCRF page. All events in the 
clinical database regardless of when they occurred will be provided in data 
listings. Adverse events will be classified according to the MedDRA to the levels 
of SOC and PT. SOC will be sorted alphabetically and PT within each SOC will 
be sorted by overall descending order of frequency. 
Pre-treatment AEs are defined as AEs that started during the pre-treatment 
period (date of informed consent up to the time before the first administration of 
the study product. Pre-treatment AEs, if any, will be listed only.  
Treatment-emergent adverse events (TEAEs) are those with onset after the first 
dose of study product. Only treatment-emergent events will be summarized.  
An overall summary will be presented which gives the number and percentage of 
subjects that experienced any TEAE, experienced any treatment related TEAE, 
permanently discontinued treatment due to a TEAE, interrupted treatment due to 
a TEAE, experienced a serious AE (SAE), and AEs leading to death. 
The number and percentage of subjects experiencing one or more events will be 
tabulated by SOC and PT. In addition, similar tables by SOC and PT will be 
displayed further by maximum severity, and by closest relationship to treatment. 
For summary, the TEAEs with relationship to treatment reported as “None” or 
“Unlikely” are considered “Not Related”, and “Possible”, “Probable”, or “Highly 
Probable” are considered “Related”. 
Summary tables will be prepared also for the number and percentage of subjects 
experiencing one or more events classified as: On Treatment Period (AEs started 
between the day of first administration of the study product and the day of last 
administration of the study product), and On Follow-up Period (AEs started after 
the day of last administration of the study product). 
In summary tables for ocular adverse events, AEs occurring in both eyes will be 
summarized once at the greater severity or closer relationship to study drug.  
The number of and percentage of subjects experiencing AEs leading to 
premature discontinuation from the study will be tabulated and listed. 




 
 
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10 REFERENCES 
Impact of Dry Eye on Everyday Life (IDEEL) Questionnaire User Manual, Manual 
AC6262A version 2, 2 February 2012. 
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia 
X. Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L). Quality of Life Research. 2011, 20(10):1727-36  
 


 
 
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Appendix 1: Schedule of Evaluations (from Protocol) 
 


 
 
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Appendix 2 Shells for Tables, Listing, and Figures 
List of tables 
 
Table 
Number 
Table Title 
Analysis 
Population 
14.1.1 
Analysis Populations 
Screened 
14.1.2 
Subject Disposition 
Screened 
14.1.3 
Visit Participation 
Full Analysis Set 
14.1.4 
Demographics 
Full Analysis Set 
14.1.5.1 
Medical History 
Full Analysis Set 
14.1.5.2 
Ocular History 
Full Analysis Set 
14.1.6.1.1 Ocular Prior Medications 
Full Analysis Set 
14.1.6.1.2 Non-ocular Prior Medications 
Full Analysis Set 
14.1.6.2.1 Ocular Concomitant Medications 
Full Analysis Set 
14.1.6.2.2 Non-ocular Concomitant Medications 
Full Analysis Set 
14.1.7.1 
Treatment Exposure of Study Product 
Full Analysis Set 
14.1.7.2 
Washout Use of Artificial Tears 
Full Analysis Set 
14.1.7.3 
Treatment Compliance of Study Product 
Full Analysis Set 
14.2.1.1.1 Percentage of Patients who Experienced with Epithelial Healing at 8 weeks 
Full Analysis Set 
14.2.1.1.2 Percentage of Patients who Experienced with Epithelial Healing at 8 weeks 
Full Treated Set 
14.2.1.1.3 Percentage of Patients who Experienced with Epithelial Healing at 8 weeks - LOCF 
Full Analysis Set 
14.2.1.1.4 Percentage of Patients who Experienced with Epithelial Healing at 8 weeks - WOCF 
Full Analysis Set 
14.2.1.2 
Percentage of Patients who Achieved Epithelial Healing at Week 8 and Remained 
Healed during Follow-up 
Full Treated Set 
14.2.1.3 
Percentage of Patients who Experienced with Epithelial Healing at 4 weeks 
Full Analysis Set 
14.2.2.1 
Percentage of Patients who Experienced with Complete Healing at 8 weeks 
Full Analysis Set 
14.2.2.2 
Percentage of Patients who Achieved Complete Healing at Week 8 and Remained 
Healed during Follow-up 
Full Treated Set 
14.2.2.3 
Percentage of Patients who Experienced with Complete Healing at 4 weeks 
Full Analysis Set 
14.2.3.1 
Corneal Sensitivity Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 
14.2.3.2 
Percentage of Patients Improved from Baseline in Corneal Sensitivity at 4, 8 and 32 
weeks 
Full Analysis Set 
14.2.4 
Schirmer I Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 
14.2.5 
TFBUT Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 
14.2.6.1 
BCDVA Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 
14.2.6.2 
Percentage of Patients Achieved a 15- letter Gain in BCDVA at 4, 8 and 32 weeks 
Full Analysis Set 
14.2.7 
IDEEL Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 
14.2.8 
EQ-5D-5L Change from Baseline to Weeks 4, 8, and 32 
Full Analysis Set 


 
 
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14.2.9 
Exposure of Artificial Tears during the Follow-up Period 
Full Treated Set 
14.3.1.1 
Summary of Treatment-Emergent Adverse Events 
Full Analysis Set 
14.3.1.2 
Frequency of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Full Analysis Set 
14.3.1.3 
Frequency of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term and by Maximum Severity 
Full Analysis Set 
14.3.1.4 
Frequency of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term and by Closest Relatedness 
Full Analysis Set 
14.3.1.5 
Frequency of Treatment-Emergent Adverse Events Leading to Permanent Withdrawal 
of Study Medication by System Organ Class and Preferred Term 
Full Analysis Set 
14.3.1.6 
Adverse Event - MedDRA Glossary 
Full Analysis Set 
14.3.2 
Listing of Serious Treatment Emergent Adverse Events 
Full Analysis Set 
14.3.3 
Intraocular Pressure Change from Baseline to Weeks 8 and 32 
Full Analysis Set 
14.3.4 
Frequency Summary of Slit-Lamp Examination Results 
Full Analysis Set 
14.3.5 
Frequency Summary of External Ocular Examination Results 
Full Analysis Set 
 
 
 
 


 
 
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List of listings 
 
Listing 
Number 
Listing Title 
Analysis 
Population 
16.2.1.1 
Subject Disposition 
Screened 
16.2.1.2 
Screen Failures 
Screened 
16.2.1.3 
Analysis Visits 
Full Analysis Set 
16.2.2.1 
Inclusion and Exclusion Criteria Exceptions 
Full Analysis Set 
16.2.2.2 
Protocol Deviations 
Full Analysis Set 
16.2.3 
Analysis Populations 
Full Analysis Set 
16.2.4.1 
Demographics 
Full Analysis Set 
16.2.4.2.1 Medical History 
Full Analysis Set 
16.2.4.2.2 Ocular History 
Full Analysis Set 
16.2.4.2.3 Initial Diagnosis Neurotrophic Keratitis or Keratopathy 
Full Analysis Set 
16.2.4.3.1 Prior Medications 
Full Analysis Set 
16.2.4.3.2 Concomitant Medications 
Full Analysis Set 
16.2.5.1 
Treatment Exposure of Study Product 
Full Analysis Set 
16.2.5.2 
Use of Artificial Tears 
Full Analysis Set 
16.2.5.3 
Study Product Accountability 
Full Analysis Set 
16.2.5.4 
Artificial Tears Accountability 
Full Analysis Set 
16.2.6.1 
Fluorescein Corneal Staining and Complete Healing 
Full Analysis Set 
16.2.6.2 
Corneal Sensitivity Testing 
Full Analysis Set 
16.2.6.3 
Best Corrected Distance Visual Acuity (BCDVA) 
Full Analysis Set 
16.2.6.4 
Tear Film Break-Up Time (TFBUT) 
Full Analysis Set 
16.2.6.5 
Schirmer Test 
Full Analysis Set 
16.2.6.6 
Impact of Dry Eye on Everyday Life (IDEEL) 
Full Analysis Set 
16.2.6.7 
EQ-5D-5L 
Full Analysis Set 
16.2.7 
Adverse Events 
Full Analysis Set 
16.2.8.1 
Intraocular Pressure (IOP) 
Full Analysis Set 
16.2.8.2 
Slit-Lamp Examination 
Full Analysis Set 
16.2.8.3 
External Ocular Examination 
Full Analysis Set 
16.2.8.4 
Urine Pregnancy Test 
Full Analysis Set 
 
 
 


 
 
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List of figures 
 
Figure 
Number Listing Title 
Analysis 
Population 
14.2.1 
Radar Plot of Mean Change from Baseline of IDEEL Subscores to Weeks 4, 8 and 32 
Full Analysis Set 
14.2.2 
Radar Plot of Mean Change from Baseline of EQ-5D-5L Dimensions to Weeks 4, 8 and 
32 
Full Analysis Set