Conditions: Healthy Volunteers
Keywords: Tolerability and PK
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
The primary objective of this study is to assess the safety and tolerability of a single short-term and a multiple dose scheme of rhNGF when administered as eye drops in healthy subjects of Japanese ethnicity.

The secondary objective of this study is to assess the pharmacokinetics of single and multiple doses of rhNGF when administered as eye drops in healthy subjects of Japanese ethnicity.

Detailed description:
This is a Phase I, randomized, double-masked, placebo-controlled eye drops administration study of rhNGF in healthy male and female subjects of Japanese Ethnicity to evaluate the Safety, Tolerability and Pharmacokinetics of Recombinant Human Nerve Growth Factor Eye Drops (rhNGF 20 μg/mL -formulation containing L-methionine as excipient) versus vehicle (vehicle control containing L-methionine as excipient) in Healthy Male and Female Volunteers of Japanese Ethnicity. The IMP was administered in the study Eye with the following scheme:

Day 1: One drop instilled into study eye (35 μL, corresponding to 0.70 μg of rhNGF).

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 μL, corresponding to 4.20 μg of rhNGF).

Total dose in the study eye will be 31 drops (1085 μL, equivalent to 21.7 μg rhNGF) over 6 days.

The reference product (vehicle) was administered in the study eye with the following scheme:

Day 1: One drop instilled into study eye (35 μL, corresponding to 0 μg of rhNGF\].

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 μL, corresponding to 0 μg of rhNGF).

A total dose of placebo vehicle in the study eye will be 31 drops (1085 μL, 0 μg rhNGF) over 6 days.

For the Fellow (Non-Study) Eye for all subjects, the scheme was the following:

Day 1: One drop instilled into a fellow eye (35 μL, corresponding to 0 μg of rhNGF).

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into a fellow eye (210 μL, corresponding to 0 μg of rhNGF).

A total dose of placebo vehicle in the fellow eye will be 31 drops (1085 μL, 0 μg rhNGF) over 6 days.

Arms:
arm 1: rhNGF 20μg/mL eye drop solution, formulation containing L-methionine as excipient. arm 2: Vehicle: formulation containing L-methionine as excipient.

Interventions: intervention 1: rhNGF 20μg/mL intervention 2: Placebo
Intervention descriptions: intervention 1: Study Eye (For subjects randomized to rhNGF group) Day 1: One drop instilled into study eye (35 μL, corresponding to 0.70 μg of rhNGF).

Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 μL, corresponding to 4.20 μg of rhNGF).

Total dose in the study eye will be 31 drops (1085 μL, equivalent to 21.7 μg rhNGF) over 6 days. intervention 2: Vehicle: formulation containing L-methionine as excipient.

Protocol document:
Prot_000.pdf: 
 
ATT 1 SOP-0994 v. 2.0 
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Version No. 1.0 – Final 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: 
Phase I, Randomized, Double-masked, Placebo-controlled Study 
(6 days) to Evaluate the Safety, Tolerability and Pharmacokinetics 
of Recombinant Human Nerve Growth Factor Eye Drops in Healthy 
Male and Female Volunteers of Japanese Ethnicity 
 
Study Number: 
NGF0117 
IND Number: 
115892 
Investigational Product: 
rhNGF 
Phase of the study: 
Phase I 
Protocol Version - Date: 
Version No. 1.0 – Final 26-Jan-2018 
 
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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CONTACT INFORMATION 
 
SPONSOR 
Dompé farmaceutici S.p.A., Via S. Martino 12, 20122 Milan, Italy 
Phone: +39.02.583831 
Fax: +39.02.58383324 
 
Medical Expert 
Flavio Mantelli – Chief Medical Officer Ophthalmology, 
Email to: flavio.mantelli@dompe.com 
or Fax: +39.02.58383324 
 
Dompé Early Clinical Development  Mauro P Ferrari– Early Clinical Development Manager 
Email to: mauro.ferrari@dompe.com 
or Fax: +39.02.58383324 
 
Dompé Drug Safety 
Laura Boga, Senior Safety Manager  
Email to: farmacovigilanza@dompe.com 
or Fax: +39.02.36026913 
 
CRO 
CROMSOURCE, Via Giorgio De Sandre 3, 37135 Verona, Italy 
Phone +39 045 8222811 
Fax +39 045 8222812 
 
Clinical Research Operations 
309 Waverley Oaks Road, Suite 101, Waltham, MA 02452, USA 
Phone +1 617 871 1128 
Fax +1 617 871 1129 
 
Antoinette Torres Frankum, Clinical Research Executive Director 
Email: Antoinette.TorresFrankum@cromsource.com 
Phone Office: +1 617 871 1128 
or Fax: 617-871-1129 
 
Jonathan Bellini – Project Manager  
Email to: Jonathan.Bellini@cromsource.com 
Phone Office: +1 626 227 1170 
Phone Direct: +1 857 259 0042 
 
Pablo Garces – Medical Monitor 
Email to: Pablo.Garces@cromsource.com 
Phone Office: +1 626 227 1170 
Phone Direct: +1 617 682 5603 
 


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Version No. 1.0 – Final 
 
Clinical Unit:  
WCCT Global, 5630 Cerritos Avenue Cypress, CA 90630, USA 
Phone: +1 877 777 9228 
 
Robina Smith, MD - Principal Investigator 
WCCT Global, 5630 Cerritos Avenue Cypress, CA 90630, USA 
Phone: +1 877 777 9228 
 
Michael Sheety, MD - Opthalmologist 
WCCT Global, 5630 Cerritos Avenue Cypress, CA 90630, USA 
Phone: +1 877 777 9228 
 
Analytical determination for PK: Maria Irene Antonangeli 
Biotech Process & Analytical Development Laboratory 
Study Director 
Dompé farmaceutici S.pA, Via Campo di Pile, Snc, 67100 L’Aquila, 
Italy 
Email to: mariairene.antonangeli@dompe.com 
Email to: franca.cattani@dompe.com 
Phone: Office: +39 0862 338 302 
Fax: +39 0862 338 219 
Anti-therapeutic antibodies determination: 
Swiss BioQuant AG 
 
Peter Sagelsdorff 
 
Kägenstrasse 18, 4153 Reinach, Schweiz, Switzerland 
 
 
 
 


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Table of Contents 
1 
STUDY SYNOPSIS .................................................................................................................... 9 
1.1 
Schedule Of Evaluations ........................................................................................................ 13 
2 
BACKGROUND INFORMATION ........................................................................................ 14 
2.1 
Nerve Growth Factor - Overview .......................................................................................... 14 
2.2 
Chemical And Formulation Data ........................................................................................... 14 
2.3 
Preclinical Pharmacokinetics ................................................................................................. 14 
2.4 
Primary Pharmacodynamics ................................................................................................... 15 
2.5 
Toxicology Summary ............................................................................................................. 15 
2.6 
A Summary Of Clinical Data ................................................................................................. 15 
2.7 
A Summary Of Toxicology Data ........................................................................................... 18 
2.8 
Risk - Benefit Evaluation ....................................................................................................... 18 
2.9 
Description Of The Investigational Product........................................................................... 18 
3 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ..................................... 19 
3.1 
Study Objectives .................................................................................................................... 19 
3.1.1 
Primary Objective ........................................................................................................... 19 
3.1.2 
Secondary Objective ....................................................................................................... 19 
3.2 
Study Administrative Structure .............................................................................................. 19 
3.3 
Overall Study Design ............................................................................................................. 19 
3.3.1 
Rationale for Selection of dose, control group and treatment schedule in the study ...... 19 
4 
SELECTION OF STUDY POPULATION ............................................................................ 20 
4.1 
Inclusion Criteria .................................................................................................................... 20 
4.2 
Exclusion Criteria .................................................................................................................. 21 
5 
STUDY MEDICATION ........................................................................................................... 23 
5.1 
Presentation, Storage, Packaging Of The Investigational Medicinal Product........................ 23 
5.2 
Presentation, Storage, Packaging Of The Vehicle Product .................................................... 23 
5.3 
Formulation And Packaging .................................................................................................. 24 
5.3.1 
Labeling .......................................................................................................................... 25 
5.3.2 
Supply, Storage and Handling of IMP ........................................................................... 26 
5.3.3 
Replacement Kits ........................................................................................................... 27 
5.4 
Dose, Route And Schedule Of Imp Administration ............................................................... 27 
5.4.1 
Administration route ....................................................................................................... 27 
5.4.2 
Dose regimen .................................................................................................................. 27 
5.5 
Criteria For Schedule Adjustment/Dose-Modification/ Discontinuation Of Investigational 
Product ................................................................................................................................... 28 
5.6 
Accountability Of The Investigational Product ..................................................................... 28 
5.7 
Concomitant Medication ........................................................................................................ 28 
5.7.1 
Prior and concomitant medications ................................................................................ 28 
6 
ASSIGNMENT OF SUBJECT NUMBER ............................................................................. 30 
6.1 
Randomisation ....................................................................................................................... 30 
6.2 
Treatment Allocation ............................................................................................................. 30 
6.3 
Masking .................................................................................................................................. 30 
7 
STUDY PROCEDURE AND ASSESSMENTS ..................................................................... 32 
7.1 
Screening Visit ....................................................................................................................... 32 
7.2 
Study Visits And Follow-Up Assessments ............................................................................ 32 
7.3 
Premature Discontinuation From The Study .......................................................................... 36 
7.3.1 
Primary Reason For Discontinuation From The Study .................................................. 37 
7.3.2 
Discontinuation procedures ............................................................................................ 37 
7.3.3 
Replacement ................................................................................................................... 37 
7.4 
Study Duration ....................................................................................................................... 37 


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7.5 
End Of Study .......................................................................................................................... 38 
7.6 
Domiciling And General Study Conditions ........................................................................... 38 
7.6.1 
Dietary and Fluid Restrictions ........................................................................................ 38 
7.6.2 
Physician coverage ......................................................................................................... 39 
8 
EVALUATIONS AND PROCEDURES ................................................................................. 40 
8.1 
Inclusion And Exclusion Criteria ........................................................................................... 40 
8.2 
Background Information ........................................................................................................ 40 
8.3 
Prior And Concomitant Medication ....................................................................................... 40 
8.4 
Physical Examination ............................................................................................................. 40 
8.5 
Vital Signs .............................................................................................................................. 40 
8.6 
Electrocardiographic Evaluations .......................................................................................... 41 
8.7 
Laboratory Safety Tests ......................................................................................................... 41 
8.8 
Drug Screen ............................................................................................................................ 42 
8.9 
Serology ................................................................................................................................. 42 
8.10 Pharmacokinetic Analysis ...................................................................................................... 42 
8.11 Anti-Therapeutic Antibodies (ATA) Analysis ....................................................................... 43 
8.11.1 
Total volume of blood to be taken from each subject .................................................... 43 
8.12 Ophthalmological Evaluations ............................................................................................... 44 
9 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION ..................... 49 
9.1 
Definitions .............................................................................................................................. 49 
9.2 
Recording ............................................................................................................................... 51 
9.2.1 
Relationship of Adverse Events to the Investigational Product ..................................... 51 
9.2.2 
Severity of Adverse Events ............................................................................................ 52 
9.3 
Serious Adverse Event Reporting .......................................................................................... 52 
9.3.1 
Reporting Procedure for Investigators to Dompé Drug Safety Pharmacovigilance and to 
Cromsource ............................................................................................................................ 52 
9.3.2 
Conditions that should not be reported as serious adverse events .................................. 54 
9.3.3 
Adverse events exemption .............................................................................................. 54 
9.3.4 
Reporting Procedure to IRB/IEC and to Regulatory Authorities ................................... 54 
9.4 
Unmasking Of The Study Treatment ..................................................................................... 55 
9.5 
Follow-Up Of Subjects With Adverse Events (Aes) ............................................................. 56 
9.6 
Exposure To Investigational Product During Pregnancy ....................................................... 56 
9.7 
Adverse Events Causing Treatment Discontinuation ............................................................. 56 
9.8 
Overdose ................................................................................................................................ 56 
9.9 
Termination Or Halting Of The Study ................................................................................... 57 
10 
STATISTICS ............................................................................................................................. 58 
10.1.1 
Pharmacokinetic endpoints ............................................................................................. 59 
10.1.2 
Immunogenicity endpoints ............................................................................................. 60 
10.3 Data Analysis ......................................................................................................................... 60 
11 
ETHICAL CONSIDERATIONS............................................................................................. 62 
11.1 Institutional Review Board And Independent Ethics Committee .......................................... 62 
11.2 Ethical Conduct Of The Study ............................................................................................... 62 
11.3 Data Monitoring Committee .................................................................................................. 62 
11.4 Subject Information And Consent .......................................................................................... 62 
11.5 Confidentiality ....................................................................................................................... 62 
11.6 Compensation For Medicine-Induced Injury And Indemnification ....................................... 63 
12 
DATA HANDLING AND RECORD KEEPING ................................................................... 64 
12.1 Case Report Forms ................................................................................................................. 64 
12.2 Data Management .................................................................................................................. 64 
12.3 Independent Reading Center (E.G. Independent Radiology Review) .................................... 64 
12.4 Documentation Required Prior To Initiation Of And During The Study ............................... 64 


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12.5 Essential Document Retention ............................................................................................... 65 
13 
STUDY MANAGEMENT ........................................................................................................ 66 
13.1 Monitoring ............................................................................................................................. 66 
13.2 Access To Records ................................................................................................................. 66 
13.3 Audit And Inspection ............................................................................................................. 66 
13.4 Protocol Amendments ............................................................................................................ 66 
13.5 Discontinuation Of The Study ............................................................................................... 66 
13.6 Publications ............................................................................................................................ 67 
14 
REFERENCES ......................................................................................................................... 68 
15 
APPENDICES ........................................................................................................................... 69 
15.1 Appendix 1-Sponsor Approval Page ...................................................................................... 69 
15.2 Appendix 2-Investigator’s Signature Page ............................................................................. 70 
15.3 Appendix 3-Detailed List And Timing Of Procedures .......................................................... 71 
 


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List Of Abbreviations and Definitions Of Terms 
Acronym 
Definition 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATA 
Anti-therapeutic antibody  
AUC 
Area under the curve 
AUC 
Area under the serum concentration-time curve 
AUC[0-24] 
Area under the serum concentration-time curve during 24 hours 
AUC0-tlast 
Area under the serum concentration-time curve calculated to the last 
quantifiable data point 
BCDVA 
Best Corrected Distance Visual Acuity 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CFR 
Code Of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
Clast 
Last measurable serum concentration 
Cmax 
Maximum observed serum concentration 
CRA 
Clinical Research Associate (Study Monitor) 
CRO 
Clinical Research Organisation 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria For Adverse Events  
Ctrough 
Minimum observed serum concentration at the end of the dosage interval 
D 
Day 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
e-CRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOE 
External ocular examination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETV 
Early Termination Visit 
EU 
European Union 
FDA 
(United States) Food And Drug Administration 
FO  
Fundus Ophthalmoscopic examination 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl-Transferase  
HIV 
Human Immunodeficiency Virus 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference Of Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IRB 
Independent Review Board 
ITT 
Intention To Treat 
LNGFR 
low-affinity NGF receptor 


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Acronym 
Definition 
LOT 
Local Ocular Tolerability 
mNGF 
murine Nerve Growth Factor 
MVPVU 
Materiovigilance And Pharmacovigilance Unit 
NGF 
Nerve Growth Factor 
NK 
Neurotrophic Keratitis 
NOAEL 
No-Observed-Adverse-Effect Level 
p75NTR 
p75 neurotrophin receptor 
PCI 
Percutaneous Coronary Intervention 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
RBC 
Red Blood Cell 
rhNGF 
recombinant human Nerve Growth Factor 
RP 
Retinitis Pigmentosa 
SAE 
Serious Adverse Effect 
SAS 
Statistical Analysis System 
SCG 
Superior Cervical Ganglia 
SID 
Subject Identification Number 
SIRC 
Statens Serum Institut Rabbit Cornea Cells 
SLE 
Slit Lamp Examination 
ST 
Schirmer's Test 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TFBUT 
Tear Film Break-Up Time 
tlag 
Time delay between the time of dosing and time of appearance of 
concentration in the sampling compartment 
tlast 
Time to last measurable serum concentration 
tmax 
Time to reach Cmax 
TMF 
Trial Master File 
TrkA 
Tropomyosin receptor kinase A 
VAS 
Visual Analog Scale 
WBC 
White Blood Cell 
WMA 
World Medical Association 
λz 
Terminal disposition rate constant/terminal rate constant 
 


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1 STUDY SYNOPSIS  
Study Number  
NGF0117 
Title of Study  
Phase I, Randomized, Double-masked, Placebo-controlled Study (6 days) 
to Evaluate the Safety, Tolerability and Pharmacokinetics of Recombinant 
Human Nerve Growth Factor Eye Drops in Healthy Male and Female 
Volunteers of Japanese Ethnicity 
IND No 
115892 
Study 
Centers 
(Country)  
1 center in US (enrolling subjects of Japanese ethnicity) 
Development Phase  
Phase I 
Objectives: 
The primary objective of this study is to assess the safety and tolerability 
of a single short-term and a multiple dose scheme of rhNGF when 
administered as eye drops in healthy subjects of Japanese ethnicity.  
The secondary objective of this study is to assess the pharmacokinetics of 
single and multiple doses of rhNGF when administered as eye drops in 
healthy subjects of Japanese ethnicity.  
The immunogenicity will be evaluated by determination of the anti-
therapeutic antibodies.  
 
Study Design: 
This is a Phase I, randomized, double-masked, placebo-controlled eye 
drops administration study of rhNGF in healthy male and female subjects 
of Japanese Ethnicity.  
Investigational 
medicinal 
product 
(IMP): 
rhNGF 20 µg /mL (formulation containing containing L-methionine 
as excipient ): 
Study Eye (For subjects randomized to rhNGF group) 
Day 1: One drop instilled into study eye (35 µL, corresponding to 
0.70 µg of rhNGF). 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye 
(210 µL, corresponding to 4.20 µg of rhNGF). 
Total dose in the study eye will be 31 drops (1085 µL, equivalent to 
21.7 µg rhNGF) over 6 days. 
Reference Product 
Vehicle (Vehicle control containing L-methionine as excipient): 
Study Eye (For subjects randomized to vehicle group) 
Day 1: One drop instilled into study eye (35 µL, corresponding to 0 µg of 
rhNGF]. 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 
µL, corresponding to 0 µg of rhNGF). 
Total dose of placebo vehicle in the study eye will be 31 drops (1085 µL, 
0 µg rhNGF) over 6 days. 
Fellow (Non-Study) Eye for all subjects 
Day 1: One drop instilled into fellow eye (35 µL, corresponding to 0 µg 
of rhNGF). 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into fellow eye 
(210 µL, corresponding to 0 µg of rhNGF).  
Total dose of placebo vehicle in the fellow eye will be 31 drops (1085 
µL, 0 µg rhNGF) over 6 days.  
Concomitant 
Medications 
Not allowed, except medication for the treatment of Adverse Events. 
Study Population: 
Healthy subjects will be included. 


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A total of 30 subjects will be included in the study.  
Study Duration 
Treatment duration is 6 days. 
Maximum total study duration for a subject is 63 days (9.0 weeks) from 
screening visit to the final follow-up visit at 35 to 42 days. 
The subject will be resident in the Phase I clinic for 9 days (Baseline (D-
1) to Follow-Up Visit 2 (D8).  
Study Duration is expected to be 4 months (first visit of the first subject 
to the last visit of the last subject). 
Inclusion Criteria 
To be eligible for inclusion into this study, each subject must fulfil the following inclusion criteria.  
Each subject must meet all of the following inclusion criteria at the pre-study Screening visit (within 
20 days prior to admission in the Unit for the dosing period) in order to participate in this study.  
1. Male or female subjects of Japanese ethnicity, aged between 18 and 60 years inclusive, who must 
have all four Japanese grandparents who were born in Japan.  
2. Subject has to be able to communicate well with the investigator, understands and complies with 
the requirements of the study, and understands and signs the written volunteer informed consent 
form. 
3. Subject’s systemic and ocular medical history must be considered normal in the opinion of the 
investigator at the Screening and Baseline visits. 
4. Best corrected distance visual acuity (BCDVA) score ≤ 0.00 LogMAR (≥83 ETDRS letters, 20/20 
Snellen or 1.0 decimal fraction) in each eye at the Screening and Baseline visits. 
5. Normal anterior segment on external and slit lamp examination in both eyes at the Screening and 
Baseline visits. 
6. Normal posterior segment on fundus ophthalmoscopic examination in both eyes at the Screening 
and Baseline visits. 
7. Subject must be considered in good systemic health in the opinion of the investigator at the 
Screening and Baseline visits, as determined by:  
a. Subject’s body mass index is between 18.5 and 30.4 kg/m2 inclusive 
b. A pre-study physical examination with no clinically significant abnormalities. 
c. Vital signs within clinically acceptable ranges for the purposes of the study (sitting 
systolic blood pressure [BP] ≥ 90 mmHg and ≤ 150 mmHg; diastolic BP ≥ 50 mmHg and 
≤ 95 mmHg; heart rate ≥ 40 and ≤ 100 beats per minute; oral body temperature ≥ 35.5°C 
and ≤ 37.5°C). 
d. An ECG with no clinically significant abnormalities. 
e. Pre-study clinical laboratory findings within normal range or not deemed clinically 
significant in the opinion of the investigator if outside of the normal range  
8. Woman subject who meets the criteria for post-menopausal stage (post menopause is defined as 
the period following peri-menopause, i.e. postmenopausal after 12 months without a menstrual 
period and with a serum FSH value within the reference range for postmenopausal females at 
Screening) or permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) 
or woman subject using oral, injected or implanted hormonal methods of contraception or with a 
double barrier methods of contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. A female condom and a male condom 
should not be used together as friction between the two can result in either product failing. 
9. Male subjects with female partners of child-bearing potential must use 2 different forms of highly 
effective contraception throughout the study and for a further 3 months after the follow-up visit 
and all male subjects must be willing to avoid donating sperm during this time. The following 
methods of contraception are considered to be highly effective: established use of oral, injected 
or implanted hormonal contraception; placement of an intrauterine device or intrauterine system; 
use of a barrier method of contraception (condom or occlusive cap with use of a spermicide); 
male sterilisation (post-vasectomy documentation of the absence of sperm in the ejaculate must 
be provided). 


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Exclusion criteria: 
Subjects meeting any of the following criteria at Screening will be excluded from entry into the study: 
1. Subject has had a clinically significant illness in the 6 weeks before screening in the opinion of 
the investigator. 
2. Subject is not suitable to participate in the study in the opinion of the investigator 
3. Subject has participated in any clinical study with an investigational drug/device within 3 
months prior to the first day of dosing.  
4. Subject has had a serious adverse reaction or significant hypersensitivity to any drug or 
chemically related compounds or has a clinically significant allergy to drugs, foods or other 
materials (in the opinion of the investigator).  
5. Administration of any topical ocular (prescription or over the counter including artificial tears) 
or systemic medication including herbal product or fish oil preparations within 14 days before 
the first dose of study drug. Vitamins and mineral supplements not containing other substances 
are allowed until 96 hours before each dose if considered by the Investigator unlikely to interfere 
with the study results. Paracetamol at doses of at most 2 grams per day and ibuprofen at doses 
of at most 1200 mg per day for no more than 3 consecutive days or 6 non-consecutive days are 
allowed. Oral, injectable and implantable hormonal contraceptives are allowed without 
restrictions for female subjects. Longer exclusion periods apply for:  
a. amiodarone and hydroxychloroquine (210 days),  
b. monoclonal antibodies/ immunoglobulins/ other therapeutic proteins (120 days) 
c. Experimental drugs with a half life known to the Study Unit: Five half lives plus 2 weeks 
d. Experimental drugs with a half life unknown to the Study Unit: 120 days  
e. chloroquine and flunarizine (100 days) 
f. fluoxetine (75 days),  
g. benzodiazepines different from midazolam, lorazepam and triazolam, chlorpromazine, 
mephenytoin, nortryptyline, phenobarbital, primidone, carbamazepine, phenytoin and 
phenprocoumone (35 days).  
6. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse test at any 
time during the study. 
7. Subject has a history of alcohol abuse or currently drinks in excess of 28 units per week or has 
a positive alcohol breath test at any time during the study. 
8. Subject is a smoker or has smoked in the 6 months prior to dosing. 
9. Subject who has a positive human immunodeficiency virus (HIV) screen, hepatitis B screen or 
hepatitis C screen. 
10. Subject has donated blood or blood products (e.g., plasma or platelets) within the 3 months prior 
to screening. 
11. Subject has a partner who will be pregnant or breastfeeding during the study  
12. Pregnant or breastfeeding female or those with a positive pregnancy test or who will not use a 
medically acceptable contraceptive method from selection and during the study  
13. Subject having used corticosteroid sporadically in the last 30 days whichever the route of 
administration, or any medication by ocular or nasal administration route  
14. Subjects diagnosed with any ocular disease other than refractive error  
15. Subject with history of ocular surgery, including laser refractive surgery 
16. Subject using a contact lens within 7 days prior administration of the first dose  
17. Intraocular pressure (IOP)  22 mmHg in either eye at screening or baseline 
18. Presence of any corneal opacity or corneal fluorescein staining >0.5 grade using the modified 
Oxford scale in either eye at screening or baseline 
19. Schirmer’s test without anesthesia  9 mm/5 minutes in either eye at screening or baseline 
20. Tear film break up time (TFBUT) < 8 seconds in either eye at screening or baseline 
Note: Alcoholic beverages should not be taken from 48 h before first drug administration until 
discharge from the Study center. 
 
 


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Study Procedures: 
The study will consist of a screening period of upto 20 days before admission 
[i.e., Day –21 to Day -1], a one day pre-baseline phase (Day -1) before eye 
drop application on Days 1 to 6, with follow-up visits on Days 7, 8, 16 ± 2, 
and 35 (to 42). 
A summary of the evaluations is provided in § 1.1. 
Sample Size 
No formal sample size calculation was made. Sample size considerations for 
this type of study are dependent on the common understanding on how many 
subjects one needs to demonstrate safety, tolerability and pharmacokinetics 
for the dose level investigated and the different ethnicity.  
Thirty (30) subjects randomized 2:1 (rh-NGF : vehicle) could be considered 
acceptable. Twenty (20) subjects on active (one eye active, one eye vehicle) 
and 10 on vehicle (both eyes) will be treated. 
Statistical analysis 
Data analysis:  
Descriptive statistics will include median, maximum and minimum values, 
arithmetic mean with standard deviation, geometric mean with coefficient of 
variation and confidence intervals for the geometric mean. All statistical 
calculations will be made in SAS. 
Pharmacokinetic evaluation will be done using Phoenix WinNonlin 6.4 or 
later (Pharsight Corporation, Palo Alto, CA, USA). 
 


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1.1 
Schedule Of Evaluations 
Table 1: Schedule of Assessments 
Visit  
Day (D) 
Drug/ 
Placebo 
AE/ 
Conmed 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CF
STFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
Screen 
D –21 to -2 
Informed Consent, Inclusion/Exclusion Criteria, Demography, Medical History/current medical conditions, Prior medication, Physical Exam, Serology, Drugs Abuse/pregnancy 
 
 
 
X 
X 
X 
 
 
X 
X 
X* 
X 
X 
X 
Baseline 
D -1 
Inclusion/Exclusion Criteria, Current Medical Conditions, Adverse Events, Concomitant Medication, Physical Exam, Drugs Abuse/Pregnancy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Treatment Phase 
Day 1: One drop of either rhNGF or vehicle instilled into study eye (35 µL: 0.70 µg of rhNGF) and one drop of vehicle instilled into the fellow (non-study) eye  
D1 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
Day 2,3,4,5,6: One drop of either rhNGF or vehicle six times a day (every 2h) instilled into study eye (210 µL: 4.20 µg of rhNGF) and one drop of vehicle instilled into the fellow (non-study) 
eye  
D2 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
D3 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
D4 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
D5 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
D6 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
Follow-up 
 
D7 (FU 1) 
Physical Exam 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
D8 (FU 2) 
Physical Exam 
 
X 
X 
  
X 
Y 
  
X 
X 
X 
X 
X 
  
X 
 
D16 ± 2 (FU 3) 
 
X 
X 
  
X 
Y 
 
X 
X 
X 
X 
X 
  
X 
 
 
 
D35 to 42 (FU 4) 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
ATA – Anti-therapeutic antibodies. BCVDA - Best corrected distance visual acuity (ETDRS). Drugs Abuse/pregnancy - Drugs of Abuse including Alcohol breath test, pregnancy test for females. 
ECG – Electrocardiogram. EOE - External ocular examination (motility and eyelids). FO –Fundus Ophthalmoscopic examination (*dilated FO only at Screening). IOP – Introcular Pressure. LAB - 
Laboratory Safety Tests - Hematology, Biochemistry, Urinalysis. ATA – Anti-therapeutic antibodies. LOT - Local Ocular Tolerability - Visual Analogue Scale (VAS): foreign body sensation, 
burning/stinging, itching, pain, sticky feeling, blurred vision, photophobia. If it is to be applied at a same visit as an FO or IOP examination the VAS for ocular tolerability is to be applied before the 
SLE FO and/or IOP examination. Physical exam – Physical examination, body weight, height (height is only required at screening). PK – Pharmacokinetics. Serology: Hepatitis/HIV and for 
postmenopausal females FSH Laboratory Safety Tests. SLE/CFS/TFBUT - Slit lamp examination (SLE): eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens with the instillation of 
fluorescein to evaluate corneal fluorescein staining (CS, modified Oxford scale) and tear film break-up time (TFBUT). ST - Schirmer's test (ST) without anesthesia. Vital Signs - blood pressure, pulse 
rate, respiratory rate and ear body temperature. PK timepoints: Baseline D-1: 0, 0.5, 2, 4, 8, 9, 10, 11, 12, 14, 16 hours; Treatment D1 0 (pre-dose) 0.5, 2, 4, 8, 9, 10, 11, 12, 14, 16 hours; Treatment 
D2: 0 (pre-dose) 0.5, 2, 4, 8, 9, 10, 11, 12, 14, 16 hours; Treatment D3: 0 (pre-dose) 2, 4, 6, 8. 10 hours; Treatment D4 and Treatment D5: 0 (pre-dose); Treatment D6: 0 (pre-dose), 2, 4, 6, 8, 10, 10.5, 
11, 12 hours; Follow-up D7: (FU1) 0 hours; Follow-up D8: (FU2) 0, 8 hours; Follow-up D16 +-2 (FU3): 0 hours.  
A detailed view of the evaluations is provided in Appendix 3-Detailed List And Timing Of Procedures (§ 15.3).


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2 BACKGROUND INFORMATION 
2.1 
Nerve Growth Factor - Overview  
Nerve growth factor (NGF) is a polypeptide essential for the survival and growth of sympathetic and sensory 
neurons, and for differentiation of neurons in the central nervous system. It binds with at least two classes of 
receptors: high-affinity tropomyosin receptor kinase A (TrkA), a transmembrane tyrosine kinase, and low-
affinity NGF receptor (LNGFR), also known as p75 neurotrophin receptor (p75NTR).  
NGF and TrkA are expressed in the anterior segment of the eye (iris, ciliary body, lens, cornea and 
conjunctiva), and NGF is released in the aqueous humor. Several pieces of experimental evidence suggest 
that NGF affects all tissues of the anterior ocular segments, playing a crucial role in the physiopathology of 
several anterior ocular segment diseases.  
2.2 
Chemical And Formulation Data  
As recombinant human NGF (rhNGF) production in mammalian cells does not achieve adequate yields, a 
manufacturing process based on the use of recombinant Escherichia coli (E. coli) has been developed. 
However, because the biological activity of NGF relies on the formation of three disulfide bonds, and because 
disulfide bonds cannot occur in the reducing cytosol, the purification and renaturation of NGF produced in 
E. coli is problematic. Based on the knowledge that the prosequence increases the yield and rate of refolding 
of NGF, we have developed a manufacturing process starting from proNGF. After expression of proNGF in 
E. coli, the insoluble protein is isolated in the form of insoluble inactive aggregates (inclusion bodies), 
solubilized in a strong denaturing agent and subsequently converted into the natural conformation, which is 
determined by the disulfide bridges present in the natural NGF. Biologically active rhNGF is finally obtained 
by splitting off the prosequence by enzymatic cleavage. The deoxyribonucleic acid (DNA) sequence of 
human proNGF has been optimized for E coli expression (codon adjustment) and two changes in the furin 
cleavage site, R101V and K103A, have been introduced. These two changes are important to ensure a 
homogeneous rhNGF preparation during the process with the mature protein starting with serine 105.  
2.3 
Preclinical Pharmacokinetics 
In Study A1122, Wistar rats were treated with rhNGF eye drops at ascending doses of 0.2, 0.4, 0.6, 0.8, and 
1.2 mg/mL (3 times within one day, 3 hours apart) with a 3-day wash-out period between all administrations.  
At the 0.2 mg/ml concentration, which is 10 fold that intended for clinical use, the results suggest systemic 
absorption following ocular administration. Disproportionately greater degrees of systemic exposure are seen 
at the higher doses used in animal toxicology studies.  
In Study A1119, rhNGF was administered via eye drops (into both eyes) to one male and one female New 
Zealand White rabbit at ascending doses of 0.2, 0.4, 0.6, 0.8, and 1.2 mg/mL (3 times within one day, 3 hours 
apart) with 3-day wash-out periods between all administrations.  
Overall the systemic absorption in rabbit was very marginal and not dose-proportional. 
In the toxicokinetic analysis of the four-week ocular toxicity study in rats (Study A1129), only two from the 
potential three peak concentrations could be observed due to insufficient time-points. 
Relative bioavailability of topical ocular NGF vs. an i.v. dose was estimated as follows: 
• 
12.8% – 20.7% at 0.6 mg/ml NGF. 
• 
21.5% - 35.7% at 0.8 mg/ml NGF. 
• 
22.8% - 70.9% at 1.2 mg/ml NGF (22.8% - 32.5% for females; 64.9% - 70.9% for males). 


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The Tmax range was 0.50 – 8.0 h. The reliable terminal half-life t½,z ranged between 3.0 and 4.0 h. 
rhNGF exposure tended to be more than dose-proportionally increased at incrementing doses for male rats. 
For female rats, the exposure increase approached the dose-proportional increase with variability of the data. 
No gender difference could be identified: the female / male exposure ratios were however variable. 
After 4-week repeated administration, rhNGF exposure tended to be decreased or to be stable compared with 
day 1: the AUC0-t week 4 / day 1 ratios ranged between 0.30 and 0.98. No accumulation of the test item was 
therefore observed. 
2.4 
Primary Pharmacodynamics  
rhNGF has been investigated in a range of in vitro and in vivo pharmacology studies. In the human 
Erythroleukemia cells TF-1 cell proliferation assay it was found to be more active than murine NGF. On the 
basis of the rabbit Statens Serum institut Rabbit Cornea cells (SIRC) proliferation assay it was concluded 
that rabbit SIRC cells are responsive only to mNGF, no effect being observed in response to rhNGF. 
The results of the rat superior cervical ganglia (SCG) hypertrophy test indicate that treatment with rhNGF 
and mNGF increases SCG weight dose-dependently. Morphological and histological analysis revealed a 
direct correlation between the increase of SCG weight and the extent of neuronal tissue. 
2.5 
Toxicology Summary 
In accordance with Scientific Advice from the European Medicines Agency, no safety pharmacology studies 
such as telemetry investigation have been performed; however, a modified Irwin Test was included in the 4-
week rat toxicity study by eye drop administration.  
The toxicology programme to date has included short-term intravenous studies, short-term ocular studies and 
four-week ocular studies, again in these species in rat and rabbit.  
No causes for concern emerged from these toxicology studies. The systemic (intravenous) no-observed-
adverse-effect level (NOAEL) in the rats and rabbits was shown to be 2.4 mg/kg while the local NOAEL in 
the same species was determined to be 1.2 mg/mL (equivalent to 6 μg per eye, three times daily). 
2.6 
A Summary Of Clinical Data 
rhNGF has been already studied in healthy volunteers and in different subject populations.  
In the completed Phase I study in healthy volunteers (study NGF0112), a total of 58 subjects (out of 74 
enrolled) were treated with rhNGF. Furthermore, as of January 2016, in the Phase I/II and Phase II in subjects 
with NK (REPARO study NGF0212 and study NGF0214) a total of 174 and 48 subjects respectively have 
completed the two months treatment and in the Phase I/II in subjects with RP (LUMOS study NGF0113) 50 
subjects have completed the six months treatment; furthermore, in the pilot Phase II study in subjects with 
dry eye (study NGF0213) 40 patients have completed the one month treatment with rhNGF. 
The dose that is proposed for this study (20 µg /mL) has been already tested both in healthy volunteers for 
five consecutive days and subjects for up to six months. Besides higher doses of rhNGF (up to 180 µg /mL) 
were administrated for 168 days to retinitis pigmentosa subjects. Table 2 below summarizes the subjects 
exposed to date at different rhNGF eye drops concentrations: 
In healthy volunteers no SAEs were recorded. Mild and transient ocular AEs possibly related to rhNGF 
administration were reported. rhNGF did not accumulate in serum after multiple doses and was detectable 
only in 6 subjects. Evaluation of vital signs, electrocardiograms, blood chemistry, urinalyses, and ocular 


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parameters indicated no evidence of rhNGF treatment effects. It can be concluded that at doses up to 180 
μg/ml, rhNGF eye drops were well tolerated with no detectable clinical evidence of systemic AEs. Most of 
the ocular AEs were mild in severity and transient in nature. 
In all studies rhNGF was well tolerated and the reported ocular AEs were generally transient and mostly 
mild and moderate in intensity during the controlled treatment period and the follow-up period. 
Only moderate and transient ocular AEs possibly related to rhNGF administration were reported. 
 


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Table 2: Doses of rhNGF used in previous clinical studies in Europe and US 
 
 
Doses of rhNGF in Human Healthy Volunteers 
Dose 
per  
35 μL drop 
Concentration 
Frequency of 
Dose 
Total 
Dose  
per Day 
Total Dose 
Part 0, Ascending Single Dose: 1 drop, 1 treatment day 
0.0175 μg  
0.5 μg/mL  
once  
0.0175 μg  
0.0175 μg  
0.175 μg  
5 μg/mL  
once  
0.175 μg  
0.175 μg  
0.7 μg  
20 μg/mL  
once  
0.7 μg  
0.7 μg  
Part A, Ascending Fractionated Single Dose: 1 drop, q4h (three times a day), 1 treatment day  
0.7 μg  
20 μg/mL  
q4h, 1 day  
2.1 μg  
2.1 μg  
2.1 μg  
60 μg/mL  
q4h, 1 day  
6.3 μg  
6.3 μg  
6.3 μg  
180 μg/mL  
q4h, 1 day  
18.9 μg  
18.9 μg  
Part B, Ascending Multiple Fractionated Dose: 1 drop, q4h (three times a day), 5 treatment days  
0.7 μg  
20 μg/mL  
q4h, 5 days  
2.1 μg  
10.5 μg  
2.1 μg  
60 μg/mL  
q4h, 5 days  
6.3 μg  
31.5 μg  
6.3 μg  
180 μg/mL  
q4h, 5 days  
18.9 μg  
94.5 μg  
Doses of rhNGF in Neurotrophic Keratitis Subjects  
*Phase II: 1 drop, q2h (six times a day) one eye, 56 treatment days 
0.35 μg  
10 μg/mL  
q2h, 56 days  
2.1 μg  
117.6 μg 
0.7 μg  
20 μg/mL  
q2h, 56 days  
4.2 μg  
235.2 μg 
Doses of rhNGF in patients after cataract and refractive surgery 
*Phase II: 1 drop, q2h (six times a day) one eye, 56 treatment days 
0.7 μg  
20 μg/mL  
q2h, 56 days  
4.2 μg  
235.2 μg 
Doses of rhNGF in Dry Eye pilot: 1 drop, q12h (two times a day) both eyes, 28 treatment days 
0.14 μg  
4 μg/mL  
q12h, 28 days  
0.6 μg  
15.7 μg 
0.7 μg  
20 μg/mL  
q12h, 28 days  
2.8 μg  
78.4 μg 
Doses of rhNGF in dry eye 
*Phase II: 1 drop, q2h (six times a day) one eye, 56 treatment days 
0.7 μg  
20 μg/mL  
q2h, 56 days  
4.2 μg  
235.2 μg 
Doses of rhNGF in Retinitis Pigmentosa: 1 drop, q6h (three times a day) both eyes, 168 treatment 
days,  
2.1 μg  
60 μg/mL  
q6h, 168 days 
12.6 µg  
2116.8 µg  
6.3 μg  
180 μg/mL  
q6h, 168 days  
37.8 µg  
6350.4 µg  
*Note. 174 subjects treated formulation without methionine and 48 subjects treated with formulation 
containing methionine 


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2.7 
A Summary Of Toxicology Data 
In accordance with Scientific Advice from the European Medicines Agency, no safety pharmacology studies 
such as telemetry investigation have been performed; however, a modified Irwin Test was included in the 4-
week rat toxicity study by eye drop administration.  
The toxicology programme to date has included short-term intravenous studies, short-term ocular studies and 
four-week ocular studies, again in these species in rat and rabbit.  
No causes for concern emerged from these toxicology studies. The systemic (intravenous) no-observed-
adverse-effect level (NOAEL) in the rats and rabbits was shown to be 2.4 mg/kg while the local NOAEL in 
the same species was determined to be 1.2 mg/mL (equivalent to 6 μg per eye, three times daily). 
For additional information regarding the development of rhNGF, consult the current Investigator Brochure 
(IB) [Reference: 4]. 
2.8 
Risk - Benefit Evaluation 
In the present study, potential risks of multiple rhNGF applications to healthy male and female volunteers of 
Japanese ethnicity are not expected to surpass the frequency of adverse reactions and untoward effects 
previously reported in the Phase I/II studies. 
The results of this study will allow development of rhNGF for use in the treatment of eye conditions in 
subjects with Japanese ethnicity. 
A Full Marketing Authorization for the treatment of stage 2 and 3 NK has been granted to rhNGF eye drops 
in July 2017 by the European Medicines Agency (EMA) in the European Union (EU), and the drug has been 
put on the European market in November 2017. 
2.9 
Description Of The Investigational Product 
The investigational medicinal product (IMP) consists of a sterile isotonic solution for ocular administration 
(containing L-methionine as excipient), containing rhNGF 20 μg/mL as drug substance. 
The matching placebo vehicle consists of a sterile isotonic solution containing L-methionine as excipient. 
Further information is given in § 5. 


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3 OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1 
Study Objectives  
3.1.1 Primary Objective 
The primary objective of this study is to assess the safety and tolerability of a single short-term and a multiple 
dose scheme of rhNGF when administered as eye drops in healthy subjects of Japanese ethnicity.  
3.1.2 Secondary Objective  
The secondary objective of this study is to assess the pharmacokinetics of single and multiple doses of rhNGF 
when administered as eye drops in healthy subjects of Japanese ethnicity.  
The immunogenicity will be valuated by the determination of the anti-therapeutic antibodies.  
3.2 
Study Administrative Structure 
This study will be performed at one study center located in in US, enrolling subjects of Japanese ethnicity. 
At the study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is 
conducted according to the signed Investigator agreement, the protocol, ICH-GCP guidelines [Reference: 1], 
and local regulations.  
The PI at the study center will be responsible for the management of the study, which will consist of 
maintaining the study file and the subject records, corresponding with the IRB/IEC, and completing the case 
report forms (CRFs) and reporting SAEs within 24 hours of initial awareness.  
3.3 
Overall Study Design  
This is a Phase I, randomized, double-masked, placebo-controlled eye drops administration study of rhNGF 
in healthy male and female subjects of Japanese ethnicity. 
A total of 30 subjects will be randomized in a masked manner: 20 subjects on rhNGF group and 10 on 
placebo. A study eye will be assigned to each subject by random. In the study eye, the subjects will be treated 
with:  
• 
rhNGF (active) in the rhNGF group. 
• 
vehicle (placebo) in the vehicle group. 
In parallel, the fellow-eye (non-study eye) will receive vehicle (placebo) treatment. 
3.3.1 Rationale for Selection of dose, control group and treatment schedule in the study 
The dose that is proposed for this study (20 µg /mL) has been already tested both in healthy volunteers for 
five consecutive days and subjects for up to six months.  
This dose (20 µg /mL, 1 drop in each eye, six times daily) has also been used for 56 consecutive days in 
patients with Stage 2 and 3 Neurotrophic Keratitis (NGF0214), dry eye (study NGF0216) and in patients 
after cataract and refractive surgery (NGF0116). The same dose and duration has been used in the First In 
Human study with rhNGF in healthy volunteers (NGF0112). 
Higher doses of rhNGF (up to 180 µg /mL) were administrated for 168 days to retinitis pigmentosa subjects 
(Study NGF0113). 


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4 SELECTION OF STUDY POPULATION 
The Inclusion/Exlusion are intended to identify healthy male and female volunteers of Japanese ethinicity. 
At least 6 males as well as 6 females will be included in the study to ensure, that a sufficient number of each 
gender are present in each treatment group. 
 
4.1 
Inclusion Criteria 
To be eligible for inclusion into this study, each subject must fulfil the following inclusion criteria.  
Each subject must meet all of the following inclusion criteria at the pre-study Screening visit (within 20 days 
prior to admission in the Unit for the dosing period) in order to participate in this study.  
1. Male or female subjects of Japanese ethnicity, aged between 18 and 60 years inclusive, who must have 
all four Japanese grandparents who were born in Japan.  
2. Subject has to be able to communicate well with the investigator, understands and complies with the 
requirements of the study, and understands and signs the written volunteer informed consent form. 
3. Subject’s systemic and ocular medical history must be considered normal in the opinion of the 
investigator at the Screening and Baseline visits. 
4. Best corrected distance visual acuity (BCDVA) score ≤ 0.00 LogMAR (≥83 ETDRS letters, 20/20 
Snellen or 1.0 decimal fraction) in each eye at the Screening and Baseline visits. 
5. Normal anterior segment on external and slit lamp examination in both eyes at the Screening and 
Baseline visits. 
6. Normal posterior segment on fundus ophthalmoscopic examination in both eyes at the Screening and 
Baseline visits. 
7. Subject must be considered in good systemic health in the opinion of the investigator at the Screening 
and Baseline visits, as determined by:  
a. Subject’s body mass index is between 18.5 and 30.4 kg/m2 inclusive 
b. A pre-study physical examination with no clinically significant abnormalities. 
c. Vital signs within clinically acceptable ranges for the purposes of the study (sitting systolic blood 
pressure [BP] ≥ 90 mmHg and ≤ 150 mmHg; diastolic BP ≥ 50 mmHg and ≤ 95 mmHg; heart 
rate ≥ 40 and ≤ 100 beats per minute; oral body temperature ≥ 35.5°C and ≤ 37.5°C). 
d. An ECG with no clinically significant abnormalities. 
e. Pre-study clinical laboratory findings within normal range or not deemed clinically significant 
in the opinion of the investigator if outside of the normal range  
8. Woman subject who meets the criteria for post-menopausal stage (post menopause is defined as the 
period following peri-menopause, i.e. postmenopausal after 12 months without a menstrual period and 
with a serum FSH value within the reference range for postmenopausal females at Screening) or 
permanently sterilised (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or woman subject 
using oral, injected or implanted hormonal methods of contraception or with a double barrier methods 
of contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. A female condom and a male condom should not be used together as 
friction between the two can result in either product failing. 
9. Male subjects with female partners of child-bearing potential must use 2 different forms of highly 
effective contraception throughout the study and for a further 3 months after the follow-up visit and all 
male subjects must be willing to avoid donating sperm during this time. The following methods of 


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contraception are considered to be highly effective: established use of oral, injected or implanted 
hormonal contraception; placement of an intrauterine device or intrauterine system; use of a barrier 
method of contraception (condom or occlusive cap with use of a spermicide); male sterilisation (post-
vasectomy documentation of the absence of sperm in the ejaculate must be provided).  
 
4.2 
Exclusion Criteria 
Subjects meeting any of the following criteria at Screening will be excluded from entry into the study: 
1. Subject has had a clinically significant illness in the 6 weeks before screening in the opinion of the 
investigator. 
2. Subject is not suitable to participate in the study in the opinion of the investigator 
3. Subject has participated in any clinical study with an investigational drug/device within 3 months prior 
to the first day of dosing.  
4. Subject has had a serious adverse reaction or significant hypersensitivity to any drug or chemically 
related compounds or has a clinically significant allergy to drugs, foods or other materials (in the opinion 
of the investigator).  
5. Administration of any topical ocular (prescription or over the counter including artificial tears) or 
systemic medication including herbal product or fish oil preparations within 14 days before the first dose 
of study drug. Vitamins and mineral supplements not containing other substances are allowed until 96 
hours before each dose if considered by the Investigator unlikely to interfere with the study results. 
Paracetamol at doses of at most 2 grams per day and ibuprofen at doses of at most 1200 mg per day for 
no more than 3 consecutive days or 6 non-consecutive days are allowed. Oral, injectable and implantable 
hormonal contraceptives are allowed without restrictions for female subjects. Longer exclusion periods 
apply for:  
a. amiodarone and hydroxychloroquine (210 days),  
b. monoclonal antibodies/ immunoglobulins/ other therapeutic proteins (120 days) 
c. Experimental drugs with a half life known to the Study Unit: Five half lives plus 2 weeks 
d. Experimental drugs with a half life unknown to the Study Unit: 120 days  
e. chloroquine and flunarizine (100 days) 
f. fluoxetine (75 days),  
g. benzodiazepines different from midazolam, lorazepam and triazolam, chlorpromazine, 
mephenytoin, nortryptyline, phenobarbital, primidone, carbamazepine, phenytoin and 
phenprocoumone (35 days).  
6. Subject has a significant history of drug/solvent abuse or a positive drugs of abuse test at any time during 
the study. 
7. Subject has a history of alcohol abuse or currently drinks in excess of 28 units per week or has a positive 
alcohol breath test at any time during the study. 
8. Subject is a smoker or has smoked in the 6 months prior to dosing. 
9. Subject who has a positive human immunodeficiency virus (HIV) screen, hepatitis B screen or hepatitis 
C screen. 
10. Subject has donated blood or blood products (e.g., plasma or platelets) within the 3 months prior to 
screening. 
11. Subject has a partner who will be pregnant or breastfeeding during the study  


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12. Pregnant or breastfeeding female or those with a positive pregnancy test or who will not use a medically 
acceptable contraceptive method from selection and during the study  
13. Subject having used corticosteroid sporadically in the last 30 days whichever the route of administration, 
or any medication by ocular or nasal administration route  
14. Subjects diagnosed with any ocular disease other than refractive error  
15. Subject with history of ocular surgery, including laser refractive surgery 
16. Subject using a contact lens within 7 days prior administration of the first dose  
17. Intraocular pressure (IOP)  22 mmHg in either eye at screening or baseline 
18. Presence of any corneal opacity or corneal fluorescein staining >0.5 grade using the modified Oxford 
scale in either eye at screening or baseline 
19. Schirmer’s test without anesthesia  9 mm/5 minutes in either eye at screening or baseline 
20. Tear film break up time (TFBUT) < 8 seconds in either eye at screening or baseline 
 
Note: Alcoholic beverages should not be taken from 48 h before first drug administration until discharge 
from the Study center. There are also restrictions with regard to chewing gum, heavy exercise and smoking 
(See § 7.6).  


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5 STUDY MEDICATION 
5.1 
Presentation, Storage, Packaging Of The Investigational Medicinal Product 
TEST PRODUCT 
 
IMP 
Recombinant human nerve growth factor (rhNGF), containing L-
methionine as excipient 
- 
20 μg/mL vials 
Manufacturer active 
substance 
Dompé Farmaceutici S.p.A., Italy 
Manufacturer 
finished product 
Bulk drug product is manufactured by Patheon Italia S.p.A-Italy. 
Packaging and labelling is performed by PCI Inc. USA 
Pharmaceutical form 
Sterile buffered aqueous solution 
Dose 
Study Eye (For subjects randomized to rhNGF group) 
Day 1: One drop instilled into study eye (35 µL, corresponding to 
0.70 µg of rhNGF). 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study 
eye (210 µL, corresponding to 4.20 µg of rhNGF). 
Total dose in the study eye will be 31 drops (1085 µL, equivalent 
to 21.7 µg rhNGF) over 6 days . 
Administration route 
Ophthalmic  
 
5.2 
Presentation, Storage, Packaging Of The Vehicle Product 
REFERENCE PRODUCT 
 
IMP 
Placebo vehicle, containing L-methionine as excipient 
- 
Vehicle vials  
Manufacturer active 
substance 
Dompé Farmaceutici S.p.A., Italy 
Manufacturer 
finished product 
Bulk drug product is manufactured by Patheon Italia S.p.A-Italy. 
Packaging and labelling is performed by PCI Inc. USA 
Pharmaceutical form 
Sterile buffered aqueous solution 
Dose 
Study Eye (For subjects randomized to vehicle group) 
Day 1: One drop instilled into study eye (35 µL, corresponding to 
0 µg of rhNGF]. 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study 
eye (210 µL, corresponding to 0 µg of rhNGF). 
Total dose of placebo vehicle in the study eye will be 31 drops 
(1085 µL, 0 µg rhNGF) over 6 days. 
 
Fellow (non-study) Eye for all subjects 
Day 1: One drop instilled into fellow eye (35 µL, corresponding to 
0 µg of rhNGF). 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into fellow 
eye (210 µL, corresponding to 0 µg of rhNGF). 
Total dose of placebo vehicle in the fellow eye will be 31 drops 
(1085 µL, 0 µg rhNGF) over 6 days. 
Administration route 
Ophthalmic  


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5.3 
Formulation And Packaging 
The Investigator will be provided with a Subject box containing vials of frozen IMP solutions (-20 ± 5°C) 
containing: 
• 
rhNGF, at concentrations of 20 µg /mL, for dosing the right or left eye (study eye), according to the 
randomization list, or  
• 
vehicle (placebo) for dosing the right or left eye (study eye) and for dosing the non-study eye 
according to the randomization list. 
For subjects randomized to the rhNGF treatment group, each Subject box will contain a a box of 6 vials of 
rhNGF (for one eye) and a box containing 6 vials of Vehicle for the fellow (non-study) eye.  
For subjects randomized to the Vehicle treatment group, each Subject box will contain a box of 6 vials of 
Vehicle (for one eye) and a box of 6 vials of Vehicle for the fellow (non-study) eye.  
A total of 60 kits (containing the treatment for right and left eye) will be supplied to the Pharmacy of the 
Clinical Unit. 
Syringes and adaptors will be provided separately in single sterile polyethylene packages and may be kept 
at room temperature. 
The syringe is used with an adaptor consisting of a connecting device with dual connections: one end for the 
syringe and one end for the vial.  
The Investigator will need to: 
1. Put the adaptor on the top of the vial (after removing the plastic seal) by piercing the septum 
2. Put the syringe on adaptor inlet 
3. Draw the solution contained in the vial with the syringe until this reaches its predetermined capacity 
4. Remove the syringe and use it as a dropper to administer one drop of IMP into each eye 
 


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5.3.1 Labeling 
Primary packaging: Label for vial: single panel (rh-NGF or Vehicle): 
Label for vial: single panel  
Line 
No. 
Text 
Comments 
1 
NGF0117 
  
2 
Dompé farmaceutici s.p.a 
 
3 
rhNGF 20 µg /ml or Vehicle 
 
4 
Administration eye: RIGHT or LEFT  
Active/placebo or placebo/placebo 
according to the randomization list 
stratified per eye and per subject 
5 
Eye drops (1 ml) 
 
6 
Batch: <vvvv> 
 Codified batch 
7 
Kit XXXX  
Format of kit no.: "XXXX” 
 
8 
CAUTION: New Drug-Limited by Federal (or United 
States) law to investigational use 
 
 
* The number of KIT is reported according to the randomization list that will be generated and balanced by 
gender, study eye and treatment  
 


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Secondary packaging: Six day kit (containing 6 vials): tear-off panel 
Line 
No. 
Text 
Comments 
Tear Off part of the label 
1 
Protocol no.: NGF0117 
  
To be enclosed 
2 
Sponsor: Dompé farmaceutici s.p.a, Via 
Santa Lucia, 6 - 20122 Milano, Italy 
 
To be enclosed 
3 
rhNGF 20 µg /ml or Vehicle 
 
To be enclosed 
4 
Eye drops solution (1 ml per vial) 
 
 
5 
Contains: 6 multidose vials 
 
 
6 
Directions for use: refer to dosing 
instructions 
 
 
4 
Administration eye: RIGHT or LEFT  
Active/Placebo or 
Placebo/Placebo according 
to the randomization list 
stratified per eye and per 
subject 
To be enclosed 
7 
Batch: <vvvv>\ 
 Codified batch 
To be enclosed 
8 
Kit XXXX  
Format of kit no.: "XXXX"  
 
To be enclosed 
9 
Subj. Screening #: S 
 
To be enclosed 
 
10 
Subj. Randomization #:  
 
To be enclosed 
 
11 
Store in a freezer at -20°C at the 
Investigational site 
 
 
12 
Store in a refrigerator at 2-8 °C (36°F to 
46°F) during 6 days treatment period 
 
 
13 
Do not shake 
 
 
14 
Keep out of the reach of children 
 
 
15 
For clinical trial use only 
 
 
16 
CAUTION: New Drug-Limited by 
Federal (or United States) law to 
investigational use 
 
 
 
5.3.2 Supply, Storage and Handling of IMP 
rhNGF must be stored at -20°C in an appropriate locked room accessible only to the pharmacist, the 
Investigator, or a duly designated person.  
Daily vials containing rhNGF are thawed at 2 to 8°C in the carton and protected from light. Because rhNGF 
does not contain preservatives, the contents of each vial are for daily-use only and opened vials must be 
maintained at 2 to 8°C and used within 12 hours. Agitation of vials may cause foaming and/or particle 
formation. 
Protect vials from light. Do not shake vials. 


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Administration 
Drug preparation and administration instructions will be provided separately in the Pharmacy Manual for the 
study. 
5.3.3 Replacement Kits 
Thirty additional kits will be prepared as replacements. Assignment of subject and kit number is described 
in § 6.1).  
5.4 
Dose, Route And Schedule Of Imp Administration 
5.4.1 Administration route 
The Administration route is ophthalmic, to be applied by investigator at site. 
5.4.2 Dose regimen 
In all subjects both eyes will be treated; with one eye as the study eye.  
 
All subjects will receive either rhNGF or vehicle in the study eye (right or left) according to the 
randomization list. 
 
The fellow (non-study) eye will receive vehicle.  
Both the subjects and the investigator/ophthalmologist will be masked to the study treatment and study eye 
randomization (see § 6.3) 
The exact times of study drug administration, and comments, will be recorded on the appropriate page of the 
eCRF. 
rhNGF 20 µg /mL: 
For subjects randomized to rhNGF group:  
Study Eye  
 
Day 1: One drop instilled into study eye (35 µL, corresponding to 0.70 µg of rhNGF). 
 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 µL, corresponding to 
4.20 µg of rhNGF). 
Total dose in the study eye will be 31 drops (1085 µL, equivalent to 21.7 µg rhNGF) over 6 days . 
Vehicle:  
For subjects randomized to vehicle group:  
Study Eye  
 
Day 1: One drop instilled into study eye (35 µL, corresponding to 0 µg of rhNGF]. 
 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into study eye (210 µL, corresponding to 0 µg 
of rhNGF). 
Total dose of placebo vehicle in the study eye will be 31 drops (1085 µL, 0 µg rhNGF) over 6 days. 
Fellow (non-study) Eye 


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For all subjects (subjects randomized to rhNGF group and subjects randomized to vehicle group):  
 
Day 1: One drop instilled into fellow eye (35 µL, corresponding to 0 µg of rhNGF). 
 
Day 2, 3, 4, 5, 6: One drop six times a day (every 2h) into fellow eye (210 µL, corresponding to 0 µg 
of rhNGF).  
Total dose of placebo vehicle in the fellow eye will be 31 drops (1085 µL, 0 µg rhNGF) over 6 days. 
5.5 
Criteria For Schedule Adjustment/Dose-Modification/ Discontinuation Of 
Investigational Product 
No schedule adjustment or dose adjustments are allowed. 
5.6 
Accountability Of The Investigational Product 
The Pharmacist and/or Investigator will confirm the receipt of the IMP supply in writing by signing and 
dating standard drug accountability forms. 
The Pharmacist and/or Investigator will keep a cumulative inventory and dispensing records, and will 
maintain all supplies under adequate security.  
An accurate drug disposition record will be kept, specifying the date and amount dispensed to each subject.  
Adequate record of receipt and use or loss of drug will be retained. This inventory record must be available 
for inspection by the Sponsor and regulatory inspection at any time. Copies of this record will be provided 
to the Sponsor by Cromsource throughout the duration of the study. 
At the end of the study, unused IMP will be returned to Dompé for disposal. 
5.7 
Concomitant Medication 
As a general rule, no medication other than study drug will be given during the course of the study, i.e., from 
the initial day of Screening until all of the final study evaluations have been completed. 
Following the first dose of study drug, the exceptions are the medications allowed in § 4.2 Exclusion Criteria, 
under Exclusion Criterion 5: 
 
Vitamins and mineral supplements not containing other substances are allowed until 96 hours before 
each dose if considered by the Investigator unlikely to interfere with the study results. 
 
Paracetamol at doses of at most 2 grams per day and ibuprofen at doses of at most 1200 mg per day 
for no more than 3 consecutive days or 6 non-consecutive days are allowed.  
 
Oral, injectable and implantable hormonal contraceptives are allowed without restrictions for female 
subjects. 
Decisions regarding subjects requiring concomitant medication will be discussed with the sponsor on a case-
by-case basis. The administration of any such medication (including over-the-counter medications and 
vitamins) will be clearly documented on the Prior and Concomitant Medications eCRF page. 
5.7.1 Prior and concomitant medications 
Before the administration of the first dose of study drug, the following medications have the following 
exclusion periods specified in § 4.2 Exclusion Criteria, under Exclusion Criterion 5 and 12. 


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Within 96 hours before each dose: 
Vitamins and mineral supplements not containing other substances are allowed if considered by the 
Investigator unlikely to interfere with the study results.  
Within 14 days before the first dose of study drug: 
Administration of any topical ocular (prescription or over the counter including artificial tears) or systemic 
medication including herbal product or fish oil preparations. 
Within 30 days 
Subject has corticosteroid sporadically, whichever the route of administration  
Any medication by ocular or nasal administration route. 
Exclusion periods apply for the following prior medications:  
a. amiodarone and hydroxychloroquine (210 days),  
b. monoclonal antibodies/ immunoglobulins/ other therapeutic proteins (120 days) 
c. Experimental drugs with a half life known to the Study Unit: Five half lives plus 2 weeks 
d. Experimental drugs with a half life unknown to the Study Unit: 120 days  
e. chloroquine and flunarizine (100 days) 
f. fluoxetine (75 days),  
g. benzodiazepines different from midazolam, lorazepam and triazolam, chlorpromazine, 
mephenytoin, nortryptyline, phenobarbital, primidone, carbamazepine, phenytoin and 
phenprocoumone (35 days). 


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6 ASSIGNMENT OF SUBJECT NUMBER 
After obtaining informed consent a 3 digit consecutive screening number will be assigned to each subject 
according to the sequence of study entry, starting from from S001.  
6.1 
Randomisation 
A total of 30 subjects will be randomized: 20 subjects on rhNGF treatment group and 10 on Vehicle treatment 
group. 
Eligible subjects will be randomized at the Baseline Visit in a 2:1 ratio to a respective treatment 
groupaccording to the randomization code and determined by the allocated randomization number. 
Randomization will be stratified by gender to ensure a balanced (2:1) gender distribution between treatment 
groups. With at least 6 subjects be recruited for each gender, it is ensured to have at least 4 male and 4 female 
subjects in the rhNGF group and 2 male and 2 female subjects in the Vehicle group. 
Moreover, the study eye will be randomized for each subject to left and right eye. 
During randomization, each subject will be allocated with randomization number. Together with the 
randomization number, the randomized study eye and associated kit number will be provided. 
Randomization list and study eyes as well as associated kit numbers will be be generated by a member of 
Cromsource SAS programming group not involved in the conduct of the study. A total of 60 kits (containing 
the treatment for right and left eye) will be supplied to the Pharmacy of the Clinical Unit.  
Subjects 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. 
6.2 
Treatment Allocation  
Each randomized subject will receive masked study treatment (either rhNGF eye drops 20 µg /ml or vehicle 
solution) in the study eye and vehicle in the fellow (non-study) eye according to the randomization code and 
determined by the allocated randomization number. 
6.3 
Masking 
The identity of the treatments will remain unknown to the subject, Investigator, site staff and Sponsor’s 
clinical research personnel until the study is unmasked for the final statistical analysis (after data base lock) 
except in case of specific events that will require unmasking of the subject. 
The vials containing rhNGF (20 µg /ml) or vehicle will be identical in appearance, and the contents of the 
vials will be indistinguishable. All staff directly involved in the analysis of study results will remain masked 
to treatment assignments while the study is in progress. 
In the event of a medical emergency where the knowledge of subject treatment is required to provide the 
subject with appropriate care, Investigators will have the possibility to unmask the treatment assignment for 
a specific subject. . The Investigators are encouraged to contact Cromsource staff before becoming unmasked 
if there is sufficient time.  
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. 
The investigator and Dompé Pharmacovigilance contact will be provided with Code Breakers, containing 
the treatment allocation, to be opened only in case of a medical emergency. Therefore, a copy of the sealed 


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code envelopes will be filed at the clinic, in a secure, locked place. The integrity of these Code Breakers will 
be checked by the monitor at the end of the study. 
Unmasking events will be recorded and reported in the final study report. 


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7 STUDY PROCEDURE AND ASSESSMENTS 
The schedule of study procedures and assessments is tabulated by visit in the Schedule of Evaluations in § 
1.1. 
A detailed view of the evaluations, including timings, is provided in Appendix 3-Detailed List And Timing 
Of Procedures (§ 15.3). 
The descriptions of the procedures to be performed at each visit are provided below. Note: the order detailed 
in the lists below does not reflect the order of assessment.  
7.1 
Screening Visit 
The pre-study Screening visit is to take place within 20 days prior to admission in the Unit for the dosing 
period (Baseline Day -1). 
During Screening:  
 
Informed Consent 
 
Assesment of Inclusion and Exclusion Criteria 
 
Demography 
 
Medical History / Current medical conditions 
 
Prior / Concomitant medication 
 
Physical examination and height 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 
 
ECG (12 lead) 
 
Laboratory safety tests including: Hematology, Clinical chemistry, Urine analysis, Hepatitis screen, HIV 
screen  
 
Screening for drugs of abuse including alcohol breath test 
 
Pregnancy test for female subjects and serum FSH test for postmenopausal females. 
 
Ocular examination (both eyes) including: 
 
Assessment of best corrected distance visual acuity (BCDVA)  
 
External ocular examination (EOE): motility and eyelids 
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
(Note: The SLE must be performed before IOP)  
 
Corneal fluorescein staining (CFS; modified Oxford scale) following instillation of fluorescein 
 
Tear film break-up time (TFBUT).  
 
Schirmer test (ST) without anesthesia 
 
Intraocular pressure (IOP) 
 
Dilated Fundus Ophthalmoscopic (FO) examination to assess the vitreous, retina/macula/choroid, 
and optic nerve, including cup/disc ratio 
7.2 
Study Visits And Follow-Up Assessments 
Baseline (Day -1) 
 
Review of inclusion/exclusion criteria 
 
Current Medical conditions  
 
Physical examination 
 
Adverse Events 
 
Concomitant medication 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 


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 
ECG (12 lead) 
 
Laboratory safety tests including: hematology, clinical chemistry and urine analysis 
 
Screening for drugs of abuse including alcohol breath test 
 
Pregnancy test for female subjects 
 
Blood samples for PK 
 
Blood sample for ATA 
 
Ocular examination (both eyes): 
 
BCDVA Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky 
feeling, blurred vision, photophobia) 
 
EOE: motility and eyelids 
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
(Note: The SLE must be performed before IOP)  
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Schirmer test (ST) without anesthesia 
 
Intraocular pressure (IOP) 
 
Dilated Fundus Ophthalmoscopic (FO) examination to assess the vitreous, retina/macula/choroid, 
and optic nerve, including cup/disc ratio 
 
Treatment Day 1 
One drop of rhNGF or vehicle instilled into one eye on day 1 (35 µL). 
 
Adverse Events 
 
Concomitant Medication 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 
 
ECG (12 lead) 
 
Ocular examinations (both eyes):  
 
BCVDA 
 
EOE: motility and eyelids  
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia)  
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Blood samples for PK 
 
Randomization 
 
Study drug administration 
 
Treatment Day 2 
One drop of rhNGF or vehicle instilled into one eye six times a day on 2,3,4,5,6 (every 2h; 210 µL, 
corresponding to 4.20 µg of rhNGF). 
 
Adverse Events 
 
Concomitant Medication 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 
 
ECG (12 lead) 
 
Ocular examinations (both eyes):  
 
BCVDA 
 
EOE: motility and eyelids  


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 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia)  
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Blood samples for PK  
 
Study drug administration 
 
Treatment Day 3 
One drop of rhNGF or vehicle instilled into one eye six times a day (every 2h; 210 µL, corresponding to 
4.20 µg of rhNGF). 
 
Adverse Events 
 
Concomitant Medication 
 
ECG (12 lead)  
 
Ocular examinations (both eyes):  
 
BCVDA 
 
EOE: motility and eyelids  
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia)  
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Blood samples for PK  
 
Study drug administration 
 
Treatment Day 4 
One drop of rhNGF or vehicle instilled into one eye six times a day (every 2h; 210 µL, corresponding to 
4.20 µg of rhNGF). 
 
Adverse Events 
 
Concomitant Medication 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 
 
ECG (12 Lead) 
 
Blood samples for PK  
 
Study drug administration 
 
Treatment Day 5 
One drop of rhNGF or vehicle instilled into one eye six times a day (every 2h; 210 µL, corresponding to 
4.20 µg of rhNGF). 
 
Adverse Events 
 
Concomitant Medication 
 
ECG (12 lead) 
 
Blood samples for PK  
 
Study drug administration 
 


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Treatment Day 6 
One drop of rhNGF or vehicle instilled into one eye six times a day (every 2h; 210 µL, corresponding to 
4.20 µg of rhNGF). 
 
Adverse Events 
 
Concomitant Medication 
 
Vital signs (body weight, blood pressure, pulse rate, respiratory rate and ear body temperature) measured 
after at least 3 minutes in the sitting position. 
 
ECG (12 lead) 
 
Ocular examinations (both eyes):  
 
BCVDA 
 
EOE: motility and eyelids  
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia)  
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Blood samples for PK  
 
Study drug administration 
 
Follow Up Day 7 (FU 1) 
 
Adverse Events 
 
Concomitant Medication 
 
Physical examination 
 
ECG (12 lead) 
 
Laboratory safety tests including: Hematology, Clinical chemistry, Urine analysis  
 
Ocular examinations (both eyes):  
 
BCVDA 
 
EOE: motility and eyelids  
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia)  
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Blood sample for PK 
 
Follow Up Day 8 (FU 2) 
 
Adverse Events 
 
Concomitant Medication 
 
Physical examination 
 
ECG (12 lead) 
 
Laboratory safety tests including: Hematology, Clinical chemistry, Urine analysis  
 
Blood samples for PK 
 
Ocular examination (both eyes) including: 
 
BCVDA 
 
EOE: motility and eyelids 
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia) 
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
(Note: The SLE must be performed before IOP) 


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 
CFS (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Intraocular pressure (IOP) 
 
Fundus ophthalmoscopic (FO) examination to assess the vitreous, retina/macula/choroid, and optic 
nerve, including cup/disc ratio. 
 
Follow Up Day 16±2 (FU 3) 
 
Adverse Events 
 
Concomitant Medication 
 
Physical examination 
 
ECG (12 lead) 
 
Laboratory safety tests including: Hematology, Clinical chemistry, Urine analysis  
 
Blood samples for PK 
 
Ocular examination (both eyes) including: 
 
BCVDA 
 
EOE: motility and eyelids 
 
Assessment of LOT (VAS: foreign body sensation, burning/stinging, itching, pain, sticky feeling, 
blurred vision, photophobia) 
 
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens 
(Note: The SLE must be performed before IOP) 
 
CSF (modified Oxford scale) following instillation of fluorescein 
 
TFBUT 
 
Intraocular pressure (IOP) 
 
FO to assess the vitreous, retina/macula/choroid, and optic nerve, including cup/disc ratio. 
 
Follow Up Day 35 to 42 (FU 4) 
 
Adverse Events 
 
Blood sample for ATA  
 
Early Termination Visit (ETV)  
For any subject discontinuing the study, the Investigator ask the subject to undergo, as far as possible, a final 
medical visit to examine the subject's health conditions  
a. 
This examination will verify that all values tested at screening have remained within a clinically 
acceptable range (i.e., not clinically significant changes compared to screening). The assessments 
will be conducted as detailed in Follow Up Day 16±2 (FU 3). 
b. 
Arrange for alternative medical care of the withdrawn subject, if necessary 
c. 
Report in the eCRF date and time of the last dose administration, and date and primary reason of 
study discontinuation  
d. 
Record in the eCRF any follow-up, if the subject is withdrawn for an AE. 
 
Procedures conducted at the Early Termination 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. 
7.3 
Premature Discontinuation From The Study  
It will be documented whether or not each subject completed the clinical study. If, for a subject, study 
treatment or observations are discontinued, the primary reason for discontinuation will be recorded. 


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7.3.1 Primary Reason For Discontinuation From The Study 
 Adverse event (AE): Any significant AE that, in the opinion of the Investigator or concerned subject, is 
not compatible with study continuation. For the definition of AE, please refer to § 9.1 
 Death: the absence of life or state of being dead 
 Lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 Non-compliance with study drug: an indication that a subject has not agreed with or followed the 
instructions related to the study medication 
 Physician decision: a position, opinion or judgment reached after consideration by a physician with 
reference to the subject 
 Pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in the body 
(uterus), after union of an ovum and spermatozoon, during the period from conception to birth (please 
see § 9.6 
 Protocol violation: an event or decision that stands in contrast to the guidelines set out by the protocol 
 Study terminated by the Sponsor: an indication that a clinical study was stopped by its Sponsor 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified. 
7.3.2 Discontinuation procedures 
For any subject discontinuing the study following randomization, the Investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the subject's health 
conditions This examination will verify that all values tested at screening have remained within a 
clinically acceptable range (i.e., not clinically significant changes compared to screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 report in the eCRF date and time of the last dose administration, and date and primary reason of study 
discontinuation 
 record in the eCRF any follow-up if the subject is withdrawn for an AE (as per § 9.5). 
7.3.3 Replacement 
Subjects that drop out prior to receiving the first dose will be replaced. 
7.4 
Study Duration 
The study will consist of a screening period of upto 20 days before admission [i.e., Day –21 to Day -1], a 
one day baseline phase (Day -1) before eye drop application on Days 1 to 6, with follow-up visits on days 7, 
8, 16±2, and 35±7 (ranging from 28 to 42) days. 
Treatment duration is 6 days. 
The subject will be resident in the Phase I clinic for 9 days [Baseline (D-1) to Follow-Up Visit 2 (D8].  
Maximum total study duration for a subject is 63 days (9.0 weeks) from screening visit to the follow up visit 
at 35 to 42 days. 


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Study Duration is expected to be 4 months (first visit of the first subject to the last visit of the last subject). 
7.5 
End Of Study 
For the purpose of this trial, the End of Study is defined as the date of the last visit of the last subject. 
7.6 
Domiciling And General Study Conditions 
The subjects will be confined to the study center from two days before the administration of study drug (Day 
-2) until 56 hours after last dosing (Day 8). 
Alcoholic beverages should not be taken from 48 h before first drug administration until discharge from the 
Study center. This is only a precaution for the general safety of the subjects.  
In order to avoid undesired influences on the objectives of the study, the following instructions are given: 
 
Chewing gums are not allowed at study site. 
 
Heavy exercise (meaning unusual exercise for the degree of conditioning of the individual subject) 
has to be avoided from 4 days before the start of the treatment period and while confined to the study 
center.  
 
Smoking is not allowed while confined to the study center. (Note: being a smoker, or having smoked 
in the 6 months prior to dosing. is an exclusion criteria). 
7.6.1 Dietary and Fluid Restrictions 
From the Screening visit to the treatment period, the subjects shall keep their normal dietary habits. Strenuous 
exercise should be avoided throughout the study. 
On the evening before the Baseline (Day -1) assessments (i.e. the domiciling of the subjects), subjects will 
get a standardized dinner. All first doses in a dosing day will be given after an overnight fast (only tap water 
allowed from the dinner on the day before). Breakfast will be given 2 h after the first dose on a dosing day.  
In the dosing days, 5 hours after the administration of the first dose of study drug in the day, a lunch will be 
served. This will be followed by a light snack after 10 hours and dinner 13 hours after the administration of 
the first dose of study drug in the day.  
Beverages containing xanthine or food such as coffee, tea, cola, cocoa, or chocolate are not allowed at the 
study site. Alternatively, after lunch, fruit tea decaffeinated coffee, or non-carbonated water can be 
consumed. Alcoholic beverages are not allowed in the Unit. 
The composition of meals and fluids will be provided by the study center and will be similar for all subjects 
while at the study center.  
When meal and blood draw times coincide, blood will be drawn BEFORE the meal is provided. 


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7.6.2 Physician coverage 
The investigator or designee will personally supervise the subjects during the drug administrations. A 
physician shall be available by pager at all other times throughout the study. 


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8 EVALUATIONS AND PROCEDURES 
The following evaluations and procedures will be required in this study (a schedule of these assessments is 
summarised in § 1.1 and a detailed schedule can be found in Appendix 3-Detailed List And Timing Of 
Procedures). If several assessments have to be performed at the same time, the sampling for pharmacokinetic 
analyses always has priority. In case multiple assessments are foreseen for a given time point, these 
assessments should always be performed in the same order. 
8.1 
Inclusion And Exclusion Criteria 
Subject selection is to be established by examination of the inclusion/exclusion checklist (§ 4).  
8.2 
Background Information 
This includes a complete medical history including current medical conditions, age, gender, ethnic origin, 
height (in cm), body mass index (in kg/m2 with one decimal), daily consumption of caffeine and alcohol, 
and history of smoking. 
8.3 
Prior And Concomitant Medication 
All medications (including over-the-counter drugs, herbal products, vitamins, and antacids) taken within 4 
weeks prior to the start of and throughout the study must be recorded on the case report form. Medication 
entries should be specific to product name (if a combination drug product) and spelled correctly. The dose, 
unit, frequency, route of administration, start date, discontinuation date, and indication should also be 
recorded. For medications administered only one time, the frequency column may reflect "once". 
The use of the medications with exclusion periods before dosing longer than 4 weeks will only be checked 
at Screening for eligibility but would need not to be otherwise recorded. 
8.4 
Physical Examination 
This evaluation will include an examination of general appearance, head-eyes-throat-nose-ears, skin, 
thorax/lungs, cardiovascular system, abdomen, lymph nodes, musculoskeletal system, neurological system 
and other examinations as necessary.  
Clinically significant abnormalities (or a clinically significant worsening of a physical condition), which 
were observed the first time during study will be reported as adverse event. 
8.5 
Vital Signs 
This evaluation will include body weight (in kg with one decimal), and sitting assessments of systolic and 
diastolic blood pressure and pulse rate as well as respiratory rate and body temperature. Blood pressure and 
pulse rate as well as respiratory rate will be recorded after the subject has rested in the sitting position for at 
least 3 minutes. Blood pressure should be assessed on the same arm for each time of determination using an 
automated measurement device. 
Body temperature will be assessed in the ear (normal below 37.5oC). 
Clinically significant changes (or a clinically significant worsening) in vital signs, which were observed the 
first time during study will be reported as adverse event. 


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8.6 
Electrocardiographic Evaluations  
ECG testing is planned based on the previous study in health volunteers (NGF0112), to cover a potential 
rapid absorption of rhNGF (0.5 h after dose) and to cover the multiple dose treatment during the study. 
A 12-lead standard ECG tracing with a rhythm strip will be used.  
If the QTC is greater than 450ms, the ECG will be repeated 3 times.  
The following ECG measures at each time point will be transferred in eCRF: 
 
Heart rate 
 
PR interval 
 
QRS duration 
 
QT interval 
 
QTc (Fridericia and Bazett corrections) 
The tracings will be interpreted, dated and signed prior to submission to the sponsor. Original tracings will 
accompany the original eCRF. The subject's number and initials as well as the date and actual time of the 
tracing must appear on the printout of the tracing. 
All occurring abnormalities will be identified and listed by subject and evaluation time point. 
Clinically significant changes (or a clinically significant worsening) in ECG, which were observed the first 
time during study will be reported as adverse event. 
8.7 
Laboratory Safety Tests 
The following laboratory evaluations will be performed at the study site:  
The subject need not be in fasting condition. Examinations marked with Y instead of X in Appendix 3-
Detailed List And Timing Of Procedures (§ 15.3) may be done at any time on the examination day. 
Hematology: hemoglobin, hematocrit, RBC count, reticulocyte count, WBC with differential platelet count. 
Clinical Chemistry: sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, albumin, 
total bilirubin, AST, ALT, alkaline phosphatase, GGT, FSH (only for postmenopausal females at Screening 
to confirm post-menopausal status), creatinine, BUN(urea-N), glucose, uric acid, cholesterol and high 
sensitivity C-reactive protein. 
Urinalysis Stix: pH, density, glucose, protein, blood (free Hb), bilirubin, urobilinogen, ketones, nitrites, 
leukocytes and erythrocytes. A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid 
contamination and allow a proper assessment.  
Pregnancy test (females only): Performed in serum at Screening and in Urine during the Baseline period 
For all laboratory values, date and time of laboratory sample will be documented on the eCRF. Laboratory 
results will be categorized either Normal, abnormal not clinically significant, abnormal clinical significant 
by the investigator. Each laboratory value determined in the study as well as the clinical assessments will be 
entered on the eCRF. 
Clinically significant changes (or a clinically significant worsening) in laboratory safety assessments, which 
were observed the first time during study will be reported as adverse events. 


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Values which are considered clinically significant and/ or study drug related will be noted on the eCRF. The 
investigator will record his/ her medical opinion of the clinical significance of each laboratory value outside 
of the reference range in the eCRF. This decision shall be based upon the nature and degree of the observed 
abnormality. The investigator may choose to repeat any abnormal result ONCE, in order to rule out 
laboratory error. Clinically relevant deviations of laboratory test results occurring during or at post study 
examination of the study must be reported and discussed with the sponsor’s Medical Expert. Repeated 
evaluations are mandatory until their normalization or until the time course and reason of the underlying 
process can clearly be assessed. In case of doubt, the sponsor’s Medical Expert must be contacted. 
The investigator will provide the sponsor with a copy of each laboratory's certification and a tabulation of 
the normal ranges.  
8.8 
Drug Screen 
Subjects who are found to have positive urine results for any substances of abuse (Amphetamines, 
methamphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, opiates, methadone and 
phencyclidine) at Screening or at baseline will be excluded from study entry.  
8.9 
Serology 
Hepatitis Screen 
All subjects will be screened for hepatitis B surface antigen (HBsAg) at Screening. Screening for hepatitis C 
will be based on HCV antibodies. Any subject who has a positive test result will be excluded from the study 
and referred to a specialized outreach clinic. 
HIV Screen 
Evaluation for HIV 1 and 2 will consist of an ELISA. Any subject who has a positive test result will be 
excluded from the study and referred to a specialized outreach clinic. 
8.10 Pharmacokinetic Analysis 
Serum Collection for NGF Analysis 
The concentration versus time profiles of NGF will be assessed from individual serum samples of all 
subjects. 
All blood samples will be taken by either direct stick or an indwelling cannula inserted in a forearm vein. On 
the days of pharmacokinetic profiling, a cannula will be inserted. Any missing blood draws must be reported 
on the respective eCRF section. 
Two validated ELISA tests performed at Dompé farmaceutici s.p.a. will be used for PK measurements. The 
original validated method will be the same applied to the NGF determination in serum samples taken from 
studies NGF0112 and NGF0212. A new additional validated ELISA method will be performed with the 
intention of improving the sensitivity in the determination of NGF serum levels. 
The processing, storage and shipment instructions for the pharmacokinetic samples obtained in this Study 
will be provided in the Research Specimen Manual.Briefly: each blood (5 mL) sample will be transferred to 
a polypropylene test tube and kept undisturbed at room temperature (approximately 15-30 minutes) to allow 
coagulation. The samples will then be centrifuged at 1900 g for 15 minutes at 20 ± 5ºC and the serum 
obtained from each sample will be distributed to two fresh polypropylene test tubes. two aliquots of 1 mL 
each of serum will be immediately frozen in dry ice and then stored at -70 ± 10ºC or at -20 ± 5°C until 
shipment to Dompé farmaceutici s.p.a for NGF determination by ELISA methods. 


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The aliquots will be sent in frozen condition on dry ice by a specialized courier. The temperature will be 
tracked by temperature log during shipment. 
The quantification of rhNGF in the serum samples for pharmacokinetics will be performed at: 
Biotech Process & Analytical Development Laboratory 
Dompé farmaceutici s.p.a. 
Via Campo di Pile 
67100 L’Aquila 
Italy. 
The remaining aliquots of serum samples will be stored up to one year after Clinical Study Report (CSR) 
finalization. 
8.11 Anti-Therapeutic Antibodies (ATA) Analysis 
Serum Collection for Anti-therapeutic Antibodies (ATA) Analysis 
Blood samples at baseline, and at between 35 to 42 days after the first dose of rhNGF will taken from all 
subjects for the ATA determination. 
The concentration of ATA will be assessed from individual serum samples of all subjects. 
All blood samples will be taken by either direct stick or an indwelling cannula inserted in a forearm vein. On 
the days of ATA determination, a cannula will be inserted. Any missing blood draws must be reported on 
the respective eCRF comment sheet. 
A validated ELISA assay performed by the provider will be used for anti-therapeutic antibodies (ATA) 
detection:  
Swiss BioQuant AG 
Kägenstrasse 18 
4153 Reinach, Switzerland 
The processing, storage and shipment instructions for the immunocnicity samples obtained in this Study will 
be provided in the Research Specimen Manual. 
Briefly: each blood (7.5 mL) sample will be transferred to a polypropylene test tube and kept undisturbed at 
room temperature (approximately 15-30 minutes) to allow coagulation. The samples will then be centrifuged 
at 1900 g for 15 minutes at 20 ± 5ºC and the serum obtained from each sample (at least 3.5 mL) will be 
distributed to two fresh polypropylene test tubes. two aliquots of 1.7 mL each of serum will be immediately 
frozen in dry ice and then stored at -70 ± 10ºC until shipment to the Analytical LAB for the determination 
by ELISA validated method. 
The aliquots will be sent to the bioanalytical laboratory using a specialized provider (e.g. Wourld Courier) 
in frozen condition . The temperature will be monitored by temperature log during the shipment period. 
The serum concentrations of ATA will be provided by the bioanalytical laboratory in a separate report and 
incorporated into the final CSR as an appendix. 
The remaining aliquots of serum samples will be stored up to one year after CSR finalization. 
8.11.1 Total volume of blood to be taken from each subject 
The total volume of blood to be taken from each subject during the course of the study is 400 mL, as follows: 
• 
Laboratory Assessments (including hepatitis and HIV screen): 20 mL x 5 timepoints = 100 mL 


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• 
PK determinations 5 mLx 57 time points = 285 mL  
• 
ATA 7.5 mL x 2 time points = 15 mL.  
8.12 Ophthalmological Evaluations 
Opthalmological evaluations will be performed on both eyes and will include the following, depending on 
the study day (See Appendix 3-Detailed List And Timing Of Procedures): 
Local Ocular Tolerability (LOT) score:  
 
A global ocular discomfort score will be assessed by the subject using a self-administered 100 mm visual 
analogue scale (VAS) on which 0 means no symptoms and 100 means the worst possible discomfort. 
This evaluation is to be performed before any ophthalmic assessment at a given study visit. 
 
Specific ocular symptoms to be assessed with the VAS by the subject include: 
o foreign body sensation, 
o burning/stinging, 
o itching,  
o pain,  
o sticky feeling  
o blurred vision  
o photophobia  
Best corrected distance visual acuity (BCDVA) measured using the ETDRS score 
Subjects with a BCDVA score ≤ 0.00 LogMAR (≥83 ETDRS letters, 20/20 Snellen or 1.0 decimal fraction) 
in each eye at the Screening and Baseline visits are eligible for enrollment in the study. 
Refraction and visual acuity measurements will be performed for all subjects by trained vision examiners 
only. The name and certification number of the vision examiner should be documented in the subjects’s 
visual acuity (VA) worksheet (provided by the Sponsor) at each visit. Refraction should be conducted prior 
to visual acuity testing to obtain best-corrected vision as described below. Best-corrected visual acuity is 
measured at all trial visits using standard charts, lighting, and procedures. Best correction is determined by 
careful refraction at that visit according to the standard protocol for refraction as described below. 
Refraction equipment required includes: 
 
Retroilluminated Light box and ETDRS 4 meter distance acuity chart set 
 
Trial lens frames 
 
Trial lens set with plus or minus cylinder lenses 
 
Jackson cross-cylinders of 0.25, 0.50, and 1.00 diopters 
 
Pinhole occluder 
 
Tissues or eye pads and tape 
 
A 1 meter rigid measuring stick 
Visual acuity charts: Chart 1 is used for testing the visual acuity of the RIGHT eye; Chart 2 for testing the 
LEFT eye; and Chart R (or 3) for refraction only. Subjects should not be allowed to see any of the charts 
before the examination. 
A distance of 4 meters is required between the subject’s eyes and the visual acuity chart. With the box light 
off, not more than 15 foot-candles of light (161.4 Lux) should fall on the center of the chart. To measure the 
amount of light, the room is set up for visual acuity testing, but with the box light off. The light meter is 
placed at the fourth line from the top of the chart, with its back against the chart and the reading is taken. If 
more than one line available for testing visual acuity, the visual acuity of an individual subject should be 
measured in the same line at each visit, if possible. If different lines are used to test visual acuity, they must 
each meet the same standards. 


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Retroilluminated ETDRS charts are used in this trial. The illuminator box will be either wallmounted or 
mounted on a stand. The light box should be mounted at a height such that the top of the third row letter is 
49 + 2 inches from the floor. 
The visual acuity light box is equipped with two General Electric 20-watt fluorescent tubes and ballast. Each 
tube is partly covered by a 14-inch fenestrated sleeve, which is centered on the tube and open in the back. 
This serves as a “baffle” to produce even illumination over the testing chart. Because the illumination of 
fluorescent tubes diminishes by 5 percent during the first 100 hours and by another 5 percent during the next 
2000 hours, new tubes should be kept on for 4 days (96 hours) continuously, and should be replaced once a 
year. 
A sticker should be placed on the back of the light box, indicating the date when the present tubes were 
installed. A spare set of burned in bulbs should be available on site. 
 
Detailed instructions for VA assessment 
As a reminder, Charts 1, 2 and R (or 3) are used for testing the right eye, left eye, and refraction, respectively. 
Subjects should not see the charts until the test begins. The lens correction from the subject’s refraction 
should be in the trial frame worn by the subject. 
All eyes must be tested at 4 meters first, even if the refraction was performed at 1 meter. 
The subject should be seated comfortably directly in front of the chart so that the eyes remain at the 4 meter 
distance. Testing always begins with the right eye. The fellow (non-study) eye should be occluded with a 
folded tissue or eye pad lightly taped over the eye behind the trial frame serves as an effective occluder that 
allows eccentric fixation without inadvertent use of the covered eye. After testing the right eye, occlusion of 
the right eye should be done BEFORE Chart 2 is put up for testing the left eye. 
The subject is asked to read the letters slowly, approximately one letter per second. The subject should be 
told that only one chance is given to read each letter, but may change their mind before moving to the next 
letter. If the subject is unsure about the identity of the letter, then the subject should be encouraged to guess. 
The subject should begin by reading the top line of the chart and continue reading every letter on each smaller 
line, from left to right on each line. The subject should be encouraged to continue reading even if making 
mistakes. Each letter read is counted. The examiner circles every correct letter read and totals each line and 
the whole column (0 if no letters are correct) on the provided VA worksheet. An X is put through letters read 
incorrectly. Letters, for which no guess was attempted, are not marked. When a subject reaches a level where 
he/she cannot guess, the examiner may stop the test, provided that the subject has made errors on previous 
guesses, which is a clear indication that the best visual acuity has been obtained. 
When a subject cannot read at least 20 letters on the chart at 4 meters, the subject is tested at 1 meter. The 
distance from the subject to the chart should be measured again using the rigid one meter stick. The distance 
is measured from the outer canthus to the center of the fourth letter (right eye) or the second letter (left eye) 
of the third line of the chart. The spherical correction in the trial frame should be changed by adding +0.75 
to correct for the closer test distance. The subject may fixate eccentrically or turn or shake his/her head to 
improve visual acuity. Particular care should be taken to make sure the subject does not move forward when 
testing at 1 meter. The subject should be reminded to blink. 
The examiner should not tell the subject if a letter was identified correctly. The subject may be encouraged 
by neutral comments, such as “good,” “next,” and “OK.” 
The examiner should not stand close to the chart during testing. Attention should be focused on the subject 
and the VA worksheet. If the subject has difficulty locating the next line to read, the examiner may go up to 
the chart and point briefly to the next line to be read, but then must move away from the chart. 


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When 20 or more letters are read at 4 meters the visual acuity score for that eye is recorded as the number of 
letters correct at 4 meters plus 30 (refer to the VA worksheet). The subject gets credit for the 30 letters at 1 
meter even though they did not have to read them. Otherwise, the visual acuity score is the number of letters 
read correctly at 1 meter plus the number, if any, read at 4 meters. If no letters are read correctly at either 4.0 
meters or 1 meter, then the visual acuity score is recorded as “0.” 
Clinically significant changes (or a clinically significant worsening) in BCDVA, which were observed the 
first time during study will be reported as adverse event. 
 
External ocular examination (EOE): motility and eyelids 
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. 
Clinically significant changes (or a clinically significant worsening) in EOE, which were observed the first 
time during study will be reported as adverse event. 
Slit-lamp examination (SLE)  
SLE to assess the eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens. The Slit-lamp 
examination (SLE) must be performed before the instillation of any dilating or anesthetic eye drops or the 
fluorescein agent. The subject will be seated at the slit-lamp while being examined. Grading of the eyelids, 
lashes, conjunctiva, cornea, lens, iris and anterior chamber will be done according to the following scales: 
Eyelid - Meibomian glands 
Evaluation of the central ten Meibomian gland openings in the mid-portion of the upper eyelid: 
0 = None (none are plugged). 
1 = Mild (1 to 2 glands are plugged). 
2 = Moderate (3 to 4 glands are plugged). 
3 = Severe (All glands are plugged). 
Eyelid - Erythema 
0 = None (normal). 
1 = Mild (redness localized to a small region of the lid(s) margin OR skin). 
2 = Moderate (redness of most or all lid margin OR skin). 
3 = Severe (redness of most or all lid margin AND skin). 
4 = Very severe (marked diffuse redness of both lid margin AND skin). 
Eyelid - Edema 
0 = None (normal). 
1 = Mild (localized to a small region of the lid). 
2 = Moderate (diffuse, most or all lid but not prominent/protruding). 
3 = Severe (diffuse, most or all lid AND prominent/protruding). 
4 = Very severe (diffuse AND prominent/protruding AND reversion of the lid). 
Lashes 
0 = Normal. 
1 = Abnormal (specify). 
Conjunctiva – Erythema 
0 = None (normal). 
1 = Mild (a flush reddish color predominantly confined to the palpebral or bulbar conjunctiva). 


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2 = Moderate (more prominent red color of the palpebral or bulbar conjunctiva). 3 = Severe (definite redness 
of palpebral or bulbar conjunctiva). 
Conjunctiva - Edema 
0 = None (normal). 
1 = Mild (slight localized swelling). 
2 = Moderate (moderate/medium localized swelling or mild diffuse swelling). 
3 = Severe (severe diffuse swelling). 
4 = Very severe (very prominent/protruding diffuse swelling). 
Lens 
0 = No opacification (normal lens). 
1 = Mild lens opacification. 
2 = Moderate lens opacification. 
3 = Severe lens opacification. 
N/A = Subject with artificial lens 
Iris 
0 = Normal 
1 = Abnormal. 
Anterior Chamber Inflammation (Slit beam = 0.3 mm wide, 1.0 mm long) 
0 = None (no Tyndall effect). 
1 = Mild (Tyndall effect barely discernible). 
2 = Moderate (Tyndall beam in the anterior chamber is moderately intense). 
3 = Severe (Tyndall beam in the anterior chamber is severely intense). 
 
Corneal findings of interest on the SLE include also the horizontal diameter of the cornea (measured in mm 
at the time of the SLE using a ruler). 
Clinically significant changes (or a clinically significant worsening) in SLE, which were observed the first 
time during study will be reported as adverse event. 
Corneal fluorescein staining (modified Oxford scale) 
As grading scale of the corneal and conjunctiva damage, the NEI/Industry Workshop guidelines will be used 
[Reference: 2]. The cornea is divided into five sectors (central, superior, inferior, nasal and temporal), each 
of which is scored on a scale of 0–3, with a maximal score of 15. Both nasally and temporally, the conjunctiva 
is divided into a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading 
scale of 0–3 and with a maximal score of 9 for the nasal and temporal conjunctiva. 
For a better reading it is also essential not to use an intense illumination beam, which may reduce the contrast 
and lead to an underestimation of grading [Reference: 3]. 
Clinically significant changes (or a clinically significant worsening) in corneal fluorescein staining, which 
were observed the first time during study will be reported as adverse event. 
Tear Film Break-up Time (TFBUT) 
Subjects with TFBUT < 8 seconds in either eye at the screening or baseline visit are NOT eligible for 
enrollment. 
TFBUT will be measured by determining the time to tear break-up. The TFBUT will be performed after 
instillation of 5 µl of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-
sac of each eye. The subject will be instructed to blink several times to thoroughly mix the fluorescein with 


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the tear film. In order to achieve maximum fluorescence, the examiner should wait approximately 30 seconds 
after instillation before evaluating TFBUT. With the aid of a slit lamp at 10X magnification using cobalt 
blue illumination, the examiner will monitor the integrity of the tear film, noting the time it takes to form 
lacunae (clear spaces in the tear film) from the time that the eye is opened after the last blink. This 
measurement will be performed within 10 seconds maximum. The TFBUT will be measured twice during 
the first minute after the instillation of the fluorescein. If the 2 readings differ by more than 2 seconds a third 
reading is taken. 
The TFBUT value will be the average of the 2 or 3 measurements. 
Clinically significant changes (or a clinically significant worsening) in ECG, which were observed the first 
time during study will be reported as adverse event. 
Schirmer test without anesthesia  
Schirmer test without anesthesia is only required at the screening visit. Subjects with a Schirmer test without 
anesthesia ≤ 9 mm/5 minutes in either eye at the screening visit are NOT eligible for enrollment. 
This test will be performed to measure aqueous tear secretion prior to the instillation of any dilating or eye 
drops. Both eyes may be tested at the same time. 
This test will be conducted in a dimly lit room. While the subject looks upwards, the lower lid will be drawn 
gently downwards and temporally. The rounded bent end of a sterile strip will be inserted into the lower 
conjunctival sac over the temporal one-third of the lower eyelid margin. The test should be done without 
touching directly the Schirmer test strip with the fingers to avoid contamination of skin oils. The subjects 
will be instructed to close their eyes gently. After 5 minutes have elapsed, the Schirmer test strip will be 
removed and the length of the tear absorption on the strip will be measured (millimeters/5 minutes). 
The wetting distance at 5 minutes for each eye will be recorded in the eCRF. 
Fundus ophthalmoscopic (FO) examination 
Fundus ophthalmoscopic (FO) examination will be performed to assess the vitreous, retina/macula/choroid, 
and optic nerve, including cup/disc ratio. Dilated FO will be performed at screening with non-dilated FO 
performed at other visits.  
Clinically significant changes (or a clinically significant worsening) in FO, which were observed the first 
time during study will be reported as adverse event. 
Intraocular pressure (IOP) 
Subjects with IOP  22 mmHg in either eye at the screening or baseline visit are NOT eligible for enrolment, 
Intraocular pressure (IOP) will be determined using Goldmann applanation tonometry. 
Clinically significant changes (or a clinically significant worsening) in IOP, which were observed the first 
time during study will be reported as adverse event. 


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9 EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
AE definition, classification and management will follow the Sponsor SOPs, based upon applicable local 
and international regulations. A brief summary of AE definition, classification and management is reported 
below. 
9.1 
Definitions  
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment (CFR-Code of Federal Regulations Title 21 Sec. 312.32). An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.  
Non-Serious Adverse Event (NSAE) 
A non-serious AE (NSAE) is defined as any untoward change in a subject's medical conditions that does 
not meet serious criteria noted below (e.g., is not fatal, is not life-threatening, does not require hospitalization, 
does not prolong a current hospitalization, is not disabling and is not an important medical event). 
Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is defined in line with CFR-Code of Federal Regulations Title 21 Sec. 
312.32 as any adverse experience that meets any of the following criteria: 
 
results in death; 
 
is life-threatening;  
NOTE: Life-threatening means that the subject was at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction which hypothetically might have caused death had it occurred 
in a more severe 
 
requires inpatient hospitalization or prolongation of existing hospitalization; 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency ward 
for observation and/or treatment (usually involving an overnight stay) that would not have been 
appropriate in the physician's office or an outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred, the event should be 
considered serious. 
 
results in persistent or significant disability/incapacity; 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental trauma (e.g., 
sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial 
disruption). 
 
results in a congenital anomaly/birth defect; 
 
is an important medical event  
NOTE: 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 subject’s well being and may require medical or surgical intervention to prevent one of 
the outcomes listed in the definitions for SAEs. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 


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convulsions that do not result in subject hospitalization or the development of drug dependency or drug 
abuse. 
Death shall always be reported as SAE: a death due to progression of disease would not have a causal 
relationship to the product. The investigator should report the event immediately to the sponsor, but the 
sponsor will not report the event as expedited to the regulatory authority. Cause of death shall always be 
specified when known or duly investigated. 
Sight Threatening Event 
For this study medically important events comprise the following sight threatening events, which are 
considered to be of special interest and by default are to be reported as SAEs: 
 
Adverse Events that caused a decrease in visual acuity of >30 ETDRS letters or > +0.6 LogMAR 
(compared with the last assessment of visual acuity at the last visit) lasting >1 hour 
 
Adverse Events that 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. 
Any serious adverse event or sight-threatening event occurring in a subject from the time of study medication 
administration through the last follow up visit must be reported to the Sponsor within 24 hours, even if the 
SAE or sight-threatening event does not appear to be drug-related. In the event of an SAE or sight-threatening 
event, the following steps should be taken; 
1. 
report the SAE or sight-threatening event to Dompé pharmacovigilance contact by fax or e-
mail using the SAE form. 
2. 
report the SAE or sight-threatening event to the relevant IRB according to local specific 
requirements. 
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as an adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" 
means there is evidence to suggest a causal relationship between the drug and the adverse event. . Adverse 
events are to be considered unsuspected if the relationship to the study drug as described in the table in § 
9.2.1 is none or unlikely; whereas any AE reported in the study having a possible, probable or highly probable 
relationship to study drug will be considered as an ADR.  
Unexpected Adverse Event Or Unexpected Suspected Adverse Reaction  
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure 
referred only to elevated hepatic enzymes or hepatitis. "Unexpected," as used in this definition, also refers 
to adverse events or suspected adverse reactions 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. (CFR-Code of Federal Regulations Title 
21 Sec. 312.32). The determination of expectedness should be made on the basis of the current IB [Reference: 
4]. 


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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 also meets the definition of a 
Serious Adverse Reaction. SUSARs related to the IMP qualify for regulatory reporting. 
9.2 
Recording 
AE data should be obtained through observation of the subject, from any information volunteered by the 
subject, or through subject questioning. 
All AEs (non-serious and serious) that occur during the course of the study, from the time the subject signs 
the ICF for the trial until last follow up visit, will be collected and recorded in the e-CRF. Any pre-existing 
medical conditions or signs/symptoms present in a subject prior to the start of the study (i.e., before informed 
consent is signed) should be specified in the eCRF. These conditions are considered AEs only if they increase 
either in frequency or severity once informed consent has been signed. Subsequent to signing an informed 
consent form, all untoward medical occurrences that occur during the course of the study must be 
documented on the eCRF. When possible, signs and symptoms indicating a common underlying pathology 
should be documented as one comprehensive event. Thus, any untoward medical occurrences or unfavorable 
and unintended signs, symptoms, or diseases that occur in the pretreatment, in treatment, or post treatment 
period are to be considered AEs and/or SAEs, and consequently recorded and reported as such. Should a 
non-serious AE become serious, the Investigator will then follow the same reporting procedures as for SAEs. 
Each AE will be described by:  
• 
Its duration (start and stop dates).  
• 
Severity grade, as defined in § 9.2.2.  
• 
Assessment of the adverse event relationship to the study treatment 
• 
Any action with study treatment taken as a result of the event. 
• 
Outcome. 
All AEs should be followed-up to determine outcome of the reaction. The Investigator should follow up the 
event until resolution or stabilization of the condition. It is the Investigator's responsibility to assure that the 
subjects experiencing an AE receive definite treatment for any AE, if required. 
Serious Adverse Events:  
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 
Electronic Data Capture (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 Cromsource Drug Safety and Dompé Drug Safety, within 24 hours from first knowledge.  
If the Investigator becomes aware of a related serious adverse event occurring to a subject after the treatment 
of that subject has ended, this event should be reported by the Investigator to Dompé Drug Safety, as further 
described in § 9.3.1.  
9.2.1 Relationship of Adverse Events to the Investigational Product 
The Investigator will assess the relationship between the AE and the investigational medication, according 
to the criteria in Table 3 below: 


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Table 3: 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. 
subject is a passenger in a road traffic accident or surgical intervention 
performed during the study, but planned before subject enrollment 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 more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the subject’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 subject’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
 
9.2.2 Severity of Adverse Events 
The Investigator will grade the severity of any AE using the definitions in Table 4 below. For each episode, 
the highest severity grade attained should be reported. 
Table 4: Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with subject’s usual function (awareness of 
symptoms or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with subject’s usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with subject’s usual function (incapacity to 
work or to do usual activities [unacceptable]) 
 
9.3 
Serious Adverse Event Reporting 
9.3.1 Reporting Procedure for Investigators to Dompé Drug Safety Pharmacovigilance and 
to Cromsource 
The Investigator must record and report all SAEs, regardless of presumed causal relationship, to Dompé 
Drug Safety and to Cromsource Medical Monitor, by e-mail (preferred) or fax within 24 hours from first 
knowledge of the SAE,to the following addresses:  
- by fax through the e-fax number: +1 201 326 7710 (linked to Dompé Drug Safety and to Cromsource 
Medical Monitor).  
- or, via e-mail to all following addresses:  
- farmacovigilanza@dompe.com;  
- DOMPE-NGF0117-PV@cromsource.com 
- DOMPE-NFGF0117-MM@cromsource.com 


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Contact details for safety matters are listed below: 
Dompé Contact Information 
Dompé Drug Safety 
Laura Boga, Senior Safety Manager 
Email: farmacovigilanza@dompe.com 
 
Dompé Medical Expert 
Flavio Mantelli – Chief Medical Officer Biotech, 
Email: Flavio.mantelli@dompe.com 
 
Early Clinical Development Manager 
Mauro P. Ferrari 
Email: mauro.ferrari@dompe.com  
 
Cromsource Contact Information 
For Pharmacovigilance: DOMPE-NGF0117-PV@cromsource.com 
For Medical Monitor: DOMPE-NFGF0117-MM@cromsource.com 
 
The Investigator should also report information on SAEs that continue after subject has completed his/her 
participation in the study (whether study completion or withdrawal), unless subject has withdrawn his/her 
consent. The follow-up will continue with no timelines for related SAEs, while for unrelated SAEs the type 
and extent of follow-up undertaken will be determined for each individual case and will depend upon the 
nature, severity and medical significance of the event. 
Respective IRB must also be informed of all SAEs according to local specific requirements. 
 SAE reports will be managed directly by the Dompé Drug Safety department, with Cromsource 
Materiovigilance And Pharmacovigilance Unit (MVPVU) support for follow-up requests. 
Follow-up reports (as many as required) should be completed and e-mailed / faxed following the same 
procedure above, marking a new SAE form, with follow up Number XX”, duly filled in and signed, within 
24 hours from awareness.  
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. 
Depending on the nature and seriousness of the AE, further information, including copies of appropriate 
medical records of the subject, as well as results of laboratory tests performed will need to be included in the 
subjects chart.  
Note: If a SAE is considered as not related by Investigator but Dompé/Cromsource consider the event related 
and unexpected this needs to be reported to Investigator. 
If the subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to 
Cromsource/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 subject’s medical records. 


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For pharmacovigilance purposes, all SAEs should be followed up in order to elucidate as completely and 
practically as possible their nature and/or causality until resolution of all queries, clinical recovery is 
complete, laboratory results have returned to normal, stable condition is reached or subject is lost to follow-
up. Follow-up may therefore continue until after the subject has completed the study up to 30 days after 
his/her discontinuation from the study for unrelated SAEs, and without timelines for related SAEs.  
Up to the database lock, SAE reports should be reported to Dompé Drug Safety and to Cromsource 
(MVPVU). New serious adverse event occurring after the site is closed should be reported directly to Dompé 
Drug Safety. 
In line with ICH E2A provisions, although the Investigator does not usually need to actively monitor subjects 
for AEs once the trial has ended, if the Investigator becomes aware of a SAE occurring to a subject after that 
subject has ended his/her participation in the study (whether study completion or withdrawal), the SAE 
should be reported by the Investigator to Dompé Drug Safety. Such “post-study cases” should be regarded 
for expedited reporting purposes as though they were study reports. Therefore, a causality assessment and 
determination of expectedness are needed for a decision on whether or not expedited reporting is required.  
9.3.2 Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a subject, 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: 
 
Anticipated Disease progression in oncology trials, as applicable. 
 
Trial end points 
 
AE that are considered expected as part of the trial treatment (such as standard side effects of 
chemotherapy in an oncology trial or anticipated AE related to study procedure, unless the frequency 
or intensity is unusual).  
 
Abnormal lab values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
9.3.3 Adverse events exemption 
Not applicable. 
9.3.4 Reporting Procedure to IRB/IEC and to Regulatory Authorities 
In addition to reporting the SAE to the Sponsor and Cromsource, 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 requierement, the Investigators must promptly 
report all suspected unexpected serious adverse reaction (SUSAR) to their IRB. 
In line with the Sponsor’s procedure and defined timelines, Dompé and Cromsource shall perform an 
assessment of the expectedness and the causality of each SAE report received and assess regulatory 
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Expectedness will be assessed with respect to the current IB [Reference: 4]: due to the early phase of 
development, all SAEs will be considered unexpected. 
For a SAE reported by the Investigator as not related that is subsequently revised to be related by the Dompé, 
the Investigator will receive a notification. 
Events considered “Possible,” “Probable,” and “Highly Probable” related to the IMP treatment will be 
reported to appropriate regulatory authorities. 
In line with provisions set forth in 21CFR312, Dompé Drug Safety 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 any clinical trials or any other source, as soon as possible, but in no case later than: 
(a) seven calendar days after becoming aware of the information if the event is fatal or life threatening; 
(b) fifteen calendar days after becoming aware of the information if the event is neither fatal nor life 
threatening. 
The investigator in turn shall notify the relevant IRB. 
If the results of an investigation show that an adverse drug reaction not initially determined to be reportable 
is reclassified as reportable, Dompé Drug Safety 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. 
Copies of all correspondence relating to reporting of any SUSAR to the IEC/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 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 durg 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 unblinded by Dompé Drug Safety prior to submission of a SUSAR to Regulatory 
Authorities and only cases referred to active treatment will be expeditable for regulatory reporting, in line 
with law requirements. 
Periodic Reporting to Regulatory Authorities 
Dompé Drug Safety shall be responsible to prepare and submit appropriate periodic safety updates 
(Development Safety Update Report – DSUR) to relevant Regulatory Authorities and IRB, if specifically 
requested. 
9.4 
Unmasking Of The Study Treatment 
Masked information on the identity of the assigned investigational product will be provided for each subject. 
If the treatment code needs to be broken in the interest of the subject safety, then Dompé Drug Safety must 
be informed in all cases in which the code was broken and of the circumstances involved. 
Additionally, Dompé Drug Safety may be needed to unmask the subject’s treatment if a reported SAE meets 
criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfill expedited 
regulatory reporting requirements. Unmaksed information shall not be disclosed to Investigators. 


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The identity of the treatments will remain unknown to the subject, Investigator, site staff, and Dompé’s 
clinical research personnel and Cromsource staff (apart from pharmacovigilance). 
9.5 
Follow-Up Of Subjects With Adverse Events (Aes) 
The Investigator is responsible for adequate and safe medical care of subjects 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 or until 10 days after the final visit. The 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. 
9.6 
Exposure To Investigational Product During Pregnancy 
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. 
Prior to enrollment in the clinical trial, female subjects 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 (during the study treatment period and during the follow up), female subjects are 
to be instructed to contact the Investigator immediately if they suspect they might be pregnant; in the same 
way, male subjects who become aware that the partner might be pregnant, are to be instructed to contact the 
Investigator immediately.  
The Investigator must report every pregnancy on a pregnancy report form as soon as possible (within 24 
hours from awareness of the pregnancy) to Cromsource/Dompé Drug Safety contacts reported at § 9.3.1, 
even if no AE has occurred, and follow it to term.  
The pregnancy form will be utilized to capture all pregnancy-related information until the birth of the child 
for both the subject and the partner.  
If 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 § 11.7 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 leads to the immediate cessation 
of the study treatment.  
9.7 
Adverse Events Causing Treatment Discontinuation 
If a subject is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned in 
the eCRF, and the subject must be followed up until the resolution of the AE or as instructed by the medical 
monitor. 
9.8 
Overdose 
Cases of overdose (accidental or intentional) shall be reported within 24 hours from the Investigator’s 
knowledge of its occurrence to Dompé Drug Safety and Cromsource, even if not associated with adverse 
events. 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 dose has caused an overdose as documented by adverse reaction, for the 


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purpose of this study, the administration of more than 3 times the total daily dose on any given treatment day 
should be considered as overdose. Dompé Medical Expert or Cromsource Medical Monitor shall be 
contacted in case of medical concern. 
9.9 
Termination Or Halting Of The Study 
In the event of two SAE, in separate subjects, with highly probable drug causality the study will be halted 
with immediate ceasation of dosing.  
In the event of the study being halted an expert Safety Committee will be created comprising a group of 
experts and will include the Principal Investigator, an independent specialist Opthalmologist and an 
unmasked Statistician. 
An operating procedure describing how the Safety Committee works and how it communicates with other 
study participants will be prepared. 
The Committee will review blinded study information (quarterly at a minimum), which will include: 
• 
List of any protocol violations 
• 
Numbers of patient withdrawals/reason for withdrawal. 
• 
Adverse/Serious Adverse Events  
• 
Laboratory Data 
The Safety Committee will also be able to request unblinding of patients. The operating procedure will 
document the planned flow of information in order to describe how the integrity of the study with respect to 
preventing dissemination of unblinded study information is assured. 
Following review of the safety data, the Safety Committee will prepare a written report which will be 
forwarded to Dompé advising of any recommendations regarding modifications, continuation or termination 
of the study. 
Where changes in the study conduct are recommended to Dompé, sufficient (blinded) information will be 
provided to allow Dompé to decide whether and how to implement these recommendations. 


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10  STATISTICS 
10.1 
Study endpoints 
Primary safety endpoints are: 
 
Incidence of treatment emergent adverse events (TEAEs). 
TEAEs are defined as an adverse event (AE), which start after first dose of study treatment. These 
comprise AEs during the treatment and follow-up period. 
 
 
Incidence of treatment emergent adverse events during 1st dose schedule (TEAEs Dose 1). 
TEAEs Dose 1 are defined as TEAEs, which start after first dose of study treatment and before 
administration of the first dose at Treatment Day 2. 
 
 
Incidence of treatment emergent adverse events during 2nd dose schedule (TEAEs Dose 2). 
TEAEs Dose 2 are defined as TEAEs, which start on/after the first dose at Treatment Day 2 and 
before Follow Up Day 7 (FU1) visit. 
 
Secondary safety endpoints are: 
 
Incidence of Follow-Up AEs (FUAE) 
FUAEs are defined as TEAEs which start on or after Follow Up Day 7 (FU1) visit visit. 
 
 
Incidence of ocular TEAEs by eyes. 
 
 
Course of ECG parameters ventricular rate, PR interval, QRS duration and QT interval over all visits. 
 
 
Course of vital signs parametes systolic and diastolic blood pressure, pulse rate, respiratory rate and 
body temperature over all visits. 
 
 
Changes from baseline in biochemistry parameters over all visits. 
Baseline is defined as the Laboratory assessment of Baseline (D-1) Visit 
 
 
Changes from baseline in hematology parameters over all visits. 
Baseline is defined as the Laboratory assessment of Baseline (D-1) Visit 
 
 
Shift in overall interpration of urinalysis over all visits. Laboratory assessment at Baseline (D-1) 
Visit is considered as reference for assessing the shift. 
 
 
Course of intraocular pressure by eye over all visits. 
 
 
Course of visual acuity score by eyes over all visits 
The visual acuity score will be derived as the total numbers of letters, which were read correctly at 
4 meter plus the total number of letters read at 1 meter as collected on the eCRF page. When 20 or 
more letters are read at 4 meters the visual acuity score for that eye is recorded as the number of 
letters correct at 4 meters plus 30. The subject gets credit for the 30 letters at 1 meter even though 
they did not have to read them. If no letters are read correctly at either 4.0 meters or 1 meter, then 
the visual acuity score is recorded as “0.” 
 
 
Course of LogMAR by eyes over all visits. 
The logMAR will be derived as – log (Snellen Equivalent result) 
 
 
Course of TFBUT by eye over all visits. 


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 
Course of overall NEI score by eye over all visits. 
 
Primary tolerability endpoints are: 
 
Change from baseline in VAS ocular tolerability scores at Treatment Day 2 pre-dose in study eye 
(Tolerability of 1x0.70 µg rh-NGF per day).  
Baseline is defined as the pre-treatment assessment at the Baseline (D-1) visit. 
 
 
Change from baseline in VAS ocular tolerability scores at D2 8h, D3 pre-dose, D6 pre-dose, D6 8h, 
D7 (Follow-up Day 7), D8 (Follow-up Day 8), D16 (Follow-up Day 16) in study eye (Tolerability 
of 6x0.70 µg rh-NGF per day).  
Baseline is defined as the pre-treatment assessment at the Treatment Day 2 visit. 
Secondary tolerability endpoints are: 
 
Course of VAS ocular tolerability scores by eye over all visits. 
 
 
Intraindividual change in VAS ocular tolerability scores between study eye and fellow (non-study) 
eye at all study visits. 
 
10.1.1 Pharmacokinetic endpoints 
The kinetics of single dose administration as well as multiple dose assessment will be evaluated. 
Beyond the respective rhNGF plasma levels for both ELISA methods, the following parameters will only be 
investigated for each ELISA method, if the data warrant to do so: 
 
maximum observed serum concentration (Cmax), time to reach Cmax (tmax), time elapsed between dosing 
and the first serum concentration that exceeds the assay quantification limit (tlag) as measured without 
treatment based on assessments on D-1 
 
Cmax, tmax. tlag of single dose regimen based on assessments on D1 and pre-dose of D2 
 
Cmax, tmax. tlag of multiple dose regimen based on assessments atarting with pre-dose of D2 
 
serum concentration measured before the administration of the next dose (Ctrough) as assessed at pre-dose 
visit on D2, D3, D4, D5, D6 
 
AUC[0-24] for the single dose regimen and the first day of multiple dose regimen.  
AUC[0-24] as area under the serum concentration versus time curve from time 0 h to pre-dose value of 
the next day calculated by the linear trapezoidal rule. Values below the level of quantitation will be set 
to 0. Values below the baseline concentration will be set to zero other than for the values for which no 
later values above the baseline concentration are available, which will be set to missing. 
 
AUC0-tlast for the multiple dose regimen. This is derived as area under the serum concentration versus 
time curve from time 0 h to the last data point tlast after drug administration above the limit of quantitation 
and the baseline concentration, calculated by the linear trapezoidal rule.  
Values below the baseline concentration will be set to zero other than for the values for which no later 
values  above the baseline concentration are available, which will be set to  missing 
 
AUC for the multiple dose regimen. AUC will be derived as area under the serum concentration versus 
time curve extrapolated to infinity, calculated as AUC = AUC0-tlast + Clast/λz 


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10.1.2 Immunogenicity endpoints 
For the investigation of immunogenicity, ATA serum levels will be investigated. 
10.2 
Sample Size 
No formal sample size calculation was made. Sample size considerations for this type of study are dependent 
on the common understanding on how many subjects one needs to demonstrate safety and tolerability for the 
dose level investigated and the different ethnicity.  
Thirty (30) subjects randomized 2:1 (rh-NGF : vehicle) could be considered acceptable. Twenty (20) subjects 
on active (one eye active, one eye placebo) and 10 on placebo (both eyes) each will be treated. 
10.1 Analysis Sets 
The "Safety" Set will consist of all subjects randomized into the study and receiving a dose of study 
medication. 
The "PK" Set will consist of all subjects who did not show serious protocol deviations or non-compliance or 
completed the PK sampling according to the study protocol. 
All protocol deviations that occur during the study will be considered for their severity/impact and will be 
taken into consideration when subjects are assigned to analysis sets during a blind data review meeting. 
Details of subject assignment to the analysis populations will be listed. 
10.2 Changes to the Statistical Plan 
Any deviations from the original statistical plan will be described in the Clinical Study Report. 
10.3 Data Analysis  
All endpoints of this study will be summarized using descriptive summary statistics, i.e. arithmetic mean, 
standard deviation (SD), minimum, median and maximum for quantitative variables by treatment group. If 
applicable, geometric mean together with 95% confidence interval and coefficient of variation will be 
reported. For qualitative variables, absolute and relative frequencies will be reported.  
All ocular assessments will be presented by treated and untreated eyes. No inferential analyses are forseen 
for this study. 
For event-based variables (e.g. adverse events) the number of events as well as the incidences (i.e. number 
and percentage of affected subjects) will be provided. 
All assessed data will be listed. For the analysis, no imputation of data is planned; all data will be analysed 
as collected. 
All statistical calculations will be made in SAS. 
A statistical analysis plan (SAP) will be developed and finalized before data base lock and unmasking 
describing in detail the planned statistical analysis.  
No interim analysis is planned for this study. 
Evaluation of Pharmcokinetics 


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The serum concentrations of rhNGF will be provided by the bioanalytical laboratory. Pharmacokinetic 
evaluation will be done using Phoenix WinNonlin 6.4 or later (Pharsight Corporation, Palo Alto, CA, USA). 
The analysis of pharmacokinetic parameters will be based on the difference between the measured rhNGF 
value after dosing and the value measured at the corresponding time on Day -1.  
Individual pharmacokinetic raw data will be checked for consistency by comparison with the enclosed hard 
copies. Values below the limit of quantitation and missing values will be labeled and accounted for 
accordingly during evaluation. 
Additional evaluations, such as compartmental analysis, may be performed with an exploratory purpose for 
the multiple dose regimen if the study data suggest that they are needed for a better understanding of the 
drug. Likewise, the pharmacokinetic results of this study may be later pooled with results of other studies 
for population pharmacokinetic and pharmacokinetic-pharmacodynamic analysis and modelling purposes. 
Anti-therapeutic Antibodies (ATA)  
ATA samples will be analyzed by a central bioanalytical laboratory (Swiss BioQuant AG). 
The serum concentrations of ATA will be provided by the bioanalytical laboratory in a separate report and 
incorporated into the final CSR as an appendix. 


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11 ETHICAL CONSIDERATIONS 
11.1 Institutional Review Board And Independent Ethics Committee  
Approval by the Institutional Review Board (IRB) before the start of the study will be the responsibility of 
the Principal Investigator (PI). A copy of the approval letter will be supplied to the sponsor, along with a 
roster of IRB members or the US Department of Health and Human Services (DHHS) general assurance 
number. During the course of the study, the PI will provide timely and accurate reports to the IRB on the 
progress of the study, at intervals not exceeding 1 year (or as appropriate), and will notify the IRB of serious 
adverse events (SAEs) or other significant safety findings. The study protocol, informed consent form (ICF), 
information sheet advertisements, and amendments (if any) will be approved by the IRBs at the study centers 
in conformance with Code of Federal Regulations (CFR), Title 21, Part 56.  
11.2 Ethical Conduct Of The Study  
The study will be conducted in full compliance with FDA and ICH guidelines for good clinical practice 
(GCP) [Reference: 1] and in accordance with the ethical principles that have their origins in the Declaration 
of Helsinki and 21 CFR § 312.120.  
11.3 Data Monitoring Committee 
Not applicable – there is no Data Monitoring Committee for this study. 
11.4 Subject Information And Consent  
Subjects, after being given an explanation of the study, will give voluntary and written informed consent 
before participating in any study-related procedures. A copy of the Experimental Subject’s Bill of Rights 
(Footnote 1) will provided to a subject prior to performing the consent process. 
Each subject will read or be read (if he or she cannot read or write), assent understanding of, and sign or 
thumbprint an instrument of informed consent after having had an opportunity to discuss them with the PI 
before signing; each subject will be made aware that he or she may withdraw from the study at any time.  
The informed consent statement contains all the elements of informed consent and contains all the core 
elements and mandatory statements as defined in the CFR. Signed copies of the ICF will be given to the 
subject, and both documents will be placed in the PI’s study files. A unique subject identification (SID) 
number will be assigned according to § 6 at the time the subject signs the ICF.  
11.5 Confidentiality 
All information obtained during the conduct of the study will be regarded as confidential. An agreement for 
disclosure will be obtained in writing by the subject and will be included in the ICF. Subject’s data collected 
during the study will be handled in accordance with applicable data protection laws and regulations.  
 
 
1 The Protection of Human Subjects in Medical Experimentation Act (California Health and Safety Code 
24170 – 24179.5) requires that a potential experimental subject (or subject’s conservator, guardian, or other 
representative) be provided with a list of the rights of a subject in a medical experiment. 


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On the eCRFs, subjects will be identified ONLY by the assigned subject number. If subject names are 
included on copies of documents submitted to Dompé or Cromsource, the names will be obliterated or 
masked and the assigned subject number added to the document. 
The Investigator should keep a separate log (Subject Master List) of subject’s codes, names and addresses. 
11.6 Compensation For Medicine-Induced Injury And Indemnification 
Before the trial formally starts, Dompé will take out a study-specific insurance contract according to national 
laws for subjects/Investigators/Institutions participating in the clinical trial.  
In case of questions about medical care, cost for medical care or insurance, subjects can talk to their 
Investigator. Contact details will be given in the Subject Informed Consent Document. 


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12 DATA HANDLING AND RECORD KEEPING  
12.1 Case Report Forms 
All data relating to the study will be recorded on eCRFs to be provided by Cromsource, through the EDC 
system. The PI is responsible for verifying that all data entries in the eCRFs are accurate and correct. The PI 
must sign the completed eCRF before its submission to the sponsor.  
12.2 Data Management  
Data collection will involve the use of an EDC system , to which only authorized personnel will have access. 
In addition to periodic monitoring occurring within the system by Sponsor/CRO Monitors, programmatic 
edit checks will be used to review the data for completeness, logic, and adherence to study protocol. As a 
result of this monitoring and these checks, queries may be electronically issued to the study centers and 
electronically closed by those study centers. The identifying information (assigned username, date, and time) 
for both the originator of the query (if created during the monitoring process) and the originator of the data 
change (if applicable), as well as the PI’s approval of all changes performed on his or her subjects’ data, will 
be collected.  
All data collected in the context of this study will be stored and evaluated per regulatory requirements and 
applicable guidances for electronic records. Also, data will be stored and evaluated in such a way as to 
guarantee subject confidentiality in accordance with the legal stipulations applying to confidentiality of data. 
Study records (e.g., copies of eCRFs, regulatory documents) will be retained at the study center, along with 
adequate source documentation, according to FDA and ICH requirements. All study records must be 
available for audit by Dompé farmaceutici s.p.a.; its authorized representatives; and Regulatory Inspection 
by Regulatory Authority.  
12.3 Independent Reading Center (E.G. Independent Radiology Review) 
Not applicable. 
12.4 Documentation Required Prior To Initiation Of And During The Study 
The following will be required from the Investigator prior to the initiation visit: 
 
Current, 
signed 
and 
dated 
Curriculum 
Vitae 
of 
Principal 
Investigator 
and 
any 
Sub-Investigators/co-workers. Updates should be provided at least every two years (if applicable). 
 
Normal ranges of all laboratory tests to be performed at the study site and a recent certification or 
accreditation of established quality control (or other documentation of established quality control or 
external quality assessment or other validation). Updates should be provided as soon as any reference 
value has changed. 
 
A signed page of the final protocol and any amendments. 
 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Cromsource, 
including all study specific costs. 
 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
 
A financial disclosure agreement completed and signed by the PI and all Sub-Investigators listed on 
Form FDA 1572. If applicable, the PI will provide an updated financial disclosure agreement to the 
Sponsor 1 year after the completion of the study. 


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12.5 Essential Document Retention 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP E6 R2) until at 
least 2 years after the last approval of a marketing application in an ICH region, and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the Investigational Product. These documents should be retained 
for a longer period however if required by the applicable regulatory requirements. The Investigator should 
take measures to prevent accidental or premature destruction of these documents. 
The essential documents include at least: the signed protocol, copies of the completed eCRFs, signed Subject 
Informed Consent Forms from all subjects who consented, hospital records and other source documents, and 
all other documentation included in the Investigator Site File and Pharmacy/Dispensing File. 
The Investigator will inform Dompé of the storage location of these essential documents and must contact 
Dompé before disposing of any. If the Investigator wishes to assign the files to someone else or to remove 
them to another location, he/she should consult with Dompé about this change. 
Dompé will inform the Investigator in writing when these documents no longer need to be retained. 


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13 STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013) and ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (ICH-GCP E6 (R2)) [Reference: 1] and any local regulations. 
13.1 Monitoring 
Before any subject enters the study, a representative of Cromsource, will meet with the PI and his or her staff 
to review the procedures to be followed during the study and to train them on recording the data in the eCRFs 
using the electronic data capture (EDC) system. After the first subject is enrolled, the Cromsource 
representative, a monitor, will periodically monitor the progress of the study by conducting on-site visits. 
This CRA will also be able to review query statuses remotely, possibly warranting more frequent 
communication with the PI and his or her staff. The PI will make available to the CRA the eCRFs, source 
documents, signed consent forms, and all other study-related documents. The PI and his or her staff will be 
responsible for reviewing eCRFs, resolving data queries generated by the CRA via the system, providing 
missing or corrected data, approving all changes performed on his or her data, and endorsing the subject data 
within the EDC system. This approval method will include applying an electronic signature, a uniquely 
assigned username and password that together will represent a traditional handwritten signature.  
13.2 Access To Records 
The Investigator will allow designated Cromsource representatives, including staff from the appointed 
Cromsource, and regulatory/ethics bodies to have direct access to the source documents to verify the data 
reported in the eCRFs. Source documents are the originals of any documents used by the Investigator or 
hospital/institution that allow verification of the existence of the subject and substantiate the integrity of the 
data collected during the trial. 
13.3 Audit And Inspection 
The study site may be audited by Cromsource, Dompé or inspected by a regulatory agency on one or more 
occasions The Investigator may be informed in advance of such a visit.  
13.4 Protocol Amendments 
Any amendment to this protocol will be provided to the PI in writing by Dompé farmaceutici s.p.a. No 
protocol amendment may be implemented (with the exceptions noted below) before it has been approved by 
the IRB/IEC and the signature page, signed by the PI, has been received by Dompé farmaceutici s.p.a. If the 
protocol is amended to eliminate or reduce the risk to subjects, the amendment may be implemented before 
IRB/IEC review and approval. However, the IRB/EC must be informed in writing of such an amendment, 
and approval must be obtained within reasonable time limits. Deviating from the protocol is permitted only 
if absolutely necessary for the safety or clinical management of the subjects and must immediately be 
reported to Dompé farmaceutici s.p.a. 
13.5 Discontinuation Of The Study 
Dompé farmaceutici s.p.a. reserves the right to terminate the study in its entirety or at a specific study center 
at any time on the basis of new information regarding safety or efficacy, or if study progress is unsatisfactory, 
or for other valid administrative reasons. 


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13.6 Publications 
All data generated in this study will be the property of Dompé farmaceutici s.p.a. Publication of the results 
by the PI will be subject to mutual agreement between the PI and Dompé farmaceutici s.p.a. 


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14 REFERENCES 
1. 
ICH E6 (R2) Guideline for Good Clinical Practice: ICH E6 (R2) Good clinical practice. 
EMA/CHMP/ICH/135/1995, Published 15Dec2016, Effective from 14Jun2017.  
2. 
Lemp MA (1995) Report of the National Eye Institute/Industry Workshop on clinical trials in dry 
eye. CLAO J 21: 221–232.  
3. 
Foulks GN (2003) Challenges and pitfalls in clinical trials of treatments for dry eye. Ocul Surf 1: 
20–30.  
4. 
Dompé farmaceutici s.p.a. Recombinant Human Nerve Growth Factor (rhNGF): Investigator's 
Brochure Ed. No. 42.8/EN. July 31, 2017 or later version.  
 


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15 APPENDICES 
15.1 Appendix 1-Sponsor Approval Page 
Phase I, Randomized, Double-masked, Placebo-controlled Study (6 days) to Evaluate the Safety, Tolerability 
and Pharmacokinetics of Recombinant Human Nerve Growth Factor Eye Drops in Healthy Male and Female 
Volunteers of Japanese Ethnicity 
 
 
Sponsor Medical Expert: _________________________________________ Date: _____/____/____ 
 
 
 
Flavio Mantelli, Chief Medical Officer Biotech 
 
 
Sponsor Clinical Trial Manager: _________________________________ Date: _____/____/____ 
 
 
 
Mauro P. Ferrari, Early Clinical Development Manager  
 
 
Sponsor Development Director _________________________________ Date: _____/____/____ 
 
 
 
Marcello Allegretti, Chief Scientify Officer 
 
 


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15.2 Appendix 2-Investigator’s Signature Page 
 
Investigator’s Statement 
 
I have read the study protocol: Phase I, Randomized, Double-masked, Placebo-controlled Study (6 days) to 
Evaluate the Safety, Tolerability and Pharmacokinetics of Recombinant Human Nerve Growth Factor Eye 
Drops in Healthy Male and Female Volunteers of Japanese Ethnicity 
 
Name of Principal Investigator (block letters):____________________________________________ 
 
 
Signature:  _______________________________  
Date: 
 _________________________  


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15.3 Appendix 3-Detailed List And Timing Of Procedures 
Detailed view of the evaluations 
 
SCREEN (D -21 TO -2) 
Day 
Hours 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
Screen 
D–21 to 
-2 
Informed Consent, Inclusion/Exclusion Criteria, Demography, Medical History/current medical conditions, Prior / Concomitant medication, Physical Exam and Height, Serology, Drugs 
Abuse/pregnancy 
 
 
 
 
X 
X 
X 
 
 
X 
X 
X  
(dilated) 
X 
X 
X 
 
BASELINE (D -1) 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
-Baseline 
D-1 
Inclusion/Exclusion Criteria, Current Medical Conditions, Concomitant Medication, Physical Exam, Drugs Abuse/Pregnancy 
0  
 
 
X 
X 
X 
Y 
X 
X 
X 
X 
X  
X 
X 
X 
0.5 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
2 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
4 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
8 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
9 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
10 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
16 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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TREATMENT DAY 1: ONE DROP DAILY 
Day 1: One drop of either rhNGF or vehicle instilled into study eye (35 µL: 0.70 µg of rhNGF) and one drop of vehicle instilled into the fellow (non-study) eye 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
1 
Adverse Events/ Concomitant medication 
24h (Pre-dose 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
0 (dosing)  
0  
X 
 
 
 
 
 
 
 
 
 
 
 
 
0.5 
0.5 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
2 
2 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
4 
4 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
8 
8 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
9 
9 
 
X 
 
 
 
 
 
 
 
 
 
 
 
10 
10 
 
X 
 
 
 
 
 
 
 
 
 
 
 
11 
11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12 
12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
14 
14 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
16 
16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT DAY 2 TO DAY 6: ONE DROP six TIMES DAILY 
Day 2,3,4,5,6: One drop of either rhNGF or vehicle six times a day (every 2h) instilled into study eye (210 µL: 4.20 µg of rhNGF) and one drop of vehicle instilled into the fellow (non-
study) eye  
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
2 
Adverse Events/ Concomitant medication 
0 (pre-dose) 
24 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
0 (dose) 
24 
X 
 
 
 
 
 
 
 
 
 
 
 
 
0.5 
24.5 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
2 
26 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
4 
28 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
6 
30 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
8 
32 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
10 
34 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
10.5 
34.5 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
11 
35 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12 
36 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
13 
37 
 
X 
 
 
 
 
 
 
 
 
 
 
 
14 
38 
 
X 
 
 
 
 
 
 
 
 
 
 
 
16 
40 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
3 
Adverse Events/ Concomitant medication 
0 (pre-dose) 
48 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
0 (dosing)  
48 
X 
 
 
 
 
 
 
 
 
 
 
 
 
2 
50 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
4 
52 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
6 
54 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
8 
56 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
10 
58 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
4 
Adverse Events/ Concomitant medication 
0 (pre-dose) 
72 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
0 (dosing)  
72 
X 
 
 
 
 
 
 
 
 
 
 
 
 
2 
74 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4 
76 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
6 
78 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8 
80 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
10 
82 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
5 
Adverse Events/ Concomitant medication 
0 (pre-dose) 
96 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
0 (dosing)  
96 
X 
 
 
 
 
 
 
 
 
 
 
 
 
2 
98 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4 
100 
X 
 
 
 
 
 
 
 
 
 
 
 
 
6 
102 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8 
104 
X 
 
 
 
 
 
 
 
 
 
 
 
 
10 
106 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 


rh-NGF 
Page 74 of 75 
Study No: NGF0117 
 
Protocol 
26-Jan-2018 
 
 
ATT 1 SOP-0994 v. 2.0 
CONFIDENTIAL 
Version No. 1.0 – Final 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
6 
Adverse Events/ Concomitant medication 
0 (pre-dose) 
120 
 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
0 (dosing)  
120 
X 
 
 
 
 
 
 
 
 
 
 
 
 
2 
122 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4 
124 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
6 
126 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8 
128 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
10 
130 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
10.5 
130.5 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
11 
131 
 
X 
 
 
 
 
 
 
 
 
 
 
 
12 
132 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
13 
133 
 
X 
 
 
 
 
 
 
 
 
 
 
 
14 
134 
 
X 
 
 
 
 
 
 
 
 
 
 
 
16 
136 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


rh-NGF 
Page 75 of 75 
Study No: NGF0117 
 
Protocol 
26-Jan-2018 
 
 
ATT 1 SOP-0994 v. 2.0 
CONFIDENTIAL 
Version No. 1.0 – Final 
 
FOLLOW-UP 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
7 
(FU1) 
Adverse Events/ Concomitant medication 
0 
144 
 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
8 
(FU2) 
Adverse Events/ Concomitant medication, Physical Exam, , 
0  
168 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
8 
176 
 
X 
 
 
Y 
 
X 
X 
X 
X 
X 
 
X 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
16 
+-2 
(FU3) 
Adverse Events/ Concomitant medication 
0  
360 
 
X 
 
X 
Y 
 
X 
X 
X 
X 
X 
 
X 
 
Day 
Hours 
(Day / Total) 
Drug/ 
Placebo 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS
/TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
35 to 
42 
(FU4) 
Adverse Events 
0  
816-1056 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ATA – Anti-therapeutic antibodies  
BCVDA - Best corrected distance visual acuity (ETDRS) 
Drugs Abuse/pregnancy - Drugs of Abuse including Alcohol breath test, pregnancy test for females 
ECG – Electrocardiogram 
EOE - External ocular examination (motility and eyelids) 
FO –Fundus Ophthalmoscopic (FO) examination (dilated FO only at Screening Visit) 
IOP – Introcular Pressure 
LAB - Laboratory Safety Tests - Hematology, Biochemistry, Urinalysis 
LOT - Local Ocular Tolerability - Visual Analogue Scale (VAS): foreign body sensation, 
burning/stinging, itching, pain, sticky feeling, blurred vision, photophobia. If it is to be applied at a 
same visit as an FO or IOP examination the VAS for ocular tolerability is to be applied before the 
SLE FO and/or IOP examination 
Physical exam – Physical examination, height (height is only required at screening) 
PK – Pharmacokinetics 
Serology: Hepatitis/HIV and for postmenopausal females FSH Laboratory Safety Tests 
SLE/CS/TFBUT - Slit lamp examination (SLE): eyelid margin, conjunctiva, cornea, anterior 
chamber, iris and lens with the instillation of fluorescein to evaluate corneal fluorescein staining 
(CS, modified Oxford scale) and tear film break-up time (TFBUT) 
ST - Schirmer's test (ST) without anesthesia 
Vital Signs – body weight, blood pressure, pulse rate, respiratory rate and ear body temperature 
Examinations marked with Y instead of X may be done at any time on the examination day
 
 
 

SAP_001.pdf: 
 
 
 
 
Dompé farmaceutici S.p.A. 
 
Phase I, Randomized, Double-masked, Placebo-controlled 
Study (6 days) to Evaluate the Safety, Tolerability and 
Pharmacokinetics of Recombinant Human Nerve Growth 
Factor Eye Drops in Healthy Male and Female Volunteers of 
Japanese Ethnicity 
 
 
Study No: NGF0117 
IND Number: 115892 
 
Statistical Analysis Plan 
 
 
Final 1.0 
Final Version 
27 Sep 2018 
 
 
Author: Monika Rost 
 
CROMSOURCE  
 
 




 
Dompé NGF0117 – Statistical Analysis Plan 
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TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Version History 
 
Version 
Date 
Reason for Change 
Final 1.0 
27 Sep 2018 
Initial Version 
 


 
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TF-ST-03/00-02 
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Table of Contents 
1 SOPs to be followed .......................................................................... 7 
2 Abbreviations ..................................................................................... 8 
3 Study Protocol.................................................................................. 11 
3.1 Study Objectives ............................................................................................ 11 
3.2 Study Design................................................................................................... 11 
3.3 Study Schedule ............................................................................................... 12 
3.4 Primary and Secondary Study Endpoints .................................................... 13 
3.5 Interim Analyses ............................................................................................. 15 
3.6 Changes in the Conduct of Study or Planned Analysis compared to 
Protocol ................................................................................................................. 15 
4 General Definitions .......................................................................... 16 
4.1 Report Language ............................................................................................ 16 
4.2 Analysis Software ........................................................................................... 16 
5 Data Preparation .............................................................................. 17 
5.1 Data Handling and Medical Coding ............................................................... 17 
5.2 CDISC .............................................................................................................. 17 
5.3 SAS-Programming Quality Level .................................................................. 17 
6 Analysis Sets and Subgroups ......................................................... 17 
6.1 Analysis Sets .................................................................................................. 17 
6.2 Subgroup Definitions ..................................................................................... 18 
7 Definition of Time Points and Analysis Variables.......................... 18 
7.1 Definition of Time Points ............................................................................... 18 
7.2 Analysis Variables .......................................................................................... 22 
7.2.1 Disposition and Protocol Deviations ............................................................ 22 
7.2.2 Demographics and Other Baseline Characteristics ..................................... 22 
7.2.3 Prior/Concomitant Medication ..................................................................... 23 
7.2.4 Measurements of Exposure and Treatment Compliance............................. 25 
7.2.5 Study Medication ......................................................................................... 26 
7.2.6 Primary Safety Endpoints ............................................................................ 26 
7.2.7 Primary and Secondary Tolerability Endpoints ............................................ 27 
7.2.8 Secondary Safety Endpoints – Adverse Events .......................................... 27 
7.2.9 Secondary Safety Endpoints – ECG ........................................................... 30 


 
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7.2.10 Secondary Safety Endpoints – Vital Signs ................................................ 30 
7.2.11 Secondary Safety Endpoints – Laboratory Safety Data............................. 30 
7.2.12 Secondary Safety Endpoints – Intraocular Pressure ................................. 31 
7.2.13 Secondary Safety Endpoints – Best Corrected Distance Visual Acuity 
(BCDVA)............................................................................................................... 31 
7.2.14 Secondary Safety Endpoints – Tear Film Break Up Time ......................... 32 
7.2.15 Secondary Safety Endpoints – Ocular Surface Staining............................ 33 
7.2.16 Other Safety Variables .............................................................................. 33 
7.2.17 Pharmacokinetic Endpoints ....................................................................... 36 
7.2.18 Immunogenicity Endpoints ........................................................................ 38 
8 Analysis Methods ............................................................................. 38 
8.1 General Methods ............................................................................................ 38 
8.2 Specific Methods for Primary Safety and Tolerability Analyses ................ 38 
8.3 Statistical/Analytical Issues........................................................................... 38 
8.3.1 Adjustments for Covariates ......................................................................... 38 
8.3.2 Handling of Dropouts or Missing Data ......................................................... 38 
8.3.3 Data Review ................................................................................................ 39 
8.3.4 Multicenter Studies ...................................................................................... 39 
8.3.5 Multiplicity of Endpoints ............................................................................... 39 
9 Interim Analyses .............................................................................. 39 
10 Overview of Tables, Listings and Figures .................................... 39 
10.1 Disposition of Subjects ................................................................................ 39 
10.2 Protocol Deviations ...................................................................................... 40 
10.3 Inclusion and Exclusion Criteria ................................................................. 40 
10.4 Demographic and Other Baseline Characteristics .................................... 40 
10.4.1 Demographic and other Background Information ...................................... 40 
10.4.2 Medical History and Other Medical Conditions .......................................... 40 
10.4.3 Prior/Concomitant Medications .................................................................. 40 
10.5 Exposure and Compliance to Study Medication ........................................ 41 
10.6 Analysis of Primary Safety and Tolerability Assessments ....................... 41 
10.6.1 Primary and Secondary Safety Endpoints – Adverse Events .................... 41 
10.6.2 Primary and Secondary Tolerability Endpoints .......................................... 42 
10.7 Additional Secondary Safety Assessments ............................................... 42 


 
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10.7.1 ECG........................................................................................................... 42 
10.7.2 Vital Signs ................................................................................................. 42 
10.7.3 Laboratory Safety Data .............................................................................. 43 
10.7.4 Intraocular pressure .................................................................................. 43 
10.7.5 Change in BCDVA ..................................................................................... 43 
10.7.6 TFBUT ....................................................................................................... 43 
10.7.7 Ocular Surface Staining ............................................................................. 43 
10.8 Other Safety Variables ................................................................................. 43 
10.9 Pharmacokinetic Evaluations ...................................................................... 44 
10.10 Immunogenicity .......................................................................................... 44 
11 References ...................................................................................... 45 
12 Tables, Listings and Figures ......................................................... 46 
13 Appendices ..................................................................................... 50 
 


 
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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-08 
Trial Statistics File 
 


 
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2 Abbreviations 
 
Acronym 
Definition 
ADAM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATA 
Anti-therapeutic antibody 
AUC 
Area under the serum concentration-time curve 
AUC[0-24] 
Area under the serum concentration-time curve during 24 
hours 
AUC0-tlast 
Area under the serum concentration-time curve calculated to 
the last quantifiable data point 
BCDVA 
Best Corrected Distance Visual Acuity 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CFS 
Corneal Fluorescein Staining 
Clast 
Last measurable serum concentration 
Cmax 
Maximum observed serum concentration 
CSR 
Clinical Study Report 
Ctrough 
Minimum observed serum concentration at the end of the 
dosage interval 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOE 
External ocular examination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETV 
Early Termination Visit 
FO 
Fundus Ophthalmoscopic examination 
FSH 
Follicle-Stimulating Hormone 
FU 
Follow-Up 
FUAE 
Follow-Up Adverse Event 


 
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Acronym 
Definition 
GGT 
Gamma-Glutamyl-Transferase 
HBsAg 
Hepatitis B antigen 
HCV 
Hepatitis C antibodies 
HEENT 
Head Eyes Ears Nose Throat 
HIV 
Human Immunodeficiency Virus 
IOP 
Intraocular Pressure 
LOT 
Local Ocular Tolerability 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOS 
Modified Oxford Scale 
NEI 
National Eye Institute 
PK 
Pharmacokinetics 
PKS 
PK-Set 
PR 
The interval from the beginning of the P wave to the 
beginning of the QRS complex on an electrocardiogram 
PT 
Preferred Term 
QRS 
The combination of three of the graphical deflections seen on 
a typical ECG 
QT 
Measure of the time between the start of the Q wave and the 
end of the T wave 
QTc 
QT interval corrected 
QTcB 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for cube-root of the difference between 
QRS complexes 
RAND 
Randomized Subjects Set 
RBC 
Red Blood Cell 
rhNGF 
Recombinant Human Nerve Growth Factor 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SI 
International System of Units 
SLE 
Slit Lamp Examination 
SOC 
System Organ Class 


 
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Acronym 
Definition 
SOP 
Standard Operation Procedure 
ST 
Schirmer's Tear Test 
TEAE 
Treatment Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time 
tlag 
Time delay between the time of dosing and time of 
appearance of concentration in the sampling compartment 
tlast 
Time to last measurable serum concentration 
TLF 
Tables, Listings and Figures 
tmax 
Time to reach Cmax 
TOT 
Total Set 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
WHO-ATC 
World Health Organization Anatomical Therapeutic Chemical 
WHO-DRL 
WHO-drug reference list 
λz 
Terminal disposition rate constant/terminal rate constant 


 
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3 Study Protocol 
This NGF0117 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 1.0 of 
26 January 2018 and clarified in the Protocol Clarifications of 21 May 2018. 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 final analyses and which are used for inclusion in the Clinical Study Report (CSR).  
3.1 Study Objectives 
The primary objective of this study is to assess the safety and tolerability of a single short-
term and a multiple dose scheme of rhNGF when administered as eye drops in healthy 
subjects of Japanese ethnicity.  
The secondary objective of this study is to assess the pharmacokinetics of single and 
multiple doses of rhNGF when administered as eye drops in healthy subjects of Japanese 
ethnicity.  
The immunogenicity will be evaluated by determination of the anti-therapeutic antibodies. 
3.2 Study Design 
This is a Phase I, randomized, double-masked, placebo-controlled eye drops administration 
study of rhNGF in healthy male and female subjects of Japanese ethnicity. 
A total of 30 subjects will be randomized in a masked manner: 20 subjects on rhNGF group 
and 10 on placebo. A study eye will be assigned to each subject by random. In the study 
eye, the subjects will be treated with:  
 
rhNGF (active) in the rhNGF group. 
 
vehicle (placebo) in the vehicle group. 
Treatment duration is 6 days. The following study treatment will be applied to the study eye: 
 
Day 1: One drop study medication (35 µL). 
 
Day 2, 3, 4, 5, 6: One drop of study medication six times a day (every 2h). 
Total dose in the study eye will be 31 drops of study medication over 6 days. 
For the fellow eye, vehicle will be administered in parallel to all subjects following the 
identical schedule as for the study eye. 
The study will consist of a screening period of up to 20 days before admission [i.e., Day –21 
to Day -1], a one day baseline phase (Day -1) before eye drop application on Days 1 to 6, 
with follow-up visits on Days 7, 8, 16 ± 2, and 35 (to 42). 
 


 
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3.3 Study Schedule 
The protocol visit plan and specification of study procedures and examinations per visit is summarized in Table 1 below.  
Table 1: Schedule of Assessments 
Visit  
Day (D) 
Drug/ 
Placebo 
AE/ 
Conmed 
PK 
Vital 
Signs 
ECG 
LAB 
ATA 
LOT 
SLE/CFS 
TFBUT 
IOP 
FO 
BCDVA 
ST 
EOE 
Screen 
D –21 to -2 
Informed Consent, Inclusion/Exclusion Criteria, Demography, Medical History/current medical conditions, Prior medication, Physical Exam, Serology, Drugs 
Abuse/pregnancy 
 
 
 
X 
X 
X 
 
 
X 
X 
X* 
X 
X 
X 
Baseline 
D -1 
Inclusion/Exclusion Criteria, Current Medical Conditions, Adverse Events, Concomitant Medication, Physical Exam, Drugs Abuse/Pregnancy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment Phase 
Day 1: One drop of either rhNGF or vehicle instilled into study eye (35 µL: 0.70 µg of rhNGF) and one drop of vehicle instilled into the fellow (non-study) eye  
D1 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
Day 2, 3, 4, 5, 6: One drop of either rhNGF or vehicle six times a day (every 2h) instilled into study eye and one drop of vehicle six times a day (every 2 h) 
instilled into the fellow (non-study) eye  
D2 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
D3 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
D4 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
D5 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
D6 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
Follow-up 
 
D7 (FU 1) 
Physical Exam 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
X 
 
X 
 
D8 (FU 2) 
Physical Exam 
 
X 
X 
  
X 
Y 
  
X 
X 
X 
X 
X 
  
X 
 
D16 ± 2 (FU 3) 
 
X 
X 
  
X 
Y 
 
X 
X 
X 
X 
X 
  
X 
 
 
 
D35 - 42 (FU 4) 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
ATA – Anti-therapeutic antibodies. BCDVA - Best corrected distance visual acuity (ETDRS). Drugs Abuse/Alcohol breath test/pregnancy. ECG – Electrocardiogram. EOE 
- External ocular examination (motility and eyelids). FO –Fundus Ophthalmoscopic examination (*dilated FO only at Screening). IOP – Introcular Pressure. LAB - 
Laboratory Safety Tests - Hematology, Biochemistry, Urinalysis. ATA – Anti-therapeutic antibodies. LOT - Local Ocular Tolerability - Visual Analogue Scale (VAS). LOT 
always to be applied before the SLE FO and/or IOP (if applicable). Physical exam. PK – Pharmacokinetics. Serology: Hepatitis/HIV and for postmenopausal females FSH 
Laboratory Safety Tests. SLE/CFS/TFBUT - Slit lamp examination (SLE): eyelid margin, conjunctiva, cornea, anterior chamber, iris and lens with the instillation of 
fluorescein to evaluate corneal fluorescein staining and tear film break-up time (TFBUT). ST - Schirmer's test (ST) without anesthesia. Vital Signs - blood pressure, pulse 
rate, respiratory rate and oral body temperature. A detailed view of the evaluations is provided in protocol Appendix 3 – Detailed List of Procedures 


 
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3.4 Primary and Secondary Study Endpoints 
Primary safety endpoints are: 
 
Incidence of treatment emergent adverse events (TEAEs). 
TEAEs are defined as an adverse event (AE), which start after first dose of study 
treatment. These comprise AEs during the treatment and follow-up period. 
 
 
Incidence of treatment emergent adverse events during 1st dose schedule (TEAEs 
Dose 1). 
TEAEs Dose 1 are defined as TEAEs, which start after first dose of study treatment 
and before administration of the first dose at Treatment Day 2. 
 
 
Incidence of treatment emergent adverse events during 2nd dose schedule (TEAEs 
Dose 2). 
TEAEs Dose 2 are defined as TEAEs, which start on/after the first dose at Treatment 
Day 2 and before Follow Up Day 7 (FU1) visit. 
 
Secondary safety endpoints are: 
 
Incidence of Follow-Up AEs (FUAE) 
FUAEs are defined as TEAEs which start on or after Follow Up Day 7 (FU1) visit visit. 
 
 
Incidence of ocular TEAEs by eyes. 
 
 
Course of ECG parameters ventricular rate, PR interval, QRS duration and QT interval 
over all visits. 
 
 
Course of vital signs parameters systolic and diastolic blood pressure, pulse rate, 
respiratory rate and oral body temperature over all visits. 
 
 
Changes from baseline in biochemistry parameters over all visits. 
Baseline is defined as the Laboratory assessment of Baseline (D-1) Visit 
 
 
Changes from baseline in haematology parameters over all visits. 
Baseline is defined as the Laboratory assessment of Baseline (D-1) Visit 
 
 
Shift in overall interpretation of urinalysis over all visits. Laboratory assessment at 
Baseline (D-1) Visit is considered as reference for assessing the shift. 
 
 
Course of intraocular pressure by eye over all visits. 
 
 
Course of visual acuity score by eyes over all visits 
The visual acuity score will be derived as the total numbers of letters, which were 
read correctly at 4 meter plus the total number of letters read at 1 meter as collected 
on the eCRF page. When 20 or more letters are read at 4 meters the visual acuity 
score for that eye is recorded as the number of letters correct at 4 meters plus 30. 
The subject gets credit for the 30 letters at 1 meter even though they did not have to 
read them. If no letters are read correctly at either 4.0 meters or 1 meter, then the 
visual acuity score is recorded as “0.” 
 


 
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 
Course of LogMAR by eyes over all visits. 
The logMAR will be derived as – log (Snellen Equivalent result) 
 
 
Course of TFBUT by eye over all visits. 
 
 
Course of overall NEI score by eye over all visits. 
 
Primary tolerability endpoints are: 
 
Change from baseline in VAS ocular tolerability scores at Treatment Day 2 pre-dose in 
study eye (Tolerability of 1x0.70 µg rh-NGF per day).  
Baseline is defined as the pre-treatment assessment at the Baseline (D-1) visit. 
 
 
Change from baseline in VAS ocular tolerability scores at D2 8h, D3 pre-dose, D6 pre-
dose, D6 8h, D7 (Follow-up Day 7), D8 (Follow-up Day 8), D16 (Follow-up Day 16) in 
study eye (Tolerability of 6x0.70 µg rh-NGF per day).  
Baseline is defined as the pre-treatment assessment at the Treatment Day 2 visit. 
 
Secondary tolerability endpoints are: 
 
Course of VAS ocular tolerability scores by eye over all visits. 
 
 
Intraindividual change in VAS ocular tolerability scores between study eye and fellow 
(non-study) eye at all study visits. 
 
Pharmacokinetics endpoints 
 
The kinetics of single dose administration as well as multiple dose assessment will be evaluated. 
Two validated ELISA tests will be used for PK measurements. 
Beyond the respective rhNGF plasma levels for both ELISA methods, the following parameters 
will only be investigated for each ELISA method, if the data warrant to do so: 
 
maximum observed serum concentration (Cmax), time to reach Cmax (tmax), time elapsed 
between dosing and the first serum concentration that exceeds the assay quantification 
limit (tlag) as measured without treatment based on assessments on D-1 
 
Cmax, tmax. tlag of single dose regimen based on assessments on D1 and pre-dose of D2 
 
Cmax, tmax. tlag of multiple dose regimen based on assessments atarting with pre-dose of 
D2 
 
serum concentration measured before the administration of the next dose (Ctrough) as 
assessed at pre-dose visit on D2, D3, D4, D5, D6 
 
AUC[0-24] for the single dose regimen and the first day of multiple dose regimen.  
AUC[0-24] as area under the serum concentration versus time curve from time 0 h to pre-
dose value of the next day calculated by the linear trapezoidal rule. Values below the level 
of quantitation will be set to 0. Values below the baseline concentration will be set to zero 
other than for the values for which no later values above the baseline concentration are 
available, which will be set to missing. 
 
AUC0-tlast for the multiple dose regimen. This is derived as area under the serum 
concentration versus time curve from time 0 h to the last data point tlast after drug 


 
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administration above the limit of quantitation and the baseline concentration, calculated 
by the linear trapezoidal rule.  
Values below the baseline concentration will be set to zero other than for the values for 
which no later values  above the baseline concentration are available, which will be set 
to  
missing 
 
AUC for the multiple dose regimen. AUC will be derived as area under the serum 
concentration versus time curve extrapolated to infinity, calculated as AUC = AUC0-tlast + 
Clast/λz 
Immunogenicity 
Anti-Therapeutic Antibodies (ATA) serum levels will evaluated for immunogenicity. The 
serum concentrations of ATA will be provided by the bioanalytical laboratory in a separate 
report and incorporated into the final CSR as an appendix. 
A more detailed description on all study endpoints on derivation of study endpoints is provided 
in section 7.2 of the SAP. 
3.5 Interim Analyses 
No interim analysis is planned.  
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: 
 
Study protocol section 8.2 describes the assessment of “daily consumption of caffeine”. 
This was not collected on the eCRF and is therefore not presented in the analysis. 
 
Study protocol section 8.2 describes the assessment of “daily consumption of alcohol”. 
However, assessment of usual alcohol consumption was change to weekly 
assessment to facilitate verification of exclusion criterion 7. 
 
Study protocol section 7 describes the assessment of body weight for all scheduled 
assessment times of vital sign. However, body weight was assessed on the eCRF only 
at Screening Visit. As a consequence, no presentation of post-baseline body weight 
will be provided. 
 
No clinical interpretation are recorded for urinalysis including the endpoint “overall 
interpretation of urinalysis results”. As a consequence, this endpoint will not be 
analyzed. 
 
In the study protocol section 8.2, assessment of the horizontal diameter of the cornea 
is specified as part of the slit lamp evaluation. However, this was not collected in the 
eCRF and is therefore not part of the analysis.  
 
For Fundus Ophthalmology, the site did perform additional unscheduled assessments 
in an not-dilated manner at D1 8hr and D2 pre-dose. These assessments were done 
without any specific safety reason, so results were not entered in the eCRF as 
unscheduled assessments and are therefore not included in the data listings. 
The following refinements of the pre-planned analysis in the study protocol were implemented 
in this SAP: 


 
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 
For a better perceivability, the primary safety endpoints are rephrased to Incidence of 
Treatment Emergent Adverse Events during Single/Multiple Dose Scheme, 
respectively. 
 
In the eCRF, no start time of Adverse Event has been recorded. During SAP creation, 
this was considered as required for a precise assignment of AEs to Single-Dose or 
Multiple Dose Scheme. and multiple dose treatment phase. As a consequence, the 
start times of an AE was entered in the eCRF as free-text comment associated to the 
AE start date field. 
 
Fundus Ophthalmology was performed in a dilated manner at Screening Visit, whereas 
a non-dilated Fundus Ophthalmological assessment was done for all other study visits. 
As a consequence, data listings will clearly indicate the mode of fundus 
ophthalmological assessments. 
 
Study protocol section 8.6 describes the ECG assessments heart rate, PR interval, 
QRS duration, QT interval as well as QTc (Fridericia and Bazett corrections), whereas 
in section 10.1 ventricular rate, PR interval, QRS duration and QT interval were 
specified as secondary ECG endpoints. For the secondary endpoint analysis, all 
recorderd parameters mentioned in section 8.6 were considered as secondary safety 
endpoints. 
 
For Corneal Staining, the study protocol states in headers that a modified Oxford Scale 
is to be assessed. However, the details of assessment in section 8.12 and the study 
endpoints as described in protocol section 10.1 describes the NEI grading for corneal 
and conjunctival staining, which has been applied to the site and were analyzed 
accordingly. To accommodate for regulatory purposes, a post-hoc assessment of 
modified Oxford Scale (MOS) is performed by the investigator based on documented 
NEI source data before the BDRM.  
The MOS assessments will be used for a verification of Exclusion Criterion 18 
“Presence of any corneal opacity or corneal fluorescein staining > 0.5 grade using the 
modified Oxford Scale in either eye at screening or baseline” during the BDRM.  
For the analysis, NEI scales will be analysed as planned in the study protocol. The 
collected MOS values will be mapped into SDTM version only. 
 
4 General Definitions 
4.1 Report Language 
The TLFs as output of the analyses will be prepared in English. 
4.2 Analysis Software  
The statistical analysis will be performed using the SAS® statistical software package 
(Statistical Analysis System, Version 9.3 or later). 
Pharmacokinetic derivations will be done using Phoenix WinNonlin 6.4 or later (Pharsight 
Corporation, Palo Alto, CA, USA) by a subcontractor 
 


 
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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 approach 
by: 
• 
Full independently double programmed reproduction of CDISC: 
o 
SDTM datasets 
o 
ADaM datasets 
o 
Tables and Figures 
• 
Listings will not be double programmed. 
• 
All tables, figures 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. 
6 Analysis Sets and Subgroups 
6.1 Analysis Sets 
The Total Set (TOT) will include all subjects that have signed informed consent. 
The Randomized Subjects Set (RAND) will include all subjects, which have been randomized 
to a study treatment. 
If a subject is re-screened, the subject is formally dropped out of the study as screening failure 
and will be re-included with a new screening number. Details on re-screened subjects will be 
documented during the BDRM based on a detailed file note provided by clinical operations. 
The Safety Set (SAF) will consist of all subjects randomized into the study and receiving a 
dose of study medication in at least one eye. 
The PK-Set (PKS) will consist of all subjects who did not show serious protocol deviations or 
non-compliance and completed the PK sampling according to the study protocol. 


 
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All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis sets during a blind 
data review meeting (BDRM).  
For the analysis of the SAF and PKS, summaries by treatment group (and eye) will follow the 
treatment a subject received.  
Further analysis sets might be implemented during the BDRM, if deemed necessary as a 
consequence of treatment related protocol deviations. 
6.2 Subgroup Definitions 
No pre-planned subgroups. 
7 Definition of Time Points and Analysis Variables 
7.1 Definition of Time Points 
The study consists of 12 scheduled clinical evaluation visits as described in Table 2. 
The Date of First Study Treatment will be identified as the (earliest) date documented on the 
eCRF page “Administration of Study Drug” at D1 Visit, irrespective of the applied eye. 
The Treatment Day of an event/assessment will be calculated relative to the First Study 
Treatment. 
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. 
Relative Assessment Time of assessments is derived as the difference of the 24hr clock time 
on a respective day minus the time of the First Study Treatment at D1 Visit in hours utilizing 1 
decimal. For example, if the time of First Study Treatment at D1 Visit was on 8:00 hr and the 
time of Baseline 0.5 hour was on 8:30 hr, then the Relative Assessment time will be 0.5 hours. 
So, the Relative Assessment Time is presenting the relative time within a visit day. 
Relative Treatment Time Single Dose Scheme (hr) will be derived for all PK assessments 
and is defined as difference of the Date/Time of the assessment minus the time of First Study 
Treatment at D1 Visit in hours utilizing 1 decimal. For example, if the time of First Study 
Treatment at D1 Visit was on 8:00 hr and the time of D2 Pre-Dose was on 07:00 hr on the next 
day, then the Relative Treatment Time Single Dose Scheme will be 23.0 hours. So, the 
Relative Treatment time Single Dose Scheme presents the Time to First Study Treatment.  
Relative Treatment Time Multiple Dose Scheme (hr) will be derived for all assessments on 
or after D2 and is defined as difference of the Date/Time of the assessment minus the time of 
First Study Treatment at D2 Visit in hours utilizing 1 decimal. For example, if the time of First 
Study Treatment at D2 Visit was on 8:00 hr and the time of D3 Pre-Dose was on 07:00 hr on 
the next day, then the Relative Treatment Time Single Dose Scheme will be 23.0 hours. So, 
the Relative Treatment time Multiple Dose Scheme presents the Time to First Study Treatment 
of the Multiple Dose Scheme. 


 
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For any subject discontinuing the study, the Investigator ask the subject to undergo, as far as 
possible, a final medical visit to examine the subject’s health conditions  
a. 
This examination will verify that all values tested at screening have remained within a 
clinically acceptable range (i.e., not clinically significant changes compared to 
screening). The assessments will be conducted as detailed in Follow Up Day 16±2 (FU 
3). 
b. 
Arrange for alternative medical care of the withdrawn subject, if necessary 
c. 
Report in the eCRF date and time of the last dose administration, and date and primary 
reason of study discontinuation  
d. 
Record in the eCRF any follow-up, if the subject is withdrawn for an AE. 
 
Procedures conducted at the Early Termination 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. 
All assessments except event type data will be analyzed according to the nominal visit identifier 
on the eCRF 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 subjects, who terminate study prematurely. For these subjects, the 
records collected at the Early Termination Visit will be shifted to the next applicable visit 
assessment according to Table 2. If this is not possible, the last record will be treated as 
Unscheduled Assessments based on the rules below. 
Unscheduled Assessments will not be considered for by-visit analyses but all collected data 
will be listed. Additional assessments at a given visit will be labelled under the respective Visit 
label. However, the respective timepoint will be labelled as “xx hr U1”, “xx hr U2”, etc. with xx 
indicating the number of the last scheduled assessment time before the unscheduled 
assessment plus a consecutive sequence number.  
Unscheduled Assessments which were not taken on a scheduled visit will be labelled as 
“Unscheduled Visit x.01 U1”, “Unscheduled Visit x.02 U1”, “Unscheduled Visit y.01 U1” etc. 
indicating the number of the last preceding visit plus a consecutive sequence number. If more 
than one unscheduled assessment is done at the same day, the assessments will be labeled 
consecutively “Unscheduled Visit x.01 U1”, “Unscheduled Visit x.01 U2”. 
The Treatment Period starts with the first intake of study medication and ends before the first 
assessment of the D7 visit. Any assessment before the first intake of study medication is 
allocated to the Screening Period. The Follow-Up Period of the study will start with the first 
assessment on the D7 visit. 
Moreover, the Treatment Period is divided into Treatment Period of the Single Dose 
Scheme, which ends before the first intake of study medication on D2 and the Treatment 
Period of the Multiple Dose Scheme, which starts with the first intake of study medication on 
D2. 
If not stated otherwise in subsequent sections, Baseline is defined as the first assessment of 
the D-1 Visit. 
Change from Baseline is defined as the difference between an assessment and the 
respective first assessment at the Baseline Visit. 
Change from Multiple Dose Baseline is defined as the difference between an assessment 
and the respective Pre-Dose assessment at the D2 Visit. 


 
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A Time-Matched Change from Baseline is defined as the difference between an assessment 
and the respective assessment at the corresponding time-point at the Baseline Visit. 
 
Table 2: Study Visits 
Scheduled 
Visit   
Scheduled 
Visit Label 
Scheduled Relative 
Assessment Times 
within Visit 
Comments 
Screening Visit 
Screening 
Before Baseline Visit 
Acceptable time window for 
screening visit: Treatment Day -21 
to Treatment Day -2 
Baseline Visit 
D-1 
0 hr 
0.5 hr 
2 hr 
4 hr 
8 hr 
9 hr 
10 hr 
11 hr 
12 hr 
14 hr 
16 hr 
Acceptable time window:  
Day before first dose 
Treatment Day 1 
D1 
Pre-Dose 
0 hr 
0.5 hr 
2 hr 
4 hr 
8 hr 
9 hr 
10 hr 
11 hr 
12 hr 
14 hr 
16 hr 
Dosing should occur at 0 hr 
Time of dosing should be identical 
to respective time point at baseline 
visit. 
Treatment Day 2 
D2 
Pre-Dose 
0 hr 
0.5 hr 
2 hr 
4 hr 
6 hr 
8 hr 
10 hr 
10.5 hr 
11 hr 
12 hr 
13 hr 
14 hr 
16 hr 
Dosing should occur at 0, 2, 4, 6, 8, 
10 hr. 
Time of dosing should be identical 
to respective time points at baseline 
visit. 


 
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Scheduled 
Visit   
Scheduled 
Visit Label 
Scheduled Relative 
Assessment Times 
within Visit 
Comments 
Treatment Day 3 
D3 
Pre-Dose 
0 hr 
2 hr 
4 hr 
6 hr 
8 hr 
10 hr 
Dosing should occur at 0, 2, 4, 6, 8, 
10 hr. 
Time of dosing should be identical 
to respective time points at baseline 
visit. 
Treatment Day 4 
D4 
Pre-Dose 
0 hr 
2 hr 
4 hr 
6 hr 
8 hr 
10 hr 
Dosing should occur at 0, 2, 4, 6, 8, 
10 hr. 
Time of dosing should be identical 
to respective time points at baseline 
visit. 
Treatment Day 5 
D5 
Pre-Dose 
0 hr 
2 hr 
4 hr 
6 hr 
8 hr 
10 hr 
Dosing should occur at 0, 2, 4, 6, 8, 
10 hr. 
Time of dosing should be identical 
to respective time points at baseline 
visit. 
Treatment Day 6 
D6 
Pre-Dose 
0 hr 
2 hr 
4 hr 
6 hr 
8 hr 
10 hr 
10.5 hr 
11 hr 
12 hr 
13 hr 
14 hr 
16 hr 
Dosing should occur at 0, 2, 4, 6, 8, 
10 hr. 
Time of dosing should be identical 
to respective time points at baseline 
visit. 
Follow-up Visit 1 
FU1 
0 hr 
Acceptable time window: treatment 
day 7 
Assessment times should be 
identical to respective time points at 
baseline visit. 
Follow-up Visit 2 
FU2 
0 hr 
8 hr 
Acceptable time window: treatment 
day 8 
Assessment times should be 
identical to respective time points at 
baseline visit. 


 
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Scheduled 
Visit   
Scheduled 
Visit Label 
Scheduled Relative 
Assessment Times 
within Visit 
Comments 
Follow-up Visit 3 
FU3 
0 hr 
Acceptable time window: treatment 
day 14-18 
Assessment times should follow 
respective time point at baseline 
visit. 
Follow-up Visit 4 
FU4 
0 hr 
Acceptable time window: treatment 
day 35-42 
Assessment times should follow 
respective time point at baseline 
visit. 
Early Termination 
ETV 
- 
Early termination visit. 
 
7.2 Analysis Variables 
This section describes all variables that are used for analysis as well as their source data 
variables. For each variable it is specified how missing values will be handled, if applicable. 
7.2.1 Disposition and Protocol Deviations 
Disposition parameters were recorded on the eCRF Page “End of Study”. 
Study discontinuations were recorded for all subjects who provided informed consent.  
A subject discontinued the study prematurely, if the question “Did the subject complete the 
study” was answered as ‘No’. A subject is considered as study completer, if the question “Did 
the subject complete the study” was answered as ‘Yes’. 
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’, 
‘NonCompliance’, ‘Study terminated by the sponsor’, ‘Study terminated by the investigator’, 
‘Other’. 
If the eCRF question “Was the emergency envelope opened during the study?” was answered 
‘Yes’, the subject will be considered as unmasked. 
The eligibility of all subjects for entry into the study will be assessed at the Screening visit and 
confirmed at the Baseline Visit on the eCRF Pages “Inclusion Criteria” and “Exclusion Criteria”. 
Protocol deviations were collected during the study and reviewed during the BDRM according 
to a separate BDRM plan. During the BDRM, identification of protocol deviations and further 
categorization of deviations for TLF output will be performed. For the analysis, all protocol 
deviations as documented in the BDRM minutes will be presented. 
7.2.2 Demographics and Other Baseline Characteristics 
Demographics 
Demographic characteristics were recorded on the eCRF page “Demography”. 
Gender (‘Male’, ‘Female’), Ethnicity (‘Japanese’, ‘Not Japanese’), All 4 Grandparents born in 
Japan (‘Yes’, ‘No’) will be analyzed as recorded on the eCRF. 


 
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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. 
Other Background Information 
Body height and weight are recorded on the eCRF page “Vital Signs” at the Screening Visit. 
Based on this, the BMI (kg/m2) at Screening is derived as Weight at Screening (kg) / (Height 
at Screening [cm] * 0.01)2. BMI will be presented with 1 decimal of precision. 
Smoking habits and alcohol consumption are recorded on the eCRF page “Demography” at 
Screening Visit. 
For the analysis, the number of alcohol units will be presented. For this, subjects who answered 
the question “Is the subject an alcohol consumer” with ‘No’ will be imputed by 0 alcohol units. 
An alcohol breath test is performed at Screening and Baseline Visit and is recorded on the 
eCRF page “Alcohol Breath Test”.  
An urine drug screening is performed at Screening and Baseline Visit and is recorded on the 
eCRF page “Drugs of Abuse”. 
Medical history and other medical conditions 
The study eye (‘Left Eye’, ‘Right Eye’) as randomized will be presented according to the 
assigned randomization number on the eCRF page “Randomization”. 
Schirmer’s tear test assessing the wetting distance at 5 min (mm) is performed at Screening 
and Baseline Visit and is recorded on the eCRF page “Schirmer Tear Test”.  
Medical history is recorded on the “Medical history” eCRF page. Medical history contains 
information about conditions that a subject might have suffered prior to Screening Visit, or 
conditions that are ongoing at the time of the Screening Visit. The medical 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 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. 
For females, a serum pregnancy test was performed at Screening and a urine pregnancy test 
is performed at Baseline Visit. Both tests are documented on the eCRF pages “Serum/Urine 
Pregnancy Test”, respectively. 
At Screening Visit, a test for Hepatitis B antigen (HBsAg) and Hepatitis C antibodies (HCV) as 
well as a combined screening test for HIV1 and HIV2 was performed in blood serum and 
documented on eCRF page “Serology”.  
7.2.3 Prior/Concomitant Medication 
Prior and Concomitant medication data will be collected throughout the study on the 
“Prior / Concomitant Medications” eCRF page. 
All medications (including over-the-counter drugs, herbal products, vitamins, and antacids) 
taken within 4 weeks prior to the start of and throughout the study must be recorded on the 
case report form. The use of the medications with exclusion periods before dosing longer than 


 
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4 weeks will only be checked at Screening for eligibility but would need not to be otherwise 
recorded. 
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:  
o Start Date of Medication – Date of First Study Treatment + 1 
If the Start Date of the Medication is greater than or equal to the Date of First 
Study Treatment (see section 7.1) 
o Start Date of Medication – Date of First Study Treatment 
If the Start Date of the Medication is less than the Date of First Study Treatment. 
 
Stop Day is defined as:  
o Stop Date of Medication – Date of First Study Treatment + 1 
If the Stop Date of the medication is greater than or equal to the Date of First 
Study Treatment 
o Stop Date of Medication – Date of First Study Treatment 
If the Stop Date of the Medication is less than the Date of First Study Treatment. 
‘Prior medications’ are medications that were started before and stopped before or on the day 
of First Study Treatment Administration. 
‘Concomitant medications’ include all medications that a subject used during the Treatment or 
Follow-Up Period of the study.  
Any medication started prior to first study treatment, which was not discontinued on/before 
Date of First Study Treatment, will be considered as ‘Concomitant’. Moreover, any medication 
started at any time after the First Study Treatment will be considered ‘Concomitant’. 
Medications started and stopped on the day of First Study Treatment 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: 


 
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 
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. 
 
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. 
7.2.4 Measurements of Exposure and Treatment Compliance 
Exposure 
Exposure will be presented by displaying Individual Study Duration, Number of Drops Single 
Dose Scheme in Study Eye/Non-Study Eye, Number of Drops Multiple Dose Scheme in Study 
Eye/Non-Study Eye, which will be derived as follows  
 
Individual Study Duration: 
Date of Study Discontinuation/Completion (as recorded on eCRF Page “End of 
Study”) – Date of Informed Consent (as recorded on eCRF Page “Informed Consent”) 
+ 1.  
 
Number of Drops Single Dose Scheme in Study Eye: 
Number of records on eCRF Page “Administration of Study Drug” at D1 Visit, which are 
indicating an administration of study medication in the study eye according to the 
assigned randomization number documented on the eCRF Page “Randomization”; 0 if 
no administration is indicated (i.e. no data record found or box ‘Not Done’ is ticked). 
For the single dose scheme only 1 drop should be applied according to the protocol.  
 
 
Number of Drops Single Dose Scheme in Non-Study Eye: 
Number of records on eCRF Page “Administration of Study Drug” at D1 Visit, which are 
indicating an administration of study medication in the non-study eye according to the 
assigned randomization number documented on the eCRF Page “Randomization”; 0 if 
no administration is indicated (i.e. no data record found or box ‘Not Done’ is ticked). 
For the single dose scheme 1 drop should be given according to the protocol.  
 
 
Number of Drops Multiple Dose Scheme in Study Eye: 
Number of records on all eCRF pages “Administration of Study Drug” at D2, D3, D4, 
D5, D6 visits, which are indicating an administration of study medication in the study 
eye according to the assigned randomization number documented on the eCRF Page 
“Randomization”; 0 if no administration is indicated at all visits (i.e. no data record found 
or box ‘Not Done’ is ticked). For the multiple dose scheme, 30 drops should be given 
according to the protocol. 
 
 
Number of Drops Multiple Dose Scheme in Non-Study Eye: 


 
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Number of records on all eCRF pages “Administration of Study Drug” at D2, D3, D4, 
D5, D6 visits, which are indicating an administration of study medication in the non-
study eye according to the assigned randomization number documented on the eCRF 
Page “Randomization”; 0 if no administration is indicated at all visits (i.e. no data record 
found or box ‘Not Done’ is ticked). For the multiple dose scheme, 30 drops should be 
given according to the protocol. 
 
Compliance 
For the evaluation of compliance, the following derivations will be created: 
 
Compliance Single Dose Scheme in Study Eye (%): 
is defined as 100* Number of Drops Single Dose Scheme in Study Eye. 
 
Compliance Single Dose Scheme in Non-Study Eye (%): 
is defined as 100* Number of Drops Single Dose Scheme in Non-Study Eye. 
 
Compliance Multiple Dose Scheme in Study Eye (%): 
is defined as 100* Number of Drops Multiple Dose Scheme in Study Eye/ 30. 
 
Compliance Multiple Dose Scheme in Non-Study Eye (%): 
is defined as 100* Number of Drops Multiple Dose Scheme in Non-Study Eye/ 30. 
For the analysis, the proportion of 100% compliant subjects will be presented per aspect 
based on these derivations.  
 
7.2.5 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 label 
Associated Treatment 
rhNGF 
rhNGF 20 µg/m:single drop on D1, one drop six times a day on 
D2, D3, D4, D5, D6 
Vehicle 
Vehicle control: single drop on D1, one drop six times a day on 
D2, D3, D4, D5, D6 
 
7.2.6 Primary Safety Endpoints 
For this study, the incidence of the following events will serve as primary safety endpoints: 
 
Treatment emergent adverse events (TEAEs) as defined in section 7.2.8. 
 
TEAEs during single dose scheme (TEAEs Single Dose): 
these comprise all TEAEs, which start after first dose of study treatment and before 
the date/time of administration of the first dose at Treatment Day 2. In case of missing 
time, a TEAEs with a start date of the day of  D1 Visit will be considered as TEAEs 
Single Dose. 
 
 
TEAEs during multiple dose scheme (TEAEs Multiple Dose): 
these comprise all TEAEs during the treatment period, which start after the date/time 
of first dose of study treatment at D2 Visit. In case of missing time, a TEAEs with a 
start date on the day of D2 up to D6 Visit will be considered as TEAEs Multiple Dose. 


 
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7.2.7 Primary and Secondary Tolerability Endpoints 
A global ocular discomfort score will be assessed by the subject using a self-administered 
100 mm visual analogue scale (VAS) on which 0 means no symptoms and 100 means the 
worst possible discomfort. This evaluation is to be performed before any ophthalmic 
assessment at a given study visit. 
 
The VAS Ocular tolerability scores will be collected on the eCRF page “Visual Analogue 
Scale Ocular Tolerability” per eye for the symptoms: 
 
Foreign body sensation 
 
Burning/stinging 
 
Itching 
 
Ocular pain 
 
Sticky feeling 
 
Blurred vision 
 
Photophobia 
 
The assessments should be performed at Baseline Visit 0hr, D1 8hr, D2 Pre-Dose, D2 8hr, 
D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, Fu3 0hr. 
The Overall VAS Ocular Tolerability Score acts as a global discomfort score and is defined as 
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. 
The primary tolerability endpoints for the assessment of the single dose scheme are defined 
as Change from Baseline of the D2 Pre-Dose value in the study eye. Baseline is defined as 
the corresponding assessment at Baseline Visit 0hr. This will be derived for the Overall VAS 
Ocular Tolerability Score as well as for each single symptom scale. 
The primary tolerability endpoints for the assessment of the multiple dose scheme are defined 
as Change from Multiple Dose Baseline, i.e. the difference between the considered VAS score 
in the study eye at D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, Fu3 0hr 
and the D2 Pre-Dose value in the study eye. This will be derived for the Overall VAS Ocular 
Tolerability Score as well as for each single symptom scale. 
Secondary tolerability endpoints are: 
 
the raw VAS ocular tolerability scores in Study Eye and Non-Study Eye at all 
scheduled visits. 
 
the intra-individual differences in VAS ocular tolerability scores between Study Eye 
and Non-Study Eye at all study visits. 
7.2.8 Secondary Safety Endpoints – Adverse Events 
General Definitions 
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: 


 
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 
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. 
 
For this study medically important events comprise the following sight threatening 
events, which are considered to be of special interest (AESI) and by default are to be 
reported as SAEs: 
o Adverse Events that caused a decrease in visual acuity of >30 ETDRS letters 
or > +0.6 LogMAR (compared with the last assessment of visual acuity at the 
last visit) lasting >1 hour 
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 as all ocular event, with a ticked box 
‘Medically significant or important medical condition’ in the eCRF section “SAE criteria”.  
This definition will be verified during the BDRM. 
 
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 Subject” the box ‘Subject Withdrawn’ is ticked. 
 
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’. 


 
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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 but on or before the D6 Visit. A TEAE in Treatment Period will be identified, if the 
eCRF question “Did the event occurred:” was answered with ‘During Treatment Period’. 
TEAEs in Follow-Up Period (FUAE) 
This is defined as a TEAE with a start date on or after D7 Visit. A 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. 


 
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Secondary Safety Endpoints 
The incidence of FUAEs as well as the Incidence of ocular TEAEs occurring in study eye and 
non-study eye will serve as secondary study endpoints following the definitions specified 
above. 
7.2.9 Secondary Safety Endpoints – ECG 
A 12-lead standard ECG tracing with a rhythm strip will be used.  
The following ECG measures at each time point were transferred in eCRF: 
 
Heart rate (ECG Heart Rate) 
 
PR interval 
 
QRS duration 
 
QT interval 
 
QTc (Fridericia and Bazett corrections) 
Clinically significant changes (or a clinically significant worsening) in ECG, which were 
observed the first time during study will be reported as adverse event. 
ECG was assessed at Screening Visit, D-1 0hr, D-1 0.5hr, D-1 2hr, D-1 4hr, D-1 8hr, 
D1 Pre-Dose, D1 0.5hr, D1 2hr, D1 4hr, D1 8hr, D1 14hr, D2 Pre-Dose, D2 0.5hr, D2 4hr, 
D2 8hr, D2 10hr, D2 10.5hr, D2 12hr, D3 Pre-Dose, D4 Pre-Dose, D4 4hr, D4 8hr, 
D5 Pre-Dose, D6 Pre-Dose, D6 4hr, D6 8hr, D6 10hr, D6 10.5hr, D6 12hr, FU1 0hr, FU2 0hr. 
FU3 0hr and is documented on eCRF Page “ECG”. 
For the secondary evaluations the documented parameters ECG Heart Rate (bpm), PR 
interval (msec), QRS duration (msec), QT interval (msec), QTcB and QTcF (msec) will be 
described as well as corresponding Changes from Baseline (D-1 0hr). 
7.2.10 Secondary Safety Endpoints – Vital Signs 
Vital Signs evaluation included body weight (in kg with one decimal), and sitting assessments 
of systolic and diastolic blood pressure and pulse rate as well as respiratory rate and oral body 
temperature. Blood pressure and pulse rate as well as respiratory rate will be recorded after 
the subject has rested in the sitting position for at least 3 minutes. Blood pressure should be 
assessed on the same arm for each time of determination using an automated measurement 
device. 
Body temperature were assessed orally (normal below 37.5oC). 
Clinically significant changes (or a clinically significant worsening) in vital signs, which were 
observed the first time during study will be reported as adverse event. 
Vital Signs (with the exception of body weight) were assessed at Screening Visit, D-1 0hr, D-
1 0.5hr, D-1 2hr, D-1 4hr, D-1 8hr,  D1 0.5hr, D1 2hr, D1 4hr, D1 8hr, D1 14hr, D2 Pre-Dose, 
D2 0.5hr, D2 4hr, D2 8hr, D2 10hr, D2 10.5hr, D2 12hr, D4 4hr, D4 8hr, D6 4hr, D6 8hr, D6 
10hr, D6 10.5hr, D6 12hr and is documented on eCRF Pages “Vital Signs”. Body weight is 
collected on the same eCRF at Screening Visit only. 
For the secondary evaluations the documented parameters systolic and diastolic blood 
pressure (mmHg), pulse rate (bpm), respiratory rate (breaths/min), as well as oral body 
temperature (°C) will be described as well as corresponding Changes from Baseline (D-1 0hr). 
7.2.11 Secondary Safety Endpoints – Laboratory Safety Data 
The following laboratory evaluations will be performed at the study site:  


 
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Haematology: hemoglobin, hematocrit, RBC count, reticulocyte count, WBC with differential 
platelet count. 
Biochemistry : sodium, potassium, chloride, calcium, inorganic phosphorus, total protein, 
albumin, total bilirubin, AST, ALT, alkaline phosphatase, GGT, FSH (only for postmenopausal 
females at Screening to confirm post-menopausal status), creatinine, BUN(urea-N), glucose, 
uric acid, cholesterol and high sensitivity C-reactive protein. 
Urinalysis Stix: pH, density, glucose, protein, blood (free Hb), bilirubin, urobilinogen, ketones, 
nitrites, leukocytes and erythrocytes. A midstream urine sample (approx. 30 mL) will be 
obtained, in order to avoid contamination and allow a proper assessment.  
The subject need not be in fasting condition. 
Laboratory results will be categorized either as normal, abnormal not clinically significant, 
abnormal clinical significant by the investigator. Each laboratory value determined in the study 
as well as the clinical assessments will be entered on the eCRF. 
Clinically significant changes (or a clinically significant worsening) in laboratory safety 
assessments, which were observed the first time during study will be reported as adverse 
events. 
The investigator may choose to repeat any abnormal result ONCE, in order to rule out 
laboratory error. Repeated evaluations are mandatory until their normalization or until the time 
course and reason of the underlying process can clearly be assessed. 
Laboratory Safety Assessments are performed at Screening Visit, Baseline Visit, FU1, FU2, 
FU3 and are documented on eCRF Pages “Haematology”. “Chemistry” and “Urinalysis”, 
respectively. These assessment may be done at any time on the scheduled examination day. 
For the presentation of data, the clinical evaluation as documented on the eCRF page will be 
utilized, i.e. no derivation of Normal/Abnormal values will be done for analysis purposes. As a 
consequence, a missing clinical evaluation will be presented as missing. 
For this single center study, the laboratory parameters will be presented in the units, in which 
they were collected, i.e. no transformation into SI units will be performed. 
For the secondary evaluations, all observed hematology and biochemistry parameters (except 
FSH-test) will be described as well as corresponding Changes from Baseline (D-1). 
The documented results for FSH and urinalysis will be listed. 
7.2.12 Secondary Safety Endpoints – Intraocular Pressure 
Intraocular Pressure testing will be performed per eye using Goldmann Tonometer and the 
resulting values (mmHg) are recorded on the eCRF page “Intraocular Pressure” at Screening 
Visit, Baseline 0hr, FU2 8 hr, FU3 0 hr. 
Clinically significant changes (or a clinically significant worsening) in IOP, which were observed 
the first time during study will be reported as adverse event. 
The change from baseline will be derived per eye for all scheduled post-baseline visits as 
differences from Baseline (D-1 0hr). 
7.2.13 Secondary Safety Endpoints – Best Corrected Distance Visual Acuity (BCDVA) 
Vision must be measured for each eye separately 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). 


 
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Clinically significant changes (or a clinically significant worsening) in BCDVA, which were 
observed the first time during study will be reported as adverse event. 
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. 
If no letter were read at 4 and 1 meter, the best visual potential ability of the subject 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 subject only 
ability for counting fingers is reported, logMAR will be set to 2.00; if for a subject only 
recognition of hand motion is reported, logMAR will be set to 3.00 (Holladay 1997). 
Visual acuity is assessed for each eye at Screening Visit, Baseline Visit 0hr, D1 8hr, D2 Pre-
Dose, D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, FU3 0hr and are 
documented on the eCRF page “Best Corrected Distance Visual Acuity”. 
The change from baseline will be derived for Visual Acuity Score and LogMAR per eye for all 
scheduled post-baseline visits as differences from Baseline (D-1 0hr). 
7.2.14 Secondary Safety Endpoints – Tear Film Break Up Time 
TFBUT will be measured per eye by determining the time to tear break-up. The TFBUT will be 
performed after instillation of 5 µl of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye. The subject will be instructed to blink several times 
to thoroughly mix the fluorescein with the tear film. In order to achieve maximum fluorescence, 
the examiner should wait approximately 30 seconds after instillation before evaluating TFBUT. 
With the aid of a slit lamp at 10X magnification using cobalt blue illumination, the examiner will 
monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in 
the tear film) from the time that the eye is opened after the last blink. This measurement will 
be performed within 10 seconds maximum. The TFBUT will be measured twice during the first 
minute after the instillation of the fluorescein. If the 2 readings differ by more than 2 seconds 
a third reading is taken. The TFBUT value will be the average of the 2 or 3 measurements. 
Clinically significant changes (or a clinically significant worsening) in TFBUT, which were 
observed the first time during study will be reported as adverse event. 
 
TFBUT is assessed for each eye at Screening Visit, Baseline Visit 0hr, D1 8hr, D2 Pre-Dose, 
D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, F U2 8hr, FU3 0hr and is documented 
on the eCRF page ”Tear Film Break Up Time”. 
For the secondary analysis, the mean TFBUT (sec) value will be derived from the 2 or 3 
documented single values per eye and will be presented with same number of digits as done 
for the raw values (i.e. 2 digits). The calculated average as provided in the eCRF will not be 
used for the analysis. 
The change from baseline will be derived for mean TFBUT (sec) per eye for all scheduled post-
baseline visits as differences from Baseline (D-1 0hr). 


 
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7.2.15 Secondary Safety Endpoints – Ocular Surface Staining 
As grading scale of the corneal and conjunctiva damage, the NEI/Industry Workshop 
guidelines will be used [2]. The cornea is divided into five sectors (central, superior, inferior, 
nasal and temporal), each of which is scored on a scale of 0–3, with a maximal score of 15.  
For the investigation of the conjunctiva, the nasally and temporally conjunctiva is divided into 
a superior paralimbal area, an inferior paralimbal area and a peripheral area with a grading 
scale of 0–3 and with a maximal score of 9 for the nasal and temporal conjunctiva, respectively.  
Briefly, on the grading scale used grade 0 reflects normal/healthy situation, whereas grade 3 
reflects a severe damage in each considered sector. 
Corneal Staining will be derived as sum of scores of the five corneal sectors (central, superior, 
inferior nasal and temporal) ranging from 0 to 15. Corneal Staining score will only be 
calculated, if all 5 sector scores are available.  
Conjunctival Staining will be derived as sum of scores of the conjunctival area (nasal-
superior paralimbal, nasal-inferior paralimbal, nasal-peripheral, temporal-superior paralimbal, 
temporal-inferior paralimbal, temporal-peripheral) ranging from 0 to 18. Conjunctival Staining 
will only be calculated, if all 6 area scores are available.  
Both scores will be derived for each eye separately. No imputation will be envisaged for these 
parameters. 
Ocular Surface Staining is assessed for each eye at Screening Visit, Baseline Visit 0hr, D1 8hr, 
D2 Pre-Dose, D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, FU3 0hr and are 
documented on the eCRF page “Corneal Fluorescein Staining”. 
The change from baseline in corneal staining as well as conjunctival staining will be derived 
per eye for all scheduled post-baseline visits as differences from Baseline (D-1 0hr). 
7.2.16 Other Safety Variables 
External Ocular Examination (EOE) 
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. Clinically significant changes (or a clinically significant worsening) in EOE, which were 
observed the first time during study will be reported as adverse event. 
Motility of extraocular muscle and appearance/function of eye lids is assessed separately for 
each eye at Screening Visit, Baseline Visit 0hr, D1 8hr, D2 Pre-Dose, D2 8hr, D3 Pre-Dose, 
D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, FU3 0hr 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’. 
 


 
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 
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 was performed separately for each eye at Screening Visit, Baseline Visit 
0hr, D1 8hr, D2 Pre-Dose, D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, FU3 
0hr and is recorded on the eCRF page “Slit Lamp Examination (Biomicroscopy)”. 
The following assessments will be performed: 
Eye Structure 
Rating 
Eyelid - Meibomian Glands 
0 = None (none are plugged) 
1 = Mild (1 to 2 glands are plugged) 
2 = Moderate (3 to 4 glands are plugged) 
3 = Severe (All glands are plugged)  
Eye Lid – Erythema 
0 = None (normal) 
1 = Mild (redness localized to a small region of the lid(s) 
margin OR skin) 
2 = Moderate (redness of most of all of lid margin OR skin) 
3 = Severe (redness of most or all of lid margin AND skin) 
4 = Very Severe (marked diffuse redness of both the lid 
margin AND skin)  
Eye Lid – Edema 
0 = None (normal) 
1 = Mild (localized to a small region of the lid) 
2 = Moderate (diffuse, most or all lid but not 
prominent/protruding) 
3 = Severe (diffuse, most or all lid AND 
prominent/protruding) 
4 = Very Severe (diffuse AND prominent/protruding AND 
reversion of fhe lid  


 
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Eye Structure 
Rating 
Lashes 
0 = Normal 
1 = Abnormal (specify) 
Conjunctiva – Erythema 
0 = None (normal) 
1 = Mild (a flush reddish color predominantly confined to the 
palpebral or bulbar conjunctiva) 
2 = Moderate (More prominent red color of the palpebral or 
bulbar conjunctiva) 
3 = Severe (definite redness of palpebral or bulbar 
conjunctiva)) 
Conjunctiva – Edema 
0 = None (normal) 
1 = Mild (slight localized swelling) 
2 = Moderate (moderate/medium localized swelling or mild 
diffuse swelling) 
3 = Severe (severe diffuse swelling) 
4 = Very severe (very prominent/protruding diffuse swelling) 
Lens 
0 = No Opacification (normal lens) 
1 = Mild Lens Opacification 
2 = Moderate Lens Opacification 
3 = Severe Lens Opacification 
4 = N/A Subject with Artificial Lens 
In addition there is also a field to specify Other findings 
Iris 
0 = Normal 
1 = Abnormal 
Anterior Chamber 
Inflammation 
0 = None (no Tyndall Effect) 
1 = Mild (Tyndall Effect barely discernable) 
2 = Moderate (Tyndall beam in the anterior chamber is 
moderately intense) 
3 = 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. 
Clinically significant changes (or a clinically significant worsening) in SLE, which were 
observed the first time during study will be reported as adverse event. 
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. 
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. 


 
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Eye Structure 
Rating 
Vitreous 
0 = Normal 
1 = Abnormal (specify) 
2 = Not done/Non-Evaluable 
Retina / Macula 
0 = Normal 
1 = Abnormal (specify) 
2 = Not done/Non-Evaluable 
Choroid 
0 = Normal 
1 = Abnormal (specify) 
2 = Not done/Non-Evaluable 
Optic Nerve 
0 = Normal 
1 = Abnormal (specify) 
2 = Not done/Non-Evaluable 
Cup/Disc Ratio 
0 = Normal 
1 = Abnormal (specify) 
2 = Not done/Non-Evaluable 
In addition, the Cup/Disc Ratio is recorded 
 
Dilated FO will be performed at Screening Visit with non-dilated FO performed at 
Baseline Visit 0 hr, FU2 8hr and FU3 0hr. Clinically significant changes (or a clinically 
significant worsening) in FO, which were observed the first time during study will be reported 
as adverse event. 
Physical Examination 
Physical Examination includes an examination of general appearance, head-eyes-throat-nose-
ears (HEENT), skin, thorax/lungs, cardiovascular system, abdomen, lymph nodes, 
musculoskeletal system, neurological system and other examinations as necessary.  
The clinical evaluation (‘Normal’, ‘Abnormal, Not Clinically Significant’, ‘Abnormal, clinically 
significant’). It is collected on eCRF Page “Physical Examination” at Screening Visit, 
Baseline Visit, FU1, FU2 and FU3. 
Clinically significant abnormalities (or a clinically significant worsening of a physical condition), 
which were observed the first time during study will be reported as adverse event. 
7.2.17 Pharmacokinetic Endpoints 
Two validated ELISA tests performed at Dompé farmaceutici s.p.a. will be used for PK 
measurements. The original validated method (ELISA I) will be the same applied to the NGF 
determination in serum samples taken from studies NGF0112 and NGF0212. A new additional 
validated ELISA method (ELISA II) will be performed with the intention of improving the 
sensitivity in the determination of NGF serum levels. 
Pharmacokinetics blood samples were taken on Baseline Visit 0 hr, 0.5 hr, 2 hr, 4 hr, 8 hr, 9 hr, 
10 hr, 11 hr, 12 hr, 14 hr and 16 hr, for assessment of single dose scheme at D1 Pre-Dose, 
0.5 hr, 2 hr, 4 hr, 8 hr, 9 hr, 10 hr, 11 hr, 12 hr, 14 hr and 16 hr, for multiple dose scheme at 
D2 Pre-Dose, 0.5 hr, 2 hr, 4 hr, 6hr, 8 hr, 9 hr, 10 hr, 10.5hr, 11 hr, 12 hr, 13hr, 14 hr and 16 hr, 
D3 Pre-Dose, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, D4 Pre-Dose, D5 Pre-Dose, D6 Pre-Dose, 4 hr, 8 hr, 
10 hr, 10.5hr, 11 hr, 12 hr, 13 hr, 14 hr and 16 hr, FU1 0hr, FU2 0 hr and 8 hr, FU3 0hr. 


 
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The assessment times are documented on eCRF Pages “Pharmacokinetics – Anti-Therapeutic 
Antibodies”, the rhNGF serum concentration assessed via both ELISA methods will be 
provided as external Excel files by Dompé. To maintain masking, these files will be provided 
for BDRM purposes in a masked manner by utilizing a dummy subject identification. For the 
final analysis, the Excel Files will contain the correct subject identification number. 
The concentration versus time profiles of NGF will be assessed from individual serum samples 
of all subjects. As a general principle, the nominal assessment times will be used. 
For the rhNGF serum levels according to ELISA I and ELISA II time-matched changes from 
baseline will be presented for the PKS (excluding blood samples at 6 hr, 10.5hr and 13 hr). 
For this purposes, values below the limit of detection will be set to a value of 1 pg/ml. However, 
for listings values below the limit of detection will be presented as “< 32 pg/ml’ for ELISA I 
levels and ‘< 15 pg/ml’ for ELISA II. 
A binary variable ‘Presence of rhNGF’ will be derived for each ELISA with ’No’ indicating a 
value below the limit of detection and ‘Yes’ indicating a value above the limit of detection. 
Beyond the respective rhNGF plasma levels for both ELISA methods, the following parameters 
will only be investigated for each ELISA method, if the data warrant to do so: 
 
maximum observed serum concentration (Cmax), time to reach Cmax (tmax), time elapsed 
between dosing and the first serum concentration that exceeds the assay quantification 
limit (tlag) as measured without treatment based on assessments on D-1 
 
Cmax, tmax. tlag of single dose regimen based on assessments on D1 and pre-dose of D2 
 
Cmax, tmax. tlag of multiple dose regimen based on assessments atarting with pre-dose of 
D2 
 
serum concentration measured before the administration of the next dose (Ctrough) as 
assessed at pre-dose visit on D2, D3, D4, D5, D6 
 
AUC[0-24] for the single dose regimen and the first day of multiple dose regimen.  
AUC[0-24] as area under the serum concentration versus time curve from time 0 h to pre-
dose value of the next day calculated by the linear trapezoidal rule. Values below the level 
of quantitation will be set to 0. Values below the baseline concentration will be set to zero 
other than for the values for which no later values above the baseline concentration are 
available, which will be set to missing. 
 
AUC0-tlast for the multiple dose regimen. This is derived as area under the serum 
concentration versus time curve from time 0 h to the last data point tlast after drug 
administration above the limit of quantitation and the baseline concentration, calculated 
by the linear trapezoidal rule.  
Values below the baseline concentration will be set to zero other than for the values for 
which no later values  above the baseline concentration are available, which will be set 
to  
missing 
 
AUC for the multiple dose regimen. AUC will be derived as area under the serum 
concentration versus time curve extrapolated to infinity, calculated as AUC = AUC0-tlast + 
Clast/λz 
The kinetics of single dose administration as well as multiple dose assessment will be evaluated. 


 
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The analysis of pharmacokinetic parameters will be based on the difference between the 
measured rhNGF value after dosing and the value measured at the corresponding time on 
Day  -1.  
Values below the limit of quantitation and missing values will be labeled and accounted for 
accordingly during evaluation. 
Additional evaluations, such as compartmental analysis, may be performed with an exploratory 
purpose for the multiple dose regimen if the study data suggest that they are needed for a 
better understanding of the drug. Likewise, the pharmacokinetic results of this study may be 
later pooled with results of other studies for population pharmacokinetic and pharmacokinetic-
pharmacodynamic analysis and modelling purposes. 
If required, more details on the PK evaluation will be provided in an appendix to the SAP, which 
will be finalized before unmasking of the study. 
7.2.18 Immunogenicity Endpoints 
ATA blood samples were taken on Baseline Visit 0 hr, and FU4 0hr. 
The assessment times are documented on eCRF Pages “Pharmacokinetics – Anti-Therapeutic 
Antibodies”, the ATA levels will be provided as Excel files by external provider after the study 
has been unmasked for listing purposes. 
8 Analysis Methods 
8.1 General Methods 
All endpoints of this study will be summarized using descriptive summary statistics, i.e. 
arithmetic mean, standard deviation (SD), minimum, median and maximum for quantitative 
variables by treatment group. If applicable, geometric mean together with 95% confidence 
interval and coefficient of variation will be reported for pharmacokinetic parameters. For 
qualitative variables, absolute and relative frequencies will be reported. Percentages will be 
based on the number of subjects in the respective treatment group. 
For event-based variables (e.g. adverse events) the number of events as well as the 
incidences (i.e. number and percentage of affected subjects) will be provided. 
Ocular assessments will be generally be presented separately by Study Eye and Non-Study 
Eye. All assessed data will be listed. 
8.2 Specific Methods for Primary Safety and Tolerability Analyses 
No inferential analyses are foreseen for this study. However, 95% confidence intervals for the 
geometric mean are calculated for pharmacokinetic analysis. 
8.3 Statistical/Analytical Issues  
8.3.1 Adjustments for Covariates 
Not applicable as no inferential analyses are foreseen.  
8.3.2 Handling of Dropouts or Missing Data 
For the analysis, no imputation of data is planned; all data will be analysed as collected. 


 
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8.3.3 Data Review 
In order to perform the statistical analysis of the final analysis, a decision needs to be made 
on evaluability of subjects and visits prior to locking the database and breaking the code for 
the masked study medication. In particular, a review of protocol deviations is required to 
evaluate the validity of planned analysis needs to be identified and corresponding actions 
needs to be defined, if any. This will be done at the Blind Data Review Meeting. 
Performance of the Blind Data Review Meeting will require a clean database, i.e. all data are 
available including masked PK data of both assays, coded and no data queries are open.  
No data entry should be performed between the data base Soft Lock and database lock. 
Exception would be Queries, which raised during the BDRM requiring a solution before data 
base Lock. 
The scope of the BDRM will be: 
 
Evaluation of Re-Screened subjects 
 
Check correct assignment of allocated treatment and study eye 
 
Check protocol deviations and define analysis sets 
 
Review and confirmation of AESIs (sight threatening events) 
More details on scope and performance of data review meetings will be described in a separate 
BDRM plan. 
After the BDRM was performed, all decisions were summarized in BDRM Minutes, which were 
approved before the database was locked for the analysis.  
8.3.4 Multicenter Studies 
Not applicable since this is a monocentric study.  
8.3.5 Multiplicity of Endpoints 
Not applicable as not inferential statistics will be performed. 
9 Interim Analyses 
No interim analysis is planned for this study. 
10 Overview of Tables, Listings and Figures  
In this section, TLFs are presented content wise. The full set of TLFs are 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 are presented in a separate document. 
10.1 Disposition of Subjects 
Based on the Total Set, a disposition summary of subjects includes the number (n) and 
percentage (%) of subjects in all analysis sets defined in Section 6.1. All percentages will be 
based on the number of subjects randomized. For the Total Set only the number of subjects 
will be presented. 
The primary reason for study discontinuation will be summarized for the SAF providing counts 
(n) and percentages (%). This summary will also include counts and percentages for unmasked 
subjects. 


 
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A listing will be present for the Total Set displaying the allocation to study treatment and study 
eye as well as the assignment of subjects to the respective analysis cohorts. 
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 treatment day of study termination/completion. 
10.2 Protocol Deviations 
The number of subjects who had at least one major as well as minor protocol deviation and all 
categories of Protocol Deviations will be summarized by counts (n) and percentages (%) for 
the SAF. Percentages will be calculated based on the number of subjects in the SAF. 
A listing presents all Protocol Deviation data for the SAF. 
10.3 Inclusion and Exclusion Criteria 
Two listings will be provided for all subjects in the SAF displaying status of violated Inclusion 
and Exclusion criteria, respectively. 
10.4 Demographic and Other Baseline Characteristics 
10.4.1 Demographic and other Background Information 
Age at Screening Visit (years), Ethnicity (‘Japanese’, ‘Non-Japanese’), BMI (kg/m²) and 
number of alcohol units will be summarized per treatment group and overall by summary 
statistics or absolute counts (n) and percentages (%) for the SAF. 
All demographic data, body weight and height at Screening as well as other background 
information will be listed for the SAF. 
10.4.2 Medical History and Other Medical Conditions 
The selected study eye will be summarized per treatment group and overall by absolute counts 
(n) and percentages based on the SAF. 
Medical History will be summarized per treatment group and overall by absolute counts (n) and 
percentages (%) for the number of subjects with at least one medical history event for the SAF. 
Percentages will be calculated based on the number of subjects in the population. 
A listing will present all reported, derived and coded medical history data based on the SAF. 
In addition, all data recorded and derived for Schirmer’s tear test, pregnancy tests and serology 
assessments (HBsAg, HCV, HIV1/2) will be listed for the SAF. 
10.4.3 Prior/Concomitant Medications 
Prior and Concomitant medications will be summarized by treatment group and overall for the 
SAF separately on a per-subject basis (i.e. if a subject 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 subjects 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 subjects in the SAF. 
A Listing will present all documented medication data for the SAF and will include a flag for 
Prior medication. 


 
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10.5 Exposure and Compliance to Study Medication  
For exposure, the variables Individual Study Duration, Number of Drops Single Dose Scheme 
in Study Eye/Non-Study Eye, Number of Drops Multiple Dose Scheme in Study Eye/Non-Study 
Eye will be summarized for the SAF per treatment group. 
For compliance, the proportions of 100% compliant subjects in the SAF for the single dose as 
well as the multiple dose scheme will be summarized by treatment group separately for study 
eye and non-study Eye by absolute counts (n) and percentages (%). 
A listing will present for all SAF subjects all records documented on the eCRF Page 
“Administration of Study Drug” as well as the corresponding derived parameters. 
10.6 Analysis of Primary Safety and Tolerability Assessments 
10.6.1 Primary and Secondary Safety Endpoints – Adverse Events 
The incidences of the primary and secondary endpoints TEAEs, TEAEs Single Dose, TEAEs 
Multiple Dose, FUAEs, Ocular TEAEs in Study Eye, Ocular TEAEs in Non-Study Eye will be 
presented for the SAF by study treatment and overall displaying the number of events as well 
as the number and percentages of subjects with at least one event. 
In addition a general overview will be provided for AEs, non TEAEs, TEAEs during Treatment 
Period, TEAEs leading to premature withdrawal of the study treatment. TEAEs leading to study 
discontinuation, serious TEAEs, Fatal TEAEs, treatment related TEAEs, treatment related 
serious TEAEs, Ocular TEAEs, TEAEs of special interest and Mild, Moderate and Severe 
TEAEs will be given by study treatment and overall for subjects in the SAF. For each event, 
the number and percentages of subjects with at least one event as well as the total number of 
events will be displayed.  
Detailed adverse event descriptive tables on will be summarized separately for each study 
treatment and overall for the following events: 
 
TEAEs 
 
TEAEs Single Dose 
 
TEAEs Multiple Dose 
 
FUAEs 
 
Ocular TEAEs 
 
Ocular TEAEs in Study Eye 
 
Ocular TEAEs in Non-Study Eye 
 
TEAEs by severity. 
 
Treatment related TEAEs. 
 
Serious TEAEs (only if reported). 
 
Treatment related serious TEAEs (only if reported) 
 
TEAEs leading to premature withdrawal of the Study Treatment. 
 
TEAEs leading to study discontinuation. 


 
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They will be summarized on a per-subject basis (i.e. if a subject 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 subjects with at least 
one AE, and per SOC and per PT within SOC, for the SAF. Percentages will be based on 
the number of subjects in the population. In addition number of events will be provided. 
Descriptive tables will be ordered by descending frequency of the overall number of 
subjects within each SOC regardless of treatment group, and then ordered within each 
SOC by the overall number of subjects within each PT regardless of treatment group. In 
the event of equal frequencies tables will be ordered by active treatment frequency and 
then alphabetically. 
Listings will present all Adverse Event data for the SAF by subject.  
In addition specific listings will be created for: 
 
Ocular TEAEs 
 
TEAEs leading to premature withdrawal of study treatment 
 
TEAEs leading to study treatment interruption 
 
TEAEs related to study treatment 
 
Serious AEs (only if reported) 
 
Serious TEAEs related to study treatment (only if reported) 
 
Fatal AEs (only if reported) 
10.6.2 Primary and Secondary Tolerability Endpoints 
The primary endpoints Change from Baseline of VAS Tolerability Scores in Study Eye at D2 
Pre-Dose Visit and Changes from Multiple Dose Baseline of VAS Tolerability Scores in Study 
Eye at D2 8hr, D3 Pre-Dose, D6 Pre-Dose, D6 8hr, FU1 0hr, FU2 8hr, Fu3 0hr visits will be 
summarized for the SAF by treatment group. 
For secondary analyses, the VAS tolerability Scores will be summarized for all scheduled 
assessment times by treatment separately for Study Eye and Non-Study Eye as well as the 
intra-individual differences between the eyes in subjects included in the SAF. 
All collected and derived tolerability data will be listed for the SAF. 
10.7 Additional Secondary Safety Assessments 
10.7.1 ECG 
For secondary analyses, the raw values as well as the changes from baseline of the endpoints 
ECG Heart Rate, PR interval, QRS duration, QT interval, QTcB interval, QTcF interval will be 
summarized by treatment for the SAF. 
All collected and derived ECG data including investigator’s interpretation will be listed for the 
SAF. 
10.7.2 Vital Signs 
For the secondary analyses, the raw values as well as the changes from baseline of the 
endpoints systolic and diastolic blood pressure (mmHg), pulse rate (bpm), respiratory rate 
(breaths/min) and oral body temperature (°C) will be summarized by treatment for the SAF. 


 
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All collected and derived vital signs data will be listed for the SAF. 
10.7.3 Laboratory Safety Data 
For the secondary analyses, the raw values as well as the changes from baseline haematology 
and chemistry (except of FSH) will be summarized by treatment for the SAF. 
All collected and derived laboratory safety data will be listed for the SAF. 
10.7.4 Intraocular pressure 
Intraocular Pressure is summarized for the SAF by Study Eye/Non-Study Eye and 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 for the SAF. 
10.7.5  Change in BCDVA 
For the SAF, the Visual Acuity Score and logMAR will be summarized per Study Eye/Non-
Study Eye respectively for each treatment group at all scheduled study visits as well as 
changes from baseline for all Post Baseline Visits.  
All raw as well as derived BCDVA data will be listed for the SAF. 
10.7.6 TFBUT 
For the SAF, the Average TFBUT value will be summarized per Study Eye/Non-Study Eye 
respectively for each treatment group at all scheduled study visits as well as changes from 
baseline for all Post Baseline Visits.  
All documented TFBUT values including all derivations will be listed for the SAF. 
10.7.7 Ocular Surface Staining 
For the SAF, corneal and conjunctival staining will be summarized per Study Eye/Non-Study 
Eye respectively for each treatment group at all scheduled study visits as well as changes from 
baseline for all Post Baseline Visits.  
All documented staining results including all derivations will be listed for the SAF. 
10.8 Other Safety Variables 
External Ocular Examination (EOE) 
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 Study Eye as well as the Non-Study Eye. This analysis will be performed on the 
SAF. These data will also be listed for the SAF. 
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 for the SAF by treatment group and 
study visit for the Study Eye as well as for the Non-Study. 
Moreover, these data will be listed for the SAF.  


 
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Slit Lamp Evaluation 
All grading assessments of different eye structure (excluding assessment for other structures) 
will be summarized descriptively for the SAF by treatment group and study visit for the Study 
Eye as well as the Non-Study Eye.  
All data recorded on the eCRF page ‘Slit Lamp Examination (Biomicroscopy)’ will be listed for 
the SAF. 
Fundus Ophthalmology 
All data including details on detected abnormalities recorded on the eCRF will be listed for the 
SAF clearly indicating the mode of assessment (Dilated/Not-Dilated). 
Physical Examination 
All physical examination data recorded on the eCRF will be listed for the SAF. 
10.9 Pharmacokinetic Evaluations 
All pharmacokinetic evaluations will be presented for the PKS. 
Summary descriptive statistics for both absolute and time-matched changes from baseline will 
be provided by treatment for rhNGF serum concentrations ELISA I as well as ELISA II at all 
scheduled time points including geometric mean, coefficient of variation and 95% confidence 
intervals for the geometric mean. 
In addition, presence of rhNGF concentrations will be summarized by treatment group for 
ELISA I and ELISA II concentrations at each scheduled assessment time.  
Serum concentration versus time profiles will be presented on linear and log/linear scale for 
each individual with at least one value above detection level as well as geometric mean and 
median values for each time-point by treatment group. For individual plots, actual sampling 
times will be used. For the plots of geometric mean, scheduled sampling times will be used. 
All recorded PK data will be listed for the SAF, clearly indicating subjects not included in the 
PKS. 
Further PK analysis might be performed according to an appendix of the SAP, if indicated. 
10.10 Immunogenicity 
All recorded ATA concentrations will be listed for the SAF, clearly indicating subjects not 
included in the PKS. 
 
 


 
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11 References 
1 
Holladay, JT (1997) Proper Method for Calculating Average Visual Acuity. Journal of 
Refractive Surgery, 13, pp. 388-391 
2 
Lemp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in 
dry eye. CLAO J1995, 21(4):221–32. 


 
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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. 
 
TLF number 
Title 
Analysis Set 
U/R 
Tables 
 
 
 
Table 14.1-1.1 
Summary of Subject Disposition 
TOT 
U 
Table 14.1-1.2 
Summary of Study Discontinuation 
SAF 
U 
Table 14.1-2.1 
Summary of Protocol Deviations 
SAF 
U 
Table 14.1-3.1 
Summary of Demographics and 
Other Background Information 
SAF 
U 
Table 14.1-4.1 
Summary of Selected Study Eyes 
SAF 
U 
Table 14.1-5.1 
Summary of Medical History 
SAF 
U 
Table 14.1-6.1 
Summary of Prior Medications 
SAF 
R 
Table 14.1-6.2 
Summary of Concomitant 
Medications 
SAF 
U 
Table 14.1-7.1 
Summary of Exposure 
SAF 
U 
Table 14.1-7.2 
Summary of Compliance 
SAF 
U 
Table 14.2-01.1 
Summary of Primary and AE Related 
Secondary Endpoints 
SAF 
U 
Table 14.2-02.1 
Overall Summary of Adverse Events 
SAF 
U 
Table 14.2-03.1 
Summary of TEAEs by System 
Organ Class and Preferred Term 
SAF 
U 
Table 14.2-04.1 
Summary of TEAEs Single Dose by 
System Organ Class and Preferred 
Term 
SAF 
R 
Table 14.2-05.1 
Summary of TEAEs Multiple Dose by 
System Organ Class and Preferred 
Term 
SAF 
R 
Table 14.2-06.1 
Summary of FUAEs by System 
Organ Class and Preferred Term 
SAF 
R 
Table 14.2-07.1 
Summary of Ocular TEAEs by 
System Organ Class and Preferred 
Term 
SAF 
R 


 
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TLF number 
Title 
Analysis Set 
U/R 
Table 14.2-08.1 
Summary of Ocular TEAEs in Study 
Eye by System Organ Class and 
Preferred Term 
SAF 
R 
Table 14.2-09.1 
Summary of Ocular TEAEs in Non-
Study Eye by System Organ Class 
and Preferred Term 
SAF 
R 
Table 14.2-10.1 
Summary of TEAEs by Severity, 
System Organ Class and Preferred 
Term 
SAF 
U 
Table 14.2-11.1 
Summary of Treatment Related 
TEAEs by System Organ Class and 
Preferred Term 
SAF 
R 
Table 14.2-12.1 
Summary of TEAEs leading to 
Premature Withdrawal of Study 
Treatment by System Organ Class 
and Preferred Term 
SAF 
R 
Table 14.2-13.1 
Summary of TEAEs leading to Study 
Discontinuation by System Organ 
Class and Preferred Term 
SAF 
R 
Table 14.3-1.1 
Summary of VAS Ocular Tolerability 
Scores 
SAF 
U 
Table 14.3-1.2 
Summary of Changes from Single 
dose Baseline in VAS Ocular 
Tolerability Scores (Single Dose) 
SAF 
U 
Table 14.3-1.3 
Summary of Changes from Multiple 
Dose Baseline in VAS Ocular 
Tolerability Scores 
SAF 
U 
Table 14.3-1.4 
Summary of Intraindividual 
Differences between Eyes in VAS 
Ocular Tolerability Scores 
SAF 
U 
Table 14.4-1.1 
Summary of ECG Parameters 
SAF 
U 
Table 14.4-1.2 
Summary of Changes from Baseline 
in ECG Parameters 
SAF 
U 
Table 14.4-2.1 
Summary of Vital Signs 
SAF 
U 
Table 14.4-2.2 
Summary of Changes from Baseline 
in Vital Signs 
SAF 
U 
Table 14.4-3.1 
Summary of Haematology 
SAF 
U 
Table 14.4-3.2 
Summary of Changes from Baseline 
in Haematology 
SAF 
U 
Table 14.4-4.1 
Summary of Biochemistry 
SAF 
U 


 
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TLF number 
Title 
Analysis Set 
U/R 
Table 14.4-4.2 
Summary of Changes from Baseline 
in Biochemistry 
SAF 
U 
Table 14.4-5.1 
Summary of Intraocular Pressure 
SAF 
U 
Table 14.4-5.2 
Summary of Changes from Baseline 
in Intraocular Pressure 
SAF 
U 
Table 14.4-6.1 
Summary of BCDVA Score 
SAF 
U 
Table 14.4-6.2 
Summary of Changes from Baseline 
in BCDVA Score 
SAF 
U 
Table 14.4-7.1 
Summary of LogMAR 
SAF 
U 
Table 14.4-7.2 
Summary of Changes from Baseline 
in LogMAR 
SAF 
U 
Table 14.4-8.1 
Summary of TFBUT 
SAF 
U 
Table 14.4-8.2 
Summary of Changes from Baseline 
in TFBUT 
SAF 
U 
Table 14.4-9.1 
Summary of Corneal and 
Conjunctival Staining 
SAF 
U 
Table 14.4-9.2 
Summary of Changes from Baseline 
in Cornal and Conjunctival Staining 
SAF 
U 
Table 14.5-1.1 
Summary of Motility of Extraocular 
Muscle 
SAF 
U 
Table 14.5-2.1 
Summary of Appearance and 
Function of Eyelid 
SAF 
U 
Table 14.5-3.1 
Summary of Slit Lamp Examination 
SAF 
U 
Table 14.6-1.1 
Summary of rhNGF titres ELISA I 
PKS 
U 
Table 14.6-1.2 
Summary of time-matched changes 
from Baseline in rhNGF titres ELISA 
I 
PKS 
U 
Table 14.6-1.3 
Summary of Presence of rhNGF 
Titres ELISA I 
PKS 
U 
Table 14.6-2.1 
Summary of rhNGF titres ELISA II 
PKS 
U 
Table 14.6-2.2 
Summary of time-matched changes 
from Baseline in rhNGF titres ELISA 
II 
PKS 
U 
Table 14.6-2.3 
Summary of Presence of rhNGF 
Titres ELISA II 
PKS 
U 
Figures 
 
 
 
Figure 14.1-1.1 
Plot of Geometric Mean and Median 
of rhNGF Titres by Time – ELISA I 
PKS 
U 


 
Dompé NGF0117 – Statistical Analysis Plan 
Version 1.0 Final, 27Sep2018 
CONFIDENTIAL 
Page 49 of 50 
_____________________________________________________________________________________________________________________________________
 
 
 
 
 
 
 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
TLF number 
Title 
Analysis Set 
U/R 
Figure 14.1-1.2 
Individual rhNGF concentrations vs 
time plot – ELISA I (subjects with 
titres above detection level) 
PKS 
U 
Figure 14.1-2.1 
Plot of Geometric Mean and Median 
of rhNGF Titres by Time – ELISA II 
PKS 
NU 
Figure 14.1-2.2 
Individual rhNGF concentrations vs 
time plot – ELISA II (subject with 
titres above detection level) 
PKS 
NU 
Listings 
 
 
 
Listing 16.1.7-1.1 
Randomized Allocation of Study 
Treatment and Study Eye 
TOT 
U 
Listing 16.2.01-1.1 
Listing of Study Completion and 
Unmasking 
TOT 
U 
Listing 16.2.02-1.1 
Listing of Protocol Deviations 
SAF 
U 
Listing 16.2.02-2.1 
Listing of Deviations from Inclusion 
Criteria 
SAF 
U 
Listing 16.2.02-2.2 
Listing of Presence of Exclusion 
Criteria 
SAF 
U 
Listing 16.2.03-1.1 
Listing of Demographic Data 
SAF 
U 
Listing 16.2.03-2.1 
Listing of Smoking habits and 
alcohol consumption 
SAF 
U 
Listing 16.2.03-3.1 
Listing of Results of Alcohol Breath 
Test and Drug Screen 
SAF 
U 
Listing 16.2.04-1.1 
Listing of Medical History 
SAF 
U 
Listing 16.2.04-2.1 
Listing of Schirmer’s Tear Test 
SAF 
U 
Listing 16.2.04-3.1 
Listing of Pregnancy Tests Results 
(Females only) 
SAF 
U 
Listing 16.2.04-4.1 
Listing of Results of Serology 
SAF 
U 
Listing 16.2.05-1.1 
Listing of Prior and Concomitant 
Medication 
SAF 
U 
Listing 16.2.06-1.1 
Listing of Study Drug Administration 
SAF 
U 
Listing 16.2.07-1.1 
Listing of Adverse Events 
SAF 
U 
Listing 16.2.07-1.2 
Listing of Action Taken due to 
Adverse Events 
SAF 
U 
Listing 16.2.07-2.1 
Listing of Ocular TEAEs 
SAF 
R 
Listing 16.2.07-3.1 
Listing of TEAES leading to 
Premature Withdrawal of Study 
Treatment 
SAF 
R 


 
Dompé NGF0117 – Statistical Analysis Plan 
Version 1.0 Final, 27Sep2018 
CONFIDENTIAL 
Page 50 of 50 
_____________________________________________________________________________________________________________________________________
 
 
 
 
 
 
 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
TLF number 
Title 
Analysis Set 
U/R 
Listing 16.2.07-4.1 
Listing of TEAEs leading to Study 
Treatment Interruption 
SAF 
R 
Listing 16.2.07-5.1 
Listing of Treatment Related TEAEs 
SAF 
R 
Listing 16.2.08-1.1 
Listing of VAS Ocular Tolerability 
Scores 
SAF 
U 
Listing 16.2.08-2.1 
Listing of ECG Assessments 
SAF 
U 
Listing 16.2.08-3.1 
Listing of Vital Signs 
SAF 
U 
Listing 16.2.08-4.1 
Listing of Haematology Parameters 
SAF 
U 
Listing 16.2.08-4.2 
Listing of Biochemistry Parameters 
SAF 
U 
Listing 16.2.08-4.3 
Listing of Urinalysis Parameters 
SAF 
U 
Listing 16.2.08-5.1 
Listing of Intraocular Pressure 
SAF 
U 
Listing 16.2.08-6.1 
Listing of BCDVA Assessments 
SAF 
U 
Listing 16.2.08-6.2 
Listing of BCDVA Score, Snellen 
Equivalent and LogMAR 
SAF 
U 
Listing 16.2.08-7.1 
Listing of TFBUT Assessments 
SAF 
U 
Listing 16.2.08-8.1 
Listing of Ocular Surface Staining: 
Corneal Staining 
SAF 
U 
Listing 16.2.08-8.2 
Listing of Ocular Surface Staining: 
Conjunctival Staining 
SAF 
U 
Listing 16.2.09-1.1 
Listing of Motility of Extraocular 
Muscle 
SAF 
U 
Listing 16.2.09-2.1 
Listing of Appearance and Function 
of Eyelids 
SAF 
U 
Listing 16.2.09-3.1 
Listing of Slit Lamp Examination – 
Part I 
SAF 
U 
Listing 16.2.09-3.2 
Listing of Slit Lamp Examination – 
Part II 
SAF 
U 
Listing 16.2.09-4.1 
Listing of Fundus Ophthalmology 
SAF 
U 
Listing 16.2.09-5.1 
Listing of Physical Examination 
SAF 
U 
Listing 16.2.10-1.1 
Listing of rhNGF titres 
PKS 
U 
Listing 16.2.10-2.1 
Listing of ATA results 
SAF 
U 
 
13 Appendices 
None