Clinical trial NCT02855450
Conditions: Glaucoma
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2016-12-01; Completion date: 2018-05-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess the safety and tolerability of a 180μg/ml TID dose regimen of recombinant human nerve growth factor (rhNGF) eye drop solution administered over 8 weeks versus a vehicle control in patients with progressive primary open-angle glaucoma despite IOP control.

The secondary objectives are to measure the changes in BCDVA, visual field, ERG and structural changes in ganglion cell layer and nerve fiber layer thickness measured by optical coherence tomography. The secondary outcomes will be examined at 1, 4 and 8 weeks of therapy, and at 4 and 24 weeks after cessation of therapy (Week 12 visit and Week 32 visit), and will include functional assessments to investigate evidence of a persistent biological effect after discontinuation of the study treatment.

Detailed description:
This is an 8 Week phase Ib, monocentric, randomized, double-masked, vehicle controlled, parallel groups, study with a 24 Week follow-up period to evaluate the safety and potential efficacy of a 180 μg/ml recombinant human nerve growth factor (rhNGF) eye drops solution versus vehicle in 60 study participants with chronic primary open angle glaucoma.

Participants may qualify with either progressive optic neuropathy despite maximal current therapy (i.e. IOP reduction), or with stabilized IOP but diminished vision (central or peripheral).

Participants with a qualifying eye will be randomized 2:1 to topical recombinant human nerve growth factor (rhNGF) therapy or vehicle placebo control. Examinations for safety and efficacy will occur one week following initiation of therapy, and at 4, 8, 12 and 32 weeks.

All participants in either arm will be followed clinically at 4 weeks after cessation of therapy.

Arms: arm 1: rhNGF (Recombinant Human Nerve Growth Factor) 180 μg/ml eye drops solution arm 2: Ophthalmic Placebo solution
Interventions: intervention 1: rhNGF intervention 2: Vehicle
Intervention descriptions: intervention 1: Recombinant Human Nerve Growth Factor 180μg/ml (one 35 μl drop equals to 6.30 μg of rhNGF) reconstituted solution three times a day (TID) for 8 weeks of treatment. intervention 2: Ophthalmic Placebo solution of the same composition as the test product with the exception of rhNGF reconstituted solution times a day (TID) for 8 weeks of treatment.

Protocol documents:
Prot_000.pdf: 
 
NGF0314 
Phase Ib NGF-Glaucoma 
CONFIDENTIAL 
 
Protocol Final Version 2.0 dated 04 November 2016 
 
 
 
 
Page 1 of 69 
CLINICAL STUDY PROTOCOL 
Study Title 
An 8 Week phase Ib, monocentric, randomized, double-masked, vehicle 
controlled, parallel group, study with a 24 Week  follow-up period to evaluate 
the safety and potential efficacy of a 180 µg/ml recombinant human nerve 
growth factor (rhNGF) eye drops solution versus vehicle in patients with 
glaucoma 
 
 
 
Protocol Number: 
NGF0314 
Study Phase:  
Ib 
Sponsor Name:  
Dompé farmaceutici S.p.A. 
 
Via S. Martino 12-12/A, 20122 Milan, Italy 
 
Phone: +39 02 583831; Fax: +39 02 58383324 
 
IND Number: 
124304 
Investigational Product: 
recombinant human Nerve Growth Factor (rhNGF) 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or 
confidential information  that is the property of (Dompé farmaceutici S.p.A.). It is 
understood that the information will not be used, divulged, or published without prior 
written consent of Dompé farmaceutici S.p.A., except to the extent such disclosure is 
required by applicable laws and regulations. 


 
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SPONSOR CONTACT INFORMATION 
 
Pharmacovigilance 
Dr. Laura Boga 
 
 
Dompé Drug Safety 
 
 
Dompé farmaceutici S.p.A. - Milan  
 
 
Fax: +39 02 36026913 
 
 
e-mail: farmacovigilanza@dompe.com 
 
 
Medical Expert  
Dr. Flavio Mantelli 
 
Dompé US, New York, NY 
 
+1 646 656 1999 
 
e-mail: flavio.mantelli@dompe.com 
 
Trial Manager 
Dr. Paolo Battigello 
 
Dompé farmaceutici S.p.A. - Milan 
 
+39 02 58383422 
 
e-mail: paolo.battigello@dompe.com  
 


 
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CONTACT INFORMATION PROVIDERS 
CLINICAL RESEARCH 
 
 
CROMSOURCE Srl 
ORGANIZATION (CRO) 
 
 
Street: Giorgio De Sandre, 3 
 
 
 
VERONA 
 
 
 
ITALY 
 
Pharmacovigilance email: DOMPE-NGF-GLA-PV@cromsource.com 
Medical Monitor email: DOMPE-NGF-GLA-MM@cromsource.com 
 
 
 
 
 
CONTACT INFORMATION OF PRINCIPAL INVESTIGATOR: 
 
 
Prof. Jeffrey L. Goldberg, MD, PhD 
Professor and Chair, Department of 
Ophthalmology 
Byers Eye Institute at Stanford University 
2452 Watson Court 
Palo Alto, CA 94303 
Jeffrey.Goldberg@Stanford.edu 
T: 650-723-6137 
F: 650-565-8297 (clinic) 


 
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PROTOCOL APPROVAL SIGNATURES 
 
SPONSOR: 
 
Name:     ___________________________________            Title:      ___________________ 
 
Signature:  _______________________________  
Date: 
 _________________________  
 
 
Name:     ___________________________________            Title:      ___________________ 
 
Signature:  _______________________________  
Date: 
 _________________________  
 
 
 
CLINICAL CENTER:  PRINCIPAL INVESTIGATOR 
I have read study protocol NGF0314 “An 8 Week phase Ib, monocentric, randomized, 
double-masked, vehicle controlled, parallel group, study with a 24 Week follow-up period to 
evaluate the safety and potential efficacy of a 180 µg/ml recombinant human nerve growth 
factor (rhNGF) eye drops solution versus vehicle in patients with glaucoma” and agree to 
conduct the study as outlined in the protocol, and in accordance with the Declaration of 
Helsinki, ICH-GCP, United States of America Legislation and any local regulations, being 
responsible for personally supervise the study conduct and ensure study staff complies with 
protocol requirement.  
 
Name of Principal Investigator:  
 ________________________________________  
 
 
Signature:  _______________________________  
Date: 
 _________________________  
 
 
 
 
  
 
 


 
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TABLE OF CONTENT 
Contents 
1. PROTOCOL SYNOPSIS ....................................................................................................................... 8 
2. STUDY PLAN...................................................................................................................................... 14 
3. ABBREVIATIONS .............................................................................................................................. 15 
4. INTRODUCTION ................................................................................................................................ 17 
5. ETHICS ............................................................................................................................................... 22 
6. PROTOCOL AMENDMENTS ............................................................................................................. 23 
7. PATIENT POPULATION .................................................................................................................... 23 
7.1 INCLUSION CRITERIA 
23 
7.2 EXCLUSION CRITERIA 
24 
8.  TREATMENTS ADMINISTERED ..................................................................................................... 26 
8.1. 8 WEEK RANDOMIZED CONTROLLED TREATMENT PERIOD 
26 
8.1.1. Study medication .................................................................................................. 26 
8.1.2. Other medications ................................................................................................. 27 
8.2. 24 WEEK FOLLOW-UP PERIOD 
27 
9. INVESTIGATIONAL PRODUCT ........................................................................................................ 28 
9.1. IDENTITY OF STUDY TREATMENT 
28 
9.1.1. Dose Selection Rationale ...................................................................................... 28 
9.1.2. Treatment Dispensing and Dosing ...................................................................... 29 
9.1.3. Usage ...................................................................................................................... 30 
9.1.4. Precautions of Use ................................................................................................. 31 
9.1.5. Storage ................................................................................................................... 32 
9.1.6. Accountability Procedures ................................................................................... 32 
9.1.7. Assessment of Compliance ................................................................................... 33 
9.1.8. Patient Confidentiality and Methods Used to Minimize Bias ........................... 33 
10. STUDY PROCEDURES ..................................................................................................................... 35 
10.1. OUTLINE OF STUDY 
35 
10.1.1. 8 Week Randomized, Double-Masked Controlled Treatment Period ............ 35 
10.1.2. 24 Week Follow-Up Period ................................................................................ 35 
10.2. VISIT AND EXAMINATIONS 
36 


 
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10.2.1. Baseline (Screening) Visit ................................................................................... 36 
10.2.2. Day 0 (Therapy Initiation) Visit (scheduled procedures may be performed over 
2 consecutive days if needed) ............................................................................... 37 
10.2.3. Week 1 Visit (with a window of ±2 Days, scheduled procedures may be 
performed over 2 consecutive days if needed) Week 4 Visit (with a window of 
±4 Days, scheduled procedures may be performed over 2 consecutive days if 
needed) ................................................................................................................. 39 
10.2.4. Week 8 Visit (with a window of ±7 Days, scheduled procedures may be 
performed over 2 consecutive days if needed) ..................................................... 40 
10.2.5. Masked Follow-Up Period - Week 12 Visit (with a window of ±7 Days, 
scheduled procedures may be performed over 2 consecutive days if needed) .... 41 
10.2.6. Unmasked Follow-Up Period - Week 32 Visit (with a window of ±7 Days, 
scheduled procedures may be performed over 2 consecutive days if needed) .... 41 
10.3 END OF TRIAL 
42 
10.4. UNSCHEDULED VISITS 
43 
10.5. DISCONTINUED PATIENTS 
43 
10.6. CLINICAL STUDY TERMINATION 
43 
11. ANALYSIS PLAN .............................................................................................................................. 45 
11.1. SUBJECT EVALUABILITY 
45 
11.2. ANALYSIS DATA SETS 
45 
11.3. HANDLING OF MISSING DATA 
45 
11.4. SAMPLE SIZE JUSTIFICATION 
45 
11.5. STATISTICAL ANALYSIS 
47 
11.5.1. General Principles .............................................................................................. 47 
11.5.2. Demographic and Baseline Characteristics ...................................................... 47 
11.5.3. Extent of Exposure ............................................................................................. 47 
11.5.4. Safety Analysis .................................................................................................... 48 
11.5.5 Efficacy Analysis .................................................................................................. 49 
12. EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION ........................................ 51 
12.1. DEFINITIONS 
51 
12.1.1. Adverse Event ..................................................................................................... 51 
12.1.2. Adverse Drug Reaction ...................................................................................... 51 
12.1.3. Serious Adverse Events ...................................................................................... 51 
12.1.4. Unexpected Adverse Events ............................................................................... 52 
12.1.5 Suspected unexpected serious adverse reaction ................................................ 52 
12.1.6. Adverse Events of Special Interest (Sight-threatening Events) ...................... 53 
12.2. MONITORING FOR ADVERSE EVENTS 
53 
12.3. RECORDING 
54 
12.3.1. Relationship of AEs to the Investigational Product ......................................... 54 


 
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12.3.2. Severity of AEs .................................................................................................... 55 
12.4 Serious Adverse Event Reporting Procedure (from Investigator to CRO/Dompé) 55 
12.4.1. Reporting Procedure from Investigator to Dompé and CRO ......................... 56 
12.4.2 Conditions that should not be reported as serious adverse events .................. 56 
12.4. 3. Expedited Reporting Procedure to IRB and to Regulatory Authorities ....... 57 
12.4.4.. Periodical Reporting to Regulatory Authorities ............................................. 58 
12.5. UNMASKING OF THE STUDY TREATMENT 
59 
12.6. FOLLOW-UP OF PATIENTS WITH ADVERSE EVENTS 
59 
12.6. PREGNANCY IN THE CLINICAL TRIAL 
60 
12.7. ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
61 
12.8. OVERDOSE 
61 
13. DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS .................................................... 62 
13.1 COMPLETION OF SOURCE DOCUMENTS AND CASE REPORT FORMS 
62 
13.2. DATA REVIEW AND CLARIFICATIONS 
62 
13.3 AUDIT PLANS 
63 
13.4. REGULATORY DOCUMENTATION AND RECORDS RETENTION 
63 
13.5. COMPENSATION FOR MEDICINE-INDUCED INJURY AND 
INDEMNIFICATION 
64 
13.6. STUDY REPORT AND PUBLICATION POLICY 
64 
13.7. CONFIDENTIALITY 
65 
14. REFERENCES .................................................................................................................................. 66 
15. APPENDIX A..................................................................................................................................... 69 


 
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1. PROTOCOL SYNOPSIS 
Protocol: 
NGF-Glaucoma 
Study Code: 
NGF0314 
Protocol Title: 
An 8 Week phase Ib, monocentric, randomized, double-masked, vehicle controlled, 
parallel groups, study with a 24 Week follow-up period to evaluate the safety and 
potential efficacy of a 180 µg/ml recombinant human nerve growth factor (rhNGF) 
eye drops solution versus vehicle in patients with glaucoma 
Investigational 
product: 
Recombinant human 
nerve growth factor 
(rhNGF) 
Study Phase: 
 I 
II 
 III 
 IV 
 N/A 
Description of 
Investigational 
Product 
Sterile isotonic aqueous solution for ocular administration containing rhNGF 180 
µg/ml or Vehicle 
Objective(s): 
Primary objectives: 
The primary objective is to evaluate the safety and tolerability of NGF vs vehicle. 
 
 
Secondary objectives: 
The secondary objectives are:  
• Mean, median, and distribution of change in BCDVA.  
• Changes in visual field using perimetry. 
• Changes in ERG including pattern ERG. 
And structural assessments: 
• Changes in ganglion cell layer and nerve fiber layer thickness measured by optical 
coherence tomography. 
Exploratory objective: 
• Changes in mitochondrial redox potential measured through adaptive optics 
scanning laser ophthalmoscope (SLO) imaging. 
Study Design:  
This is a masked, randomized, single-dose, monocentric trial of 60 study 
participants with chronic primary open angle glaucoma. Participants may qualify 
with either progressive optic neuropathy despite maximal current therapy (i.e. IOP 
reduction), or with stabilized IOP but diminished vision (central or peripheral). 
Participants with a qualifying eye will be randomized 2:1 to topical recombinant 
human nerve growth factor (rhNGF) therapy or vehicle placebo control. 
Examinations for safety and efficacy will occur one week following initiation of 
therapy, and at 4, 8, 12 and 32 weeks. All participants in either arm will be 
followed clinically at 4 weeks after cessation of therapy. 
No. of Subjects  
Randomized: 60 (40:20 patients per arm) to active treatment (180 µg/ml) or vehicle 
three times a day (TID), respectively. 
Region(s): 
USA 


 
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Study 
Population: 
Adult patients with chronic primary open angle glaucoma with documented 
evidence of clinical progression prior to enrollment despite maximal current therapy 
(i.e. IOP reduction), or with stabilized IOP but diminished vision (central or 
peripheral).   
Total duration 
of the study: 
Maximum total study duration 32 weeks (8 months). 
There will be three periods in this study:  
1) a 8 week phase Ib double-masked, randomized, controlled treatment period.  
and 
2) a 4 week masked follow-up period.  
and 
3) a 20 week unmasked follow-up period. 
Treatments: 
Test product: rhNGF 180 µg/ml eye drops solution 
Administration: 
Topical, ocular 
Duration 
 
of 
controlled 
treatment 
period: 
8 weeks 
Quantity/Dosag
e: 
Eligible patients will self-administer 1 drop of rhNGF 180 µg/ml 
three times a day (TID) for 8 weeks in both eyes. 
Control: Vehicle  
Administration: 
Topical, ocular 
Duration 
of 
controlled 
treatment 
period: 
8 weeks 
Quantity/Dosag
e: 
Eligible patients will self-administer 1 drop of vehicle three 
times a day (TID) for 8 weeks in both eyes. 


 
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Subject 
Selection: 
Inclusion Criteria: 
1. Patients 18 years of age or older. Participant must understand and sign the 
informed consent. If the participant’s vision is impaired to the point where 
he/she cannot read the informed consent document, the document will be read 
to the participant in its entirety. 
2. Participant’s clinical diagnosis must be consistent with glaucoma characterized 
by the following features:  
a) clinical evidence of progressive RGC dysfunction and degeneration using 
visual field and/or a structural modality. There must be at least 3 reliable visual 
fields within 14 months prior to entering into the study.  
b) residual visual field preservation in at least 1 quadrant.  
3. Participant must be medically able to undergo the testing and study procedures 
required in the flowsheet of exam procedures. 
4. Females of childbearing potential must agree to use an effective form of birth 
control. 


 
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Exclusion Criteria: 
1. 
Participant has another optic nerve or retinal degenerative disease or co-morbidity 
causing significant vision loss, irrespective of whether it is currently treated or 
untreated, that could limit the possibility of visual recovery.  
2. 
Participant is blind in one eye. 
3. 
Participant has a requirement of acyclovir and/or related products during study 
duration. 
4. 
Participant has evidence of corneal opacification or lack of optical clarity. 
5. 
Participant has undergone lens removal in the last 3 months, with or without intra-
ocular lens implantation, or has undergone intra-ocular lens replacement within 3 
months, or has undergone any other ocular surgery within 9 months prior to 
initiation of study drug. 
6. 
Participant is receiving systemic steroids or other immunosuppressive 
medications. 
7. 
Participant is currently participating in or has within the last 3 months participated 
in any other clinical trial of a non-clinically approved drug by ocular or systemic 
administration. 
8. 
Participant has uveitis or other ocular inflammatory disease. 
9. 
Participant has diabetic macular edema. 
10. Participant has a history of ocular herpes zoster. 
11. Participant is on chemotherapy. 
12. Participant has a history of malignancy, not counting basal cell carcinomas, 
UNLESS it was treated successfully 2 years prior to inclusion in the trial. 
13. Known hypersensitivity to one of the components of the study or procedural 
medications.  
14. History of drug, medication or alcohol abuse or addiction. 


 
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15. Females of childbearing potential (those who are not surgically sterilized or post-
menopausal for at least 1 year) are excluded from participation in the study if they 
meet any one of the following conditions: 
a. are currently pregnant or, 
b. have a positive result on the urine pregnancy test at the Screening/Baseline Visit 
or, 
c. intend to become pregnant during the study treatment period or, 
d. are breast-feeding or, 
e. not willing to use highly effective birth control measures, such as:  Hormonal 
contraceptives – oral, implanted, transdermal, or injected and/or mechanical 
barrier methods – spermicide in conjunction with a barrier such as a condom or 
diaphragm or IUD during the entire course of and 30 days after the study 
treatment periods.  
Important Notes: 
All females of childbearing potential must consent to a urine pregnancy test upon 
entering and exiting the study treatment period. Females of childbearing potential 
must agree to immediately inform the Investigator if they become pregnant during the 
study. 
For non-sexually active females, abstinence may be regarded as an adequate method 
of birth control; however, if the patient becomes heterosexually active during the study 
treatment period, she must agree to use adequate birth control methods as defined 
above for the remainder of the study treatment period. 
Pregnancy should be avoided in patients or partners during the first month after 
completing the treatment with the Investigational Product. 


 
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Assessments: 
Safety 
 
Adverse events 
 
Best corrected distance visual acuity (BCDVA) 
 
Intraocular pressure (IOP) 
 
Slit lamp examination (SLE) 
 
External ocular examination 
 
Humphrey Visual Field 24-2 or 10-2 
 
Dilated fundus ophthalmoscopy 
 
Ocular Coherence Tomography (OCT)  
 
Mitochondrial redox potential 
 
Electroretinogram (ERG) 
 
Ocular tolerability using visual analogue scale (VAS) 
Endpoints 
Safety Endpoints:  
Safety will be assessed by the following outcomes (occurrence of these outcomes 
does not necessarily require cessation of therapy): 
• Unexpectedly severe progression of optic neuropathy as measured by central 
vision loss, by visual field testing, or by examination of the optic nerve. 
• Intolerance or allergy to the drug. 
• Adverse events affecting ocular function or eye pressure, which differ from those 
expected in the course of glaucoma, which are thought to be potentially related to 
the drug. 
• Local or systemic toxicities considered serious adverse events that are potentially 
related to the drug. Elevation of intraocular pressure, although not seen previously 
in human use and not expected in this population, will be considered for cessation 
of therapy in patients with glaucoma. 
Data on all adverse events will be collected regardless of severity or potential 
relationship to the drug. 
Tolerability will be assessed through a Visual Analog Scale (VAS) 
 
Sample size: 
As the objectives of this study are to evaluate the safety and explore the 
biological effects of a single rhNGF dosage, sample size was calculated 
based on clinical feasibility and no formal sample size calculation has been 
performed. 
Proposed sample size is of 60 patients adequate to make appropriate estimation of 
study variables.  
Statistical 
methods: 
Safety and efficacy data will be analyzed by descriptive statistics. All analyses will 
be detailed in the statistical analysis plan (SAP) and reported at the end of the study.  
All exploratory efficacy variables will be tabulated with the appropriate descriptive 
statistics and appropriate inferential tests with 95% confidence limits of the 
difference between treatments will be produced. 
 


 
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2. STUDY PLAN 
SCHEDULED VISIT WEEK 
Baseline Visit 
(Screening)1 
Day 0 
Therapy Initiation 
Week 1 ( 2 days) 
Week 4 (4 days) 
Week 8 ( 7 days) 
Week 12 ( 7 days) 
Week 32 ( 7 days) 
GENERAL ASSESSMENTS 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Inclusion / Exclusion criteria 
X 
X 
 
 
 
 
 
Pregnancy test (if applicable) 
 
X 
 
 
X 
 
 
Demographics, Medical History, Medications2 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
VISUAL SYSTEM EXAMS 
 
 
 
 
 
 
 
Best Corrected Distance Visual Acuity (BCDVA) 
X 
X 
 
 
X 
X 
X 
IntraOcular Pressure (IOP)3 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination (SLE) 
X 
X 
X 
X 
X 
X 
X 
External ocular examination 
X 
X 
X 
X 
X 
X 
X 
Humphrey 24-2 or 10-2 Visual Field4 
X5 
X 
X6 
X7 
Dilated Fundus Ophthalmoscopy  
X 
X 
 
 
X 
X 
X 
OCT (retinal thickness) 
 
X 
 
 
X 
X 
X 
Mitochondrial redox potential 
 
X 
 
X 
X 
X 
X 
Full field and pattern ERG8 
 
X 
 
 
X 
X 
X 
STUDY THERAPY 
 
 
 
 
 
 
 
Visual Analogue Scale (VAS) for ocular tolerability 
 
X 
X 
X 
X 
X 
 
Study drug dispensing9 
 
X 
 
X 
 
 
 
Assess medication dosing compliance10 
 
 
 
X 
X 
 
 
 
1  
Baseline Screening Visit will occur within 4 weeks prior to initiating therapy. 
2  
Demographic information to be collected only at screening visit including medications taken 
within the preceding 30 days. 
3 
IOP testing will be performed using Goldmann Tonometer. 
4 
Visual Field testing will be performed using Sita Standard. 
5 
2 fields on different days for a total of 3 before initiating treatment. 
6 
3 fields within 4 weeks until the end of treatment. 
7 
3 fields within 4 weeks until the end of follow-up. 
8 
Full-field performed once at Therapy Initiation (Day 0) visit, at Week 8, at Week 12 and at 
Week 32. 
9 
At Day 0 instruct the patient to self-administer drug at home and return to next planned visit. 
10 
At Week 4 and 8 patient will be instructed to return all used and unused IP and the freezer bag. 
Table Note: Required procedures for a scheduled visit may be performed over 2 consecutive days.


 
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3. ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AEF 
Adverse Event Form 
AM 
Ante Meridien 
BCDVA 
Best Corrected Distance Visual Acuity 
ºC 
Degrees Celsius 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ERG 
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
g 
Grams 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
h 
Hour(s) 
HIV 
Human Immunodeficiency Virus 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUD 
Intra Uterine Device 
kg 
Kilogram 
mg 
Milligram 
mNGF 
Murine Nerve Growth Factor 
ml 
Milliliter 
mmHg 
Millimeters of Mercury 
ng 
Nanogram 
P75 NTR 
p75 neurotrophin receptor 
PM 
Post Meridien 
RGC 
Retinal Ganglion Cell 
rhNGF 
Recombinant Human Nerve Growth Factor  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SLO 
Scanning laser ophthalmoscope 


 
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SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TID 
Ter In Die (i.e. Three times a day) 
TrKA 
Tyrosine Kinase Receptor A 
VAS 
Visual Analogue Scale 
WFI 
Water for injection 
µg 
Microgram 


 
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4. INTRODUCTION 
Glaucoma is the leading cause of irreversible blindness in the world. [Quigley HA, 1996] 
This chronic and progressive disease is an optic neuropathy considered a neurodegenerative 
disease in which glutamate toxicity and increased apoptosis lead to a progressive loss of 
retinal ganglion cells (RGC) and loss of axons of the optic nerve, with a progressive and 
consequent deficit of the peripheral and central visual field. [Lambiase A, 2010] Glaucoma is 
an insidious disease with no warning symptoms: thus, the presence of one or more major risk 
factors (including elevated intraocular pressure, ageing, black race, a family history of 
glaucoma, increased corneal thickness) should alert physicians to periodically check for 
progressive optic nerve damage. In fact, early diagnosis of an elevated intraocular pressure 
may significantly reduce the risk of progressive nerve degeneration and visual field loss. 
[Weinreb Rn, 2004] In fact, intraocular pressure is the only risk factor that can be actually 
modified and is the only current target of glaucoma treatments. Nevertheless, it must be 
underlined that up to 20% glaucoma patients show progression of visual field defects with 
RGC and optic nerve degeneration despite successful management of ocular hypertension. 
[Collaborative Normal-Tension Glaucoma Study Group, 1998] In fact, elevated IOP is 
thought to be only the primum movens that triggers a cascade of events leading to optic nerve 
damage [Kwon YH, 2009] and, to date, there is no treatment available to restore neural 
function. 
As a consequence, an approach that would significantly improve the treatment of this 
challenging disease would involve neuroprotection with exogenous neurotrophic factors. In 
fact, neuroprotection has gained substantial interest in recent years as a therapeutic approach 
to prevent neuronal degeneration and loss of function in glaucoma.  
Specifically, recent studies reporting the differentiation, survival and function of retinal 
ganglion cells are regulated by survival growth factors, including neurotrophins, raised the 
possibility that neuroprotection could be a viable treatment approach in patients with 
glaucoma and other optic neuropathies [Roberti G, 2014]. Evidence obtained in animals with 
experimentally induced retinal cell degeneration and in rodents with inherited retinal diseases, 
indicate that a number of soluble factors, including brain derived neurotrophic factor (BDNF), 
b-fibroblast growth factor (b-FGF), nerve growth factor (NGF), transforming growth factor-b 
(TGF-b), tumor necrosis factor a (TNF-a), vascular endothelial factor (VEGF), neuropetide-Y 
(NPY), and ciliary neurotrophic factor (CNTF) can protect retinal cell degeneration alone or 
in combination  with other growth factors. [Lavail MM, 2005].  


 
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NGF is a leading neurotrophin well known to promote survival, function and differentiation 
of central and peripheral neurons [Levi-Montalcini R, 1987]. NGF and both its receptors, 
TrkA and p75, are widely expressed in the central visual pathways as well as in the optic 
nerve and retina [Lambiase A, 2010]. Moreover, NGF has been shown to modulate the 
development and differentiation of the retina and optic nerve, and to promote the survival and 
recovery of retinal ganglion cells [Lambiase A, 2009]. In addition, intravitreal NGF injection 
enhances BDNF, β-FGF, TGF-β, VEGF and NP-Y, suggesting that the neuroprotectant effect 
of NGF may also be exerted through the stimulation of other biological mediators [Lenzi L, 
2005].  
More noteworthy, it has been the demonstrated in different animal models that topically 
applied NGF eye drops can reach the retina and optic nerve in sufficient concentrations to 
exert a pharmacologic effect, thereby, opening new perspectives for the treatment of retinal 
and optic nerve diseases [Lambiase A, 2005].  
In addition, Lambiase and colleagues investigated the presence of NGF in the aqueous humor 
and evaluated the protective effect of endogenous and exogenous NGF in retinal damage 
using an experimental animal model of intraocular hypertension in rabbits [Lambiase A, 
1997]. They showed that the highest NGF level was observed after 4 days of intraocular 
hypertension and histological examination revealed that the number of retinal RGC remained 
unchanged during the first 4 days but decreased significantly after 10 days. This study also 
showed that retro-ocular administration of NGF reduced RGC loss, whereas intraocular 
injection of NGF antibodies, that inhibit endogenus NGF, exacerbated the retinal insult.  
These preliminary results suggested that NGF may be helpful in developing a new clinical 
approach to the treatment of human hypertensive ocular diseases.  
Subsequently, after reporting that topical eye drop application of NGF could reach brain 
cholinergic neurons and suggesting that high molecular weight proteins could be safely 
delivered into the brain via the ocular surface to promote the recovery of damaged brain cells, 
Sposato et al. (2009) used a rat model of glaucoma as an approach to investigate the effects of 
glaucoma on cells of the lateral geniculate nucleus (LGN) and visual cortex (VC) and for 
understanding the role of topically-applied NGF eye drops on neurodegenerative diseases. 
[Sposato V, 2009] 
They found that glaucoma reduces the concentration of NGF in the cerebrospinal fluid (CSF), 
LGN and VC, without causing significant changes in NGF serum levels. Topical ocular NGF 
application for 35 consecutive days enhanced the concentration of NGF in the CSF of 


 
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glaucomatous rats and normalized its presence in the VC and LGN. Exogenous NGF 
application induced up-regulation of TrkA in the LGN (but not in the VC), enhanced the 
expression of p75 in the LGN and reduced its presence in the VC.  
Recently, Lambiase and colleagues [Lambiase A, 2009] also demonstrated that topical 
application of exogenous NGF to the eye prevents RGC degeneration in an experimental rat 
model of glaucoma. In this study, the beneficial effect of NGF on RGC survival was induced 
by the inhibition of RGC apoptosis, as shown by the reduction in TUNEL immunostaining 
and the greater retinal Bcl-2/Bax ratio.  
Based on these findings they used the same dosage regimen to treat 3 glaucoma patients with 
rapid and progressive visual field loss despite successful control of intraocular pressure.  
In line with the above findings, several preliminary reports of patients treated with topically 
applied NGF provide human evidence that the neurotrophic protein appears to reach the back 
of the eye in humans and could be a promising treatment for posterior segment ocular 
diseases.  Specifically, in 6 patients, (5 children and 1 adult) with severe visual impairment 
due to compressive optic neuropathy associated with optic nerve glioma treatment with 10 
day courses of topically applied NGF resulted in improved vision and optic nerve function as 
measured objectively by distance visual acuity, visual field and visual evoked potential (VEP) 
and improvement persisted up to 1 to 3 months before returning to baseline after the 
discontinuation of the treatment [Falsini, 2011; Chiaretti et al, 2011]. In 4 patients with 
advanced glaucoma progressing on maximum medical therapy treatment with topical NGF 4 
time daily over 3 months was also reported to result in improved visual function.  Upon the 
discontinuation of treatment, patients showed an improvement in optic nerve function (VEP 
and PERG).  Moreover, at the 6 month follow-up patients maintained improvement in the 
optic nerve function and additionally showed improvement in visual function (visual acuity 
and visual field) suggesting a delayed or continued biologic effect of the NGF after the 
discontinuation of the treatment [Lambiase et al, 2009].  
The NGF so far applied in the cited preclinical and clinical studies has been a murine NGF 
[Lambiase A, 1998] extracted and purified from the male mouse submaxillary glands 
following the Bocchini&Angeletti method.  Murine NGF is 98% unglycosilated, and this 
unglycosilated fraction has full biological activity [Bocchini V, 1969]. NGF is highly 
conserved across different species and the two NGF forms, human and murine, show a 90% 
homology in the amino-acid sequence [Ullrich A, 1983]. Since maintaining an adequate 
supply of murine NGF would be a hindrance for the clinical development of NGF, a 
recombinant human form of NGF (rhNGF) has been developed by Dompé. Recombinant 


 
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human NGF (rhNGF) manufactured by Dompé is expressed in E. coli as a pro-protein. The 
pro-NGF is first isolated from inclusion bodies of E. coli, solubilized in a strong denaturing 
agent and subsequently refolded into the natural conformation. Subsequently, the pro-
sequence is removed with trypsin generating recombinant mature human NGF, which is then 
further purified to obtain the API protein solution. The rhNGF formulated as an eye drops 
solution is being developed for the treatment of anterior and posterior segment ocular diseases 
such as neutrotrophic keratitis, dry eye disease, optic neuropathy and RP.  While a topical 
formulation of rhNGF directed towards the treatment of ocular disease represents a novel 
therapeutic approach, the development and utilization of rhNGF in patients is not 
unprecedented. Clinical data are available in the literature from rhNGF expressed in Chinese 
hamster ovary (CHO) cells that was investigated in several hundreds of patients for the 
treatment of HIV- or diabetes-related peripheral neuropathy.  In clinical trials rhNGF 
expressed in CHO cells was subcutaneously administered at doses up to 0.3 g/kg three times 
a week for 6 months [Apfel, 1998] or 0.1 g/kg three times per week for 48 weeks [Apfel, 
2000].  The tolerability of systemically administered CHO- derived rhNGF was favorable 
with local pain at the injection site being the most common side effect.  Arthralgia, myalgia, 
myasthenia, asthenia and peripheral edema were other systemic rhNGF related adverse events 
recorded in less than 15% of studied patients [Apfel, 1998; McArthur, 2000; Apfel, 2000; 
Schifitto, 2001]. 
The E. coli-derived rhNGF being developed for the treatment of ocular diseases has the same 
unglycosilated molecular structure as mNGF and the same amino acid sequence as the 
systemically administered CHO expressed rhNGF previously evaluated in patients.  In in vitro 
preclinical studies both E. coli and CHO expressed rhNGF have been demonstrated to have 
similar activity to mNGF.  In preclinical toxicology and safety studies performed in rats and 
rabbits with the E.coli derived rhNGF no ocular or systemic safety concerns have been 
identified.  Of note, in a pharmacokinetic study evaluating the ocular biodistribution of 
topically applied rhNGF in rats of the three dose concentrations (20, 50 and 200 µg/ml) 
administered six times during the course of one day only the highest dose was detectable in 
the retina.  In a phase I, randomized, double-masked, placebo-controlled combined single and 
multiple ascending dose study to evaluate the safety, tolerability and pharmacokinetics of 
rhNGF (E. coli-derived) in healthy male and female volunteers, study subjects were treated in 
one eye with rhNGF (0.5 to 180 µg/ml) ranging from one drop daily to one drop three times a 
day over five days with the fellow eye receiving an identical placebo regimen.  Following 
treatment subjects were followed up to one month.  During the study there were no systemic 
or ocular safety concerns and no clinically significant changes in ocular examinations were 


 
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noted.  No serious adverse events were reported.  Adverse events were mild in intensity and 
transient in nature.  Reported ocular adverse events likely attributed to rhNGF include 
feelings of ocular pain, tenderness, soreness, pressure, burning, warmth and itchiness 
following instillation of the study medication. No evidence of systemic absorption or 
immunogenicity has been demonstrated in the serum of subjects tested to date.  
Similar to studies evaluating murine NGF, recently, E. coli-derived rhNGF administered 
topically, has been shown to be protective against photoreceptor degeneration in a rat model 
of optic nerve damage (partial optic nerve transection). Specifically, in a collaboration with 
Dompé the Cordeiro lab at University College London has demonstrated under masked 
experiments that topical rhNGF eye drops at 60μg/ml and 180μg/ml significantly reduces 
RGC apoptosis, increases RGC survival following partial optic nerve transection. 
Furthermore, they showed that it reduces secondary degeneration of RGC loss at 21 days in 
his model. In these studies, following the partial optic nerve transection animals were 
randomly divided into 4 treatment groups, with 6 animals per treatment group (no treatment, 
vehicle, NGF 180µg/ml eye drops, NGF 60µg/ml eye drops). The adminstrators of the 
treatment were blinded to identity of treatment throughout the project with labels covered 
with colour codes. Treatments were started on the day of optic nerve damage, and eye drops 
were given to both eyes, 2-times/per day, every day for 21 days. Apoptosing RGCs were 
evaluated in vivo using fluorescently labeled annexin-V, while RGC survival was assessed ex 
vivo using confocal microscopy in whole retinal whole-mounts stained with a monoclonal 
anti-mouse Brn3-a primary antibody and Alexa Fluor-643 conjugated secondary antibody.  
Based on the available preclinical and clinical data showing the lack of significant systemic or 
ocular safety concerns associated with rhNGF and the potential for clinical improvement in 
glaucoma patients the benefit/risk ratio evaluating rhNGF in patients with glaucoma, a 
progressively debilitating and blinding condition with no proven effective medical or surgical 
treatment, can be high. Although no safety concerns emerged with the use of rhNGF at 180 
µg/ml for 5 days in healthy subjects and, additionally, a multicenter masked randomized 
clinical trial where rhNGF at 180 µg/ml was administered for 24 weeks in patients affected by 
retinitis pigmentosa confirming the findings of the phase I study in which no evidence of 
systemic absorption or immunogenicity was demonstrated, no related serious adverse events 
were reported, and adverse events were mild in intensity, transitory, and consisted mostly of 
ocular pain, irritation, itching and photophobia following instillation, for ethical reasons this 
study was designed as a phase I segment in glaucoma patients since no data is available on the 
use of rhNGF in patients with a history of increased intraocular pressure and progressive optic 
nerve disease. 


 
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5. ETHICS 
This clinical study will be conducted in accordance with the principles of the Declaration of 
Helsinki, and in compliance with the International Conference on Harmonization (ICH) E6 
Good Clinical Practice (GCP) as described in 21 CFR §312 Consolidated Guideline and other 
regulations as applicable. The Investigator and all clinical study staff will conduct the clinical 
study in compliance with the protocol. The Investigator will ensure that all personnel 
involved in the conduct of the study are qualified to perform their assigned responsibilities 
through relevant education, training, and experience. Before initiating the clinical study, this 
protocol, the informed consent form any other written information given to patients, and any 
advertisements planned for patient recruitment must be approved by and by the Institutional 
Review Board (IRB) of the study sites. The Investigator must provide documentation of the 
IRB approval to Dompé. The approval must be dated and must identify the applicable 
protocol, amendments (if any), informed consent form, all applicable recruiting materials and 
written information for patient. The IRB must be provided with a copy of the Investigator’s 
Brochure, any periodic safety updates, and all other information as required by local 
regulation and/or the IRB. At the end of the study, the Investigator will notify the IRB about 
the study completion. The IRB also will be notified if the study is terminated prematurely. 
Finally, the Investigator will report to the IRB on the progress of the study at intervals 
stipulated by the IRB. 
Voluntary informed consent will be obtained from every patient (and/or impartial witness, as 
applicable) prior to the initiation of any study-related procedures. The Investigator must have 
a defined process for obtaining consent. Specifically, the Investigator, or designee, will 
explain the clinical study to each potential patient and the patient must indicate voluntary 
consent by signing and dating the approved informed consent form. The patient must be 
provided an opportunity to ask questions to the Investigator, and if required by local 
regulation, to other qualified personnel. The Investigator must provide the patient with a copy 
of the consent form written in a language the patient can understand. The consent document 
must meet all applicable local laws and will provide patients with information regarding the 
purpose, procedures, requirements, and restrictions of the study, along with any known risks 
and potential benefits associated with the investigational product and the established 
provisions for maintaining confidentiality of personal information. Patients will be told about 
the voluntary nature of participation in the study and will be provided with contact 
information for the appropriate individuals should questions or concerns arise during the 
study. The patient also will be told that their records may be accessed by appropriate 


 
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authorities and Dompé-designated personnel. The Investigator must keep the original, signed 
copy of the consent and must provide a duplicate copy to each patient. 
6. PROTOCOL AMENDMENTS 
Modification of the protocol is prohibited without prior written agreement in the form of a 
protocol amendment. All amendments will be created by Dompé and must be approved by the 
national competent authorities and/or IRB prior to implementation except when required to 
mitigate immediate safety risks or when the changes involve only logistical or administrative 
revisions. 
Amendments may necessitate that the informed consent and other study-related material be 
revised. If the consent form is revised, all patients currently enrolled in the study may be 
required by the IRB to sign the approved, revised informed consent form. 
7. PATIENT POPULATION 
Adult patients with chronic primary open angle glaucoma with documented evidence of 
clinical progression prior to enrollment despite maximal current therapy (i.e. IOP reduction), 
or with stabilized IOP but diminished vision (central or peripheral).  60 patients (2:1 
randomization active vs placebo) will be enrolled in the study.   
To participate in the study, patients must be 18 or older with primary open angle glaucoma 
with documented evidence of clinical progression (i.e. progressive optic ).  
Patients must fulfill all of the study inclusion and none of the exclusion criteria listed in the 
protocol synopsis in Section 1 and below. If a patient can’t read the informed consent due to 
poor vision, he/she can received the information verbally by another person but this procedure 
has to be documented, signed and dated by the independent person reading the document. 
7.1 INCLUSION CRITERIA 
1- Patients 18 years of age or older. Participant must understand and sign the informed 
consent. If the participant’s vision is impaired to the point where he/she cannot read the 
informed consent document, the document will be read to the participant in its entirety. 
2- Participant’s clinical diagnosis must be consistent with glaucoma characterized by the 
following features: a) clinical evidence of progressive RGC dysfunction and degeneration 
using visual field and/or a structural modality. There must be at least 3 reliable visual fields 
within 14 months prior to entering into the study; b) residual visual field preservation in at 
least 1 quadrant. 


 
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3- Participant must be medically able to undergo the testing required in the flowsheet of exam 
procedures. 
4- Females of childbearing potential must agree to use an effective form of birth control. 
7.2 EXCLUSION CRITERIA 
1- Participant has another optic nerve or retinal degenerative disease or co-morbidity causing 
significant vision loss, irrespective of whether it is currently treated or untreated, that could 
limit the possibility of visual recovery. 
2- Participant is blind in one eye. 
3- Participant has a requirement of acyclovir and/or related products during study duration. 
4- Participant has evidence of corneal opacification or lack of optical clarity. 
5- Participant has undergone lens removal in the last 3 months, with or without intra-ocular 
lens implantation, or has undergone intra-ocular lens replacement within 3 months, or has 
undergone any other ocular surgery within 9 months prior to initiation of study drug. 
6- Participant is receiving systemic steroids or other immunosuppressive medications. 
7- Participant is currently participating in or has within the last 3 months participated in any 
other clinical trial of a non-clinically approved drug by ocular or systemic administration. 
8- Participant has uveitis or other ocular inflammatory disease. 
9- Participant has diabetic macular edema. 
10- Participant has a history of ocular herpes zoster. 
11- Participant is on chemotherapy. 
12- Participant has a history of malignancy, not counting basal cell carcinomas, UNLESS it 
was treated successfully 2 years prior to inclusion in the trial. 
13- Known hypersensitivity to one of the components of the study or procedural medications. 
14- History of drug, medication or alcohol abuse or addiction. 
15- Females of childbearing potential (those who are not surgically sterilized or post-
menopausal for at least 1 year) are excluded from participation in the study if they meet any 
one of the following conditions: 


 
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a. are currently pregnant or, 
b. have a positive result on the urine pregnancy test at the Screening/Baseline Visit or, 
c. intend to become pregnant during the study treatment period or, 
d. are breast-feeding or, 
e. not willing to use highly effective birth control measures, such as:  Hormonal 
contraceptives – oral, implanted, transdermal, or injected and/or mechanical barrier 
methods – spermicide in conjunction with a barrier such as a condom or diaphragm or 
IUD during the entire course of and 30 days after the study treatment periods.  
 
Important Notes: 
All females of childbearing potential must consent to a urine pregnancy test upon entering 
and exiting the study treatment period. Females of childbearing potential must agree to 
immediately inform the Investigator if they become pregnant during the study. 
For non-sexually active females, abstinence may be regarded as an adequate method of birth 
control; however, if the patient becomes heterosexually active during the study treatment 
period, she must agree to use adequate birth control methods as defined above for the 
remainder of the study treatment period. 
 
Pregnancy should be avoided in patients or partners during the first month after completing 
the treatment with the Investigational Product. 
 


 
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8.  TREATMENTS ADMINISTERED 
Upon entry into the study, patients will be assigned randomization numbers in the appropriate 
numerical sequence by the Investigator. Each eligible subject will be assigned to a 
randomization number according to the sequence of study entry, from 01 to 60. 
8.1. 8 WEEK RANDOMIZED CONTROLLED TREATMENT PERIOD  
The 8 week (2 months) double-masked, randomized, controlled treatment period, (hereafter, 
also referred to as the controlled treatment period) will be followed by a 24 week (6 months) 
follow-up period. Enrolled patients will be randomized at baseline in a 2:1 ratio to the active 
treatment arm (rhNGF 180 µg/ml, one drop TID) or the vehicle control arm (vehicle, one 
drop TID in the affected eye(s)) as shown below in the Table 8.1-1. 
Table 8.1-1. – Treatment Arms 
Treatment arm 
Treatments 
1. Active 
180 µg/ml rhNGF, one drop TID (in both eyes if bilateral 
disease) 
2. Control 
Vehicle control, one drop TID  (in both eyes if bilateral disease) 
 
8.1.1. Study medication  
This study is designed as a phase Ib 8 week monocentric, randomized, double-masked, 
vehicle controlled, parallel groups study (referred to as the controlled treatment period) 
followed by a 24 week follow-up period (4 weeks masked follow-up and additional 20 weeks 
unmasked follow-up).  
The 60 consecutively enrolled patients will be randomized in a 2:1 ratio to the active 
treatment arm (rhNGF 180 µg/ml, one drop TID) or to the vehicle arm (vehicle, one drop 
TID) during the 8 week treatment period.  
On the Day 0 Visit the first 2 doses (1 dose = 1 drop) of study medication will be 
administered in the clinic by study site personnel and the patient will be monitored for 
adverse events. In the absence of any clinically significant side effects in the opinion of the 
investigator the patient will be dispensed their study medication and instructed to self-
administer the 3rd dose of Day 0 at home 6 hours after the 2nd dose of study medication was 
given. The patient will also be instructed to return to the study clinic after 1 week for Week 1 
Visit. 


 
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Patients enrolled in the study will continue their 8 week treatment and will later enter the 24 
week follow-up period without interruption. 
8.1.2. Other medications 
Upon enrolment, the previous topical glaucoma medications of patients will be continued 
normally, however, it will be required that previous topical ophthalmic medications used for 
intraocular pressure control will not be changed during the course of the study. Any other 
topical ocular treatment not related to intraocular pressure control for glaucoma, that is used 
before enrollment, will need to be discontinued and patients will only be allowed to use the 
study medication provided by Dompé and preservative-free artificial tears during the course 
of randomized controlled treatment period.  
No rescue medication is planned for this study. 
 
8.2. 24 WEEK FOLLOW-UP PERIOD 
At the conclusion of the controlled treatment period at Week 8, patients will be discontinued 
from study treatment. During the 24 week follow-up period (Weeks 9-32) the patients will be 
followed without any protocol required study medication, however, preservative-free artificial 
tears (not provided by Dompé) may be prescribed as needed as at the discretion of the study 
investigator. 
The first 4 weeks of the follow up period will be referred to as masked follow-up (and 
patients treatment will be kept masked) while the following 20 weeks will be referred to as 
unmasked follow-up (patients treatment will be unmasked at week 12) and the database will 
be locked. The database will be locked and the study will be complete after the last 
randomized patient has completed 4 weeks of the follow up period (Week 12 Visit). 
However, after the database lock patients still in the follow up period will continue with 
scheduled visits for the remainder of the 24 week follow up period. 
 


 
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9. INVESTIGATIONAL PRODUCT 
9.1. IDENTITY OF STUDY TREATMENT 
The Test product is a form of recombinant human Nerve Growth Factor (rhNGF) produced in 
E.coli developed by Dompé R&D Laboratories. rhNGF is a sterile 0.18 mg/mL single use 
lyophilized preparation, packaged in a glass vial, and administered after reconstitution with 
0.3 ml of sterile WFI contained into a glass prefilled syringe.  The WFI prefilled syringe is 
used with an adaptor consisting of a connecting device with dual connections: one end for the 
glass-syringe and one end for the vial. The drug product will be manufactured under 
environmental and process aseptic conditions in accordance with GMP guidelines to obtain a 
final sterile drug product. 
Test product: 
Recombinant human nerve growth factor 180µg/ml 
(one 35 µl drop equals to 6.30 µg of rhNGF) 
reconstituted solution 
Vehicle Control: 
Ophthalmic 
Placebo 
solution 
of 
the 
same 
composition as the test product with the exception of 
rhNGF reconstituted solution  
Investigational product will be provided as a 4-weeks kit formed by two boxes: the first box 
containing the vials (lyophilized product) and the second box containing adaptors and 
prefilled 0.3 ml WFI syringes. Each vial after reconstitution contains a volume of 0.3 ml 
rhNGF 180 µg/ml or control. A training manual for investigators with detailed instructions on 
how to reconstitute the eye drops from the lyophilized product is provided in Appendix A. 
The clinical labeling of the investigational product will be done in a manner that protects the 
masking of the study medication. It will include a statement of caution and describe 
particulars applicable to regulatory requirements (e.g.: kit number, protocol number, storage 
conditions, name and address of the sponsor, statement that the product is for investigational 
use only, etc.).  
9.1.1. Dose Selection Rationale 
The rationale for the rhNGF eye drops solution dosages to be investigated in this study (180 
µg/ml) is derived from the results of in vivo pharmacology studies, preclinical safety and 
toxicity studies and a phase I, randomized, double-masked, vehicle-controlled study of 
rhNGF in healthy volunteers demonstrating no significant ocular or systemic safety concerns 
with the proposed therapeutic dose. 
 


 
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In a preclinical models, we have investigated the effective dose-regimen of rhNGF by 
measuring the activation of the high affinity NGF receptor as well as apoptosis biomarkers 
expressed in the retina of rats with inherited retinal degeneration and with an induced damage 
of the optic nerve (partial optic nerve transection). 
 
Among the different rhNGF dose regimen tested, only the dose of 180µg/ml given three times 
a day for three consecutive days induced significant activation of the NGF receptors well as 
downregulation of pro-apototic biomarkers. Additionally, published reports of patients with 
advanced optic neuropathies treated with mNGF 200 µg/ml 3 or 4 times a day for variable 
time periods showing visual function improvements provide objective human evidence that 
topically applied NGF can achieve pharmacologically active concentrations in the back of the 
eye. In a preclinical study utilizing radiolabeled rhNGF to investigate the disposition of 
rhNGF in the eye of the 3 concentrations evaluated (20, 50 and 200 µg/ml) only the 200 
µg/ml dose was detectable in the back of the eye. So, while it is clear that topically applied 
NGF can reach the back of the eye and exert a therapeutic effect, based on the available 
preclinical and clinical data it is currently unclear which concentration of topical rhNGF will 
yield the most effective treatment benefit in patients with glaucoma. Therefore, the objective 
of this study is to assess the safety and potential efficacy of a 180 µg/ml rhNGF treatment to 
determine its safety for use in subsequent phase 2 and 3 clinical trials in this indication.    
9.1.2. Treatment Dispensing and Dosing 
Eligible patients will be randomized and randomization numbers will be assigned to the 
patients by the investigator in ascending sequential order. Each eligible subject will be 
assigned to a randomization number according to the sequence of study entry, from 01 to 60. 
Randomization code break envelopes will be provided to the Investigator with the IMP in the 
event unmasking is required.  
The patients will be dispensed a 4 week supply of study medication on the Day 0 visit and at 
Weeks 4 as shown in Table 9.1.2-1.  


 
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Table 9.1.2-1 - Kit Assignments 
Weekly visit 
# of kits 
Day 0 - Randomization /  
Therapy initiation Visit 
1 kit 
Week 4 Visit 
1 kit 
 
Study medications that will be dispensed to the patient during the study visits will be 
distributed in refrigerated bags. In addition to the study medication to be administered in the 
clinic on the day of the study visit, patients will also be instructed to bring back to the clinic at 
each study visit all the used and unused vials by placing them in the refrigerated bag that was 
given at the Day 0 visit (so that it can be used for dispensing the next kit, if applicable).  
Each 4 week kit will be composed of 1 box containing a total of 90 single-use vials of the 
randomized / assigned medication for daily treatment during 4 weeks and 1 box containing 
the same number of adaptors and prefilled 0.3 ml WFI syringe. 
All patients will be dosed one drop (35 µl) three times a day (TID) in each eye during the 8 
weeks, randomized, double-masked, controlled treatment period.  
9.1.3. Usage  
All study drugs used in this study are for topical ocular usage only. Dispensing of the study 
medications to the patients will be performed as described in Section 9.1.2 and table 9.1.2-1.   
All patients will be dosed one drop (35 µl) TID in each eye every morning, afternoon and 
evening as shown in the Table 9.1.3-1. The timing of instillation should be adjusted if a 
patient’s awakening and/or bedtime differs.  
Patients will begin treatment in the clinic at the Day 0 visit, where he/she will be shown how 
to resuspend the lyophilized molecule and instill the eyedrops in the eyes. For this purpose, a 
training manual with detailed instructions on how to reconstitute the eye drops will be 
provided to the investigators (see Appendix A). Patients will then be instructed to self-
administer the study medication one drop three times a day through 8 Weeks of the controlled 
treatment period.  During the 8 week controlled treatment period patients will be instructed to 
return to the clinic on the monthly visits with the used kits and empty (used) vials as well as 


 
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with the daily kit of study medication and vials to be used on the day of the study visit in the 
refrigerated bag that will be given when the study medication is dispensed. 
 
Table 9.1.3-1. – Dosing Schedule 
TREATMENT  
TREATMENT DOSING SCHEDULE 
rhNGF 180 µg/ml or Vehicle 
Morning (approximately 8 AM) 
Afternoon (approximately 2 PM) 
Evening (approximately 8 PM) 
 
9.1.4. Precautions of Use  
In rats and rabbits no evidence of systemic toxicity was observed following treatment with 
intravenous rhNGF at doses up to 2.4 mg/kg.  In the same species, no local ocular toxicity 
was observed following treatment with topical rhNGF eye drops at concentrations up to 1.2 
mg/ml. In a phase I, randomized, double-masked, vehicle-controlled study of rhNGF in 
healthy volunteers no ocular or systemic toxicity was demonstrated in patients administered 
topical rhNGF up to 180 µg/ml 3 times a day for 5 days. Being a recombinant protein, rhNGF 
it is not expected to be mutagenic, therefore, reproductive toxicity and teratogenicity studies 
have not been performed.  However, as a precaution, the investigational product should not be 
handled by pregnant females, should be kept away from children and contact with the skin or 
mucosae other than that for required for topical ocular administration should also be avoided. 
In case of accidental spills or contact cleanse/wash the exposed area with tap water and soap. 


 
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9.1.5. Storage 
Investigational product must be stored in a secure area at the investigational site as per the 
labeling instructions. A temperature probe and data logger will accompany the drug on 
shipment.  It is essential that the Investigational sites verify the temperature range reached 
during shipment, so that potential stability concerns during shipment can be discovered and 
appropriate action taken. The box of the investigational product containing the lyophilized 
preparation must be stored at 2-8°C at the Investigational sites (preferably at the pharmacy of 
the hospital), whereas the box containing the prefilled syringes and adaptors may be kept at 
room temperature. Eligible patients will receive the first 4-week kit of study medications in a 
refrigerated bag containing the investigational product.  The vehicle control will be also 
dispensed in a refrigerated bag. The patient will be instructed to store the study medication 
(the box of the investigational product containing the lyophilized preparation) at home in the 
refrigerator at 2-8 °C for the entire 4 weeks until next visit. The box containing the prefilled 
syringes and adaptors may be kept at room temperature. When the patients will start to use the 
study medications at home each day they will remove from the refrigerator only the vials to 
be used over the course of the day. Patients will use one vial to instill one drop in both eyes 
three times per day. 
A daily temperature log will be maintained at the site for documenting appropriate storage 
conditions and will be made available for the study monitor to inspect. Any deviations from 
the recommended storage conditions should be immediately reported to Dompé and the use of 
the drug suspended until authorization for its continued use has been given by Dompé. 
Investigational products will be supplied as a lyophilized preparation in glass vials together 
with a prefilled 0.3 ml sterile WFI syringes and adaptors. The vials will be labeled with the 
appropriate clinical study labeling. The vehicle of rhNGF will be supplied in glass vials 
identical to those containing rhNGF with a prefilled 0.3 ml WFI syringes and adaptors. The 
vials containing the vehicle will be labeled with the appropriate clinical study labeling. 
Investigational product will be kept in an identical box to ensure double-masking. 
9.1.6. Accountability Procedures 
Upon receipt, the study staff designated by the Investigator will inventory the clinical 
investigational products, and complete and sign the Receipt of Clinical Study Investigational 
products Section of the appropriate form in use. A copy of the form will be maintained in the 
Investigator’s records and the original will be provided to the CRO, delegated by Dompé. 


 
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The designated study staff must keep a complete and accurate accountability of all 
investigational products used on the investigational products Dispensing Log. In no case will 
the investigational products be used in any unauthorized situation. Investigational products 
returned to the Dompé for destruction will be recorded in the Return of Clinical 
Investigational products Form. These records will be made available to the study monitor for 
the purpose of accounting for all study investigational products. The study monitor will 
account for all investigational products. 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.  
Investigational product which has been dispensed to a patient and returned unused will not be 
re-dispensed to a different patient.  
Unused investigational products must not be discarded or used for any purpose other than the 
present study.  Any remaining investigational products at the end of the trial will be returned 
to Dompé or disposed of as determined by Dompé for destruction. 
9.1.7. Assessment of Compliance 
Patient compliance with the study medication will be assessed at each study visit following 
the dispensing of the study medication for self-administration. Compliance with the study 
medication dosing schedule will be verified by the monitor during on-site monitoring visits, 
as per records in the eCRF, versus accountability records. 
9.1.8. Patient Confidentiality and Methods Used to Minimize Bias 
During the 8 week, randomized, double-masked controlled treatment period the study 
treatments will be unknown to the patient, the Investigator and the site staff. The identity of 
the treatments will remain unknown to the patient, Investigator, site staff and Dompé’s 
clinical research personnel until the study is unmasked after the last enrolled patient 
completes week 12 visit (end of the masked follow-up) and the database is locked, except in 
case of specific events that will require unmasking of the patient(s).  
The vials of rhNGF (180µg/ml) and the vials containing the vehicle of rhNGF will be 
identical in appearance and the contents of the vials will be indistinguishable. Dompé and 
CRO Biostatistics staff who are directly involved in the analysis of study results will remain 
masked to treatment assignments until the end of the masked follow-up. 


 
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A list of sequential kit numbers will be generated by a member of the CRO SAS 
programming group not involved in the conduct of the study. Each kit number will be 
randomly associated with a treatment group. Patients will be assigned to treatment in 
numerical order. A tear-off label from the kit box, with the kit number, will be attached to the 
investigational product dispensing log. 
If the Investigator becomes unmasked for any reason, this information will be recorded on 
source data and in the eCRF of the study, specifying the date and the reason.  
In the event of a medical emergency where the knowledge of patient treatment is required to 
provide the patient with appropriate care, Investigators will have the possibility to unmask the 
treatment assignment for a specific patient.  See Paragraph 12.5 for information on unmasking 
procedure. 


 
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10. STUDY PROCEDURES 
10.1. OUTLINE OF STUDY 
The study will be conducted as a 8 week monocentric, randomized, vehicle controlled, 
double-masked, parallel groups study followed by a 24-week follow-up period. The study will 
be considered completed when the last enrolled patient completes their final study visit at 
Week 32 of the follow-up period.  
 
The 8 week controlled treatment period will include 7 scheduled clinical evaluation visits: 
Baseline Screening Visit, Day 0-Therapy Initiation Visit, Week 1, Week 4, Week 8, Week 12 
and 32 Visits. Week 1 Visit has a window of ±2 days, Week 4 Visit has a window of ±4 days, 
while Week 8, 12, 32 Visits have a window of ±7 days, at the discretion of the investigator, 
required procedures for a scheduled visit may be performed over 2 consecutive days  
10.1.1. 8 Week Randomized, Double-Masked Controlled Treatment Period 
Enrolled patients will be randomized at baseline in a 2:1 ratio to the active treatment arm 
(rhNGF 180 µg/ml three times a day in both eyes) or the vehicle during the 8 week controlled 
treatment period as shown in the following table: 
 
Treatment Arms 
Treatments 
1 
180 µg/ml rhNGF one drop three times a day in both eyes 
2 
Vehicle one drop three times a day in both eyes 
 
At the conclusion of the randomized, double-masked, controlled treatment period all patients 
will discontinue the study medication and enter a 24 week follow-up period (4 weeks masked 
follow-up and additional 20 weeks unmasked follow-up. 
10.1.2. 24 Week Follow-Up Period 
During the 24 week follow-up period, patients will be followed without any protocol required 
study medication; however, preservative-free artificial tears (not provided by Dompé) may be 
prescribed as needed at the discretion of the study investigator. 
Two clinical evaluation visits are foreseen at week 12 and 32.


 
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10.2. VISIT AND EXAMINATIONS 
10.2.1. Baseline (Screening) Visit 
1. Informed Consent  
Explain the purpose and nature of the study, and have the patient or legally authorized 
representative read, sign, and date the IRB approved informed consent document. If 
applicable, a witness will also sign and date the informed consent document. Provide 
a photocopy of the signed document to the patient and place the original signed 
document in the patient chart. 
2. Inclusion/Exclusion Criteria  
Screen the patient for protocol inclusion/exclusion criteria as per paragraph 7.1 and 
7.2. 
3. Demographics, Medical History, Medications   
Document demographic information and medical history, including information on 
all concomitant and previous medications used within the past 30 days. Include herbal 
therapies, vitamins, and all over-the-counter as well as prescription medications.    
4. Record Adverse Events 
5. Ophthalmic Examinations 
The following examination/procedures will be performed on BOTH EYES unless 
otherwise indicated: 
a) Best-Corrected Distance Visual Acuity (BCDVA) 
Vision must be measured 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.   
b) Visual Field Testing 
Visual fields will be evaluated using static (Humphrey visual field 24-2 or 10-
2) perimetry. Two perimetries will be performed on different days for a total 
of 3 before initiating treatment. 
Visual field testing should precede the administration of any eye drops to 
dilate or anesthetize the eye, or any examination requiring contact with the 
eye. 
Visual Field testing will be performed using Sita Standard. 
c) External Ocular Examination  


 
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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. 
d) Slit Lamp Examination (SLE) (biomicroscopy) 
SLE will assess eyelids, lashes, conjunctiva, cornea, lens, iris and anterior 
chamber.  SLE must be performed before the instillation of any dilating or 
anesthetic eye drops or the fluorescein agent. 
e) Intraocular Pressure (IOP) 
IOP testing will be performed using Goldmann Tonometer after the 
instillation of a topical anesthetic. 
f) Dilated Fundus Ophthalmoscopy 
Fundus ophthalmoscopy to assess the retina, macula, choroid and optic nerve 
head will be performed after dilation of the pupil.  
10.2.2. Day 0 (Therapy Initiation) Visit (scheduled procedures may be performed over 2 
consecutive days if needed) 
1. Inclusion/Exclusion Criteria: Screen the patient for protocol inclusion/exclusion 
criteria as per paragraph 7.1 and 7.2. 
2. 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.   
3. Randomization: At the end of the Day 0, Baseline/Randomization Visit, if the 
patient qualifies for randomization in the study, proceed to randomize the patient; 
randomization numbers will be assigned to the patients by the investigator in 
ascending sequential order. 
4. Ophthalmic Examinations 
The following examination/procedures will be performed on BOTH EYES unless 
otherwise indicated: 
g) Best-Corrected Distance Visual Acuity (BCDVA) 
Vision must be measured 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.   
h) Visual Field Testing 


 
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Visual fields will be evaluated using static (Humphrey visual field 24-2 or 10-
2) perimetry. Visual field testing should precede the administration of any eye 
drops to dilate or anesthetize the eye, or any examination requiring contact 
with the eye. 
Visual Field testing will be performed using Sita Standard. 
i) 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. 
j) Slit Lamp Examination (SLE) (biomicroscopy) 
SLE will assess eyelids, lashes, conjunctiva, cornea, lens, iris and anterior 
chamber.  SLE must be performed before the instillation of any dilating or 
anesthetic eye drops or the fluorescein agent. 
k) Intraocular Pressure (IOP)   
IOP testing will be performed using Goldmann Tonometer after the 
instillation of a topical anesthetic. 
l) Dilated Fundus Ophthalmoscopy 
Fundus ophthalmoscopy to assess the retina, macula, choroid and optic nerve 
head will be performed after dilation of the pupil.  
m) Ocular Coherence Tomography 
Spectral domain OCT acquisitions of macula and optic nerve head will be 
performed to evaluate changes in ganglion cell layer and nerve fiber layer 
thickness. 
n) Mitochondrial redox potential 
Changes in mitochondrial redox potential measured through adaptive optics 
scanning laser ophthalmoscope (SLO) imaging. 
o) Electroretinography (ERG) 
A full field and pattern ERG will be performed according to international 
standards at the Day 0 examination.  Prior to the ERG procedure patients will 
be treated with anesthetic and dilating drops. 
5. Study Drug Dispensing: Randomized patients will be dispensed study medication on 
the day of Therapy Initiation Visit. 
6. Instructions to Patient: Schedule the patient to return for Week 1 Visit.  Instruct the 
patient to self-administer the last dose (third) of day 0 at home 6 hours after the 


 
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second dose and the study medication one drop three times a day starting at home 
starting on Day 1, the following day.  
7. Visual Analogue Scale (VAS) VAS will be used to determine ocular tolerability to 
the study medication. It will be assessed by the patient using a self-administered 100 
mm VAS on which 0 means no symptoms and 100 means the worst possible 
discomfort in either eye. This evaluation is to be performed before any ophthalmic 
examinations. 
8. Medical History, Medications: Record any change ocular or systemic medical 
history or in concurrent ocular or non-ocular medications. 
9. Record Adverse Events 
 
Instruct and remind the patient to come back to the clinic at the week 4 visit   with the 
used kits and empty (used) vials as well as with the daily kit of study medication and 
vials to be used on the day of the study visit in the refrigerated bag provided. At week 4 
the patient receives additional medication to be used for the following 4 weeks. 
 
At all applicable visits instruct the patient to return to the clinic with the 4 weeks kit of 
study medication in the refrigerated bag. 
10.2.3. Week 1 Visit (with a window of ±2 Days, scheduled procedures may be performed 
over 2 consecutive days if needed) Week 4 Visit (with a window of ±4 Days, scheduled 
procedures may be performed over 2 consecutive days if needed) 
1. Medical History, Medications  (Week 1 & 4 Visits) 
Record any change ocular or systemic medical history or in concurrent ocular or non-
ocular medications. 
2. Record Adverse Events (Week 1 & 4 Visits) 
3. Verify patient study medication dosing compliance (Week 4 Visit Only) 
4. VAS (Week 1 & 4 Visits) 
5. Ophthalmic Examinations: The following examination/procedures will be 
performed on  BOTH EYES: 
a) Humphrey Visual Field 24-2 or 10-2 (3fields within 4 weeks until the end 
of treatment); Visual Field testing will be performed using Sita Standard 
b) External Ocular Examination (Week 1 & 4 Visits) 
c) Slit Lamp Examination (Week 1 & 4 Visits) 
d) IOP (Week 1 & 4 Visits)IOP testing will be performed using Goldmann 
Tonometer after the instillation of a topical anesthetic. 


 
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Mitochondrial redox potential (Week 4 Visit Only): changes in 
mitochondrial redox potential measured through adaptive optics scanning 
laser ophthalmoscope (SLO) imaging. 
 
6. Study Drug Dispensing and Compliance (Week 4 Visit Only) 
7. Instructions to Patient (Week 1 & 4 Visits) 
At Day 0 (Therapy initiation) visit and each visit thereafter schedule patient for next 
visit. 
10.2.4. Week 8 Visit (with a window of ±7 Days, scheduled procedures may be performed 
over 2 consecutive days if needed) 
1. Medical History, Medications  
2. Record Adverse Events 
3. Verify patient study medication dosing compliance 
4. VAS 
5. Ophthalmic Examinations 
The following examination/procedures will be performed on BOTH EYES: 
a) 
Best-Corrected Distance Visual Acuity (BCDVA) 
b) Humphrey Visual Field 24-2 or 10-2 (3 perimetries within 4 weeks until the 
end of treatment); Visual Field testing will be performed using Sita Standard 
c) External Ocular Examination 
d) Slit Lamp Examination (biomicroscopy) 
e) Intraocular Pressure (IOP); IOP testing will be performed using Goldmann 
Tonometer after the instillation of a topical anesthetic. 
f) Dilated Fundus Ophthalmoscopy 
g) Ocular Coherence Tomography 
h) Mitochondrial redox potential: changes in mitochondrial redox potential 
measured through adaptive optics scanning laser ophthalmoscope (SLO) 
imaging. 
i)  ERG A full field and pattern ERG will be performed according to 
international standards at the Day 0 examination.  Prior to the ERG procedure 
patients will be treated with anesthetic and dilating drops. 
8. Pregnancy Test 
9. Instructions to Patients 
Schedule patient to return for the week 12 visit (± 7 Days) in follow-up visit. 


 
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END OF 8 WEEK RANDOMIZED, DOUBLE-MASKED,CONTROLLED TREATMENT 
PERIOD 
 
10.2.5. Masked Follow-Up Period - Week 12 Visit (with a window of ±7 Days, scheduled 
procedures may be performed over 2 consecutive days if needed) 
1. Medical History, Medications 
2. Record Adverse Events 
3. Ophthalmic Examinations: 
a) BCDVA  
b) Humphrey Visual Field 24-2 or 10-2 (3 perimetries within 4 weeks until the 
end of treatment); Visual Field testing will be performed using Sita Standard 
c) External ocular examination 
d) Slit Lamp Examination 
e) Intraocular pressure (IOP); IOP testing will be performed using Goldmann 
Tonometer after the instillation of a topical anesthetic. 
f) Dilated Fundus Ophthalmoscopy  
g) Ocular Coherence Tomography 
h) Mitochondrial redox potential: changes in mitochondrial redox potential 
measured through adaptive optics scanning laser ophthalmoscope (SLO) 
imaging. 
i) ERG  
j) VAS 
 
10.2.6. Unmasked Follow-Up Period - Week 32 Visit (with a window of ±7 Days, 
scheduled procedures may be performed over 2 consecutive days if needed) 
1. Medical History, Medications 
2. Record Adverse Events 
3. Ophthalmic Examinations: 
a) BCDVA  
b) Humphrey Visual Field 24-2 or 10-2 (3 perimetries within 4 weeks until the 
end of follow-up); Visual Field testing will be performed using Sita Standard 
c) External ocular examination 
d) Slit Lamp Examination 


 
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e) Intraocular pressure (IOP); IOP testing will be performed using Goldmann 
Tonometer after the instillation of a topical anesthetic. 
f) Dilated Fundus Ophthalmoscopy  
g) Ocular Coherence Tomography 
h) Mitochondrial redox potential: changes in mitochondrial redox potential 
measured through adaptive optics scanning laser ophthalmoscope (SLO) 
imaging. 
i) ERG  
 
10.3 END OF TRIAL 
For the purpose of this trial, the end of study is defined as the date of the last visit of the last 
patient of the follow up period.  


 
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10.4. UNSCHEDULED VISITS 
If a subject returns to the clinic prior to their next scheduled study visit for assessment of an 
adverse event, an Unscheduled Visit should be conducted. Procedures conducted at the 
Unscheduled Visit are at the discretion of the Investigator and may be among the study 
procedures or additional procedures not performed during the study but deemed necessary by 
the investigator. The clinical information obtained during any unscheduled visit is to be 
recorded in the electronic Case Report Forms. If the patient is discontinued at the unscheduled 
visit, the eCRFs for the Week 8 visit should be completed if the withdrawal occurs at Week 8; 
for all other patients the Early Exit Visit should be completed. 
10.5. DISCONTINUED PATIENTS 
Discontinued patients are those who withdraw or are withdrawn from the study after the 
Randomization Visit. Patients may discontinue from the study at any time for any reason. 
Patients also may be discontinued from the study at any time if, in the opinion of the 
Investigator, their continued participation poses a risk to their health. Patients may also be 
discontinued from the study if lost to follow-up. Female patients will be withdrawn in case 
they become pregnant during the study. Discontinued patients will not be replaced (i.e., their 
patients numbers will not be re-assigned/re-used). 
Any patient who exits early from the study must undergo all procedures outlined at Week 8 
Visit if the discontinuation occurs at or before Week 8 Visit; the Week 8 Visit assessments 
should be completed for all patients, as assessments of the Early Exit Visit. Additionally, the 
Exit Form must be completed. 
Finally, to ensure the safety of all patients who discontinue early, Investigators should assess 
each patient and, if necessary, advise them of any therapies and/or medical procedures that 
might be needed to maintain their health. 
10.6. CLINICAL STUDY TERMINATION 
If the clinical study is prematurely terminated or suspended, Dompé will inform the 
Investigator and the regulatory authorities of the termination/suspension and the reason(s) for 
the termination/suspension. The Investigator should promptly notify the IRB of the trial 
termination or suspension and of the reasons. Dompé reserves the right to close an 
investigational site or terminate the study in its entirety at any time, for any reasonable cause. 
Reasons for the closure of an investigational site or termination of a study may include:  


 
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• Successful completion of the study 
• The study’s enrolment goals are met 
• The Investigator fails to comply with the protocol or GCP guidelines in accordance 
with the ethical principles that have their origins in the Declaration of Helsinki and 
21 CFR §312  
• Safety concerns 
• Sufficient data suggesting lack of efficacy 
• Inadequate recruitment of patients/subjects by the Investigator 
The Investigator may also terminate the study at his/her site for reasonable cause. If Dompé 
terminates the study for safety reasons, it will immediately notify the Investigator(s) by 
telephone and subsequently will provide written confirmation of and instructions for study 
termination. 
 


 
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11. ANALYSIS PLAN 
The primary objective of the study is to assess the safety and tolerability of a 180µg/ml TID 
dose regimen of recombinant human nerve growth factor (rhNGF) eye drop solution 
administered over 8 weeks versus a vehicle control in patients with progressive primary open-
angle glaucoma despite IOP control. 
The secondary objectives are to measure the changes in BCDVA, visual field, ERG and 
structural changes in changes in ganglion cell layer and nerve fiber layer thickness measured by 
optical coherence tomography.  The secondary outcomes will be examined at 1, 4 and 8weeks of 
therapy, and at 4 and 24 weeks after cessation of therapy (Week 12 visit and Week 32 visit), and 
will include functional assessments to investigate evidence of a persistent biological effect after 
discontinuation of the study treatment. 
11.1. SUBJECT EVALUABILITY 
Evaluability for all patients and visits will be determined prior to locking the database and 
breaking the code for masked study medication. 
11.2. ANALYSIS DATA SETS 
The Safety population will include all patients who receive at least one dose of study 
medication. This safety population will be used in the analysis of all safety endpoints. 
The Intent-to-treat (ITT) population will include all randomized patients and will be used for all 
exploratory efficacy analyses. 
11.3. HANDLING OF MISSING DATA 
All data obtained will be used in the analysis and no imputation will be carried out for missing 
data. 
11.4. SAMPLE SIZE JUSTIFICATION 
As the objectives of this study are to evaluate the safety and explore the biological effects of a 
single rhNGF dosage sample size was calculated based on clinical feasibility and no formal 
sample size calculation has been performed. 
Proposed sample size is adequate to make appropriate estimation of study variables. 


 
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However, considering that the active comparator has already proven safe and effective at the 
dosage being tested in this study and there is a solid scientific rationale for treating patients 
suffering of glaucoma with rhNGF, to make the trial more attractive to patients, the 
randomization has been set to a 2:1 active vs vehicle. 


 
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11.5. STATISTICAL ANALYSIS 
Data base will be locked after all patients have completed their Week 12 Visit and main 
objectives analysis will be performed on unmasked data. At the end of the study (i.e. after all 
patients have completed Week 32 Visit), an updated analysis will be performed presenting the 
complete study data. All analysis will be detailed in a statistical analysis plan (SAP). All 
exploratory efficacy variables will be tabulated with the appropriate descriptive statistics at the 
0, 4, 8, 12 and 32 weeks timepoints and appropriate inferential tests with 95% confidence limits 
of the difference between treatments will be produced. 
11.5.1. General Principles 
All patient data collected on the eCRF will be listed by patient, treatment group and center. 
Appropriate descriptive statistics will be produced, according to the variable. For continuous 
data the mean, standard deviation, median and range (minimum and maximum) will be 
presented. For categorical data, frequencies and percentages will be presented. If appropriate, 
95% confidence intervals around the mean or the proportions will be presented. 
In tabulations, denominators for calculation of percentages will be taken as the number of non-
missing responses in the specified analysis population and treatment group unless otherwise 
stated. 
Unless otherwise specified, the significance level used for statistical testing will be 5% and two-
sided tests will be used. 
All variables recorded in the follow-up period will be presented using appropriate descriptive 
statistics, and no formal statistical testing will be performed. 
Full details of all planned data summaries and analyses, with any changes in analyses as detailed 
below will be reported and justified in the Statistical Analysis Plan (SAP).  
11.5.2. Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized for all patients in the safety 
population, by treatment group. 
11.5.3. Extent of Exposure 


 
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Extent of exposure, number of days on study medication, is defined as the difference in days 
between the date of the last instillation of study medication and the date of the first instillation of 
study medication, plus one. For each treatment group, extent of exposure will be summarized 
using N, mean, standard deviation, median, minimum and maximum values. 
11.5.4. Safety Analysis 
Safety variables will be presented for the Safety population. 
The primary safety endpoint in this study is Adverse Events (AEs). AEs will be recorded at the 
scheduled study visits and may also be recorded at any unscheduled visit that occurs during the 
study.  
AEs will be presented, by treatment group, in terms of the incidence, severity and relationship to 
the study drug, overall and by SOC (System Organ Class) and preferred term.  Serious AEs 
(SAEs) will be presented in the same way. All adverse events will be reported by MedDRA 
preferred term. 
The following adverse event summary tables and listings will be provided: 
Tables: 
•  Frequency and Incidence of Subjects with Adverse Events 
•  Frequency and Incidence of Subjects Discontinued Due to Adverse Events 
•  Frequency and Incidence of Subjects with Serious Adverse Events 
•  Adverse Events by Coded Adverse Event and SOC 
•  Overall Frequency and Incidence of Adverse Events  
•  Overall Frequency and Incidence of Adverse Events by Severity 
•  Overall Frequency and Incidence of Treatment-Related Adverse Events 
•  Overall Frequency and Incidence of Adverse Events Occurring at Rates Greater Than 
or Equal to 1.0% 
•  Overall Frequency and Incidence of Adverse Events by Age 
 


 
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Listings: 
•  Concomitant Diseases and Medications for Subjects with Adverse Events by 
Investigator and by Subject 
•  Coded and Descriptive Terms of Adverse Events by Investigator and by Subject 
•  Deaths, Other Serious or Clinically Significant Adverse Events 
•  Adverse Events by Investigator and by Subject 
In addition to reporting of adverse events for any untoward (unfavorable and unintended) 
medical occurrences, adverse events will also be reported for any clinically relevant change from 
baseline in any assessment evaluated during the study, based upon an assessment by the 
Investigator. 
Ocular tolerability as measured by the VAS will be analyzed by means of analysis of variance, 
including terms for treatment, time, and treatment by time interaction. 
Best corrected distance visual acuity, external ocular examination, slit lamp examination, 
intraocular pressure, and dilated fundus ophthalmoscopy, will be presented with the appropriate 
descriptive statistics and shift tables will be used to present shifts from before and after treatment 
at each recording time points. 
11.5.5 Efficacy Analysis 
Exploratory efficacy evaluations will be obtained through longer-term observations of change in 
visual acuity and disease modification, that will be collected over a total of 32 weeks as 
secondary outcomes.  These secondary outcomes of efficacy will be examined, applicable, at 1, 
4and 8 weeks on therapy, and at 4 and 24 weeks (Week 12 visit and Week 32 visit) after 
cessation of therapy, and will include functional assessments:  
• Mean, median, and distribution of change in BCDVA.  
• Changes in visual field using perimetry.  
• Changes in ERG including pattern ERG. 
And structural assessments: 
• Changes in ganglion cell layer and nerve fiber layer thickness measured by optical 
coherence tomography. 


 
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• Changes in mitochondrial redox potential measured by visible light adaptive optics 
approach, combined with in-line OCT.  


 
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12. EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION  
12.1. DEFINITIONS 
12.1.1. Adverse Event  
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject who is administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE, therefore, can be any unfavorable or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not related to the medicinal product. 
12.1.2. Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is any noxious and unintended response to an Investigational 
Medicinal Product (IMP) which is a reasonably likely to have been caused by the drug, at any 
dose administered. The definition covers also medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product.  For the purposes of IND 
safety reporting, “reasonable possibility” means there are facts (evidence) or arguments to 
suggest a causal relationship between the drug and the adverse event. 
12.1.3. Serious Adverse Events  
A serious adverse event (SAE) is defined as any adverse experience that, in view of either the 
Investigator or Sponsor, meets any of the following criteria: 
•  Results in death. 
•  Is life-threatening. 
NOTE: Life-threatening means that the patient was at immediate risk of death from 
the reaction as it occurred, i.e., it does not include an event which hypothetically 
might have caused death had it occurred in a more severe form. 
•  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 
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 •  Results in persistent or significant disability/incapacity or a substantial disruption of 
a person’s ability to conduct normal life functions. 
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 an important medical event. An important medical event 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 (see 
Par. 12.4.2). 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 and a cause of death shall always be specified when 
known. 
12.1.4. Unexpected Adverse Events  
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure 
(reference safety information) or is not listed at the specificity or severity that has been observed 
and listed in the Investigator Brochure. Events that are mentioned in the Investigator Brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation are 
considered unexpected (21 CFR312.32(a)). 
12.1.5 Suspected unexpected serious adverse reaction 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an adverse reaction that 
is both unexpected (not consistent with the applicable product information) and meets the 


 
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definition of a Serious Adverse Reaction. The determination of expectedness should be made on 
the basis of the IB (reference safety information). 
12.1.6. Adverse Events of Special Interest (Sight-threatening Events)  
The following adverse events are considered to be of special interest and by default are to be 
reported as SAEs (medically important criteria): 
 
Adverse Events that cause an unexpectedly severe progression of optic neuropathy as 
measured by central vision loss (i.e. decrease in visual acuity of >30 ETDRS letters or   
> +0.6 LogMAR lasting >1 hour compared with the last assessment of visual acuity at 
the last visit), by visual field testing, or by examination of the optic nerve.  
 
Adverse Events that cause a decrease in visual acuity to the level of Light Perception or 
worse lasting >1 hour. 
 
Adverse Events that require 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, may require medical intervention 
to prevent permanent loss of sight. 
During the study all sight threatening events will be considered equivalent to a SAE and will be 
reported following the procedures described below for the reporting of a SAE.   
12.2. MONITORING FOR ADVERSE EVENTS 
At each visit following study informed consent form signature, after the patient 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 patient's medical health. 
Changes in any protocol-specific ocular or systemic parameter evaluated during the study are to 
be reviewed by the Investigator. In addition, the patient’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 


 
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relevant is to be reported as an AE. These clinically relevant changes will be reported regardless 
of causality. 
 
The Investigator should 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. 
 
In line with ICH E2A provisions, although the Investigator does not usually need to actively 
monitor subjects for adverse events once the trial has ended, if the Investigator becomes aware 
of a serious adverse event occurring to a subject after the treatment of that subject has ended, the 
SAE should be reported by the Investigator to the Sponsor. Such “post-study cases” should be 
regarded for expedited reporting purposes as though they were study reports. Therefore, a 
causality assessment (by the Investigator and by Dompé) and determination of expectedness (by 
Dompé) are needed for a decision on whether or not expedited reporting is required. 
12.3. RECORDING  
Adverse Events: all AEs (non-serious and serious) which occur during the course of the study 
will be recorded in the eCRF. Any pre-existing medical conditions or signs/symptoms present in 
a patient prior to the start of the study (i.e., before informed consent is signed), should be entered 
in the baseline history section of the eCRF of the EDC system. Subsequent to signing an 
informed consent form, all untoward medical occurrences that occur during the course of the 
study must be documented on an Adverse Event Form (AEF) in the eCRF of the EDC system. A 
separate AEF must be filled out for each event. When possible, signs and symptoms indicating a 
common underlying pathology should be documented as one comprehensive event. For each 
recorded event, the AE documentation must include the onset date, outcome, resolution date (if 
event is resolved), intensity (i.e., severity), any action with study treatment taken as a result of 
the event, and an assessment of the adverse event relationship to the study treatment.  
12.3.1. Relationship of AEs to the Investigational Product 
The Investigator will assess the relationship between the AE and the investigational medication, 
according to the criteria in Table below: 


 
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Relationship of the Adverse Event to the IMP 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the investigational 
product, e.g. patient is a passenger in a road traffic accident or surgical 
intervention performed during the study, but planned before patient 
enrolment into the study  
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 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 
investigational product  and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of 
investigational product and, if applicable, re-appears upon repeat 
exposure 
 
An ADR is defined as an adverse experience which is reasonably likely to have been caused by 
the drug. Events considered “Possible”, “Probable” and “Highly Probable” related to the IMP 
treatment and implying a reasonable possibility, if considered serious and unexpected, will be 
reported to appropriate regulatory authorities. 
12.3.2. 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. 
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]) 
 
12.4 Serious Adverse Event Reporting Procedure (from Investigator to CRO/Dompé) 


 
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12.4.1. Reporting Procedure from Investigator to Dompé and CRO 
The Investigator must record all SAEs, including sight-threatening events, occurring at any time 
during the study regardless of presumed causal relationship, on the Serious Adverse Event form 
in the eCRF of the EDC system within 24 hours of learning of the event; information on the 
SAE must also be recorded on a specific Non-Carbon Repeat SAE form (included in the 
Investigator’s Site File) and forwarded to CRO Drug Safety and Dompé Drug Safety, within 24 
hours from first knowledge, to the following addresses: 
- by fax through the e-fax number: +1 347 294 3328 (linked to Dompé Drug Safety and to CRO 
Drug Safety). 
- or, via e-mail to all following addresses:  
 
farmacovigilanza@dompe.com;  
 
DOMPE-NGF-GLA-PV@cromsource.com;  
 
DOMPE-NGF-GLA-MM@cromsource.com. 
In case of unmasking by the investigator, the investigator will fill in the SAE form and all the 
other related documents (query template, narrative etc) with only the kit number of the treatment 
taken by the patient, without disclosing the treatment. 
  
The EDC system will ensure that an automatic email will be generated and sent directly to the 
Dompé pharmacovigilance, trial management, and CRO accountable to receive the study safety 
information and to prompt a review of the reported SAE by the Medical Expert.  
Follow-up reports (as many as required) should be completed and faxed/e-mailed following the 
same procedure 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 
adverse event, i.e. the most relevant one. If other events are listed in the same report, the 
Investigator, along with their relatedness to the Investigational Product, should identify which 
adverse events are serious and which are non-serious. In any case, the Investigator is requested 
to record his/her opinion about the relatedness of the observed event(s) with the investigational 
medication. 
An assessment of expectedness and causality of each serious adverse event will be performed 
case by case by Dompé/CRO. For SAE reported by an Investigator as not related that is 
subsequently revised to be related by Dompé, the Investigator will receive a notification. 
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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 and that therefore are not clinically significant. 
12.4. 3. Expedited Reporting Procedure to IRB and to Regulatory Authorities 
In addition to reporting the SAE to Dompé (and the CRO), the Investigator must also comply 
with the requirements related to the reporting of SAEs to the 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. 


 
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 
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 IRB.  
If the results of an investigation show that an ADR not initially determined to be reportable is 
reclassified as reportable, the Sponsor 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. 
Considering the number of patients enrolled and that the study is monocentric, to prevent any 
risk to compromise the integrity of the study, Dompé will notify the Investigator in a blinded 
fashion of any SUSAR (determined by the Sponsor as related).  
Copies of all correspondence relating to reporting of any SUSARs to the 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, in particular 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. 
Treatment will be unmasked by Sponsor Pharmacovigilance prior to submission of a SUSAR to 
Regulatory Authorities and only cases referred to active treatment will be considered expeditable 
for regulatory reporting, in line with law requirements. 
 
12.4.4.. 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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12.5. UNMASKING OF THE STUDY TREATMENT 
Individual envelopes identified with the subject assignment number have been prepared. Each 
one includes the identity of the treatment assigned to each subject. These envelopes, duly closed 
and sealed, are included into the investigator’s File. 
During the study the integrity of the envelopes will be regularly checked by CRO Monitor 
during the visits at site. At the end of the study all the individual envelopes must be returned to 
Dompé. 
The sealed envelope can only be opened in case of emergency, when knowledge of the treatment 
identity is essential for treating the subject. 
A copy of the Individual envelopes identified with the subject assignment number will be also 
sent to the Dompé Pharmacovigilance Responsible. Dompé Pharmacovigilance will unmask a 
patient treatment only for safety reason and will document envelope opening. 
If the treatment code needs to be broken in the interest of patient safety for a medical 
emergency, the Investigator is allowed to break the treatment code for the specific patient, even 
before informing the Sponsor. The Investigator must always notify the Sponsor, so that the 
reason for any premature unmasking can be documented, by means of a communication to 
CRO/Dompé Drug Safety to the addresses specified at Par. 12.4.1 and to Dompé Medical 
Expert.  
The Investigator will inform the Dompé representative (Dompé Medical Expert) if an 
emergency unmasking was performed without revealing the treatment identity, but only 
referring to the kit number involved in the unmasking in order to avoid a dissemination of 
unmasked information. 
Additionally, Dompé Drug Safety may need to unmask the patient’s treatment if a reported SAE 
meets criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfill 
expedited regulatory reporting requirements. Unmasked information shall not be disclosed to 
Investigators. 
The identity of the treatments will remain unknown to the patient, Investigator, site staff, CRO 
and Dompé’s Development personnel until the study is unmasked after the last enrolled patient 
completes week 12 visit and the database is locked (end of the masked follow-up); afterwards, 
20 additional weeks of follow-up (unmasked follow-up period). 
12.6. 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 


 
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Investigator should follow up the event until resolution or stabilization of the condition.  It is the 
Investigator's responsibility to assure that the subjects experiencing AEs receive definite 
treatment for any AE, if required. 
If patient was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to 
CRO/Dompé 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 CRO/Dompé Drug Safety with an appropriate written 
communication, whenever he 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. Follow-up SAE information should be entered into the EDC and communicated 
through the specific Non-Carbon Repeat SAE form to CRO/Dompé Drug Safety within 24 hours 
from awareness to the addresses specified at Par. 12.4.1. 
For pharmacovigilance purposes, all SAEs should be followed-up in order 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 patient has withdrawn his/her consent. 
12.6. PREGNANCY IN THE CLINICAL TRIAL 
Women of childbearing potential are not excluded from the study as long as 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 in paragraph 7.2. 
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 
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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 CRO/Dompé Drug Safety contacts reported 
at Paragraph 12.4.1, even if no AE has occurred, and follow it to term. If, however, the 
pregnancy is associated with an SAE (eg, 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 12.4.1 with the appropriate serious criterion (eg, hospitalization) indicated on the SAE 
report form. Miscarriage, stillbirth and any malformation/disease must be reported as a SAE. 
Any pregnancy during the 8-week treatment period leads to the immediate exclusion from the 
trial. 
A form prepared by Dompé will be utilized to capture all pregnancy-related information until the 
birth of the child. 
12.7. 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 eCRF, and the patient must be followed up until the resolution of the AE or as 
instructed by the medical monitor. 
12.8. OVERDOSE  
Cases of overdose (accidental or intentional) which result in serious adverse reactions are to be 
handled following emergency procedures, and reported 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 drug intake with suicidal intentions and consequent drug overdose. 
Since in the preclinical toxicology studies in animals and in the multiple ascending dose study 
performed in healthy volunteers none of the doses has caused an overdose, as documented by 
adverse reaction, for the purpose of this study it has been defined that the administration of more 
than 3 times the total daily dose on any given treatment day will be reported as an overdose.  
Overdose shall be reported, even if not associated with adverse reactions, within 24 hours, in a 
SAE form, to CRO/Dompé Drug Safety contacts reported at Paragraph 12.4.1 and to Dompé 
Medical Expert, who should be contacted to discuss corrective treatment, if necessary. 
 


 
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13. DATA HANDLING AND ADMINISTRATIVE REQUIREMENTS 
13.1 COMPLETION OF SOURCE DOCUMENTS AND CASE REPORT FORMS 
The nature and location of all source documents will be identified to ensure that original data 
required to complete the eCRFs exist and are accessible for verification by the site monitor. If 
source documents are kept on electronic records, a verification of the electronic database 
software used at each site must be performed in advance of starting the study. At a minimum, 
source documents should include the following information for each patient: 
 
Patient identification (name, sex, race/ethnicity) 
 
Subject identification number (randomization number) 
 
Documentation of patient eligibility 
 
Documentation relevant to informed consent signature 
 
Dates of visits 
 
Documentation that protocol specific procedures were performed 
 
Results of study parameters, as required by the protocol 
 
Trial medication accountability records 
 
Documentation of AEs and other safety parameters (if applicable) 
 
Records regarding medical histories and the use of concomitant therapies prior 
to and during the study  
 
Date of trial completion and reason for early discontinuation, if applicable.  
It is required that the author of an entry in the source documents is identifiable. Direct access to 
source documentation (medical records) must be allowed for the purpose of verifying that the 
data recorded on the eCRF are consistent with the original source data. 
With the EDC system, the sites will be given access to complete online the eCRFs; only 
designated individuals may complete the eCRFs. The eCRFs will be submitted at regular 
intervals based upon the clinical trial visit schedule. It is expected that all data reported will have 
corresponding entries in the source documents and that the Principal Investigator will review the 
reported data and certify that the eCRFs are accurate and complete. No patient identifiers should 
be recorded on the eCRFs beyond patient number, and demographic information. 
13.2. DATA REVIEW AND CLARIFICATIONS  
The eCRF data will be reviewed against the patient source data by the study monitors to ensure 
completeness and accuracy. After monitoring has occurred at the clinical sites and the eCRFs 


 
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have been submitted, additional data clarifications may be needed. Data clarifications are 
documented and are part of each patient eCRFs. 
13.3 AUDIT PLANS 
Audit activities will be performed by Dompé Quality Assurance or by CRO or other third party 
delegated by Dompé under the supervision of Dompé Quality Assurance.  
On one or more occasions the study site may be audited by Dompé (or designee). The 
Investigator will be informed in advance of audit visits. 
Additionally the study site may be inspected by a regulatory agency on one or more occasions. 
13.4. REGULATORY DOCUMENTATION AND RECORDS RETENTION 
The Investigator is required to maintain up-to-date, complete regulatory documentation as 
indicated by Dompé and the Investigator’s files will be reviewed as part of the ongoing study 
monitoring. Financial information is not subject to regulatory inspection and should be kept 
separately. Additionally, the Investigator must keep study records and source documents until 
Dompé provides written approval for their destruction. The essential documents include at least: 
the signed protocol, signed Patient Informed Consent Forms from all patients who consented, 
hospital records and other source documents, and all other documentation included in the 
Investigator Site File and Pharmacy/Dispensing File. If the Investigator retires, relocates, or for 
any other reason withdraws from responsibility of keeping the study records, Dompé must be 
notified and suitable arrangements made for retention of study records and source documents 
needed to comply with national and international regulations (2 years after discontinuing clinical 
development or after the latest marketing approval). 
Dompé will inform the Investigator in writing when these documents no longer need to be 
retained. 


 
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13.5. 
COMPENSATION 
FOR 
MEDICINE-INDUCED 
INJURY 
AND 
INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance contract covering 
the amount requested by the respective 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. 
Insurance and any updates will be provided to the Investigator before trial commencement for 
filing into the Investigator Site File.  
13.6. STUDY REPORT AND PUBLICATION POLICY 
The data resulting from this study will be the proprietary information of Dompé and will be 
made public after all data have been analyzed and the study results are available. Any 
manuscript, abstract or other publication or presentation of results or information arising in 
connection with the study must not be presented or published in any form, by the investigator or 
any other person, without the prior approval of Dompé and must therefore be submitted to 
Dompé for review and comment at least 45 days prior to submission for publication or 
presentation. At the end of the study, a clinical study report will be written by Dompé or its 
designee. The draft reports will be discussed with the coordinating investigators. 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 


 
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Page 65 of 69 
13.7. 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 
Patient Informed Consent Document.  Patient’s data collected during the study will be handled 
in accordance with applicable data protection laws and regulations.  
On the eCRFs, patients will be identified ONLY by the assigned patient number.  If patient 
names are included on copies of documents submitted to Dompé (or to the CRO appointed by 
Dompé), the names will be obliterated or masked and the assigned patient number added to the 
document. 
 


 
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Page 66 of 69 
14. REFERENCES 
Apfel, 1998 - Apfel SC, Kessler JA, Adornato BT, Litchy WJ, Sanders C, Rask CA. - 
Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF 
Study Group. Neurology 1998;51:695-702. 
Apfel 2000 - Apfel SC, et al, for the rhNGF Clinical Investigator Group. Efficacy and safety of 
recombinant human nerve growth factor in patients with diabetic polyneuropathy. A randomized 
Controlled Trial. JAMA 2000;284:2215-21. 
Bocchini V, 1969 – Bocchini V., Angeletti P.U. - The nerve growth factor:Purification as a 
30,000-molecular-weight protein - Proc Natl Acad Sci U S A. 1969; 64:787-794. 
Chiaretti et al, 2011 - Chiaretti A., Falsini B., Servidei S., Marangoni D., Pierri F. and Riccardi 
R. (2011) Nerve Growth Factor Eye Drop Administration Improves Visual Function in a Patient 
With Optic Glioma. Neurorehabilitation and Neural Repair 2011, 25(4) 386–390. 
Collaborative Normal-Tension Glaucoma Study Group, 1998 - The effectiveness of intraocular 
pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 
1998;126(4):498-505. 
Falsini, 2011 - Falsini B. et al. Topical Nerve Growth Factor as a Visual Rescue Strategy in 
Pediatric Optic Gliomas: A Pilot Study Including Electrophysiology. Neurorehabilitation and 
Neural Repair 2011, 25(6) 512– 520. 
Kwon YH - Kwon YH, Fingert JH, Kuehn MH, Alward WL. Primary open-angle glaucoma. N 
Engl J Med. 2009;360(11):1113-24. 
Lambiase A, 1997 - Lambiase A, Centofanti M, Micera A, Manni GL, Mattei E, De Gregorio A, 
de Feo G, Bucci MG, Aloe L. Nerve growth factor (NGF) reduces and NGF antibody 
exacerbates retinal damage induced in rabbit by experimental ocular hypertension. Graefe’s 
Arch Clin Exp Ophthalmol. 1997;235:780-785. 
Lambiase A, 2009 - Lambiase A, Aloe L, Centofanti M, Parisi V, Mantelli F, Colafrancesco V, 
Manni GL, Bucci MG, Bonini S, Levi-Montalcini R. - Experimental and clinical evidence of 
neuroprotection by nerve growth factor eye drops: Implications for glaucoma - Proc Natl Acad 
Sci U S A. 2009 Aug 3. 


 
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Lambiase A, 2005 - Lambiase A, Tirassa P, Micera A, Aloe L, Bonini S. - Pharmacokinetics of 
conjunctivally applied nerve growth factor in the retina and optic nerve of adult rats - Invest 
Ophthalmol Vis Sci. 2005 Oct;46(10):3800-6. 
Lambiase A, 1998 - Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. - Topical treatment 
with nerve growth factor for corneal neurotrophic ulcers - N Engl J Med. 1998 Apr 
23;338(17):1174-80. 
Lambiase A, 2010 - Lambiase A, Mantelli F, Bonini S. - Nerve growth factor eye drops to treat 
glaucoma. - Drug News Perspect. 2010 Jul-Aug;23(6):361-7. 
Lavail MM, 2005 - Lavail MM. - Survival factors for treatment of retinal degenerative disorders: 
preclinical gains and issues for translation into clinical studies - Retina. 2005 Dec;25(8 
Suppl):S25-S26. 
Lenzi L, 2005 - Lenzi L, Coassin M, Lambiase A, Bonini S, Amendola T, Aloe L - Effect of 
exogenous administration of nerve growth factor in the retina of rats with inherited retinitis 
pigmentosa - Vision Res. 2005 Jun;45(12):1491-500. 
Levi-Montalcini R, 1987 - Levi-Montalcini R. - The nerve growth factor 35 years later - 
Science. 1987 Sep 4;237(4819):1154-62. 
McArthur, 2000 - McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, 
Hollander H, Marra C, Rubin M, Cohen BA, Tucker T, Navia BA, Schifitto G, Katzenstein D, 
Rask C, Zaborski L, Smith ME, Shriver S, Millar L, Clifford DB, Karalnik IJ. A phase II trial of 
nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials 
Group Team 291. Neurology 2000; 54:1080-88. 
Quigley HA, 1996 - Quigley HA. Number of people with glaucoma worldwide. Br J 
Ophthalmol. 1996;80(5):389-93. 
Roberti G, 2014 - Roberti G, Mantelli F, Macchi I, Massaro-Giordano M, Centofanti M. Nerve 
Growth Factor Modulation of Retinal Ganglion Cell Physiology. J Cell Physiol. 2014 Feb 6. 
Schifitto, 2001 - Schifitto G, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander 
H, Marra CM, Rubin M, Cohen BA, Tucker T, Koralnik IJ, Katzenstein D, Haidich B, Smith 
ME, Shriver S, Millar L, Clifford DB, McArthur JC; AIDS Clinical Trials Group Team 291. 
Long-term treatment with recombinant nerve growth factor for HIV-associated sensory 
neuropathy. Neurology. 2001 Oct 9;57(7):1313-6. 


 
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Sposato V, 2009 - Sposato V, Parisi V, Manni L, Antonucci MT, Di Fausto V, Sornelli F, Aloe 
L. Glaucoma alters the expression of NGF and NGF receptors in visual cortex and geniculate 
nucleus of rats: effects of eye NGF application. Vision Research. 2009;49:54-63. 
Ullrich A, 1983 - Ullrich A, Gray A, Berman C, Coussens L, Dull TJ. - Sequence homology of 
human and mouse beta-NGF subunit genes - Cold Spring Harb Symp Quant Biol. 1983;48 Pt 
1:435-42. 
Weinreb RN, 2004 - Weinreb RN, Khaw PT. Primary open-angle glaucoma. Lancet. 
2004;363(9422):1711-20. 
  


 
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15. APPENDIX A 
 
 
 
Instructions for the reconstitution of freeze-dried drug product 
1) take out vial, syringe and adaptor from relative secondary packaging 
2) put the adaptor on the top of the vial (after removing the plastic seal) by piercing the 
septum 
3) put the syringe on adaptor inlet 
4) deliver the syringe content in the vial and gently shake until the powder dissolves 
5) put the vial/syringe assembly upside down and withdraw part of the content 
6) remove the syringe and use it as a dropper  
 
1 
 
 
 
 
2 
 
 
 
 
 
3 
4 
 
 
 
 
5 
 
 
 
 
 
6 

SAP_001.pdf: 
 
 
 
 
Dompé farmaceutici S.p.A. 
 
An 8 Week phase Ib, monocentric, randomized, double-
masked, vehicle controlled, parallel group, study with a 24 
Week  follow-up period to evaluate the safety and potential 
efficacy of a 180 µg/ml recombinant human nerve growth 
factor (rhNGF) eye drops solution versus vehicle in 
patients with glaucoma 
 
 
Protocol/CIP No: NGF0314 
IND Number: 124304 
 
Statistical Analysis Plan 
 
 
Version 1.0 
Final 
09 Feb 2018 
 
 
Author: Paul Koopman/Monika Rost 
 
CROMSOURCE  
 
 






 
Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Version History 
 
Version 
Date 
Reason for Change 
Final 1.0 
09 Feb 2018 
Initial Version 
 
CONFIDENTIAL 
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_____________________________________________________________________________________________________________________________________ 
 
 
 


 
Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Table of Contents 
1 SOPs to be followed .......................................................................... 7 
2 Abbreviations ..................................................................................... 8 
3 Protocol / Clinical Investigation Plan .............................................. 10 
3.1 Study Objectives ............................................................................................ 10 
3.2 Study Design................................................................................................... 10 
3.3 Study Schedule ............................................................................................... 10 
3.4 Primary and Secondary Outcomes ............................................................... 13 
3.5 Interim Analyses ............................................................................................. 13 
3.6 Changes in the Conduct of Study or Planned Analysis compared to 
Protocol ................................................................................................................. 13 
4 General Definitions .......................................................................... 14 
4.1 Report Language ............................................................................................ 14 
4.2 Analysis Software ........................................................................................... 15 
5 Data Preparation .............................................................................. 16 
5.1 Data Handling and Medical Coding ............................................................... 16 
5.2 CDISC .............................................................................................................. 16 
5.3 SAS-Programming Quality Level .................................................................. 16 
6 Analysis Sets and Subgroups ......................................................... 17 
6.1 Analysis Sets .................................................................................................. 17 
6.2 Subgroup Definitions ..................................................................................... 17 
7 Definition of Time Points and Analysis Variables.......................... 18 
7.1 Definition of Time Points ............................................................................... 18 
7.2 Analysis Variables .......................................................................................... 19 
7.2.1 Disposition and Protocol Deviations ............................................................ 19 
7.2.2 Demographics ............................................................................................. 20 
7.2.3 Glaucoma History and Other Medical/Surgical History ................................ 20 
7.2.4 Concomitant Medication .............................................................................. 20 
7.2.5 Measurements of Exposure and Treatment Compliance............................. 22 
7.2.6 Study Medication ......................................................................................... 24 
7.2.7 Primary Safety Outcomes ............................................................................ 24 
7.2.8 Primary Tolerability Outcome ...................................................................... 25 
7.2.9 Exploratory Secondary Efficacy Outcomes ................................................. 25 
7.2.10 Safety Variables – Adverse Events ........................................................... 27 
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7.2.11 Other Safety Parameters ........................................................................... 29 
8 Analysis Methods ............................................................................. 33 
8.1 General Methods ............................................................................................ 33 
8.2 Specific Methods for Primary Safety and Tolerability Analyses ................ 33 
8.3 Specific Methods for Exploratory Efficacy Analyses .................................. 34 
8.4 Statistical/Analytical Issues........................................................................... 34 
8.4.1 Adjustments for Covariates ......................................................................... 34 
8.4.2 Handling of Dropouts or Missing Data ......................................................... 34 
8.4.3 Data Review ................................................................................................ 34 
8.4.4 Multicentre Studies ...................................................................................... 35 
8.4.5 Multiplicity of Endpoints ............................................................................... 35 
9 Main Objective and Final Analyses ................................................. 36 
9.1 Main Objective Analysis ................................................................................ 36 
9.2 Final Analysis ................................................................................................. 36 
10 Overview of Tables, Listings and Figures .................................... 36 
10.1 Disposition of Patients ................................................................................. 36 
10.2 Protocol Deviations ...................................................................................... 37 
10.3 Inclusion and Exclusion Criteria ................................................................. 37 
10.4 Demographic and Other Baseline Characteristics .................................... 37 
10.4.1 Demographic Characteristics .................................................................... 37 
10.4.2 Glaucoma and Other Medical/Surgical History .......................................... 37 
10.4.3 Prior/Concomitant Medications .................................................................. 38 
10.5 Exposure and Compliance to Study Medication ........................................ 38 
10.6 Primary Study Outcomes ............................................................................. 38 
10.6.1 Primary Safety Outcomes .......................................................................... 38 
10.6.2 Primary Tolerability Outcomes .................................................................. 38 
10.7 Secondary Explorative Efficacy Outcomes ................................................ 38 
10.7.1 Change in Best-Corrected Distance Visual Acuity ..................................... 39 
10.7.2 Changes in Visual Field Testing ................................................................ 39 
10.7.3 Changes in ERG ....................................................................................... 39 
10.7.4 Ocular Coherence Tomography (OCT) ..................................................... 39 
10.8 Adverse Events and Further Safety Assessments .................................... 40 
10.8.1 Adverse Events ......................................................................................... 40 
10.8.2 Laboratory Assessments ........................................................................... 41 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
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10.8.3 BCDVA assessments for Safety Evaluation .............................................. 41 
10.8.4 External Ocular Examination ..................................................................... 41 
10.8.5 Slit Lamp Examination ............................................................................... 41 
10.8.6 Intraocular Pressure .................................................................................. 42 
10.8.7 Dilated Fundus Ophthalmoscopy .............................................................. 42 
11 References ...................................................................................... 43 
12 Tables, Listings and Figures ......................................................... 44 
13 Appendices ..................................................................................... 48 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
1 SOPs to be followed 
The statistical analysis will be carried out according to the following CROMSOURCE 
standard operation procedures (SOPs): 
 
SOP number 
SOP title 
SOP-ST-03 
Statistical Analysis Plan 
SOP-ST-04 
SAS Programming and Validation 
SOP-ST-05 
Data Review Meeting 
SOP-ST-06 
Study Unblinding for Analysis 
SOP-ST-07 
Statistical Report 
SOP-ST-08 
Trial Statistics File 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
2 Abbreviations 
 
Acronym 
Definition 
ADAM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
BCDVA 
Best Corrected Distance Visual Acuity 
BDRM 
Blind Data Review Meeting 
CDISC 
Clinical Data Interchange Standards Consortium 
CSF 
Central Subfield Thickness 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ERG 
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
HVF 
Humphrey Visual Field 
I 
Inferior 
IIM 
Inferior of Inner Ring 
IN 
Inferior Nasal 
INF 
Inferior 
IOM 
Inferior of Outer Ring 
IOP 
Intraocular Pressure 
IT 
Inferior Temporal 
ITT 
Intent-to-Treat Set 
MRP 
Mitochondrial Redox Potential 
N 
Nasal 
NIM 
Nasal of Inner Ring 
NOM 
Nasal of Outer Ring 
OCT 
Ocular Coherence Tomography 
PT 
Preferred Term 
QC 
Quality Control 
rhNGF 
Recombinant Human Nerve Growth Factor 
RNFL 
Retinal Nerve Fiber Layer 
S 
Superior 
SAE 
Serious Adverse Event 
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Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Acronym 
Definition 
SAF 
Safety Set 
SAF-F 
Patients in the SAF, who entered the Follow-Up Period 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SDTM 
Study Data Tabulation Model 
SIM 
Superior of Inner Ring 
SN 
Superior Nasal 
SOC 
System Organ Class 
SOM 
Superior of Outer Ring 
SOP 
Standard Operation Procedure 
ST 
Superior Temporal 
SUP 
Superior 
T 
Temporal 
TEAE 
Treatment Emergent Adverse Event 
TID 
Ter In Die (i.e. Three times a day) 
TIM 
Temporal of Inner Ring 
TLF 
Tables, Listings and Figures 
TOM 
Temporal of Outer Ring 
TOT 
Total Set 
USPON 
Unexpected Severe Progression of Optic Neuropathy 
VAS 
Visual Analogue Scale 
WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
3 Protocol / Clinical Investigation Plan 
This NGF0314 study is conducted under the sponsorship of Dompé farmaceutici S.p.A. The 
clinical monitoring, data management, statistical analysis and medical writing are performed 
by CROMSOURCE under contract and in collaboration with Dompé farmaceutici S.p.A. 
This Statistical Analysis Plan (SAP) provides a complete, expanded and detailed description 
of the planned statistical methods outlined in the study protocol Final Version 2.0 of 
04 November 2016. Text that has been copied from the protocol is formatted in italics to 
indicate that it is identical to the protocol, which will ease the review and will avoid 
unnecessary alterations to text approved in the protocol. 
It lists all Tables, Listings and Figures (TLFs), which will be produced by CROMSOURCE for 
the main objective and final analyses and are used for inclusion in the Clinical Study Report 
(CSR) and/or Statistical Report. This excludes presentation of results from mitochondrial 
redox potential (MRP), which will be reported separately. 
3.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of a 180µg/ml TID 
dose regimen of recombinant human nerve growth factor (rhNGF) eye drop solution 
administered over 8 weeks versus a vehicle control in patients with progressive primary 
open-angle glaucoma despite IOP control. 
The secondary objectives are to measure the changes in BCDVA, visual field, ERG and 
structural changes in changes in ganglion cell layer and nerve fiber layer thickness measured 
by optical coherence tomography. The secondary outcomes will include functional 
assessments to investigate evidence of a persistent biological effect after discontinuation of 
the study treatment. 
3.2 Study Design 
This is a masked, randomized, single-dose, monocentric phase 1b trial of 60 study 
participants with chronic primary open angle glaucoma. Participants may qualify with either 
progressive optic neuropathy despite maximal current therapy (i.e. IOP reduction), or with 
stabilized IOP but diminished vision (central or peripheral). Participants with a qualifying eye 
will be randomized 2:1 to topical recombinant human nerve growth factor (rhNGF) therapy or 
vehicle placebo control. Eligible patients will self-administer 1 drop of study medication three 
times a day in both eyes for 8 weeks of treatment. Examinations for safety and efficacy will 
occur one week following initiation of therapy, and at 4, 8, 12 and 32 weeks. All participants 
in either arm will be followed clinically at 4 weeks after cessation of therapy. 
3.3 Study Schedule 
The protocol visit plan and specification of study procedures and examinations per visit is 
summarized in Table 1 below. Required procedures for a scheduled visit may be performed 
over 2 consecutive days. The Day 0 Therapy Initiation Visit will usually take 2 consecutive 
days, the 1st day to perform ophthalmologic assessments, to decide on eligibility and to 
assign randomization at the end of the day, starting the treatments at the beginning of the 2nd 
day. Administration of the first 2 doses will be performed at site, whereas all consecutive 
doses will be self-administered by patients. 
If a patient returns to the clinic prior to their next scheduled study visit for assessment of an 
adverse event, an Unscheduled Visit should be conducted. Procedures conducted at the 
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Version 2.0, date 15/DEC/2014 
Unscheduled Visit are at the discretion of the Investigator and may be among the study 
procedures or additional procedures not performed during the study but deemed necessary 
by the investigator. The clinical information obtained during any unscheduled visit is to be 
recorded in the electronic Case Report Forms. 
Any patient who exits early from the study must undergo all procedures outlined at Week 8 
Visit if the discontinuation occurs at or before Week 8 Visit; the Week 8 Visit assessments 
should be completed for all patients, as assessments of the Early Exit Visit. Additionally, the 
Exit (End of Study) Form must be completed. 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Table 1:  Schedule of Events 
Scheduled Visit Week 
Baseline Visit 
(Screening)1 
Day 0 
Therapy Initiation 
Week 1 (± 2 days) 
Week 4 (±4 days) 
Week 8 (± 7 days) 
Week 12 (± 7 days) 
Week 32 (± 7 days) 
General Assessments 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Inclusion / Exclusion criteria 
X 
X 
 
 
 
 
 
Pregnancy test (if applicable) 
 
X 
 
 
X 
 
 
Demographics, Medical History, Medications2 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
Visual System Exams 
 
 
 
 
 
 
 
Best Corrected Distance Visual Acuity (BCDVA) 
X 
X 
 
 
X 
X 
X 
Intraocular Pressure (IOP)3 
X 
X 
X 
X 
X 
X 
X 
Slit lamp examination 
X 
X 
X 
X 
X 
X 
X 
External ocular examination 
X 
X 
X 
X 
X 
X 
X 
Humphrey 24-2 or 10-2 Visual Field4 
X5 
X 
X6 
X7 
Dilated Fundus Ophthalmoscopy  
X 
X 
 
 
X 
X 
X 
OCT (retinal thickness) 
 
X 
 
 
X 
X 
X 
Mitochondrial redox potential 
 
X 
 
X 
X 
X 
X 
Full field and pattern ERG8 
 
X 
 
 
X 
X 
X 
Study Therapy 
 
 
 
 
 
 
 
Visual Analogue Scale (VAS) for ocular tolerability 
 
X 
X 
X 
X 
X 
 
Study drug dispensing9 
 
X 
 
X 
 
 
 
Assess medication dosing compliance10 
 
 
 
X 
X 
 
 
 
1  
Baseline Screening Visit will occur within 4 weeks prior to initiating therapy. 
2  
Demographic information collected only at screening visit including medications taken within the preceding 30 days. 
3 
IOP testing will be performed using Goldmann Tonometer. 
4 
Visual Field testing will be performed using Sita Standard. 
5 
2 fields on different days for a total of 3 before initiating treatment. 
6 
3 fields within 4 weeks until the end of treatment. 
7 
3 fields within 4 weeks until the end of follow-up. 
8 
Full-field performed once at Therapy Initiation (Day 0) visit, at Week 8, at Week 12 and at Week 32. 
9 
At Day 0 instruct the patient to self-administer drug at home and return to next planned visit. 
10 
At Week 4 and 8 patient will be instructed to return all used and unused investigational product and the freezer bag. 
 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
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Version 2.0, date 15/DEC/2014 
3.4 Primary and Secondary Outcomes 
The primary objective is to evaluate the safety and tolerability of rhNGF vs Vehicle.  
The primary safety outcomes of the study are:  
• 
Unexpectedly severe progression of optic neuropathy as measured by central 
vision loss, by visual field testing, or by examination of the optic nerve 
• 
Intolerance or allergy to the drug 
• 
Adverse events affecting ocular function or eye pressure, which differ from those 
expected in the course of glaucoma, which are thought to be potentially related to 
the drug 
• 
Local or systemic toxicities considered serious adverse events that are potentially 
related to the drug 
The primary tolerability outcome of the study are: 
• 
Outcome from Ocular tolerability questionnaire using visual analogue scales (VAS) 
Exploratory secondary efficacy outcomes based on functional and structural assessments of 
the study are: 
• 
Change in BCDVA 
• 
Changes in visual field using perimetry  
• 
Changes in ERG including pattern ERG 
• 
Changes in ganglion cell layer and nerve fiber layer thickness measured by optical 
coherence tomography (OCT) 
• 
Changes in mitochondrial redox potential (not considered in this SAP) 
Details for all specified primary and secondary outcomes are provided in section 7.2 of the 
SAP. 
3.5 Interim Analyses 
No interim analysis is planned.  
However, the database will be locked after all patients have completed their Week 12 Visit 
and main objectives analysis will be performed on unmasked data. A Blind Data Review 
Meeting will take place after the last enrolled patient completes Week 12 Visit and before 
unmasking of the study 
At the end of the study (i.e. after all patients have completed Week 32 Visit), an updated 
analysis will be performed presenting the complete study data. 
Further details on the two distinguished analyses are provided in section 9 of this SAP. 
3.6 Changes in the Conduct of Study or Planned Analysis compared to 
Protocol 
The following changes of the study conduct did affect the planned analysis: 
• 
Mitochondrial Redox potential: during the set-up process of the eCRF, test type and 
Index number were identified as endpoints to evaluate MRP. However, it was not 
possible at the site to identify an index number for each patient for data entry to the 
eCRF. In July 2017, it was decided by the sponsor, that no data will be entered on the 
eCRF and reporting of MRP assessments will be performed separately by the 
investigator. 
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• 
Changes in ERG including pattern ERG: during the set-up process of the eCRF, it 
was planned to assess the following data from performed ERG into the eCRF: 
Result (Normal/Abnormal), Amplitude A1-B1 Photopic 3.0 (0.5 Hz), Latency ISO-B1 
Photopic 3.0 (0.5 Hz), Amplitude ISO-B1 Scotopic 0.01 (0.5 Hz), Latency ISO-B1 
Scotopic 0.01 (0.5 Hz), Amplitude ISO-B1 Photopic 3.0 Flicker 30Hz, Latency ISO-B1 
Photopic 3.0 Flicker 30 Hz, Amplitude N1-P1 wave oscillatory potential (1 Hz), 
Latency N1-P1 wave oscillatory potential (1 Hz). 
In July 2017, based on investigator’s proposal, it was decided to use phototopic 
negative response number (phNR) as a more relevant measure of assessing ERG 
changes (Kim, Park, Ohn, 2010), which will be chosen for analysis and be recorded 
on the eCRF alternatively. 
• 
Humphrey Visual Field assessment (HVF): it was recognized at site, that for patients 
with low vision, HVF assessment could not be performed according to SITA-
Standard. For these patients the FASTPAC standard will be applied (see protocol 
clarification letter as of 04AUG2017). The output for these assessments differ from 
SITA standard by not providing information on mean deviation, standard deviation 
and 
visual 
field 
index. 
The eCRF was changed to enable a proper statistical evaluation by adding applied 
algorithm (SITA/FASTPAC) and a qualitative evaluation of the change in visual fields 
(pre-treatment assessment/improved/no change/worsened, not assessable) to enable 
a statistical evaluation of secondary endpoint “Change in HVF”. However, completion 
of this qualitative assessment was refused by the investigator. According to sponsor’s 
decision on 17NOV2017, results of HVF assessments will not be analysed but listed 
only. 
This does not affect the evaluation of primary outcome “Unexpected severe 
progression of optic neuropathy measured on HVF or optic nerve examination”.  
The following refinements of the pre-planned analysis in the study protocol were 
implemented in this SAP: 
• 
The study protocol defines the Safety Set as all treated patients. However, the Safety 
Set will serve a primary analysis cohort for the primary study objectives. To ensure 
formal maintenance of randomization, the Safety Set will be refined to “all randomized 
patients who received at least one study treatment”. It is notable, that randomization 
and dispensation of first study medication are both performed at site within one 
process. So, it is not expected that a patient would be treated without being 
randomized.  
• 
Study protocol section 11.5.4 provides specifications of tables and listings for 
displaying documented AEs. This presentation of data will be aligned to data 
presentation of other studies investigating rhNGF to facilitate data interpretation. This 
change is purely organizational without omitting any data presentation described in 
the study protocol with one exception: due to the relative few numbers of patients, no 
separate listing of concomitant disease and medications will be provided for patients 
with adverse events.  
4 General Definitions 
4.1 Report Language 
The TLFs as output of the analyses will be prepared in English. 
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Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
4.2 Analysis Software  
The statistical analysis will be performed using the SAS® statistical software package 
(Statistical Analysis System, Version 9.3 or later). 
 
 
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5 Data Preparation 
5.1 Data Handling and Medical Coding 
For data quality control and medical coding, please refer to the Data Management Plan, 
including the Data Validation Plan in its most recent version. 
5.2 CDISC 
All output as defined in the SAP will be generated based on CDISC ADaM datasets following 
ADaM implementation Guide 1.0, as per contract with Dompé farmaceutici S.p.A. SDTM 
programming will follow SDTM version 1.3 together with SDTM implementation guide 3.1.3. 
Specifications for the ADaM datasets (as well as SDTM datasets) are described in a 
separate document. 
5.3 SAS-Programming Quality Level 
The following quality level of programming deliverables will be applied, as per contract with 
Dompé Farmaceutici S.p.A. All statistical output will receive a tailored Quality Control (QC) 
approach by: 
• 
Full independently double programmed reproduction of CDISC: 
o 
SDTM datasets 
o 
ADaM datasets 
• 
Full independently double programmed reproduction of results of  
o 
Primary endpoint analysis and its underlying analysis dataset(s) and table(s),  
o 
Randomization merging 
o 
Analysis population merging, and  
o 
Visit windows programming  
• 
Listings will not be double programmed. 
• 
All other tables will be given a reduced QC involving independent reproduction (i.e. 
double programming or manual cross checking a subset of patients) of approximately 
20% of the summary results (selection to be agreed upon with the sponsor). 
• 
All tables and listings will undergo comparison with specification (i.e. SAP and 
templates), cross checking with other tables and listings, a sensibility review and 
SAS-log review. 
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6 Analysis Sets and Subgroups 
6.1 Analysis Sets 
Evaluability for all patients and visits will be determined during a Blind Data Review Meeting, 
which will take place before unmasking the study for the main objective analysis (i.e. 
comprising data up to Week 12 Visit). 
The Total Set (TOT) will include all patients that have signed informed consent. 
The Intent-to-treat Set (ITT) will include all randomized patients and will be used for all 
exploratory efficacy analyses. All analyses based on the ITT will be summarized by the 
treatment randomized. 
The Safety Set (SAF) will include all randomized patients who receive at least one dose of 
study medication. This safety population will be used in the analysis of all safety endpoints.  
A subset of all patients in the SAF, who entered the Follow-Up Period (SAF-F), will be used 
in addition to present event-type analyses of the Follow-Up Period. A patient will therefore be 
considered as entering the Follow-Up Period, if he/she did not terminated the study at or 
before the Week 8 visit.  
All analyses based on the SAF and SAF-F will be summarized by the treatment received. 
For the study, both eyes are under investigation. For each patient, a Primary (Study) Eye and 
a corresponding Secondary Eye will be defined during a Blind Data Review Meeting (BDRM) 
to enable a patient based presentation of statistical analyses. 
For each patient, an eye will be considered as Primary Eye, if 
• 
the eye was treated and  
• 
the investigator considered this eye as qualifying eye. 
If both eyes are considered as qualifying eye, the right eye will be chosen. 
The other eye will then be considered as Secondary Eye, if the eye was treated. If the other 
eye was not treated with study medication, no Secondary Eye will be assigned for this 
patient. 
6.2 Subgroup Definitions 
For the presentation of adverse events by age, age categories ‘≤ 65 years’ and ‘>65 years’ 
will be applied. 
 
 
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7 Definition of Time Points and Analysis Variables 
7.1 Definition of Time Points 
The study consists of 7 scheduled clinical evaluation visits: Screening Visit, Baseline Visit 
(Therapy Initiation), Week 1, Week 4, Week 8, Week 12 and Week 32 Visit. Week 1 Visit has 
a window of ±2 days, Week 4 Visit has a window of ±4 days, while Week 8, 12, 32 Visits 
have a window of ±7 days, at the discretion of the investigator, required procedures for a 
scheduled visit may be performed over 2 consecutive days. 
If a patient returns to the clinic prior to their next scheduled study visit for assessment of an 
adverse event, an Unscheduled Visit should be conducted. Procedures conducted at the 
Unscheduled Visit are at the discretion of the Investigator. 
Any patient who exits early from the study must undergo all procedures outlined at Week 8 
Visit if the discontinuation occurs at or before Week 8 Visit. 
All assessments except event type data will be analysed according to the nominal Visit 
identifier on the CRF page, irrespective of meeting the time window as specified in the study 
plan and of having the procedures performed over 1 or 2 consecutive days. 
This rule does not hold for patients, who terminate study during treatment. For these 
patients, the visit needs to be shifted to Week 1, Week 4 or Week 8 visit depending on the 
visit window specified below. 
Unscheduled visits will not be considered for by-visit analyses but all collected data will be 
listed. Documented unscheduled visits will be labelled as “Unscheduled Visit x.01”, 
“Unscheduled Visit x.02”, “Unscheduled Visit y.01” etc. indicating the number of the last 
preceding visit plus a consecutive sequence number. 
The Baseline value is generally defined as the last non-missing measurement collected or 
derived prior to the first Study Treatment Administration as recorded on eCRF page 
“Administration of Study Drug’ in variables Date/Time of Application of First Dose. 
The Treatment Day of an event/assessment will be calculated relative to the First Study 
Treatment [defined as Variable “Date of First Dose Treatment’, recorded on “Study Drug 
Dosing Dates’ eCRF form]. 
The Treatment Day of events/assessments occurring before the First Study Treatment will be 
calculated as: 
• 
Treatment Day = (Date of assessment/event - Date of First Study Treatment). 
For events/assessments occurring on or after First Study Treatment Administration, 
Treatment Day will be calculated as: 
• 
Treatment Day = (Date of assessment/event - Date of First Study Treatment) + 1. 
 
 
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Table 2: Study Visits 
Scheduled Visit   
Scheduled 
Visit Label 
Scheduled 
Study Day 
Visit Window 
Screening Visit 
Screening 
Before 
Baseline Visit 
Up to 4 weeks before date of Baseline Visit 
Baseline Visit Day 0 
Baseline 
0 
Date of Baseline Visit – Date of First Study 
Treatment in [-1, 0] 
Week 1 
Week 1 
7 
Visit date – Date of First Study Treatment in 
[5 – 9] 
Week 4 
Week 4 
28 
Visit date – Date of First Study Treatment in 
[24 – 32] 
Week 8 
Week 8 
56 
Visit date – Date of First Study Treatment in 
[49 – 63] 
Follow-up Visit Week 12 
Week 12 
84 
Visit date – Date of First Study Treatment in 
[77 – 91] 
Follow-up Visit Week 32 
Week 32 
224 
Visit date – Date of First Study Treatment in 
[217 – 231] 
Documented unscheduled Visits will be labeled as “Unscheduled Visit x.01”, “Unscheduled Visit x.02”, 
“Unscheduled Visit y.01”… . 
Date of First Study Treatment is to be taken from eCRF page “Study Drug Dosing Dates’. 
 
7.2 Analysis Variables 
This section describes all variables that are used for analysis as well as their source data 
variables. The other (raw) data variables will be described in section 10. For each variable it 
is specified how missing values will be handled, if applicable. 
7.2.1 Disposition and Protocol Deviations 
Disposition parameters are recorded on the eCRF Page ‘End of Study’. 
Study discontinuations will be defined only for randomized patients.  
A patient discontinued the study prematurely, if the question ‘Did the patient complete the 
study’ was answered as ‘No’. A patient is considered as study completer, if the question ‘Did 
the patient complete the study’ was answered as ‘Yes’. Otherwise the patient is considered 
as ‘Ongoing’. 
Primary Reason for Study Discontinuation is documented on the eCRF Page ‘End of Study’ 
in categories ‘Adverse Event’, ‘Lost to Follow-Up’, ‘Decision unrelated to an Adverse Event’, 
‘Non-Compliance’, ‘Study terminated by the sponsor’, ‘Study terminated by the investigator’, 
‘Other’. 
If the date of study discontinuation/study completion as documented on the eCRF page ‘End 
of Study’ is less or equal than 63 days after the date of first study drug administration as 
documented on eCRF Page ‘Study Drug Dosing Dates’, discontinuation will be considered as 
‘During Treatment Period’, otherwise it will be considered as ‘During Follow-Up Period’. 
A patient is considered as Completer of the Treatment Period, if he has a documented Week 
8 Visit and did not discontinue the study during the treatment period. 
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If the eCRF question ‘Was the emergency envelope opened during the study?’ was 
answered ‘Yes’, the patient will be considered as unmasked. 
Protocol deviations will be collected during the study and reviewed during the BDRM 
according to a separate BDRM plan. During the BDRM, identification of CSR reportable 
protocol deviations and further categorization of deviations for TLF output will be performed. 
For the analysis, the CSR reportable protocol deviations as documented in the BDRM 
minutes will be presented. 
7.2.2 Demographics 
Demographic characteristics are recorded on the eCRF page “Demography”. 
Gender (Male, Female), Ethnicity (‘Hispanic, Latino, Spanish’, ‘Not Hispanic, Latino, 
Spanish’), and Race (‘White’, ‘Black or African American’, ‘Asian’, ‘Native Hawaiian or Other 
Pacific Islander’, ‘American Indian or Alaska Native’, ‘Other’) will be analyzed as recorded on 
the eCRF. 
Age (years) at Screening is calculated as: 
• 
INT((date of informed consent - date of birth)/365.25). 
In case of incomplete dates, missing days will be set to 1st and missing months will 
be set to July. 
7.2.3  Glaucoma History and Other Medical/Surgical History 
Details on Glaucoma history are recorded on eCRF Page ‘Glaucoma History’. 
Analysis variables for Glaucoma history are: 
• 
Presence of chronic primary open angle glaucoma (Yes/No) as documented on the 
eCRF Page. 
• 
Symptomatic Eyes (Right Eye only, Left Eye only, Both Eyes) derived from the 
respective eCRF question 
• 
Primary Eye (Right Eye, Left Eye) as defined in the BDRM minutes. 
• 
Secondary Eye (Right Eye, Left Eye, None) as defined in the BDRM minutes 
All other medical history is recorded on the “Medical history” eCRF page, whereas surgical 
history is recorded on the ‘Surgical History’ eCRF Page. Medical history contains information 
about conditions that a patient might have suffered prior to Baseline visit, or conditions that 
are ongoing at the time of the Baseline visit. The medical history terms as well as surgical 
history terms as specified by the investigator will be coded to a Preferred Term (PT) and a 
System Organ Class (SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) 
thesaurus.  
If no coding information will be available for a specific medical/surgical history record, the 
record will be presented as ‘Uncoded Record’. However, for final TLFs it is anticipated that all 
medical/surgical history records are coded. 
7.2.4 Concomitant Medication 
Prior and Concomitant medication data will be collected throughout the study on the ‘Prior / 
Concomitant Medications’ CRF page. 
All medications will have a calculated start and stop day to enable categorization of the 
medications as ‘Prior’ or ‘Concomitant’: 
• 
Start Day is defined as:  
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o Start Date of Medication – Date of First Study Treatment Administration + 1 
If the Start Date of the Medication is greater than or equal to the Date of First 
Study Treatment Administration as provided on eCRF page ‘Study Drug 
Dosing Dates’ 
o Start Date of Medication – Date of Study Treatment Administration 
If the Start Date of the Medication is less than the Date of Study Treatment 
Administration as provided on eCRF page ‘Study Drug Dosing Dates’ 
• 
Stop Day is defined as:  
o Stop Date of Medication – Date of First Study Treatment Administration + 1 
If the Stop Date of the medication is greater than or equal to the Date of First 
Study Treatment Administration as provided on eCRF page ‘Study Drug 
Dosing Dates’ 
o Stop Date of Medication – Date of Study Treatment Administration 
If the Stop Date of the Medication is less than the Date of Study Treatment 
Administration as provided on eCRF page ‘Study Drug Dosing Dates’ 
‘Prior medications’ are medications that were started before and stopped before or on the 
day of First Study Treatment Administration as provided on eCRF page ‘Study Drug Dosing 
Dates’. 
‘Concomitant medications’ include all medications that a patient used during the Treatment 
or Follow-Up Period of the study.  
Any medication started prior to First Study Treatment Administration (as provided on eCRF 
page “Study Drug Dosing Dates’), which was not discontinued on/before Date of First Study 
Treatment administration, will be considered as ‘Concomitant’. Moreover, any medication 
started at any time after the First Study Treatment Administration (as provided on eCRF 
page ‘Study Drug Dosing Dates’) will be considered ‘Concomitant’. 
Medications started and stopped on the day of First Study Treatment Administration (as 
provided on eCRF page ‘Study Drug Dosing Dates’) will be considered to be ‘Concomitant’. 
The Investigator Terms (Medication Name, and Indication) will be coded to a World Health 
Organization Anatomical Therapeutic Chemical (WHO-ATC) Drug class, a WHO-ATC Drug 
number and a WHO Drug Name (Preferred Term) using the WHO-DRL Drug Dictionary.   
Missing Codes or Medication Dates Imputation: 
In the event that coding information will not be available for a specific concomitant 
medication, the concomitant medications will be presented as ‘Uncoded Medication’. 
However, for final TLFs it is anticipated that all medication records are coded.  
Missing and/or incomplete dates for prior and concomitant medications will be imputed for 
calculating relative start and stop days only. Dates will be listed as missing/incomplete [with 
“-“ replacing missing information] but the Start/Stop Day listed between square brackets to 
denote it was calculated based on missing data (i.e. [-28], [1], [Ongoing]).  
Missing and/or incomplete dates will be imputed in a manner that assumes the worst case 
scenario.  
Technically, incomplete stop dates will be imputed as follows: 
• 
For a missing day (but month and year is available), it will be assumed that 
medication have been stopped on the last day of the respective month. 
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• 
For a missing month (but year is available), it will be assumed that medication have 
stopped on 31st December of the respective year.  
• 
For a completely missing stop date, the medication will be assumed to be ongoing. 
 
Similarly, incomplete start dates will be imputed as follows: 
• 
For a missing start day (but month and year is available), onset is assumed on the 
first day of the respective month. 
• 
For a missing start month (but year is available), onset is assumed on 1st January of 
the respective year.  
• 
For a completely missing start date, no imputation is performed. However, the 
medication will be considered as concomitant, unless indicated different by stop date. 
7.2.5 Measurements of Exposure and Treatment Compliance 
The patients will be dispensed a 4 week supply of study medication (1 kit) on the Day 0 visit 
and at Weeks 4. 
Patients will also be instructed to bring back to the clinic at each study visit all the used and 
unused vials. 
Each 4 week kit will be composed of 1 box containing a total of 90 single-use vials of the 
randomized / assigned medication for daily treatment during 4 weeks and 1 box containing 
the same number of adaptors and prefilled 0.3 ml WFI syringe. 
All patients will be dosed one drop (35 µl) three times a day (TID) in each eye during the 8 
weeks treatment period. 
Exposure 
Information on Exposure will be derived from information on eCRF Pages ‘Study Drug 
Dosing Dates’ (Date of First Study Drug Administration, Date of Last Study Drug 
Administration), ‘End of Study’ (Date of Study Discontinuation/Completion), ‘Study Visits’ 
(Date of Week 8) as well as ‘Study Drug Dosing and Accountability’ (Date of Vial 
Dispensed/Returned, Days without Treatment). 
Exposure will be presented by displaying Duration of Treatment Period, Duration of Follow-
up Period, Extent of Exposure and Days on Study Medication, which will be derived as 
follows  
• 
Duration of Treatment Period: 
Week 8 Visit Date or Date of Study Discontinuation/Completion – Date of First Study 
Drug Administration + 1, whatever is earlier.  
 
• 
Duration of Follow-Up Period: 
Date of Study Discontinuation/Completion – Date of Week 8, for all patients who have 
completed the treatment period and terminated the study (regularly or prematurely) 
For patients who did not complete the treatment period, Duration of Follow-Up Period 
is set to 0. 
Main Objectives Analysis only: if a patient has not completed the study yet, the last 
documented visit during Follow-Up Period (including unscheduled visits) will be 
considered for calculating Duration of Follow-Up Period. 
 
• 
Extent of Exposure (days) = (Date of Last Study Treatment – Date of First Study 
Treatment Administration + 1), 
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If Date of Last Study Treatment is missing (e.g. due to Lost to Follow-Up), Date of 
Study Discontinuation/Completion or Date of Last Study Drug Return (as documented 
on the eCRF Page ‘Study Drug Dosing and Accountability'’) will be used, whatever is 
earlier. 
 
• 
Days on Study Medication = Sum of (Date of Vial Returned – Date of Vial Dispension 
– Days without Treatment) +1 for all lines in eCRF Page ‘Study Drug Dosing and 
Accountability’.  
If no Vials are dispensed, Days on Study Medication will be set to 0. In case of 
incomplete/inconsistent documentation on eCRF, Days on Study Medication will be 
set to Missing. 
 
Compliance 
Patient compliance with the study medication will be assessed at each study visit following 
the dispensing of the study medication for self-administration. For each kit dispensed, the 
eCRF page ‘Study Drug Dosing and Accountability’ records per return visit: 
• 
Date dispensed 
• 
Kit number received 
• 
Number of vials dispensed 
• 
Date returned 
• 
Number of vials returned 
• 
Number of vials unused 
• 
Number of days without treatment 
Compliance will be evaluated according to the following formula: 
Compliance (%) = 100 * 
Number of vials dispensed – Number of unused vials returned 
Number of expected days on treatment 
 
The number of expected days on treatment will be set to 56. For each patient, the number of 
vials dispensed will be derived as the sum of provided numbers in the column “# Vials 
Dispensed” on the eCRF Page ‘Study Drug Dosing and Accountability; the number of unused 
vials returned will be derived as the sum of provided numbers in the column “# Vials Unused” 
on the eCRF Page ‘Study Drug Dosing and Accountability’. 
Compliance will be presented categorical as <80%, ≥80%. 
 
 
 
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7.2.6 Study Medication 
‘Table 3: Study Treatments’ shows the Study Treatments and how they will be labelled in 
all TLF outputs. 
Table 3: Study Treatments 
 
Treatment arm 
Treatments 
rhNGF 
180 µg/ml rhNGF, one drop TID 
Vehicle 
Vehicle control, one drop TID 
 
7.2.7 Primary Safety Outcomes 
The primary safety outcomes of the study are:  
Unexpected severe progression of optic neuropathy (USPON) 
Unexpected Severe Progression of Optic Neuropathy will be measured a) by a central vision 
loss; b) by visual field testing; and/or c) by examination of the optic nerve. It is recorded per 
eye on the Follow-Up Visits of the eCRF pages ‘Best Corrected Distance Visual Acuity’, 
‘Humphrey Visual Field Monitoring’, ‘Electroretinography’ and Ocular coherence tomography’ 
via a tick box ‘Was an unexpected severe progression measured…’ (Yes/No). 
USPON will be investigated only for treated eyes, i.e. if an eye is not treated, the respective 
tick box will not be considered for definition of primary outcome. 
For a patient, USPON occurred, if in any of the following assessments the respective 
question on unexpected severe progression is answered ‘Yes’: 
a) from BCDVA assessments: eCRF question is ticked ‘Yes' for at least one treated eye 
at any Follow-Up Visit after first study treatment administration (including 
unscheduled visits). 
b) from HVF assessments: eCRF questions is ticked ‘YES’ for at least one treated eye 
in at least one assessment during Treatment or Follow-Up Period (i.e. performed after 
first study treatment administration). An assessment is considered as performed 
during Follow-Up Period, if Test Date and Test time as documented on eCRF Page 
‘Humphrey Visual Field Monitoring’ was after Week 8 Visit (See also Section 7.2.9 for 
Details).  
c) from ERG assessments: eCRF question is ticked ‘Yes' for at least one treated eye at 
any Follow-Up Visit after first study treatment administration (including unscheduled 
visits). 
d) from OCT assessments: eCRF question is ticked ‘Yes' for at least one treated eye at 
any Follow-Up Visit after first study treatment administration (including unscheduled 
visits). 
As supportive variable, the occurrence of USPON during Treatment Period will be derived, 
which is defined as an USPON, which was recorded between the first study treatment 
administration and Week 8 Visit/Study termination Visit (for patient withdrawn during the 
treatment period). 
Intolerance or allergy to the drug 
The occurrence of intolerance and allergy to the drug will be identified during the BDRM by 
reviewing reported Preferred Terms of Treatment Emergent Adverse Events (for definition 
see Section: 7.2.10).  
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Adverse events affecting ocular function or eye pressure, which differ from those 
expected in the course of glaucoma, which are thought to be potentially related to the 
drug (Unexpected Related AEs affecting ocular function/eye pressure) 
The occurrence of these events will be identified via the respective question on the AE form. 
It is expected, that only adverse events, which are occurring during treatment period, will be 
flagged for this endpoint by the investigator. So, no separate analysis is foreseen by study 
period.  
Local or systemic toxicities considered serious adverse events that are potentially 
related to the drug 
The occurrence of local and systemic toxicities will be identified via the respective question 
on the AE form. It is expected, that only adverse events, which are occurring during 
treatment period, will be flagged for this endpoint by the investigator. So, no separate 
analysis is foreseen by study period.  
7.2.8 Primary Tolerability Outcome 
VAS Ocular Tolerability Score 
Visual Analogue Scale (VAS) will be used to determine ocular tolerability to the study 
medication. It will be assessed by the patient using a self-administered 100 mm VAS on 
which 0 means no symptoms and 100 means the worst possible discomfort in either eye. 
This evaluation is to be performed before any ophthalmic examinations. 
The VAS Ocular tolerability scores will be collected on the eCRF page ‘Visual Analogue 
Scale Ocular Tolerability‘ per eye for the symptoms: 
1) foreign body sensation 
2) burning/stinging 
3) itching 
4) ocular pain 
5) sticky feeling 
6) blurred vision 
7) photophobia 
 
The Overall VAS Ocular Tolerability Score is the mean of all VAS Ocular Tolerability 
symptom scores per visit per eye. In case of missing symptom scores, the mean will be 
calculated on the remaining VAS scores if at least 5 out of 7 scores are non-missing. 
Change from baseline is derived for overall score as well as for all 7 symptom scores will be 
derived as the difference between the respective values at a scheduled Follow-Up and 
Baseline Visit. 
7.2.9 Exploratory Secondary Efficacy Outcomes 
The following examination/procedures will be performed on both eyes and results and 
derived values as defined below in this section will be derived for each eye individually. 
Changes in Best-Corrected Distance Visual Acuity 
Vision must be measured using ETDRS visual acuity chart at 4 meters (13 feet) and, if 
indicated, also at 1 meter (i.e. when less than 20 letters were read at 4m). Results are 
documented on the eCRF page ‘Best Corrected Distance Visual Acuity’. 
In case both tables on the eCRF page have been completed (at 4 meter and at 1 meter) then 
the visual acuity score is the sum of the total number of correct letters from both tables. 
If only the table at 4 meter is completed and the overall number of letters read is 20 or above 
then the Visual Acuity Score is the number of total letters read at 4 meter plus 30. 
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If no letter were read at 4 and 1 meter, the best visual potential ability of the patient is 
selected from: a) count fingers; b) hand motion; c) light perception; or d) no light perception. 
The Visual Acuity Score is then set to 0. 
The Snellen Equivalent is defined as the acuity equivalent for the smallest line with 1 or no 
error. The logarithm of the minimal angle of resolution (logMAR) is calculated as “- log 
(Snellen Equivalent)” with two decimals precisions. The logMAR ranges from 0.30 (20/10) to 
1.60 (20/800) and an increase in logMAR reflects a worsening of visual acuity. If for a patient 
only ability for counting fingers is reported, logMAR will be set to 2.00; if for a patient only 
recognition of hand motion is reported, logMAR will be set to 3.00 (Holladay 1997). 
For Visual Acuity Score and logMAR, change from baseline will be calculated as difference 
for Week 8, Week 12 and Week 32 Visit.  
For safety evaluation, also the incidence of Substantial Worsening of Visual Acuity during 
Treatment will be derived at each Follow-Up Visit. A Substantial Decrease of Visual Acuity 
during Treatment is defined as: 
• 
Decrease in BCDVA score of more than 30 compared to Baseline or 
• 
Increase in LogMar of more than 0.6 compared to the Baseline or 
• 
Decrease of Visual Acuity from at least Hand Motion to the Level of Light Perception 
or worse compared to Baseline 
at any assessment (scheduled and unscheduled) after first Study Drug Administration up to 
and including Week 8 Visit. 
A similar derivation will be performed for the incidence of Substantial Worsening of Visual 
Acuity during Follow-up Period considering all Assessments after Week 8 and Last Study 
Visit during the Follow-Up Period. 
It needs to be noted that a Substantial Worsening of Visual Acuity as defined here will not 
necessarily implies an adverse event of special interest (AESI) or an USPON, as this 
definition is addressing a general worsening compared to start of study, whereas AESI and 
USPON are considering substantial changes from the last observed visit. 
Changes in Visual field using Perimetry  
Visual fields will be evaluated using static (Humphrey) perimetry and results are on the eCRF 
pages ‘Humphrey Visual Field Monitoring’ and ‘Humphrey Visual Field’. Two perimetries will 
be performed on different days for a total of 3 before initiating treatment and these will be 
reported as Baseline assessments. During treatment 3 assessments will be performed within 
4 weeks.  During follow up 3 perimetries will be performed within 4 weeks. 
Humphrey Visual Field testing will be performed using SITA Standard. If a patient has a low 
vision and cannot perform the test via SITA Standard, the test is performed with the 
FASTPAC Standard. On the eCRF it is recorded which test type has been used. 
All HVF assessments will be assigned to the respective study period according to the 
following rules: 
• 
Screening Period: Date/Time of HVF assessment will be before Date/Time of First 
Study drug administration as documented on eCRF Page ‘Administration of Study 
Drug’ 
• 
Treatment Period: Date/Time of HVF assessment on/after Date/Time of First Study 
Drug Administration (as documented on eCRF Page ‘Administration of Study Drug’ 
and on/before Date of Week 8 Visit. If a patient did not perform a Week 8 Visit, all 
assessments after first Study Drug Intake will be assigned to the Treatment Period. 
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• 
Follow-up Period: Date/Time of HVF assessment after Date of Week 8 Visit. 
Based on this assignment, the occurrence of USPON assessed via HVF will be determined. 
Electroretinography (ERG) 
A full field and pattern ERG will be performed according to international standards. On the 
eCRF page ‘Electroretinography’ only the PhNR result will be recorded in format 5.2 and 
used for statistical analysis. 
For PhNR, the change from baseline will be calculated as differences for Week 8, Week 12 
and Week 32 Visits. 
Optical Coherence Tomography (OCT) 
Spectral domain OCT acquisitions of macula and optic nerve head will be performed to 
evaluate changes in ganglion cell layer and nerve fiber layer thickness. 
Retinal nerve fiber layer (RNFL) Thickness (μm, format 6.2) is recorded in the eCRF page 
‘Ocular Coherence Tomography’ as follows: 
• 
four RNFL Quadrants, namely superior (S), nasal (N), temporal (T) and inferior (I) 
• 
twelve RNFL Clock Hours (1 to 12) 
• 
average RNFL Thickness as measured by the OCT machine 
From PanoMap analysis, Macular Thickness (μm, format 6.2) is recorded in the eCRF page 
‘Ocular Coherence Tomography’ as follows: 
• 
nine Areas, namely superior of outer ring (SOM), nasal of outer ring (NOM), inferior of 
outer ring (IOM), temporal of outer ring (TOM), superior of inner ring (SIM), nasal of 
inner ring (NIM), inferior of inner ring (IIM), temporal of inner ring (TIM) and central 
subfield thickness (CSF) 
From Ganglion Cell OU analysis, Macular Cube Thickness (μm, format 6.2) is recorded in the 
eCRF page ‘Ocular Coherence Tomography’ as follows: 
• 
six Areas, namely superior (SUP), superior temporal (ST), inferior temporal (IT), 
inferior (INF), inferior nasal (IN) and superior nasal (SN) 
For all these variables, change from baseline will be calculated as differences for Week 8, 
Week 12 and Week 32 assessments. 
7.2.10 Safety Variables – Adverse Events 
AE data are collected on the ‘Adverse Events’ eCRF page. The AE Description (Investigator 
term) will be analyzed on PT and SOC level using MedDRA. 
Based on the information provided on the ‘Adverse Events’ eCRF page, the following 
definitions will be utilized: 
• 
An ocular event will be identified, if the question ‘Is this an ocular event?’ is answered 
‘Yes’. 
• 
An AE with missing severity will be counted as severe.  
• 
A Serious Adverse Event (SAE) is any adverse event where the question ‘Is the event 
serious?’ has been answered as ‘Yes’. If this question is not answered the event will 
be considered as ‘Serious’ for analysis purposes. 
• 
The following adverse events are considered to be of special interest (AESI) and by 
default shall be reported as SAEs (medically important criteria): 
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o Adverse Events that cause an unexpectedly severe progression of optic 
neuropathy as measured by central vision loss (i.e. decrease in visual acuity 
of >30 ETDRS letters or   > +0.6 LogMAR lasting >1 hour compared with the 
last assessment of visual acuity at the last visit), by visual field testing, or by 
examination of the optic nerve.  
o Adverse Events that cause a decrease in visual acuity to the level of Light 
Perception or worse lasting >1 hour. 
o Adverse Events that require 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. 
o Adverse Events associated with severe intraocular inflammation (i.e., 4+ 
anterior chamber cell/flare or 4+ vitritis). 
o Adverse Events that, in the opinion of the investigator, may require medical 
intervention to prevent permanent loss of sight. 
For analysis purposes, AESI will be identified by ticked box ‘Medically significant or 
important medical condition’ in the eCRF section ‘SAE criteria’. This means in 
particular, that all AESIs will be considered as SAEs. 
• 
An AE leading to premature withdrawal of the study treatment is defined as an AE 
where in the eCRF section ‘Action taken with study treatment’ the boxes ‘Withdrawn’ 
and ‘Permanently’ are ticked.  
• 
An AE leading to study treatment interruption is defined as an AE where in the eCRF 
section ‘Action taken with study treatment’ the boxes ‘Withdrawn’ and ‘Temporarily’ 
are ticked.  
• 
An AE leading to study discontinuation is defined as an AE where in the eCRF 
section ‘Action regarding Patient’ the box ‘Patient Withdrawn’ is ticked (this should 
match with the primary reason for early withdrawal of ‘Adverse Event’ on the End of 
Study eCRF page). 
• 
An AE is classified as ‘Related’ to Study Treatment if the relationship to study 
medication recorded as ‘Possible’ or ‘Probable’ or ‘Highly Probable’. An AE will be 
classified as unrelated to study medication if the relationship to study medication was 
recorded as ‘None’ or ‘Unlikely’. AEs with missing relationship to study treatment will 
be counted as ‘Related’ to Study Treatment. 
• 
A Fatal AE is defined as an AE where the outcome is recorded as ‘Fatal’.  
These definitions will apply accordingly also for the subsequent sub-classes of AEs. 
Non Treatment-emergent adverse events (Non-TEAEs) 
A Non-TEAE is defined as any AE, which started before the first administration of study 
treatment. An AE is considered as Non-TEAE, if the eCRF question ‘Did the event occur:’ 
was answered with ‘Before Treatment Period’. 
Treatment-emergent adverse events (TEAEs) 
A treatment-emergent adverse event is defined as an AE that started on or after the date of 
the First Study Treatment Administration. An AE is considered as TEAE, if the eCRF 
question ‘Did the event occurred:’ was answered either with ‘During Treatment Period’ or 
‘During Follow-Up Period’.  
TEAEs in Treatment Period 
This is defined as a TEAE (as defined above) that started on or after the date of the First 
Study Treatment Administration but on or before the Week 8 Study Visit. A TEAE in 
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Treatment Period will be identified, if the eCRF question ‘Did the event occurred:’ was 
answered with ‘During Treatment Period’. 
TEAEs in Follow-Up Period 
This is defined as an TEAE with a start date after the Week 8 Visit. An TEAE will be 
considered as TEAE in Follow-Up Period, if eCRF question ‘Did the event occur:’ was 
answered with ‘During Follow-Up Period’. 
For listing purposes, treatment day of onset of AE will be derived according to the definition 
given in section 7.1. 
Missing Codes or Incomplete AE start dates: 
In the event that coding information will not be available for a specific AE, the event will be 
presented as ‘Uncoded Event’. However, for final TLFs it is anticipated that all events are 
coded. 
If the eCRF question ‘Did the event occur:’ was not answered, AEs will be classified to sub-
class Non-TEAE, TEAE in Treatment Period or In Follow-Up Period based on the AE onset 
date utilizing the definitions given above. If this is not possible, the event will be classified as 
TEAE in Treatment Period. 
Missing and/or incomplete AE onset dates will be imputed for calculating relative start and 
stop days only. Dates will be listed as missing/incomplete [with “-“ replacing missing 
information] but the onset Day listed between square brackets to denote it was calculated 
based on missing data (i.e. [1]).  
Missing and/or incomplete dates will be imputed in a manner that assumes the worst case 
scenario: 
• 
For a missing start day (but month and year is available), onset is assumed on the 
first day of the respective month.  
• 
For a missing start month (but year is available), onset is assumed on 1st January of 
the respective year.  
• 
For a completely missing start date, no imputation will be performed.  
If for Non-TEAEs this procedure results in an onset date before date of informed consent, 
informed consent date will be used. 
If for TEAEs in the Treatment Period this procedure results in an onset date before date of 
first study treatment, date of first study treatment will be used. 
If for TEAEs in the Follow-Up Period this procedure results in an onset date before date of 
Week 8 visit, date of Week 8 visit will be used. 
7.2.11 Other Safety Parameters 
Best Corrected Distance Visual Acuity 
For additional safety variables associated to BCDVA assessment please refer to 
section 7.2.9. 
External Ocular Examination 
External Ocular Examination assesses 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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Motility of extraocular muscle and appearance/function of eye lids is assessed separately for 
each eye at each Study Visit and is recorded on the eCRF pages ‘External Ocular 
Examination’ and ‘Appearance and Function of Eyelids’. 
For the analysis, the motility of the extraocular muscle will be evaluated by the field of 
movements Right and up (‘Normal’, ‘Abnormal’), Right (‘Normal’, ‘Abnormal’), Right and 
Down (‘Normal’, ‘Abnormal’), Left and Up (‘Normal’, ‘Abnormal’), Left (‘Normal’, ‘Abnormal’), 
Left and Down (‘Normal’, ‘Abnormal’) as documented at the eCRF. No imputation will be 
envisaged for these parameters. 
Appearance and function of eyelids will be summarized by the following parameters: 
• 
Incidence of proven eyelid deformity/abnormality, which will be considered as 
present, if the question ‘Evidence of eyelid deformity or abnormality’ on the eCRF 
page ‘Appearance and Function of Eyelids’ is answered ‘Yes’. 
 
• 
Incidence of abnormal motor function of eyelids (i.e. upper lid elevation and forceful 
lid closure), which will be considered as present, if the question ‘Motor function of 
eyelids’ on the eCRF page ‘Appearance and Function of Eyelids’ is answered 
‘ABNORMAL’. 
 
• 
Incidence of corneal exposure in case of closed eyelids, which will be considered as 
present, if the question ‘Is there corneal exposure when the eyelids are closed?’ on 
the eCRF page ‘Appearance and Function of Eyelids’ is answered ‘Yes’. 
 
• 
Incidence of proven punctal occlusion, which will be considered as present, if the 
question ‘Is there evidence of punctal occlusion?’ on the eCRF page ‘Appearance 
and Function of Eyelids’ is answered ‘Yes’. 
 
• 
Incidence of punctal plugs, which will be considered as present, if the box ‘Punctal 
plugs’ is ticked on the eCRF page ‘Appearance and Function of Eyelids’. 
 
• 
Incidence of thermal or surgical occlusion, which will be considered as present, if the 
box ‘Thermal or surgical occlusion’ is ticked on the eCRF page ‘Appearance and 
Function of Eyelids’. 
 
• 
Incidence of Other punctal occlusion, which will be considered as present, if the 
respective ‘Other’ box is ticked on the eCRF page ‘Appearance and Function of 
Eyelids’. 
 
Slit Lamp Examination 
Slit lamp examination is performed separately for each eye at each Study Visit and is 
recorded on the eCRF page ‘Slit Lamp Examination (Biomicroscopy)’. 
The following assessments will be performed: 
Eye Structure 
Rating 
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Eye Structure 
Rating 
Eye Lids 
1 = None (normal) 
2 = Mild (redness localized to a small region of the lid(s) margin OR 
skin) 
3 = Moderate (redness of most of all of lid margin OR skin) 
4 = Severe (redness of most or all of lid margin AND skin) 
5 = Very Severe (marked diffuse redness of both the lid margin AND 
skin)  
Lashes 
1 = Normal 
2 = Abnormal (specify) 
Conjunctiva 
1 = None 
2 = Mild  
3 = Moderate  
4 = Severe  
Cornea 
1 = Normal 
2 = Abnormal  
Lens 
1 = No Opacification (normal lens) 
2 = Mild Lens Opacification 
3 = Moderate Lens Opacification 
4 = Severe Lens Opacification 
5 = Cataract Extraction with Intraocular Lens Implant 
In addition there is also a field to specify Other findings 
Iris 
1 = Normal 
2 = Abnormal 
Anterior Chamber 
Inflammation 
1 = None (no Tyndall Effect) 
2 = Mild (Tyndall Effect barely discernable) 
3 = Moderate (Tyndall beam in the anterior chamber is moderately 
intense) 
4 = Severe (Tyndall beam in the anterior chamber is severely intense) 
Other 
Specification and assessment of other investigated eye structure 
 
For each eye structure, the investigator will have the opportunity to tick also ‘Not done/Not 
evaluable’, which will be treated as ‘Missing’ for analysis purposes. 
All grading assessments of different eye structures will be evaluated as collected on the 
eCRF. No imputation will be envisaged for these parameters. 
No aggregated presentation is planned for other assessments done during Slit lamp 
evaluation. 
 
Intraocular Pressure (IOP) 
Intraocular Pressure testing will be performed using Goldmann Tonometer and the resulting 
value (mmHg, format 4.1) is recorded on the eCRF page ‘Intraocular Pressure’. The change 
from baseline will be calculated as differences from Baseline. 
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Dilated Fundus Ophthalmoscopy 
Fundus ophthalmoscopy to assess the eye structure will be performed and results recorded 
on the eCRF page ‘Fundus Ophthalmoscopy’ by utilizing the following assessments. 
Eye Structure 
Rating 
Vitreous 
1 = Normal 
2 = Abnormal (specify) 
3 = Not done/Non-Evaluable 
Retina / Macula 
1 = Normal 
2 = Abnormal (specify) 
3 = Not done/Non-Evaluable 
Choroid 
1 = Normal 
2 = Abnormal (specify) 
3 = Not done/Non-Evaluable 
Optic Nerve 
1 = Normal 
2 = Abnormal (specify) 
3 = Not done/Non-Evaluable 
Cup/Disc Ratio 
1 = Normal 
2 = Abnormal (specify) 
3 = Not done/Non-Evaluable 
For abnormal values the Cup/Disc Ratio will be 
included in the ‘Specify’ field. 
 
All grading assessments of different eye structures will be evaluated as collected on the 
eCRF. No imputation will be envisaged for these parameters. Information on Cup/Disc Ratio 
will be listed only, as no investigator assessment on abnormality was performed. 
No aggregated presentation is planned for recorded details. 
 
 
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8 Analysis Methods 
8.1 General Methods 
For the study, both eyes are under investigation. For analysis purposes all eye-related 
assessments will be displayed separately by Primary/Secondary Eye. Untreated eyes will not 
be considered for analysis and be listed only indicated with ‘Untreated’. 
For continuous variables, the mean, standard deviation, minimum, median and maximum will 
be presented by treatment group, together with the total number of observations and the 
number of missing and non-missing values. Unless otherwise specified minimum and 
maximum values will be reported to the same number of decimal places as the recorded 
measurements, mean and median are reported to one more decimal place and standard 
deviation one additional decimal place more than the mean. 
For categorical variables, absolute and relative frequencies will be reported by treatment 
group. Relative frequencies will be based on all observations and reported as a percentages 
to one decimal place. Unless otherwise specified, percentages will be based on the number 
of patients with data in the considered analysis set and will not be calculated for missing 
categories. 
Incidences over a specific time interval like adverse events, medical history and concomitant 
medication will be reported on a patient basis. The percentages will be calculated using the 
number of patients in the treatment group for the considered analysis set as denominator. 
For the presentation of incidences during the Follow-Up Period, the SAF-F set will be used, 
which results in a reduction of the denominator to the number of patients in the SAF, who 
have entered the Follow-Up Period. 
All hypotheses will be tested at a 5% level of significance using a two-sided test.   
P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be 
reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999. 
Statistical significance will be declared if the rounded p-value will be less than 0.050 unless 
stated otherwise. Two-sided 95% confidence intervals of the differences between the 
treatment groups will be calculated as indicated in sections 8.2 and 8.3. 
Post-Text TLFs will be provided in collated electronic MS Word .rtf files (i.e. table columns 
and rows appear as free text instead of MS Word Table format). 
8.2 Specific Methods for Primary Safety and Tolerability Analyses 
All primary safety and tolerability analyses will be performed on the SAF. 
Generally, the analysis of the Primary Eye will be considered as the primary result, whereas 
the analyses in Secondary Eye will be considered as supportive. 
No statistical inference is foreseen for the analyses of primary safety outcomes. 
For the VAS Tolerability Scores, the change from baseline in the respective score will be 
compared between treatment groups in an explorative manner per Eye and Visit. 
The null hypothesis will be tested that there is no difference between rhNGF and Vehicle in 
the mean overall change from baseline between both treatments with respect to evaluated 
score: 
H0: µ rhNGF = µ Vehicle 
H1: µ rhNGF ≠ µ Vehicle 
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Where µ is the mean change from baseline at considered visit within the given treatment 
group. This hypothesis will be tested with an Analysis of the Covariance (ANCOVA) with 
treatment and respective baseline value in the model. 
The Least-squares means estimate of the treatment effect and the treatment group 
difference (both with 95% confidence intervals) will be reported. The analysis will be 
performed in the SAF.  
These analyses will be performed for the Overall Tolerability Score as well as for all 
subscores per eye for the Week 1, Week 4 and Week 8 visits. 
8.3 Specific Methods for Exploratory Efficacy Analyses 
Generally, the analysis of the Primary Eye will be considered as the primary result, whereas 
the analyses in Secondary Eye will be considered as supportive. Exploratory efficacy 
analysis will be performed on the ITT. 
A similar analysis as foreseen for VAS tolerability scores (see section 8.2) will be performed 
for exploratory efficacy outcomes at Week 8. This comprises the following inferential 
analyses: 
• 
Change from Baseline in Visual Acuity Score at Week 8 
• 
Change from Baseline in LogMAR at Week 8 
• 
Change from Baseline in PhNR at Week 8 
• 
Change from Baseline in Average RNFL Thickness, all single quadrants and clock 
hours at Week 8 
• 
Changes form Baseline in Macular Thickness at Week 8 for all respective areas 
• 
Changes from Baseline in Macular Cube Thickness at Week 8 for all respective areas 
8.4 Statistical/Analytical Issues  
8.4.1 Adjustments for Covariates 
No adjustment for covariates is planned.  
8.4.2 Handling of Dropouts or Missing Data 
All data obtained will be used in the analysis and no imputation will be carried out for missing 
data.  
8.4.3 Data Review 
In order to perform the statistical analysis of the main objective analysis, a decision needs to 
be made on evaluability of patients and visits prior to locking the database and breaking the 
code for the blinded study medication. In particular, data situations constituting protocol 
deviations may need to be defined. This will be done at the Blind Data Review Meeting. 
Performance of Blind Data Review Meeting for the main objectives analysis will require a 
clean database, i.e. all data are available and coded and no data queries are open (on safety 
and efficacy data up to Week 12 and all AE data documented until the date of data base soft 
lock).  
No data entry should be performed between the data base Soft Lock for Main Objectives 
analysis and database lock for Main Objective Analysis. Exception would be Queries, which 
raised during the BDRM requiring a solution before data base Lock. 
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A reduced Data Review will be performed before the data base lock for the final analysis 
focusing on review of data issues. More details on scope and performance of data review 
meetings will be described in a separate BDRM plan. 
After the BDRM is performed, all decisions will be summarized in BDRM Minutes, which will 
be approved before the database will be locked for the analysis.  
8.4.4 Multicentre Studies 
Not applicable since this is a monocentric study.  
8.4.5 Multiplicity of Endpoints 
Due to this is being a Phase I safety and tolerability study, no adjustment of any p-values will 
be made to account for inflation of the Type 1 error rate arising from multiple endpoint 
testing. 
 
 
 
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9 Main Objective and Final Analyses 
9.1 Main Objective Analysis 
The database will be locked after all patients have completed their Week 12 Visit and main 
objectives analysis will be performed on unmasked data. 
For visit-based tables, only study visits up to Week 12 will be presented for the analysis. 
However, for event-type data (i.e. adverse events and concomitant medication) and the 
assessment of primary safety outcomes (i.e. AE, BCDVA, ERG, OCT and HVF 
assessments), also data AFTER Week 12 Visit will be considered. 
For the listings, all data as recorded in the data base will be reported. Respective footnotes 
will be added to the output to indicate that calculated figures of data after Week 12 needs to 
be considered as preliminary. As a consequence, interpretation of provided TLFs in the CSR 
should focus on the results of data assessed before Week 12. 
9.2 Final Analysis 
At the end of the study (i.e. after all patients have completed Week 32 Visit), an updated 
analysis will be performed presenting the complete study data. Section 12 indicates which 
TLFs will be reproduced because they will contain additional data from the period after the 
first 12 weeks until Week 32. These newly produced TLFs will be reported in a Statistical 
Report that is to be considered as an addendum to the CSR. 
10 Overview of Tables, Listings and Figures  
In this section, TLFs will be presented content wise. The full set of TLFs will be tabulated in 
section 12, where it will also be indicated whether the item is unique (or first mentioned) or a 
repeat. Mock shells for unique TLFs will be presented in a separate document. 
10.1 Disposition of Patients 
Patient disposition data will be collected on the ‘End of Study’ eCRF page when a patient 
completed or discontinued from the study. Whether the patient completed the study is 
recorded along with the single primary reason for withdrawal. It is also recorded whether the 
emergency envelope was opened during the study and if so, the date and reason of 
unmasking has been provided. 
A disposition summary of patients includes the number (n) and percentage (%) of patients in 
all analysis sets defined in Section 6.1. All percentages will be based on the number of 
patients randomized, i.e. ITT. Percentages will not be shown for the Total Set. 
The primary reason for study discontinuation will also be summarized for the ITT separately 
by study periods providing counts (n) and percentages (%). This summary will also include 
counts and percentages for unmasking. 
A listing presents for the ITT the randomized allocation to study treatment as well as 
dispensing of kit numbers. Furthermore, a listing is provided displaying assignment of 
patients to SAF and ITT. 
For the Total Set, a listing will be provided by summarizing study termination/completion 
information, date of informed consent (from eCRF page ‘Informed Consent’), unmasking 
information and duration of study periods. 
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10.2 Protocol Deviations 
The number of patients who had at least one CSR reportable protocol deviation and all 
categories of Protocol Deviations will be summarized by counts (n) and percentages (%) for 
the ITT. Percentages will be calculated based on the number of patients in the ITT. 
A listing presents all Protocol Deviation data for the ITT. 
10.3 Inclusion and Exclusion Criteria 
The eligibility of all patients for entry into the study will be assessed at the Screening visit and 
confirmed at the Day 0 Therapy Initiation visit by the inclusion and exclusion criteria 
(‘Inclusion/Exclusion Criteria’ eCRF page).  
Two listings will be provided for all patients in the ITT displaying status of Inclusion and 
Exclusion criteria, respectively. 
10.4 Demographic and Other Baseline Characteristics 
10.4.1 Demographic Characteristics 
The following demographic variables will be collected on eCRF page ‘Demography’ or 
derived as detailed in section 7.2.2: Date of Birth, Gender (‘Male’, ‘Female’), Race [‘White’, 
‘Black or African American’, ‘Asian’, ‘Native Hawaiian or Other Pacific Islander’, ‘American 
Indian or Alaska Native’ or ‘Other (with specification text box)’ ], Ethnicity (‘Hispanic, Latino or 
Spanish’, ‘Not Hispanic, Latino or Spanish’), Age at Screening (years).  
Demographic data including collected and derived, continuous and categorical variables will 
be summarized per treatment group and overall by summary statistics or absolute counts (n) 
and percentages (%) for the SAF. 
A listing presents all demographic data for the ITT. 
10.4.2 Glaucoma and Other Medical/Surgical History 
10.4.2.1 Glaucoma History 
Presence of Chronic Primary Open Angle Glaucoma, Symptomatic Eyes, Primary Eye and 
Secondary Eye will be summarized for the SAF and listed for the ITT. A listing will present all 
recorded glaucoma history data including details of other diagnosis than chronic primary 
open angle glaucoma, if any. 
10.4.2.2 Medical/Surgical History   
The medical and surgical history terms will be coded to a PT and SOC. 
Medical History will be summarized per treatment group and overall by absolute counts (n) 
and percentages (%) for the number of patients with at least one medical history event for 
the SAF. Percentages will be calculated based on the number of patients in the population. 
A listing presents all reported medical history data based on the ITT. 
Surgical History will be summarized per treatment group and overall by absolute counts (n) 
and percentages (%) for the number of patients with at least one surgical history event for 
the SAF. Percentages will be calculated based on the number of patients in the population. 
A listing presents all reported surgical history data based on the ITT. 
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10.4.3 Prior/Concomitant Medications 
Further to section 7.2.4, the ‘Prior and Concomitant Medications’ eCRF records information 
on total daily dose, dose unit and other dose unit and whether the medication is to treat eyes, 
and if so, which eyes are involved.  
Prior and Concomitant medications will be summarized by treatment group and overall for 
the SAF separately on a per-patient basis (i.e. if a patient reported the same medications 
repeatedly the medications will be counted only once at the specific level of display). 
Absolute counts (n) and percentages (%) will be presented for the number of patients taking 
at least one medication and per WHO Drug class 2 (ATC therapeutic main class) and per 
WHO Drug Name (Preferred Term) within ATC Drug class 2. Percentages will be calculated 
based on the number of patients in the SAF. 
A Listing will present all documented medication data for the ITT and will include a flag for 
Prior medication. 
10.5 Exposure and Compliance to Study Medication  
The exposure variables Duration of Treatment Period, Duration of Follow-up Period, Extent 
of Exposure and Days on Study Medication will be summarized for the SAF per treatment 
group. 
Compliance will be summarized for the ITT as counts and percentages in categories as 
defined in section 7.2.5. The percentages will be based on the number of patients in the ITT. 
All eCRF data related to the assessment of exposure and compliance will be listed for all 
patients in the ITT. In addition, all data recorded on eCRF page ‘Administration of Study 
Drug’ including details on first 2 doses of study drug administration at site and occurrence of 
immediate AEs will be listed for all patients in the ITT. 
10.6 Primary Study Outcomes 
10.6.1 Primary Safety Outcomes 
The incidence of USPON, USPON during treatment period, Intolerance/Allergy to the drug, 
Unexpected Related AEs affecting ocular function/eye pressure, Local toxicities and 
systemic toxicities will be summarized for SAF by counts and percentages of affected 
patients per treatment group. In addition, number of reported events will be provided. 
A listing will be provided for the SAF summarizing all incidences on the patient level. The 
original source of presented events will be flagged in respective listings for AEs, BCDVA, 
HVF, ERG and OCT, respectively. 
10.6.2 Primary Tolerability Outcomes 
The Overall VAS Ocular Tolerability Scores as well as the seven symptoms scores will be 
summarized per Primary/Secondary Eye and treatment group for the SAF at each scheduled 
study visit. In addition, Change from Baseline summaries will be provided together with 
respective inferential statistics for the SAF as described in section 8.2. 
All data of tolerability will be listed for all patients of the SAF. 
10.7 Secondary Explorative Efficacy Outcomes 
All exploratory efficacy analysis will be performed on the ITT by Primary and Secondary Eye 
according to the treatment randomized. 
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10.7.1 Change in Best-Corrected Distance Visual Acuity 
The Visual Acuity Score and logMAR are summarized per Primary/Secondary Eye 
respectively for each treatment group at all scheduled study visits and changes from baseline 
for Visual Acuity Score and LogMAR at week 8, week 12 and week 32.  
No imputation for missing values will be performed for these analysis. For safety tables 
associated for BCDVA please refer to section 10.8. 
A listing will be provided describing all recorded data as well as changes from baseline for 
the ITT. 
10.7.2 Changes in Visual Field Testing 
All HVF data will be listed for the ITT by date and eye including derived information on 
corresponding treatment period and occurrence of USPON. No changes from baseline will 
be calculated for these data. 
10.7.3 Changes in ERG 
PhNR results as well as changes from baseline will be summarized for Primary/Secondary 
Eye respectively for each treatment group at all scheduled visits. 
A listing will present all recorded ERG results for the ITT flagging also records reflecting the 
occurrence of USPON due to ERG assessments. 
10.7.4 Ocular Coherence Tomography (OCT) 
All 17 (4+12+1) RNFL variables will be summarized by Primary/Secondary Eye for each 
treatment group at all scheduled visits as well as changes from baseline at Week 8, Week 12 
and Week 32. 
A listing will present the above variables over time for each eye as well as the changes from 
baseline for these variables for all patients in the ITT. 
All nine 
variables 
associated with PanoMap analysis 
will be summarized 
by 
Primary/Secondary Eye for each treatment group at all scheduled visits and changes from 
baseline at Week 8, Week 12 and Week 32. 
A listing will present all PanoMap assessments as well as the changes from baseline for all 
patients in the ITT. 
All 6 variables associated with Ganglion Cell Analysis will be summarized by 
Primary/Secondary Eye for each treatment group at all scheduled visits and changes from 
baseline at week 8, week 12 and week 32. 
A listing will present all Ganglion Cell Analysis results as well as the changes from baseline 
for all patients in the ITT.  
All assessments associated with an USPON will be flagged in the 3 listings describing OCT 
results. 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
10.8 Adverse Events and Further Safety Assessments 
10.8.1 Adverse Events 
10.8.1.1 Brief Summary of Adverse Events 
An overview summary will be provided for the SAF by presenting of events as well as 
number and percentages of affected patients for AEs, TEAEs, TEAEs in the Treatment 
Period, TEAEs in the Follow-Up Period, TEAEs leading to Premature Withdrawal of Study 
Treatment, TEAEs leading to Study Discontinuation, Treatment Related TEAEs, Serious 
AEs, Serious TEAEs, Treatment Related Serious TEAEs Fatal AEs, AESIs, TEAEs by 
severity, TEAEs in the Treatment Period by severity, TEAEs in the Follow-Up Period by 
severity, TEAEs by age category, TEAEs in the Treatment Period by age category, TEAEs in 
the Follow-Up Period by age category. 
10.8.1.2 Display of Adverse Events 
Adverse event descriptive tables will be summarized separately for each study treatment and 
overall.  
They will be summarized on a per-patient basis (i.e. if a patient reported the same event 
repeatedly the event will be counted only once at the specific level of display). Absolute 
counts (n) and percentages (%) will be presented for the number of patients with at least one 
adverse event, and per SOC and per PT within SOC, for the SAF. Percentages will be based 
on the number of patients in the population. In addition, number of events will be provided. 
Descriptive tables will be ordered by descending frequency of the overall number of patients 
within each SOC regardless of treatment group, and then ordered within each SOC by the 
overall number of patients within each PT regardless of treatment group. In the event of 
equal frequencies tables will be ordered by active treatment frequency and then 
alphabetically. 
The following tables will be provided: 
• 
AEs for the SAF 
• 
TEAEs for the SAF 
• 
Treatment related TEAEs for the SAF 
• 
TEAEs leading to premature withdrawal of Study Treatment for the SAF 
• 
TEAEs leading to study discontinuation for the SAF 
• 
Serious TEAEs for the SAF 
• 
TEAEs by severity for the SAF 
• 
TEAEs by age category (‘≤ 65 years’ vs ‘>65 years’) for the SAF 
• 
TEAEs in the Treatment Period for the SAF 
• 
TEAEs in the Treatment Period by severity for the SAF 
• 
TEAEs in the Treatment Period by age category (‘≤ 65 years’ vs ‘>65 years’) for the 
SAF 
• 
TEAEs in the Follow-Up Period for the SAF-F 
• 
TEAEs in the Follow-Up Period by severity for the SAF-F 
• 
TEAEs in the Follow-Up Period by age category (‘≤ 65 years’ vs ‘>65 years’) for the 
SAF-F 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
  
10.8.1.3 Listing of Adverse Events 
The following listings will be presented for patients in the SAF: 
• 
AEs 
• 
TEAEs leading to premature withdrawal of study treatment 
• 
TEAEs leading to study treatment interruption 
• 
Treatment Related TEAEs 
• 
Serious AEs 
• 
Fatal AEs. 
10.8.2 Laboratory Assessments 
A listing will be provided for female patients in the SAF displaying the results of pregnancy 
test assessments during study as documented on the eCRF Page ‘Urine Pregnancy Test’. 
10.8.3 BCDVA assessments for Safety Evaluation 
The incidences of Substantial Decrease of Visual Acuity during Treatment and Substantial 
Decrease of Visual Acuity during Follow-Up will be summarized by Primary/Secondary Eye 
for the SAF. Each occurrence of a Substantial Decrease will be flagged in the corresponding 
listing describing BCDVA assessments for the ITT. 
10.8.4 External Ocular Examination 
All evaluations of the motility of extraocular muscle Right and Up, Right, Right and Down, 
Left and Up, Left, Left and Down will be summarized descriptively by treatment group and 
study visit for the Primary Eye as well as the Secondary Eye. This analysis will be performed 
on the SAF. In addition, a shift table will be provided displaying the status of all scheduled 
Post-Baseline Visits in relation to the Baseline status. The percentages are based on the 
number of SAF patients in the respective baseline stratum of considered treatment group. 
These data will also be listed. 
Incidences of proven eyelid deformity/abnormality, abnormal motor function of eyelids, 
corneal exposure in case of closed eyelid, proven punctal occlusion, punctal plugs, thermal 
or surgical occlusion or other punctal occlusion will be presented by treatment group and 
study visit for the Primary Eye as well as for the Secondary Eye. In addition, a shift table 
(Presence, Absence of considered abnormality) will be provided displaying the status of all 
scheduled Post-Baseline visits in relation to the Baseline status. 
Incidences will be calculated as number and percentages of affected patients in respective 
treatment groups of the SAF. The percentages in the shift tables are based on the number of 
SAF patients in the respective baseline stratum of considered treatment group. The analysis 
will be performed on the SAF. Moreover, these date will be listed.  
10.8.5 Slit Lamp Examination 
All grading assessments of different eye structure (excluding assessment for other 
structures) will be summarized descriptively by treatment group and study visit for the 
Primary Eye as well as the Secondary Eye. In addition, a shift table will be provided 
displaying the status of all scheduled post-baseline visits in relation to the baseline status. 
The percentages are based on the number of SAF patients in the respective baseline 
stratum of considered treatment group. These analyses will be performed on the SAF.  
All data recorded on the eCRF page ‘Slit Lamp Examination (Biomicroscopy)’ will be listed 
for the SAF. 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
10.8.6 Intraocular Pressure 
Intraocular Pressure is summarized for the SAF by Primary/Secondary Eye for each 
treatment group at all visits as well as changes from baseline at all post-baseline visits. 
A listing will present all documented assessments of intraocular pressure as well as the 
respective changes from baseline. 
10.8.7 Dilated Fundus Ophthalmoscopy 
All grading assessments performed during Dilated Fundus Ophthalmoscopy will be 
summarized descriptively by treatment group and study visit for the Primary Eye as well as 
the Secondary Eye. In addition, a shift table will be provided displaying the status of all 
scheduled post-baseline visits in relation to the baseline status. The percentages are based 
on the number of SAF patients in the respective baseline stratum of considered treatment 
group. These analyses will be performed on the SAF.  
All data including details on detected abnormalities recorded on the eCRF page ‘Dilated 
Fundus Ophthalmology’’ will be listed for the SAF. 
 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
11 References 
1 
Cox, D. R. and Snell, E. J., The Analysis of Binary Data, Second Edition, London: 
Chapman & Hall, 1989 
2 
Holladay, JT (1997) Proper Method for Calculating Average Visual Acuity. Journal of 
Refractive Surgery, 13, pp. 388-391 
3 
Kim, HD et al. (2010) Clinical Applications of Photopic Negative Response (PhNR) 
for the Treatment of Glaucoma and Diabetic Retinopathy, Korean J Ophthalmol 
24(2), pp. 89-95 
CONFIDENTIAL 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
12 Tables, Listings and Figures  
In agreement with Medical Writing, numbering of the actual output will be accommodated to 
numbering into appendices 14 and 16. 
In the column U/R it is indicated whether the item is U=Unique TLF (or first instance of a 
table to be repeated) or R=Repeat item. 
In the column SR it is indicated whether the item will be repeated for the Final Analysis 
(Y=yes, N=no). 
 
TLF number 
Title 
Analysis 
Set 
U/R 
SR 
Tables 
 
 
 
 
Table 14.1-1.1 
Summary of Patient Disposition 
TOT 
U 
N 
Table 14.1-1.2 
Summary of Study Discontinuation 
ITT 
U 
Y 
Table 14.1-2.1 
Summary of Protocol Deviations 
ITT 
U 
Y 
Table 14.1-3.1 
Summary of Demographic Data 
SAF 
U 
N 
Table 14.1-4.1 
Summary of Glaucoma History 
SAF 
U 
N 
Table 14.1-5.1 
Summary of Medical History 
SAF 
U 
N 
Table 14.1-5.2 
Summary of Surgical History 
SAF 
U 
N 
Table 14.1-6.1 
Summary of Prior Medications 
SAF 
U 
N 
Table 14.1-6.2 
Summary of Concomitant Medications 
SAF 
R 
Y 
Table 14.1-7.1 
Summary of Exposure 
SAF 
U 
Y 
Table 14.1-7.2 
Summary of Compliance 
ITT 
U 
N 
Table 14.2-1.1 
Summary of Primary Safety Outcomes 
SAF 
U 
Y 
Table 14.2-2.1 
Summary of VAS Ocular Tolerability Scores 
SAF 
U 
N 
Table 14.2-2.2 
Summary of Changes from Baseline in VAS 
Ocular Tolerability Scores 
SAF 
U 
N 
Table 14.2-2.3 
Analysis of Changes from Baseline in VAS 
Ocular Tolerability Scores 
SAF 
U 
N 
Table 14.2-3.1 
Summary of BCDVA Scores 
ITT 
U 
Y 
Table 14.2-3.2 
Summary of Changes from Baseline in BCDVA 
Scores 
ITT 
U 
Y 
Table 14.2-3.3 
Analysis of Changes from Baseline in BCDVA 
Scores 
ITT 
U 
N 
Table 14.2-4.1 
Summary of LogMAR 
ITT 
U 
Y 
Table 14.2-4.2 
Summary of Changes from Baseline in LogMAR 
ITT 
U 
Y 
Table 14.2-4.3 
Analysis of Changes from Baseline in LogMAR 
ITT 
U 
N 
Table 14.2-5.1 
Summary of PhNR 
ITT 
U 
Y 
Table 14.2-5.2 
Summary of Changes from Baseline in PhNR 
ITT 
U 
Y 
Table 14.2-5.3 
Analysis of Changes from Baseline in PhNR 
ITT 
U 
N 
CONFIDENTIAL 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
TLF number 
Title 
Analysis 
Set 
U/R 
SR 
Table 14.2-6.1 
Summary of RNFL Variables 
ITT 
U 
Y 
Table 14.2-6.2 
Summary of Changes from Baseline in RNFL 
Variables 
ITT 
U 
Y 
Table 14.2-6.3 
Analysis of Changes from Baseline in RNFL 
Variables 
ITT 
U 
N 
Table 14.2-7.1 
Summary of PanoMap Variables 
ITT 
U 
Y 
Table 14.2-7.2 
Summary of Changes from Baseline in PanoMap 
Variables 
ITT 
U 
Y 
Table 14.2-7.3 
Analysis of Changes from Baseline in PanoMap 
Variables 
ITT 
U 
N 
Table 14.2-8.1 
Summary of Ganglion Cell Variables 
ITT 
U 
Y 
Table 14.2-8.2 
Summary of Changes from Baseline in Ganglion 
Cell Variables 
ITT 
U 
Y 
Table 14.2-8.3 
Analysis of Changes from Baseline in Ganglion 
Cell Variables 
ITT 
U 
N 
Table 14.3.1-01.1 
Overall Summary of Adverse Events 
SAF 
U 
Y 
Table 14.3.1-02.1 
Summary of Adverse Events by System Organ 
Class and Preferred Term 
SAF 
U 
Y 
Table 14.3.1-03.1 
Summary of TEAEs by System Organ Class and 
Preferred Term 
SAF 
R 
Y 
Table 14.3.1-04.1 
Summary of Treatment Related TEAEs by 
System Organ Class and Preferred Term 
SAF 
R 
Y 
Table 14.3.1-05.1 
Summary of TEAEs leading to Premature 
Withdrawal of Study Treatment by System Organ 
Class and Preferred Term 
SAF 
R 
Y 
Table 14.3.1-06.1 
Summary of TEAEs leading to Study 
Discontinuation by System Organ Class and 
Preferred Term 
SAF 
R 
Y 
Table 14.3.1-07.1 
Summary of Serious TEAEs by System Organ 
Class and Preferred Term 
SAF 
R 
Y 
Table 14.3.1-08.1 
Summary of TEAEs by Severity, System Organ 
Class and Preferred Term 
SAF 
U 
Y 
Table 14.3.1-09.1 
Summary of TEAEs by Age Category, System 
Organ Class and Preferred Term 
SAF 
U 
Y 
Table 14.3.1-10.1 
Summary of TEAEs in the Treatment Period by 
System Organ Class and Preferred Term 
SAF 
R 
N 
Table 14.3.1-11.1 
Summary of TEAEs in the Treatment Period by 
Severity, System Organ Class and Preferred 
Term 
SAF 
R 
N 
Table 14.3.1-12.1 
Summary of TEAEs in the Treatment Period by 
Age Category, System Organ Class and 
Preferred Term 
SAF 
R 
N 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
TLF number 
Title 
Analysis 
Set 
U/R 
SR 
Table 14.3.1-13.1 
Summary of TEAEs in the Follow-Up Period by 
System Organ Class and Preferred Term 
SAF-F 
R 
Y 
Table 14.3.1-14.1 
Summary of TEAEs in the Follow-Up Period by 
Severity, System Organ Class and Preferred 
Term 
SAF-F 
R 
Y 
Table 14.3.1-15.1 
Summary of TEAEs in the Follow-up Period by 
Age Category, System Organ Class and 
Preferred Term 
SAF-F 
R 
Y 
Table 14.3.2-1.1 
Summary of Substantial Worsening of Visual 
Acuity  
SAF 
U 
Y 
Table 14.3.3-1.1 
Summary of Motility of Extraocular Muscle 
SAF 
U 
Y 
Table 14.3.3-1.2 
Shift Table for Motility of Extraocular Muscle 
SAF 
U 
Y 
Table 14.3.3-2.1 
Summary of Appearance and Function of Eyelid 
SAF 
U 
Y 
Table 14.3.3-2.2 
Shift Table for Appearance and Function of 
Eyelid 
SAF 
U 
Y 
Table 14.3.4-1.1 
Summary of Slit Lamp Examination 
SAF 
U 
Y 
Table 14.3.4-1.2 
Shift Table for Slit Lamp Examination 
SAF 
U 
Y 
Table 14.3.5-1.1 
Summary of Intraocular Pressure 
SAF 
U 
Y 
Table 14.3.5-1.2 
Summary of Changes from Baseline in 
Intraocular Pressure 
SAF 
U 
Y 
Table 14.3.6-1.1 
Summary of Dilated Fundus Ophthalmology 
SAF 
U 
Y 
Table 14.3.6-1.2 
Shift Table for Dilated Fundus Ophthalmology 
SAF 
U 
Y 
Listings 
 
 
 
 
Listing 16.1.7-1.1 
Randomized Allocation to Treatment and 
Assigned Kit Numbers 
ITT 
U 
N 
Listing 16.2.1-1.1 
Listing of Study Completion, Unmasking and 
Duration of Study Periods 
TOT 
U 
Y 
Listing 16.2.2-1.1 
Listing of Protocol Deviations 
ITT 
U 
Y 
Listing 16.2.2-1.2 
Listing of Inclusion Criteria 
ITT 
U 
N 
Listing 16.2.2-1.3 
Listing of Exclusion Criteria 
ITT 
U 
N 
Listing 16.2.3-1.1 
Listing of Allocation to Analysis Sets 
TOT 
U 
N 
Listing 16.2.4-1.1 
Listing of Demographic Data 
ITT 
U 
N 
Listing 16.2.4-2.1 
Listing of Glaucoma History 
ITT 
U 
N 
Listing 16.2.4-3.1 
Listing of Medical History 
ITT 
U 
N 
Listing 16.2.4-3.2 
Listing of Surgical History 
ITT 
U 
N 
Listing 16.2.4-4.1 
Listing of Prior and Concomitant Medication 
ITT 
U 
Y 
Listing 16.2.5-1.1 
Listing of Exposure, Compliance and Days on 
Study Treatment 
ITT 
U 
N 
Listing 16.2.5-1.2 
Listing of First Study Drug Administration 
ITT 
U 
N 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
TLF number 
Title 
Analysis 
Set 
U/R 
SR 
Listing 16.2.6-1.1 
Listing of Primary Safety Outcomes 
SAF 
U 
N 
Listing 16.2.6-2.1 
Listing of VAS Ocular Tolerability Scores 
SAF 
U 
N 
Listing 16.2.7-1.1 
Listing of BCDVA Assessments 
ITT 
U 
Y 
Listing 16.2.7-1.2 
Listing of BCDVA Scores, Snellen Equivalent 
and LogMAR 
ITT 
U 
Y 
Listing 16.2.8-1.1 
Listing of HVF Assessments 
ITT 
U 
Y 
Listing 16.2.9-1.1 
Listing of ERG Assessments 
ITT 
U 
Y 
Listing 16.2.10-1.1 
Listing of OCT Assessments – Part I 
ITT 
U 
Y 
Listing 16.2.10-2.1 
Listing of OCT Assessments – Part II 
ITT 
U 
Y 
Listing 16.2.10-3.1 
Listing of OCT Assessments – Part III 
ITT 
U 
Y 
Listing 16.2.11-1.1 
Listing of Adverse Events 
SAF 
U 
Y 
Listing 16.2.11-1.2 
Listing of Action Taken due to Adverse Events 
SAF 
U 
Y 
Listing 16.2.11-2.1 
Listing of TEAES leading to Premature 
Withdrawal of Study Treatment 
SAF 
R 
N 
Listing 16.2.11-3.1 
Listing of TEAEs leading to Study Treatment 
Interruption 
SAF 
R 
N 
Listing 16.2.11-4.1 
Listing of Treatment Related TEAEs 
SAF 
R 
Y 
Listing 16.2.11-5.1 
Listing of Serious AEs 
SAF 
R 
Y 
Listing 16.2.11-6.1 
Listing of Fatal AEs 
SAF 
R 
Y 
Listing 16.2.12-1.1 
Listing of Pregnancy Tests (Females only) 
SAF 
U 
N 
Listing 16.2.13-1.1 
Listing of Motility of Extraocular Muscle 
SAF 
U 
Y 
Listing 16.2.13-2.1 
Listing of Appearance and Function of Eyelids 
SAF 
U 
Y 
Listing 16.2.14-1.1 
Listing of Slit Lamp Examination – Part I 
SAF 
U 
Y 
Listing 16.2.14-1.2 
Listing of Slit Lamp Examination – Part II 
SAF 
U 
Y 
Listing 16.2.15-1.1 
Listing of Intraocular Pressure 
SAF 
U 
Y 
Listing 16.2.16-1.1 
Listing of Dilated Fundus Ophthalmology 
SAF 
U 
Y 
 
 
 
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Dompé NGF0314 – Statistical Analysis Plan 
Version 1.0 Final, 09Feb2018 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
13 Appendices 
None 
CONFIDENTIAL 
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