Conditions: Ocular Discomfort
Keywords: Ocular discomfort after cataract and refractive surgery cataract surgery refractive surgery
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The primary objective of this exploratory study is to assess preliminary efficacy and safety of rhNGF when administered as eye drops to patients after cataract and refractive surgery.

The main criteria for evaluation were:

* Change from baseline in SANDE scores for severity and frequency assessed at 8 weeks of treatment (primary efficacy endpoint)
* Changes in Cornea vital staining with fluorescein (National Eye Institute \[NEI\] scales) assessed at 8 weeks of treatment (co-primary efficacy endpoint)
* Changes in conjunctiva vital staining with fluorescein (NEI scales) (secondary efficacy endpoint);
* Changes in Tear Film Break-Up Time (TFBUT)(secondary efficacy endpoint);
* Changes in Cochet-Bonnet corneal aesthesiometry (secondary efficacy endpoint);
* Changes in Nerve count and morphology at scanning laser in vivo corneal confocal microscopy (only patients who had Laser-Assisted In situ Keratomileusis \[LASIK\] surgery) (secondary efficacy endpoint);
* Changes in SANDE scores (face values) for severity and frequency (secondary efficacy endpoint);
* Incidence and frequency of treatment-emergent adverse events (TEAEs), assessed throughout the study (safety endpoint).

Detailed description:
The proposed phase II study is a single-centre, randomized, double masked, parallel arm, vehicle-controlled trial, designed to evaluate the preliminary efficacy and safety of rhNGF eye drops at 20 µg/ml concentration administered six times daily for 8 weeks in patients who underwent cataract and corneal refractive surgery, both known to damage the corneal sensory nerve plexus.

After confirmation of inclusion and exclusion criteria all eligible patients will be randomized at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments administration with 4 weeks Follow-up.

Arms:
arm 1: Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily arm 2: Vehicle eye drops six times daily

Interventions: intervention 1: rhNGF intervention 2: Vehicle
Intervention descriptions: intervention 1: Eye Drop 20 μg/mL intervention 2: Vehicle Eye Drop

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL 
rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 1 of 59 
 
 
Study code NGF0116 
 
 
A 8 weeks, Phase II, single-centre, randomized, double-masked, 
vehicle-controlled, parallel group study with 4 weeks of follow-up 
to evaluate preliminary efficacy and safety of recombinant human 
Nerve Growth Factor (rhNGF) eye drops solution versus vehicle 
in patients after cataract and refractive surgery. 
 
Double-masked, single-centre, two-group, one dose, efficacy and safety study 
 
EudraCT Number: 2016-002172-27 
 
 
Test formulation: 
Recombinant human nerve growth factor (rhNGF), 20 μg/ml, 
ophthalmic sterile buffered aqueous solution, Dompé 
farmaceutici s.p.a., Italy 
 
 
Sponsor: 
Dompé farmaceutici S.p.A., Via Santa Lucia 6, 
20122 Milan, Italy 
Phone: 
+39.02.583831  
Fax:  
+39.02.58383324 
Contact: Paolo Battigello 
Email: 
paolo.battigello@dompe.com  
 
 
Principal Investigator 
Prof. Leonardo Mastropasqua, MD 
Clinica Oftalmologica - Centro regionale di Eccellenza in 
Oftalmologia 
Università G. D' Annunzio 
Via dei Vestini  
66100 Chieti, Italy  
Phone: 
+39.0871.35713581 
Fax: 
+39.0871.358794 
 
 
Development phase: 
Phase II 
 
 
Version and date: 
Final Version 3.0, 12 Apr 2017 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
Property of the Sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the Sponsor 
 
 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 2 of 59 
 
PROTOCOL APPROVAL 
 
SPONSOR 
Dompé farmaceutici S.p.A. , Italy  
 
 
Clinical Development Senior Specialist 
Paolo Battigello, M.Sc.  
 
 
 
 
Date 
 
Signature 
 
 
Medical Expert 
Flavio Mantelli, MD, PhD  
 
 
 
 
Date 
 
Signature 
 
  
INVESTIGATORS 
 
Principal Investigator  
 
Investigator Agreement: 
I have read the clinical study described herein, recognize its 
confidentiality, and agree to conduct the described trial in compliance with Good Clinical 
Practice (GCP), the ethical principles contained within the Declaration of Helsinki, this 
protocol, and all applicable regulatory requirements. 
 
 
 
Prof. Leonardo Mastropasqua, MD 
Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia 
Università G. D' Annunzio 
Chieti, Italy  
 
 
 
 
Date 
 
Signature 
 
  
 
 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 3 of 59 
CONTACTS 
 
Dompé Drug Safety  
Email to:  farmacovigilanza@dompe.com 
or Fax:  +39.02.36026913 
 
Dompé Medical Expert 
Flavio Mantelli – Chief Medical Officer Ophthalmology,  
Email to:  flavio.mantelli@dompe.com 
or Fax:  +39.02.58383324 
 
Dompé Clinical Development 
Paolo Battigello – Clinical Development Senior Specialist 
Email to: paolo.battigello@dompe.com 
or Fax:  +39.02.58383324 
 
CRO: 
CROMSOURCE 
 
Mauro D’Apolito – Clinical Research Senior Director 
Email to: mauro.dapolito@cromsource.com 
Or Fax: +39.045.8222812 
 
Maria Conson - Project Manager 
Email to: maria.conson@cromsource.com 
 
CromSource Pharmacovigilance 
Email to: NGF0116-PV@cromsource.com 
or Fax: +39 045 82 50 574 
 
CromSource Medical Monitor 
Email to: NGF0116-MM@cromsource.com 
or Fax: +39 045 82 50 574 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 4 of 59 
Study Synopsis 
 
Title: A 8 weeks, Phase II, single-centre, randomized, double-masked, vehicle-controlled, 
parallel group study with 4 weeks of follow-up to evaluate preliminary efficacy and safety of 
recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle in patients 
after cataract and refractive surgery. 
Protocol number: NGF0116 
EudraCT Code: 2016-002172-27 
Clinical phase: Phase II 
Study design: Double-masked, single-centre, two-group, one dose, efficacy and safety study 
Study Centre: Clinica Oftalmologica - Centro regionale di Eccellenza in Oftalmologia - 
Università G. D'Annunzio – Chieti, Italy 
Principal Investigator: Prof. Leonardo Mastropasqua, MD - Clinica Oftalmologica - Centro 
regionale di Eccellenza in Oftalmologia - Università G. D' Annunzio 
- Chieti, Italy 
Investigational product(s):  
TEST 
PRODUCT:  
Recombinant human nerve growth factor (rhNGF) ophthalmic sterile 
buffered aqueous solution, Dompé farmaceutici S.p.A, Italy, 20 μg/mL 
vials (Group 1) 
Background information 
NGF is a polypeptide discovered in the early 1950s by R. Levi Montalcini. NGF acts through 
specific high affinity (i.e., TrkA) and low affinity (i.e., p75NTR) NGF receptors which are 
expressed not only on nerve fibres but also on anterior segment of the eye (iris, ciliary body, 
lens, cornea and conjunctiva) and by the lacrimal gland providing the rationale for use of NGF 
in the treatment of diseases of the anterior segment of the eye. Murine NGF (mNGF) extracted 
and purified from the male mouse submaxillary gland was administered to over a hundred 
patients (45 published) with stage 2 and stage 3 neurotrophic keratitis (NK) in form of eye drops 
at a concentration of 200 µg/mL in balanced salt solution in two uncontrolled, unmasked, open-
label studies. Compelling results were observed with all affected eye(s) healed from persistent 
epithelial defects. Tolerability was good with only mild, local and transient side effects. As for 
dry eye disease, administration of NGF to dogs where dry eye had been surgically induced 
resulted in enhanced production and functional characteristics of tear film, with an associated 
improvement of ocular surface signs.  
Based on these data, the Company has developed a recombinant human NGF (rhNGF) 
expressed in E. coli for treatment of NK. 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 5 of 59 
A phase I, masked placebo controlled clinical study in 74 healthy volunteers after single and 
multiple dose of different concentrations of rhNGF eye drops showed a safety profile rhNGF 
eye drops (Study NGF0112). A Phase I/II multicentre, double-masked, vehicle controlled study 
to evaluate the safety and efficacy of rhNGF at 10 and 20 μg/mL six times a day in 174 patients 
with stage 2 and 3 NK (study NGF0212) has been completed in 2015 demonstrating that rhNGF 
was very well tolerated also in patients with NK. 
In addition to NK, rhNGF, in the same formulation (containing L-methionine) proposed for the 
present study, has been evaluated in a Phase I/II study in retinitis pigmentosa (RP) patients at 
the doses of 60 and 180 μg/mL, and in a phase II study in neurotrophic keratitis patients at the 
same concentration of the present study, 20 μg/mL (6 times a day). 
An open uncontrolled study showed that 4 weeks treatment with rhNGF eye drops at 20 μg/mL 
and 4 μg/mL) concentrations was safe and effective in improving symptoms, corneal staining 
and tear function in patients with dry eye as compared to baseline (NGF0213). 
Study Design and Methodology  
The proposed phase II study is a single-centre, randomized, double masked, parallel arm, 
vehicle-controlled trial, designed to evaluate the preliminary efficacy and safety of rhNGF eye 
drops at 20 µg/ml concentration administered six times daily for 8 weeks in patients who 
underwent cataract and corneal refractive surgery, both known to damage the corneal sensory 
nerve plexus. 
After confirmation of inclusion and exclusion criteria all eligible patients will be randomized 
at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments 
administration with 4 weeks Follow-up. 
 
 
 
  
 
 
Treatment: either rhNGF eye drops 20 µg/ml or vehicle six times daily for 8 weeks.  
Follow-up: 4 weeks with no further treatment except artificial tears (use recorded in drops/day). 
After baseline (day 0), enrolled patients will be evaluated for safety and efficacy at week 4 (day 
282), week 8 (day 562) or early exit and at 4 weeks (day 842) after the end of study 
treatment. 
Follow-up 
4 weeks 
Treatment 
8 weeks 
Randomization 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 6 of 59 
Treatment Groups  
Eligible patients will be randomized to either rhNGF eye drops 20 µg/ml or vehicle:  
Group 1: rhNGF 20 µg/mL: One drop (40 µL) corresponding to 0.80 µg of rhNGF will be 
instilled into each eligible eye six times a day (every 2h), for a total daily dose of 9.6 µg (both 
eyes, if applicable), for 56 consecutive days.  
Group 2: Vehicle: One drop (40 µL) will be instilled into each eligible eye six times a day 
(every 2h). 
In all patients, both eyes will be treated, if meet the eligibility criteria. If only one eye is eligible, 
then only that eye will be treated. 
In the 4 week follow up no further treatment is planned except artificial tears, per Investigator 
decision. Administration of such medications will be recorded in eCRF (number of drops per 
day). 
Primary Objective 
The primary objective of this study is to assess efficacy and safety of rhNGF when administered 
as eye drops to patients after cataract and refractive surgery. 
Study end-points 
Clinical efficacy and safety parameters will be evaluated at each time point (days 0, 28±2, 56±2 
and 28±2 days after discontinuation of treatment) with the following endpoints: 
Primary efficacy end-point: 
 Change from baseline in SANDE scores for severity and frequency assessed at 8 weeks of 
treatment  
Co-primary Efficacy Endpoint 
 Changes in Cornea vital staining with fluorescein (National Eye Institute [NEI] scales) 
assessed at 8 weeks of treatment 
Secondary efficacy end-points: 
 Changes Conjunctiva vital staining with fluorescein (National Eye Institute [NEI] scales) 
 Changes in Tear Film Break-Up Time (TFBUT) 
 Changes in Cochet-Bonnet corneal aesthesiometry 
 Changes in Nerve count and morphology at scanning laser in vivo corneal confocal 
microscopy (only patients who had LASIK surgery) 
 Changes in SANDE scores (face values) for severity and frequency 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
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Safety end-point: 
 Incidence and frequency of Treatment-Emergent Adverse Events (TEAEs), assessed 
throughout the study 
Details of efficacy and safety analyses will be presented in the Statistical Analysis Plan finalised 
before Database Lock. 
Number of Subjects 
In total 180 post cataract or refractive surgery patients will be enrolled in the study with 120 
patients to be treated with rhNGF and 60 patients treated with vehicle. 
Sample size calculation 
Sample size  was calculated by assuming at single eye level a mean difference from baseline 
mean SANDE scores of -30±20 in the rhNGF groups versus -20±20 in vehicle group (80% 
power, alpha =0.05; 2-sided test), considering that the active comparator has already proven 
safe and effective in dry eye patients. The sample size has been calculated based on a 2:1 
randomization by the following  formula:  
n1 = (0.5) × n × (1 + k) 
n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 63 and k= n1 /n2 = 2/1=2. Therefore n1= 
94,5 and n2=47.25.  Assuming a 5% drop out rate, a total of 100 patients will be enrolled in 
active arm and 50 in the vehicle arm. This calculation is based on one study eye per patient. 
Whereas also two study eyes per patient may occur, that will increase power to above 80%). 
 
However, in order to provide the mean of detecting a significant difference also on a clinical 
sign of the effect of the rhNGF therapy (namely Co-primary Efficacy Endpoint cornea and 
conjunctiva vital staining with fluorescein (National Eye Institute [NEI] scales)), sample size 
calculation was also performed by assuming, at single eye level, a mean difference from 
baseline in Cornea NEI scale scores of -3.9±2.2 in the rhNGF groups versus -2.9±2.2 in vehicle 
group (80% power, alpha =0.05; 2-sided test), considering that the active comparator has 
already proven safe and effective in dry eye patients. The sample size has been calculated based 
on a 2:1 randomization by the following formula:  
n1 = (0.5) × n × (1 + k) 
n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 76 and k= n1 /n2 = 2/1=2. Therefore n1= 114 
and n2=57.  Assuming a 5% drop out rate, a total of 120 patients will be enrolled in active arm 
and 60 in the vehicle arm. This calculation is based on one study eye per patient. Whereas also 
two study eyes per patient may occur, that will increase power to above 80%). 
 
Considering the two calculations performed to determine the sample size, in this study will be 
enrolled 180 patients (120 patients enrolled in active arm and 60 in the vehicle arm) in order to 
detect both changes at the same time in the variables. 
 
No adjustment for multiplicity has been made considering that rhNGF efficacy is to be 
evaluated on the contemporaneous change of both variables (see ICH-E9) 
 
 
 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
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Main selection criteria 
Inclusion Criteria: 
1. Male or female ≥18 years old 
2. Patients who are characterized by the following clinical features: 
a. History of cataract or refractive corneal surgery in the study eye(s) in the previous 
6 months; 
b. Mean Symptom Assessment in Dry Eye (SANDE) score for severity and frequency 
of at least 30 at baseline 
3. The same eye (study eye) must fulfill all the above criteria 
4. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at 
the time of study enrolment 
5. Female patients must have negative pregnancy urine test if at childbirth potential. 
6. Only patients who satisfy all requirements for informed consent may be included in the 
study. Written Informed Consent must be obtained before the initiation of any study-
specific procedures. 
7. Patients must have the ability and willingness to comply with study procedures. 
Exclusion Criteria: 
1. Any ocular disease other than Dry Eye requiring treatment with topical medications in either 
eye at the time of study enrolment. 
2. Any active ocular infection or active inflammation in either eye unrelated to Dry Eye. 
3. Presence or history of any systemic or ocular disorder, condition or disease (with particular 
attention to malignancies and neuro-oncological diseases) that could possibly interfere with 
the conduct of the required study procedures or the interpretation of the study results. 
4. Use of therapeutic or Refractive Contact lenses in either eye at the time of study enrolment; 
5. History of ocular surgery in the study eye(s), excluding corneal refractive or cataract 
procedures, within 90 days of study enrolment.  
6. Females of childbearing potential (those who are not surgically sterilized or post-
menopausal for at least 1 year) are excluded from participation in the study if they meet any 
one of the following conditions:  
a. are currently pregnant or,  
b. have a positive result at the urine pregnancy test (Baseline/Day 0) or,  
c. intend to become pregnant during the study treatment period or,  
d. are breast-feeding or, 
e. are not willing to use highly effective birth control measures, such as: hormonal 
contraceptives - oral, implanted, transdermal, or injected - and/or mechanical barrier 
methods - spermicide in conjunction with a barrier such as a condom or diaphragm 
or IUD - during the entire course of and 30 days after the study treatment periods.  
7. Participation in another clinical study at the same time as the present and within 30 days of 
study enrolment;  
8. History of drug, medication or alcohol abuse or addiction. 
Data analysis 
Statistical analysis of demographic, efficacy and safety data will be defined in the statistical 
analysis plan and will be performed using SAS, Version 9.1.3 Service Pack 4 for Windows (or 
higher). The data documented in this study will be summarized using classic descriptive 
statistics for quantitative variables and frequencies for qualitative variables. 
Details on the final study analysis will be provided in the study Statistical Analysis Plan. 


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 9 of 59 
Study Schedule 
 
 
 
 
Study procedures 
Baseline 
Visit  
(Day 0) 
Week 4 
(Day 28±2) 
Week 8** 
(ETV)   
(Day 56±2) 
Week 12 
(Follow-up Visit) 
(Day 84±2) 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
 
Randomization 
X 
 
 
 
Demographics 
X 
 
 
 
Ocular and General Medical 
History 
X 
 
 
 
Previous and Concomitant 
Ocular And Systemic 
Medications 
 
X 
 
X 
X 
X 
Frequency of artificial tear use 
X 
X 
X 
X 
Record Adverse Events (AEs) 
X 
X 
X 
X 
Verify patient study medication 
dosing compliance 
 
X 
X 
 
SANDE  questionnaire 
X 
X 
X 
X 
Best Corrected Distance  Visual 
Acuity (BCDVA) 
X 
 
X 
X 
Cochet-Bonnet aesthesiometry 
X 
 
X 
 
External Ocular Examination 
X 
X 
X 
X 
Slit Lamp Examination (SLE) 
X 
X 
X 
X 
Fluorescein staining (NEI scale) 
X 
X 
X 
X 
Tear Film Break-up Time 
(TFBUT) 
X 
X 
X 
X 
Corneal confocal microscopy* 
X 
 
X 
 
Study drug dispensation 
 X  
X  
 
 
* Only for patients who underwent LASIK surgery 
** ETV – Early Termination  Visit to be performed according to Visit Week 8 procedures, if 
premature treatment discontinuation occurs. 
Note: Patient diary will be reviewed for potential AEs, and details as applicable 
Abbreviations:  SANDE - Symptom Assessment In Dry Eye  


 
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rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 10 of 59 
 
TABLE OF CONTENTS 
 
Page 
STUDY SYNOPSIS 
4 
STUDY SCHEDULE 
9 
1 
INTRODUCTION 
14 
1.1 
Background Information 
14 
 
Nerve growth factor - overview 
14 
 
Chemical and formulation data 
14 
 
Previous experience in humans with rhNGF 
14 
1.2 
Study Rationale 
15 
 
Dose and Schedule Rationale 
15 
1.3 
Risks and benefits 
16 
2 
STUDY OBJECTIVES 
17 
2.1 
Primary efficacy end-point 
17 
 
Co-primary efficacy end-point 
17 
2.2 
Secondary efficacy end-points 
17 
2.3 
Safety end-point 
18 
3 
CLINICAL SUPPLIES 
19 
3.1 
Treatment 
19 
 
Description of products 
19 
 
Dose regimen 
19 
 
Route and method of administration 
19 
3.2 
Packaging, labelling, distribution and storage 
20 
 
Formulation and packaging 
20 
 
Labelling, Storage and handling 
20 
 
Storage and handling 
21 
3.3 
Drug accountability 
22 
4 
INVESTIGATIONAL PLAN 
23 
4.1 
Overall study design 
23 
4.2 
Discussion of design 
23 
5 
STUDY POPULATION 
24 
5.1 
Target population 
24 
5.2 
Inclusion criteria 
24 
5.3 
Exclusion criteria 
24 
 
History of drug, medication or alcohol abuse or addiction.Allowed/Disallowed 
treatments 
25 
6 
STUDY SCHEDULE 
26 
6.1 
Study visits and procedures 
26 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
30 
7.1 
Ophthalmological Evaluations 
30 
 
External Ocular Examination 
30 
 
Symptom Assessment in Dry Eye (SANDE): 
30 
 
Best corrected distance visual acuity (BCDVA): 
30 
 
Slit-lamp examination (SLE) 
32 
 
Tear Film Break Up Time (TFBUT) 
33 
 
Corneal sensitivity 
33 
 
Ocular surface staining (NEI score) 
34 
 
Corneal confocal microscopy (only for patients who underwent LASIK surgery) 
34 
8 
ASSIGNMENT OF STUDY TREATMENT 
35 
8.1 
Randomization 
35 
8.2 
Treatment allocation 
35 


 
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Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
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8.3 
Masking 
35 
9 
EVALUATION PARAMETERS 
36 
9.1 
Study variables 
36 
 
Primary variables 
36 
 
Co-primary variable 
36 
 
Secondary variables 
36 
10 
STATISTICAL METHODS 
37 
10.1 
Analysis Sets 
37 
 
Definitions 
37 
 
Reasons for exclusion from the Full Analysis Set 
37 
 
Reasons for exclusion from the Per Protocol set 
38 
10.2 
Sample size and power considerations 
38 
10.3 
Compliance with IMP administration 
39 
10.4 
Demographic, baseline and background characteristics 
39 
10.5 
Analysis of ophthalmological evaluations 
39 
10.6 
Safety and tolerability evaluation 
40 
11 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
41 
11.1 
Definition and handling of AEs and SAEs 
41 
 
Adverse Events 
41 
 
Adverse Drug Reaction 
41 
 
Serious Adverse Event (SAE) 
41 
 
Suspected serious unexpected adverse reaction 
42 
11.2 
Adverse Events of Special Interest (Sight-threatening Events) 
42 
11.3 
Adverse Events (AE) Monitoring 
43 
11.4 
Recording 
43 
11.5 
Serious Adverse Event Reporting 
44 
 
Reporting Procedure for Investigators to Sponsor or CRO 
44 
 
Conditions that should not be reported as serious adverse events 
46 
 
Reporting Procedure to IEC and to Regulatory Authorities 
46 
11.6 
Follow-up of Patients with Adverse events 
47 
11.7 
Pregnancy in the Clinical Trial 
47 
11.8 
Adverse Events Causing Treatment Discontinuation 
47 
11.9 
Overdose 
48 
12 
DATA MANAGEMENT PROCEDURES 
49 
12.1 
Data collection – eCRFs 
49 
12.2 
Unique subject identifier 
49 
12.3 
Database management 
49 
 
Coding dictionaries 
50 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
51 
13.1 
Monitoring 
51 
13.2 
Quality Control and Quality Assurance 
51 
13.3 
Applicable SOPs 
51 
13.4 
Data access 
51 
13.5 
Audits and inspections 
52 
14 
ETHICAL CONSIDERATIONS 
53 
14.1 
Ethics and Good Clinical Practice (GCP) 
53 
14.2 
Informed consent 
53 
14.3 
Insurance policy 
54 
14.4 
Withdrawal of patients 
54 
 
Primary reason for discontinuation 
54 
 
Discontinuation procedures 
54 
 
Replacement 
55 
14.5 
Study termination 
55 
15 
ADMINISTRATIVE PROCEDURES 
56 


 
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Final Version 3.0 12 Apr 2017 
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15.1 
Protocol amendments 
56 
15.2 
Study documentation and record keeping 
56 
15.3 
Confidentiality and data protection 
56 
15.4 
Publication policy 
57 
15.5 
Liability Statement 
57 
15.6 
Financing of the Study 
58 
15.7 
Responsibilities of the Investigator 
58 
15.8 
Final study report 
58 
16 
REFERENCES 
59 
 TABLES 
 Page 
Table 3.2.1.1 
Investigational Medicinal Product delivery plan ............................................................ 20 
Table 11.4.1 
Relationship of the Adverse Event to the Investigational Product ................................. 44 
Table 11.4.2 
Intensity (Severity) of the Adverse Event ...................................................................... 44 
 


 
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Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
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 LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BCDVA 
Best Corrected Distance Visual Acuity 
CDISC 
Clinical Data Interchange Standards Consortium 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organisation 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
iv 
intravenous 
LNGFR 
Low-Affinity Nerve Growth Factor Receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Millimetres  
mNGF 
Murine Nerve Growth Factor 
μg 
Micrograms 
NA 
Not Applicable 
NEI 
National Eye Institute 
NGF 
Nerve Growth Factor 
NK 
Neurotrophic Keratitis  
OTC 
Over The Counter 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
PR 
Pulse rate 
rhNGF 
Recombinant human nerve growth factor 
RP 
Retinitis Pigmentosa 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment In Dry Eye 
SBP 
Systolic Blood Pressure 
SLE 
Slit Lamp Examination 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
TFBUT 
Tear Film Break Up Time 
trkA 
neurotrophic tyroSine kinase receptor type 1 
VA 
Visual Acuity 
VAS 
Visual analogical scale 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 


 
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Final Version 3.0 12 Apr 2017 
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1 
 INTRODUCTION 
1.1 
Background Information 
 
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: TrkA, a transmembrane tyrosine kinase and p75 LNGFR 
(for "low-affinity nerve growth factor receptor") often abbreviated as 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 humour. 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. 
 
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 has 
been developed. However, because the biological activity of NGF relies on the formation of 
three disulphide bonds and because disulphide 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 pro-NGF. After expression of pro-NGF in E. 
coli, the insoluble protein is isolated in the form of insoluble inactive aggregates (inclusion 
bodies), solubilised in a strong denaturing agent and subsequently converted into the natural 
conformation, which is determined by the disulphide bridges present in the natural NGF. 
Biologically active rhNGF is finally obtained by splitting off the prosequence by enzymatic 
cleavage. The 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 rh-NGF preparation 
during the process with the mature protein starting with Serine 105. 
The Investigational Medicinal Product (IMP) consists of a sterile isotonic solution for ocular 
administration (containing L-methionine as excipient), containing rhNGF at 20 µg/mL i.e. 
0.020 mg/mL) as drug substance.  
 
Previous experience in humans with rhNGF 
NGF acts through specific high affinity (i.e., TrkA) and low affinity (i.e., p75NTR) NGF 
receptors which are expressed not only on nerve fibres but also on anterior segment of the eye 
(iris, ciliary body, lens, cornea and conjunctiva) and by the lacrimal gland providing the 
rationale for use of NGF in the treatment of diseases of the anterior segment of the eye. Murine 
NGF (mNGF) extracted and purified from the male mouse submaxillary gland was 
administered to over a hundred patients (45 published) with stage 2 and stage 3 neurotrophic 


 
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keratitis (NK) in form of eye drops at a concentration of 200 µg/mL in balanced salt solution in 
two uncontrolled, unmasked, open-label studies. Compelling results were observed with all 
affected eyes healed from persistent epithelial defects. Tolerability was good with only mild, 
local and transient side effects. As for dry eye disease, administration of NGF to dogs where 
dry eye had been surgically induced resulted in enhanced production and functional 
characteristics of tear film, with an associated improvement of ocular surface signs. 
Based on these data, Dompé has developed a recombinant human NGF (rhNGF) expressed in 
E. coli for treatment of NK. 
A phase I, masked placebo controlled clinical study in 74 healthy volunteers after single and 
multiple dose of different concentrations of rhNGF eye drops showed a safety profile rhNGF 
eye drops (Study NGF0112). A Phase I/II multicentre, double-masked, vehicle controlled study 
to evaluate the safety and efficacy of rhNGF at 10 and 20 μg/mL six times a day in 174 patients 
with stage 2 and 3 NK (study NGF0212) has been completed in 2015 demonstrating that rhNGF 
was very well tolerated also in patients with NK. 
In addition to NK, rhNGF, in the same formulation (containing L-methionine) proposed for the 
present study, has been evaluated in a Phase I/II study in retinitis pigmentosa (RP) patients at 
the doses of 60 and 180 μg/mL and in a phase II study in neurotrophic keratitis patients at the 
same concentration of the present study, 20 μg/mL (6 times a day). 
An open uncontrolled study showed that 4 weeks treatment with rhNGF eye drops at 20 μg/mL 
and 4 μg/mL) concentrations was safe and effective in improving symptoms, corneal staining 
and tear function in patients with dry eye as compared to baseline (NGF0213). 
1.2 
Study Rationale 
The data reported above, together with the evidence of rhNGF eye drop effectiveness in the 
treatment of patients affected by corneal ulcers and dry eye disease make rhNGF a strong 
candidate for the treatment of patients who underwent cataract and corneal refractive surgery, 
both known to damage the corneal sensory nerve plexus. 
As part of the development plan to evaluate the potential efficacy of the rhNGF solution, the 
present exploratory study was designed in order to further evaluate the potential efficacy and 
safety of rhNGF eye drops in this population of patients. 
For additional information regarding the development of rhNGF, please consult the current 
Investigator Brochure. 
 
Dose and Schedule Rationale 
The dose proposed for this trial is 20 µg/mL (1 drop/eye, six times daily for 8 weeks). 
In previous studies with Dompé rhNGF in human volunteers, the compound has been 
administered in a wide range of doses after single and multiple administrations up to 180 µg/mL 
(three times daily for five days, one eye).  
In the Phase I/II of the NK studies (NGF0212 and NGF0214), rhNGF administered at 20 µg/mL 
(six times daily for 8 weeks, one eye) demonstrated to be safe and well tolerated at this dose 
regime.  


 
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1.3 
Risks and benefits 
In the present study, potential risks of multiple rhNGF applications to post cataract and 
refractive surgery patients are expected not to surpass in frequency the adverse reactions and 
the untoward effects reported in the Phase I study (NGF0112). 
The post cataract and refractive surgery patients participating in this study may potentially 
benefit from the application of rhNGF for 56 days and restoration of the damages to the corneal 
sensory nerve plexus associated with the surgery.  


 
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2 
 STUDY OBJECTIVES 
The primary objective of this study is to assess the preliminary efficacy and safety of rhNGF 
when administered as eye drops to patients who underwent cataract and corneal refractive 
surgery. 
2.1 
Primary efficacy end-point 
Following refractive surgery, due to the iatrogenic surgical damage to corneal sensory nerves, 
a variable percentage of patients complain of dry eye symptoms that often do not correlate with 
specific ocular surface signs. 
Therefore, a validated symptoms' questionnaire has been chosen to assess the preliminary 
efficacy of rhNGF eye drops in this clinical trial. 
The two-item SANDE (Symptom Assessment in Dry Eye) is a validated questionnaire that has 
been widely reported to be quick, easy to perform for patients, and equally efficacious in scoring 
dry eye symptoms compared with the Ocular Surface Disease Index (OSDI), another validated 
questionnaire based on 12 questions that is commonly used in clinical trials on dry eye patients. 
However, while OSDI is designed for ocular surface disease in general, the SANDE 
questionnaire is designed specifically for dry eye symptoms, which are those commonly 
reported after corneal and refractive surgery procedures, including cataract surgery. 
 
Preliminary evaluation of the clinical efficacy throughout the study on the basis of the following 
symptoms assessment: 
 Change from baseline in SANDE scores for severity and frequency assessed at 8 weeks of 
treatment  
 Assessments of SANDE score will be performed on days 0, 28±2, 56±2 and 28±2 days 
after discontinuation of treatment. 
 
Co-primary efficacy end-point 
Preliminary evaluation of the clinical efficacy throughout the study on the basis of the following 
sign assessment: 
 Changes in Cornea vital staining with fluorescein (National Eye Institute [NEI] scales) 
assessed at 8 weeks of treatment 
2.2 
Secondary efficacy end-points 
Additional evaluation of the clinical efficacy throughout the study will be performed on the 
basis of the following assessments: 
 Changes in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute 
[NEI] scales) 
 Changes in Tear Film Break-Up Time (TFBUT) 


 
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 Changes in Cochet-Bonnet corneal aesthesiometry 
 Changes in Nerve count and morphology at scanning laser in vivo corneal confocal 
microscopy (only patients who had LASIK surgery) 
 Changes in SANDE scores (face values) for severity and frequency 
2.3 
Safety end-point 
 Incidence and frequency of Treatment-emergent adverse events (TEAEs), assessed 
throughout the study 


 
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3 
 CLINICAL SUPPLIES 
3.1 
Treatment 
 
Description of products 
The analytical certificates will be enclosed with the investigational medicinal product (IMP).  
Test product 
TEST PRODUCT 
 
IMP 
Recombinant human Nerve Growth Factor (rhNGF), 
containing L-methionine as excipient 
- 
20 μg/mL vials (Group 1), 
- 
Vehicle vials (Group 2) 
Manufacturer active 
substance 
Dompé farmaceutici S.p.A., Italy 
Manufacturer 
finished product 
Bulk drug product manufactured by Patheon Italia S.p.A-
Italy; 
Packaging and labelling performed by Monteresearch s.r.l. 
Italy 
Pharmaceutical form 
sterile buffered aqueous solution 
Dose 
6 times per day for 8 weeks 
Administration route 
Ophthalmic  
 
Dose regimen 
The maximum dosing scheme of the different study groups is summarized in the following 
table: 
 
Group 
Doses to be 
tested 
Dose (µg / day / eye) 
Total daily dose (µg)/ 
both eyes 
Total dose 
(µg)/both eyes 
in 56 days 
Group 1 
20 µg/mL(a) 
4.80 µg 
9.60 µg 
537.6 µg 
Group 2 
Not 
Applicable 
Not Applicable 
Not Applicable 
Not Applicable 
(a) 1 drop/eye=40 µL 
 
Route and method of administration 
Administration route and dose regimen for Groups 1 and 2 will be as follows:  


 
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Group 1: rhNGF 20 µg/mL: One drop (40 µL) corresponding to 0.80 µg of rhNGF will be 
instilled into each eligible eye six (both eyes, if applicable) times a day (every 2h), for a total 
daily dose of 9.6 µg (both eyes, if applicable), for 56 consecutive days. Total dose will be 537.6 
µg/56 days if both eyes are treated.  
 
Group 2: Vehicle: One drop (40 µL) will be instilled into each eligible eye (both eyes, if 
applicable) six times a day (every 2h). 
 
Enrolled patients will self-administer the eye drops at home into both eyes unless only one eye 
meets the eligibility criteria (in both group 1 and 2). 
The Investigator will check that all patients take the IMP appropriately verifying the diary and 
the used and/or unused medication returned. 
3.2 
Packaging, labelling, distribution and storage 
 
Formulation and packaging 
The Investigator will be provided with frozen IMP solutions (-20 ± 5°C) containing rhNGF at 
20 µg/mL (for the dosing Group 1) and vehicle (for group 2) in one monthly box containing 4 
weekly boxes. 
One monthly box including four weekly boxes containing the treatments for each day will be 
delivered to the patient at each study visit according to the following scheme: 
Table 3.2.1.1 
Investigational Medicinal Product delivery plan 
Box delivery  
Boxes to be provided 
Day 0  
Week 1, Week 2, Week 3, Week 4 (Day 0 - Day 28 ± 2) - 1 Box rhNGF/Vehicle 
Day 28 ± 2 
Week 5, Week 6, Week 7, Week 8 (Day 29 - Day 56 ± 2) - 1 Box rhNGF/Vehicle 
 
Each weekly box will contain a total of 7 vials of rhNGF (Group 1) or Vehicle (Group 2). 
 
Labelling, Storage and handling 
Labelling 
The medication labelling will report all the information requested according to the Annex 13 to 
the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4) as follows: 
a. 
Name, address and telephone number of the Sponsor, contract research organisation or 
Investigator (the main contact for information on the product, clinical study) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the 
case of open studies, the name and strength 
c. 
The batch code number to identify the contents and packaging operation 


 
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d. A study reference code allowing identification of the study, site, Investigator and Sponsor 
if not given elsewhere 
e. 
The study patient identification study number and where relevant, the treatment period  
f. 
Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study patient or person administering the product) 
g. “For clinical study use only” or similar wording 
h. The storage conditions 
i. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
j. 
“Keep out of reach of children” 
 
Labels will be in local language. 
 
Storage and handling 
The Pharmacist and/or Investigator will be responsible for receipt, proper storage and usage of 
study drug.  
The investigational product must be stored at -20 ± 5 °C at the Investigational sites, in an 
appropriate locked room accessible only to the pharmacist, the Investigator or a duly designated 
person.  
A temperature probe and data logger will accompany the drug on shipment. It is essential that 
the Investigational sites will verify the temperature excursion during shipment vs. the 
acceptable storage conditions, in order to identify potential stability concerns during shipment. 
These must be immediately communicated to the Sponsor that will decide upon appropriate 
actions to be taken. The IMP will be stored in a locked place, sheltered from light. The vials 
will be not shaken since agitation of vials may cause foaming and/or particle formation.  
On Day 0 and at Week 4 visits the patients will receive from the study personnel 4 weekly 
boxes containing the study medications in a refrigerated bag. The refrigerated bag will be used 
to ensure that the medications will maintain refrigeration temperatures during transport to the 
patient’s home.  
Patient should bring the study medication, one monthly box containing 4 weekly kits, at home 
as soon as possible and immediately store it in a freezer at -20 ± 5 °C. 
The weekly kit in use must be kept at 2-8°C for 7 days, the daily vial can be kept at room 
temperature before the patient will use the single vial for each instillation (both eye) as far as 
12 hours are not exceeded.  
Together with the IMP weekly box, the patients will be provided with a sufficient number of 
syringes and adaptors to be used for the administration of the IMP for the following 4 weeks. 
Syringes and adaptors will be provided separately in single sterile PE 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. Patients will need to: 


 
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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 
5) the syringe must be discharged after each administration to both eyes, if applicable 
3.3 
Drug accountability 
After receipt of the IMP supply, the pharmacist and/or Investigator will confirm in writing by 
signing and dating standard drug accountability forms. 
Every four weeks from the start of the treatment the patients will return the used or unused 
study boxes to the Investigator.  
The Pharmacist and/or Investigator, who will keep a cumulative inventory and dispensing 
records, will maintain all supplies under adequate security.  
The Investigator will maintain an accurate record about the shipment and dispensing of the test 
drug, using a drug accountability ledger. An accurate drug disposition record will be kept 
specifying the date and amount dispensed to each patients.  
Adequate record of receipt, use, return 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 the CRO at the conclusion of the study. 
At each scheduled visit the diary should be reviewed with the patient for completeness. Missing 
information should not be provided during the diary check but reported as missing 
Partially used or unused study drug boxes will be returned to the Sponsor, at the end of the 
study.  
At the conclusion of the study, and if appropriate during the course of the study, the Investigator 
will complete the drug accountability forms. Within one month after completion of the trial the 
unused study medication will be shipped to the Sponsor or will be destroyed after authorisation 
by the Sponsor by an authorised company according to GCP regulations. 


 
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4 
 INVESTIGATIONAL PLAN 
4.1 
Overall study design 
This is a Phase II study, single-centre, randomized, double masked, parallel arm, vehicle-
controlled trial. 
Randomization will be 2:1 of 180 post cataract or refractive surgery patients to rhNGF eye 
drops solution at 20 µg/ml (120 patients) or vehicle eye drops solution (60 patients) 6 times per 
day for 8 weeks. 
The patients will be involved in the study for a maximum of 12 weeks from Day 0 visit to Week 
12 follow-up visit.  
4.2 
Discussion of design 
The proposed phase II study is a single-centre, randomized, double masked, parallel arm, 
vehicle-controlled trial, designed to evaluate the preliminary efficacy and safety of rhNGF eye 
drops at 20 µg/ml concentration administered six times daily for 8 weeks in patients’ eyes who 
underwent cataract and corneal refractive surgery, both known to damage the corneal sensory 
nerve plexus. 
Patients will be evaluated at baseline (day 0), week 4 (282 days), week 8 (day 56±2) or early 
exit and 4 weeks (day 842) after the end of study treatment. 


 
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5 
 STUDY POPULATION 
5.1 
Target population 
Male and female patients ≥ 18 years old, who had undergone post cataract and refractive 
surgery. 
5.2 
Inclusion criteria 
To be enrolled in this study, patients must fulfil all these criteria: 
1. Male or female ≥18 years old 
2. Patients who are characterized by the following clinical features: 
a. History of cataract or refractive corneal surgery in the study eye(s) in the previous 
6 months; 
b. Mean Symptom Assessment in Dry Eye (SANDE) score for severity and frequency 
of at least 30 at baseline 
3. The same eye (study eye) must fulfill all the above criteria 
4. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at 
the time of study enrolment 
5. Female patients must have negative pregnancy urine test if at childbirth potential. 
6. Only patients who satisfy all requirements for informed consent may be included in the 
study. Written Informed Consent must be obtained before the initiation of any study-
specific procedures. 
7. Patients must have the ability and willingness to comply with study procedures. 
5.3 
Exclusion criteria 
Patients meeting any of these criteria will not be enrolled in the study: 
1. Any ocular disease other than Dry Eye requiring treatment with topical medications in 
either eye at the time of study enrolment. 
2. Any active ocular infection or active inflammation in either eye unrelated to Dry Eye. 
3. Presence or history of any systemic or ocular disorder, condition or disease (with particular 
attention to malignancies and neuro-oncological diseases) that could possibly interfere with 
the conduct of the required study procedures or the interpretation of the study results. 
4. Use of therapeutic or Refractive Contact lenses in either eye at the time of study enrolment; 
5. History of ocular surgery in the study eye(s), excluding corneal refractive or cataract 
procedures, within 90 days of study enrolment.  
6. Females of childbearing potential (those who are not surgically sterilized or post-
menopausal for at least 1 year) are excluded from participation in the study if they meet any 
one of the following conditions:  
a. are currently pregnant or,  
b. have a positive result at the urine pregnancy test (Baseline/Day 0) or,  
c. intend to become pregnant during the study treatment period or,  
d. are breast-feeding or, 


 
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e. are not willing to use highly effective birth control measures, such as: hormonal 
contraceptives - oral, implanted, transdermal, or injected - and/or mechanical barrier 
methods - spermicide in conjunction with a barrier such as a condom or diaphragm or 
IUD - during the entire course of and 30 days after the study treatment periods.  
7. Participation in another clinical study at the same time as the present and within 30 days of 
study enrolment;  
8. History of drug, medication or alcohol abuse or addiction. 
 
History of drug, medication or alcohol abuse or 
addiction.Allowed/Disallowed treatments 
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". 
Any systemic or topical ocular treatment is allowed, as prescribed by the treating physician 
both during treatment and follow-up periods. 
 


 
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6 
 STUDY SCHEDULE 
The schedule of the study is summarized at the end of the synopsis (page 9). 
6.1 
Study visits and procedures 
Each enrolled patient will undergo 4 visits. 
Maximum study duration will be 12 weeks, Baseline/Day 0 visit included. A written informed 
consent will be obtained before any study assessment or procedure. 
The first patient first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened patient. The last patient last visit (LSLV) is defined as the last visit performed 
at the clinical centre (or the telephonic follow-up, if applicable) by the last patient, i.e. the last 
visit foreseen by the study protocol, independently of the fact that the patient is a completer or 
a withdrawn patient. 
The following phases, visits and procedures will be performed: 
 
 Interventional phase 
 Baseline/Day 0 Visit - Day 0 
 Week 4 Visit - Day 28 ± 2 
 Week 8 Visit - Day 56 ± 2/Early Termination Visit (ETV). In case of study 
discontinuation patients will undergo the assessments foreseen at Week 8 visit. 
 
 Follow-up phase 
 Week 12 Visit Follow-Up - Day 84 ± 2 
 
 


 
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Day 
Procedures/Assessments 
Baseline Visit 
Day 0 
 Explanation to the patient of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number allocation (as S001, S002, etc.) 
 Demographic data 
 Medical and surgical history/current medical conditions 
 Prior/concomitant medications 
 AE monitoring 
 Ocular examination of both eyes: 
1. Assessment by Symptom Assessment iN Dry Eye (SANDE) 
2. Assessment of best corrected distance visual acuity (BCDVA) 
3. Slit lamp examination (SLE) to assess the Eyelid - Meibomian glands, 
Eyelid – Erythema, Eyelid - Oedema Lashes, Conjunctiva Erythema, Lens, 
Iris, Anterior Chamber 
4. External Ocular Examination 
5. Corneal Confocal Microscopy (Only for patients who underwent LASIK 
surgery) 
Ten minutes break 
6. Tear Film Break Up Time (TFBUT) 
Five minutes break 
7. Corneal sensitivity (Cochet-Bonnet)  
Ten minutes break  
8. Ocular surface staining (NEI score) 
Ten minutes break  
 Frequency of patient’s own artificial tear use (to be reported in eCRF) 
 Pregnancy test for female patients. 
 Patient eligibility: Inclusion/exclusion criteria evaluation 
 Assignment of study eye(s) (Note: if both eyes are eligible, study treatment 
will be administered to both eyes, and each eye will be considered as "study 
eye") 
 Randomization 
 Study Drug Dispensation 
 
Note: At the study visit the Investigator will provide each patient with diary and 
one monthly box of the study drug for the following 4 weeks together with an 
adequate number of adaptors and syringes. 
After visit completion patients will start topical ocular treatment as per 
instructions and will self-administer at home the IMP. Patients will return to the 
clinical site on Day 28 ± 2 (Week 4 Visit). 
The patients will be instructed to fill in the diary with time of self-administration, 
potential AE occurrence, concomitant medication intake and the quantity of 
artificial tears used, and to return the refrigerated box on the Week 4 visit. 
At home  
Days 0-
28±2 
 Self-administration at home of the IMP, six times daily every 2 h in every 
study eye (diary) 
 Artificial tears use (diary) 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
Data will be recorded by the patient on the patient’s diary. 


 
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Day 
Procedures/Assessments 
Week 4 Visit  
Day 28±2 
 Assessment of compliance to treatment (from patient diary and IMP 
reconciliation from returned weekly boxes) 
 Current medical conditions 
 Concomitant medications 
 AE monitoring 
 Ocular examination of both eyes: 
1. Assessment by Symptom Assessment iN Dry Eye (SANDE) 
2. Slit lamp examination (SLE) to assess the Eyelid - Meibomian glands, 
Eyelid – Erythema, Eyelid - Oedema Lashes, Conjunctiva Erythema, Lens, 
Iris, Anterior Chamber 
3. External Ocular Examination 
Ten minutes break 
4. Tear Film Break Up Time (TFBUT) 
Ten minutes break  
5. Ocular surface staining (NEI score) 
Ten minutes break  
 Frequency of patient’s own artificial tear use (to be reported in eCRF) 
 Pregnancy test for female patients. 
 Study Drug Dispensation 
 
Note: At the study visit the Investigator will provide each patient with diary and 
one monthly box of the study drug for the following 4 weeks together with an 
adequate number of adaptors and syringes. 
After visit completion the patients will continue study treatment as per 
instructions and will self-administer at home the IMP. Patients will return to the 
clinical site on Day 56 ± 2 (Week 8 Visit). 
The patients will be instructed to fill in the diary with time of self-administration, 
potential AE occurrence, concomitant medication intake and the quantity of 
artificial tears used. 
At home 
Days 28±2 
-56±2 
 Self-administration at home of the IMP, six times daily every 2 h (diary) in 
every study eye 
 Artificial tears use (diary) 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
Data will be recorded by the patient on the patient’s diary. 


 
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Day 
Procedures/Assessments 
Week 8 Visit 
Day 56±2 
 
Or 
 
Early 
termination 
(if 
applicable) 
In case of study early discontinuation (at any time) patients will undergo the 
assessments foreseen at Week 8 visit. 
 
 Compliance to treatment (from patient diary and control of returned weekly 
boxes) 
 current medical conditions 
 concomitant medications 
 AE monitoring 
 Ocular examination in both eyes: 
1. Assessment by Symptom Assessment iN Dry Eye (SANDE) 
2. Assessment of best corrected distance visual acuity (BCDVA) 
3. Slit lamp examination (SLE) to assess the Eyelid - Meibomian glands, 
Eyelid – Erythema, Eyelid - Oedema Lashes, Conjunctiva Erythema, Lens, 
Iris, Anterior Chamber 
4. External Ocular Examination 
5. Corneal Confocal Microscopy (Only for patients who underwent LASIK 
surgery) 
Ten minutes break 
6. Tear Film Break Up Time (TFBUT) 
Five minutes break 
7. Corneal sensitivity (Cochet-Bonnet)  
Ten minutes break  
8. Ocular surface staining (NEI score) 
Ten minutes break  
 Frequency of patient’s own artificial tear use (to be reported in eCRF) 
 Pregnancy test for female patients. 
 
Note: The Investigator will deliver to the patients the diary. 
Patients will return to the clinical site on Day 84 ± 2 (Week 12 Visit). 
The patients will be instructed to fill in the diary with AE occurrence, concomitant 
medication intake and the quantity of artificial tears used. 
At home 
Days 56±2-
84±2 
 Artificial tears use (diary) 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
Data will be recorded by the patient on the patient’s diary. 
Week 12 Visit 
Follow-Up 
Day 84±2 
 Current medical conditions 
 Prior/concomitant medications 
 AE monitoring 
 Ocular examination in both eyes: 
1. Assessment by Symptom Assessment iN Dry Eye (SANDE) 
2. Assessment of best corrected distance visual acuity (BCDVA) 
3. Slit lamp examination (SLE) to assess the Eyelid - Meibomian glands, 
Eyelid – Erythema, Eyelid - Oedema Lashes, Conjunctiva Erythema, Lens, 
Iris, Anterior Chamber 
4. External Ocular Examination 
Ten minutes break 
5. Tear Film Break Up Time (TFBUT) 
Ten minutes break  
6. Ocular surface staining (NEI score) 
Ten minutes break  
 Frequency of patient’s own artificial tear use (to be reported in eCRF) 
 


 
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7 
 DESCRIPTION OF SPECIFIC PROCEDURES 
7.1 
Ophthalmological Evaluations 
Ocular evaluations will be performed on both eyes even if just one eye is eligible (determined 
as study eye). The assessments must always be performed according the sequence detailed in 
Par 6.1. The assessment will be performed at Day 0 Baseline Visit, Week 4 Visit, Week 8 Visit 
and at Week 12 Visit.  The ophthalmological assessment will include: 
 
External Ocular Examination 
External Ocular Examination assesses the motility of the extraocular muscles and the 
appearance and function of the eyelids before the instillation of any dilating or anaesthetic eye 
drops. 
 
Symptom Assessment in Dry Eye (SANDE): 
The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to 
evaluate both dry eye intensity and frequency by using a 100 mm VAS. The patient symptoms 
of ocular dryness and/or irritation will be quantified on the scale based on two questions that 
assess both severity and frequency of symptoms. A VAS is a measurement instrument that tries 
to measure a characteristic or attitude that is believed to range across a continuum of values and 
cannot easily be directly measured. For example, the amount of irritation that a patient feels 
ranges across a continuum from none to an extreme amount of irritation. From the patient's 
perspective this spectrum appears continuous (i.e. their irritation does not take discrete jumps, 
as a categorization of none, mild, moderate and severe would suggest). It was to capture this 
idea of an underlying continuum that the VAS was devised.  
For the assessment, the patients mark on the 100 mm VAS line the point that they feel represents 
their perception of their current state. The VAS score is determined by measuring in millimetres 
from the left hand end of the line to the point that the patient marks. The SANDE scores will 
be then evaluated for the 2 questions severity (0-100) and frequency (0-100). Note: the 
AVERAGE value of severity and frequency scores will be used for verifying inclusion 
criterion #2 at Day 0 visit. 
 
Best corrected distance visual acuity (BCDVA):  
Refraction and visual acuity measurements will be performed for all patients by trained vision 
examiners only. Refraction should be conducted prior to visual acuity testing to obtain best-
corrected vision as described below. Best-corrected visual acuity is measured at Day 0 Baseline 
Visit, Week 8 Visit and at Week 12 Visit 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. 


 
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Equipment 
Refraction equipment required includes:  
 Retroilluminated Light box and ETDRS 4 metre 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 metre 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. Patients should not be allowed to 
see any of the charts before the examination.  
A distance of 4 metres is required between the patient’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 centre 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 metre 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 patient 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.  
Retroilluminated ETDRS charts are used in this trial. The illuminator box will be either wall-
mounted 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 centred 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. Patients should not see the charts until the test begins. The lens correction from 
the patient’s refraction should be in the trial frame worn by the patient.  
All eyes must be tested at 4 metres first, even if the refraction was performed at 1 metre.  
The patient should be seated comfortably directly in front of the chart so that the eyes remain 
at the 4 metre distance. Testing always begins with the right eye. The fellow 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 


 
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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 patient is asked to read the letters slowly, approximately one letter per second. The patient 
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 patient is unsure about the identity of the letter, then the 
patient should be encouraged to guess.  
The patient 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 patient 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 patient reaches a level where he/she cannot 
guess, the examiner may stop the test, provided that the patient has made errors on previous 
guesses, which is a clear indication that the best visual acuity has been obtained.  
When a patient cannot read at least 20 letters on the chart at 4 metres, the patient is tested at 1 
metre. The distance from the patient to the chart should be measured again using the rigid one 
metre stick. The distance is measured from the outer canthus to the centre 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 
patient may fixate eccentrically or turn or shake his/her head to improve visual acuity. Particular 
care should be taken to make sure the patient does not move forward when testing at 1 metre. 
The patient should be reminded to blink. 
The examiner should not tell the patient if a letter was identified correctly. The patient 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 patient and the VA worksheet. If the patient 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.  
When 20 or more letters are read at 4 metres the visual acuity score for that eye is recorded as 
the number of letters correct at 4 metres plus 30 (refer to the VA worksheet). The patient gets 
credit for the 30 letters at 1 metre even though they did not have to read them. Otherwise, the 
visual acuity score is the number of letters read correctly at 1 metre plus the number, if any, 
read at 4 metres. If no letters are read correctly at either 4.0 metres or 1 metre, then the visual 
acuity score is recorded as “0.” 
 
Slit-lamp examination (SLE) 
The slit lamp examination must be performed before the instillation of any dilating or anesthetic 
eye drops or the fluorescein agent. 
The patient will be seated at the slit lamp while being examined. Eyelids, lashes, conjunctiva, 
cornea, lens, iris and anterior chamber will be evaluated.  


 
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Tear Film Break Up Time (TFBUT)  
TFBUT will be measured by determining the time to tear break-up. The TFBUT will be 
performed after instillation of 5 l of 2% sodium fluorescein solution into the inferior 
conjunctival cul-de-sac of each eye. The patient 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. 
Relevant TFBUT findings will be entered in the eCRF. 
 
Corneal sensitivity  
For the assessment of corneal sensation the Luneau Cochet-Bonnet aesthesiometer (Western 
Ophthalmics Corporation©) should be used. 
The Cochet-Bonnet aesthesiometer contains a thin, retractable, nylon monofilament that 
extends up to 6 cm in length. Variable pressure can be applied to the cornea by adjusting the 
monofilament length. The monofilament length ranges from 6 to 0.5 cm. As the monofilament 
length is decreased the pressure increases from 11 mm/g to 200 mm/g.  
Corneal sensation will be measured in both eyes in each of the four quadrants of the cornea 
using the Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye 
drops.  
Steps for using the Cochet Bonnet aesthesiometer: extend the filament of the aesthesiometer to 
full length of 6 cm. Slowly advance the monofilament towards the eye until the tip 
perpendicularly touches the corneal surface. Continue to exert a slight pressure until obtaining 
an inflection deviation of the filament of about 4% (i.e. the first visible inflection). If a positive 
reaction to the touch of cornea is elicited proceed to step 3. If a positive reaction is not achieved 
proceed to step 2. (NOTE: A positive response is any action indicating corneal sensation 
whether communicated verbally or physically).  
Retract the filament incrementally in 0.5 cm and repeat this step until the patient gives a positive 
reaction indicating that the contact of the monofilament on the cornea has been sensed. (NOTE: 
The shorter filament lengths indicate decreased corneal sensation). 
Record the length of the filament in cm at which the patient sensed the contact with the cornea. 
Repeat steps 1-3 in each of the 4 corneal quadrants (superior nasal, inferior nasal, superior, 
temporal and inferior temporal) in the study eye(s) and in each of the 4 corneal quadrants of the 
other eye (not the study eye, if applicable).  
To clean the instrument, please refer to your national standards for devices that contact the eye 
and tears or follow the suggested manufacturer’s recommendations.   


 
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The length of the filament in cm at which the patient corneal sensation was observed for the 
tested area of the cornea will be entered into the eCRF.  
Corneal sensitivity findings will be entered in the eCRF. 
 
Ocular surface staining (NEI score) 
As grading scale of the corneal and conjunctiva damage, the NEI/Industry Workshop guidelines 
will be used. 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.  
Ideally the grading should be performed between one and four minutes after staining. 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 
 
Corneal confocal microscopy (only for patients who underwent LASIK 
surgery) 
In vivo scanning confocal microscopy will be performed bilaterally in the central cornea to 
more closely examine the corneal epithelium, sub-basal nerve plexus, stroma and endothelium 
with particular attention given to the presence and density of corneal nerves. Prior to the 
procedure patients will be treated with anesthetic drops and a viscoelastic liquid gel will be 
applied to the cornea as an immersion substance for the microscope lens. 


 
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8 
ASSIGNMENT OF STUDY TREATMENT 
8.1 
Randomization 
After obtaining informed consent a consecutive screening number will be assigned to each 
patient according to the sequence of study entry, from S001 onwards (S002, S003 etc.). After 
confirming eligibility for the study, patient will be randomized (2:1 to rhNGF eye drops solution 
at 20 µg/ml (120 patients) or vehicle eye drops solution (60 patients) to be administered 6 times 
per day per study eye (or both eyes if applicable) for 8 weeks) and allocated with a consecutive 
randomization number of the randomization list starting with 001 onwards (002, 003 etc.). 
8.2 
Treatment allocation 
After successful completion of screening each eligible patient will be assigned a patient number 
(randomization number) according to the sequence of study entry (randomization), from 001 to 
180. Drop outs will not be replaced after randomization. 
8.3 
Masking 
For the whole duration of the trial treatments will be unknown to the patient, the Investigator 
and the site staff. The identity of the treatments will remain unknown to the patient, Investigator, 
site staff and Sponsor’s clinical research personnel until the study is unmasked for the final 
statistical analysis (data base lock) except in case of specific events that will require unmasking 
of the patient. 
The vials of rhNGF (20 µg/ml) and the vials containing the vehicle of rhNGF will be identical 
in appearance and the contents of the vials will be indistinguishable. All staff who is directly 
involved in the analysis of study results will remain masked to treatment assignments while the 
study is in progress. 
A list of sequential kit numbers will be generated by a member of the CRO SAS programming 
group not involved in the conduct of the study. Each kit number will be randomly associated 
with a treatment group. Patients will be assigned to treatment in numerical order. A tear-off 
label from the kit box, with the kit number, will be attached to the investigational product 
dispensing log. 
If the Investigator becomes unmasked for any reason, this information will be recorded on 
source data and in the eCRF of the study, specifying the date and the reason.  
In the event of a medical emergency where the knowledge of patient treatment is required to 
provide the patient with appropriate care, Investigators will have the possibility to unmask the 
treatment assignment for a specific patient.  If there is sufficient time, the Investigators are 
encouraged to contact the CRO staff to discuss individual case before unmasking concerned 
patient.  


 
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9 
EVALUATION PARAMETERS 
9.1 
Study variables 
 
Primary variables 
 Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 Symptom Assessment iN Dry Eye (SANDE) – mean changes from baseline will be 
evaluated for severity and frequency (for primary week 8 endpoint analysis, LOCF will be 
imputed for early end-of treatment data) 
 
Co-primary variable 
 Cornea vital staining with fluorescein (National Eye Institute [NEI] scales) – mean changes 
from baseline will be evaluated at week 8 for Co-primary endpoint analysis, LOCF will be 
imputed for early end-of treatment data) 
 
Secondary variables 
 Conjunctiva vital staining with fluorescein (National Eye Institute [NEI] scales) 
 Tear Film Break-Up Time (TFBUT) 
 Cochet-Bonnet corneal aesthesiometry 
 Nerve count and morphology at scanning laser in vivo corneal confocal microscopy (only 
patients who had LASIK surgery) 
 
Evaluations will be performed on week 4, week 8 and 4 weeks after discontinuation of treatment 
(week 12). 


 
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10 
STATISTICAL METHODS 
The data documented in this study will be summarized using descriptive summary statistics, 
i.e. arithmetic mean, SD, CV (%), minimum, median and maximum values for quantitative 
variables, and frequencies for qualitative variables. In case a patient has two study eyes, its 
quantitative efficacy data will be regarded as within subject duplicates, allowing more precise 
patient values as well as the splitting of the SD into a within-subject and between-subject 
component. 
The statistical analysis will be performed using SAS® version 9.1.3 Service Pack 4 for 
Windows® or higher.  
A statistical analysis plan (SAP) will be issued before database lock and de-masking. Final 
statistical analysis on the study primary, co-primary and secondary variables will be presented 
in detail in the SAP.  
10.1 
Analysis Sets 
 
Definitions 
A patient will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
A patient will be defined as eligible if he/she meets all the inclusion criteria and dose not fulfil 
any of the exclusion criteria for at least one eye (defined as study eye). Otherwise he/she will 
be defined as a screen failure.  
A patient will be defined as enrolled in the study if he/she is randomized.  
 Enrolled set: all enrolled patients.  
 Safety Set (SAF): all enrolled patients who receive at least one dose of the investigational 
medicinal product(s) at the study eye(s). This analysis set will be used for demographic, 
baseline and background characteristics and the safety analysis 
 Full Analysis Set (FAS): all patients in the SAF, who have at least one post-baseline 
efficacy measurement. This analysis set will be used for the primary and co-primary 
efficacy analysis. 
 Per Protocol set (PP): all patients in the FAS who fulfil the study protocol requirements in 
terms of investigational medicinal product intake and collection of primary and co-primary 
efficacy data and with no major deviations that may affect study results. This analysis set 
will be used for supportive efficacy analysis 
Each patient will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled Set, 
SAF, FAS and PP. Patients will be evaluated according to the treatment they will actually 
receive. 
 
Reasons for exclusion from the Full Analysis Set 
Reasons for the exclusion from the Full Analysis Set are the following: 


 
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 
failure to take at least one dose of the IMP at any study eye 
 
lack of any efficacy data post enrolment 
 
failure to satisfy major inclusion/exclusion criteria (eligibility violations). Patients who fail 
to satisfy an inclusion/exclusion criterion may be excluded from the analysis without the 
possibility of introducing bias only under the following circumstances: 
 
the inclusion/exclusion criterion was measured prior to enrolment 
 
the detection of the relevant eligibility violations can be made completely 
objectively 
 
all detected violations of the particular inclusion/exclusion criterion are excluded 
 
Reasons for exclusion from the Per Protocol set 
Reasons for the exclusion from the Per Protocol set will be determined in the Blind Data Review 
Meeting and can be the following: 
 
lack of compliance with IMP administration (see § 10.3) 
 
exposure to an IMP dose different from the one assigned to the patient 
 
missing primary or co-primary efficacy data 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
intake of prohibited medications 
10.2 
Sample size and power considerations 
Sample size was calculated by assuming at single eye level a mean difference from baseline 
mean SANDE scores of -30±20 in the rhNGF groups versus -20±20 in vehicle group (80% 
power, alpha =0.05; 2-sided test), considering that the active comparator has already proven 
safe and effective in dry eye patients. The sample size has been calculated based on a 2:1 
randomization by the following formula:  
n1 = (0.5) × n × (1 + k) 
n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 63 and k= n1 /n2 = 2/1=2. Therefore n1= 
94,5 and n2=47.25.  Assuming a 5% drop out rate, a total of 100 patients in the active arm and 
50 in the vehicle arm are required. This calculation is based on one study eye per patient. 
Whereas also two study eyes per patient may occur, that will increase power to above 80%). 
 
However, in order to provide the mean of detecting a significant difference also on a clinical 
sign of the effect of the rhNGF therapy (namely Co-primary Efficacy Endpoint cornea vital 
staining with fluorescein (National Eye Institute [NEI] scales)), sample size calculation was 
also performed by assuming, at single eye level, a mean difference from baseline in Cornea NEI 
scale scores of -3.9±2.2 in the rhNGF groups versus -2.9±2.2 in vehicle group (80% power, 
alpha =0.05; 2-sided test), considering that the active comparator has already proven safe and 
effective in dry eye patients. The sample size has been calculated based on a 2:1 randomization 
by the following formula:  
n1 = (0.5) × n × (1 + k) 


 
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n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 76 and k= n1 /n2 = 2/1=2. Therefore n1= 114 
and n2=57.  Assuming a 5% drop out rate, a total of 120 patients in active arm and 60 in the 
vehicle arm are required. This calculation is based on one study eye per patient. Whereas also 
two study eyes per patient may occur, that will increase power to above 80%). 
 
Considering the two calculations performed to determine the sample size, in this study will be 
enrolled 180 patients (120 patients enrolled in active arm and 60 in the vehicle arm) in order to 
detect both changes at the same time in the variables. 
 
 
10.3 
Compliance with IMP administration 
The assessment of patients’ compliance to the IMP will be made by determining the number of 
study medication vials dispensed to the patient at Day 0 baseline Visit, Week 4 Visit and the 
number of unused study medication vials returned at Week 4 Visit and Week 8 Visit, 
respectively. Compliance will be evaluated according to the following formula: 
 
 treatment
on
 
days
scheduled
of
Number
returned
 
 vials
unused
 
of
Number 
-
dispensed
 
 vials
of
Number 
Compliance 
 
 
Gross non compliance will be defined as compliance lower than 80% or greater than 120% and 
in case of non compliance the patient will be excluded from the Per Protocol Set (see § 10.1.3). 
Since this definition does not warrant that the study eye(s) treatment is compliant, if indicated 
the SAP will contain further definitions based upon the diary card information. 
10.4 
Demographic, baseline and background characteristics 
Demographic and baseline characteristics will be examined per treatment group according to 
qualitative or quantitative data. Qualitative data will be listed and summarized in contingency 
tables. Quantitative data will be listed and summarized using descriptive statistics. 
10.5 
Analysis of ophthalmological evaluations  
All efficacy variables will be summarized for all study eye(s) together using descriptive 
statistics for quantitative variables, and frequencies for qualitative variables by treatment and 
evaluation time point. Changes from baseline (Day 0 Baseline Visit assessment) will be 
presented as well, if applicable. 
No adjustment for multiplicity has been made considering that rhNGF efficacy is to be 
evaluated on the contemporaneous change of both variables (see ICH-E9). 
Additional details on the analyses will be provided in the statistical analysis plan. 


 
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10.6 
Safety and tolerability evaluation 
AEs 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
TEAEs are all events occurring or worsening after the first dose of the IMP. 
Individual AEs/TEAEs will be listed in patient data listings. TEAEs will be summarized by 
treatment. The number and percentage of patients with any AE and the number of TEAEs will 
be tabulated by SOC and PT, seriousness, relationship to treatment and severity.  


 
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11 
EVALUATION OF ADVERSE EVENTS AND SAFETY 
INFORMATION 
11.1 
Definition and handling of AEs and SAEs  
 
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
trial patient administered a medicinal product, which does not necessarily have a causal 
relationship with the study treatment (Directive 2001/20/EC). 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. 
 
Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is any noxious and unintended response to an Investigational 
Medicinal Product (IMP) which is a reasonably likely to have been caused by the drug, at any 
dose administered.   
For the purposes of reporting to the concerned Authorities, “reasonable possibility” means there 
are facts (evidence) or arguments to suggest a causal relationship between the drug and the 
adverse event (reference: par. 11.4 and 11.5). 
 
Serious Adverse Event (SAE)  
A serious adverse event (SAE) is defined in line with Directive 2001/20/EC as any adverse 
experience that meets any of the following criteria: 
 
 results in death 
 is life-threatening  
(NOTE: Life-threatening means that the patient was at immediate risk of death from the 
reaction as it occurred, i.e., it does not include 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 out-patient 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfils any other serious criteria, the event is serious. When 
in doubt as to whether “hospitalization” occurred, the event should be considered 
serious 
 


 
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 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, diarrhoea, 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 patient’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 
convulsions that do not result in patient hospitalization or the development of drug 
dependency or drug abuse) 
 
Pre-planned hospitalization or hospitalization for routine treatment or monitoring of the studied 
indication, not associated with any deterioration in condition are not considered to be SAEs 
(see Par. 11.5.2). These events must be recorded in the AE page of the eCRF where a variable 
will be ticked to indicate that they are not SAEs. 
If a SAE results in death, the event shall be reported as SAE and cause of death shall always be 
investigated and specified as soon as known, as applicable. 
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event or 
adverse drug reaction that does not meet the criteria listed above for a serious adverse 
event/serious adverse drug reaction. 
 
Suspected serious unexpected adverse reaction 
A Suspected Serious Unexpected adverse reaction (SUSAR) is defined as an adverse reaction 
that is both unexpected (not consistent with the applicable product information) and also meets 
the definition of a Serious Adverse Reaction. 
The determination of expectedness should be made on the basis of the IB. 
11.2 
Adverse Events of Special Interest (Sight-threatening Events) 
The following adverse events are considered to be of special interest and by default shall be 
reported as SAEs (medically important criteria): 
 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 
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 Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse lasting >1 hour 
 Adverse Events that required surgical intervention (e.g., conventional surgery, vitreous tap 
or biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) 
to prevent permanent loss of sight 
 Adverse Events associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis) 
 Adverse Events that, in the opinion of the Investigator, may require medical intervention to 
prevent permanent loss of sight. 
 
11.3 
Adverse Events (AE) Monitoring 
At each post-baseline visit, after the patient has had the opportunity to spontaneously mention 
any problems, the Investigator or appropriate designee should inquire about AEs by asking the 
standard questions:  
 
 “Have you had any health problems since your last study visit?” 
 “Have there been any changes in the medicines you take since your last study visit?”  
 
AEs should be reported for any clinically relevant change in concomitant medication(s) that is 
the result of an untoward (unfavourable and unintended) change in patient's medical conditions. 
Changes in any protocol-specific ocular or systemic parameter evaluated during the study are 
to be reviewed by the Investigator. In addition, the patient’s responses to any questionnaire 
utilized during the study are to be reviewed by the Investigator. Any untoward (unfavourable 
and unintended) change in a protocol-specific parameter or questionnaire response that is 
clinically relevant is to be reported as an AE. These clinically relevant changes will be reported 
regardless of causality. 
11.4 
Recording 
Adverse Events:  
All AEs (non-serious and serious) which occur during the course of the study will be recorded 
in the eCRF. Any pre-existing medical conditions or signs/symptoms present in a patient prior 
to the start of the study (i.e., before informed consent is signed) until completion of the follow 
up period, should be specified in the eCRF. 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. For each recorded event, the AE 
documentation must include the onset date, outcome, resolution date (if event is resolved), 
intensity (i.e., severity), any action with study treatment taken as a result of the event, and an 
assessment of the adverse event relationship to the study treatment.  
Relationship of AEs to the Investigational Product 
The Investigator will assess the relationship between the AE and the investigational medication, 
according to the criteria in Table below: 


 
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Table 11.4.1 
Relationship of the Adverse Event to the Investigational Product 
None (Intercurrent 
Event) 
An event that is not and cannot be related to the investigational product, e.g. patient 
is a passenger in a road traffic accident 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality 
with temporal relationship to drug administration which makes a causal relationship 
improbable and in which other drugs, chemicals or underlying disease provide 
plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s condition or 
treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of investigational product 
and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of investigational 
product and, if applicable, re-appears upon repeat exposure 
 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below. For 
each episode, the highest severity grade attained should be reported. 
Table 11.4.2 
Intensity (Severity) of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of symptoms 
or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough discomfort 
to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to work 
or to do usual activities [unacceptable]) 
 
11.5 
Serious Adverse Event Reporting 
 
Reporting Procedure for Investigators to Sponsor or CRO  
The Investigator must record all SAEs, including sight-threatening events, occurring at any time 
during the study regardless of presumed causal relationship, both in the dedicated section of 
eCRF and on a specific Non-Carbon Repeat Serious Adverse Event form (included in the 
Investigator’s Site File) within 24 hours of learning of the event. Within 24 hours from first 
knowledge of the SAE, the Investigator shall send the filled in and signed SAE form to the 
CRO and to the Sponsor at the following addresses: 
 
Dompé Drug Safety  
Email to:  farmacovigilanza@dompe.com 
or Fax:  +39.02.36026913 
 
 


 
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CromSource Drug Safety 
Email to: NGF0116-PV@cromsource.com 
or Fax: +39 045 82 50 574 
 
Dompé Medical Expert 
Flavio Mantelli – Chief Medical Officer Ophthalmology,  
Email to:  flavio.mantelli@dompe.com 
or Fax:  +39.02.58383324 
 
CromSource Medical Monitor 
Email to: NGF0116-MM@cromsource.com 
or Fax: +39 045 82 50 574 
 
Dompé Clinical Development 
Paolo Battigello – Clinical Development Senior Specialist 
Email to: paolo.battigello@dompe.com 
or Fax:  +39.02.58383324 
 
If assistance is needed with the reporting of a SAE, contact details for the CRO/Sponsor are 
provided in the section “Contact Information”.  
Serious adverse events will be managed directly by the Dompé Drug Safety department, with 
CRO support for Follow Up requests. 
The Investigator should also report information on SAEs that continue after patient has 
completed his/her participation in the study (whether study completion or withdrawal), unless 
patient has withdrawn his/her consent. 
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. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does 
not usually need to actively monitor patients for AEs once the trial has ended, if the Investigator 
becomes aware of a SAE occurring to a patient after that patient has ended his/her participation 
in the study (whether study completion or withdrawal), the SAE should be reported by the 
Investigator to 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. 
Copies of all correspondence relating to reporting of any SAEs should be maintained in the 
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Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to 
be SAE and shall not be reported as such, but only need to be recorded in the eCRF: 
 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 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, abnormal lab values or test results that do not induce clinical signs and/or symptoms 
and require intervention/therapy, i.e. are clinically significant shall not be considered SAE: 
 
Reporting Procedure to IEC and to Regulatory Authorities 
During the course of the clinical trial, Dompé shall report any serious unexpected suspected 
adverse reaction (SUSAR) to Eudravigilance Clinical Trial Module and to the concerned IEC 
which approved the protocol as soon as possible and in no event later than: 
 
(a)  seven calendar days after becoming aware of the information if the event is fatal or 
life threatening; and 
(b)  fifteen calendar days after becoming aware of the information if the event is neither 
fatal nor life threatening. 
 
Dompé shall, within eight days after having informed the IEC/Competent Authority under 
paragraph (a) and within fifteen days under paragraph (b), submit a complete report in respect 
of that information that includes an assessment of the importance and implication of any 
findings, made on the basis of follow up information provided by the Investigator. 
Dompé shall be responsible for cross trial reporting, as necessary. 
Dompé shall assess SAE report received for relationship with IMP and expectedness. 
Expectedness will be assessed with respect to the current Investigator’s Brochure: due to the 
early phase of development, all SAEs will be considered unexpected. 
For serious adverse event reported by the Investigator as not related that is subsequently revised 
to be related by the Sponsor, 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. 
Treatment will be unblinded by Sponsor Pharmacovigilance prior to submission of a SUSAR 
to Regulatory Authorities and European IECs and only cases referred to active treatment will 
be expeditable for regulatory reporting, in line with law requirements. 


 
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The Sponsor shall be responsible to prepare and submit periodical update reports as appropriate 
to Investigator and to Competent Authority and Ethics Committee. 
11.6 
Follow-up of Patients with Adverse events 
The Investigator is responsible for adequate and safe medical care of patients during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the trial. All AEs should be followed-up to determine outcome of the reaction 
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 patients 
experiencing AEs receive definite treatment for any AE, if required. 
Follow-up reports (as many as required) should be completed and faxed/e-mailed following 
the same procedure above, marking the SAE form as “follow up Number XX”. 
11.7 
Pregnancy in the Clinical Trial 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are summarized 
in the protocol’s exclusion criteria. 
Prior to enrolment in the clinical trial, female patients of childbearing potential and their 
partners must be advised of the importance of avoiding pregnancy during the entire course of 
the study treatment and for the 30 days after the study treatment period ends and of the potential 
risks associated with an unintentional pregnancy. During the trial, female patients are to be 
instructed to contact the Investigator immediately if they suspect they might be pregnant; in the 
same way, male patients who become aware that the partner might be pregnant, are to be 
instructed to contact the Investigator immediately.  
The Investigator must report every pregnancy on a pregnancy report form (included in the 
Investigator’s Site File) as soon as possible (within 24 hours of learning of the pregnancy to the 
CRO/Dompé Drug Safety contacts reported at Paragraph 11.5.1, even if no AE has occurred, 
and follow it to term. If, however, the pregnancy is associated with an SAE (eg, if the mother 
is hospitalized for dehydration), in addition to the pregnancy report form, a separate SAE report 
form must be filed as described in Section 11.5.1 with the appropriate serious criterion (eg, 
hospitalization) indicated on the SAE report form. Miscarriage, stillbirth and any 
malformation/disease must be reported as a SAE. Any pregnancy occurring to a female patient 
leads to the immediate cessation of study treatment. 
11.8 
Adverse Events Causing Treatment Discontinuation 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and 
reasoned in the eCRF, and the patient must be followed up until the resolution of the AE or as 
instructed by the medical monitor. 


 
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11.9 
Overdose  
Cases of overdose (accidental or intentional) which result in serious adverse events are to be 
handled following emergency procedures, and reported within 24 hours from the Investigator’s 
knowledge of its occurrence. This includes reports related to drug intake through different 
routes (e.g. ingestion), or drug intake with suicidal intentions and consequent drug overdose. 
Since in the preclinical toxicology studies in animals and in the multiple ascending dose study 
performed in healthy volunteers none of the dose has caused an overdose as documented by 
adverse reaction, for the purpose of this study we define that the administration of more than 3 
times the total daily dose on any given treatment day will be reported as an overdose, even if 
not associated with adverse reactions, and shall be reported to Dompé’s clinical research 
personnel and CRO by e-mail or fax within 24 hours using the SAE form, in order to have 
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12 
 DATA MANAGEMENT PROCEDURES 
12.1 
Data collection – eCRFs 
The Investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the eCRFs. He must also check that the data reported in the eCRFs correspond to 
those in the patients’ source documents.  
An electronic case report form (eCRF) will be provided for each subject.  
All protocol-required information collected during the study must be entered by the 
Investigator, or designated representative, in the eCRF. Details of eCRF completion and 
correction will be explained to the Investigator. If the Investigator authorizes other persons to 
make entries in the eCRF, the names, positions, signatures, and initials of these persons must 
be supplied to the Sponsor.  
The Investigator, or designated representative, should complete the eCRF pages as soon as 
possible after information is collected, preferably on the same day that a study subject is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
12.2 
Unique subject identifier 
All the patients who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. The unique subject identifier for study site consists of the Sponsor 
study code (i.e. NGF0116), the 4-digit screening number (e.g. S001, S002, etc.) and, if 
applicable, the 3-digit subject study number (e.g. 001, 002, etc.).  
Study code, screening number and subject study number are separated by slashes (e.g. 
“NGF0116/S001/001”). The last 5 digits of the unique subject identifier (randomized subjects), 
corresponding to the subject screening and subject study numbers separated by a slash, or the 
last 3 digits of the unique subject identifier (not randomized subjects), corresponding to the 
subject screening number, will appear as subject identifier in the individual listings and figures 
of the clinical study report and will be used to identify the subjects in in-text tables or wording 
(if applicable). 
12.3 
Database management 
Data management of all data captured within the eCRF will be performed by the CRO with the 
OmniComm TrialMaster™ . CRO will update and verify the database and create the final SAS 
data sets. The tabulation datasets and analysis datasets created according to the standard CDISC 
(STDM and ADaM) will be provided to the Sponsor with all the other study documentation.  


 
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Coding dictionaries 
Medical/surgical history and underlying diseases, physical examination abnormalities and AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA™). 
Prior and concomitant medications will be coded using the WHO Drug Dictionary Enhanced 
(WHODDE). Version of coding dictionaries will be stated in the SAP and the study report. 


 
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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
13.1 
Monitoring 
The monitoring visits will be conducted by a local monitor.  
Monitoring will comply with ICH-GCP chapter 5.18 requirements for what concerns 
monitoring purpose, selection and qualifications of monitors, extent and nature of monitoring, 
monitoring procedures, monitoring reports. 
Adequate time and availability for monitoring activities should be ensured by the Investigator 
and key study personnel. 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the Investigator will assure support to the monitor at all times. 
The Investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorised individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the Sponsor could perform 
some quality control activities to verify the compliance with the study procedures and the ICH-
GCP guidelines.  
13.2 
Quality Control and Quality Assurance  
The CRO has implemented and maintains a Quality System that includes quality controls and 
audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOA principles (Attributable-Legible-
Contemporaneous-Original-Accurate). 
13.3 
Applicable SOPs 
The Sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for review, if required. 
13.4 
Data access 
The Investigator and the CRO will ensure that all raw data records, medical records, eCRFs and 
all other documentation that is relevant to this study will be made accessible to monitoring 
activities, audits, IEC review, and regulatory inspection. 


 
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13.5 
Audits and inspections 
The Sponsors, independent bodies acting on behalf of the Sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
The study may also be inspected by regulatory authorities.  
The Investigators agrees, by written consent to this protocol, to fully co-operate and support 
audits and inspections compliance checks by allowing authorised individuals to have access to 
all the study documentation. 
 


 
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14 
 ETHICAL CONSIDERATIONS 
14.1 
Ethics and Good Clinical Practice (GCP) 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The approval of the study protocol by the relevant Local Research Ethics Committees 
Authorities will be obtained before the start of the study. 
Study notification to the Competent Authorities will be performed according to the Italian 
current regulations. 
The present clinical study will be carried out according to the general principles of “ICH Topic 
E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status September 1997 and 
post Step errata (linguistic corrections), July 2002. 
14.2 
Informed consent 
Before being enrolled into the clinical study, the patients must have expressed their consent to 
participate, after the Investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the EC and regulatory authorities. 
It will include all the elements required by law according to the ICH-GCP recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment 
 any potential negative effects attributable to the study treatment 
 the freedom to ask for further information at any time 
 the patients’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of patient insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the patients and the time 
will be recorded. 
The Investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the Investigator and the patients.  
A copy of the signed form will be given to the patient. 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the Investigator's study file according to the regulatory requirements (see § 15.2). 
The Investigator will allow inspection of the forms by authorized representatives of the 
Sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 


 
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14.3 
Insurance policy 
An insurance cover has been issued in favour of the patients participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
14.4 
Withdrawal of patients 
It will be documented whether or not each patient completed the clinical study. If, for a patient, 
study treatment or observations are discontinued, the primary reason for discontinuation will 
be recorded. 
 
Primary reason for discontinuation 
 Adverse event: Any significant adverse event that in the opinion of the Investigator or 
concerned patient is not compatible with study continuation. For the definition of AE, please 
refer to § 11.1.1. 
 death: the absence of life or state of being dead 
 safety concerns related to IMP 
 lack of efficacy: the lack of expected or desired effect related to a therapy 
 lost to follow-up: the loss or lack of continuation of a patient to follow-up 
 non-compliance with study drug: an indication that a patient 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 patient 
 pregnancy: pregnancy is the state or condition of having a developing embryo or foetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth (please see § 11.7) 
 protocol violation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by Sponsor: an indication that a clinical study was stopped by its 
Sponsor 
 withdrawal by patient: study discontinuation requested by a patient for whatever reason 
 other: different than the ones previously specified 
 
Discontinuation procedures 
For any patient discontinuing the study, the Investigator will:  
 ask the patient to undergo, as far as possible, a final medical visit to examine the patient's 
health conditions This examination will verify that all values tested at baseline have 


 
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remained within a clinically acceptable range (i.e. not clinically significant changes 
compared to baseline) 
 arrange for alternative medical care of the withdrawn patient, 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 patient is withdrawn for an AE 
 
Replacement 
Discontinued patients will not be replaced. 
14.5 
Study termination 
The study will be considered terminated at the date of the last visit of the last patient or upon 
completion of any follow-up procedure described in the protocol. The Investigator and the 
Sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. Reasons 
for discontinuation have to be documented appropriately. In this event, no further patients will 
receive doses of the study drugs, and patients already having received a dose of study drug will 
not receive any further doses of the study IMP but will undergo all safety assessments scheduled 
after the last dose of study drug, up to an including the end of study examination. 


 
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15 
 ADMINISTRATIVE PROCEDURES 
15.1 
Protocol amendments 
In order to obtain interpretable results, neither the Investigator nor the Sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the Investigator and the Sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
All amendments will be sent to the EC and concerned Competent Authorities. 
15.2 
Study documentation and record keeping 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported in the eCRFs and in all required reports. 
The Investigator must keep source documents for each patient in the study. All information on 
the eCRFs must be traceable to these source documents, which are generally stored in the 
patient's medical file. The source documents should contain all demographic and medical 
information, including ophthalmic assessments, etc., and the original signed informed consent 
forms. 
Data reported on the eCRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained. 
The Investigator and the Sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of patients 
including ophthalmic assessments, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification 
code, eCRFs, curricula vitae of the Investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
The Investigator and the Sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
Study documents must be retained by the Investigator and the Sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
Investigator and the Sponsor agree to adhere to these requirements. 
15.3 
Confidentiality and data protection 
By signing this protocol, the Investigator and the CRO agree to keep all the information 
provided by the Sponsor in strict confidentiality and to request similar confidentiality from 


 
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his/her staff. Study documents provided by the Sponsor (protocols, IB, eCRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the Sponsor to the Investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the Sponsor, except for the extent necessary to obtain the informed 
consent from the patients wishing to participate in the study. 
Data on patients collected on the eCRFs during the study will be documented in an anonymous 
way (see § 12.2). If, as an exception, it becomes necessary to identify a patient for safety or 
regulatory reasons, the monitor, the Sponsor and the Investigator will be bound to keep this 
information confidential. 
15.4 
Publication policy 
The Sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the Investigator publishing in peer reviewed 
journals; presenting results at scientific congresses; and posting information and results on 
internet-based public registers and databases. 
In any case, study results will be communicated in full to the competent Health Authorities by 
the submission of a complete Clinical Study Report. 
As the Sponsor agrees that the study results can be published by the Investigator(s), the 
Investigator agrees to submit any manuscript (abstract, publication, paper etc.) to the Sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical trial results are reported in an objective, 
accurate and balanced manner. The Sponsor reviews proposed manuscripts prior to submission 
within a reasonable period of time (30-90 business days in relation with the complexity of the 
work). 
The Investigator(s) will also be provided by the Sponsor with the clinical study report and the 
results of any additional analysis, tables, figures etc. undertaken for the purposes of the article, 
in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the Sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures etc.) to seek necessary intellectual property 
protection. This is because early disclosure of such a data could, in some circumstances, prevent 
or negatively impact patentability 
15.5 
Liability Statement  
On behalf of the Sponsor, the investigational sites will take out reasonable third-party liability 
insurance cover in accordance with all local legal requirements. The civil liability of the 
Investigators, the persons instructed by them and the hospital, practice or institute in which they 
are employed and the liability of the Sponsor in respect of financial loss due to personal injury 
and other damage which may arise as a result of the carrying out of this study are governed by 
the applicable local laws. 
As a precautionary measure, the Investigators, the persons instructed by them and the hospital, 
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Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 58 of 59 
this study to the extent that the claims are not covered by their own professional indemnity 
insurance. 
15.6 
Financing of the Study 
The financial aspects of this study are described in detail in the contract between Sponsor and 
CRO and between CRO and clinical site involved in this study.  
15.7 
Responsibilities of the Investigator 
The Investigator is aware of his/her responsibility towards the Sponsor for all the actions 
delegated by him/her to other members of his/her staff assigned to the conduct of the study. 
Except where specifically required, the wording "Investigator" used in this protocol and in the 
eCRF, refers to the Investigator or the qualified person designated by him/her, who may carry 
out activities relevant to the clinical trial and sign the study documents on his/her behalf. 
The Investigator is obliged to conduct the study in compliance with the study protocol and in 
adherence to GCP (ICH E6) and with the principles of the Declaration of Helsinki (1964) and 
subsequent revisions as well as in respect of applicable legislation. 
15.8 
Final study report 
The final Clinical Study Report will be written by the CRO and then approved by Dompé 
farmaceutici S.p.A. and the Principal Investigator. It will be written in compliance with the ICH 
E3 guideline for both content and format. 


 
CONFIDENTIAL 
rhNGF in Post Cataract and Refractive Surgery 
Sponsor code NGF0116 
Final Version 3.0 12 Apr 2017 
Page 59 of 59 
16 
 REFERENCES 
1. Lambiase A, Bonini S, Manni L, Ghinelli E, Tirassa P, Rama P, Aloe L. Intraocular 
production and release of nerve growth factor after iridectomy. Invest Ophthalmol Vis Sci 
2002; 43:2334–40. 
2. Qi H, Chuang EY, Yoon KC, de Paiva CS, Shine HD, Jones DB, Pflugfelder SC, Li DQ. 
Patterned expression of neurotrophic factors and receptors in human limbal and corneal 
regions. Mol Vis 2007; 13:1934-41. 
3. Nguyen D, Beuerman HRW, Thompson HW, DiLoreto DA. Growth factor and 
neurotrophic factor mRNA in human lacrimal gland. Cornea 1997; 16:192–9. 
4. Ghinelli E, Johansson J, Rios JD, Chen LL, Zoukhri D, Hodges RR, Dartt DA. Presence 
and localization of neurotrophins and neurotrophin receptors in rat lacrimal gland. Invest 
Ophthalmol Vis Sci 2003; 44:3352–7. 
5. Vesaluoma M, Muller L, Gallar J, Lambiase A, Moilanen J, Hack T, Belmonte C, Tervo 
T. Effects of oleoresin capsicum pepper spray on human corneal morphology and 
sensitivity. Invest Ophthalmol Vis Sci 2000; 41: 2138–47. 
6. de Castro F, Silos-Santiago I, Lopez de Armentia M, Barbacid M, Belmonte C. Corneal 
innervation and sensitivity to noxious stimuli in trkA knockout mice. Eur J Neurosci 
1998;10: 146–52. 
7. Bocchini V, Angeletti PU. The nerve growth factor: purification as a 30,000-molecular-
weight protein. Proc Natl Acad Sci U S A 1969; 64:787-94 
8. Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L. Topical treatment with nerve growth 
factor for neurotrophic corneal ulcers. New Engl J Med 1998;338:1174-80. 
9. Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve growth 
factor for neurotrophic keratitis. Ophthalmology2000;107:1347-51 
10. Coassin M et al., Efficacy of topical nerve growth factor treatment in dogs affected by dry 
eye. Graefe’s Arch Clin Exp Ophthalmol 2005; 243:151-5  
11. Ferrari MP, Mantelli F, Sacchetti M, Antonangeli MI, Cattani F, D'Anniballe G, Sinigaglia 
F, Ruffini PA, Lambiase A. Safety and pharmacokinetics of escalating doses of human 
recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial. 
BioDrugs. 2014 Jun;28(3):275-83. 
12. Amparo F et al. Ophthalmology, 2015 Jul; 122(7):1498-503. 
13. Schaumberg DA et al. Ocul Surf, 2007 Jan; 5(1):50-7 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
Dompé Farmaceutici S.p.a. 
 
A 8 weeks, Phase II, single-centre, randomized, double-
masked, vehicle-controlled, parallel group study with 4 
weeks of follow-up to evaluate preliminary efficacy and 
safety of recombinant human Nerve Growth Factor (rhNGF) 
eye drops solution versus vehicle in patients after cataract 
and refractive surgery 
 
 
Protocol/CIP No: NGF0116 
Clinical Trials No: NCT03035864  
 
 
Statistical Analysis Plan 
 
 
Version 1.0 
Final  
11JUL2017 
 
 
Author: Elisa Rizzo/Monika Rost 
 
CROMSOURCE  


 
 
 
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__________________________________________________________________________________________________________________________________ 
 
 
TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
Signature Page 
 
 
Signatures for Dompé 
 
 
 
  
Paolo Battigello 
 
Signature 
 Date (ddMMMyyyy) 
Clinical Development Senior 
Specialist 
 
 
  
 
 
 
  
Flavio Mantelli 
 
Signature 
 Date (ddMMMyyyy) 
Chief Medical Officer –
Ophthalmology  
 
 
  
 
 
 
Signatures for CROMSOURCE 
 
 
 
  
Roberta Baronio 
 
Signature 
 Date (ddMMMyyyy) 
Head of Biostatistics and 
Programming Unit  
 
 
  
 
 
 
  
Monika Rost 
 
Signature 
 Date (ddMMMyyyy) 
Senior Statistician 
 
 
  
 


 
 
 
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__________________________________________________________________________________________________________________________________ 
 
 
TF-ST-03/00-02 
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Table of Contents 
1 SOPs to be followed .......................................................................... 5 
2 Abbreviations ..................................................................................... 6 
3 Protocol / Clinical Investigation Plan ................................................ 7 
3.1 Study Objectives .............................................................................................. 7 
3.2 Study Design..................................................................................................... 7 
3.3 Study Schedule ................................................................................................. 9 
3.4 Efficacy and Safety Endpoints ...................................................................... 10 
3.5 Interim Analyses ............................................................................................. 10 
3.6 Sample Size estimation .................................................................................. 10 
3.7 Changes in the Conduct of Study or Planned Analysis compared to 
protocol/CIP .......................................................................................................... 11 
4 General Definitions .......................................................................... 12 
4.1 Report Language ............................................................................................ 12 
4.2 Analysis Software ........................................................................................... 12 
5 Data Preparation .............................................................................. 13 
5.1 Data Handling and Medical Coding ............................................................... 13 
5.2 CDISC .............................................................................................................. 13 
5.3 SAS-Programming Quality Level .................................................................. 13 
6 Analysis Sets and Subgroups ......................................................... 14 
6.1 Analysis Sets .................................................................................................. 14 
6.2 Subgroup Definitions ..................................................................................... 15 
7 Definition of Time Points and Analysis Variables.......................... 16 
7.1 Definition of Time Points ............................................................................... 16 
7.2 Analysis Variables .......................................................................................... 17 
7.2.1 Disposition parameters ................................................................................ 17 
7.2.2 Demographic Characteristics ...................................................................... 17 
7.2.3 History of Corneal Surgery and other Medical History ................................. 17 
7.2.4 Prior and Concomitant Medication .............................................................. 18 
7.2.5 Measurements of Exposure and Treatment Compliance............................. 19 
7.2.6 Study Medication ......................................................................................... 20 
7.2.7 Efficacy Variables ........................................................................................ 20 
7.2.8 Safety Variables .......................................................................................... 22 


 
 
 
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8 Analysis Methods ............................................................................. 29 
8.1 General Methods ............................................................................................ 29 
8.2 Specific Methods for Efficacy Analyses ....................................................... 29 
8.2.1 Statistical/Analytical Issues ......................................................................... 30 
8.3 Specific Methods for Safety Analyses .......................................................... 30 
9 Overview of Tables, Listings and Figures ...................................... 31 
9.1 Disposition of Patients ................................................................................... 31 
9.2 Protocol Deviations and Patient Eligibility ................................................... 31 
9.3 Demographic and Other Baseline Characteristics ...................................... 31 
9.3.1 Demographic Characteristics ...................................................................... 31 
9.3.2 History of Corneal surgery and other Medical History ................................. 32 
9.3.3 Prior and Concomitant Medications ............................................................. 32 
9.4 Measurements of Exposure and Treatment Compliance ............................ 32 
9.5 Efficacy Results .............................................................................................. 32 
9.5.1 Primary Efficacy Analysis ............................................................................ 32 
9.5.2 Co-Primary Efficacy Analysis ...................................................................... 33 
9.5.3 Secondary Efficacy Analysis ....................................................................... 33 
9.6 Safety Results ................................................................................................. 34 
9.6.1 Adverse Events ........................................................................................... 34 
9.6.2 Clinical Laboratory Evaluation ..................................................................... 35 
9.6.3 Best Corrected Visual Acuity ....................................................................... 35 
9.6.4 Slit Lamp Examination ................................................................................. 35 
9.6.5 External Ocular Examinations ..................................................................... 35 
10 References ...................................................................................... 36 
11 Tables, Listings and Figures ......................................................... 37 
12 Appendices ..................................................................................... 40 
 


 
 
 
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TF-ST-03/00-02 
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1 SOPs to be followed 
The statistical analysis will be carried out according to the following CROMSOURCE 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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TF-ST-03/00-02 
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2 Abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event Of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCDVA 
Best Corrected Distance Visual Acuity 
BDRM 
Blind Data Review Meeting 
CDISC 
Clinical Data Interchange Standards Consortium 
CFB 
Change from Baseline 
CIP 
Clinical Investigational Plan 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
IMP 
Investigational Medicinal Product 
LASIK 
Laser-assisted in situ keratomileusis 
LOCF 
Last Observation Carried Forward 
MMP 
Matrix Metallopeptidase 9 
NEI 
National Eye Institute 
PPS 
Per Protocol Analysis Set 
PT 
Preferred Term 
QC 
Quality Control 
SAE 
Serious Adverse Effect 
SAF 
Safety Set 
SANDE 
Symptom Assessment In Dry Eye 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SDTM 
Study Data Tabulation Model 
SLE 
Slit Lamp Examination 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time 
TLF 
Tables, Listings And Figures 
VAS 
Visual Analog Scale 
WHO 
World Health Organisation 
 


 
 
 
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TF-ST-03/00-02 
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3 Protocol / Clinical Investigation Plan 
This NGF0116 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 3.0 (dated 
12Apr2017). 
It lists all Tables, Listings and Figures (TLFs) of the final analysis, which are intended to be 
included in the Clinical Study Report. All TLFs will be produced by CROMSOURCE. 
Analysis of changes in nerve count and morphology at scanning laser in vivo corneal 
confocal microscopy is not covered by this SAP. Confocal microscopy assessment will be 
reported in a separate part of the CSR. 
3.1 Study Objectives 
The primary objective of this study is to assess efficacy and safety of rhNGF when 
administered as eye drops to patients after cataract and refractive surgery.  
The objectives are reflected by the endpoints as stated in section 3.4. 
3.2 Study Design 
This is a Phase II, single-centre, randomized, double-masked, parallel-arm, vehicle-
controlled trial, designed to evaluate the preliminary efficacy and safety of rhNGF eye drops 
at 20 µg/ml concentration administered six times daily for 8 weeks in patients who underwent 
cataract and corneal refractive surgery, both known to damage the corneal sensory nerve 
plexus. 
Eligible patients will be randomized 2:1 to either rhNGF eye drops 20 µg/ml (120 patients) or 
vehicle (60 patients) six times daily and treated for 8 weeks: 
Group 1: rhNGF 20 µg/mL: One drop (40 µL) corresponding to 0.80 µg of rhNGF will be 
instilled into each eligible eye six times a day (every 2h), for a total daily dose of 9.6 µg (both 
eyes, if applicable), for 56 consecutive days.. 
Group 2: Vehicle: One drop (40 µL) will be instilled into each eligible eye six times a day 
(every 2h). 
In all patients, both eyes will be treated, if meet the eligibility criteria. If only one eye is 
eligible, then only that eye will be treated. 
In the 4 week follow up no further treatment is planned except artificial tears, per Investigator 
decision. Administration of such medications will be recorded in eCRF (number of drops per 
day). 
Drop-Outs after randomization will not be replaced. 
 
 


 
 
 
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The study flow chart is given below: 
Figure 3.2.1 Study flow chart 
 
 
 
  
 
 
Treatment 
8 weeks 
Follow-up 
4 weeks 
Randomization 


 
 
 
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3.3 Study Schedule 
Table 1: Study procedures (from study protocol) 
Study procedures 
Baseline 
Visit  
(Day 0) 
Week 4 
(Day 28±2) 
Week 8** 
(ETV)   
(Day 56±2) 
Week 12 
(Follow-up Visit) 
(Day 84±2) 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Urine Pregnancy Test 
X 
X 
X 
 
Randomization 
X 
 
 
 
Demographics 
X 
 
 
 
Ocular and General Medical 
History 
X 
 
 
 
Previous and Concomitant 
Ocular And Systemic 
Medications 
 
X 
 
X 
X 
X 
Frequency of artificial tear use 
X 
X 
X 
X 
Record Adverse Events (AEs) 
X 
X 
X 
X 
Verify patient study medication 
dosing compliance 
 
X 
X 
 
SANDE  questionnaire 
X 
X 
X 
X 
Best Corrected Distance  Visual 
Acuity (BCDVA) 
X 
 
X 
X 
Cochet-Bonnet aesthesiometry 
X 
 
X 
 
External Ocular Examination 
X 
X 
X 
X 
Slit Lamp Examination (SLE) 
X 
X 
X 
X 
Fluorescein staining (NEI scale) 
X 
X 
X 
X 
Tear Film Break-up Time 
(TFBUT) 
X 
X 
X 
X 
Corneal confocal microscopy* 
X 
 
X 
 
Study drug dispensation 
 X  
X  
 
 
* Only for patients who underwent laser-assisted in situ keratomileusis (LASIK) surgery 
** ETV – Early Termination Visit to be performed according to Visit Week 8 procedures, if premature treatment 
discontinuation occurs. 
Note: Patient diary will be reviewed for potential AEs, and details as applicable 
Abbreviations:  SANDE - Symptom Assessment In Dry Eye  


 
 
 
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3.4 Efficacy and Safety Endpoints 
In the study protocol the following study endpoints are specified. 
Clinical efficacy and safety parameters will be evaluated at each time point (days 0, 28±2, 
56±2 and 28±2 days after discontinuation of treatment) with the following endpoints: 
Primary Efficacy Endpoint 
 
Change from baseline in Symptom Assessment in Dry Eye (SANDE) scores for 
severity and frequency assessed at 8 weeks of treatment 
 
Co-primary Efficacy Endpoint 
 
Changes in Cornea vital staining with fluorescein (National Eye Institute (NEI) scales) 
assessed at week 8 
 
Secondary Endpoints 
 
Changes in SANDE scores (face values) for severity and frequency 
 
Changes in Conjunctival vital staining with fluorescein (NEI scales) 
 
Changes in Tear film break-up time (TFBUT)  
 
Changes in Cochet-Bonnet corneal aesthesiometry 
 
Changes in Nerve count and morphology at scanning laser in vivo corneal confocal 
microscopy (only patients who had LASIK surgery) – not covered by this SAP. 
Safety Endpoint 
 
Incidence and frequency of Treatment-emergent adverse events (TEAEs), assessed 
throughout the study 
3.5 Interim Analyses 
No interim analyses are planned. 
3.6 Sample Size estimation 
Sample size was calculated by assuming at single eye level a mean difference from baseline 
mean SANDE scores of -30±20 in the rhNGF groups versus -20±20 in vehicle group (80% 
power, alpha =0.05; 2-sided test), considering that the active comparator has already proven 
safe and effective in dry eye patients. The sample size has been calculated based on a 2:1 
randomization by the following formula:  
n1 = (0.5) × n × (1 + k) 
n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 63 and k= n1 /n2 = 2/1=2. Therefore n1= 
94,5 and n2=47.25.  Assuming a 5% drop out rate, a total of 100 patients in the active arm 
and 50 in the vehicle arm are required.  
 


 
 
 
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However, in order to provide the mean of detecting a significant difference also on a clinical 
sign of the effect of the rhNGF therapy (namely Co-primary Efficacy Endpoint cornea vital 
staining with fluorescein (National Eye Institute [NEI] scales)), sample size calculation was 
also performed by assuming, at single eye level, a mean difference from baseline in Cornea 
NEI scale scores of -3.9±2.2 in the rhNGF groups versus -2.9±2.2 in vehicle group (80% 
power, alpha =0.05; 2-sided test), considering that the active comparator has already proven 
safe and effective in dry eye patients. The sample size has been calculated based on a 2:1 
randomization by the following formula:  
n1 = (0.5) × n × (1 + k) 
n2 = (0.5) × n × (1 + (1/k)) 
with n1= active treatment and n2= vehicle and n= 76 and k= n1 /n2 = 2/1=2. Therefore n1= 
114 and n2=57.  Assuming a 5% drop out rate, a total of 120 patients in active arm and 60 in 
the vehicle arm are required. This calculation is based on one study eye per patient. 
(Whereas also two study eyes per patient may occur, that will increase power to above 80%). 
 
Considering the two calculations performed to determine the sample size, in this study will be 
enrolled 180 patients (120 patients enrolled in active arm and 60 in the vehicle arm) in order 
to detect both changes at the same time in the variables. 
 
3.7 Changes in the Conduct of Study or Planned Analysis compared to 
protocol/CIP 
This SAP implements the subsequent deviations and clarifications from the analysis 
specification of the study protocol: 
 
For the SAP, study endpoints are presented as provided in the protocol synopsis and 
protocol section 2 (study objectives).  
 
Definition of Screen Failures. In the study protocol (section 10.1.1) a screen failure is 
defined as patient who is not eligible, i.e. is not respecting all the inclusion/exclusion 
criteria. According to the study protocol, such patients should not be randomized and 
enrolled.  
To streamline presentation of patient flow for reporting and to extend definition also 
for protocol deviations, screen failure will be defined as screened patients, who are 
not randomized. By this, patients, who were randomized although they did not comply 
with eligibility criteria will not be considered as screen failure. On the contrary, 
patients, who comply with all eligibility criteria but dropped out from the study before 
randomization (e.g. due to consent withdrawal) will be considered as screen failure.  
 
 Definition of compliance: in section 10.3, the study protocol demands further 
compliance definitions based on diary card information to investigate compliance with 
study eye treatment. However, as no eye-specific assessments were recorded on 
diary card, no such definitions were established. 
 
In the study protocol, no inferential analyses are specified. However, purely 
exploratory 95% confidence intervals and hypothesis testing for the difference 
between treatment groups will be implemented in the SAP on sponsor’s request. 
These inferential procedures will be purely exploratory without adjusting for type I 
error rate. 


 
 
 
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4 General Definitions 
4.1 Report Language 
All TLFs 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). 


 
 
 
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5 Data Preparation 
5.1 Data Handling and Medical Coding 
For data quality control and medical coding please refer to the Data Management Plan 
including the Data Validation Plan in its most recent version. 
5.2 CDISC 
All output as defined in the SAP will be generated based on CDISC ADaM datasets following 
ADaM implementation Guide 1.0, as per contract with Dompé farmaceutici S.p.A.. SDTM 
programming will follow SDTM version 1.3 together with SDTM implementation guide 3.1.3. 
Specifications for the ADaM datasets (as well as SDTM datasets) are described in a 
separate document. 
5.3 SAS-Programming Quality Level 
The following quality level of programming deliverables will be applied, as per contract with 
Dompé Farmaceutici S.p.A.. All statistical output will receive a tailored Quality Control (QC) 
approach by: 
 
Full independently double programmed reproduction (QC) of CDISC: 
o SDTM datasets 
o ADaM datasets 
 
Full independently double programmed reproduction (QC) of results of all tables and 
inferential analyses 
 
Listings will not be double programmed. However, complex listings for BDRM 
requiring a complex selection will undergo a fully independent double programmed 
QC. 
 
All tables and listings will undergo comparison with specification (i.e. SAP and 
templates), cross checking with other tables and listings, a sensibility review and 
SAS-log review by a senior statistician. 


 
 
 
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6 Analysis Sets and Subgroups 
6.1 Analysis Sets 
A patient will be defined as screened after the signature of the informed consent, regardless 
of the completion of all the screening procedures. A patient will be defined as screen failure, 
if he was screened but not enrolled in the study. 
 
Enrolled Set: 
A patient will be defined as enrolled in the study if he/she is randomized. This analysis set 
will be used for presentation of study disposition. 
If not stated otherwise, analyses based on the Enrolled Set will be summarized by the 
treatment randomized. 
 
Safety Set (SAF): 
The Safety Set will be defined as all enrolled patients who receive at least one dose of the 
investigational medicinal product (IMP) at the study eye(s). This analysis set will be used for 
the demographic, baseline and background characteristics and safety analysis. All analyses 
based on the SAF will be summarized by the treatment received. 
 
Full Analysis Set (FAS): 
The Full Analysis Set will be defined as all patients in the SAF, who have at least one post-
baseline efficacy measurement in a study eye. This analysis set will be used for the primary 
and co-primary efficacy analysis and all other efficacy analyses. All efficacy analyses based 
on the FAS will be summarized by the treatment randomized. 
 
Per Protocol Set (PPS): 
The Per Protocol Set will be defined as all patients in the FAS who fulfill the study protocol 
requirements in terms of investigational medicinal product intake and collection of primary 
and co-primary efficacy data and with no major deviations that may affect study results. This 
analysis set will be used for supportive efficacy analysis. All efficacy analysis based on the 
PPS will be summarized by the treatment randomized. 
 
Each patient could either have 1 or 2 study eyes eligible for the analysis. For each patient a 
main (study) eye will be identified to enable a patient based presentation of analysis.  
For patients with only 1 study eye (i.e. treated eye), this eye will be defined as ‘Main Eye’. 
For patients with 2 study eyes, the study eye with the higher corneal staining score at 
baseline will be considered as ‘Main Eye’ unless corneal staining score is not available at 
Week 8 Visit for this eye. 
In this case, the other eye will be considered as ‘Main Eye’. If both eyes are equally worse, 
the right eye will be the ‘Main Eye’. 
The eye not selected as ‘Main Eye’, will be called ‘Secondary Eye’. 


 
 
 
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After all patients have completed study and prior to database lock, a blinded data review 
meeting (BDRM) will be performed to assign patients to analysis sets and to define ‘Main 
Eyes’. Details of BDRM will be specified in a separate BDRM-plan. 
 
The BDRM plan may consider the following criteria for exclusion of a patient from the PPS: 
 
lack of compliance with investigational medical product administration 
A compliance below 80% or greater than 120% will lead to exclusion from the PPS 
(compliance definition please refer to section 7.2.5). 
 
exposure to an IMP dose different from the one assigned to the patient 
 
missing primary or co-primary efficacy data 
 
failure to satisfy any inclusion/exclusion criteria (eligibility violations) 
 
intake of prohibited medications 
 
Moreover, a review of protocol deviations and potential consequences for the analysis will be 
evaluated during the BDRM. The results of the BDRM will be summarized in BDRM Minutes, 
which will be finalized before unmasking. 
 
6.2 Subgroup Definitions 
For supportive efficacy analysis, subgroup of patients with ‘1 study eye only’ vs. ‘2 study 
eyes’ will be utilized. 


 
 
 
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7 Definition of Time Points and Analysis Variables 
7.1 Definition of Time Points 
Analyses of endpoints will be performed based on evaluations obtained on days 0, 282, 
562 and 28±2 days after discontinuation of study treatment. 
Baseline will be defined as the value collected at the Baseline Visit. Study day 1 is, 
subsequently defined as the day after the Baseline Visit. 
The Treatment Day of an event/assessment will be calculated relative to the First Study 
Treatment Administration as specified on the eCRF page ‘Study Drug Dosing Dates’, 
The Treatment day of events/assessments occurring before the First Study Treatment 
Administration was calculated as: 
 
Treatment Day = (Date of assessment/event - Date of First Study Treatment 
Administration). 
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 
Administration) + 1. 
Visits will be analysed as they were collected. Unscheduled visits during study treatment will 
be considered for imputation purposes only (Last-observation carried forward).  
For dropout patients, the last study visit is documented on the eCRF in the Week 8 Visit 
section. In this case, the visit needs to be shifted to Week 4 or Week 12 visits or 
Unscheduled Visit depending on the visit window specified below. 
Conformance with the visit schedule will be evaluated during the BDRM. In case of 
substantial deviations from visit schedule, a supportive analysis will be considered to 
investigate influence of these deviations on primary as well as secondary endpoints and 
documented in BDRM minutes. 
Study completers will be defined as patients, who answered the question “Did the patient 
complete the study” on the eCRF page ‘End of Study’ as YES. 
Table 2: Study Visits 
Scheduled Visit   
Scheduled 
Visit Label 
Scheduled 
Study Day 
Visit Window 
Baseline Visit Day 0 
Baseline 
0 
Study day = 0 
Week 4 
Week 4 
28 
Study day in [26 – 30] 
Week 8 
Week 8 
56 
Study day in [54 – 58] 
Follow-up Visit Week 12 
Week 12 
84 
Difference Date Week 12 – Date of Last 
Study intake in [26 – 30]  
Documented unscheduled Visits will be labeled as “Unscheduled Visit 1”, “Unscheduled Visit 2”….. 
For Visit Window Week 12, Date of Last Study Intake as specified on eCRF Page “Study Drug Dosing Dates” 
 
 
 


 
 
 
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7.2 Analysis Variables 
This chapter describes all endpoints which will be summarized as described in section 9. 
7.2.1 Disposition parameters 
Disposition parameters are recorded on the eCRF Page ‘End of Study’. 
Study discontinuations will be defined only for patients in the Enrolled Set. A patient 
discontinued the study prematurely, if the question ‘Did the patient complete the study’ was 
answered as ‘No’. 
Primary Reason for Study Discontinuation is documented on the eCRF Page ‘End of Study’ 
in categories ‘Adverse Event’, ‘Lost to Follow-Up’, ‘Decision unrelated to an Adverse Event’, 
‘Non-Compliance’, ‘Study terminated by the sponsor’, ‘Study terminated by the investigator’, 
‘Other’. 
If the study day of discontinuation as documented on the eCRF page is below 54 days, 
discontinuation will be considered as ‘During Treatment Period’, otherwise it will be 
considered as ‘During Follow-Up Period’. 
If the eCRF question ‘Was the emergency envelope opened during the study?’ was 
answered ‘Yes’, the patient will be considered as unmasked. 
 
7.2.2 Demographic Characteristics 
Demographic characteristics are recorded on the eCRF page “Demography”. 
Gender (Male, Female), Ethnicity (‘Hispanic, Latino, Spanish’, ‘Not Hispanic, Latino, 
Spanish’), and  Race (‘White’, ‘Black or African American’, ‘Asian’, ‘Native Hawaiian or Other 
Pacific Islander’, ‘American Indian or Alaska Native’, ‘Other’) will be analyzed as recorded on 
the eCRF. 
Age (years) will be calculated at Baseline as: 
 
the integer part of (Date of Baseline Visit - date of birth)/365.25. 
In case of incomplete dates, missing days will be set to 1st and missing months will 
be set to July. 
7.2.3 History of Corneal Surgery and other Medical History 
The details of Corneal Surgery are recorded on the eCRF page “Medical history”.  
The following parameters will be analysed: 
 
Patients with previous cataract surgery (Yes/No) 
 
Eyes involved in previous cataract surgery per patient (Right Eye only, Left Eye only, 
Both Eyes) 
 
Patients with previous refractive surgery (Yes/No) 
 
Eyes involved in previous refractive surgery per patient (Right Eye only, Left Eye 
only, Both Eyes) 
 
Patients with previous LASIK surgery (Yes/No) 


 
 
 
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 
Eyes involved in previous LASIK surgery per patient (Right Eye only, Left Eye only, 
Both Eyes) 
 
Identification of study eye(s) (‘Right eye’, ‘Left eye’) is recorded on the “Study Eye” eCRF 
page and will be analyzed as derived categories ‘Both Eyes’, ‘Left Eye only’, ‘Right Eye only’. 
All other medical history is recorded on the “Medical history” eCRF page.  
Medical history contains information about conditions that a patient might have suffered prior 
to Baseline visit, or conditions that are ongoing at the time of the Baseline visit. 
The medical history terms as 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.  
In the event that coding information will not be available for a specific medical history record, 
the record will be presented as ‘Uncodable Record’). However, for final TLFs it is anticipated 
that all medical history records are coded. 
 
7.2.4 Prior and Concomitant Medication 
Prior and Concomitant medication data will be collected throughout the study on the ‘Prior 
and 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. 
Prior medications are defined as medications that were stopped before the date of first study 
treatment administration, i.e. stopped on treatment day 1 or before. 
Concomitant medications comprise all medications that a patient used at any stage during 
the treatment or Follow-up period, i.e. medications, which are ongoing at treatment day 1 or 
medications which started on or after treatment day 1. 
Relative start and stop day of a medication will be defined as the corresponding treatment 
day as specified in section 7.1. If for a medication ‘Ongoing’ duration is specified, no stop day 
will be calculated. 
From the above follows that a medication can either be prior or concomitant. 
The Investigator Terms (Generic Medication Name, and Indication) will be coded using the 
Enhanced WHO-Drug Dictionary, B-Files, Version MARCH/2016. 
Prior and concomitant medication data will be summarized by WHO-ATC class 2 
(Therapeutic Main Class) and WHO drug name (Preferred Term). 
 
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 ‘Uncodable 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]).  


 
 
 
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Missing and/or incomplete dates will be imputed in a manner that assumes the worst case 
scenario.  
Technically, incomplete stop dates will be imputed as follows: 
 
For a missing day (but month and year is available), it will be assumed that 
medication have been stopped on the last day of the respective month. 
 
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 as being 
ongoing. 
 
Similarly, incomplete start dates will be imputed as follows: 
 
For a missing start day (but month and year is available), onset is assumed on the 
first day of the respective month. 
 
For a missing start month (but year is available), onset is assumed on 1st January of 
the respective year.  
 
For a completely missing start date, no imputation is performed. However, the 
medication will be considered as concomitant, unless indicated different by stop date. 
 
7.2.5 Measurements of Exposure and Treatment Compliance 
Exposure 
Exposure will be summarized by the parameters Treated Eyes and Treatment Duration. 
Information about the type of eyes treated are recorded on the eCRF page ‘Study Eye’ at the 
Baseline Visit. Generally, all eligible eyes should be treated. The parameter Treated Eyes will 
be presented in the following categories: 
 
Both eyes: answer to eCRF question ‘Which eye(s) will be treated’ is Right Eye and 
Left Eye. 
 
Left eye only: answer to eCRF question ‘Which eye(s) will be treated’ is only Left Eye.  
 
Right eye only: answer to eCRF question ‘Which eye(s) will be treated’ is only Right 
Eye.  
Treatment duration will be derived based on dates of first and last study treatment 
administration recorded on the ‘Study Drug Dosing Dates’ eCRF page. It will be calculated as 
 
Date of Last Study Treatment Administration – Date of First Study Treatment 
Administration +1. If a patient has not received any study treatment in any eye, 
treatment duration will be set to 0. 
 
Compliance 
The assessment of patients’ compliance to the IMP will be made by determining the number 
of study medication vials dispensed to the patient at Day 0 baseline Visit, Week 4 Visit and 
the number of unused study medication vials returned at Week 4 Visit and Week 8 Visit, 


 
 
 
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respectively. This information is collected on eCRF page ‘Study Drug Dosing and 
Accountability’. 
Compliance will be evaluated according to the following formula: 
Compliance (%) = 100 * 
Number of vials dispensed – Number of unused vials returned 
Number of expected days on treatment 
 
The number of expected days on treatment will be set to 56. For each patient, the number of 
vials dispensed will be derived as the sum of provided numbers in the column “# Vials 
Dispensed” on the eCRF Page ‘Study Drug Dosing and Accountability; the number of unused 
vials returned will be derived as the sum of provided numbers in the column “# Vials Unused” 
on the eCRF Page ‘Study Drug Dosing and Accountability’. 
 
Compliance will be presented categorical as <80%, 80-120%, >120%. 
No further analyses will be planned on compliance. All other collected data including diary 
information on treatment compliance will be evaluated during the BDRM for relevant protocol 
deviations and will be listed. 
 
7.2.6 Study Medication 
Table 3: Study Treatments’ shows the Study Treatments and how they will be labelled in all 
TLF outputs.  
Table 3: Study Treatments  
Study Treatment 
Study Treatment Label 
rhNGF 20µg/mL 
rhNGF 
Vehicle 
Vehicle 
 
7.2.7 Efficacy Variables  
Primary Endpoints: SANDE Score 
The Symptom Assessment in Dry Eye (SANDE) questionnaire is a short questionnaire to 
evaluate both dry eye intensity and frequency by using a 100 mm visual analogue scale 
(VAS). The patient symptoms of ocular dryness and/or irritation will be quantified on the 
scale based on two questions that assess both severity and frequency of symptoms.  
For the assessment, the patients mark on the 100 mm VAS line the point that they feel 
represents their perception of their current state. The VAS score is determined by measuring 
in millimeters from the left hand end of the line to the point that the patient marks. The 
SANDE scores will be then evaluated for the 2 questions severity (0-100) and frequency (0-
100). 
The SANDE score will be assessed at Baseline, Week 4, Week 8 and Week 12 visit and is 
recorded on the eCRF page ‘Symptoms Assessment in Dry Eye’. At each visit, only one 
assessment is performed aggregating the situation for both eyes (i.e. no separate 
assessment per study eye). 
Primary endpoints will be defined as: 


 
 
 
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 
Change from Baseline in SANDE frequency score at Week 8  
 
Change from Baseline in SANDE severity score at Week 8 
If at least one SANDE assessment is missing at Week 8, the values of the last post-baseline 
assessment (including those from unscheduled visits) with non-missing values for frequency 
and severity will be imputed (LOCF). No imputation is performed in case of a missing 
baseline value (as defined in section 7.1). 
Additionally, SANDE frequency and severity scores as well as respective changes from 
Baseline will be evaluated without any imputation for Week 4, Week 8 and Week 12, 
respectively. 
 
Co-Primary Efficacy Endpoint: Corneal Staining (NEI Scale) 
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.  
Briefly, on the grading scale used grade 0 reflects normal/healthy situation, whereas grade 3 
reflects a severe damage in each considered sector. 
Ocular Surface Staining is assessed separately for each eye at Baseline, Week 4, Week 8 
and Week 12 visit and is recorded on the eCRF page ‘Ocular Surface Staining (NEI score)’. 
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 will only be 
calculated, if all 5 sector scores are available. If at least one corneal staining assessment is 
missing at Week 8, the values of the last post-baseline assessment (including those from 
unscheduled visits) with non-missing values for frequency and severity will be imputed 
(LOCF). 
Co-Primary endpoint will be defined as: 
 
Change from Baseline (CFB) in Corneal Staining at Week 8 for Main Eye. 
In addition, the endpoint Change from Baseline in Corneal Staining at Week 8 for Secondary 
Eye will be considered as descriptive supportive analysis (only for patients in Subgroup 2 
eyes treated).  
To estimate the between patient variability, the Individual Mean Change will be derived for 
the subgroup of patients in the FAS with 2 eyes treated, as: 
 
Mean of CFB Main eye and CFB Secondary Eye, per patient at Week 8 
To estimate the within patient variability, the Individual Difference in CFB for Corneal Staining 
between Study Eyes will be derived for the subgroup of patients in the FAS with 2 eyes 
treated, as: 
 
CFB Main eye - CFB Secondary Eye, per patient at Week 8 
Additionally, Corneal Staining scores as well as respective Changes from Baseline will be 
evaluated for Week 4, Week 8 and Week 12, respectively. No imputation will be envisaged 
for these endpoints. 
Secondary Endpoints: Conjunctival Staining (NEI Scale) 
As grading scale of the corneal and conjunctiva damage, the NEI/Industry Workshop 
guidelines will be used [2].  


 
 
 
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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, respectively.  
Briefly, on the grading scale used grade 0 reflects normal/healthy situation, whereas grade 3 
reflects a severe damage in each considered sector. 
Ocular Surface Staining is assessed separately for each eye at Baseline, Week 4, Week 8 
and Week 12 visit and is recorded on the eCRF page ‘Ocular Surface Staining (NEI score)’. 
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. 
Secondary endpoint will then be defined as: 
 
Change from Baseline in Conjunctival Staining at Week 8 for the Main Eye as well as 
for the Secondary Eye for Week 4, Week 8 and Week 12, respectively. 
No imputation will be envisaged for these parameters. 
 
Secondary Endpoint: Tear Film Break-Up Time (TFBUT) 
TFBUT will be measured by determining the time to tear break-up. 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 recorded on the 
eCRF Page ‘Tear Film Break Up Time‘ will be the average of the 2 or 3 measurements. 
A TFBUT > 10 seconds will represent normal values, whereas values ≤ 10 seconds are likely 
for Dry Eyes. 
TFBUT is assessed separately for each eye at Baseline, Week 4, Week 8 and Week 12 visit. 
TFBUT value as well as respective Changes from Baseline will be evaluated for Week 4, 
Week 8 and Week 12, respectively. No imputation will be envisaged for this parameter. 
 
Secondary Endpoint: Corneal sensitivity 
Corneal sensitivity is measured continuously in cm by the Cochet-Bonnet aesthesiometer at 
Day 0 and Week 8 visits in each of the four quadrants of the cornea: Superior nasal, inferior 
nasal, superior temporal, inferior temporal. It is assessed separately for each study eye. 
Corneal sensitivity values as well as respective Changes from Baseline will be evaluated for 
Day 0 and Week 8 visits, respectively. No imputation will be envisaged for this parameter. 
 
7.2.8 Safety Variables 
Adverse Events (AE) 
AE data are collected on the ‘Adverse Events’ eCRF page. Corrective medications or 
procedures due to an AE are documented on the eCRF pages ‘Prior and Concomitant 
Medications’ and ‘Concomitant Procedures’ respectively. 


 
 
 
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The AE Description (Investigator term) will be analyzed on Preferred Term (PT) and System 
Organ Class (SOC) level using MedDRA. 
Based on the information provided on the ‘Adverse Events’ eCRF page, the following 
definitions will be utilized: 
 
An ocular event will be identified, if the question ‘Is this an ocular event?’ is answered 
‘Yes’. 
 
An AE with missing severity will be counted as severe.  
 
A Serious Adverse Event (SAE) is any adverse event where the question ‘Is the event 
serious?’ has been answered as ‘Yes’. If this question is not answered the event will 
be considered as ‘Serious’ for analysis purposes. 
 
The following adverse events are considered to be of special interest (AESI) and by 
default shall be reported as SAEs (medically important criteria): 
o AEs 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 AEs that caused a decrease in visual acuity to the level of Light Perception or 
worse lasting >1 hour 
o AEs that required surgical intervention (e.g., conventional surgery, vitreous tap 
or biopsy with intravitreal injection of anti-infectives, or laser or retinal 
cryopexy with gas) to prevent permanent loss of sight 
o AEs associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis) 
o AEs that, in the opinion of the Investigator, may require medical intervention to 
prevent permanent loss of sight. 
For analysis purposes, AESI will be identified by ticked box ‘Medically significant or 
important medical condition’ in the eCRF section ‘SAE criteria’. This means in 
particular, that all AESIs will be considered as SAEs. 
 
An AE leading to premature withdrawal of the study treatment is defined as an AE 
where in the eCRF section ‘Action taken with study treatment’ the boxes ‘Withdrawn’ 
and ‘Definitely’ are ticked.  
 
An AE leading to study treatment interruption is defined as an AE where in the eCRF 
section ‘Action taken with study treatment’ the boxes ‘Withdrawn’ and ‘Temporarily’ 
are ticked.  
 
An AE leading to study discontinuation is defined as an AE where in the eCRF 
section ‘Action regarding Patient’ the box ‘Patient Withdrawn’ is ticked (this should 
match with the primary reason for early withdrawal of ‘Adverse Event’ on the End of 
Study eCRF page). 
 
An AE is classified as ‘Related’ to Study Treatment if the relationship to study 
medication recorded as ‘Possible’ or ‘Probable’ or ‘Highly Probably’. 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’.  


 
 
 
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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. They are identified by the ticked box ‘Before Treatment Period’ in the eCRF 
Section ‘Did the event occurred:’. 
 
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. A TEAE will be identified, if The eCRF question 
‘Did the event occurred:’ was answered either with ‘During Treatment period’ or ‘During 
Follow-Up Period’.  
The incidence and frequency of TEAEs will serve as safety endpoint of the study. 
 
TEAEs in the Treatment Period 
This will be defined as a TEAE (as defined above) with a start date on or after the date of first 
study treatment administration and before the Week 8 Visit. It will be identified, if eCRF 
question ‘Did the event occurred:’ was answered with ‘During Treatment period’. 
TEAEs in the Follow-up Period 
This is defined as a TEAE (as defined above) with a start date on or after the Week 8 Visit. It 
will be identified, if eCRF question ‘Did the event occurred:’ was answered with ‘During 
Follow-Up period’. 
For listing purposes, treatment day of onset of AE will be presented 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 ‘Uncodable 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-TEAEs, TEAE in the Treatment Period or TEAE in the 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 the 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.  


 
 
 
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 
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 ‘During 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 ’During Follow-Up period’ this procedure results in an onset date before date 
of Week 8 visit, date of Week 8 visit will be used. 
 
Best Corrected Visual Acuity (BCDVA) 
Best-corrected visual acuity is measured at Day 0 Baseline, Week 8 and Week 12 visit using 
standard charts, lighting, and procedures. All eyes must be tested at 4 meters first. When a 
patient cannot read at least 20 letters on the chart at 4 meters, the patient is tested at 1 
meter.  
In addition, the Snellen Equivalent is collected, which is based on smallest line read correctly 
(i.e. no or max. 1 error). The Scale is categorical and does not easily lend itself to statistical 
analysis or easy comparison but the logarithm of the minimal angle of resolution (logMAR) 
scale allows visual acuity to be assessed as a continuous measurement. 
Visual acuity is recorded on the eCRF page ‘Best Corrected Distance Visual Acuity’. 
For the analysis, the BCDVA score and the logMAR as well as respective changes from 
baseline will be evaluated at Week 8 and Week 12. No imputation will be envisaged for these 
endpoints. 
The BCDVA 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 (i.e. BCDVA score) for 
that eye is recorded as the number of letters correct at 4 meters plus 30. The patient 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.” 
The logMAR will be derived as – log (Snellen Equivalent result). For this derivation the 
Snellen equivalent result is presented as fraction as documented in the eCRF field ‘Snellen 
Equivalent Result’. LogMAR values derived from Snellen equivalent results range from -0.3 
(20/10) to 1.6 (20/800) and will by rounded by 2 decimals. An increase in logMAR reflects a 
worsening of visual acuity. 
If for a patient only ability for counting fingers is reported, logMAR will be set to 2; if for a 
patient only recognition of hand motion is reported, logMAR will be set to 3 [1]. 
 
Slit lamp examination 
Slit lamp examination is performed separately for each eye at Baseline, Week 4, Week 8 and 
Week 12 visit and is recorded on the eCRF page ‘Slit Lamp Examination (Biomicroscopy)’. 
Grading of the eyelids, lashes, conjunctiva, cornea, lens, iris and anterior chamber will be 
done according to the following scales:  


 
 
 
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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).  
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  
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).  
Lens  
0 = No opacification (normal lens).  
1 = Mild lens opacification.  
2 = Moderate lens opacification.  
3 = Severe lens opacification. 
Iris  
0 = Normal  
1 = Abnormal. 
Anterior Chamber Inflammation  


 
 
 
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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).  
 
All grading assessments of different eye structures will be evaluated as collected on the 
eCRF at Baseline Visit, Week 4, Week 8 and Week 12. No imputation will be envisaged for 
these parameters. 
No aggregated presentation is planned for other assessments done during Slit lamp 
evaluation. 
External ocular examination 
External Ocular Examination assesses the motility of the extraocular muscles and the 
appearance and function of the eyelids before the instillation of any dilating or anesthetic eye 
drops. 
Motility of extraocular muscle and appearance/function of eye lids is assessed separately for 
each eye at Baseline, Week 4, Week 8 and Week 12 visit and is recorded on the eCRF 
pages ‘External Ocular Examination’ and ‘Appearance and Function of Eyelids’. 
For the analysis, the Motility of the Extraocular Muscle will be evaluated by the field of 
movements Right and up (‘Normal’, ‘Abnormal’), Right (‘Normal’, ‘Abnormal’), Right and 
Down (‘Normal’, ‘Abnormal’), Left and Up (‘Normal’, ‘Abnormal’), Left (‘Normal’, ‘Abnormal’), 
Left and Down (‘Normal’, ‘Abnormal’) as documented at the eCRF at Baseline Visit, Week 4, 
Week 8 and Week 12. No imputation will be envisaged for these parameters. 
Appearance and Function of Eyelids will be summarized by the following parameters: 
 
Incidence of proven eyelid deformity/abnormality, which will be considered as 
present, if the question ‘Evidence of eyelid deformity or abnormality’ on the eCRF 
page ‘Appearance and Function of Eyelids’ is answered ‘Yes’. 
 
 
Incidence of abnormal motor function of eyelids (i.e. upper lid elevation and forceful 
lid closure), which will be considered as present, if the question ‘Motor function of 
eyelids’ on the eCRF page ‘Appearance and Function of Eyelids’ is answered 
‘ABNORMAL’. 
 
 
Incidence of corneal exposure in case of closed eyelids, which will be considered as 
present, if the question ‘Is there corneal exposure when the eyelids are closed?’ on 
the eCRF page ‘Appearance and Function of Eyelids’ is answered ‘Yes’. 
 
 
Incidence of proven punctual occlusion, which will be considered as present, if the 
question ‘Is there evidence of punctual occlusion?’ on the eCRF page ‘Appearance 
and Function of Eyelids’ is answered ‘Yes’. 
 
 
Incidence of punctual plugs, which will be considered as present, if the box ‘Punctual 
plugs’ is ticked on the eCRF page ‘Appearance and Function of Eyelids’. 
 


 
 
 
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 
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 punctual occlusion, which will be considered as present, if the 
respective ‘Other’ box is ticked on the eCRF page ‘Appearance and Function of 
Eyelids’. 
 


 
 
 
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8 Analysis Methods 
8.1 General Methods 
All analyses for this exploratory study will be done by using appropriate descriptive statistics 
by study group. All results will be summarized in tables. Patient individual data will be 
provided in Listings. No graphs are envisaged for this study. 
For continuous variables, the mean, standard deviation, coefficient of variation (in %), 
minimum, median and maximum will be presented, together with the total number of 
observations and the number of missing and non-missing values. Unless otherwise specified 
minimum and maximum values will be reported to the same number of decimal places as the 
recorded measurements, mean and median are reported to one more decimal place and 
standard deviation one additional decimal place more than the mean.  
For categorical variables, absolute and relative frequencies will be reported. Relative 
frequencies will be based on all observations and reported as a percentages to one decimal 
place. Unless otherwise specified, percentages will be based on the number of patients in 
considered analysis set including also percentages for missing categories. Only categories 
with non-null values will be presented in summary tables. 
Incidences like adverse events, medical history and concomitant medications will be reported 
on a subject basis. The percentages will be calculated using the number of patients in the 
considered analysis data set. 
8.2 Specific Methods for Efficacy Analyses 
As a general principle, all efficacy analyses will be performed on a patient-level, considering 
the Main Eye for the analysis of Co-Primary and Secondary efficacy endpoint. Efficacy data 
in Secondary eye will be present as descriptive summaries and listed.  
For the primary and co-primary efficacy endpoints, mean change from baseline will be 
compared between treatment groups. The null hypothesis will be tested that there is no 
difference between rhNGF and vehicle in the mean overall CFB between both treatments: 
H0:  rhNGF =  Vehicle 
H1:  rhNGF   Vehicle 
Where  is the mean change from baseline at considered visit within the given treatment. 
This hypothesis will be tested exploratory at a 5% level of significance with an Analysis of the 
Covariance (ANCOVA) with treatment, respective baseline value and eye subgroup (1 vs 2 
study eyes treated) in the model.  
The Least-squares means estimate of the treatment effect and the treatment group 
difference (both with 95% confidence intervals) will be reported. P-values will be rounded to 
three decimal places. If a p-value is less than 0.001 it will be reported as “<0.001”. Due to the 
high numbers of observations, the assumption of normality is assumed. 
The ANCOVA analysis will be performed for the following endpoints: 
 
Change from Baseline in SANDE Frequency and Severity Score at Week 8 (LOCF) 
for the FAS as exploratory primary efficacy analyses 
 
Change from Baseline in SANDE Frequency and Severity Score at Week 8 (LOCF) 
for the PPS as supportive to primary efficacy analyses 


 
 
 
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 
Change from Baseline in SANDE Frequency and Severity Score (without imputation) 
at Week 8 for the FAS as supportive to primary efficacy analyses 
 
Change from Baseline in Corneal Staining at Week 8 (LOCF) for the FAS as 
exploratory to co-primary efficacy analyses 
 
Change from Baseline in Corneal Staining at Week 8 (LOCF) for the PPS as 
supportive to co-primary efficacy analyses 
 
Change from Baseline in Corneal Staining (without imputation) at Week 8 for the FAS 
as supportive to co-primary efficacy analyses 
 
8.2.1 Statistical/Analytical Issues  
8.2.1.1 Adjustments for Covariates 
Not alpha adjustment is envisaged, as all statistical hypotheses testing will be performed in 
an exploratory manner. 
8.2.1.2 Handling of Dropouts or Missing Data 
In the derivation of endpoints there will be no replacement of missing data except for primary 
endpoint CFB in SANDE Frequency and Severity Score and co-primary efficacy endpoint 
CFB in Corneal Staining, age, adverse event dates as well as concomitant medication dates. 
Details of applied imputations are described in the respective sections of chapter 7.2. 
8.2.1.3 Multiple Comparisons/Multiplicity 
Due to this being an exploratory study, no adjustment of any p-values will be made to 
account for inflation of the Type 1 error rate arising from multiple comparisons or multiple 
endpoint testing. 
 
8.3 Specific Methods for Safety Analyses 
As a generally principle, adverse event data will be analyzed separately by study period 
(Non-TEAE, TEAE).  
All other safety assessments will be summarized by Visit and Eye (Main Eye/Secondary 
Eye).  
According to the study protocol, both eyes of a patient should be treated, if eligible. However, 
there might be the situation, that one eye will not be treated. If a visit-based safety 
assessment was performed in an eye, which has not been treated with study medication, it 
will not be included in descriptive summaries but displayed in listings. Such assessments will 
be flagged in the listings accordingly. 


 
 
 
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9 Overview of Tables, Listings and Figures  
This section describes the TLFs per topic with variables and populations used. For the 
content, titles and layout of tables see the table shells, which will be added as appendix to 
this document. 
9.1 Disposition of Patients 
A disposition summary of patients includes the number (n) and percentage (%) of patients 
screened, screen failures, included in the Enrolled Set, included in the SAF, FAS as well as 
in the PPS as defined in section 6.1. Presentation will be provided by study treatment and 
overall. Percentages, if applicable, will be based on the total number of patients (of 
considered treatment group) included in the Enrolled Set. A listing will also be provided for 
this information on individual patient level for the Enrolled Set. 
A summary of study discontinuation will be provided for the Enrolled Set including number 
and percentage of discontinuations study during treatment period, primary reason for study 
discontinuation during treatment period, discontinuations during the Follow-Up period, 
primary reason for study discontinuation during the Follow-Up Period as well as study 
completers. Moreover, number and percentages of patients who were unmasked during 
study will be provided. Presentation will be provided by study treatment and overall. 
Percentages will be based on the total number of patients (of considered treatment group) 
included in the Enrolled Set.  
A listing will also be provided for this information added by the date of first and last study 
medication intake as documented on the eCRF page ‘Study Drug Dosing Dates’. 
For Screen failure a listing will be provided including the primary reason for discontinuation.  
9.2 Protocol Deviations and Patient Eligibility 
Protocol Deviations that might affect the efficacy of treatment will be reviewed during BDRM. 
A major protocol deviation will lead to an exclusion from the PPS.  
The number of patients in the FAS who had at least one Major Protocol Deviation as well as 
a specific type of protocol deviation (as defined during the BDRM) will be summarized by 
absolute counts (n) and percentages (%) and displayed by treatment group and overall. 
Percentages will be based on the number of patients in the FAS.  
A listing will be provided presenting all protocol deviation data for the Enrolled Set. 
The eligibility of all patients for entry into the study will be assessed at the Baseline visit by 
the inclusion and exclusion criteria (‘Inclusion Criteria’ and ‘Exclusion Criteria’ eCRF pages). 
Two listing will be presented including all patients of the Enrolled Set, who fail/meet at least 
one Inclusion or Exclusion criteria, along with all their deviating Inclusion and Exclusion 
responses, respectively. 
9.3 Demographic and Other Baseline Characteristics 
9.3.1 Demographic Characteristics 
Demographic data age, gender, ethnicity as well as race will be summarized by treatment 
group and overall for the SAF by treatment group and overall. Demographic Data will also be 
listed. 


 
 
 
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9.3.2 History of Corneal surgery and other Medical History 
Summary statistics will be provided for patients with previous cataract surgery and involved 
eyes per patient, patients with previous refractive surgery and involved eyes per patient and 
patients with previous LASIK surgery and involved eyes per patient as well as identified 
Study Eyes per patient (‘Left Eye only’, ‘Right Eye only’, ‘Both Eyes’) and Identified Main Eye 
(‘Left Eye’, ‘Right Eye’ as defined in section 6.1) by treatment group and overall for patients 
in the SAF. A listing will also be provided. 
Other Medical History will be summarized for the SAF by treatment group and overall on a 
per-patient basis (i.e. if a patient reported the same event repeatedly the event will be 
counted only once at the specific level of display). Absolute counts (n) and percentages (%) 
will be presented for the number of patients with at least one Medical History event, and per 
SOC and per PT within SOC. 
A listing presents all medical history data for the SAF.  
9.3.3 Prior and Concomitant Medications 
Prior and Concomitant Medications will be summarized for the SAF on a per-patient basis 
(i.e. if a patient reported the same medication repeatedly the medication will be counted only 
once at the specific level of display). Absolute counts (n) and percentages (%) will be 
presented for the number of patients with at least one medication, and per WHO-ATC Drug 
Class 2 (ATC therapeutic main class) and per WHO-DD Drug Name (Preferred Term) within 
WHO-ATC Drug Class 2. 
A Listing will be presented for Prior and Concomitant medications of patients in the SAF 
providing all collected details on the eCRF. 
9.4 Measurements of Exposure and Treatment Compliance  
Exposure will be evaluated by summary statistics for the parameters Treated Eyes and 
Treatment Duration by treatment group. This analysis will be performed for the SAF. This 
information will be listed. 
Compliance will be summarized categorical (<80%, 80-120%, >120%) for the FAS by 
treatment group. This information as documented on the eCRF Page ‘Study Drug Dosing 
and Accountability’ will be listed for the SAF accordingly. 
Further information on compliance as recorded on the eCRF Page ‘Diary Information’ and 
‘Exposure’ at Week 4 and Week 8 will be listed for the SAF. 
Further information on compliance as recorded on the eCRF Page ‘Patient Diary’ at Week 4 
and Week 8 will be listed for the SAF. 
 
9.5 Efficacy Results 
9.5.1 Primary Efficacy Analysis 
Results of the SANDE Frequency and SANDE Severity Score at Week 8 (absolute values as 
well as changes from baseline) will be summarized descriptively by treatment group. For the 
primary analysis LOCF is applied as described in section 7.2.7. The exploratory p-value and 
estimates for treatment effect as well as treatment group difference resulting from the 
ANCOVA analysis specified in section 8.2 will be reported in addition for Week 8 Visits. 
Primary analysis will be performed on the FAS. 


 
 
 
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For supportive purposes, this analysis of Week 8 results will be repeated for the PPS to 
investigate the effect of protocol deviations on the results. 
If the covariate ‘Number of Study Eyes’ would result in a significant effect, the ANCOVA 
analysis will be repeated for each subgroup separately. 
A similar analysis will be performed for the SANDE Frequency and SANDE Severity Score 
(without imputation) at Week 8. This analysis will be performed for the FAS only. 
A descriptive analysis will be performed for the SANDE Frequency and SANDE Severity 
Score (without imputation) at Baseline, Week 4 and Week 12 as well as respective CFB 
without performing statistical inference. This analysis will be performed for the FAS only. All 
data on SANDE Scores will be listed on the FAS, indicating clearly imputed values. 
9.5.2 Co-Primary Efficacy Analysis 
Results of the co-primary endpoint Change from Baseline in Corneal Staining at Week 8 will 
be summarized descriptively by treatment group for Main Eye and Secondary Eye for the 
FAS.  
For the co-primary analysis LOCF is applied as described in section 7.2.7. The exploratory p-
value and estimates for treatment effect as well as treatment group difference resulting from 
the ANCOVA analysis specified in section 8.2 will be reported in addition for the Main-Eye 
results at Week 8. 
For supportive purposes, this analysis of Main Eye results at Week 8 will be repeated for the 
PPS to investigate the effect of protocol deviations on the results. 
If the covariate ‘Number of Study Eyes’ would result in a significant effect, the ANCOVA 
analysis will be repeated for each subgroup separately. 
To investigate the influence of within and between patient variability, a descriptive analysis 
will be presented based on subgroup of patients in the FAS with 2 study eyes including CFB 
in Corneal Staining in Main Eye, Secondary Eye as well as the Individual Mean Change (i.e. 
mean of change in Main and Secondary Eye in each patient) and Individual Difference 
between Study Eyes at Week 8. 
A similar analysis will be performed for the absolute values as well as for CFB in Corneal 
Staining (without imputation) at Week 4, Week 8 and Week 12. ANCOVA analysis will be 
performed for CFB at Week 8 in the Main Eye. This analysis will be performed for the FAS 
and all data will be listed for the FAS. 
9.5.3 Secondary Efficacy Analysis 
The secondary endpoints Conjunctival Staining, TFBUT as well as Corneal Sensitivity 
endpoints (absolute values as well as CFB) will be summarized descriptively for patients in 
the FAS by treatment group and study visit for Main Eye and Secondary Eye. No inference 
will be performed for these parameters. 
Listing on secondary efficacy endpoints including assessments for Main Eye and Secondary 
Eye will be provided for FAS, in addition. 


 
 
 
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9.6 Safety Results 
9.6.1 Adverse Events 
9.6.1.1 Brief Summary of Adverse Events 
Reporting of AEs is focused to treatment emergent AEs. 
An overview of AEs, TEAEs, TEAEs during Treatment Period, TEAEs during Follow-up 
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, TEAEs of special interest and Mild, Moderate and Severe TEAEs will 
be given by study treatment and overall for patients in the SAF. For each events, the number 
and percentages of patients with at least one event as well as the total number of events will 
be provided.  
9.6.1.2 Display of Adverse Events 
Adverse event descriptive tables will be summarized separately for each study treatment and 
overall.  
They will be summarized on a per-patient basis (i.e. if a patient reported the same event 
repeatedly the event will be counted only once at the specific level of display). Absolute 
counts (n) and percentages (%) will be presented for the number of patients with at least one 
Adverse event, and per SOC and per PT within SOC, for the SAF. Percentages will be based 
on the number of patients in the population. In addition number of events will be provided. 
Descriptive tables will be ordered by descending frequency of the overall number of patients 
within each SOC regardless of treatment group, and then ordered within each SOC by the 
overall number of patients within each PT regardless of treatment group. In the event of 
equal frequencies tables will be ordered by active treatment frequency and then 
alphabetically. 
The following tables will be provided: 
 
Non-TEAE 
 
TEAEs 
 
TEAEs by severity. 
 
Treatment related TEAEs. 
 
Serious TEAEs. 
 
Treatment related serious TEAEs 
 
TEAEs that occur with a relative frequency in the active treatment of at least twice the 
relative frequency in the vehicle group.  
 
TEAEs leading to premature withdrawal of the Study Treatment. 
 
TEAEs leading to study discontinuation. 
 
TEAEs during Treatment Period 
 
TEAEs during Follow-up Period. 
 


 
 
 
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9.6.1.3 Listings of Adverse Events 
Listings will present all Adverse Event data for the SAF by patient.  
In addition specific listings will be created for: 
 
TEAEs leading to premature withdrawal of study treatment 
 
TEAEs leading to study treatment interruption 
 
TEAEs related to study treatment 
 
Serious AEs 
 
Serious TEAEs related to study treatment 
 
 Fatal TEAEs 
Corrective procedures as documented on the eCRF page ‘Concomitant Procedures’ will be 
listed for all patients in the SAF. 
9.6.2 Clinical Laboratory Evaluation 
A Listing will be provided for patients in the SAF displaying the results of pregnancy tests at 
Baseline, Week 4 and Week 8 as documented on the eCRF Page ‘Urine Pregnancy Test’. 
9.6.3 Best Corrected Visual Acuity  
BCDVA score and logMAR (absolute values as well as changes from baseline) will be 
summarized descriptively by treatment group and study visit for the Main Eye as well as the 
Secondary Eye. This analysis will be performed on the SAF. All BCDVA data will be listed. 
9.6.4 Slit Lamp Examination  
All grading assessments of different eye structure (excluding assessment for Other 
structures) will by will be summarized descriptively by treatment group and study visit for the 
Main Eye as well as the Secondary eye. This analysis will be performed on the SAF.  
All data recorded on the eCRF page ‘Slit Lamp Examination (Biomicroscopy)’ will be listed. 
9.6.5 External Ocular Examinations  
All evaluations of the motility of extraocular muscle Right and Up, Right, Right and Down, 
Left and Up, Left, Left and Down will by will be summarized descriptively by treatment group 
and study visit for the Main Eye as well as the Secondary Eye. This analysis will be 
performed on the SAF. These data will also be listed. 
Incidences of proven eyelid deformity/abnormality, abnormal motor function of eyelids, 
corneal exposure in case of closed eyelid, proven punctual occlusion, punctual plugs, 
thermal or surgical occlusion or other punctual occlusion will be presented by treatment 
group and study visit for the Main Eye as well as for the Secondary Eye.  
Incidences will be calculated as number and percentages of affected patients. The analysis 
will be performed on the SAF. Moreover, these date will be listed.  
 
 


 
 
 
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10 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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11 Tables, Listings and Figures  
Details on Tables and Listings (TLFs) will be provided in a separate document and are 
attached as appendix to this SAP. 
TLF Number 
Title 
List of Tables 
Table 14.1-1.1 
Summary of Patient Disposition 
Table 14.1-1.2  
Summary of Study Discontinuation (Enrolled Set) 
Table 14.1-2.1 
Summary of Protocol Deviations (FAS) 
Table 14.1-3.1 
Summary of Demographic Data (Enrolled Set) 
Table 14.1-4.1 
Summary of History of Corneal Surgery (SAF) 
Table 14.1-5.1 
Summary of Medical History (SAF) 
Table 14.1-6.1 
Summary of Prior Medications (SAF) 
Table 14.1-6.2 
Summary of Concomitant Medications (SAF) 
Table 14.1-7-1 
Summary of Treatment Compliance (FAS) 
Table 14.2-1.1  
Summary of SANDE Scores at Week 8 (LOCF) (FAS) 
Table 14.2-1.2  
Summary of Change from Baseline of SANDE Scores at Week 8 (LOCF) 
(FAS) 
Table 14.2-1.2.1  
Summary of Change from Baseline of SANDE Scores at Week 8 in 
Subgroups (LOCF) (FAS) 
Table 14.2-1.3  
Summary of SANDE Scores at Week 8 (LOCF) (PPS) 
Table 14.2-1.4  
Summary of Change from Baseline of SANDE Scores at Week 8 (LOCF) 
(PPS) 
Table 14.2-2.1  
Summary of SANDE Scores by Visit (Observed) (FAS) 
Table 14.2-2.2  
Summary of Change from Baseline of SANDE Scores by Visit (Observed) 
(FAS) 
Table 14.2-3.1 
Summary of Corneal Staining at Week 8 (LOCF) (FAS) 
Table 14.2-3.2 
Summary of Change from Baseline of Corneal Staining at Week 8 (LOCF) 
(FAS) 
Table 14.2-3.2.1 
Summary of Change from Baseline of Corneal Staining at Week 8 in 
Subgroups (LOCF) (FAS) 
Table 14.2-3.3 
Summary of Corneal Staining at Week 8 (LOCF) (PPS) 
Table 14.2-3.4 
Summary of Change from Baseline of Corneal Staining at Week 8 (LOCF) 
(PPS) 
Table 14.2-3.5 
Summary of Change from Baseline of Corneal Staining at Week 8 in 
Subgroup of Patients with 2 Study Eyes (LOCF) (FAS) 
Table 14.2-4.1 
Summary of Corneal Staining by Visit (Observed) (FAS) 
Table 14.2-4.2 
Summary of Change from Baseline of Corneal Staining (Observed) (FAS) 
Table 14.2-5.1 
Summary of Conjunctival Staining by Visit (FAS) 
Table 14.2-5.2 
Summary of Change from Baseline of Conjunctival Staining by Visit (FAS) 


 
 
 
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TLF Number 
Title 
Table 14.2-6.1 
Summary of Other Secondary Efficacy Endpoints by Visit (FAS) 
Table 14.2-6.2 
Summary of  Change from Baseline of Other Secondary Efficacy 
Endpoints by Visit (FAS) 
Table 14.3.1-1.1 
Summary of Exposure (SAF) 
Table 14.3.2-1.1 
Overall Summary of Adverse Events (SAF) 
Table 14.3.2-2.1 
Summary of Non-TEAEs by System Organ Class and Preferred Term 
(SAF) 
Table 14.3.2-3.1 
Summary of TEAEs by System Organ Class and Preferred Term (SAF) 
Table 14.3.2-4.1 
Summary of Treatment Related TEAEs by System Organ Class and 
Preferred Term (SAF) 
Table 14.3.2-5.1 
Summary of Serious TEAEs by System Organ Class and Preferred Term 
(SAF) 
Table 14.3.2-6.1 
Summary of Serious Treatment Related TEAEs by System Organ Class 
and Preferred Term (SAF) 
Table 14.3.2-7.1 
Summary of TEAEs with a Relative Frequency in the Active Treatment 
Group of At Least Twice the Relative Frequency in the Vehicle group by 
System Organ Class and Preferred Term (SAF) 
Table 14.3.2-8.1 
Summary of TEAEs Leading to Premature Withdrawal of the Study 
Treatment by System Organ Class and Preferred Term (SAF) 
Table 14.3.2-9.1 
Summary of TEAEs Leading to Study Discontinuation by System Organ 
Class and Preferred Term (SAF) 
Table 14.3.2-10.1 
Summary of TEAEs during Treatment Period by System Organ Class and 
Preferred Term (SAF) 
Table 14.3.2-11.1 
Summary of TEAEs during Follow-Up Period by System Organ Class and 
Preferred Term (SAF) 
Table 14.3.2-12.1 
Summary of TEAEs by Severity, System Organ Class and Preferred Term 
(SAF) 
Table 14.3.3-1.1 
Summary of BCDVA score (SAF) 
Table 14.3.3-1.2 
Summary of Change from Baseline of BCDVA (SAF) 
Table 14.3.3-2.1 
Summary of logMAR (SAF) 
Table 14.3.3-2.2 
Summary of Change from Baseline of LogMAR (SAF) 
Table 14.3.4-1.1 
Summary of Slit Lamp Examination (SAF) 
Table 14.3.5-1.1 
Summary of Motility of Extraocular Muscle (SAF) 
Table 14.3.5-2.1 
Summary of Appearance and Function of Eyelid (SAF) 
List of Listings 
Listing 16.1.7-1.1 
Randomized Allocation to Treatment and assigned kit numbers (Enrolled 
Set) 
Listing 16.2.1-1.1 
Listing of Screening Failure 
Listing 16.2.1-1.2 
Listing of Study Completion (Enrolled Set) 
Listing 16.2.2-1.1 
Listing of Protocol Deviations (Enrolled Set) 


 
 
 
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TLF Number 
Title 
Listing 16.2.2-1.2 
Listing of Inclusion Criteria Deviations at Baseline (Enrolled Set) 
Listing 16.2.2-1.3 
Listing of Exclusion Criteria Deviations at Baseline (Enrolled Set) 
Listing 16.2.3-1.1 
Listing of Allocation to Analysis Sets (Enrolled Set) 
Listing 16.2.4-1.1 
Listing of Demographic Data (SAF) 
Listing 16.2.4-2.1 
Listing of History of Corneal Surgery (SAF) 
Listing 16.2.4-3.1 
Listing of Medical History (SAF) 
Listing 16.2.4-4.1 
Listing of Prior and Concomitant Medications (SAF) 
Listing 16.2.5-1.1 
Listing of Exposure and Treatment Compliance (SAF) 
Listing 16.2.5-1.2 
Listing of Treated Eyes, Self Administration and Diary summary 
information (SAF) 
Listing 16.2.5-1.3 
Listing of Patient Diary Entries (SAF) 
Listing 16.2.6-1.1 
Listing of SANDE Scores (FAS) 
Listing 16.2.6-2.1 
Listing of Ocular Surface Staining: Corneal Staining (FAS) 
Listing 16.2.6-2.2 
Listing of Ocular Surface Staining: Conjunctival Staining (FAS) 
Listing 16.2.6-2.3 
Listing of TFBUT and Corneal Sensitivity (FAS) 
Listing 16.2.7-1.1 
Listing of Adverse Events (SAF) 
Listing 16.2.7-1.2 
Listing of TEAEs Leading to Premature Withdrawal of Study Treatment 
(SAF) 
Listing 16.2.7-1.3 
Listing of TEAEs Leading to Study Treatment Interruption (SAF) 
Listing 16.2.7-1.4 
Listing of TEAEs Related to Study Treatment (SAF) 
Listing 16.2.7-1.5 
Listing of Serious AEs (SAF) 
Listing 16.2.7-1.6 
Listing of Serious TEAEs Related to Study Treatment (SAF) 
Listing 16.2.7-1.7 
Listing of Fatal TEAEs (SAF) 
Listing 16.2.7-2.1 
Listing of Action taken due to AEs (SAF) 
Listing 16.2.7-2.2 
Listing of Corrective Procedures Related to AEs (SAF) 
Listing 16.2.8-1.1 
Listing of Urine Pregnancy Test (Females in SAF) 
Listing 16.2.9-1.1 
Listing of BCDVA assessments (SAF) 
Listing 16.2.9-1.2 
Listing of BCDVA score, Snellen Scale and logMAR (SAF) 
Listing 16.2.10-1.1 
Listing of Slit Lamp Examination – Part I (SAF) 
Listing 16.2.10-1.2 
Listing of Slit Lamp Examination – Part II (SAF) 
Listing 16.2.11-1.1 
Listing of Motility of Extraocular Muscle (SAF) 
Listing 16.2.11-2.1 
Listing of Appearance and Function of Eyelids (SAF) 
 
 


 
 
 
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TF-ST-03/00-02 
Version 2.0, date 15/DEC/2014 
12  Appendices 
 
Statistical Analysis Plan: Tables, Listings and Figures Mock Shells Attachment (Separate 
Document)