Clinical trial NCT03982368
Conditions: Dry Eye Syndrome
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2019-06-10; Completion date: 2020-07-15
Enrollment: 261 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to assess the efficacy and safety of rhNGF eye drops at 20 μg/ml concentration administered two or three times daily for 4 weeks in patients with moderate to severe dry eye.

Detailed description:
This is a 4 weeks, Phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with 12 weeks of follow-up, designed to perform dose-ranging and to evaluate safety and efficacy of recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle, in patients with moderate to severe dry eye (DE).

Test product is rhNGF 20 μg/ml; reference product is vehicle. Test and reference will be instilled in both eyes according to the following scheme:

Group 1: one drop of rhNGF 20 μg/ml is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Group 2: one drop of rhNGF 20 μg/ml is instilled in both eyes two times daily (in the morning and in the evening) plus one drop (40 μL) of vehicle (placebo) is instilled in both eyes once daily in the afternoon.

Group 3: one drop (40 μL) of vehicle (placebo) is instilled in both eyes three times daily (every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).

Approximate randomization 1:1:1 of 261 patients to rhNGF eye drops solution 20 μg/ml TID (87 patients) or rhNGF eye drops solution 20 μg/ml BID + vehicle eye drop SID (86 patients) or vehicle eye drops solution (88 patients) TID for 4 weeks was applied.

Arms: arm 1: One drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) arm 2: One drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily (BID) plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (OD) (every 6-8 hours) arm 3: Vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours)
Interventions: intervention 1: rhNGF 20 μg/ml intervention 2: rhNGF 20 μg/ml + vehicle intervention 3: Vehicle
Intervention descriptions: intervention 1: one drop of rhNGF 20 μg/ml will be instilled in both eyes three times daily (every 6-8 hours) intervention 2: one drop of rhNGF 20 μg/ml will be instilled in both eyes two times daily plus one drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours).

rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the afternoon. intervention 3: one drop of vehicle will be instilled in both eyes three times daily (every 6-8 hours)

Protocol documents:
Prot_000.pdf: 
16.1.1 
Protocol and Protocol Amendments 
The latest version of the protocol used during the study is provided in this section. Previous 
versions of the protocol are available on request. 
Protocol NGF0118 Version 2 dated 08-August-2019 
 
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CLINICAL STUDY PROTOCOL 
 
Title: A 4 week, Phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel 
group study with 12 weeks of follow-up to evaluate safety and efficacy of recombinant human 
Nerve Growth Factor (rhNGF) eye drops solution versus vehicle in patients with moderate to 
severe dry eye (DE). 
 
 
 
 
Study Number: 
NGF0118  
 
IND: 
115892 
 
Investigational Product: 
rhNGF  
 
Phase of the study: 
 II 
 
 
Protocol Version - Date: 
Version No. 2.0 – 08/AUG/2019 
 
As per Final Amendment no. 1 – 08/AUG/2019 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential information 
that is the property of Dompé farmaceutici s.p.a. It is understood that the information will not be used, 
divulged, or published without prior written consent of Dompé farmaceutici s.p.a., except to the extent such 
disclosure is required by applicable laws and regulations. 
 
 
 
 
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NGF0118 
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DESCRIPTION OF CHANGES  
 
Version  
Modification  
Date of 
Revision  
Application  
1.0 
Final Version 
22-JAN-
2018 
NA 
1.1 
Section 5.2.1.4 - line N° 5: typing error “merked” modified as 
“marked” 
Section 5.3 – 7th paragraph: typing error “……pipettes (6 per vial) and 
disinfectant wipes (6 per vial)” modified as “……pipettes (1 per vial) 
and disinfectant wipes (1 per vial)” 
23-JAN-
2018 
NA 
1.2 
Section 5.2.1.1 – typing error “NIMP Primary Packaging, Single Pane 
Label For Single Vial (Blink® Tears)” has been modified as “NIMP 
Secondary Packaging, Single Pane Label For Single Vial (Blink® 
Tears)” 
Section 5.2.1.1 – add the following line to the labels of NIMP: “For 
clinical trial use only” 
Section 5.2.1.4 – label, line 7  – typing error “Batch <vvvv>/” has been 
modified as “Batch <vvvv>”.  
Section 5.2.1.4 – label, line 9 (Subj. Screening # S) and 10  
(Subj. Randomization # R) has been modified as line 9: 
Unique Patient N° - according CRO randomization 
procedure.  
Section 5.1.1 - “Administration route” typing error “Ophthalmic” has 
been modified as “Ocular”. 
Section 5.1.2 – “Pharmaceutical form” – “Sterile buffered acqueous 
solution” has been modified as “Eye drops Sterile buffered acqueous 
solution”.  
Section 5.1.2  - “Administration route” typing error “Ophthalmic” has 
been modified as “Ocular”. 
04-FEB-
2019 
Submitted 
to FDA on 
20FEB2019 
1.3 
Dr. Pier Adelchi Ruffini, as Global Head Clinical Development and Beth 
Butler, as  Clinical Development Manager, have been added as part of 
Dompé team.   
Section 4.1 – IC N° 5 “Best corrected distance visual acuity (BCDVA) 
score of ≥ 0.1 decimal units in both eyes at the time of study enrolment” 
has been modified as “Best corrected distance visual acuity (BCDVA) 
score of ≥ 0.1 decimal units (20/200 Snellen value) in both eyes at the 
time of study enrolment”.  
Section 7.1.3 – typing error “Number of drop out due to worsening in 
symptom scores (SANDE) and/or NEI score ≥ 50% assessed at  week 2” 
has been modified as “Number of patients experienced a  worsening in 
13-
MAR-
2019 
 
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symptom scores (SANDE) and/or NEI score ≥ 50% assessed at  week 2.  
 Section 6.1 and 6.2 – information about the check and collection of 
patient’s diary has been added.  
 Section 5.1.1 and 6.2 — the following sentence has been added “The 
patient, only if strictly needed, can administer additional drops and must 
document in the patient’s diary the n° of additional drops administered 
for each eye”. 
Section 5.3 – typing error, the following sentence has been deleted “[…] 
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.” 
Section 6 – a definition of First Patient In has been added. 
 Section 8.2 – typing error in numbering the visit. 
Section 2 – “Check and retrieval of patient’s diary” has been added.  
Section 6.3.1 – “Disease progression or worsening” has been added as 
primary reason of discontinuation. 
Section 5.4.2 – typing error, from “The exact time of study drug  
administration […]” has been corrected to “Information about the  study 
drug administration […]”. 
Section 5.2.1. – added information about the coloured vials. 
2.0 
General  
The typing errors have been corrected in all text where present. 
The sections have been re-numbered where necessary. 
The table of contents has been updated. 
The list of abbreviations and definition of terms has been updated. 
Section 1 Study Centers: the sentences has been modify as follows: “8-
12 study sites in US” 
Section 1 Number of Patients: the section is modified as follows: 
“Eligible patients will be randomized in a 1:1:1 ratio to either rhNGF 
eye drops solution 20 µg/ml TID (⁓100 patients) or rhNGF eye drops 
solution 20 µg/ml BID plus vehicle eye drop solution SID (⁓100 
patients) or vehicle eye drop solution TID (⁓100 patients). 
Randomization will be stratified according to absence/presence of a 
documented diagnosis of Primary Sjögren's Syndrome to ensure 
balanced 
assignment 
across 
treatment 
groups 
proportional 
assignment. A minimum 60 patients (20 per group) with Primary 
Sjögren's Syndrome should be included. The enrollment of patients 
will be scheduled in order to assure an inclusion of approximately 240 
patients without Primary Sjögren's Syndrome diagnosis and at least 
60 patients  with Primary Sjögren's Syndrome.” 
Section 1.  Inclusion criteria #7: the following criteria has been modified 
deleting:“IEC.”   
08-
AUG-
2019 
Will be 
Submitted 
to FDA 
with 
mid of 
August 
2019 
 
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Section 1. Main Inclusion criteria: the following criteria has been added 
as number 9: “Primary Sjögren's Syndrome Patients:  
x 
Patients with a documented diagnosis of Primary Sjögren's 
Syndrome according to the American-European Consensus 
Group Sjögren's Syndrome Criter ia (Appendix 3; must meet 
either 4 out of 6 total criteria OR 3 out of 4 signs). Note: 
Subjects who are on systemic (oral) therapy for the treatment 
of Sjögren's Syndrome must be on stable systemic treatment 
defined as the same treatment for the immediately prior 90 
days”  
Section 1  Exclusion criteria #4: the sentence as been modified as 
follows: “History of severe systemic allergy or severe ocular allergy 
(including seasonal conjunctivitis) or chronic conjunctivitis and/or 
keratitis other than dry eye”  
Section 1: Main Exclusion criteria #8 – The criteria has been modified 
as follows: “Patient had a serious adverse reaction or significant 
hypersensitivity to any drug or chemically related compounds or had a 
clinically significant allergy to drugs, foods, amide local anesthetics or 
other materials including commercial artificial tears, in particular 
commercial artificial tears containing carboxymethylcellulose (CMC) 
(in the opinion of the investigator).” 
Section 1: Main Exclusion criteria #9 – bullet point - b.has been 
modified as follows “b. have a positive result at the urine pregnancy test 
(Screening/Baseline Day 1) or,”  
Section 1:  Exclusion criteria #15: the criteria is modified as follows: 
“15. Participation in a clinical trial with a new active substance during the 
past 6 months 60 days” 
Section 1: Duration of Study:  a time window is specified for the wash-
out period:  “Wash-out period (from day -8 to day-1): 7+2 days with no 
further treatment except commercially available preservative free 
artificial tears. NB: the wash-out should not be less than 7 days  
Section 1  Study population: The following sentence has been added: 
“At least 60 out of 300 patients with a documented diagnosis of 
Primary Sjögren's Syndrome”  
Section 1: Safety Endpoint: has been modifies as follows: “Incidence 
and frequency of Treatment-emergent adverse events (TEAEs), 
assessed throughout the study. 
Section: 1: Statistical Methods: The first paragraph has been modified 
as follows: “The data collected in this study will be summarized using 
number of observations, mean, standard deviation (SD), median, 
minimum, and maximum values for quantitative variables, and 
frequencies for qualitative variables.” 
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The second paragraph has been modified as follows:“1) Statistical 
Methods - Efficacy analysis  
Primary endpoints will be analyzed using analysis of variance including 
only the treatment as main factor followed by pre-planned comparisons 
from Vehicle and rhNGF dosages according to Williams procedure. In 
addition, the  primary endpoint will be summarized using descriptive 
statistics for continuous variables by treatment and visit. The change 
from baseline value will also be summarized for all post-baseline 
visits.  
An explorative sensitivity analyses of primary endpoint will be 
conducted including in the analysis of variance the absence/presence 
of diagnosis of Primary Sjögren's Syndrome and its interaction with 
treatments as covariates. If the interaction term is statistically 
significant (at the 0.10 level given its explorative nature), the 
treatment effects within patients with and without Primary Sjögren's 
Syndrome will be provided.” 
The following paragraph has been added as third paragraph  
“Secondary endpoints will be presented with the appropriate 
descriptive statistics and inferential statistics appropriate for the 
nature of variable analyzed will be done in order to test treatment 
effect.”  
Section: 2. The second column title has been modified as follows:“Visit 1 
Baseline Day 1*” 
Section: 2. In the last line of schedule the following specification has been 
added:  
“*) visit window of +2 days;” 
Section 2.– line Ocular and Systemic Medical History: Delete “X” on 
colum Visit 1 Baseline Day 1. 
Section 3.1 –  the section has been modified as follows: “The study 
objective is to assess the efficacy and safety of rhNGF when administered 
as eye drops to patients with moderate to severe dry eye and to 
exploratively evaluate the preliminary efficacy data also in a group of 
dry eye patients with diagnosis of Primary Sjögren's Syndrome (14)” 
Section 3.2 – the first sentecce has been nodified as follows: “This study 
will be performed at 8/12 study centers located in the USA“ 
Section 3.3 –  the section has been modified to specify the time window 
for the wash-out: second sentence “Patients will be evaluated at screening 
visit (day -8), baseline (day 1+2), ….” 
Second paragraph “…free artificial tears for a period of 7 days - 9 days 
as maximum (day -8 to day -1+2) until the baseline visit (day 1). At the 
end of the wash out period (day -8 to day -1+2),…” 
Section: 3.3 The last  paragraph has been modified as follows: 
“Following the completion of the double-blind treatment patients will 
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be followed up for safety assessments for an additional 12 weeks post 
treatment and will be evaluated at the end of the safety follow-up period. 
During the safety follow-up period patients will not use further treatment 
except preservative free artificial tears provided by the Sponsor three 
times daily (morning, afternoon, evening ).” 
Section: 3.3 figure 1 has been modified to specify a time window for the 
wash-out period. 
 
Section: 4:  The following paragraphs will be added:  
“The safety and efficacy of rhNGF eye drops will be investigated also 
in a specific subgroup of patients with hyposecretive dry eye, i.e., 
patients with dry eye due to primary Sjögren's syndrome (2, 14). To 
gain information on the safety and efficacy of rhNGF in this subgroup 
of patients at least sixty (60) patients with a documented diagnosis of 
Primary Sjögren's Syndrome are out of 300 total patients are needed. 
It should be noted that patients with this type of dry eye could have 
already been enrolled based on the inclusion/exclusion criteria of the 
previous version of the study protocol. This amendment is applied 
only to set a minimum prespecified number of patients with Primary 
Sjögren's Syndrome.  The nature of the resulting statistical analysis 
in this subgroup of patients will be explorative. 
Including at least y 60 subjects with documented diagnosis of Primary 
Sjögren's Syndrome within the total sample size (20%) will have no 
impact on the initial assumptioms concerning sample size for the 
following reasons: 
x 
The previous study (NGF0216), on which sample size 
assumptions have been based (see section 9.1), reports a 
similar prevalence of patients with Primary Sjögren's 
Syndrome in their medical history (⁓25% in the FAS 
population). 
x 
As dry eye due to Sjogren’s syndrome is a hyposecretive form 
of the disease, the primary endpoint is appropriate for both 
the whole study population and the subgroup with Sjögren's 
syndrome” 
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x 
As anticipated, the same patients could have already been 
enrolled based on the previously applied and approved 
inclusion/exclusion criteria 
Section 4.1 Inclusion criteria: the following criteria has been added as 
number 6: “Subjects with a diagnosis of Primary Sjögren's Syndrome 
according the American-European Consensus Group Sjögren's 
Syndrome Criter ia (Appendix 3; must meet either 4 out of 6 total 
criteria OR 3 out of 4 signs). Note: Subjects who are on systemic (oral) 
therapy for the treatment of Sjögren's Syndrome must be on stable 
systemic treatment defined as the same treatment for the immediately 
prior 90 days.” 
Section 4.1 Inclusion criteria: general: the numbering of the inclusion 
criteria is revised accondingly. 
Section 4.2 Exclusion criteria: general: the numbering of the exclusion 
criteria is revised accondingly. 
Section 4.2 Exclusion criteria #4: to better explain the sentence has been 
modified as follows: “History of severe systemic allergy or severe ocular 
allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or 
keratitis other than dry eye” 
Section 4.2 Exclusion criteria #9 – bullet point - b. has been modify as 
follows: “b. have a positive result at the urine pregnancy test 
(Screening/Baseline Day 1) or,”  
Section 4.2 Exclusion criteria #15:  the sentence as been modified as 
follows: “Participation in a clinical trial with a new active substance 
during the past 60 days 
The following section has been added as section “4.3: ELIGIBLE EYE  
Process for determining the eligible eye: assuming that all the 
inclusion/exclusion criteria are met in both eyes, the worse eye 
(eligible eye) will be determined at the baseline visit using a 
stepladder approach, as follows: 
1. Schirmer’s Test (since this is the primary endpoint)-Worse eye 
determined as eye with lower Schirmer I score. If 
Schirmer I score is the same in both eyes, worse eye will 
be determined by NEI score (cornea+conjunctival 
staining). 
2. NEI score (cornea+conjunctival staining).  
If all of the above are identical, determination of the worse eye will 
be based on the Investigator’s judgement, then simply use the right 
eye as the eligible eye.” 
Section 4 - general: the numbering of the section are revised 
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accondingly 
Section 4.4 RANDOMISATION  – [page 28] 
The following paragraphs have been modified as follows:  
 “Eligible patients will be randomized in a 1:1:1 ratio to either rhNGF 
eye drops solution 20 µg/ml TID (⁓100 patients) or rhNGF  eye drops 
solution 20 µg/ml BID plus vehicle eye drop solution SID (⁓100 patients) 
or vehicle eye drop solution TID (⁓100 patients).” 
Randomization will be stratified according to absence/presence of a 
documented diagnosis of Primary Sjögren's Syndrome to ensure 
balanced assignment across treatment groups.  
Each randomized patient will be allocated with randomization number, 
according to the stratified randomization list. Drop outs after 
randomization will not be replaced.” 
The following paragraph have been add as last paragraph:  
“The enrollment of patients will be scheduled in order to assure an 
inclusion of approximately 240 patients wthout Primary Sjögren's 
Syndrome diagnosis and at least 60 patients  with Primary Sjögren's 
Syndrome. “ 
Section 4.5 MASKING  
The third paragraph has been modified as follows:  
“The investigator will be provided with an access, password 
protected, to the RAVE Randomization and Trial Supply 
Management system (RAVE RSTM) so only in case of a medical 
emergency the Investigator can open the treatment allocation for a 
specific patient.  
Besides also Dompé Pharmacovigilance contact person will be 
provided with an access, password protected, to the RAVE 
Randomization and Trial Supply Management system (RAVE 
RSTM) so if required by the Pharmacovigilance activities the 
Pharmacovigilance contact person can open the treatment allocation 
for a specific Patient.” 
Section 6.1  
Screening visits - Procedure/Assessments:  
The sentence following sentence has been deleted: “Ocular and Systemic 
Medical History” 
Screening visits - Procedure/Assessments:  
The sentence” Previous ocular and systemic medication” as bben 
mofided as follows:   “previous ocular and systemic medication (prior 
to start the study)”  
The sentence regarding the ocular surface staining has been modified to 
better clarify the test to be performed:  “Ocular surface staining (NEI 
score - corneal and conjunctival fluorescein staining)” 
Visit 1 baseline - Procedure/Assessments:   
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The sentence” Ocular and systemic medication” as bben mofided as 
follows:   “Previous ocular and systemic medication (prior to start the 
study”  
The sentence regarding the ocular surface staining has been modified to 
better clarify the test to be performed:  “Ocular surface staining (NEI 
score - corneal and conjunctival fluorescein staining)”  
The order of the procedure has been revised to clarify that the patient 
elegiliby should be performed after the ocular the systemic and ocular 
assessment:  
The following procedures will be performed (order below is mandatory): 
¾ Pregnancy test for female patients of childbirth potential 
¾ Ocular and systemic medical history 
¾ Previous ocular and systemic medications (prior to the treatment) 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the eyelid (Meibomian glands), 
eyelid (erythema), eyelid (edema), lashes, conjunctiva erythema, lens, 
iris, anterior chamber, corneal horizontal diameter 
x TFBUT 
x Ocular surface staining (NEI score – corneal and conjunctival 
fluorescein staining) 
x Schirmer test II (with anesthesia) 
x Laser scanning confocal microscopy to assess goblet cells density 
(only selected sites)  
x Corneal endothelium and stroma evaluation (only the sites having a 
confocal microscope will do this type of evaluation)  
¾ Patient eligibility: Inclusion/exclusion criteria evaluation 
¾ Randomization 
¾ Study drug dispensation 
¾ Preservative free artificial tears dispensation  
¾ AE collection 
Visit 2 Week 2 - Procedure/Assessments    
The sentence regarding the slit-lamp examination as been modified as 
follows: Slit-lamp examination (SLE) to assess the eyelid (Meibomian 
glands), eyelid (erythema), eyelid (edema), lashes, conjunctiva erythema, 
lens, iris, anterior chamber, corneal horizontal diameter. 
The sentence regarding the ocular surface staining has been modified to 
better clarify the test to be performed:  “Ocular surface staining (NEI 
score - corneal and conjunctival fluorescein staining)”  
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Visit 3 Week 4 - Procedure/Assessments 
The sentence regarding the slit-lamp examination as been modified as 
follows:Slit-lamp examination (SLE) to assess the eyelid (Meibomian 
glands), eyelid (erythema), eyelid (edema), lashes, conjunctiva erythema, 
lens, iris, anterior chamber, corneal horizontal diameter. 
The sentence regarding the ocular surface staining has been modified to 
better clarify the test to be performed:  “Ocular surface staining (NEI 
score - corneal and conjunctival fluorescein staining)”  
Section 6.2: 
Visit 4 Follow up Week 8 - Procedure/Assessments 
Visit 5 Follow up Week 12 - Procedure/Assessments 
Visit 6 Follow up Week 16 - Procedure/Assessments 
The following sentences has been modified as follows: “Slit-lamp 
examination (SLE) to assess the eyelid (Meibomian glands), eyelid 
(erythema), eyelid (edema), lashes, conjunctiva erythema, lens, iris, 
anterior chamber, corneal horizontal diameter. 
The following sentences has been modified as follows: “Ocular surface 
staining (NEI score - corneal and conjunctival fluorescein staining)”  
Section 6.3.2.       Discontinuation procedures  [page 49] 
The last bullet point has been modified as follows:  
 “record in the eCRF any follow-up if the patient is withdrawn for an AE. 
AE’s should be followed until resolution.” 
Section 7.1.3.: The last bullet point has been modified as follows:  
 “Change from baseline in goblet cells density Vs week 4.” 
The following section has been added as section 7.1.5 
“7.1.5. Stratification according to absence /presence of Primary 
Sjögren's Syndrome 
x 
The primary, secondary, explorative and safety endpoints (see 
7.1.1, .7.1.2 7.13 & 7.1.4) will be also evaluated within each 
stratification subgroup (absence/presence of Primary Sjögren's 
Syndrome). 
Section 9: 
The first paragraph has been modified has follows: 
“The data collected in this study will be summarized using number of 
observations, mean, standard deviation (SD), median, minimum, and 
maximum values for quantitative variables, and frequencies for 
qualitative variables.” 
Section 9.1.:  The second paragraph, first bullet point has been modified 
as follows:“The probability level (α) for one-sided test is set at 0.025 
(see table 12.1.2 at page 298 in Chow et al., 2008) and the power level 
at approximately 90%.” 
The following paragraph has been added as last paragraph: 
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“The inclusion of approximately 60 subjects with documented 
diagnosis of Primary Sjögren's Syndrome within the planned 300 
patients will have no impact on the initial study assumptions 
(Standard Deviation of 10.78 and DELTA of 5.3 mm) because the 
patients could have been enrolled based on the previous criteria on 
which sample size was based. Moreover, a similar prevalence of 
patients with Primary Sjögren's Syndrome has already been reported 
in the NGF0216 medical history (⁓25% of patient the FAS 
population).” 
Section 9.2. The first paragraph has been modified as follows:  
“The Screened Population will consist of all patients with the 
signature of the informed consent, the assignment of a PID number 
and regardless the completion of all the screening procedures.”  
The second  paragraph has been modified as follows: “The Eligible 
Population will consist of all patients with all inclusion/exclusion 
criteria met. Otherwise the patientspatient will be defined as 
screening failure.”  
Section 9.3. The  formula has been implemented has follows: 
𝐎𝐯𝐞𝐫𝐚𝐥𝐥 𝐜𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞 
= 𝟏𝟎𝟎∗
(𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐯𝐢𝐚𝐥𝐬 𝐝𝐢𝐬𝐩𝐞𝐧𝐬𝐞𝐝 –  𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟 𝐮𝐧𝐮𝐬𝐞𝐝 𝐯𝐢𝐚𝐥𝐬 𝐫𝐞𝐭𝐮𝐫𝐧𝐞𝐝)
𝟑∗(𝑵𝒖𝒎𝒃𝒆𝒓𝒔 𝒐𝒇 𝒅𝒂𝒚𝒔 𝒐𝒏 𝒕𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕)
 
 
𝐂𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞 𝐟𝐨𝐫 𝐭𝐡𝐞 𝐞𝐥𝐢𝐠𝐢𝐛𝐥𝐞 𝐞𝐲𝐞 
= 𝟏𝟎𝟎∗
(𝐍𝐮𝐦𝐛𝐞𝐫 𝐨𝐟  𝐝𝐫𝐨𝐩𝐬 𝐚𝐝𝐦𝐢𝐧𝐢𝐬𝐭𝐞𝐫𝐞𝐝 𝐭𝐨 𝐭𝐡𝐞 𝐞𝐥𝐢𝐠𝐢𝐛𝐥𝐞 𝐞𝐲𝐞)
𝟑∗(𝑵𝒖𝒎𝒃𝒆𝒓𝒔 𝒐𝒇 𝒅𝒂𝒚𝒔 𝒐𝒏 𝒕𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕)
” 
 
Section 9.4.1.: The first paragraph has been modified has follows: “The 
Enrolled Set will consist of all patients who signed the ICF. This 
analysis set will be used for demographic, baseline and background 
characteristics.” 
The second paragraph has been modified as follows:Safety Population -
The Safety Population (SAF) will consist of all randomized patients 
who took at least one dose of IP. This analysis set will be used for the 
safety analysis. Patients will be analyzed according to the treatment 
received.” 
The third paragraphhas been modified has follows:  
“Full Analysis Set - Full Analysis Set (FAS) will consist of all 
randomized patients who took at least one dose of IP and who have at 
least one post-baseline efficacy measurement for the primary 
endpoint. This analysis set will be used for the primary efficacy 
analysis. Patients will be analyzed according to the randomized 
treatment.” 
The fourth  paragraph has been modified as follows:  
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“Per Protocol Set - “Per Protocol Set (PP) will consist of all patients 
in the FAS who fulfil the study protocol requirements in terms of 
investigational medicinal product intake and collection of primary 
efficacy data and with no major deviations that may affect study 
results. This analysis set will be used for supportive efficacy analysis. 
Patients will be analyzed according to the treatment received. 
Each patient will be coded by the Syneos Health statistician as valid 
or not valid for the Enrolled Set, SAF, FAS and PP.” 
Section 9.4.3.:The third bullet point has been modified as follows: 
“major 
deviation 
from 
inclusion/exclusion 
criteria 
(eligibility 
violations).” 
Section 9.4.4.: The paragraph has been modified as follows:  
 “Demographic and baseline characteristics will be descriptively 
summarized per treatment group according to their nature.”  
Section 9.5.: The  paragraph has been modified as follows::  
“Primary endpoint will be analyzed using analysis of variance 
including only the treatment as main factor followed by pre-planned 
comparisons from Vehicle and rhNGF dosages according to Williams 
procedure.In addition, primary endpoint will be summarized using 
descriptive statistics for continuous variables by treatment and visit. 
The change from baseline value will also be summarized for all post-
baseline visits. 
An explorative sensitivity analysis of primary endpoint will be 
conducted including in the analysis of variance the absence/presence 
of diagnosis of Primary Sjögren's Syndrome and its interaction with 
treatments as covariates. If the interaction term is statistically 
significant (at the 0.10 level given its explorative nature), the 
treatment effects within patients with and without Primary Sjögren's 
Syndrome will be provided. 
Secondary endpoints will be presented by means of appropriate 
descriptive statistics.  
Changes from baseline in global SANDE score, Schirmer test II, NEI 
scales, TFBUT,  IDEEL, PGIC and EQ-5D-3L scores 4 will be 
analyzed in a similar manner as the Change from baseline in 
Schirmer test I (primary endpoint) in order to test treatment effect. 
Difference between treatment groupsgroup (Each active dose vs 
Placebo), in the percentage of patients who experienced a worsening 
in SANDE scores and/or NEI score will be tested using a chi-square 
test.  
Explorative endpoints will be summarized by means of appropriate 
descriptive statistics. Any statistical testing will be descriptive in 
nature. 
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Additional details on the analyses will be provided in the statistical 
analysis plan.” 
Section 9.5.1: The send and third paragraphs have been modified from: 
“Treatment-emergent AEs are all events occurring or worsening after 
the first dose of the IMP. 
Treatment-emergent AEs will be summarized by treatment group. 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. Individual AEs will be listed in patient data listings.” 
A new section has been added:  
“Section 9.5.3     Subgroup analysis  
Sub-group analyses of primary, secondary and explorative endpoints 
will be performed on patients with the Sjögren's syndrome for 
explorative purpose. Statistical details will be reported in the SAP” 
Section 13:Reference 2: The reference has been updated as follows 
TFOS DEWS II REPORT. Ocul Surf 2017; 15(3):269-283 
Section 13: the following reference has been added:”14. Vitali C, 
Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren’s 
syndrome: a revised version of the European criteria proposed by the 
American-European Consensus Group. Ann Rheum Dis 2002; 61:554–
558.  
Section 14.1: the following sentence hasebeen modify as follows: “Elisa 
Greco, Clinical Research Specialist” 
The following section 14.3 has been added: “Appendix 3 American-
European Consensus Criteria for Sjögren’s Syndrome” 
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CONTACT INFORMATION 
SPONSOR 
Medical Expert 
Clinical Development 
Manager  
SAE Reporting 
Dompé farmaceutici S.p.A., Via S. Martino 12, 20122 Milan, Italy 
Phone: +39.02.583831 
Fax: +39.02.58383324 
Flavio Mantelli – Chief Medical Officer 
Email to: flavio.mantelli@dompe.com 
or Fax: +39.02.58383324 
Pier Adelchi Ruffini – Global Head Clinical Development 
Email to: pieradelchi.ruffini@dompe.com 
or Fax: +39.02.58383324 
Mauro P Ferrari– Clinical Senior Development Manager 
Email to: mauro.ferrari@dompe.com 
or Fax: +39.02.58383324 
Elisa Greco- Clinical Research Officer 
Email to: elisa.greco@dompe.com 
or Fax: +39.02.58383324 
Beth Butler – Clinical Development Manager 
Email to: beth.butler@dompe.com 
Laura Boga, Senior Safety Manager  
Email to: farmacovigilanza@dompe.com 
or Fax: +39.02.36026913 
CLINICAL RESEARCH 
ORGANIZATION 
Syneos Health,  
Corporate Headquarters 1030 Sync Street Morrisville, NC 27560 
     Phone: +1 919 876 9300 
 Fax: +1 919 876 9360 
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Table of Contents 
DESCRIPTION OF CHANGES  .......................................................................................................... 2 
CONTACT INFORMATION ............................................................................................................. 14 
Table of Contents ................................................................................................................................. 15 
List of Abbreviations and Definitions of Terms   .............................................................................. 19 
1. 
STUDY SYNOPSIS ......................................................................................................... 21 
2. 
SCHEDULE OF EVALUATIONS ................................................................................. 28 
2.1. 
BACKGROUND INFORMATION .................................................................................. 29 
2.1.1. 
Nerve Growth Factor - Overview ...................................................................................... 29 
2.1.2. 
Chemical And Formulation Data ....................................................................................... 29 
2.1.3. 
Rationale for rhNGF therapy in patients with dry eye ....................................................... 30 
2.2. 
A SUMMARY OF CLINICAL DATA ............................................................................. 31 
2.3. 
STUDY RATIONALE ...................................................................................................... 32 
2.3.1. 
Risk assessment/benefit evaluation.................................................................................... 32 
2.3.2. 
Description of the Investigational Product ........................................................................ 33 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ............................ 34 
3.1. 
STUDY OBJECTIVES ...................................................................................................... 34 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE ................................................................... 34 
3.3. 
OVERALL STUDY DESIGN ........................................................................................... 34 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study ......... 36 
4. 
SELECTION OF STUDY POPULATION ................................................................... 37 
4.1. 
INCLUSION CRITERIA .................................................................................................. 37 
4.2. 
EXCLUSION CRITERIA ................................................................................................. 38 
4.3. 
ELIGIBLE EYE ................................................................................................................. 40 
4.4. 
ASSIGNMENT OF PATIENT NUMBER ........................................................................ 40 
4.5. 
RANDOMISATION .......................................................................................................... 40 
4.6. 
MASKING ......................................................................................................................... 41 
5. 
STUDY MEDICATION .................................................................................................. 42 
5.1. 
DESCRIPTION OF PRODUCT ........................................................................................ 42 
5.1.1. 
Presentation of Non Investigational Medicinal Product (NIMP) ....................................... 42 
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5.1.2. 
Presentation of Investigational Medicinal Product ............................................................ 42 
5.2. 
FORMULATION AND PACKAGING ............................................................................ 44 
5.2.1. 
Labeling ............................................................................................................................. 44 
5.3. 
STORAGE AND HANDLING OF IMP ........................................................................... 48 
5.4. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION ................................ 50 
5.4.1. 
Administration route .......................................................................................................... 50 
5.4.2. 
Dose regimen ..................................................................................................................... 50 
5.5. 
ACCOUNTABILITY OF THE IMP ................................................................................. 50 
5.6. 
CONCOMITANT MEDICATION .................................................................................... 51 
6. 
STUDY PROCEDURE AND ASSESSMENTS ............................................................ 52 
6.1. 
SCREENING AND RANDOMIZATION VISITS ........................................................... 53 
6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS .................................................. 55 
6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT ................................ 60 
6.3.1. 
Primary Reason For Discontinuation From The Study ...................................................... 60 
6.3.2. 
Discontinuation procedures ............................................................................................... 61 
6.3.3. 
Replacement procedure ...................................................................................................... 61 
6.4. 
END OF STUDY ............................................................................................................... 61 
7. 
ENDPOINTS .................................................................................................................... 62 
7.1. 
STUDY ENDPOINTS ....................................................................................................... 62 
7.1.1. 
Primary endpoint................................................................................................................ 62 
7.1.2. 
Secondary endpoints .......................................................................................................... 62 
7.1.3. 
Exploratory endpoint ......................................................................................................... 62 
7.1.4. 
Safety endpoint .................................................................................................................. 63 
7.1.5. 
Stratification according to absence /presence of Primary Sjögren's Syndrome ................. 63 
8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION ............ 64 
8.1. 
DEFINITIONS................................................................................................................... 64 
8.2. 
ADVERSE EVENT (AE) MONITORING ....................................................................... 66 
8.3. 
RECORDING .................................................................................................................... 67 
8.3.1. 
Relationship of AEs to the Investigational Product ........................................................... 68 
8.3.2. 
Severity of AEs .................................................................................................................. 68 
8.4. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 69 
8.4.1. 
Reporting Procedure for Investigators to Dompé and CRO .............................................. 69 
8.4.2. 
Conditions that should not be reported as serious adverse events ..................................... 70 
8.4.3. 
Reporting Procedure to IRB and to Regulatory Authorities .............................................. 71 
8.4.4. 
Periodical Reporting to Regulatory Authorities ................................................................ 72 
8.5. 
UNMASKING OF THE STUDY TREATMENT ............................................................. 72 
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8.6. 
FOLLOW-UP OF PATIENTS WITH ADVERSE EVENTS (AES) ................................ 72 
8.7. 
PREGNANCY IN THE CLINICAL TRIAL ..................................................................... 73 
8.8. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ....................... 73 
8.9. 
OVERDOSE ...................................................................................................................... 74 
9. 
STATISTICS .................................................................................................................... 75 
9.1. 
SAMPLE SIZE .................................................................................................................. 75 
9.2. 
POPULATION .................................................................................................................. 76 
9.3. 
COMPLIANCE WITH IMP ADMINISTRATION .......................................................... 76 
9.4. 
STATISTICAL METHODOLOGY .................................................................................. 77 
9.4.1. 
Definitions ......................................................................................................................... 77 
9.4.2. 
Reasons for exclusion from the Full Analysis Set ............................................................. 77 
9.4.3. 
Reasons for exclusion from the Per Protocol set ............................................................... 77 
9.4.4. 
Demographic and baseline characteristics ......................................................................... 78 
9.5. 
ANALYSIS OF OPHTHALMOLOGICAL EVALUATIONS ......................................... 78 
9.5.1. 
Analysis of safety variables ............................................................................................... 79 
9.5.2. 
Analysis of Quality of Life variables ................................................................................. 79 
9.5.3. 
Subgroup analysis .............................................................................................................. 79 
9.5.4. 
Changes to the statistical plan ............................................................................................ 79 
10. 
ETHICAL CONSIDERATIONS .................................................................................... 80 
10.1. 
INSTITUTIONAL REVIEW BOARD .............................................................................. 80 
10.2. 
ETHICAL CONDUCT OF THE STUDY ......................................................................... 80 
10.3. 
DATA MONITORING COMMITTEE ............................................................................. 80 
10.4. 
PATIENT INFORMATION AND CONSENT ................................................................. 80 
10.5. 
CONFIDENTIALITY ....................................................................................................... 81 
10.6. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION81 
11. 
DATA HANDLING AND RECORD KEEPING .......................................................... 82 
11.1. 
CASE REPORT FORMS .................................................................................................. 82 
11.2. 
DATA MANAGEMENT .................................................................................................. 82 
11.3. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING THE 
STUDY .............................................................................................................................. 82 
11.4. 
ESSENTIAL DOCUMENT RETENTION ....................................................................... 83 
12. 
STUDY MANAGEMENT ............................................................................................... 84 
12.1. 
MONITORING .................................................................................................................. 84 
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12.2. 
ACCESS TO RECORDS ................................................................................................... 84 
12.3. 
AUDIT AND INSPECTION ............................................................................................. 84 
12.4. 
PROTOCOL AMENDMENTS ......................................................................................... 84 
12.5. 
DISCONTINUATION OF THE STUDY ......................................................................... 85 
12.6. 
PUBLICATIONS............................................................................................................... 85 
13. 
REFERENCES................................................................................................................. 86 
14 
APPENDICES .................................................................................................................. 87 
14.1 APPENDIX 1-SPONSOR APPROVAL PAGE ............................................................................ 87 
14.2 APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE ............................................................ 88 
14.3 APPENDIX 3AMERICAN-EUROPEAN CONSENSUS CRITERIA FOR SJÖGREN’S 
SYNDROME ..................................................................................................................... 89 
 
 
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List of Abbreviations and Definitions of Terms 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BCDVA 
Best Corrected Distance Visual Acuity  
BID 
Bis in die 
CFR 
Code of Federal Regulations 
CMC 
Carboxymethylcellulose 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
DE 
Dry Eye 
DHHS 
Department of Health and Human Services 
DNA 
Deoxyribonucleic 
 DSUR 
 Development Safety Update Report 
e-CRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
EQ-5D-3L 
EuroQol group 5 Dimensions 3 Level 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETV 
Early Termination Visit 
FAS 
Full Analysis set 
FDA 
Food and Drug Administration 
FPI 
First Patient In 
FPFV 
First Patient First Visit 
FU 
Follow Up 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDEEL 
Impact of Dry Eye on Everyday Life 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUD 
Intra Uterine Device 
LNGFR 
Low-affinity NGF receptor 
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LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for regulatory activities 
NEI 
National Eye Institute 
NIMP 
Non Investigational Medicinal Product 
NK 
Neurotrophic Keratitis  
PI 
Principal Investigator 
PID 
Patient Identification number 
PGIC 
Patient global Impression of Change 
PP 
Per Protocol Population 
PT 
Preferred term  
p75NTR 
p75 neurotrophin receptor 
rhNGF 
recombinant human Nerve Growth Factor 
RP 
Retinitis pigmentosa  
SAE 
Serious Adverse Event 
SAF 
Safety population 
SANDE 
Symptom Assessment in Dry Eye 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SID 
Semel in die 
SLE 
Slit-lamp examination 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Advers Event 
TFBUT 
Tear Film Break-Up Time  
TID 
Tris in die  
TrkA 
Tropomyosin receptor kinase A 
Vs 
Versus 
§ 
Section 
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1. STUDY SYNOPSIS  
 
CLINICAL STUDY SYNOPSIS:  
Study Number  
NGF0118 
Title of Study  
A 4 weeks, Phase II, multicenter, randomized, double-
masked, vehicle-controlled, parallel group study with 12 
weeks of follow-up to evaluate safety and efficacy of 
recombinant human Nerve Growth Factor (rhNGF) eye drops 
solution versus vehicle, in patients with moderate to severe 
dry eye (DE). 
IND N° 
115892 
Study Centers (Country)  
8-12 study sites in US 
Development Phase  
Phase II 
Objective  
The primary objective of this study is to assess the efficacy 
and safety of rhNGF eye drops at 20 µg/ml concentration 
administered two or three times daily for 4 weeks in patients 
with moderate to severe dry eye. The trial is designed to 
perform dose ranging. 
Study Design and 
Methodology  
This is a phase II,  multicenter, randomized, double masked, 
parallel arm, vehicle-controlled trial. 
Number of Patients  
Eligible patients will be randomized in a 1:1:1 ratio to either 
rhNGF eye drops solution 20 µg/ml TID (⁓100 patients) or 
rhNGF  eye drops solution 20 µg/ml BID plus vehicle eye drop 
solution SID (⁓100 patients) or vehicle eye drop solution TID 
(⁓100 patients). 
Randomization 
will 
be 
stratified 
according 
to 
absence/presence of a documented diagnosis of Primary 
Sjögren's Syndrome to ensure balanced assignment across 
treatment groups. 
A minimum of 60 patients (20 per group) with Primary 
Sjögren's Syndrome should be included. 
The enrollment of patients will be scheduled in order to assure 
an inclusion of approximately 240 patients without Primary 
Sjögren's Syndrome diagnosis and at least 60 patients  with 
Primary Sjögren's Syndrome. 
Main Inclusion criteria  
1. Male or female aged ≥ 18 years 
2. Patients with moderate to severe dry eye characterized by the following clinical features: 
a. Corneal and/or conjunctival staining with fluorescein using National Eye 
Institute (NEI) grading system > 3 
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b. SANDE questionnaire >25 mm 
c. Schirmer test I (without anaesthesia) >2mm <10 mm/5 minutes 
d. Tear film break-up time (TFBUT) < 10 seconds in the worse eye 
3. The same eye (eligible eye) must fulfill all the above criteria  
4. Patients diagnosed with dry eye at least 6 months before enrolment (current use or 
recommended use of artificial tears for the treatment of Dry Eye) 
5. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 
Snellen value) in both eyes at the time of study enrolment 
6. If a female of childbearing potential, have a negative pregnancy test  
7. Only patients who satisfy all Informed Consent requirements may be included in the 
study. The patient and/or his/her legal representative must read, sign and date the 
Informed Consent document before any study-related procedures are performed. The 
Informed Consent form signed by patients and/or legal representative must have been 
approved by the IRB for the current study 
8. Patients must have the ability and willingness to comply with study procedures. 
9. Primary Sjögren's Syndrome Patients:   
x 
Patients with a documented diagnosis of Primary Sjögren's Syndrome according the 
American-European Consensus Group Sjögren's Syndrome Criteria (Appendix 3; 
must meet either 4 out of 6 total criteria OR 3 out of 4 signs). Note: Subjects who 
are on systemic (oral) therapy for the treatment of Sjögren's Syndrome must be on 
stable systemic treatment defined as the same treatment for the immediately prior 90 
days. 
 
Main exclusion criteria 
1. Inability to speak and understand the local language sufficiently to understand the nature 
of the study, to provide written informed consent, and to allow the completion of all study 
assessments;  
2. Evidence of an active ocular infection, in either eye  
3. Presence of any other ocular disorder or condition requiring topical medication during the 
entire duration of study 
4. History of severe systemic allergy or severe ocular allergy (including seasonal 
conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry eye 
5. Intraocular inflammation defined as Tyndall score >0   
6. History of malignancy in the last 5 years 
7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with 
glycemia out of range, thyroid malfunction..) or judged by the investigator to be 
incompatible with the study (e.g. current systemic infections) or with a condition 
incompatible with the frequent assessment required by the study 
8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or 
chemically related compounds or had a clinically significant allergy to drugs, foods, 
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amide local anesthetics or other materials including commercial artificial tears, in 
particular commercial artificial tears containing carboxymethylcellulose (CMC) (in the 
opinion of the investigator) 
9. 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,  
have a positive result at the urine pregnancy test (Screening/Baseline Day 1) or,  
intend to become pregnant during the study treatment period or,  
are breast-feeding or, 
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 
10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the 
conduct of the study, confound the interpretation of the study results, or endanger the 
patient’s well-being  
11. Use of topical cyclosporine, topical corticosteroids or any other topical drug for the 
treatment of dry eye in either eye within 30 days of study enrolment 
12. Contact lenses or punctum plug use during the study (previous use not an exclusion 
criteria but must be discontinued at the screening visit) 
13. History of drug addiction or alcohol abuse 
14. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 
90 days before the screening visit 
15. Participation in a clinical trial with a new active substance including medical devices 
during the past  60 days 
16. Participation in another clinical trial study at the same time as the present study 
Test/Reference Product, 
Dosage and Mode of 
Administration  
Test product is rhNGF 20 µg/ml; reference product is vehicle. 
Test and reference will be instilled in both eyes according to 
the following scheme:  
Group 1:  one drop of rhNGF 20 µg/ml will be instilled in 
both eyes three times daily (every 6-8 hours, e.g. 
7:00 am, 02:00 pm; 09:00 pm).  
Group 2:  one drop of rhNGF 20 µg/ml will be instilled in 
both eyes two times daily plus one drop (40 µL) of 
vehicle will be instilled in both eyes once daily 
(every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 
pm). 
NB: rhNGF will be instilled in the morning and in 
the evening while the vehicle will be instilled in 
the afternoon.  
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Group 3: vehicle eye one drop will be instilled in both eyes     
three times daily (every 6-8 hours, e.g. 7:00 am, 
02:00 pm; 09:00 pm). 
The IMP will be provided in a monthly box containing 28 
daily boxes. Each daily box contains three marked vials one 
for each administration (e.g. 1- Morning, 2- Afternoon and 3- 
Evening). Together with the IMP monthly box, the patients 
will be provided with a sufficient number of pipette and 
adaptors to be used for the administration of the IMP.  
Duration of Study 
Patients will be evaluated at screening visit (day -8), baseline 
(day 1+2), week 2 (day 14r2), week 4 (day 28r2) or early 
exit and week 8 (day 56±2), 12 (day 84r4) and 16 (day 
112r7) weeks of follow-up. 
Screning Visit (day -8): all procedure for inclusion will be 
performed.  
Wash-out period (from day -8 to day-1): 7 +2 days with no 
further treatment except commercially available preservative 
free artificial tears. NB: the wash-out should not be less than 
7 days 
Treatment: eligible patients will be randomized 1:1:1 and 
treated for 4 weeks with either rhNGF eye drops 20 µg/ml 
TID, rhNGF eye drops 20 µg/ml BID and vehicle SID  or 
vehicle TID.  
During the treatment period only the experimental IMP is 
allowed. But, if strictly needed, the patient can use 
commercially available preservative free artificial tears, 
provided by Sponsor.  
Follow up: 12 weeks post treatment with no further treatment 
except commercially available preservative-free artificial 
tears provided by the Sponsor three times daily.  
The patient, only if strictly needed, can administer additional 
drops and must document in the patient’s diary the n° of 
additional drops administered for each eye.Maximum total 
study duration: 17 weeks. 
Study population 
Male and female with moderate to severe dry eye will be 
included. A total of 300 patients will be enrolled. At least 60 
out of 300 patients with a documented of Primary Sjögren's 
Syndrome should be included . 
  
 
Primary Efficacy Endpoint 
 
Primary end-point: 
1.  Change from baseline in Schirmer I test (without 
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anesthesia) Vs week 4.  
Secondary Efficacy Endpoints  
Secondary end-points: 
1. Change from baseline in Symptoms questionnaire 
(SANDE) scores for severity and frequency Vs week 
4;  
2. Change from baseline in Schirmer II test (with 
anesthesia) Vs week 4; 
3.  Change from baseline in Cornea and conjunctiva vital 
staining with fluorescein (National Eye Institute 
[NEI] scales) Vs week 4; 
4.  Change from baseline in Tear Film Break-Up Time 
(TFBUT) Vs week 4  
5. Number of patients who experienced  a worsening in 
symptom scores (SANDE) and/or NEI score ≥ 50% 
assessed at  week 4; 
6. Quality of life (Impact of Dry Eye on Everyday Life 
(IDEEL) questionnaire;  
7. Patient global Impression of change (PGIC);  
8. EQ-5D-3L. 
Exploratory Endpoints 
1. Correlation between sign and symptom scores; 
2. Proportion and frequency of preservative free artificial 
tears use (n° drops/day) during the treatment period; 
3. Frequency of preservative free artificial tears use (n° 
drops/day) during the follow up period. 
4. Change from baseline in Schirmer I test (without 
anesthesia) Vs week 2;  
5. Change from baseline in Symptoms questionnaire 
(SANDE) scores for severity and frequency Vs week 
2;  
6. Change from baseline in Cornea and conjunctiva vital 
staining with fluorescein (National Eye Institute 
[NEI] scales) Vs week 2; 
7. Change from baseline in Tear Film Break-Up Time 
(TFBUT) Vs week 2; 
8. Number of patients who experienced a  worsening in 
symptom scores (SANDE) and/or NEI score ≥ 50% 
assessed at  week 2; 
9. Change from baseline in goblet cells density Vs week 
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4.  
Safety Endpoint 
1. Incidence and frequency of Treatment-emergent 
adverse events (TEAEs), assessed throughout the 
study. 
Statistical Methods 
The data collected in this study will be summarized using 
number of observations, mean, standard deviation (SD), 
median, minimum, and maximum values for quantitative 
variables, and frequencies for qualitative variables. 
 
1) Efficacy analysis 
Primary endpoints will be analyzed using analysis of 
variance including only the treatment as main factor followed 
by pre-planned comparisons from Vehicle and rhNGF 
dosages according to Williams procedure. In addition, 
primary endpoint will be summarized using descriptive 
statistics for continuous variables by treatment and visit. The 
change from baseline value will also be summarized for all 
post-baseline visits. 
An explorative sensitivity analysis of primary endpoint will 
be conducted including in the analysis of variance the 
absence/presence of diagnosis of Primary Sjögren's 
Syndrome and its interaction with treatments as covariates. If 
the interaction term is statistically significant (at the 0.10 
level given its explorative nature), the treatment effects 
within patients with and without Primary Sjögren's Syndrome 
will be provided. 
It will be summarized using descriptive statistics for 
continuous variables by treatment and visit. The change from 
baseline value will also be summarized for all post-baseline 
visits. 
Secondary endpoints will be presented with the appropriate 
descriptive statistics and inferential statistics appropriate for 
the nature of variable analyzed will be done in order to test 
treatment effect.   
 
Explorative endpoints will be summarized by means of 
appropriate descriptive statistics. Any statistical testing will 
be descriptive in nature. 
 
2) Safety analysis 
AEs 
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Adverse events (AEs) will be coded by System Organ Class 
(SOC) and Preferred Term (PT), using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Individual AEs will be listed in patient data listings.  AEs will 
be summarized by treatment group. 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.  
 
3) Quality of life analysis  
Data recorded in the questionnaires of quality of life will be 
presented with appropriate descriptive statistics and 
processed with appropriate inferential test. 
 
 
 
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2. SCHEDULE OF EVALUATIONS 
 
Study procedures 
Screening 
(Day-8) 
Visit 1 
Baseline 
Day 1* 
Visit 2 
Week 2 
Visit 3 
End of 
treatment 
Week 4a 
Visit 4 
follow-up 
Week 8a 
Visit 5 
follow-up 
Week 12b 
 
Visit 6 
follow-up 
Week 16c 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Ocular and Systemic 
Medical History 
X 
 
 
 
 
 
 
Previous Ocular And 
Systemic Medications 
X 
X 
 
 
 
 
 
SANDE 
X 
X 
X 
X 
X 
X 
X 
IDEEL 
X 
X 
 
X 
X 
X 
X 
EQ-5D-3L 
X 
X 
 
X 
X 
X 
X 
PGIC 
 
 
 
X 
X 
X 
X 
BCDVA 
X 
X 
X 
X 
X 
X 
X 
External Ocular 
Examination 
X 
X 
X 
X 
X 
X 
X 
Schirmer test I 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Examination 
X 
X 
X 
X 
X 
X 
X 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
Fluorescein staining (NEI 
scale) 
X 
X 
X 
X 
X 
X 
X 
Schirmer test II 
 
X 
 
X 
 
 
X 
Confocal microscopy to 
assess goblet cells density d 
 
X 
 
X 
 
 
X 
Corneal endothelium and 
stroma evaluation as per 
confocal microscopy e 
 
X 
 
X 
 
 
X 
Study drug dispensation 
 
Xf 
 
 
 
 
 
Verify patient study 
medication dosing 
compliance 
 
 
 
X 
 
 
 
Concomitant Ocular And 
Systemic Medications 
 
 
X 
X 
X 
X 
X 
Frequency of preservative 
free artificial tears use (n° 
drops/day) 
 
 
Xg 
Xg 
Xh 
Xh 
Xh 
Check and retrieval of 
patient’s diary 
 
 
Xi 
X 
X 
X 
X 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
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Study procedures 
Screening 
(Day-8) 
Visit 1 
Baseline 
Day 1* 
Visit 2 
Week 2 
Visit 3 
End of 
treatment 
Week 4a 
Visit 4 
follow-up 
Week 8a 
Visit 5 
follow-up 
Week 12b 
 
Visit 6 
follow-up 
Week 16c 
 
*) visit window of +2 days;  a) Visit window of ± 2 days; b) Visit window of ± 4 days; c) Visit window of  ± 7 days; d) 
only selected sites; e) Only the sites having a confocal microscope will do this type of evaluation; f) a monthly box will 
be given to the patients;       g) During the treatment period patients can use, if strictly needed, the preservative free 
artificial tears; h) During the follow up period it is allowed to use the preservative free artificial tears; i) During the visit 
2, week 2, the PI or a delegate must only check if the patient has correctly completed the diary.  
 
2.1. 
BACKGROUND INFORMATION 
2.1.1. 
Nerve Growth Factor - Overview  
 
Nerve growth factor (NGF) is a polypeptide essential for the survival and growth of sympathetic 
and sensory neurons, and for differentiation of neurons in the central nervous system. It binds with 
at least two classes of receptors: high-affinity tropomyosin receptor kinase A (TrkA), a 
transmembrane tyrosine kinase, and low-affinity NGF receptor (LNGFR), also known as p75 
neurotrophin receptor (p75NTR).  
NGF and TrkA are expressed in the anterior segment of the eye (iris, ciliary body, lens, cornea and 
conjunctiva), and NGF is released in the aqueous humor. Several pieces of experimental evidence 
suggest that NGF affects all tissues of the anterior ocular segments, playing a crucial role in the 
physiopathology of several anterior ocular segment diseases.  
 
2.1.2. 
Chemical And Formulation Data  
 
As recombinant human NGF (rhNGF) production in mammalian cells does not achieve adequate 
yields, a manufacturing process based on the use of recombinant Escherichia coli (E. coli) has been 
developed. However, because the biological activity of NGF relies on the formation of three 
disulfide bonds, and because disulfide bonds cannot occur in the reducing cytosol, the purification 
and renaturation of NGF produced in E. coli is problematic. Based on the knowledge that the 
prosequence increases the yield and rate of refolding of NGF, we have developed a manufacturing 
process starting from proNGF. After expression of proNGF in E. coli, the insoluble protein is 
isolated in the form of insoluble inactive aggregates (inclusion bodies), solubilized in a strong 
denaturing agent and subsequently converted into the natural conformation, which is determined by 
the disulfide bridges present in the natural NGF. Biologically active rhNGF is finally obtained by 
splitting off the prosequence by enzymatic cleavage. The deoxyribonucleic acid (DNA) sequence of 
human proNGF has been optimized for E coli expression (codon adjustment) and two changes in 
the furin cleavage site, R101V and K103A, have been introduced. These two changes are important 
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to ensure a homogeneous rhNGF preparation during the process with the mature protein starting 
with serine 105.  
2.1.3. 
Rationale for rhNGF therapy in patients with dry eye 
 
Dry eye is a chronic inflammatory condition of the ocular surface with severe symptoms and visual 
impairment, leading to worse efficiency to perform duties for an average of 184 work days and 
resulting in an average loss of productivity estimated in 5,000USD per year per patient (1).  
Dry eye results from systemic diseases (Sjögren's syndrome, rheumatoid arthritis, systemic lupus 
erythematosus, Stevens-Johnson syndrome, thyroid disease, Bell's palsy), ocular conditions 
(Meibomian gland dysfunction, blepharitis, ocular rosacea, corneal dystrophies), elective surgeries 
(refractive surgery, blepharoplasty), eyelid conditions (lagophthalmos, entropion/ectropion), cranial 
surgeries, side effects of drugs (antihistamines, diuretics, beta-blockers), ocular injuries and burns, 
chemotherapy and radiation, aging, menopause, etc. (2).  
Dry eye pathogenesis is multifactorial; however, a number of common mechanisms can be identified: 
(i) chronic inflammation of the conjunctiva; (ii) decrease of ocular surface sensitivity; (iii) impairment 
of quantity of tears and/or quality of the tear film, including tear film hyperosmolarity; (iv) changes 
of conjunctival epithelium with squamous metaplasia and decrease of goblet cells density; (v) corneal 
epithelium damage.  
Until now, treatment has been limited to the use of artificial tears to temporarily improve lubrication 
of the ocular surface, or the use of steroids to decrease the inflammatory reaction. However, chronic 
use of steroids is associated with severe complications such as cataract and glaucoma (2). 
Cyclosporine eye drop therapy for dry eye patients has been approved in the United States but not in 
Europe. This drug seems to affect only inflammation and tear film production, without any effect on 
ocular surface sensitivity or the corneal epithelium. On the other hand, experimental and clinical 
evidence suggests that NGF may affect all the pathogenic mechanisms of dry eye, potentially 
restoring ocular surface homeostasis (3). 
Indeed, several studies have shown that NGF is involved in the regulation of tear film production. In 
fact, NGF, TrkA and p75, as well as other neurotrophins (NTs) and related receptors, are expressed 
by the rat lacrimal gland tissue; moreover, NGF has been quantified in human tears, indicating that 
NGF is basally released by the lacrimal gland (4,5,6). These data suggest that NGF may play a role 
in the maintenance of the tear film and in its alterations in drying ocular surface diseases. Specifically, 
considering that NGF potentially affects all the components of the ocular surface (cornea, 
conjunctiva, lacrimal gland, and sensory innervation), it might play an important role during dry eye 
disease. In line with this hypothesis: 1) NGF eye drop administration in a dog experimental model of 
dry eye increases tear production, conjunctival goblet cell density and corneal transparency (7, 2), an 
increased tear concentration of NGF has been reported in patients affected by keratoconjuctivita sicca 
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(8;9), NGF stimulates glycoconjugate secretion by conjunctival goblet cells, without affecting cell 
proliferation (10). 
 
2.2. 
A SUMMARY OF CLINICAL DATA  
rhNGF has been already studied in healthy volunteers and in different subject populations.  
In the completed Phase I study in healthy volunteers (study NGF0112), a total of 58 subjects (out of 
74 enrolled) were treated with single and multiple dose of different concentrations of rhNGF eye 
drops showing a good safety profile.  
Furthermore, a Phase I/II multicenter, 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 of 
Neurotrophic Keratitis NK (study NGF0212) was completed in 2015 demonstrating that rhNGF was 
very well tolerated and effective in patients with NK. A successful confirmatory study (NGF0214) 
was completed in 2016 and marketing authorization for rhNGF 20 μg/mL eye drops has been granted 
by EMA in July 2017 for treatment of moderate to severe NK. 
In addition to NK, rhNGF eye drops have been evaluated in a Phase I/II study in retinitis pigmentosa 
(RP) patients at the doses of 60 and 180 μg/mL (NGF0113), and in a phase I/II study in glaucoma at 
the dose of 60μg/mL (NGF0314). An open arm, 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 severe dry eye disease as compared to 
baseline (NGF0213). These results prompted to the conduction of two additional phase II RCTs in 
patients with dry eye disease (NGF0216) and in patients with ocular discomfort symptoms following 
refractive surgery (NGF0116) which confirmed the favourable tolerability profile of rhNGF eye drops 
at a concentration of 20 μg/mL up to 6 times daily for 8 weeks.  
In the double-masked vehicle-controlled Phase II study NGF0216 no major differences were 
observed in term of efficacy when comparing the two regimens (6 vs. 2 times/day) and treatment 
durations (8 vs. 4 weeks) in a subset of patients with similar characteristics (hyposecretive dry eye 
with Schirmer test <10mm/5min).  
The results of these two studies in dry eye disease patients, as well as the results on reflex tear 
secretion obtained in the neurotrophic keratitis trials NGF0212 and NGF0214, suggest that the rhNGF 
may be a safe and effective treatment for patients with hyposecretive dry eye disease. 
In all studies rhNGF was well tolerated and the reported ocular AEs were generally transient and 
mostly mild and moderate in intensity during the controlled treatment period and the follow-up 
period. 
Only moderate and transient ocular AEs possibly related to rhNGF administration were reported. 
In the  Phase I study in healthy volunteers of Japanese ethnicity (study NGF0117) a total of 30 subjects 
were enrolled. 20 subjects were treated with  single dose of rhNGF (formulation containing L-
methionine as excipient) at concentration 20 μg/mL and a total of 10 subjects were treated with 
placebo. During the studyno adverse events  occurred.   Single and multiple doses of rhNGF delivered 
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topically as eye drops were safe and well tolerated by healthy subjects of Japanese ethnicity. No 
clinically important changes in ECG were observed after dosing with rhNGF. There was no apparent 
relationship between treatment and plasma rhNGF levels, and this study did not give any indication 
for an immunogenic potential of rhNGF in humans after ophthalmic treatment. 
2.3. 
STUDY RATIONALE 
The data reported above, together with the evidence of rhNGF eye drop effectiveness in the treatment 
of patients affected by corneal epithelial defects and ulcers, make rhNGF a strong candidate for the 
treatment of dry eye disease (11, 12, 13). 
As part of the development plan, the present study was designed in order to evaluate the efficacy and 
safety of rhNGF eye drops 20 µg/mL in patients with moderate to severe dry eye. 
For additional information regarding the development of rhNGF, please consult the current IB. 
2.3.1. 
Risk assessment/benefit evaluation 
The study is considered a low risk interventional trial. It is conducted with a dose of medicinal product 
already tested and already authorized in some European countries and recently by FDA for NK 
treatment.  
The study is conducted in severe to moderate dry eye, a disease not approved, however 2 preliminary 
clinical studies were already conducted in patients with dry eye demonstrating that rhNGF is very 
well tolerated in this condition. 
The risk of this study is  comparable to the risk of the standard of care, in fact the dose proposed in 
this protocol is rhNGF 20 µg/mL three drops per day (both eyes), which is well below the dose 
approved for the treatment of NK (rhNGF 20 µg/mL six drops/eye per day). 
Considering what is discussed above no particular safety risks are foreseen with respect to the safety 
profile of the marketed product (OXERVATE® 20 µg/mL). 
 
The patients with dry eye participating in this study may potentially benefit from the application of 
rhNGF for 28 days.  
 
The following potential study risks were evaluated: 
 
1) Participant well-being e.g.- risk-benefit balance - burden of study visits  
2) Lifestyle requirements- Study specific procedures which carry risk -additional to 
standard care (es: week of run in) 
3) Complexity of study procedures  
4) Education, training, experience and resources of all investigator site staff in GCP and 
study procedures 
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5) Manufacture and distribution of the product(s), storage at the study site (e.g. availability 
of Frezeer at the study sites).  
 
The details will be described in the Risk Management Plan. 
2.3.2. 
Description of the Investigational Product 
 
The investigational medicinal product (IMP) consists of a sterile isotonic solution for ocular 
administration, containing rhNGF 20 μg/mL (containing L-methionine as excipient) as drug 
substance. 
The matching placebo vehicle consists of a sterile isotonic solution (containing L-methionine as 
excipient). 
Further information are given in paragraph 5. 
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3. OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES  
The study objective is to assess the efficacy and safety of rhNGF when administered as eye drops to 
patients with moderate to severe dry eye and to exploratively evaluate the preliminary efficacy data 
also in a group of  dry eye patients with diagnosis of Primary Sjögren's Syndrome(14). 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE 
This study will be performed at 8-12 study centers located in the USA. At each study center, the 
Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted 
according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.  
The PI at each study center will be responsible for the management of the study, which will consist 
of maintaining the study file and the patient records, corresponding with the IRB, and completing 
the case report forms (eCRFs) and reporting SAEs within 24 hours of initial awareness.  
The PI is responsible for supervising any individual or party to whom the investigator delegates trial 
related duties and functions conducted at the trial site. 
If the investigator/institution retains the services of any individual or party to perform trial-related 
duties and functions, the investigator/institution should ensure this individual or party is qualified to 
perform those trial-related duties and functions and should implement procedures to ensure the 
integrity of the trial-related duties and functions performed and any data generated. 
3.3. 
OVERALL STUDY DESIGN  
 
This is a phase II, multicenter, randomized, double masked, vehicle controlled, parallel group study 
designed to perform dose ranging and evaluate efficacy of rhNGF eye drops at 20 µg/mL concentration 
administered two or three times daily for 4 weeks in patients with moderate to severe dry eye. 
Patients will be evaluated at screening visit (day -8), baseline (day 1+2), week 2 (day 14±2), week 4 
(day 28±2) or early withdrawal and week 8 (day 56±2), week 12 (day 84±4), week 16 (day 112±7) of 
follow up. 
During the screening (day -8) all procedures for inclusion will be performed. From the day of 
screening the patients will stop any kind of further treatment, except commercially available 
preservative free artificial tears for a period of 7 days and 9 days as maximum (day -8 to day -1+2) 
until the baseline visit (day 1). At the end of the wash out period (day -8 to day -1+2) , patients 
meeting the entry criteria for this study will be randomized 1:1:1 and treated for 4 weeks with either 
rhNGF eye drops 20 µg/mL TID, rhNGF eye drops 20 µg/mL BID and vehicle SID or vehicle TID.  
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During the 4 weeks of masked treatment only the administration of IMP it is allowed. Nevertheless, 
if strictly needed, the patient can take  preservative free artificial tears (provided by the Sponsor). The 
use (n° drops/day) of preservative free artificial tears will be clearly documented in a patient’s diary 
and in the eCRF.  
 
Following the completion of the double-blind treatment patients will be followed up for safety 
assessments for an additional 12 weeks post treatment and will be evaluated at the end of the safety 
follow-up period. During the safety follow-up period patients will not use further treatment except 
preservative free artificial tears provided by the Sponsor three times daily (morning, afternoon, 
evening ).  
The use of preservative free artificial tears will be clearly documented in a patient’s diary and in the 
eCRF. 
The total duration of the study is 17 weeks.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1:Study duration  
 
 
 
 
 
 
 
Day 1 
+2 
Week 4 
 ± 2 days 
Week 8 
 ± 2 days 
Week 12  
± 4 days 
Week 16  
± 7 days 
Day -8 
Screening 
Visit 1 
Baseline  
Randomization 
Visit 3 
End of  
treatment  
Visit 5 
Follow up  
Visit 6 
Follow up 
Follow-up Phase  
Treatment Phase 
Visit 4 
Follow up 
Visit 2 
Week 2 
 ± 2 days 
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3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study 
 
The dose proposed in this study (rhNGF 20 µg /mL) has already been tested both in heathy volunteers 
for five consecutive days (NGF0112 and NGF0117) and in patients affected by several ocular surface 
diseases, including dry eye. 
rhNGF 20 µg /mL (one drop in each eye six times daily for 8 weeks), was also tested in the Phase I/II 
of the NK studies (NGF0212 and NGF0214), dry eye (NGF0216) and in patients after cataract and 
refractive surgery (NGF0116). 
rhNGF 20 µg/mL administered two times daily, demonstrated to be safe and well tolerated 
(NGF0213)  will also ensure the lubrification of the ocular surface in the present study where the use 
of artificial tears will be not allowed during the treatment period.  
Higher doses of rhNGF (up to 180 µg /mL) were administrated to patients with diseases of the back 
of the eye, such as retinitis pigmentosa (Study NGF0213) for up to 168 days. 
 
The 20 μg/ml concentration of rhNGF is well sustained by the current manufacturing process and is 
the lowest used in a commercial formulation.  
A dose regimen of 2 or 3 drops per day of rhNGF eye drops and a treatment duration of 4 weeks have 
been selected based on the results of the previous clinical trials described above. 
The administration of a total of 3 drops per day for all the study arms has been chosen to guarantee 
to patients randomized to the vehicle arm to have the minimum amount of lubrication that is 
compatible with symptoms’ relief. A double-blind study design was adopted to minimize systematic 
bias. Randomization is expected to minimize patient selection bias and increase baseline 
comparability between treatment groups. The use of placebo control is critical to the study design for, 
providing an accurate estimate of the additive benefit of pharmacotherapy.   
The use of the drug’s vehicle as placebo helps in making the latter as indistinguishable from the 
rhNGF solution. 
Patients with insufficient therapeutic response, tolerability issues, or worsening of symptoms may be discontinued at 
any time during the study. 
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4. SELECTION OF STUDY POPULATION 
 
Male and female ≥ 18 years with moderate to severe dry eye will be included. A total of 300 patients 
will be enrolled.  
The safety and efficacy of rhNGF eye drops will be investigated also in a specific subgroup of patients 
with hyposecretive dry eye, i.e., patients with dry eye due to primary Sjögren's syndrome (2, 14). To 
gain information on the safety and efficacy of rhNGF in this subgroup of patients at least sixty (60) 
patients with a documented diagnosis of Primary Sjögren's Syndrome are out of 300 total patients are 
needed. It should be noted that patients with this type of dry eye could have already been enrolled 
based on the inclusion/exclusion criteria of the previous version of the study protocol. This 
amendment is applied only to set a minimum prespecified number of patients with Primary Sjögren's 
Syndrome.  The nature of the resulting statistical analysis in this subgroup of patients will be 
explorative. 
Including at least y 60 subjects with documented diagnosis of Primary Sjögren's Syndrome within the 
total sample size (20%) will have no impact on the initial assumptioms concerning sample size for 
the following reasons: 
x The previous study (NGF0216), on which sample size assumptions have been based (see 
section 9.1), reports a similar prevalence of patients with Primary Sjögren's Syndrome in their 
medical history (⁓25% in the FAS population). 
x As dry eye due to Sjogren’s syndrome is a hyposecretive form of the disease, the primary 
endpoint is appropriate for both the whole study population and the subgroup with Sjögren's 
syndrome.  
x As anticipated, the same patients could have already been enrolled based on the previously 
applied and approved inclusion/exclusion criteria. 
 
4.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria: 
1. Male or female aged ≥ 18 years 
2. Patients with moderate to severe dry eye characterized by the following clinical features: 
a. Corneal and/or conjunctival staining with fluorescein using National Eye Institute 
(NEI) grading system > 3 
b. SANDE questionnaire >25 mm 
c. Schirmer test I (without anaesthesia) >2 mm <10 mm/5 minutes  
d.  Tear film break-up time (TFBUT) < 10 seconds in the worse eye 
3. The same eye (eligible eye) must fulfill all the above criteria 
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4. Patients diagnosed with dry eye at least 6 months before enrolment (current use or 
recommended use of artificial tears for the treatment of Dry Eye) 
5. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen 
value) in both eyes at the time of study enrolment  
6. If a female of childbearing potential, have a negative pregnancy test  
7. Only patients who satisfy all Informed Consent requirements may be included in the study. 
The patient and/or his/her legal representative must read, sign and date the Informed Consent 
document before any study-related procedures are performed. The Informed Consent form 
signed by patients and/or legal representative must have been approved by the IRB for the 
current study 
8. Patients must have the ability and willingness to comply with study procedures. 
9. Primary Sjögren's Syndrome Patients: 
x patients with a documented diagnosis of Primary Sjögren's Syndrome according the 
American-European Consensus Group Sjögren's Syndrome Criteria (Appendix 3; must 
meet either 4 out of 6 total criteria OR 3 out of 4 signs). Note: Subjects who are on 
systemic (oral) therapy for the treatment of Sjögren's Syndrome must be on stable systemic 
treatment defined as the same treatment for the immediately prior 90 days. 
4.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study: 
1. Inability to speak and understand the local language sufficiently to understand the nature of 
the study, to provide written informed consent, and to allow the completion of all study 
assessments  
 
2. Evidence of an active ocular infection, in either eye  
 
3. Presence of any other ocular disorder or condition requiring topical medication during the 
entire duration of study 
 
4. History of severe systemic allergy or severe ocular allergy (including seasonal conjunctivitis) 
or chronic conjunctivitis and/or keratitis other than dry eye 
 
5. Intraocular inflammation defined as Tyndall score >0 
 
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6. History of malignancy in the last 5 years 
 
7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with 
glycemia out of range, tyroid malfunction..) or judged by the investigator to be incompatible 
with the study (e.g. current systemic infections) or with a condition incompatible with the 
frequent assessment required by the study 
 
8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically 
related compounds or had a clinically significant allergy to drugs, foods, amide local 
anesthetics or other materials including commercial artificial tears, in particular commercial 
artificial tears containing carboxymethylcellulose (CMC) (in the opinion of the investigator) 
 
9. 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 (Screening/Baseline day 1) 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.  
 
10. Any concurrent medical condition that, in the judgment of the PI, might interfere with the 
conduct of the study, confound the interpretation of the study results, or endanger the patient’s 
well-being  
 
11. Use of topical cyclosporine, topical corticosteroids or any other topical drug for the treatment 
of dry eye in either eye within 30 days prior to study enrolment 
 
12. Contact lenses or punctum plug use during the study (previous use not an exclusion criteria 
but must be discontinued at the pre-screening visit) 
 
13. History of drug addiction or alcohol abuse 
 
14. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 90 
days before the pre-screening visit 
 
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15. Participation in a clinical trial with a new active substance including medical devices during 
the past 60 days 
 
16. Participation in another clinical trial study at the same time as the present study 
4.3. 
ELIGIBLE EYE 
Assuming that all the inclusion/exclusion criteria are met in both eyes, the worse eye (eligible eye) 
will be determined at the baseline visit using a stepladder approach, as follows: 
1. 
Schirmer’s Test (since this is the primary endpoint)-Worse eye determined as eye with 
lower Schirmer I score. If Schirmer I score is the same in both eyes, worse eye will be 
determined by NEI score (cornea+conjunctival staining). 
2. 
NEI score (cornea+conjunctival staining).  
If all of the above are identical, determination of the worse eye will be based on the Investigator’s 
judgement, then simply use the right eye as the eligible eye. 
4.4. 
ASSIGNMENT OF PATIENT NUMBER 
Each patient who provides written consent to participate in this study will be assigned a unique 5-
digit PID number (e.g. 01-001) consisting of a 2-digit study center number followed by the 3-digit 
screening number assigned sequentially by each study center, from 001 to 300.  
4.5. 
RANDOMISATION 
Eligible patients will be randomized in a 1:1:1 ratio to either rhNGF eye drops solution 20 µg/ml TID 
(⁓100 patients) or rhNGF  eye drops solution 20 µg/ml BID plus vehicle eye drop solution SID (⁓100 
patients) or vehicle eye drop solution TID (⁓100patients). 
Randomization will be stratified according to absence/presence of a documented diagnosis of Primary 
Sjögren's Syndrome to ensure balanced assignment across treatment groups. 
Each randomized patient will be allocated with randomization number, according to the stratified 
randomization list. Drop outs after randomization will not be replaced. 
Randomization list as well as associated kit numbers will be be generated by a member of Syneos 
Health Biostatistics department, not involved in the conduct of the study.  
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.  
The enrollment of patients will be scheduled in order to assure an inclusion of approximately 240 
patients without Primary Sjögren's Syndrome diagnosis and at least 60 patients  with Primary 
Sjögren's Syndrome. 
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4.6. 
MASKING 
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 (after 
data base lock) except in case of specific events that will require unmasking of the patient. 
The vials containing rhNGF (20 µg/ml) or vehicle will be identical in appearance, and the contents 
of the vials will be indistinguishable. All staff directly involved in the analysis of study results will 
remain masked to treatment assignments while the study is in progress. 
A list of sequential kit numbers will be generated by a member of the Syneos Health 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. 
The investigator will be provided with an access, password protected, to the RAVE Randomization 
and Trial Supply Management system (RAVE RSTM) so only in case of a medical emergency the 
Investigator can open the treatment allocation for a specific patient.  
Besides also Dompé Pharmacovigilance contact person will be provided with an access, password 
protected, to the RAVE Randomization and Trial Supply Management system (RAVE RSTM) so if 
required by the Pharmacovigilance activities the Pharmacovigilance contact person can open the 
treatment allocation for a specific Patient. 
 
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. The Investigators are encouraged to contact Syneos Health staff 
before becoming unmasked if there is sufficient time. 
If the Investigator becomes unmasked for any reason, this information will be recorded on source 
data and in the eCRF of the study, specifying the date and the reason.  
 
Unmasking events will be recorded and reported in the final study report. 
 
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5. STUDY MEDICATION 
5.1. 
DESCRIPTION OF PRODUCT 
5.1.1. 
Presentation of Non Investigational Medicinal Product (NIMP) 
TEST PRODUCT 
 
NIMP 
 
Blink® Tears  
Pharmaceutical form 
 
Eye Drops Solution 
Administration 
 
One drop of Blink® Tears will be instilled in both eyes 
during the 4 weeks of masked treatment, only if strictly 
needed by the patient.  
One drop of Blink® Tears will be instilled in both eye TID 
(morning, afternoon and evening) during the 12 weeks of 
follow up. The patient, only if strictly needed, can 
administer additional drops and must document in the 
patient’s diary the n° of additional drops administered for 
each eye. 
Administration route 
 
 
 
Ocular  
 
 
 
 
 
 
 
5.1.2. 
Presentation of Investigational Medicinal Product 
 
TEST PRODUCT 
 
IMP 
Recombinant human nerve growth factor (rhNGF), 
containing L-methionine as excipient (20 μg/mL) and/or 
Placebo vehicle, containing L-methionine as excipient 
(Vehicle vials). 
 
Manufacturer active 
substance 
 
Dompé Farmaceutici S.p.A., Italy 
Dompé farmaceutici s.p.a.  
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NGF0118 
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Manufacturer 
finished product 
 
Bulk drug product is manufactured by Patheon, part of 
Thermo Fisher Scientific -Italy. 
Secondary packaging and labelling is performed by 
AndersonBrecon Inc.- PCI USA  
 
 
 
Pharmaceutical form 
Eye drops sterile buffered aqueous solution 
 
Dose 
Test and reference will be instilled in both eyes according to 
the following scheme:  
Group 1: one drop of rhNGF 20 µg/ml will be instilled in 
both eyes three times daily (every 6-8 hours, e.g. 
7:00 am, 02:00 pm; 09:00 pm).  
Group 2: one drop of rhNGF 20 µg/ml will be instilled in 
both eyes two times daily plus one drop (40 µL) of 
vehicle will be instilled in both eyes once daily 
(every 6-8 hours, e.g. 7:00 am, 02:00 pm; 09:00 
pm). 
NB: rhNGF will be instilled in the morning and in 
the evening while the vehicle will be instilled in the 
afternoon.  
Group 3: vehicle eye one drop will be instilled in both eyes    
three times daily (every 6-8 hours, e.g. 7:00 am, 
02:00 pm; 09:00 pm). 
 
Administration route 
 
 
 
Ocular 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.2. 
FORMULATION AND PACKAGING  
The Investigator will be provided with a subject monthly box, containing 4 weekly boxes, containing 
7 daily boxes. Each daily box contains three marked vials (e.g. 1- Morning, 2- Afternoon and 3- 
Evening) of frozen IMP solutions (-20 ± 5°C) containing:  
  
• 
rhNGF, at concentrations of 20 µg /mL, and/or  
• 
vehicle (placebo). 
Together with the IMP monthly box, the patients will be provided with a sufficient number of pipette 
and adaptors to be used for the administration of the IMP. 
Pipette and adaptors will be provided separately in single sterile polyethylene packages and may be 
kept at room temperature. 
The pipette is used with an adaptor consisting of a connecting device with dual connections: one 
end for the pipette and one end for the vial.  
The patient will need to: 
 
1. Put the adaptor on the top of the vial (after removing the plastic seal) by piercing the septum 
2. Put the pipette on adaptor inlet 
3. Draw the solution contained in the vial with the pipette until this reaches its predetermined 
capacity 
4. Remove the pipette and use it as a dropper to administer one drop of IMP into each eye. 
5.2.1. 
Labeling  
5.2.1.1. 
NIMP Secondary packaging, single pane label for single vial (Blink® Tears) 
Line 
No. 
Text 
1 
NGF0118 
2 
Dompé farmaceutici s.p.a 
3 
Blink® Tears  
4 
Unique Patient N° - 
5 
Eye drops solution 
6 
To be used ONLY during the masked treatment* 
7 
FOR OCULAR USE ONLY- LEAFLET: information for user 
8 
For clinical trial use only 
* the patient can use the Blink ® Tears during the masked treatment only if strictly needed according the product leaflet 
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Line 
No. 
Text 
1 
NGF0118 
2 
Dompé farmaceutici s.p.a 
3 
Blink® Tears  
4 
Unique Patient N° - 
5 
Eye drops solution 
6 
To be used ONLY during the Follow up period* 
7 
Morning/afternoon/evening  
8 
FOR OCULAR USE ONLY- LEAFLET: information for user 
9 
For clinical trial use only 
 
* the patient must use the Blink ® Tears during the Follow up period, three times daily (morning, afternoon and 
evening) 
 
 
5.2.1.2. 
Primary packaging, single pane label for single vial (rh-NGF or Vehicle) 
 
Line 
No. 
Text 
Comments 
1 
NGF0118 
  
2 
Dompé farmaceutici s.p.a 
 
3 
rhNGF 20 µg /ml and/or Vehicle 
 
4 
Administration eye: RIGHT and LEFT  
 
6 
Eye drops solution  
 
7 
Batch: <vvvv>  
 Codified batch 
8 
Kit XXXX * 
Format of kit no.: "XXXX” 
 
10 
Morning/afternoon/evening** 
 
13 
CAUTION: New Drug-Limited by Federal (or United 
States) law to investigational use 
 
 
* The number of KIT will be reported according to the randomization list that will be generated  
** Each vial will be a marked vial, one for each administration: morning, afternoon, evening. The vial will be a 
coloured vial one colour for each administration as follow: White-morning, yellow-afternoon and light blu-evening. 
Dompé farmaceutici s.p.a.  
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5.2.1.2. 
Secondary packaging, single pane label for daily box (3 marked vials of rh-NGF and/or 
Vehicle) 
 
Line 
No. 
Text 
Comments 
1 
NGF0118 
  
2 
Dompé farmaceutici s.p.a 
 
3 
rhNGF 20 µg /ml and/or Vehicle 
 
4 
Administration eye: RIGHT and LEFT  
 
6 
Eye drops solution  
 
7 
Batch: <vvvv>  
 Codified batch 
8 
Kit XXXX * 
Format of kit no.: "XXXX” 
 
9 
Store in a refrigerator at 2-8 °C (36°F to 46°F) or at room 
temperature not exceeding 12 hours 
 
10 
Do not shake 
 
11 
Keep out of reach of children 
 
12 
CAUTION: New Drug-Limited by Federal (or United 
States) law to investigational use 
 
 
* The number of KIT will be reported according to the randomization list that will be generated  
 
 
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5.2.1.3. 
Tertiary packaging, single panel label for weekly box (7 daily boxes) 
 
Line 
No. 
Text 
Comments 
1 
NGF0118 
  
2 
Dompé farmaceutici s.p.a 
 
3 
rhNGF 20 µg /ml and/or Vehicle 
 
4 
Administration eye: RIGHT and LEFT  
 
6 
Eye drops solution 
 
7 
Batch: <vvvv>  
 Codified batch 
8 
Kit XXXX * 
Format of kit no.: "XXXX” 
 
9 
Store in a refrigerator at 2-8 °C (36°F to 46°F) for 7 days 
 
10 
Do not shake 
 
11 
Keep out of  reach of children 
 
12 
CAUTION: New Drug-Limited by Federal (or United 
States) law to investigational use 
 
 
* The number of KIT will be reported according to the randomization list that will be generated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.2.1.4. 
Quaternary packaging, tear- off label  monthly box (4 weekly boxes, 28 days of treatment 
Line 
No. 
Text 
Comments 
Tear Off part of the label 
1 
Protocol no.: NGF0118 
  
To be enclosed 
2 
Sponsor: Dompé farmaceutici s.p.a, Via 
Santa Lucia, 6 - 20122 Milano, Italy 
 
To be enclosed 
3 
rhNGF 20 µg /ml and/or Vehicle 
 
To be enclosed 
4 
Eye drops solution 
 
 
5 
Contains 4 weekly boxes. One of each 
contains 7 daily boxes that contains 3 
marked vials 
 
 
6 
Directions for use: refer to dosing 
instructions 
 
 
4 
Administration eye: RIGHT and LEFT  
The administration will be 
according to the 
randomization list: Active 
for group 1; Active/Placebo 
for group 2 and Placebo for 
group 3.  
To be enclosed 
7 
Batch: <vvvv>  
 Codified batch 
To be enclosed 
8 
Kit XXXX  
Format of kit no.: "XXXX"  
 
To be enclosed 
9 
 Unique Patient N° - 
 
To be enclosed 
 
10 
Store in a freezer at -20°C +/- 5° C  
 
 
11 
Do not shake 
 
 
12 
Keep out of reach of children 
 
 
13 
For clinical trial use only 
 
 
14 
CAUTION: New Drug-Limited by 
Federal (or United States) law to 
investigational use 
 
 
 
5.3. 
 STORAGE AND HANDLING OF IMP 
The Pharmacist and/or Investigator will be responsible for receipt, proper storage, and usage of study 
drug, as well as for the IMP distribution, collection of used and unused vials and final disposal of the 
remaining IMP.  
Dompé farmaceutici s.p.a.  
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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 1 (baseline visit), the study personnel will give to the patient the monthly boxes containing 
the study medications 
Patient should bring the study medication, one monthly box, at home as soon as possible and 
immediately store it in a freezer at -20 ± 5 °C. 
The weekly box must be kept at 2-8°C for 7 days protected from light; the daily box can be kept at 
room temperature,  before the patient will use the single vial for each instillation (both eyes) as long 
as 12 hours are not exceeded. Agitation of vials may cause foaming and/or particle formation. Drug 
preparation and administration instructions will be provided separately to the site and to the 
patients.  
 
Together with the IMP monthly box, the patient will also receive a separate kit of vial adapters (one 
per vial), pipettes (1 per vial) and disinfectant wipes (1 per vial). 
IMP eye drops solution instruction will be provided to patients.  
Patients will use one vial to instill one drop in both eyes (group 1: rhNGF TID; group 2: rhNGF BID 
and vehicle SID; group 3: vehicle TID) between 7 AM and 9 PM (every 6-8 hours) for 4 weeks . 
The IMP contains L-methionine as an excipient. The contents of each vial are for the daily 
administration to both eyes only. After the last administration the used vial should be returned to the 
original medication box and is not to be reused. 
Any deviations from the recommended storage conditions should be immediately reported by the 
pharmacist to the Sponsor and Investigator, and the use of the drug should be suspended until they 
have given authorization for its continued use. The IMP supplies are to be used only in accordance 
with this protocol. The Investigator will not use any drug samples for other purposes (e.g., treating 
patients or deviating from the protocol with regard to dose regimen, duration of treatment, etc.). Under 
no circumstances will the Investigator give any drug samples to a third party. 
Dompé farmaceutici s.p.a.  
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5.4. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
5.4.1. Administration route 
The Administration route is ophthalmic, the first administration is to be applied by investigator at 
site. 
5.4.2. Dose regimen 
In all patients both eyes will be treated for a period of 4 weeks. 
 
The dosing scheme of the different study groups is summarized below: 
 
Group 1: one drop of rhNGF 20 µg/ml will be instilled in both eyes three times daily (every 6-8 
hours, e.g. 7:00 am, 02:00 pm; 09:00 pm).  
Group 2: one drop of rhNGF 20 µg/ml will be instilled in both eyes two times daily plus one drop 
(40 µL) of vehicle will be instilled in both eyes once daily (every 6-8 hours, e.g. 7:00 am, 
02:00 pm; 09:00 pm). 
NB: rhNGF will be instilled in the morning and in the evening while the vehicle will be 
instilled in the afternoon.  
Group 3: vehicle eye one drop will be instilled in both eyes  three times daily (every 6-8 hours, e.g. 
7:00 am, 02:00 pm; 09:00 pm). 
 
During the 4 weeks of masked treatment only the administration of IMP  is allowed. Nevertheless, if 
strictly needed, the patient can take a preservative free artificial tears (provided by the Sponsor). The 
use (n° drops/day) of preservative free artificial tears will be clearly documented in a patient’s diary 
and in the eCRF.  
Both the patients and the investigator will be masked to the study treatment. 
Information about the  study drug administration, and comments, will be recorded on the 
appropriate page of the eCRF. 
 
5.5. 
ACCOUNTABILITY OF THE IMP 
The Pharmacist and/or Investigator will confirm the receipt of the IMP supply in writing by signing 
and dating standard drug accountability forms. 
At the week 4 (end of treatment visit) the patient will return the used or unused study boxes/vials to 
the Investigator.  
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The Pharmacist and/or Investigator will keep a cumulative inventory and dispensing records, and will 
maintain all supplies under adequate security.  
An accurate drug disposition record will be kept, specifying the date and amount dispensed to each 
patient.  
Adequate record of receipt and use or loss of drug will be retained. This inventory record must be 
available for inspection by the Sponsor and regulatory inspection at any time. Copies of this record 
will be provided to the Sponsor by Syneos Health throughout the duration of the study. 
At the scheduled visit, the patient diary should be reviewed by the Investigator with the patient for 
completeness. Missing information should not be provided during the diary check but reported as 
missing. 
At the conclusion of the study, and during the course of the study, the Investigator will complete the 
drug accountability forms. Partially used or unused study drug boxes will be verified by the 
Investigator and  within one month after completion of the trial the partially used and unused study 
medication will be shipped to the Sponsor or will be destroyed after authorization by the Sponsor by 
an authorized company according to GCP regulations. 
5.6. 
CONCOMITANT MEDICATION 
 
As a general rule, no ophthalmic medication other than study drug will be given to the patient from 
the screening day until all of the final study evaluations have been completed, except for 
preservative free artificial tears.  
The preservative free artificial tears will be provided by the Sponsor and can be used according to 
the following scheme: 
1) During the 4 weeks of masked treatment, only if strictly needed, the patient will instill one 
drop in both eyes. 
2) During the 12 weeks of Follow up period one drop will be instilled in both eyes TID 
(morning, afternoon and evening).  
The use (n° drops/day) of preservative free artificial tears will be clearly documented in the 
patient’s diary and eCRF.  
 
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 will be clearly documented on the 
Concomitant Medications eCRF page. 
Medication entries should be specific to product name (if a combination drug product) and spelled 
correctly. The dose, unit, frequency, route of administration, start date, discontinuation date, and 
indication should also be recorded. For medications administered only one time, the frequency 
column may reflect "once." 
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6. STUDY PROCEDURE AND ASSESSMENTS 
 
The first patient first visit (FPFV) is defined as the 1st visit performed at one of the clinical centers by 
the 1st screened patient. The last patient, last visit (LPLV) is defined as the last visit performed at one 
of the clinical centers by the last patient (i.e., the last visit foreseen by the study protocol), 
independently of whether the patient completed or withdrew from the study. The First Patient In (FPI) 
is defined as the first randomized patient at one of the clinical centers.  
Patients will be evaluated according to the following scheme: 
 
Interventional phase 
¾ Screening visit (day -8),  
¾ Baseline (day 1+2),  
¾ Week 2 (day 14r2 ), 
¾ Week 4 (day 28r2 ) or early exit 
 
Follow up visits 
¾ Week 8 (day 56±2),  
¾ Week 12 (day 84r4)  
¾ Week 16 (day 112r7)  
 
The schedule of study procedures and assessments is tabulated by visit in the Schedule of Evaluations 
in § 2.0.  
The descriptions of the procedures to be performed at each visit are provided below. 
 
 
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6.1. 
SCREENING AND RANDOMIZATION VISITS 
During the screening visit (day -8) all procedures for inclusion will be performed. From the day of 
screening the patients will stop any kind of further ophthalmic treatment, until all of the final study 
evaluations have been completed, except preservative free artificial tears (wash out period from day 
-8 to day -1 +2). The wash out period should not be less than 7 days and more than 9 days.  
At the end of the screening period, patients meeting the entry criteria for this study will be 
randomized 1:1:1 and treated for 4 weeks with either rhNGF eye drops 20 µg/mL TID, rhNGF eye 
drops 20 µg/mL BID and vehicle SID or vehicle TID. 
 
Day 
Procedures/Assessments 
Screening visit  
Day -8 
The following procedures will be performed (order below is mandatory): 
¾ Explanation to the patient of study aims, procedures and possible risks 
¾ Informed consent signature 
¾ Screening number allocation  
¾ Patient eligibility: Inclusion/exclusion criteria evaluation 
¾ Pregnancy test for female patients of childbirth potential 
¾ Demographic data 
¾ Ocular and systemic medical history 
¾ Previous ocular and systemic medications (prior to start the study) 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the eyelid (Meibomian glands), eyelid 
(erythema), eyelid (edema), lashes, conjunctiva erythema, lens, iris, anterior 
chamber, corneal horizontal diameter 
x TFBUT 
x Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
¾ AE collection 
 
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Day 
Procedures/Assessments 
Visit 1 Baseline 
Day 1 +2 
 
The following procedures will be performed (order below is mandatory): 
 
¾ Pregnancy test for female patients of childbirth potential 
¾ Previous ocular and systemic medications (prior to start the treatment) 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the eyelid (Meibomian glands), eyelid 
(erythema), eyelid (edema), lashes, conjunctiva erythema, lens, iris, anterior 
chamber, corneal horizontal diameter 
x TFBUT 
x Ocular surface staining (NEI score – corneal and conjunctival fluorescein 
staining  ) 
x Schirmer test II (with anesthesia) 
x Laser scanning confocal microscopy to assess goblet cells density (only 
selected sites)  
x Corneal endothelium and stroma evaluation (only the sites having a confocal 
microscope will do this type of evaluation)  
¾ Patient eligibility: Inclusion/exclusion criteria evaluation 
¾ Randomization 
¾ Study drug dispensation 
¾ Preservative free artificial tears dispensation  
¾ AE collection 
 
The Investigator will dispense to the patients their monthly box containing the study 
drug for the following 4 weeks  together with an adequate number of adapters and 
pipettes. The Investigator will dispense to the patients the preservative free artificial 
tears to be used only if strictly needed by the patient (the patient must follow the 
instruction in the product leaflet ). After completing baseline evaluation patients will 
be administered, by PI, with the study treatment as per instructions, and will self-
administer at home the subsequent doses. Patients will return to the clinical site on 
Day 14 (±2)  (Week 2, visit 2). 
The patients will be instructed to enter  information of self-administration (if the 
administration has been occur per eye), AE occurrence,  concomitant medication 
intake and possible self-administration of preservative free artificial tears into the 
diary. The diary will be given from the PI or delegate during this visit.  
 
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6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS 
After the first two weeks of treatment the patient will undergo  a medical assessment during the visit 
2 (week 2). Following the completion of the double-blind treatment (visit 3, week 4), patients will be 
followed up for safety assessments for an additional 12 weeks post treatment and will be evaluated at 
the end of the safety follow-up period. During the safety follow-up period patients will not use further 
ophthalmic treatment except preservative free artificial tears, provided by Sponsor, one drop instilled 
in both eyes three times daily (morning, afternoon and evening). The patient, only if strictly needed, 
can administer additional drops and must document in the patient’s diary the n° of additional drops 
administered for each eye. 
 
 
Day 
Procedures/Assessments 
At home 
Days 0-14 
±2 
¾ Self-administration at home of the IMP, three times daily every 6-8 h for both eyes 
(diary) 
¾ Recording any new or changes in concomitant medications (diary) 
¾ Recording any unusual medical conditions  - AE monitoring (diary) 
¾ Recording possible use of preservative free artificial tears (diary). 
Data will be recorded by the patient in the patient’s diary. 
Visiti 2 Week 2 
Day 14±2 
The following procedures will be performed (order below is mandatory): 
 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
x Tear Film Break-up Time (TFBUT) 
x Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
¾ Concomitant ocular and systemic medications 
¾ Frequency of patient’s  artificial tear use during first 2  weeks of treatmen (to 
be reported in eCRF) 
¾ AE monitoring 
 
During the visit 2, week 2, the patient must bring the diary assigned during the 
previous visit. The PI or a delegate must check if patient has correctly complete the 
diary. If not, the site staff must retrain the patient.  
At completion of the assessment the patient will be discharged and will be asked to 
return for the end of treatment visit on day 28±2 (Visit 3 week 4). 
 
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Day 
Procedures/Assessments 
At home  
Days 14 ±2– 
28 ± 2 
¾ Self-administration at home of the IMP, three times daily every 6-8 h for both eyes 
(diary) 
¾ Recording any new or changes in concomitant medications (diary) 
¾ Recording any unusual medical conditions  - AE monitoring (diary) 
¾ Recording possible use of preservative free artificial tears (diary). 
Data will be recorded by the patient on the patient’s diary. 
Visit 3  week 4  
Day 28±2  
  
The following procedures will be performed (the below order is  mandatory): 
 
¾ Ocular examination of both eyes: 
x 
Assessment by SANDE questionnaire 
x 
Assessment by IDEEL questionnaire 
x 
Assessment by EQ-5D-3L questionnaire 
x 
Assessment by PGIC questionnaire 
x 
Assessment of best corrected distance visual acuity (BCDVA) 
x 
External Ocular Examination 
x 
Schirmer test  I (without anesthesia)  
x 
Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, Anterior 
Chamber, Corneal Horizontal Diameter 
x 
Tear Film Break-up Time (TFBUT) 
x 
Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
x 
Schirmer test II (with anesthesia) 
x 
Laser scanning confocal microscopy to assess goblet cells density(only 
selected sites)  
x 
Corneal endothelium and stroma evaluation (only the sites having a confocal 
microscope will do this type of evaluation) 
¾ Assessment of compliance to treatment (from patient diary and IMP reconciliation 
from returned weekly boxes) 
¾ Concomitant ocular and systemic medications 
¾ Frequency of patient’s artificial tear use during the last 2  weeks of treatment  (to be 
reported in eCRF). 
¾ AE monitoring 
 
During visit 3, week 4, PI or delegate must check and collect the first patient’s diary 
concerning the treatment period.  
At completion of the assessment the patient will be discharged and will be asked to 
return for the follow up visit on day 56±2 (Visit 4 week 8). 
The Investigator will dispense to the patients the preservative free artificial tears 
(Blink ® Tears) to be self-administered three times daily, one drop in both eyes during 
the first 4 weeks of Follow up. The PI or delegate has to explain to the patients that, 
only if strictly needed, they can administer an additional numbers of drops of Blink ® 
Tears, by documenting all information in the patient’s diary.  
 
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Day 
Procedures/Assessments 
At home 
Days 28 ±2– 
56 ± 4 
¾ Recording any new or changes in concomitant medications (diary) 
¾ Recording any unusual medical conditions  - AE monitoring (diary) 
¾ Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 
Visit 4 Follow up week 8 
 
Day 56± 4 
The following procedures will be performed (the below order is  mandatory): 
 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment by PGIC questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
x Tear Film Break-up Time (TFBUT) 
¾ Ocular surface staining (NEI score - corneal and conjunctival fluorescein staining) 
¾ Concomitant ocular and systemic medications 
¾ Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF). 
¾ AE monitoring 
 
During visit 4, week 8, PI or delegate must check and collect the second patient’s 
diary concerning the first follow up period. 
The Investigator will dispense to the patient the preservative free artificial tears (Blink 
® Tears) to be self-administered three times daily, one drop in both eye during the 
second 4 weeks of Follow up. The PI or delegate has to explain to the patients that, 
only if strictly needed, they can administer an additional numbers of drops of Blink ® 
Tears, by documenting all information in the patient’s diary.  
 
At home  
Days 56 ±4– 
84 ± 4 
¾ Recording any new or changes in concomitant medications (diary) 
¾ Recording any unusual medical conditions  - AE monitoring (diary) 
¾ Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 
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Day 
Procedures/Assessments 
Visit 5 Follow up week 12  
 
Day 84 ± 4 
 
The following procedures will be performed (the below order is  mandatory): 
 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment by PGIC questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia)  
x Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
x Tear Film Break-up Time (TFBUT) 
¾ Ocular surface staining (NEI score - corneal and conjunctival fluoresce instaining) 
¾ Concomitant ocular and systemic medications 
¾ Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF). 
¾ AE monitoring 
 
During visit 5, week 12, PI or delegate must check and collect the third patient’s diary 
concerning the second follow up period. 
The Investigator will dispense to the patient the preservative free artificial tears (Blink 
® Tears) to be self-administered three times daily, one drop in both eye during the last 
weeks of Follow up. The PI or delegate has to explain to the patients that, only if 
strictly needed, they can administer an additional numbers of drops of Blink ® Tears, 
by documenting all information in the patient’s diary. 
 
At home  
Days 84 ±4– 
112 ± 7 
¾ Recording any new or changes in concomitant medications (diary) 
¾ Recording any unusual medical conditions  - AE monitoring (diary) 
¾ Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 
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Day 
Procedures/Assessments 
Visit 6 Follow up week 16 
Final visit or early termination visit (ETV) 
Day 112 ± 7 
The final visit is defined as the visit performed 84 ± 7 days after the last IMP 
administration (i.e., at day 112 ± 7). In case of premature study discontinuation, 
patients will undergo an early termination visit (ETV or end of study EOS as per 
eCRF). 
 
The following procedures will be performed (the below order is  mandatory): 
 
¾ Pregnancy test for female patients of childbirth potential 
¾ Ocular examination of both eyes: 
x Assessment by SANDE questionnaire 
x Assessment by IDEEL questionnaire 
x Assessment by EQ-5D-3L questionnaire 
x Assessment by PGIC questionnaire 
x Assessment of best corrected distance visual acuity (BCDVA) 
x External Ocular Examination 
x Schirmer test  I (without anesthesia) 
x Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
x Tear Film Break-up Time (TFBUT) 
x Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
x Schirmer test  II (with anesthesia) 
x Laser scanning confocal microscopy to assess goblet cells density (only 
selected sites)  
x Corneal endothelium and stroma evaluation (only the sites having  a confocal 
microscope will do this type of evaluation) 
¾ Concomitant ocular and systemic medication 
¾ Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF) 
¾ AE monitoring 
 
During visit 6, week 16, PI or delegate must check and collect the last patient’s diary 
concerning the third follow up period. 
 
 
 
 
 
 
 
 
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6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT 
6.3.1. 
Primary Reason For Discontinuation From The Study 
A premature discontinuation will occur when a patient who signed the ICF ceases participation in the 
study, regardless of circumstances, before the completion of the study protocol procedures. Patients 
can be prematurely discontinued from the study for one of the following reasons:  
 
¾ Adverse event (AE): Any significant AE that, in the opinion of the Investigator or concerned 
patient,  is not compatible with study continuation. 
¾ Disease progression or worsening, that according to the opinion of the Investigator is not 
compatible with study continuation.. 
¾ Death. 
¾ Lost to follow-up (Every effort must be made to contact the patient; a registered letter must be 
sent). 
¾ Non-compliance with study drug: an indication that a patient has not agreed with or followed 
the instructions related to the study medication. 
¾ Physician decision: a position, opinion or judgment reached after consideration by a physician 
with reference to the patient. 
¾ Severe Protocol violation: an event or decision that stands in contrast to the guidelines set out 
by the protocol. 
¾ Study terminated by the Sponsor: an indication that a clinical study was stopped by Sponsor. 
¾ Withdrawal of consent: study discontinuation requested by a patient for whatever reason. 
¾ Other reasons, such as administrative reasons or pregnancy.  
 
Before removal, each case should first be discussed with Dompé farmaceutici s.p.a. 
The reasons for premature discontinuation from the study will be reflected on the Study Termination 
Record of the eCRF. Unless the patient has withdrawn consent, the follow up visit assessments should 
be performed as detailed in § 6. 
 
The investigator should advise patients that prematurely discontinue on any therapies or treatments 
for their condition and refer them for further treatment as appropriate 
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6.3.2. 
Discontinuation procedures 
For any patient discontinuing the study following randomization, the Investigator will:  
 
¾ ask the patient to undergo, as far as possible, a final medical visit (ETV) to examine the patient's 
health conditions. This examination will verify that all values tested at screening have remained 
within a clinically acceptable range (i.e., not clinically significant changes compared to 
screening). 
¾ arrange for alternative medical care of the withdrawn patient, if necessary. 
¾ report in the eCRF date and time of the last dose administration, and date and primary reason of 
study discontinuation. 
¾ record in the eCRF any follow-up if the patient is withdrawn for an AE. AE’s should be followed 
until resolution. 
 
 
6.3.3. Replacement procedure 
Patients in this study who prematurely discontinue treatment will not be replaced. 
 
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. 
 
6.4. 
END OF STUDY 
Patients completing the double-blind treatment (Visits 1 Baseline to Visit 6 Follow up) will be 
considered completers.  
For the purpose of this trial, the End of Study is defined as 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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7. ENDPOINTS 
7.1. 
STUDY ENDPOINTS 
The study objective is to assess the efficacy and safety of rhNGF when administered as eye drops to 
patients with moderate to severe dry eye. 
Evaluation of the clinical efficacy and safety during and at the end of treatment with rhNG, will be 
performed on the basis of the following assessments at each time point. 
Evaluations will be performed on day -8 (screening), day 1+2 (visit baseline), day 14±2 (week 2), 
day 28±2   (week 4 End of treatment), day 56±4 (week 8 Visit 4 FU), day 84±4 (week 12 Visit 5 FU), 
day 112±7 (week 16 Visit 6 FU), according to the schedule of evaluation (§ 2) 
7.1.1. 
Primary endpoint 
x Change from baseline in Schirmer test I (without anesthesia) Vs week 4. 
7.1.2. 
Secondary endpoints 
x Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency 
assessed at 4 weeks of treatment; 
x Change from baseline in Schirmer II test (with anesthesia) Vs week 4; 
x Change from baseline in Corneal and conjunctiva vital staining with fluorescein (National Eye 
Institute [NEI] scales) Vs week 4; 
x Change from baseline in Tear Film Break up time (TFBUT) Vs week 4; 
x Number of patients who experienced a worsening in symptom scores (SANDE) and/or NEI 
score >= 50% assessed at week 4; 
x Quality of life (Impact of Dry Eye on Everyday Life (IDEEL) questionnaire;  
x Patient global Impression of change (PGIC); 
x  EQ-5D-3L. 
7.1.3. 
Exploratory endpoint 
x Correlation between sign and symptoms scores; 
x Proportion and frequency of preservative free artificial tears use (n° drops/day) during the 
treatment period; 
x Frequency of preservative free artificial tears use (n° drops/day) during the follow up period. 
x Change from baseline in Schirmer test I (without anesthesia) Vs week 2; 
x Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency 
assessed at 2 weeks of treatment ; 
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x Change from baseline in Corneal and conjunctiva vital staining with fluorescein (National Eye 
Institute [NEI] scales) Vs week 2; 
x Change from baseline in Tear Film Break up time (TFBUT) Vs week 2; 
x Number of patients who experienced a worsening in symptom scores (SANDE) and/or NEI 
score >= 50% assessed at week 2; 
x Change from baseline in goblet cells density Vs week 4 
7.1.4. 
Safety endpoint 
x Incidence and frequency of Treatment-emergent adverse events (TEAEs), assessed throughout 
the study. 
7.1.5. 
Stratification according to absence /presence of Primary Sjögren's Syndrome 
x The primary, secondary, explorative and safety endpoints (see 7.1.1, .7.1.2 7.1.3 & 7.1.4) will be 
also evaluated within each stratification subgroup (absence/presence of Primary Sjögren's 
Syndrome).. 
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8. EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
8.1. 
DEFINITIONS  
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 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 product, whether or not related to the medicinal product.  
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as any noxious and unintended response to a medicinal 
product related to any dose. Any responses to a medicinal product means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product. For the purposes of IND safety reporting, “reasonable 
possibility” means there are facts (evidence) or arguments to suggest a causal relationship between 
the drug and the adverse event..  Adverse events are to be considered unrelated if the relationship to 
the study drug, as described in the table in § 8.2.1,  is none or unlikely; whereas any AE reported in 
the study having a possible, probable or highly probable relationship to study drug will be considered 
as an ADR. The determination of expectedness should be made by the Sponsor on the basis of the IB. 
Serious Adverse Event 
A Serious Adverse Event (SAE) is defined in line with (CFR - Code of Federal Regulations Title 
21 Sec. 312.32) as any adverse experience that, in the view of either the Investigator or sponsor, meets 
any of the following criteria:: 
x results in death, 
x is life-threatening (i.e. the patient was at immediate risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it were more severe), 
x requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency 
ward for observation and/or treatment (usually involving an overnight stay) that would not have 
been appropriate in the physician's office or an outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” occurred, the event 
should be considered serious. 
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x results in persistent or significant disability/incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental 
trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption 
x is a congenital anomaly/birth defect, 
x 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 wellbeing 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. 
8.3.2).   
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.  
Death shall always be reported as SAE and cause of death shall always be specified when known. 
Unexpected Adverse Event/Reaction 
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure or is not listed 
at the specificity or severity that has been observed and listed in the Investigator Brochure. Events 
that are mentioned in the Investigator Brochure (section Reference Safety Information)  as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation are considered 
unexpected (21 CFR312.32(a)). 
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. 
As mentioned, the determination of expectedness should be made on the basis of the IB (section 
Reference Safety Information)  . 
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Adverse Events (AEs) 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): 
¾ 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 
¾ AEs that caused a decrease in visual acuity to the level of Light Perception or worse lasting >1 
hour 
¾ 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 
¾ AEs associated with severe intraocular inflammation (i.e., 4+ anterior chamber cell/flare or 4+ 
vitritis) 
¾ AEs that, in the opinion of the Investigator, may require medical intervention to prevent 
permanent loss of sight. 
8.2. 
ADVERSE EVENT (AE) MONITORING 
At visit 3 (end of treatment), visit 4 (FU), vist 5 (FU) and visit 6 (FU), 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:  
x “Have you had any health problems since your last study visit?” 
x “Have there been any changes in the medicines you take since your last study visit?”  
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result 
of an untoward (unfavorable and unintended) change in 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 (unfavorable and unintended) change in a protocol-
specific parameter or questionnaire response that is clinically relevant is to be reported as an AE. 
These clinically relevant changes will be reported regardless of causality. 
All AEs should be followed-up to determine outcome of the reaction.  
In order to collect as complete as possible information in the clinical study database, all ADRs and SAEs 
ongoing at the time the subject’s study participation ends should be evaluated within 10 days after the 
final visit. After this period, all unresolved ADRs and SAEs will be reported as “ongoing” in the eCRF. 
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8.3. 
RECORDING 
AE data should be obtained through observation of the patient, from any information volunteered by 
the patient, or through patient questioning. 
 
Adverse Events: 
All AEs (non-serious and serious) that occur during the course of the study will be recorded in the 
eCRF. Any pre-existing medical conditions or signs/symptoms present in a patient prior to the start 
of the study (i.e., before informed consent is signed) should be specified in the dedicated eCRF 
sections. Subsequent to signing an informed consent form, all untoward medical occurrences that 
occur during the course of the study must be documented on eCRF. AEs will be collected till last 
Follow Up visit (week 16). 
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 adverseevent 
relationship to the study treatment. 
 
 
Serious Adverse Events: 
The Investigator must record all SAEs, including sight-threatening events, occurring at any time 
during the study regardless of presumed causal relationship, on the Serious Adverse Event form in 
the eCRF of the EDC system within 24 hours of learning of the event; information on the SAE must 
also be recorded on a specific Non-Carbon Repeat SAE form (included in the Investigator’s Site File). 
 
 
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8.3.1. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the possible relationship between the AE and the investigational 
medication, according to the criteria in Table below: 
Relationship of the Adverse Event to the IMP 
None 
(Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, e.g. 
patient is a passenger in a road traffic accident or surgical intervention performed 
during the study, but planned before patient enrolment into the study 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test 
abnormality with temporal relationship to drug administration which makes a 
causal relationship improbable and in which other drugs, chemicals or underlying 
disease provide more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s condition 
or treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational 
Product and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
 
An ADR is defined as an adverse experience which is reasonably likely to have been caused by the 
drug. Events considered “Possible”, “Probable” and “Highly Probable” related to the IMP treatment 
and implying a reasonable possibility, if considered unexpected, will be reported to appropriate 
regulatory authorities. 
8.3.2. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below. For each 
episode, the highest severity grade attained should be reported. 
Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of symptoms 
or signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to work 
or to do usual activities [unacceptable]) 
 
 
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8.4. SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators to Dompé and CRO 
The Investigator must report all SAEs filling in and signing a SAE Report form, including sight 
threatening events, regardless of presumed causal relationship, to Dompé Drug Safety and Syneos 
Health Pharmacovigilance, by e-mail (preferred) or fax within 24 hours of learning of the event. 
Contact details for SAE reporting are provided below: 
Syneos Safety reporting 
safetyreporting@syneoshealth.com 
Dompé Contact information 
Dompé Drug Safety  
Laura Boga, Senior Safety Manager  
Email: farmacovigilanza@dompe.com 
or Fax: +39.02.36026913 
Dompé Medical Expert  
Flavio Mantelli – Chief Medical Officer, 
Email:  flavio.mantelli@dompe.com 
or Fax: +39.02.58383324 
Pier Adelchi Ruffini – Global Head Clinical Development 
Email: pieradelchi.ruffini@dompe.com 
or Fax: +39.02.58383324 
Dompé Clinical Development 
Email: elisa.greco@dompe.com/ mauro.ferrari@dompe.com/ beth.butler@dompe.com 
or Fax: +39.02.58383324 
Respective IRB must also be informed of all SAEs according to local specific requirements. 
If assistance is needed with the reporting of a SAE,  Syneos Health/Sponsor may be contacted at the 
addressed provided above  
Serious adverse events will be managed directly by the Dompé Drug Safety department, with Syneos 
Health 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. 
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Follow-up reports (as many as required) should be completed and faxed/e-mailed following the same 
procedure above, marking the SAE form as “follow up Number XX”.   
Whenever more than one SAE is observed, the Investigator should identify which is the primary 
adverse event, i.e. the most relevant one. If other events are listed in the same report, the Investigator, 
along with their relatedness to the Investigational Product, should identify which adverse events are 
serious and which are non-serious. In any case, the Investigator is requested to record his/her opinion 
about the relatedness of the observed event(s) with the investigational medication. 
An assessment of expectedness and causality of each serious adverse event will be performed case 
by case by Dompé/Syneos Health. For SAE reported by the Investigator as not related that is 
subsequently assessed to be related by Dompé, the Investigator will receive a notification. Depending 
on the nature and seriousness of the AE, further information, including copies of appropriate medical 
records of the patient, as well as results of laboratory tests performed will need to be included in the 
patients chart. If the patient was hospitalized, a copy of the discharge summary should be available, 
if possible. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not 
usually need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes 
aware of a SAE occurring to a patient after that patient has ended his/her participation in the study 
(whether study completion or withdrawal), the SAE should be reported by the Investigator to the the 
Dompé/Syneos Health Pharmacovigilance. Such “post-study cases” should be regarded for expedited 
reporting purposes as though they were study reports. Therefore, a causality assessment and 
determination of expectedness are needed for a decision on whether or not expedited reporting is 
required.  
8.4.2. 
Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be 
SAE and shall not be reported as such, but only need to be recorded in the eCRF: 
x 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.  
x Hospitalization for routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition. 
x 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. 
x Hospitalization for general care not associated with any deterioration in condition.  
x 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.  
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In addition, the following situation shall not be considered SAE: 
 
x Trial end points 
x Abnormal test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are not clinically significant. 
8.4.3. 
Reporting Procedure to IRB and to Regulatory Authorities 
In addition to reporting the SAE to Dompé, the Investigator must also comply with the requirements 
related to the reporting of SAEs to the IRB which approved the study. The requirements of IRBs vary 
from one IRB to another; however, as a minimum requirement, the Investigators must promptly report 
all suspected unexpected serious adverse reaction (SUSAR) to their IRB. 
In line with provisions set forth in 21CFR312, Dompé shall notify all participating Investigators in 
an IND safety report of any suspected adverse reaction that is both serious and unexpected  and of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than:  
x seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; to be followed by any relevant information within eight days. 
x fifteen calendar days after becoming aware of the information if the event is serious but neither 
fatal nor life threatening. 
The Investigators in turn shall notify their IRB.  
If the results of an investigation show that an ADR not initially determined to be reportable is 
reclassified as reportable, the Sponsor shall report such reaction in a written safety report as soon as 
possible, but in no event later than 7/15 calendar days after the determination is made. 
Treatment will be unblinded by Dompé Drug Safety Pharmacovigilance prior to submission of a 
SUSAR to Regulatory Authorities and only cases referred to active treatment will be considered 
expeditable for regulatory reporting, in line with law requirements. 
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in 
the Investigator’s Files. 
Dompé shall also notify FDA in an IND safety report of potential serious risks, from clinical trials or 
any other source, as soon as possible after Dompé determines that the information qualifies for 
reporting, in particular shall notify of: 
x any suspected adverse reaction that is both serious and unexpected. Dompé must report an 
adverse event as a suspected adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event.  
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x findings from other studies that suggest a significant risk in humans exposed to the drug. Such a 
finding would result in a safety-related change in the overall conduct of the clinical investigation.  
x findings from animal or in vitro testing that suggest a significant risk in humans exposed to the 
drug 
x increased rate of occurrence of serious suspected adverse reactions. 
8.4.4. 
Periodical Reporting to Regulatory Authorities 
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety Update 
Report – DSUR) to relevant Regulatory Authorities.  
8.5. 
UNMASKING OF THE STUDY TREATMENT 
Masked information on the identity of the assigned investigational product will be provided for each 
patient. If the treatment code needs to be broken in the interest of patient safety, Dompé must be 
informed in all cases in which the code was broken and of the circumstances involved. 
Additionally, Dompé Drug Safety may be need to unmask the patient’s treatment if the a reported 
SAE meets criteria of a Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfil 
expedited regulatory reporting requirements. Unmasked information shall not be disclosed to 
Investigators. 
The identity of the treatments will remain unknown to the patient, Investigator, site staff and Dompé’s 
clinical research personnel and Syneos Health staff (apart from pharmacovigilance). 
8.6. 
FOLLOW-UP OF PATIENTS WITH ADVERSE EVENTS (AES) 
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. 
If patient was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to 
Syneos Health/Dompé as soon as it becomes available. In addition, a letter from the Investigator that 
summarizes the events related to the case as well as results of any relevant laboratory tests also may 
be requested. Further, depending upon the nature of the SAE, Dompé may request copies of applicable 
segments of the patient’s medical records. 
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For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as completely and 
practically as possible their nature and/or causality until resolution of all queries, clinical recovery is 
complete, laboratory results have returned to normal, stable condition is reached or the subject is lost to 
follow-up. Follow-up may therefore continue until after the subject has left the study up to  10 days after 
his/her discontinuation from the study for unrelated SAEs, and without timelines for related SAEs, unless 
the patient denies consent. 
8.7. 
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 enrollment 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 (during the study treatment period and during the 
follow up), female patients are to be instructed to contact the Investigator immediately if they suspect 
they might be pregnant; in the same way, male patients who become aware that the partner might be 
pregnant, are to be instructed to contact the Investigator immediately.  
The Investigator must report every pregnancy on a pregnancy report form as soon as possible 
(within 24 hours of learning of the pregnancy) to  Syneos Health/Dompé Drug Safety contacts 
reported at Paragraph 8.4.1, even if no AE has occurred, and follow it to term.  
The pregnancy form will be utilized to capture all pregnancy-related information until the birth of 
the child for both the patient and the partner.  
If the pregnancy is associated with a 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 § 8.4 
with the appropriate serious criterion (eg, hospitalization) indicated on the SAE report form. 
Miscarriage, stillbirth and any malformation/disease must be reported as a SAE. Any pregnancy leads 
to the immediate cessation of the study treatment.  
8.8. 
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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8.9. 
OVERDOSE  
Cases of overdose (accidental or intentional) which may or may not result in serious adverse reactions 
are to be reported to Sponsor Drug Safety/Syneos Health by email or fax, following the same 
procedure for SAE, within 24 hours from the Investigator’s knowledge of its occurrence. This 
includes reports related to 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. 
The Investigator shall provide in the SAE form information about symptoms, corrective treatment 
and outcome of overdose. 
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9. 
STATISTICS 
 
The data documented in this study will be summarized using number of observations, mean, standard 
deviation (SD), median, minimum, and maximum values for quantitative variables, and frequencies 
for qualitative variables. 
A statistical analysis plan (SAP) will be developed and finalized before database lock and de-
masking. Final statistical analysis on the study variables will be presented in detail in the SAP.  
9.1. 
SAMPLE SIZE 
In order to evaluate the minimal effective daily dose of rhNGF eye drops, a Williams design has been 
chosen [15; 16]. For this study three treatment groups has been considered: rhNGF eye drops solution 
20 µg/ml TID; rhNGF  eye drops solution 20 µg/ml BID plus vehicle eye drop solution SID; vehicle 
eye drop solution TID. 
To this purpose, the sample size has been determined applying the formula eported in the publication 
Chow et al., 2008 at page 301 [17].  
 
The sample size calculation for the primary variable is based on the following assumptions: 
 
 The probability level (α) for one-sided test is set at 0.025 (see table 12.1.2 at page 298 in Chow 
et al., 2008) and the power level at approximately 90%. 
 
 DELTA, in change from baseline between treatments, of 5.3 and Standard Deviation for DELTA 
of 10.78. Both DELTA parameters are derived from results of co-variance analysis obtained from 
study NGF0216 in the subset of hyposecretive patients (i.e. excluding “evaporative-only” 
patients). 
 
According to this calculation, 87 patients per treatment group (for a total of 261 patients) are 
adequate to observe the planned difference assumed for the minimum effective daily dose. 
Assuming a drop-out of ⁓15%, a total of 300 is the target number of patients proposed to be 
enrolled.  
 
The inclusion of at least 60 subjects with documented diagnosis of Primary Sjögren's Syndrome 
within the planned 300 patients will have no impact on the initial study assumptions (Standard 
Deviation of 10.78 and DELTA of 5.3 mm) because the patients could have been enrolled based on the 
previous criteria on which sample size was based. Moreover, a similar prevalence of patients with 
Primary Sjögren's Syndrome has already been reported in the NGF0216 medical history (⁓25% of 
patient the FAS population).  
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9.2. 
POPULATION 
Screened Population  
The Screened Population will consist of all patients with the signature of the informed consent, the 
assignment of a PID number and regardless the completion of all the screening procedures.  
Eligible Population 
The Eligible Population will consist of all patients with all inclusion/exclusion criteria met. Otherwise 
the patient will be defined as screening failure.  
 Randomized Population  
The Randomized Population will consist of all patients in the Screened Population who were assigned 
a randomization number.  
9.3. 
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 1 Visit 1 baseline and the number of unused study 
medication vials returned at Week 4 Visit 3 End of treatment. The percentage Compliance will be 
evaluated according to the following formula: 
𝐎𝐯𝐞𝐫𝐚𝐥𝐥 𝐜𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞= 𝟏𝟎𝟎∗(Number of vials dispensed –  Number of unused vials returned)
𝟑∗(𝑵𝒖𝒎𝒃𝒆𝒓𝒔 𝒐𝒇 𝒅𝒂𝒚𝒔 𝒐𝒏 𝒕𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕)
 
 
𝐂𝐨𝐦𝐩𝐥𝐢𝐚𝐧𝐜𝐞 𝐟𝐨𝐫 𝐭𝐡𝐞 𝐞𝐥𝐢𝐠𝐢𝐛𝐥𝐞 𝐞𝐲𝐞= 𝟏𝟎𝟎∗(Number of  drops administered to the eligible eye)
𝟑∗(𝑵𝒖𝒎𝒃𝒆𝒓𝒔 𝒐𝒇 𝒅𝒂𝒚𝒔 𝒐𝒏 𝒕𝒓𝒆𝒂𝒕𝒎𝒆𝒏𝒕)
 
 
Gross non compliance will be defined as compliance lower than 80% or greater than 120% and in 
case of gross non compliance the patient will be excluded from the Per Protocol. Since this definition 
does not warrant that the study eye treatment is compliant, if indicated the SAP will contain further 
definitions based upon the diary card information. 
 
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9.4. 
STATISTICAL METHODOLOGY 
9.4.1. 
Definitions 
Enrolled Set  
The Enrolled Set will consist of all patients who signed the ICF. This analysis set will be used for 
demographic, baseline and background characteristics. 
Safety Population 
The Safety Population (SAF) will consist of all randomized patients who took at least one dose of IP. 
This analysis set will be used for the safety analysis. Patients will be analyzed according to the 
treatment received. 
Full Analysis Set 
Full Analysis Set (FAS) will consist of all randomized patients who took at least one dose of IP and 
who have at least one post-baseline efficacy measurement for the primary endpoint. This analysis set 
will be used for the primary efficacy analysis. Patients will be analyzed according to the randomized 
treatment. 
Per Protocol Set 
Per Protocol Set (PP) will consist of all patients in the FAS who fulfil the study protocol requirements 
in terms of investigational medicinal product intake and collection of primary efficacy data and with 
no major deviations that may affect study results. This analysis set will be used for supportive efficacy 
analysis.Patients will be analyzed according to the treatment received. 
Each patient will be coded by the Syneos Health statistician as valid or not valid for the Enrolled Set, 
SAF, FAS and PP. 
9.4.2. 
Reasons for exclusion from the Full Analysis Set 
Reasons for the exclusion from the Full Analysis Set are the following: 
¾ 
failure to take at least one dose of the IMP at the study eye 
¾ 
lack of any efficacy data post enrollment. 
9.4.3. 
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: 
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¾ 
lack of compliance with IMP administration  
¾ 
missing primary efficacy data 
¾ 
major deviation from inclusion/exclusion criteria (eligibility violations) 
¾ 
intake of prohibited medications. 
9.4.4. 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be descriptively summarized per treatment group 
according to their nature.  
9.5. 
Analysis of ophthalmological evaluations  
Primary endpoint will be analyzed using analysis of variance including only the treatment as main 
factor followed by pre-planned comparisons from Vehicle and rhNGF dosages according to Williams 
procedure. In addition, primary endpoint will be summarized using descriptive statistics for 
continuous variables by treatment and visit. The change from baseline value will also be summarized 
for all post-baseline visits. 
An explorative sensitivity analysis of the primary endpoint will be conducted including in the analysis 
of variance the absence/presence of diagnosis of Primary Sjögren's Syndrome and its interaction with 
treatments as covariates. If the interaction term is statistically significant (at the 0.10 level given its 
explorative nature), the treatment effects within patients with and without Primary Sjögren's 
Syndrome will be provided. 
 
Secondary endpoints will be presented by means of appropriate descriptive statistics.  
Changes from baseline in global SANDE score, Schirmer test II, NEI scales, TFBUT,  IDEEL, PGIC 
and EQ-5D-3L scores 4 will be analyzed in a similar manner as the Change from baseline in Schirmer 
test I (primary endpoint) in order to test treatment effect. Difference between treatment groups (Each 
active dose vs Placebo), in the percentage of patients who experienced a worsening in SANDE scores 
and/or NEI score will be tested using a chi-square test. 
 
Explorative endpoints will be summarized by means of appropriate descriptive statistics. Any 
statistical testing will be descriptive in nature. 
 
Additional details on the analyses will be provided in the statistical analysis plan. 
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9.5.1. 
Analysis of safety variables 
x AEs 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs are all events occurring or worsening after the first dose of the IMP. 
Treatment-emergent AEs will be summarized by treatment group. 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. Individual AEs will be listed in patient data listings.   
9.5.2. 
 Analysis of Quality of Life variables  
Data record in the questionnaires of quality of life will be presented with appropriate descriptive 
statistics and processed with appropriate inferential test. 
 
9.5.3. 
Subgroup analysis 
Sub-group analyses of primary, secondary, explorative endpoints and safety endpoints will be 
performed on patients with the Sjögren's syndrome  for explorative purpose. Statistical details will be 
reported in the SAP. 
 
9.5.4. 
Changes to the statistical plan 
Any deviations from the original statistical plan will be escribed in the Clinical Study Report. 
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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INSTITUTIONAL REVIEW BOARD  
Approval by the Institutional Review Board (IRB) before the start of the study will be the 
responsibility of the Principal Investigator (PI). A copy of the approval letter will be supplied to the 
sponsor, along with a roster of IRB members or the US Department of Health and Human Services 
(DHHS) general assurance number. During the course of the study, the PI will provide timely and 
accurate reports to the IRB on the progress of the study, at intervals not exceeding 1 year (or as 
appropriate), and will notify the IRB of serious adverse events (SAEs) or other significant safety 
findings. The study protocol, informed consent form (ICF), information sheet advertisements, and 
amendments (if any) will be approved by the IRBs at the study centers in conformance with Code of 
Federal Regulations (CFR), Title 21, Part 56.  
10.2. 
ETHICAL CONDUCT OF THE STUDY  
The study will be conducted in full compliance with FDA and ICH guidelines for good clinical 
practice (GCP) and in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki and 21 CFR § 312.120.  
10.3. 
DATA MONITORING COMMITTEE 
A Data Monitoring Committee is not required for this trial considering the following point: 
x The drug under investigation is well characterized and known for not harming patients 
x Tis clinical trial does not foresee an interim analysis 
x The study design is not complex and already performed in other clinical trial in DED 
x The study does not have a long duration. 
10.4. 
PATIENT INFORMATION AND CONSENT  
Patients, after being given an explanation of the study, will give voluntary and written informed 
consent before participating in any study-related procedures. A copy of the Experimental Subject’s 
Bill of Rights (Footnote 1) will provided to a subject prior to performing the consent process. 
Each patient will read or be read (if he or she cannot read or write), assent understanding of, and sign 
or thumbprint an instrument of informed consent and after having had an opportunity to discuss them 
 
 
1 The Protection of Human Subjects in Medical Experimentation Act (California Health and Safety Code 24170 – 
24179.5) requires that a potential experimental subject (or subject’s conservator, guardian, or other representative) be 
provided with a list of the rights of a subject in a medical experiment. 
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with the PI before signing; each patient will be made aware that he or she may withdraw from the 
study at any time.   
The informed consent statement contains all the elements of informed consent and contains all the 
core elements and mandatory statements as defined in the CFR. Signed copies of the ICF and the 
form will be given to the patient, and both documents will be placed in the Investigator’s site files. A 
unique patient identification (PID) number will be assigned according to § 4.3 of the protocol at the 
time the patient signs the ICF.  
10.5. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. An 
agreement for disclosure will be obtained in writing by the patient and will be included in the ICF. 
Patient’s data collected during the study will be handled in accordance with applicable data protection 
laws and regulations.  
On the CRFs patients will be identified ONLY by the assigned patient number. If patient names are 
included on copies of documents submitted to Dompé farmaceutici s.p.a. or Syenos Health, the names 
will be obliterated or masked and the assigned patient number added to the document. 
The Investigator should keep a separate log (Patient Master List) of patient’s codes, names and 
addresses. 
10.6. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance contract according to 
national laws for patients/Investigators/Institutions participating in the clinical trial.   
In case of questions about medical care, cost for medical care or insurance, patients can talk to their 
Investigator. Contact details will be given in the Patient Informed Consent Document. 
 
 
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11. 
DATA HANDLING AND RECORD KEEPING  
11.1. 
CASE REPORT FORMS 
All data relating to the study will be recorded on eCRFs to be provided by  Syneos Health, through 
the EDC system. The PI is responsible for verifying that all data entries in the eCRFs are accurate 
and correct. The PI must sign the completed eCRF before its submission to the sponsor.  
11.2. 
DATA MANAGEMENT  
Data collection will involve the use of an EDC system , to which only authorized personnel will have 
access. In addition to periodic monitoring occurring within the system by Syneos Health Monitors, 
programmatic edit checks will be used to review the data for completeness, logic, and adherence to 
study protocol. As a result of this monitoring and these checks, queries may be electronically issued 
to the study centers and electronically closed by those study centers. The identifying information 
(assigned username, date, and time) for both the originator of the query (if created during the 
monitoring process) and the originator of the data change (if applicable), as well as the PI’s approval 
of all changes performed on his or her patients’ data, will be collected.  
All data collected in the context of this study will be stored and evaluated per regulatory requirements 
and applicable guidances for electronic records. Also, data will be stored and evaluated in such a way 
as to guarantee patient confidentiality in accordance with the legal stipulations applying to 
confidentiality of data. Study records (e.g., copies of eCRFs, regulatory documents) will be retained 
at the study center, along with adequate source documentation, according to FDA and ICH 
requirements. All study records must be available for audit  by Dompé farmaceutici s.p.a.; its 
authorized representatives; and Regulatory Inspection by Regulatory Authority.  
The investigator/institution should maintain adequate and accurate source documents and trial records 
that include all pertinent observations on each of the site’s trial subjects. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data 
should be traceable, should not obscure the original entry, and should be explained if necessary via 
an audit trail. 
11.3. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING THE 
STUDY 
The following documents will be required from the Investigator prior to the initiation visit: 
- 
Current, signed and dated Curriculum Vitae of Principal Investigator and any 
Sub-Investigators/co-workers. Updates should be provided at least every two years. 
- 
A signed page of the final protocol and any amendments. 
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- 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Syneos 
Health, including all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
- 
A financial disclosure agreement completed and signed by the PI and all Sub-Investigators 
listed on Form FDA 1572. If applicable, the PI will provide an updated financial disclosure 
agreement to the Sponsor 1 year after the completion of the study. 
11.4. 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP E6 R2) 
until at least 2 years after the last approval of a marketing application in an ICH region, and until 
there are no pending or contemplated marketing applications in an ICH region, or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the Investigational Product. 
These documents should be retained for a longer period however if required by the applicable 
regulatory requirements. The Investigator should take measures to prevent accidental or premature 
destruction of these documents. 
The essential documents include at least: the signed protocol, copies of the completed eCRFs, signed 
Patient Informed Consent Forms from all patients who consented, hospital records and other source 
documents, and all other documentation included in the Investigator Site File and 
Pharmacy/Dispensing File. 
The Investigator will inform Dompé farmaceutici s.p.a. of the storage location of these essential 
documents and must contact Dompé farmaceutici s.p.a. before disposing of any. If the Investigator 
wishes to assign the files to someone else or to remove them to another location, he/she should consult 
with Dompé farmaceutici s.p.a. about this change. 
Dompé farmaceutici s.p.a. will inform the Investigator in writing when these documents no longer 
need to be retained. 
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12. 
STUDY MANAGEMENT 
 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013) and ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (ICH-GCP E6-R2) and any local regulations. 
12.1. 
MONITORING 
Before any patient enters the study, a representative of Syneos Health, will meet with the PI and his 
or her staff to review the procedures to be followed during the study and to train them on recording 
the data in the eCRFs using the electronic data capture (EDC) system. After the first patient is 
enrolled, the Syneos Health representative, a monitor, will periodically monitor the progress of the 
study by conducting on-site visits. This CRA will also be able to review query statuses remotely, 
possibly warranting more frequent communication with the PI and his or her staff. The PI will make 
available to the CRA the eCRFs, source documents, signed consent forms, and all other study-related 
documents. The PI and his or her staff will be responsible for reviewing eCRFs, resolving data queries 
generated by the CRA via the system, providing missing or corrected data, approving all changes 
performed on his or her data, and endorsing the patient data within the EDC system. This approval 
method will include applying an electronic signature, a uniquely assigned username and password 
that together will represent a traditional handwritten signature.  
12.2. 
ACCESS TO RECORDS 
The Investigator will allow designated Dompé farmaceutici s.p.a. representatives, including staff 
from Syneos Health, and regulatory/ethics bodies to have direct access to the source documents to 
verify the data reported in the eCRFs. Source documents are the originals of any documents used by 
the Investigator or hospital/institution that allow verification of the existence of the patient and 
substantiate the integrity of the data collected during the trial. 
12.3. 
AUDIT AND INSPECTION 
The study site may be audited by Syneos Health on behalf of the Dompé farmaceutici s.p.a. or 
inspected by a regulatory agency on one or more occasions. The Investigator may be informed in 
advance of such a visit.  
12.4. 
PROTOCOL AMENDMENTS 
Any amendment to this protocol will be provided to the PI in writing by Dompé farmaceutici s.p.a. 
No protocol amendment may be implemented (with the exceptions noted below) before it has been 
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approved by the IRB and the signature page, signed by the PI, has been received by Dompé 
farmaceutici s.p.a. If the protocol is amended to eliminate or reduce the risk to patients, the 
amendment may be implemented before IRB review and approval. However, the IRB must be 
informed in writing of such an amendment, and approval must be obtained within reasonable time 
limits. Deviating from the protocol is permitted only if absolutely necessary for the safety or clinical 
management of the patients and must immediately be reported to Dompé farmaceutici s.p.a. 
12.5. 
DISCONTINUATION OF THE STUDY 
Dompé farmaceutici s.p.a. reserves the right to terminate the study in its entirety or at a specific 
study center at any timeon the basis of new information regarding safety or efficacy, or if study 
progress is unsatisfactory, or for other valid administrative reasons. 
12.6. 
PUBLICATIONS 
All data generated in this study will be the property of Dompé farmaceutici s.p.a. Publication of the 
results by the PI will be subject to mutual agreement between the PI and Dompé farmaceutici s.p.a. 
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 FDA 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. 
 
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13. 
REFERENCES 
1 
Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care 2008; 
14(3 Suppl):S102-6. Review.  
2 
TFOS DEWS II REPORT. Ocul Surf 2017; 15(3):269-283...  
3 
Lambiase A, Sacchetti M and Bonini S, Nerve growth factor therapy for corneal disease, Curr Opin 
Ophthalmol 2012, 23:296–302.  
4 
Nguyen D, Beuerman HRW, Thompson HW, et al. Growth factor and neurotrophic factor mRNA in 
human lacrimal gland. Cornea 1997; 16(2):192–9.  
5 
Ghinelli E, Johansson J, Rios JD et al. Presence and localization of neurotrophins and neurotrophin 
receptors in rat lacrimal gland. Invest Ophthalmol Vis Sci 2003; 44(8):3352–7.  
6 
Vesaluoma M, Müller L, Gallar J et al. Effects of oleoresin capsicum pepper spray on human corneal 
morphology and sensitivity. Invest Ophthalmol Vis Sci 2000, 41(8): 2138–47.  
7 
Coassin M, Lambiase A, Costa N, et al. Efficacy of topical nerve growth factor treatment in dogs affected 
by dry eye. Graefe’s Arch Clin Exp Ophthalmol 2005;243(2):151-5.   
8 
Lee HK, Ryu IH, Seo KY, et al. Topical 0.1% prednisolone lowers nerve growth factor expression in 
keratoconjunctivitis sicca patients. Ophthalmology 2006; 113(2):198-205.   
9 
Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic 
keratitis. Ophthalmology 2000; 107:1347-51.  
10 Rios JD, Ghinelli E, Gu J et al. Role of neurotrophins and neurotrophin receptors in rat conjunctival goblet 
cell secretion and proliferation. Invest Ophthalmol Vis Sci 2007; 48(4):1543-51.  
11 Lambiase A, Rama P, Bonini S, et al.Topical treatment with nerve growth factor for neurotrophic corneal 
ulcers. New Engl J Med 1998; 338(17):1174-80.  
12 Lambiase A, Bonini St, Aloe L, et al. Anti-inflammatory and healing properties of nerve growth factor in 
immune corneal ulcers with stromal melting. Arch Ophthalmol. 2000; 118(10) p1446-1449.  
13 Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for neurotrophic 
keratitis. Ophthalmology 2000; 107:1347-51.  
14 Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjögren’s syndrome: a revised version 
of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 
61:554–558.  
15 Williams DA.  A test for differences between treatment means when several dose levels are compared 
with a zero dose control.  1971. Biometrics 27, 103-117 
16 Williams DA. The comparison of several dose levels with a zero dose control.  1972. Biometrics 28, 519-
531.  
17 Shein-Chung Chow, Jun Shao, Hansheng Wang;  Samples Size Calculations in Clinical Research - 
Marcel Dekker, Inc. 2003I, SBN: 0-8247-0970-5, p. 186-189. 
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14.2 APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
I have read study protocol NGF0118 from the title “A 4 week, Phase II, multicenter, randomized, 
double-masked, vehicle-controlled, parallel group study with 12 weeks of follow-up to evaluate safety 
and efficacy of recombinant human Nerve Growth Factor (rhNGF) eye drops solution versus vehicle, 
in patients with moderate to severe dry eye (DE)” and agree to conduct the study as outlined in the 
protocol, and in accordance with the Declaration of Helsinki, ICH-GCP E6 (R2) and any local 
regulations, being responsible for personally supervise the study conduct and ensure study staff 
complies with protocol requirement. 
 
 
Name of Principal Investigator (block letters):____________________________________________ 
 
 
 
Signature:  _______________________________  
Date: 
 _________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.3 APPENDIX 3AMERICAN-EUROPEAN CONSENSUS CRITERIA FOR SJÖGREN’S 
SYNDROME 
 
Reference:  Vitali C, et al. Classification criteria for Sjogren’s syndrome: a revised version of the 
European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 
61:554-558. 
In order to make a diagnosis of Sjögren’s syndrome, the following criteria must be met: 
I. Ocular Symptoms (at least one) 
x Symptoms of dry eyes for at least 3 months 
x A foreign body sensation in the eyes 
x Use of artificial tears 3 or more times per day 
II. Oral Symptoms (at least one) 
x Symptoms of dry mouth for at least 3 months 
x Recurrent or persistently swollen salivary glands 
x Need for liquids to swallow dry foods 
III. Ocular Signs (at least one) 
x Abnormal Schirmer’s test, (without anesthesia; ≤5 mm/5 minutes) 
x Positive vital dye staining of the eye surface 
IV. Histopathology 
x Lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm2) 
V. Oral Signs (at least one) 
x Unstimulated whole salivary flow (≤1.5 mL in 15 minutes) 
x Abnormal parotid sialography 
x Abnormal salivary scintigraphy 
VI. Autoantibodies (at least one) 
x Anti-SSA (Ro) or Anti-SSB (La), or both 
For a primary Sjögren’s syndrome diagnosis: 
x Any 4 of the 6 criteria, must include either item IV (Histopathology) or VI (Autoantibodies) 
x Any 3 of the 4 objective criteria (III, IV, V, VI)  
 
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For a secondary Sjögren’s syndrome diagnosis: 
x In patients with another well-defined major connective tissue disease, the presence of one 
symptom (I or II) plus 2 of the 3 objective criteria (III, IV and V) is indicative of secondary 
SS. 
Exclusion Criteria 
x Past head and neck radiation treatment 
x Hepatitis C infection 
x Acquired immunodeficiency syndrome (AIDS) 
x Pre-existing lymphoma 
x Sarcoidosis 
x Graft versus host disease 
x Current use of anticholinergic drugs 
 
 
Dompé farmaceutici s.p.a.  
Recombinant Human Nerve Growth Factor (rhNGF) 
NGF0118 
Final
____________________________________________________
___________________________________________________
____________________________________________________
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SAP_001.pdf: 
 
 
 
 
 
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Statistical Analysis Plan for Interventional Studies 
 
Sponsor Name: Dompé farmaceutici S.p.A 
 
Protocol Number: NGF0118 
Protocol Title: A 4 week, Phase II, multicenter, randomized, double-masked, vehicle-controlled, 
parallel group study with 12 weeks of follow-up to evaluate safety and efficacy of recombinant human 
Nerve Growth Factor (rhNGF) eye drops solution versus vehicle in patients with moderate to severe 
dry eye (DE). 
 
Protocol Version and Date: Version 2.0, Final 08-Aug-2019 
 
Syneos Health Project Code: 7000843 
 
Authors: Fabienne BAELEN, Principal Biostatistician  
 
Giovanni GOISIS, Principal Biostatistician CRO NT (version 1.2) 
 
 
 
 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Dompé farmaceutici S.p.A. 
Acceptance of this document constitutes agreement by the recipient that no information contained 
herein will be published or disclosed without prior written authorization from an official of Dompé 
farmaceutici S.p.A.  However, this document may be disclosed to appropriate Institutional Review 
Board and Ethics Committees or duly authorized representatives of a national regulatory authority 
under the condition that they are requested to keep it confidential. In the event of an actual or 
suspected breach of this obligation, Syneos Health should be notified promptly. 


Statistical Analysis Plan for Interventional Studies 
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Revision History 
Version # 
Date 
(DD-Mmm-YYYY) 
Document Owner 
Revision Summary 
1.1 
29 May 2020 
 
Update of SAP due to COVID-19 pandemic  
1.2 
17 Sep 2020 
 
Sensitivy analysis on robustness of primary analysis and 
statistical tests (descriptive in nature) have been added. 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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I confirm that I have reviewed this document and agree with the content. 
 
Approvals 
Syneos Health Approval 
 
 
 
 
 
Fabienne Baelen, Principal Biostatistician 
Lead  Biostatistician  
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 Dompé farmaceutici S.p.A Approval 
 
 
 
 
 
 
 
 
Elisa Greco, Clinical Development Specialist  
Sponsor Contact  
 
Signature 
 
Date (DD-Mmm-YYYY) 
 
 
 
 
 
 
 
 
Giovanni Goisis, Principal Biostatistcian 
CROS NT 
Sponsor Contact  
 
Signature 
 
Date (DD-Mmm-YYYY) 
 


Statistical Analysis Plan for Interventional Studies 
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Table of Contents 
Revision History ...................................................................................................................................... 2 
Approvals ............................................................................................................................................... 3 
 
Glossary of Abbreviations ............................................................................................................. 7 
 
Purpose ......................................................................................................................................... 9 
 
Study Objectives ......................................................................................................................... 10 
 
Endpoints..................................................................................................................................... 16 
 
Analysis Sets ............................................................................................................................... 17 
 
General Aspects for Statistical Analysis ...................................................................................... 18 


Statistical Analysis Plan for Interventional Studies 
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Demographic, Other Baseline Characteristics and Medication ................................................... 21 
 
Efficacy ........................................................................................................................................ 23 


Statistical Analysis Plan for Interventional Studies 
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Safety .......................................................................................................................................... 36 
 
Interim Analyses .......................................................................................................................... 38 
 
Changes from Analysis Planned in Protocol ............................................................................... 39 
 
Reference List ............................................................................................................................. 40 
 
Programming Considerations ...................................................................................................... 41 
 
Quality Control ............................................................................................................................. 45 
 
Index of Tables ............................................................................................................................ 46 
 
Index of Figures ........................................................................................................................... 55 
 
Index of Listings .......................................................................................................................... 57 
 
Appendices .................................................................................................................................. 59 
 


Statistical Analysis Plan for Interventional Studies 
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Glossary of Abbreviations 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BCDVA 
Best Corrected Distance Visual Acuity  
BID 
Bis in die 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
DHHS 
Department of Health and Human Services 
DE 
Dry Eye 
EC 
Ethics Committee 
eCRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEOR 
Health Economics and Outcomes Research 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDEEL 
Impact of Dry Eye on Everyday Life 
IP/IMP 
Investigational Product/ Investigational Medicinal Product 
IRB 
Institutional Review Board 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEI 
National Eye Institute 
NIMP 
Non Investigational Medicinal Product 
NK 
Neurotrophic Keratitis  


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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PI 
Principal Investigator 
PGIC 
Patient Global Impression of Change 
PP 
Per Protocol Set 
PT 
Preferred Term 
rhNGF 
Recombinant human nerve growth factor  
RP 
Retinitis pigmentosa  
SAF 
Safety Set 
SANDE 
Symptom Assessment in Dry Eye 
SD 
Standard Deviation 
SID 
Semel in die 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time  
TID 
Tris in die  
 
 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Purpose 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, summary tables 
and figures which will be produced, and the statistical methodologies that will be used, are complete, in 
line with study protocol version 2.0 of 08 August 2019, and appropriate to allow valid conclusions 
regarding the study objectives. 
Due to restrictions in the hospital clinical routines related to COVID-19 pandemic started in March 2020, 
Dompé has decided to stop prematurely enrollement in the study in order to comply with quarantine 
measures of each country and avoid risks of infection of COVID-19 illness itself for all involved subjects. 
The study stopped to 261 patients instead of 300 originally planned; last subject enrolled was on March 
25th, 2020. On March 9th, 2020 256 patients were randomized. Among them 185 had completed the 
study and 44 were early terminated subjects. So only 27 subjects are ongoing and 5 not randomized at 
the time of national emergency due to COVID-19. 
Patients affected by COVID-19 will be identified using through Adverse form and Meddra coding 
(Peferred Term = ‘Coronavirus infection’). 
 
Data collection and management of visits during COVID-19 pandemic 
When possible, subject visits should occur in person, but in order to avoid any issues (e.g. unexpected 
site closure) that may affect subjects treatment, safety and data collection, Dompé allowed sites to 
perform remote subjects visits when an in-person visit(s) is not able to occur.  
Remote subject visits is organized in advance as a preventive action plan should the sites close 
unexpectedly or a subject is unable/unwilling to come to the site for a visit(s). 
If an in-person subject visit cannot occur as scheduled or be scheduled out of window because of site 
closure or of a subjects inability/unwillingness to come to the site, than a telephone (remote) visit should 
occur in place of the onsite visit(s). 
When a site deems that a remote subject visit is required, SANDE questionnaire, IDEEL, EQ-5D-3L 
PGIC and diaries will be completed by the subject at home. Once the completed questionnaires and 
diaries are received by the site, the site should set up a telephone visit with the subject  to review the 
completed questionnaire and diaries and evaluate the safety. 
 
Responsibilities 
Syneos Health will perform the statistical analyses and are responsible for the production and quality 
control of all tables, figures, and listings.  
 
Timings of Analyses 
The primary analysis of safety and efficacy data is planned after all patients complete the final study 
visit or terminate early from the study. 
 


Statistical Analysis Plan for Interventional Studies 
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Study Objectives 
 
Study Objective 
The study objective is to assess the efficacy and safety of recombinant human nerve growth factor 
(rhNGF) when administered as eye drops to patients with moderate to severe dry eye and to 
exploratively evaluate the preliminary efficacy data also in a group of dry eye patients with diagnosis 
of Primary Sjögren's Syndrome. 
 
Brief Description 
This is a phase II, multicenter, randomized, double-masked, vehicle-controlled, parallel group study 
designed to perform dose ranging and evaluate efficacy of rhNGF eye drops at 20 µg/mL concentration 
administered two or three times daily for 4 weeks in patients with moderate to severe dry eye. 
Patients will be evaluated at screening visit (day -8), baseline (Day 1), Week 2 (14 ± 2), Week 4 (Day 
28 ± 2) or early withdrawal and Week 8 (Day 56 ± 2), Week 12 (Day 84 ± 4), Week 16 (Day 112 ± 7) of 
follow-up. 
 
Patient Selection 
 
Inclusion Criteria 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria:  
 
1. Male or female aged ≥ 18 years.  
2. Patients with moderate to severe dry eye characterized by the following clinical features:  
a. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) 
grading system > 3;  
b. Symptom Assessment in Dry Eye (SANDE) questionnaire > 25 mm; 
c. Schirmer test I (without anaesthesia) > 2 mm < 10 mm/5 minutes;  
d. Tear film break-up time (TFBUT) < 10 seconds in the worse eye.  
3. The same eye (eligible eye) must fulfill all the above criteria.  
4. Patients diagnosed with dry eye at least 6 months before enrolment (current use or recommended 
use of artificial tears for the treatment of dry eye).  
5. (For patients already enrolled into the study under protocol 1) : Best corrected distance visual 
acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes at the time of study enrolment. 
5a. (Revised version in protocol version 2.0) : Best corrected distance visual acuity (BCDVA) score of 
≥ 0.1 decimal units (20/200 Snellen value) in both eyes at the time of study enrolment.  
 
6. If a female with childbearing potential, have a negative pregnancy test.  
7. (For patients already enrolled into the study under protocol 1) : Only patients who satisfy all 
informed consent requirements may be included in the study. The patient and/or his/her legal 
representative must read, sign and date the informed consent document before any study-related 
procedures are performed. The informed consent form (ICF) signed by patients and/or legal 
representative must have been approved by the IRB/IEC for the current study.  
7a. (Revised version in protocol version 2.0) : Only patients who satisfy all informed consent 
requirements may be included in the study. The patient and/or his/her legal representative must 
read, sign and date the informed consent document before any study-related procedures are 
performed. The informed consent form (ICF) signed by patients and/or legal representative must 
have been approved by the IRB for the current study.  


Statistical Analysis Plan for Interventional Studies 
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8. Patients must have the ability and willingness to comply with study procedures.  
 
 
9. (New criteria added in protocol version 2.0)  Primary Sjögren's Syndrome Patients:  
patients with a documented diagnosis of Primary Sjögren's Syndrome according the American-
European Consensus Group Sjögren's Syndrome Criteria (Appendix 3 of the study protocol; must 
meet either 4 out of 6 total criteria OR 3 out of 4 signs). Note: Subjects who are on systemic (oral) 
therapy for the treatment of Sjögren's Syndrome must be on stable systemic treatment defined as the 
same treatment for the immediately prior 90 days.  
 
 
 
Exclusion Criteria 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study:  
 
1. Inability to speak and understand the local language sufficiently to understand the nature of the 
study, to provide written informed consent, and to allow the completion of all study assessments. 
 
2. Evidence of an active ocular infection, in either eye. 
 
3. Presence of any other ocular disorder or condition requiring topical medication during the entire 
duration of study.  
 
4. (For patients already enrolled into the study under protocol 1) : History of severe systemic allergy or 
ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than 
dry eye.  
 
4a. (Revised version in protocol version 2.0) : History of severe systemic allergy or severe ocular 
allergy (including seasonal conjunctivitis) or chronic conjunctivitis and/or keratitis other than dry 
eye.  
 
5. Intraocular inflammation defined as Tyndall score > 0.  
 
6. History of malignancy in the last 5 years. 
 
7. Systemic disease not stabilized within 1 month before screening visit (e.g., diabetes with glycemia 
out of range, thyroid malfunction.) or judged by the investigator to be incompatible with the study 
(e.g., current systemic infections) or with a condition incompatible with the frequent assessment 
required by the study.  
 
8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically 
related compounds or had a clinically significant allergy to drugs, foods, amide local anesthetics or 
other materials including commercial artificial tears, in particular commercial artificial tears 
containing carboxymethylcellulose (in the opinion of the investigator). 
 
9. 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 (Screening/Baseline day 1) 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 
intrauterine device - during the entire course of and 30 days after the study treatment 
periods.  
 


Statistical Analysis Plan for Interventional Studies 
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10. Any concurrent medical condition that, in the judgment of the PI, might interfere with the conduct 
of the study, confound the interpretation of the study results, or endanger the patient’s well being. 
 
11. Use of topical cyclosporine, topical corticosteroids or any other topical drug for the treatment of 
dry eye in either eye within 30 days of study enrolment.  
 
12. Contact lenses or punctum plug use during the study (previous use not an exclusion criteria but 
must be discontinued at the pre-screening visit).  
 
13. History of drug addiction or alcohol abuse.  
 
14. Any prior ocular surgery (including refractive palpebral and cataract surgery) if within 90 days 
before the pre-screening visit. 
 
15. (For patients already enrolled into the study under protocol 1) : Participation in a clinical trial with a 
new active substance.  
 
15a. (Revised version in protocol version 2.0) : Participation in a clinical trial with a new active 
substance including medical devices during the past 60 days.  
 
 
16. Participation in another clinical trial study at the same time as the present study.  
 
 
Determination of Sample Size 
In order to evaluate the minimal effective daily dose of rhNGF eye drops, a Williams design has been 
chosen [1] [2]. For this study three treatment groups have been considered: rhNGF eye drops solution 
20 μg/mL TID; rhNGF eye drops solution 20 μg/mL BID plus vehicle eye drop solution SID; vehicle 
eye drop solution TID.  
 
To this purpose, the sample size has been determined applying the formula reported in the 
publication Chow et al., 2008 at page 301 [3] 
 
The sample size calculation for the primary variable is based on the following assumptions:  
 
- 
The probability level (α) for one-sided test is set at 0.025 (see table 12.1.2 at page 298 in 
Chow et al., 2008[3]) and the power level at approximately 90%.  
  
- 
DELTA, in change from baseline between treatments, of 5.3 and Standard Deviation for 
DELTA of 10.78. Both DELTA parameters are derived from results of co-variance analysis 
obtained from study NGF0216 in the subset of hyposecretive patients (i.e., excluding 
“evaporative-only” patients).  
 
According to this calculation, 87 patients per treatment group (for a total of 261 patients) are adequate 
to observe the planned difference assumed for the minimum effective daily dose. Assuming a drop-
out of about 15%, a total of 300 is the target number of patients proposed to be enrolled. 
The inclusion of at least 60 subjects with documented diagnosis of Primary Sjögren's Syndrome within 
the planned 300 patients will have no impact on the initial study assumptions (Standard Deviation of 
10.78 and DELTA of 5.3 mm) because the patients could have been enrolled based on the previous 
criteria on which sample size was based. Moreover, a similar prevalence of patients with Primary 
Sjögren's Syndrome has already been reported in the NGF0216 medical history (~25% of patient the 
FAS population). 
Impact on the power of the study due to stopping enrollment in the study to 261 randomized subjects: 


Statistical Analysis Plan for Interventional Studies 
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With 261 patients randomized, assuming a drop out rate of 15%, only 228 patients in total  (76 
patients by group) are considered adequate to observe the planned difference assumed for the 
minimum effective daily dose.  
With 76 patients by group, with a DELTA, in change from baseline between treatments of 5.3 and 
Standard Deviation for DELTA of 10.78, the power to detect a difference will be at least 85%. 
 
 
Treatment Assignment & Masking 
Eligible patients will be randomized in a 1:1:1 ratio to either rhNGF eye drops solution 20 μg/mL TID 
(100 patients) or rhNGF eye drops solution 20 μg/mL BID plus vehicle eye drop solution SID (100 
patients) or vehicle eye drop solution TID (100 patients).  
 
Following amendment n° 1 to the protocol, randomization will be stratified according to 
absence/presence of a documented diagnosis of Primary Sjögren's Syndrome.  
The study was ongoing at the time of amendment and at the beginning of September 135 patients 
had already been randomized. The randomization list generated on March 22, 2019 will be stopped 
when the last randomization number used will be at the end of a block. Moving forward, the 
replacement list will be used. According to the amendment n° 1, the replacement randomization 
schedule will be stratified according to absence/presence of a documented diagnosis of Primary 
Sjögren's Syndrome. 
Each randomized patient after amendment will be allocated with randomization number, according to 
the stratified randomization list using an Interactive Web Response System (IWRS). 
Drop outs after randomization will not be replaced.  
 
Randomization lists as well as associated kit numbers will be generated by a member of Syneos 
Health Biostatistics department, not involved in the conduct of the study.  
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. 
 
The enrollment of patients will be scheduled in order to assure an inclusion of approximately 240 
patients without Primary Sjögren's Syndrome diagnosis and at least 60 patients with Primary 
Sjögren's Syndrome. 
 
For patients already enrolled in the study, the assignment to a strata will be based on Medical history 
form (see section 8.1). 
 
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 (after data base 
lock) except in case of specific events that will require unmasking of the patient.  
 
The vials containing rhNGF (20 μg/mL) or vehicle will be identical in appearance, and the contents of 
the vials will be indistinguishable. All staff directly involved in the analysis of study results will remain 
masked to treatment assignments while the study is in progress.  
 
If the Investigator becomes unmasked for any reason, this information will be recorded on source data 
and in the electronic case report form (eCRF) of the study, specifying the date and the reason.  
Unmasking events will be recorded and reported in the final study report. 
 
 
Administration of Study Medication 
On Day 1 (baseline visit), the study personnel will give to the patient the monthly box, containing 4 
weekly boxes, each containing 7 daily boxes. Each daily box contains three marked vials (e.g., 1 - 
Morning, 2 - Afternoon and 3 - Evening) of frozen investigational medicinal product (IMP) solutions (-
20 ± 5°C) containing: 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 14 of 64 
 
• rhNGF at concentrations of 20 μg/mL, and/or 
• vehicle (placebo). 
 
Patient should bring the study medication, one monthly box, at home as soon as possible and 
immediately store it in a freezer at -20 ± 5 °C. The weekly box must be kept at 2-8°C for 7 days 
protected from light; the daily box can be kept at room temperature, before the patient will use the 
single vial for each instillation (both eyes) as long as 12 hours are not exceeded. 
 
The administration route is ophthalmic; the first administration is to be applied by investigator at site. 
In all patients, both eyes will be treated for a period of 4 weeks.  
 
The dosing scheme of the different study groups is summarized below:  
 
• 
Group 1: one drop of rhNGF 20 μg/mL will be instilled in both eyes three times daily (every 6-
8 hours, e.g., 7:00 am, 02:00 pm; 09:00 pm).  
 
• 
Group 2: one drop of rhNGF 20 μg/mL will be instilled in both eyes two times daily plus one 
drop (40 μL) of vehicle will be instilled in both eyes once daily (every 6-8 hours, e.g., 7:00 am, 
02:00 pm; 09:00 pm).  
NB: rhNGF will be instilled in the morning and in the evening while the vehicle will be instilled in the 
afternoon.  
 
• 
Group 3: vehicle eye one drop will be instilled in both eyes three times daily (every 6-8 hours, 
e.g., 7:00 am, 02:00 pm; 09:00 pm).  
 
 
 
Study Procedures and Flowchart 
Study procedures 
Screenin
g 
(Day-8) 
Visit 1 
Baselin
e 
Day 1* 
Visit 
2 
Wee
k 2 
Visit 3 
End of 
treatmen
t 
Week 4a 
Visit 4 
follow-
up 
Week 
8a 
Visit 5 
follow-
up 
Week 
12b 
 
Visit 6 
follow-
up 
Week 
16c 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Ocular and 
Systemic Medical 
History 
X 
 
 
 
 
 
 
Previous Ocular 
And Systemic 
Medications 
X 
X 
 
 
 
 
 
SANDE 
X 
X 
X 
X 
X 
X 
X 
IDEEL 
X 
X 
 
X 
X 
X 
X 
EQ-5D-3L 
X 
X 
 
X 
X 
X 
X 
PGIC 
 
 
 
X 
X 
X 
X 
BCDVA 
X 
X 
X 
X 
X 
X 
X 
External Ocular 
Examination 
X 
X 
X 
X 
X 
X 
X 
Schirmer test I 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp 
Examination 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan for Interventional Studies 
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Study procedures 
Screenin
g 
(Day-8) 
Visit 1 
Baselin
e 
Day 1* 
Visit 
2 
Wee
k 2 
Visit 3 
End of 
treatmen
t 
Week 4a 
Visit 4 
follow-
up 
Week 
8a 
Visit 5 
follow-
up 
Week 
12b 
 
Visit 6 
follow-
up 
Week 
16c 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
Fluorescein staining 
(NEI scale) 
X 
X 
X 
X 
X 
X 
X 
Schirmer test II 
 
X 
 
X 
 
 
X 
Confocal 
microscopy to 
assess goblet cells 
density d 
 
X 
 
X 
 
 
X 
Corneal 
endothelium and 
stroma evaluation 
as per confocal 
microscopy e 
 
X 
 
X 
 
 
X 
Study drug 
dispensation 
 
Xf 
 
 
 
 
 
Verify patient study 
medication dosing 
compliance 
 
 
 
X 
 
 
 
Concomitant Ocular 
And Systemic 
Medications 
 
 
X 
X 
X 
X 
X 
Frequency of 
preservative-free 
artificial tears use 
(n° drops/day) 
 
 
Xg 
Xg 
Xh 
Xh 
Xh 
Check and retrieval 
of patient’s diary 
 
 
Xi 
X 
X 
X 
X 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
*) visit window of +2 days a) Visit window of ± 2 days; b) Visit window of ± 4 days; c) Visit window of ± 7 days; d) only selected sites; 
e) Only the sites having a confocal microscope will do this type of evaluation; f) a monthly box will be given to the patients; g) During 
the treatment period patients can use, if strictly needed, the preservative-free artificial tears; h) During the follow up period it is allowed 
to use the preservative-free artificial tears; i) During the Visit 2, Week 2, the PI or a delegate must only check if the patient has correctly 
completed the diary.  
 


Statistical Analysis Plan for Interventional Studies 
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Endpoints 
 
Primary Efficacy Endpoint 
• 
Change from baseline in Schirmer test I (without anesthesia) versus Week 4.  
 
 
Secondary Efficacy Endpoints 
 
• 
Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency 
assessed at 4 weeks of treatment;  
• 
Change from baseline in Schirmer test II (with anesthesia) versus Week 4;  
• 
Change from baseline in corneal and conjunctiva vital staining with fluorescein (NEI scales) 
versus Week 4;  
• 
Change from baseline in TFBUT versus Week 4;  
• 
Number of patients who experienced a worsening in symptom scores (SANDE) and/or NEI 
score ≥ 50% as assessed at Week 4; 
• 
Quality of life (Impact of Dry Eye on Everyday Life (IDEEL) questionnaire);  
• 
Patient Global Impression of Change (PGIC);  
• 
EQ-5D-3L.  
 
 
Exploratory Endpoints 
 
• 
Correlation between sign and symptoms scores;  
• 
Proportion and frequency of preservative-free artificial tears use (n° drops/day) during the 
treatment period;  
• 
Frequency of preservative-free artificial tears use (n° drops/day) during the follow up period.  
• 
Change from baseline in Schirmer test I (without anesthesia) versus Week 2;  
• 
Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency 
assessed at 2 weeks of treatment;  
• 
Change from baseline in Corneal and conjunctiva vital staining with fluorescein (NEI score) 
versus Week 2;  
• 
Change from baseline in TFBUT versus Week 2;  
• 
Number of patients who experienced a worsening in symptom scores (SANDE) and/or NEI 
score ≥ 50% as assessed at Week 2; 
• 
Change from baseline in goblet cells density versus Week 4.  
 
 
Safety Endpoints 
• 
Incidence and frequency of treatment-emergent adverse events (TEAEs), assessed 
throughout the study.  


Statistical Analysis Plan for Interventional Studies 
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Analysis Sets 
 
Enrolled Set 
The Enrolled Set will consist of all patients who signed the ICF.  
This analysis set will be used for patients disposition and some listings. 
 
Randomized Set 
The Randomized Set will consist of all patients who signed the ICF and were subsequently 
randomized into the study, regardless of study treatment administration.   
 
Safety Analysis Set   
The Safety Analysis Set (SAF) will consist of all patients in the Randomized Set who took at least one 
dose of investigational product (IP) . This analysis set will be used for the safety analysis. Patients will 
be analyzed according to the treatment received. 
 
Full Analysis Set  
Full Analysis Set (FAS) will consist of all patients randomized who took at least one dose of IP and 
who have at least one post-baseline efficacy measurement for the primary endpoint. This analysis set 
will be used for the primary efficacy analysis. Patients will be analyzes according to the randomized 
treatment. 
 
Per Protocol Set  
Per Protocol Set (PP) will consist of all patients in the FAS who fulfil the study protocol requirements 
in terms of IMP intake and collection of primary efficacy data and with no major deviations that may 
affect study results. This analysis set will be used for supportive efficacy analysis.  
Patients will be evaluated according to the treatment dose they will actually receive.  
 
Protocol Deviations 
Important protocol deviations will be collected in the eCRF and CTMS. Each instance of a protocol 
deviation will be determined to be either significant or not. Protocol deviations linked to COVID-19 will 
be identified with “COVID-19 XXXXXX”.  
  
The major protocol deviations include, but are not limited to, the following (to be finalized before 
database lock):  
 
• 
Non compliance with IP administration (less than 80% or more than 120%); 
• 
missing primary efficacy data; 
• 
Major deviation from  inclusion/exclusion criteria (eligibility violations) (will be defined in blind 
conditions in the last blind data review meeting before database lock); 
• 
intake of prohibited medications. 
Protocol deviations will be reviewed during the course of the study and prior to database lock. 
Patients with any major protocol deviations listed above will not be included in the PP set. 
Number (%) of patients with at least one major protocol deviation  leading to exclusion of subject from 
the Per-protocol will be included in a summary table, using the FAS Set. 
All protocol deviations will be listed for all patients in the Randomized Set, including their assignment 
of minor, major, and the date the deviation occurred. 
Protocol deviations linked to COVID-19 will be listed on a separate listing in the Randomized Set. 


Statistical Analysis Plan for Interventional Studies 
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General Aspects for Statistical Analysis 
 
General Methods 
• SAS Version 9.4 or higher will be used for programming and production. 
• Unless otherwise specified, summaries will be presented for each treatment and overall. 
• Continuous variables will be summarized using the number of observations (n), n missing 
(when applicable), mean, standard deviation (SD), median, minimum, and maximum. 
Categorical variables will be summarized using number of observations (n), n missing (when 
applicable), frequency and percentages of patients. 95% and 99% confidence limits for the 
mean will be calculated based on the t-distribution, where indicated.The denominator will be 
based on the total number of patients in the treatment group or overall, or on the total number 
of subjects with non-missing data, as appropriate. 
• All relevant patient data will be included in listings including assessments of unscheduled visits. 
All patients entered into the database will be included in patient data listings. 
• See Sections 15 and 17 for the definition of planned summary tables and listings. Templates for 
each unique table and patient listing are provided in a separate document. 
 
 
Key Definitions 
 
Baseline Value 
Unless otherwise specified, the baseline value for any variable will be the last value taken prior to the 
start of medication. This includes screening assessment. Unscheduled measurements prior to first 
administration date will be considered in the calculation of baseline values. 
 
Change from Baseline and Percent Change from Baseline at a Post-Treatment Time 
Point  
Change from baseline is defined as the difference between the post-treatment value and the baseline 
value. 
Percent change from baseline is defined as 100* (change from baseline)/ score at baseline.  
 
Time Since Diagnosis of Dry Eye 
Time since diagnosis of dry eye (in months) will be calculated as 12*(date of baseline - date of dry 
eye)/365.25.  
If the date of dry eye is partially missing (month and/or day), then the following rules will be used to 
impute the start date: 
• 
Missing day: replace the missing day by 01.  
• 
Missing month : replace missing month by January  
 
Number of Days on Treatment 
Number of days on treatment is calculated as [(date of last instillation of treatment - date of first 
instillation of treatment) +1]. 
 
Compliance 
Percentage Compliance (%) will be evaluated according to the following formula: 


Statistical Analysis Plan for Interventional Studies 
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Compliance for the eligible eye = 100 ∗
(Number of  drops administered to the eligible eye)
3 ∗(𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑁𝑁 𝑜𝑜𝑜𝑜 𝑡𝑡𝑁𝑁𝑁𝑁𝑑𝑑𝑡𝑡𝑁𝑁𝑁𝑁𝑜𝑜𝑡𝑡)
 
 
 
Number of Drops/Day 
 
Drops/day during treatment period is defined as [sum of drops during treatment period / (date of Week 
4 or date of last visit during treatment period – date of baseline +1)]. 
 
Drops/day during follow up period is defined as [sum of drops during follow up period / (date of Week 
16 or date of last visit during follow up period – date of Week 4 + 1)]. 
 
 
 
Missing Data  
 
Missing Data for Efficacy 
For Schirmer test I, Schirmer test II, SANDE, fluorescein staining and TFBUT, the LOCF method will 
be used for imputing missing data in the FAS set at Week 4.  
For missing data at Week 4, the data from the previous visit (Week 2 or early discontinuation visit if 
during treatment period) will be used to estimate the missing value. If a patient has missing data for all 
post baseline visits, baseline will be carried forward (this cannot happen for the primary end-point 
because of the FAS definition). 
Several sensitivity analyses will be performed concerning the primary analysis in case of many missing 
values (decision to be made at the final blind Data Review Meeting, before data base lock).  
The following strategies will be applied: (a) an analysis restricted to the complete cases (only subjects 
having a full data set for the primary outcome will be considered); (b) an analysis of repeated measures 
performed on all subjects having at least one post-baseline efficacy measurement and assuming that 
missing data are distributed as missing at random (see Appendix 1 for the SAS code); (c) an analysis 
considering the worst case method (the worst possible value of the scale is assigned to missing values). 
For IDEEL and EQ-5D-3L questionnaires, missing data will be imputed according to the questionnaire 
manuals. 
 
 
Missing Dates for Adverse Events 
If the adverse event start date is partially or completely missing, then the following rules will be used to 
impute the start date for the purpose of determining treatment emergence status only: 
• 
If the whole start date is missing, then the start date of first drug instillation will be used. 
• 
Missing month: if the AE has occurred the same year as start date of drug instillation, replace 
the missing month of onset by the month of start date of drug instillation.   
If the AE has occurred the subsequent year after the year of start date of drug instillation, 
replace the missing month of onset by January.  
If the AE has occurred the previous year of the year of start date of drug instillation, replace the 
missing month of onset by December.  
• 
Missing day: if the AE has occurred the same month and year as start date of drug instillation 
replace the missing day of onset by the day of start date of drug instillation.   


Statistical Analysis Plan for Interventional Studies 
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• 
if according to month and year the AE has occurred  after the start date of drug instillation 
replace the missing day of onset by 01.   
• 
if according to month and year the AE has occurred  before the start date of drug instillation 
replace the missing day by the last day of the month.   
 
 
 
Visit Windows 
CRF visits will be used without establishing acceptable visit windows, because the study is short. 
 
Pooling of Centres 
Not applicable. 
 
Subgroups 
The primary, secondary, explorative and safety endpoints will be also summarized within each 
stratification subgroup (absence/presence of Primary Sjögren's Syndrome). 
In order to assess the impact of COVID-19 on primary efficacy endpoint and on safety, subgroup 
analyses will be performed (affected patients versus non affected patients) if 10% or more treated 
subjects are affected by COVID-19 during the study. 
 
 


Statistical Analysis Plan for Interventional Studies 
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Demographic, Other Baseline Characteristics and Medication 
Demographics and others baseline characteristics are presented in tables 14.1 to 14.1.3.1 (see 
section15) 
 
 
Patient Disposition and Withdrawals 
The following frequencies (number and percent) will be displayed in the patient disposition table, by 
treatment group and overall: 
• 
Number of patients enrolled;  
• 
Number of patients screen failure; 
• 
Number of patients randomized (overall and by strata); 
• 
Number (%) of patients in the FAS (Full Analysis Set) (overall and by strata);  
• 
Number (%) of patients in the PP set (overall and by strata); 
• 
Number (%) of patients in the Safety Set (overall and by strata);  
• 
Number (%) of patients who completed the study (overall and by strata); 
• 
Number (%) of patients who discontinued the study early and reasons for discontinuation 
(overall and by strata).  
The disposition analyses will be based on the Enrolled Set. 
The denominators for the percent calculations will be the number of patients in the randomized set or 
in the specific analysis set. 
Patient completion status, date of completion/discontinuation and reason for discontinuation will be 
listed.  
 
Demographic and Other Baseline Characteristics 
The following baseline and demographic characteristics will be summarized per treatment group and 
overall: 
- 
Age (years). Age is recorded directly in the database and is not calculated separately 
- 
Gender (Male, Female) 
- 
Race (American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian 
or Other Pacific Islander; White or Caucasian; Other) 
- 
Ethnicity (Hispanic, Latino or Spanish; Not Hispanic, Latino or Spanish) 
- 
Eligible eye (Right, Left) 
- 
Time since diagnosis of dry eye 
Demographic and background data will be summarized using summary statistics, as appropriate. 
 
The Full Analysis Set will be used to present these data. 
In case there is a relevant difference ( ≥ 10%) in sample size among the different datasets 
(Randomized, SAF, FAS and PP) , these data will be also presented using other sets.  
 


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Ocular and Systemic Medical History and Concomitant Diseases 
Ocular and Systemic Medical History and Concomitant Diseases are presented in tables 14.1.3.2.1 to 
14.1.3.2.2 (see section15). 
Ocular and systemic medical history will be coded to system organ class (SOC) and preferred term 
(PT) using Medical Dictionary for Regulatory Activities (MedDRA) version 21.1. 
 
Tables for ocular medical history and systemic medical history will be provided using the Safety Set. 
 
Data will be summarized, by SOC and PT and sorted alphabetically. Conditions that are reported 
more than once for a given SOC and PT will be counted only once per patient on the PT level for 
each SOC. 
The Safety Set will be used to present these data. 
A corresponding data listing will be presented for all enrolled patients.  
 
 
Medication 
Medications are presented in tables 14.1.4.1.1 to 14.1.4.2.2  (see section15). 
Prior and concomitant medications will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization Drug Dictionary (WHODRUG), 
WHODrugDDEB2 - 201901. 
A listing of prior and concomitant medications will be provided for all enrolled patients (prior 
medications) and randomized patients (concomitant medications). 
 
 
Previous Ocular and Systemic Medication 
Previous ocular and systemic medications are defined as those medications recorded on the Previous 
Ocular and Systemic Medications pages of the eCRF. 
 
Tables for previous ocular medication and previous systemic medication will be provided using the 
Safety set. 
 
For the summary tables, the count and percentage of patients under each ATC class level 2 and 
Preferred name will be summarized by treatment group.  
 
If a patient has taken prior medications more than once, the patient will be counted only once under 
any given drug class. 
 
 
Concomitant Ocular and Systemic Medication 
Concomitant ocular and systemic medications are defined as those medications recorded on the 
Concomitant Ocular and Systemic Medications pages of the eCRF. 
 
Tables for concomitant ocular medication and concomitant systemic medication will be provided using 
the Safety Set. 
 
For the summary tables, the count and percentage of patients under each ATC class level 2 and 
Preferred name will be summarized by treatment group.  
 
If a patient has taken concomitant medications more than once, the patient will be counted only once 
under any given drug class. 
 


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Efficacy 
For the purpose of efficacy analysis in this trial, the statistical analysis (both descriptive and 
inferential) will be done on the eligible eye when applicable. 
 
Results from both eyes will be presented in the listings. 
 
Primary and secondary efficacy endpoints will be summarized using the FAS and Per Protocol set. 
Efficacy endpoints will be also summarized for patients with the Primary Sjögren's syndrome and for 
patients without the Primary Sjögren's syndrome . 
 
Efficacy are presented in tables 14.2.1.1.1 to 14.2.2.15.2.3 (see section15) 
 
 
Primary Efficacy Endpoint and Analysis 
The primary efficacy endpoint is the change from baseline in Schirmer test I (without anesthesia) 
versus Week 4. The primary analysis is based on the FAS population. Missing data will be replaced 
by means of the Last Observation Carried Forward (LOCF) method. 
 
The Schirmer test I will be summarized using descriptive statistics for continuous variables by 
treatment and visit. The change from baseline value will also be summarized for all post-baseline 
visits. The same summary analysis will be provided after pooling the treated patients (20 μg/mL BID 
arm and 20 μg/mL TID) together. Comparison (descriptive in nature) of the change from baseline of 
each treatment versus placebo will be performed by means of a t-test at each timepoint.  
 
The primary analysis will be performed by means of an analysis of variance including only treatment 
as main factor followed by pre-planned comparisons from Vehicle and rhNGF dosages according to 
Williams’ procedure.  
The first comparison will compare the rhNGF TID dose to the Placebo using Williams test. 
In case of significant result then the rhNGF BID dose will be compared to the Placebo; if the result is 
not significant then the test will be stopped. 
Description of the Williams’ Test: 
µ0 = Effect of Placebo  
µ1 = Effect of rhNGF BID 
µ2 = Effect of rhNGF TID 
 
Hypotheses: 
H0: µ0 = µ1 = µ2 
H1: µ0< = µ1 ≤ µ2 
 
 
The test develops into two phases: 
* First step 
Starting from the observed means Xi, determine the maximum likelihood estimates Mi (corrected 
mean of group i after amalgamation) under the alternative hypothesis. 
 
If Xi satisfies the inequalities written in H1 then Mi = Xi 
Otherwise pool any adjacent violators into the same value: 
Mi = (ni* Xi + ni+1*Xi+1) / (ni + ni+1) where ni = sample size of group i. 
 
The process is repeated until the means are completely ordered. 
 
 
 


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* Second step  
Calculate the test statistic given by 
Tk = (Mk – X0)/ s*sqrt(1/ n0 + 1/ nk) 
 
where s = root mean square error and X0 is the observed mean in the placebo group. 
 
The fact that the kth dose level is the minimum effective dose is concluded if Tj > tj,α for all j≥k where 
the tj,α values are the critical values reported by Williams [2]). 
 
The Schirmer test I values will be also listed. 
 
An explorative sensitivity analysis of the primary endpoint will be conducted including in the analysis 
of variance the absence/presence of diagnosis of Primary Sjögren's Syndrome and its interaction with 
treatments as covariates. If the interaction term is statistically significant (at the 0.10 level given its 
explorative nature), the treatment effects within patients with and without Primary Sjögren's Syndrome 
will be provided. 
 
For patients already enrolled in the study, the assignment to a strata will be based on Medical history 
form.  
If “Primary Sjogren” is recorded in the Medical condition of the Medical history form then the patient 
will be assigned to “Presence of Primary Sjogren”; if only “Sjogren” is recorded then the patient will be 
assigned to “Absence of Primary Sjogren”.In all other cases, the patient will be assigned to “Absence 
of Primary Sjogren”. 
 
In order to assess the robustness of results of primary analysis, the Schirmer test I will be also 
evaluated by means of non parametric Fisher’s exact test after appling the following categorization at 
week 4: 
- 
A patient is defined as “Responder” if the Schirmer test I value at week 4 is greater than 10 
mm/5 minutes; 
- 
A patient is defined as “Non responder” if the Schirmer test I value at week 4 is lower or equal 
than 10 mm/5 minutes. 
 
 
Secondary Efficacy Endpoints and Analyses 
The same exploratory sensitivity analysis will be also conducted for SANDE, Schirmer Test II, Corneal 
and Conjunctiva Vital Staining and TFBUT. 
 
Change from baseline in Symptoms questionnaire (SANDE) scores for severity and 
frequency  
The SANDE questionnaire is comprised of 2 questions at each visit:  
 
(1) How often do your eyes feel dry and/or irritated?  
(2) How severe do you feel your symptoms of dryness and/or irritation are?   
 
One measure frequency of symptoms ranges from “0 mm = rarely” to “100 mm = all of the time,” and 
the other measure severity of symptoms ranges from “0 mm = very mild” to “100 mm = very severe”. 
 
The global SANDE score will be calculated by multiplying the frequency score by the severity score 
and obtaining the square root [4]. 
 
Change from baseline at Week 4 will be analyzed using analysis of variance including treatment as 
factor followed by pre-planned comparisons from Vehicle and rhNGF dosages according to Williams’ 
procedure.  
 
Descriptive statistics (actual and change from baseline) of SANDE scores will be presented by 
treatment and visit. Comparison (descriptive in nature) of the change from baseline of each treatment 
versus placebo will be performed by means of a t-test at each timepoint.  


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Symptoms questionnaire (SANDE) scores will be also listed. 
 
 
Change from Baseline in Schirmer Test II (with Anesthesia) 
The Schirmer test II (with anesthesia) will be summarized using descriptive statistics for continuous 
variables by treatment and visit. The change from baseline value will also be summarized for all post-
baseline visits. Comparison (descriptive in nature) of the change from baseline of each treatment 
versus placebo will be performed by means of a t-test at each timepoint.  
 
The Change from baseline in Schirmer test II at Week 4 will be analyzed in a similar manner as the 
Change from baseline to Week 4 in Schirmer test I. 
 
The Schirmer test II values will be also listed. 
 
 
Change from Baseline in Corneal and Conjunctiva Vital Staining with Fluorescein (NEI 
Scales) 
Corneal staining total score is defined as the sum of scores from 5 corneal areas: Central, Superior, 
Temporal, Nasal, and Inferior. The score for each area ranges from 0 to 3. Thus, the corneal staining 
total score can range from 0 to 15.  
 
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. 
Thus, the conjunctival staining total score can range from 0 to 18.  
 
Corneal and conjunctiva vital staining total score is the sum of corneal staining total score and 
conjunctiva total score. 
 
Descriptive statistics (actual and change from baseline) for Corneal and conjunctiva vital staining total 
score, corneal score and conjunctiva score will be presented by treatment and visit. Comparison 
(descriptive in nature) of the change from baseline of each treatment versus placebo will be 
performed by means of a t-test at each timepoint.  
 
The Change from baseline in Corneal and conjunctiva vital staining total score (NEI scales) at Week 4 
will be analyzed in a similar manner as the Change from baseline to Week 4 in Schirmer test I. 
The Corneal and conjunctiva vital staining score with fluorescein will be listed. 
 
 
Change from Baseline in Tear film break-up time (TFBUT) 
Descriptive statistics (actual and change from baseline) for TFBUT will be presented by treatment and 
visit. Comparison (descriptive in nature) of the change from baseline of each treatment versus 
placebo will be performed by means of a t-test at each timepoint.  
 
Change from baseline in TFBUT at Week 4 will be analyzed in a similar manner as the Change from 
baseline to Week 4 in Schirmer test I. 
TFBUT  values will be listed. 
 
 
Number of Patients who Experienced a Worsening in Symptom Scores (SANDE) and/or 
NEI Score ≥ 50% Assessed at Week 4 
Number and percentage of patients who experienced a worsening in symptom scores (SANDE) 
and/or NEI score ≥ 50% assessed at Week 4 will be summarized by treatment group. 
Difference, between treatment group (Each active dose – Placebo), in the percentage of patients who 
experienced a worsening will be tested using a chi-square test. 


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Quality of Life/Impact of Dry Eye on Everyday Life (IDEEL)  
The IDEEL questionnaire will be filled in at screening, baseline-Day1, Week 4, Week 8, Week 12 and 
Week16. 
IDEEL is a 3-module questionnaire with 57 questions, and it assesses dry eye symptoms, the effect of 
dry eye disease on quality of life, and treatment satisfaction over the last 2 weeks. The 3 modules 
consist of: 
 
• 
Dry eye Quality of Life (27 questions) comprising three sections: “Daily activities”,  “Feelings”  
and “Work”. 
 
• 
Dry eye Treatment satisfaction & Bother (10 questions) comprising two sections: “Treatment – 
In general” and “Treatment- Eye drop”. 
 
• 
Dry eye Symptom bother (20 questions). 
 
 
Module 1: 
 
Dry eye impact on daily life (27 questions) comprising 3 QoL domains:  1.a “Daily activities 
limitations”,  1.b “Emotional well being” and 1.c “Work limitations”. 
 
 
26 questions will be considered as part of one of these 3 domains. Question 22 will not be considered 
part of a domain. 
 
1.a: Daily Activities 
 
Daily activities section 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
1. Doing close work in the morning or  
afternoon (such as crossword puzzles,  
reading, looking at a computer, and/or  
sewing)  
Daily Activity 
Limitations 
IDLACT1 
Yes 
2. Doing close work in the evening or at  
night  
Daily Activity 
Limitations 
IDLACT2 
Yes 
3. Driving  
 
Daily Activity 
Limitations 
IDLACT3 
Yes 
 
 
4. Being around and/or using scented  
products (such as cologne or hairspray)  
Daily Activity 
Limitations 
IDLACT4 
Yes 
 
 
5. Working on a computer  
 
Daily Activity 
Limitations 
IDLACT5 
Yes 
6. Going somewhere where there is  
tobacco smoke or being around someone  
who smokes  
Daily Activity 
Limitations 
IDLACT6 
Yes 
7. Wearing contact lenses  
 
Daily Activity 
Limitations 
IDLACT7 
No 
8. Wearing make-up near or on my eyes  
 
Daily Activity 
Limitations 
IDLACT8 
No 


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Daily activities section 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
9. Flying on an airplane  
Daily Activity 
Limitations 
IDLACT9 
No 
 
 
 
 
Response for questions 1 to 9 (IDLACT1-
IDLACT9) 
Original response 
code 
Item score 
I did not do this activity for reasons other 
than my dry eyes 
6 
5 
None of the time 
5 
5 
A little of the time 
4 
4 
Some of the time 
3 
3 
Most of the time 
2 
2 
All of the time 
1 
1 
I can no longer do this activity due to my 
dry eyes 
0 
0 
 
 
The response option “I did not do this activity for reasons other than my dry eyes” has a response 
coded 6 but a scored item value of 5. 
The original response code is the value to be used for data-entry. The item score is used during the 
computation of the Daily Activity Limitations Scale Score. Higher item scores are intended to reflect 
better quality of life (i.e. less limitations on daily activities). 
Only 6 questions (9 (IDLACT1-IDLACT6) are included in the Daily activity Limitations scale score. 
Questions 7, 8 and 9 are excluded.  
If 50% (3) or fewer of the 6 questions used in calculating Daily Activity Limitations score have missing 
item score, then the scale score is calculated by multiplying the mean of the non missing item score 
by 20. If 4 or more of the 6 item scores are missing then the scale score is not calculated and should 
be set at missing. 
Multiplying by 20 transforms the scale score to a 0 to 100 scale, with 0 reflecting the greatest degree 
of limitations on daily activities measurable by the scale and 100 reflecting the greatest freedom from 
limitations on daily activities. 
1.b Feelings 
Feelings 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
10. Irritability  
 
Emotional Well-
Being 
IDLEMO1 
Yes 
11. Impatience  
 
Emotional Well-
Being 
IDLEMO2 
Yes 
12. Feeling sad  
 
Emotional Well-
Being 
IDLEMO3 
Yes 
 
 
13. Worry that my dry eyes will get worse  
 
Emotional Well-
Being 
IDLEMO4 
Yes 


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Feelings 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
14. Feeling annoyed  
 
Emotional Well-
Being 
IDLEMO5 
Yes 
15. Feeling like my eyes do not look nice  
 
Emotional Well-
Being 
IDLEMO6 
Yes 
 
 
16. Feeling like I have to make adjustments 
to my life  
 
Emotional Well-
Being 
IDLEMO7 
Yes 
17. Feeling different from other people 
because of my dry eyes  
Emotional Well-
Being 
IDLEMO8 
Yes 
18. Feeling like I am always aware of my 
eyes  
 
Emotional Well-
Being 
IDLEMO9 
Yes 
19. Feeling older than I really am  
 
Emotional Well-
Being 
IDLEMO10 
Yes 
20. Feeling like people look at me and think I 
am fine when I'm not  
Emotional Well-
Being 
IDLEMO11 
Yes 
21. Feeling like there is nothing I can do for 
my dry eyes  
 
Emotional Well-
Being 
IDLEMO12 
No 
 
 
 
 
Response for questions 10 to 21 
Original response 
code 
Item score 
None of the time 
4 
4 
A little of the time 
3 
3 
Some of the time 
2 
2 
Most of the time 
1 
1 
All of the time 
0 
0 
 
11 questions (IDLEMO1- IDLEMO11) are included in the Emotional Well-Being score. Question 21 
(IDLEMO12) is excluded from calculation. 
If 50% (5) or fewer of the 11 questions used in the calculation of Emotional Well-Being score have 
missing item score, then the scale score is calculated by multiplying the mean of the non missing item 
scores by 25. If 6 or more of the 11 item scores are missing then the scale score is not calculated and 
should be set at missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting the worst level of 
emotional well-being measurable by the scale and 100 reflecting the best. 
 
1.c Work 
Work 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
22. Are you currently working?  
Work limitations 
IDLWRKYN 
- 


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Work 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
 
23. Feeling distracted  
 
Work limitations 
IDLWRK1 
Yes 
24. Feeling like I couldn't concentrate  
 
Work limitations 
IDLWRK2 
Yes 
25. Having to take a break from work  
 
Work limitations 
IDLWRK3 
Yes 
26. Having to change the way I work (such 
as the way I read, look at a computer, or 
work outside)  
Work limitations 
IDLWRK4 
Yes 
 
 
27. Having to change my work environment 
(such as how close I am to an air 
conditioning or heating vent)  
Work limitations 
IDLWRK5 
Yes 
 
Response for question 22 (IDLWRKYN) 
Original response 
code 
Item score 
Yes 
1 
1 
No 
0 
0 
 
Response for questions 23 to 
27 (IDLWRK1-IDLWRK5) 
Original 
response 
code 
Item score 
If IDLWRKYN=0 
Item score 
If IDLWRKYN=1 
None of the time 
4 
Missing 
4 
A little of the time 
3 
Missing 
3 
Some of the time 
2 
Missing 
2 
Most of the time 
1 
Missing 
1 
All of the time 
0 
Missing 
0 
 
5 questions (IDLWRK1-IDLWRK5) are included in the Work Limitations domain.. 
If 50% (2) or fewer of the 5 questions used in the calculation of the Work Limitations score have 
missing item scores, then the scale score is calculated by multiplying the mean of the non missing 
item scores by 25. If 3 or more of the 5 item scores are missing then the scale score is not calculated 
and should be set to missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting the greatest degree 
of limitation at work measurable by the scale and 100 reflecting the least limitation at work. 
 
Module 2:  
 
Dry eye Treatment satisfaction & Bother module (10 questions) comprising 2 QoL domains: 2.a 
“Treatment satisfaction / Happiness” and “Treatment-related bother”. 
 
2.a Treatment  - In general  
 


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Treatment in General 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
1. OVER THE LAST TWO WEEKS, how 
often did you use treatment for your dry 
eyes?  
 
 
- 
IDLTREAT 
- 
2. I was happy with how quickly my 
treatments worked  
 
Treatment 
Satisfaction/ 
Happiness 
IDLTSA1 
Yes 
3. I was happy with how long the effects of 
my  
treatments lasted  
Treatment 
Satisfaction/ 
Happiness 
IDLTSA2 
Yes 
4. The treatments I used completely 
eliminated my dry eye symptoms  
Treatment 
Satisfaction/ 
Happiness 
IDLTSA3 
Yes 
5. The treatments I used relieved most of 
my dry eye symptoms  
Treatment 
Satisfaction/ 
Happiness 
IDLTSA4 
Yes 
 
 
6. I was bothered by how often I had to use 
dry eye  
treatments  
Treatment- Related 
Bother 
 
IDLTBO1 
Yes 
 
 
Response for question 1 
(IDLTREAT) 
Original 
response code 
Item score 
 
None of the time 
0 
0 
A little of the time 
1 
1 
Some of the time 
2 
2 
Most of the time 
3 
3 
All of the time 
4 
4 
 
 
 
Response for questions 2 to 5 
(IDLTSA1- IDLTSA4) 
Original 
response 
code 
Item score 
If IDLTREAT=0 
Item score 
If IDLTREAT NE 0 or 
missing 
None of the time 
0 
Missing 
0 
A little of the time 
1 
Missing 
1 
Some of the time 
2 
Missing 
2 
Most of the time 
3 
Missing 
3 
All of the time 
4 
Missing 
4 
Response for question 6 
(IDLTBO1) 
 
 
 
None of the time 
4 
Missing 
4 
A little of the time 
3 
Missing 
3 
Some of the time 
2 
Missing 
2 
Most of the time 
1 
Missing 
1 
All of the time 
0 
Missing 
0 
 
 
4 questions (IDLTSA1 - IDLTSA4)  are included in the Treatment Satisfaction/Happiness scale score.  


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If 50% (2) or fewer of the 4 questions used in the calculation of Treatment Satisfaction/Happiness 
score have missing item score, then the scale score is calculated by multiplying the mean of the non 
missing item score by 25. If 3 or more of the 4 item scores are missing then the scale score is not 
calculated and should be missing. 
Multiplying by 25 transform the scale score to a 0 to 100 scale, with 0 reflecting the lowest level of 
satisfaction/happiness with treatment measurable by the scale and 100 reflecting the highest level of 
satisfaction/happiness with treatment.. 
 
 
2.b Treatment- Eye Drops 
 
Treatment- Eye Drops 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
7. Do you ever use eye drops to treat your 
dry eyes?  
 
 
- 
IDLDRPYN 
- 
8. I was bothered by blurriness shortly after 
using my eye drops  
 
Treatment- Related 
Bother 
IDLTBO2 
Yes 
9. I was embarrassed when I had to use my 
eye drops  
 
Treatment- Related 
Bother 
IDLTBO3 
Yes 
10. I felt like I could not go anywhere without 
my eye drops  
Treatment- Related 
Bother 
IDLTBO4 
Yes 
 
Response for question 1 
(IDLDRPYN) 
Original 
response code 
Item score 
 
Yes 
1 
1 
No 
0 
0 
 
Response for question 8 to 10 
(IDLTBO2- IDLTBO4) 
Original 
response 
code 
Item score 
If IDLDRPYN=0 
Item score 
If IDLDRPYN NE 0 
None of the time 
4 
Missing 
4 
A little of the time 
3 
Missing 
3 
Some of the time 
2 
Missing 
2 
Most of the time 
1 
Missing 
1 
All of the time 
0 
Missing 
0 
 
 
4 questions (IDLTBO1 - IDLTBO4)  are included in the Treatment-Related Bother scale score.  
If 50% (2) or fewer of the 4 questions used in the calculation of Treatment-Related Bother scale score 
have missing item scores, then the scale score is calculated by multiplying the mean of the non 
missing item score by 25. If 3 or more of the 4 item scores are missing then the scale score is not 
calculated and should be set at missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting the greatest degree 
of treatment related bother measurable by the scale and 100 reflecting the lowest degree of 
treatment-related bother. 


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Module 3:  
 
Dry eye Symptom bother (20 questions) comprising a unique domain. 
 
 
Symptom Bother 
QOL content 
domain 
Variable 
Name 
Used in 
calculation 
of domain 
score? 
1.OVER THE LAST TWO WEEKS, how 
often did you experience dry eye symptoms?  
 
Symptom Bother 
IDLSYM1 
Yes 
2. Eyes that felt gritty or sandy  
 
Symptom Bother 
IDLSYM2 
Yes 
3. Felt like I needed to close my eyes even  
though I was not tired  
Symptom Bother 
IDLSYM3 
Yes 
4. Burning or stinging eyes  
 
Symptom Bother 
IDLSYM4 
Yes 
5. Tired eyes  
 
Symptom Bother 
IDLSYM5 
Yes 
6. Blurry vision  
 
Symptom Bother 
IDLSYM6 
Yes 
7. Itchy eyes  
 
Symptom Bother 
IDLSYM7 
Yes 
8. Irritated eyes  
 
Symptom Bother 
IDLSYM8 
Yes 
9. Eyes that felt like they had been scratched 
by something  
Symptom Bother 
IDLSYM9 
Yes 
10. Eye dryness  
 
Symptom Bother 
IDLSYM10 
Yes 
11. Mucus in, around, or coming out of my 
eyes  
 
Symptom Bother 
IDLSYM11 
Yes 
 
 
12. Puffy or swollen eyes  
 
Symptom Bother 
IDLSYM12 
Yes 
 
 
13. Eye redness  
 
Symptom Bother 
IDLSYM13 
Yes 
14. Aching or sore eyes  
 
Symptom Bother 
IDLSYM14 
Yes 
 
 
15. Felt like something was in my eye  
 
Symptom Bother 
IDLSYM15 
Yes 
16. Frequent and/or rapid blinking  
 
Symptom Bother 
IDLSYM16 
Yes 
17. Difficulty blinking because of little or no  
moisture in my eyes  
Symptom Bother 
IDLSYM17 
Yes 
18. Sensitivity to light, glare, and/or wind  
 
Symptom Bother 
IDLSYM18 
Yes 
19. Sensitivity to recirculated air (such as air  
conditioning and heat)  
Symptom Bother 
IDLSYM19 
Yes 
20. Headaches associated with dry eye 
symptoms  
 
Symptom Bother 
IDLSYM20 
Yes 
 


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Response for question 1 (IDLSYM1) 
Original response 
code 
Item score 
None of the time 
0 
0 
A little of the time 
1 
1 
Some of the time 
2 
2 
Most of the time 
3 
3 
All of the time 
4 
4 
 
 
Response for questions 2 to 20 (IDLSYM2 - 
IDLSYM20) 
Original response 
code 
Item score 
I did not have this symptom / Not applicable 
0 
0 
Not at all 
1 
1 
Slightly 
2 
2 
Moderatly 
3 
3 
Very much 
4 
4 
 
 
All questions (IDLSYM1 – IDLSYM20)  are included in the Symptom Bother scale score (IDLSYM).  
If 50% (10) or fewer of the 20 questions used in the calculation of Symptom Bother scale score have 
missing item scores, then the scale score is calculated by multiplying the mean of the non missing 
item score by 25. If 11 or more of the 20 item scores are missing then the scale score is not 
calculated and should be set at missing. 
Multiplying by 25 transforms the scale score to a 0 to 100 scale, with 0 reflecting the greatest degree 
of treatment related bother measurable by the scale and 100 reflecting the lowest degree of 
treatment-related bother. 
 
 
 
Changes from baseline in each scale score will be analyzed using an mixed model for repeated 
measures (MMRM). The analyses will include the fixed, categorical effects of treatment (3 levels: 
rhNGF 20 μg/mlTID, rhNGF 20 μg/ml BID and vehicle TID), visit (4 levels: Weeks 4, 8, 12, 16) and 
treatment by visit interaction. Subject will be considered as a random effect.The covariance matrix 
used will be "unstructured". Comparisons versus vehicle TID will be provided using least square 
means at each visit and overall. 
 
IDEEL data will be also listed. 
 
 
 
Patient Global Impression of Change (PGIC) 
Patient Global Impression of Change (PGIC) will be collected at Week 4, Week 8, Week 12 and Week 
16.  
A 7-point scale is used, representing the degree to which the general state of health have changed 
relative to start of the study. On the PGIC, 1 = very much improved and 7 = very much worse. 
A frequency table will summarize the responses for each treatment by visit. To take into account the 
ordinal nature of the response, p-values based on the Wilcoxon rank sum test comparing each rhNGF 
to Placebo will be computed.  
 
PGIC data will be also listed. 
 


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EQ-5D-3L 
EQ-5D-3L will be collected at screening, baseline, Week 4, Week 8, Week 12 and Week 16. 
 
The Questionnaire EQ-5D-3L is a 5-dimension instrument assessing quality of life.  
The 5 dimensions are Mobility, Self-Care, Usual Activity, Pain/Discomfort, and Anxiety/Depression. 
Each dimension is scored as 1 = no problem, 2 = some problem, and 3 = extreme Problem. 
No imputation will be done on missing values. 
 
Descriptive summary statistics for the single dimension scores  (“Mobility”, “Self-Care”, “Usual 
Activities”, “Pain/Discomfort” and “Anxiety/Depression”) will be presented by visit and treatment group.  
 
Shift tables comparing results from Baseline to each visit will be presented with percentages based on 
subjects with a non-missing value at Baseline and post-baseline visit. 
 
The patients provide an assessment of their best health state by means of a score between 0 and 100 
(EQ visual analogue scale – VAS).  
The change in VAS score from the baseline visit to the post-baseline visit will be analyzed using an 
mixed 
model for repeated measures (MMRM).  The analyses will include the fixed, categorical effects of 
treatment (3 levels: rhNGF 20 μg/mlTID, rhNGF 20 μg/ml BID and vehicle TID), visit (4 levels: Weeks 
4, 8, 12, 16) and treatment by visit interaction. Subject will be considered as a random effect.The 
covariance matrix used will be "unstructured". Comparisons versus vehicle TID will be provided using 
least square means at each visit and overall. 
 
EQ-5D-3L data will be listed. 
 
 
 
Exploratory Endpoint 
All exploratory endpoints will be summarized using Full Analysis Set. Statistical testing has only a 
descriptive value. 
 
Proportion and frequency of preservative-free artificial tears use (n° drops/day) during 
the treatment period 
The proportions and n° drops/day (see definition in 6.2.6) will be summarized during the treatment 
period, by treatment group. 
 
Proportion and Frequency of Preservative-Free Artificial Tears Use (n° drops/day) During 
the Follow-Up Period 
The proportions and n° drops/day (see definition in 6.2.6) will be summarized during the follow up 
period, by treatment group.  
 
Change from Baseline in Schirmer Test I (Without Anesthesia) Versus Week 2 
Change from baseline in Schirmer test I (without anesthesia) at Week 2 will be analyzed using the 
same analysis used for the primary efficacy end-point. 


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Change from Baseline in Symptoms Questionnaire (SANDE) Scores for Severity and 
Frequency Assessed at 2 Weeks  
Change from baseline in symptoms questionnaire (SANDE) scores for severity and frequency 
assessed at 2 weeks will be analyzed using the same analysis used for the primary efficacy end-
point. 
 
Change from Baseline in Corneal and Conjunctiva Vital Staining with Fluorescein (NEI 
Scales) Versus Week 2 
Change from baseline in corneal and conjunctiva vital staining with fluorescein (NEI scales) versus 
Week 2 will be analyzed using the same analysis used for the primary efficacy end-point. 
 
Change from Baseline in Tear Film Break-Up Time (TFBUT) Versus Week 2 
Change from baseline in TFBUT versus Week 2 will be analyzed using the same analysis used for the  
primary efficacy end-point. 
 
Number of Patients who Experienced a Worsening in Symptom Scores (SANDE) and/or 
NEI Score ≥ 50% Assessed at Week 2 
Number of patients who experienced a worsening in symptom scores (SANDE) and/or NEI score ≥ 
50% assessed at Week 2 will be summarized by treatment group. 
 
Change from Baseline in Goblet Cells Density at week 4 
Goblet cells density is measured at baseline, Week 4 and Week 16. 
Change from baseline in goblet cells density at Week 4 will be analyzed using the same analysis used 
for the primary efficacy end-point. 
The goblet cells density will be summarized using descriptive statistics for continuous variables by 
treatment and visit. The change from baseline value will also be summarized for all post-baseline 
visits. 
Goblet cells density will be also listed 
 
Post Hoc Endpoint 
Some correlation between sign and symptom scores could be computed for exploratory purpose. 


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Safety 
The population used for safety analyses will be the Safety Set (SS). Safety will be assessed on the 
basis of adverse events (AEs).  
Safety tables are presented in tables 14.1.5.1 and 14.1.5.2 and 14.3.1.1 to 14.3.2.4 ((see section15) 
 
 
Extent of Exposure 
The study drug administration (Day 1 to Week 4) will be captured in the patient diary including the 
administration of preservative-free artificial tears (Day 1 to Week 12). 
The extent of exposure, otherwise referred to as the time from first instillation of study medication to 
last instillation of study medication is defined as:  
Number of days on treatment = date of last instillation of treatment – date of first instillation of 
treatment +1 
 
The data will be summarized by treatment group and presence/absence of primary Sjogren. A listing 
will be also provided. 
 
 
Treatment Compliance  
The assessment of patients’ compliance to the IMP will be made by determining the number of drops 
administered to the eligible eye (see section 6.2.5). 
Gross noncompliance will be defined as compliance for the eligible eye lower than 80% or greater 
than 120% and in case of gross noncompliance the patient will be excluded from the Per Protocol set.  
 
Adverse Events / Adverse Drug Reactions 
Adverse events (AEs) will be coded by SOC and PT, using the Medical Dictionary for Regulatory 
Activities (MedDRA 21.1).  
Treatment-emergent adverse events (TEAEs) are all events occurring or worsening after the first 
dose of the IMP.  
 
TEAEs will be summarized by SOC ,PT, treatment arm and phase (Treatment phase or Follow up). 
Both the number and percentage of patients who experience the event and the number of events will 
be summarised per treatment arm. Percentages will be based on the number of patients in the Safety 
Set.  
 
All tables for TEAEs will be also summarized separately for each strata. 
 
An overall summary of the number and percentage of patients and number of the events with any 
TEAEs, potentially Related TEAEs, Serious TEAEs, Serious Potentially Related TEAEs, TEAEs 
leading to study discontinuation, TEAEs leading to death and TEAE of special interest (AESI)will be 
generated, and presented by treatment arm and phase (Treatment phase or Follow up) 
 
TEAEs will be sorted alphabetically by SOC, and then sorted alphabetically by PTs within SOC.  
 
Separate tables will be presented by severity, and for SAEs, ocular TEAEs, related ocular TEAEs, 
related TEAEs, and TEAEs leading to study discontinuation.  
 


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“Possible”, ”probable”, “highly probable” or missing relationships are to be considered as related to 
study drug for the summary tables. “None” and “unlikely” relationships are to be considered not 
related to study drug. 
Individual AEs will be listed in patient data listings. A listing of patients died due to COVID-19 will be 
also provided on randomized set. 
 
Laboratory Evaluations 
Not applicable 
 
Vital Signs  
Not applicable 
 
ECG 
Not applicable 
 
Physical Examination 
Not applicable 


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 Interim Analyses 
No interim analysis was planned  


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 Changes from Analysis Planned in Protocol 
IDEEL and EQ-5D will be analysed using a mixed model for repeated measures (MMRM) instead of 
analysis of variance as the method seems more appropriate due to the repeated measures. 
Exploratory sensitivity analysis will be also conducted for SANDE, Schirmer Test II, Corneal and 
Conjunctiva Vital Staining and TFBUT instead of only primary efficacy endpoint. 
Overall compliance will not be calculated, as we don’t have in the database the number of unused vials. 
We only have the number of vials not returned to the site whatever the reasons  
Additional analyses have been planned to investigate the impact of COVID-19 pandemic on primary 
endpoint and on patient safety profiles (in case of 10% randomized patients affected). 
Summary statistics on primary endpoint reporting the two treatment doses (20 μg/mL BID arm and 20 
μg/mL TID) pooled versus placebo has been added to see the overall effect of the rhNGF treatment.  
A sensitivity analysis on primary endpoint based on classification of patients in “Responders” and “Non 
Responders” based on the Schirmer Test I at the end of treatment has been added. This analysis will 
assess the robustness of results by considering an exact statistical method (not depending on 
assumption of normality of the data) and based on the status of the patients at the end of treatment. 


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 Reference List 
1. Williams DA. The comparison of several dose levels with a zero dose control. 1972. 
Biometrics 28, 519-531.  
2. Williams DA. A test for differences between treatment means when several dose levels are 
compared with a zero dose control. 1971. Biometrics 27, 103-117.  
3. Shein-Chung Chow, Jun Shao, Hansheng Wang; Samples Size Calculations in Clinical 
Research - Marcel Dekker, Inc. 2003I, SBN: 0-8247-0970-5, p. 186-189.  
4. F Amparo, DA Schaumberg, R Dana; Comparison of two questionnaires for dry eye symptom 
assessment: the ocular surface disease index and the symptom assessment in dry eye 
Ophthalmology 2015 July; 122 (7), 1498 - 1503 
 
 


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 Programming Considerations 
All tables, figures, listings (TFLs), and statistical analyses will be generated using SAS for Windows, 
Release 9.4. (SAS Institute Inc., Cary, NC, USA). Computer-generated table, listing and figure output 
will adhere to the following specifications. 
 
General Considerations 
• 
One SAS program can create several outputs, or a separate SAS program will be created for 
each output. 
• 
One output file can contain several outputs. 
• 
Output files will be delivered in Rich Text Format (RTF) that can be manipulated in MSWord. 
• 
Numbering of TFLs will follow ICH E3 guidance. 
 
Table, Listing, and Figure Format 
 
General 
• All TFLs will be produced in landscape format on A4 paper size, unless otherwise specified.  
• All TFLs will be produced using the Courier New font, size 8 which is the smallest acceptable 
point size for the Regulatory Authorities. 
• The data displays for all TFLs will have a minimum blank 1-inch margin on all 4 sides. 
• Headers and footers for figures will be in Courier New font, size 8 which is the smallest 
acceptable point size for the Regulatory Authorities. 
• Legends will be used for all figures with more than 1 variable, group, or item displayed. 
• TFLs will be in black and white (no color), unless otherwise specified. 
• Specialized text styles, such as bolding, italics, borders, shading, and superscripted and 
subscripted text, will not be used in the TFLs, unless otherwise specified. On some occasions, 
superscripts 1, 2, or 3 may be used (see below). 
• Only standard keyboard characters will be used in the TFLs. Special characters, such as non-
printable control characters, printer-specific, or font-specific characters, will not be used. 
Hexadecimal-derived characters will be used, where possible, if they are appropriate to help 
display math symbols (e.g., μ). Certain subscripts and superscripts (e.g., cm2, Cmax) will be 
employed on a case-by-case basis. 
• Mixed case will be used for all titles, footnotes, column headers, and programmer-supplied 
formats, as appropriate. 
 
Headers 
• All output should have the following header at the top left of each page: 
• Dompé farmaceutici S.p.A  
 Protocol NGF0118  
Draft/Final Run <date> 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 42 of 64 
• All outputs should have Page n of N at bottom right corner of each page. TFLs are internally 
paginated in relation to the total length (i.e., the page number should appear sequentially as 
page n of N, where N is the total number of pages in the table). 
• The date in which output was generated should appear along with the program name as a 
footer on each page. 
 
Display Titles 
• Each TFL is identified by the designation and a numeral. (i.e., Table 14.1.1). ICH E3 numbering 
will be used. A decimal system (x.y and x.y.z) is used to identify TFLs with related contents: for 
example, the set of tables 14.2.1.1.x (i.e. tables 14.2.1.1.1, 14.2.1.1.2, 14.2.1.1.3, …) will be for 
the primary end-point.  The title is centered. The analysis sets are identified on the line 
immediately following the title. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column header. 
•  There will be 1 blank line between the last title and the solid line in the column headers. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
 
Column Headers 
• Column headings are displayed immediately below the solid line described above in initial 
upper-case characters.  
• In the case of efficacy tables, the variable (or characteristic) column will be on the far left 
followed by the treatment group columns and total column (if applicable). P-values may be 
presented under the total column or in separate p-value column (if applicable). Within-treatment 
comparisons may have p-values presented in a row beneath the summary 14.2.statistics for 
that treatment. 
• For numeric variables, “unit” will be included in column or row heading, when appropriate. 
• Analysis set sizes will be presented for each treatment group in the column heading as (N = xx) 
(or in the row headings, if applicable). This is distinct from the ‘n’ used for the descriptive 
statistics representing the number of patients in the analysis set. 
• The order of treatments in the tables will be active treatment first and vehicle, followed by a 
total column (if applicable). 
 
Body of the Data Display 
13.2.5.1. 
General Conventions 
Data in columns of a table or listing are formatted as follows: 
• Alphanumeric values are left-justified. 
• Whole numbers (e.g., counts) are right-justified. 
• Numbers containing fractional portions are decimal aligned. 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 43 of 64 
 
13.2.5.2. 
Table Conventions 
• Units will be included where available. 
• If the categories of a parameter are ordered, then all categories between the maximum and 
minimum category are presented in the table, even if n = 0 for all treatment groups in a given 
category that is between the minimum and maximum level for that parameter. For example, the 
frequency distribution for symptom severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
Mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be presented and so 
counts of 0 will be presented as 0 and not as 0 (0%). 
• If the categories are not ordered (e.g., Medical History), then only those categories for which 
there is at least 1 patient represented in 1 or more groups are included, except for reasons for 
discontinuations where all categories will be shown. 
• Unknown or Missing categories are added to each parameter for which information is not 
available for 1 or more patients.  
• Unless otherwise specified, the estimated mean and median for a set of values are printed out 
to 1 more significant digit than the original values, and standard deviations are printed out to 2 
more significant digits than the original values. The minimum and maximum should report the 
same significant digits as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
 X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
• P-values are reported in the format: “0.xxx”, where xxx is the value rounded to 3 decimal 
places.  
• Percentage values are printed to one decimal place, in parentheses with no spaces, one space 
after the count (e.g., 7 (12.8%), 13 (5.4%)). Unless otherwise noted, for all percentages, the 
number of patients in the analysis set for the treatment group who have an observation will be 
the denominator. Percentages after zero counts should not be displayed and percentages 
equating to 100% are presented as 100%, without decimal places.  
• As general rule, the percentage of patients is calculated as a proportion of the number of 
patients assessed in the relevant treatment group (or overall) for the analysis set presented.  
• Where a category with a subheading (such as system organ class) has to be split over more 
than one page, the subheading will be followed by “(cont)” at the top of each subsequent page.  


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 44 of 64 
The overall summary statistics for the subheading should only be output on the first relevant 
page. 
13.2.5.3. 
Listing Conventions 
• Listings will be sorted for presentation in order of: patient number, treatment groups, 
visit/collection day and visit/collection time. 
• Dates are printed in SAS DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing portions of dates 
are represented on patient listings as dashes (--JUL2000). 
• All observed time values are to be presented using a 24-hour clock HH:MM or HH:MM:SS 
format (e.g., 11:26:45, or 11:26). Time will only be reported if it was measured as part of the 
study. 
• Units will be included where available. 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 45 of 64 
 Quality Control 
SAS programs are developed to produce output such as analysis data sets, summary tables, data 
listings, figures or statistical analyses.  
Programs for the production of SDTM domains, ADaM/analysis datasets and TFLs will be double-
programmed. For datasets, tables and listings, the production programming results and validation 
programming results will be compared electronically. 
A more complete overview of the development of programs is detailed in Syneos Health SOP 
Developing Statistical Programs (3907). 
Syneos Health SOPs Developing Statistical Programming Specifications (3906), Developing 
Statistical Programs (3907) and Conducting the Transfer of Biostatistical Deliverables (3908) describe 
the quality control procedures that are performed for all SAS programs and outputs. Quality control is 
defined here as the operational techniques and activities undertaken to verify that the SAS programs 
produce the output by checking for their logic, efficiency and commenting and by reviewingf the 
produced output.   


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 46 of 64 
 Index of Tables 
Table Number 
Name 
Analysis Set 
 
Topline  
14.1.1. 
Patient disposition 
Enrolled Set 
Yes 
14.1.2.1 
Major Protocol Deviations 
Full Analysis Set 
 
14.1.2.2 
Reasons for Exclusion from Analysis 
Populations 
Randomized Set 
 
14.1.3.1 
Demographic and Baseline 
Characteristics 
Full Analysis Set 
Yes 
14.1.3.2.1 
Ocular Medical History by MedDRA 
System Organ Class and Preferred 
Term  
Safety Set 
 
14.1.3.2.2 
Systemic Medical History by 
MedDRA System Organ Class and 
Preferred Term  
Safety Set 
 
14.1.4.1.1 
Summary of Previous Ocular 
medications 
Safety Set 
 
14.1.4.1.2 
Summary of Previous Systemic 
Medications 
Safety Set 
 
14.1.4.2.1 
Summary of Concomitant Ocular 
Medications  
Safety Set 
 
14.1.4.2.2 
Summary of Concomitant systemic 
medications 
Safety Set 
 
14.1.5.1 
Compliance to study treatment 
Safety Set 
 
14.1.5.2 
Exposure to Study Treatment 
Safety Set 
 
14.2.1.1. 
Analysis of Change from Baseline in 
Schirmer test I at Week 4 - Eligible 
eye 
Full Analysis Set 
Yes 
14.2.1.2 
Analysis of Change from Baseline in 
Schirmer test I  tat Week 4 - Eligible 
eye 
Per Protocol Set 
Yes 
14.2.1.3 
Exploratory Sensitivity Analysis of 
Change from Baseline in Schirmer 
test I at Week 4 - Eligible eye 
 
Full Analysis Set 
 
14.2.1.4 
Exploratory Sensitivity Analysis of 
Change from Baseline in Schirmer 
test I at Week 4 - Eligible eye 
 
Per protocol Set 
 
14.2.1.5.1 
Summary of Schirmer test I  by 
treatment and visit (mm) - Eligible 
eye 
Full Analysis Set 
Yes 
14.2.1.5.2 
Summary of Schirmer test I  by 
treatment (pooled) and visit (mm) - 
Eligible eye 
Full Analysis Set 
 
14.2.1.6 
Summary of Schirmer test I  by 
treatent and visit (mm) – Presence of 
Primary Sjogren -Eligible eye 
Full Analysis Set 
 
14.2.1.7 
Summary of Schirmer test I  by 
treatment and visit (mm) – Absence 
of Primary Sjogren- Eligible eye 
Full Analysis Set 
 
14.2.1.8 
Summary of Responders (based on 
Schirmer test I)  by treatment and 
visit (mm) - Eligible eye 
Full Analysis Set 
 
14.2.1.9.1 
Summary of Schirmer test I by 
treatment and visit - Eligible eye 
Per Protocol Set 
Yes 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 47 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.1.9.2 
Summary of Schirmer test I by 
treatment (pooled) and visit - Eligible 
eye 
Per Protocol Set 
 
14.2.1.10 
Summary of Schirmer test I by 
treatment and visit - Presence of 
Primary Sjogren - Eligible eye 
Per Protocol Set 
 
14.2.1.11 
Summary of Schirmer test I by 
treatment and visit - Absence of 
Primary Sjogren - Eligible eye 
Per Protocol Set 
 
14.2.1.12 
Summary of Responders (based on 
Schirmer test I)  by treatment and 
visit (mm) - Eligible eye 
Per Protocol Set 
 
14.2.2.1.1 
Analysis of Change from Baseline in 
symptoms questionnaire (SANDE) at 
Week 4 
Full Analysis Set 
Yes 
14.2.2.1.2 
Analysis of Change from Baseline in 
symptoms questionnaire (SANDE) at 
Week 4 
Per Protocol Set 
Yes 
14.2.2.1.3 
Exploratory Sensitivity Analysis of 
Change from baseline in symptoms 
questionnaire (SANDE) at week 4 
Full Analysis Set 
 
14.2.2.1.4 
Exploratory Sensitivity Analysis of 
Change from baseline in symptoms 
questionnaire (SANDE) at week 4 
Per Protocol Set 
 
14.2.2.1.5 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit 
Full Analysis Set 
Yes 
14.2.2.1.6 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit - Presence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.1.7 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit - Absence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.1.8 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit-  
Per Protocol Set 
Yes 
14.2.2.1.9 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit- Presence of 
Primary Sjogren 
Per Protocol Set 
 
14.2.2.1.10 
Summary of Symptoms 
Questionnaire (SANDE) by 
treatment and visit- Absence of 
Primary Sjogren 
Per Protocol Set 
 
14.2.2.2.1 
Analysis of Change in Schirmer test 
II from Baseline to Week 4 - Eligible 
eye 
Full Analysis Set 
 
14.2.2.2.2 
Analysis of Change in Schirmer test 
II from Baseline to Week 4 - Eligible 
eye 
Per Protocol Set 
 
14.2.2.2.3 
Exploratory Sensitivity Analysis of 
Change from Baseline in Schirmer 
test II at Week 4 - Eligible eye 
Full Analysis Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 48 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.2.2.4 
Exploratory Sensitivity Analysis of 
Change from Baseline in Schirmer 
test II at Week 4 - Eligible eye 
Per Protocol Set 
 
14.2.2.2.5 
Summary of Schirmer test II by 
treatment and visit - Eligible eye 
Full Analysis Set 
 
14.2.2.2.6 
Summary of Schirmer test II by 
treatment and visit - Presence of 
Primary Sjogren - Eligible eye 
Full Analysis Set 
 
14.2.2.2.7 
Summary of Schirmer test II by 
treatment and visit - Absence of 
Primary Sjogren - Eligible eye 
Full Analysis Set 
 
14.2.2.2.8 
Summary of Schirmer test II by 
treatment and visit - Eligible eye 
Per Protocol Set 
 
14.2.2.2.9 
Summary of Schirmer test II by 
treatment and visit - Presence of 
Primary Sjogren - Eligible eye 
Per Protocol Set 
 
14.2.2.2.10 
Summary of Schirmer test II by 
treatment and visit - Absence of 
Primary Sjogren - Eligible eye 
Per Protocol Set 
 
14.2.2.3.1 
Analysis of Change from baseline in 
Corneal and conjunctiva vital 
staining with fluorescein (National 
Eye Institute [NEI] scales) to Week 4 
Full Analysis Set 
 
14.2.2.3.2 
Analysis of Change from baseline in 
Corneal and conjunctiva vital 
staining with fluorescein (National 
Eye Institute [NEI] scales) to Week 4 
Per Protocol Set 
 
14.2.2.3.3 
Exploratory Sensitivity Analysis of 
Change from baseline in Corneal 
and conjunctiva vital staining with 
fluorescein (National Eye Institute 
[NEI] scales) to Week 4- Eligible eye 
Full Analysis Set 
 
14.2.2.3.4 
Exploratory Sensitivity Analysis of 
Change from baseline in Corneal 
and conjunctiva vital staining with 
fluorescein (National Eye Institute 
[NEI] scales) to Week 4 - Eligible 
eye 
Per Protocol Set 
 
14.2.2.3.5 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) 
Full Analysis Set 
 
14.2.2.3.6 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) - 
Presence of Primary Sjogren  
Full Analysis Set 
 
14.2.2.3.7 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) - 
Absence of Primary Sjogren  
Full Analysis Set 
 
14.2.2.3.8 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) 
Per Protocol Set 
 
14.2.2.3.9 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) -
- Presence of Primary Sjogren 
Per Protocol Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 49 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.2.3.10 
Summary of Corneal and conjunctiva 
vital staining with fluorescein 
(National Eye Institute [NEI] scales) - 
Absence of Primary Sjogren 
Per Protocol Set 
 
14.2.2.4.1 
Analysis of Change from baseline in 
Tear Film Break up time at week 4 - 
Eligible eye 
Full Analysis Set 
 
14.2.2.4.2 
Analysis of Change from baseline in 
Tear Film Break up time at week 4 - 
Eligible eye 
Per Protocol Set 
 
14.2.2.4.3 
Exploratory Sensitivity Analysis of 
Change from Baseline in Tear Film 
Break up time at Week 4 - Eligible 
eye 
Full Analysis Set 
 
14.2.2.4.4 
Exploratory Sensitivity Analysis of 
Change from Baseline in Tear Film 
Break up time at Week 4 - Eligible 
eye 
Per Protocol Set 
 
14.2.2.4.5 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) - Eligible eye 
Full Analysis Set 
 
14.2.2.4.6 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) - Presence of Primary 
Sjogren - Eligible eye 
Full Analysis Set 
 
14.2.2.4.7 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) - Absence of Primary 
Sjogren - Eligible eye 
Full Analysis Set 
 
14.2.2.4.8 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) - Eligible eye 
Per Protocol Set 
 
14.2.2.4.9 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) -  Presence of Primary 
Sjogren - Eligible eye 
Per Protocol Set 
 
14.2.2.4.10 
Summary of Tear Film Break up time 
(TFBUT) by treatment and visit 
(seconds) - Absence of Primary 
Sjogren -Eligible eye 
Per Protocol Set 
 
14.2.2.5.1 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 
Full Analysis Set 
 
14.2.2.5.2 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 -  Presence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.5.3 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 - Absence of 
Primary Sjogren - 
Full Analysis Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 50 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.2.5.4 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 
Per Protocol Set 
 
14.2.2.5.5 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 -  Presence of 
Primary Sjogren 
Per Protocol Set 
 
14.2.2.5.6 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 4 - Absence of 
Primary Sjogren  
Per Protocol Set 
 
14.2.2.6.1 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) questionnaire 
Full Analysis Set 
 
14.2.2.6.2 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) 
questionnaire-  Presence of Primary 
Sjogren 
Full Analysis Set 
 
14.2.2.6.3 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) 
questionnaire-  Absence of Primary 
Sjogren 
Full Analysis Set 
 
14.2.2.6.4 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) questionnaire 
Per Protocol Set 
 
14.2.2.6.5 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) questionnaire 
- Presence of Primary Sjogren 
Per Protocol Set 
 
14.2.2.6.6 
Quality of life Impact of Dry Eye on 
Everyday Life (IDEEL) questionnaire 
-Absence of Primary Sjogren 
Per Protocol Set 
 
14.2.2.7.1 
Patient global Impression of change 
(PGIC) 
 
Full Analysis Set 
 
14.2.2.7.2 
Patient global Impression of change 
(PGIC) - Presence of Primary 
Sjogren 
 
Full Analysis Set 
 
14.2.2.7.3 
Patient global Impression of change 
(PGIC) - Absence of Primary 
Sjogren 
 
Full Analysis Set 
 
14.2.2.7.4 
Patient global Impression of change 
(PGIC) 
 
Per Protocol Set 
 
14.2.2.7.5 
Patient global Impression of change 
(PGIC) - Presence of Primary 
Sjogren 
Per Protocol Set 
 
14.2.2.7.6 
Patient global Impression of change 
(PGIC)- Absence of Primary Sjogren 
Per Protocol Set 
 
14.2.2.8.1 
EQ-5D-3L – Health score 
Full Analysis Set 
 
14.2.2.8.2 
EQ-5D-3L – Health score  - 
Presence of Primary Sjogren 
Full Analysis Set 
 
14.2.2.8.3 
EQ-5D-3L – Health score - Absence 
of Primary Sjogren 
Full Analysis Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 51 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.2.8.4 
EQ-5D-3L – Health score 
Per Protocol Set 
 
14.2.2.8.5 
EQ-5D-3L – Health score - Presence 
of Primary Sjogren 
Per Protocol Set 
 
14.2.2.8.6 
EQ-5D-3L – Health score - Absence 
of Primary Sjogren 
Per Protocol Set 
 
14.2.2.8.7 
Summary statistics of EQ-5D-3L by 
dimension and level 
 
Full Analysis Set 
 
14.2.2.8.8 
Summary statistics of EQ-5D-3L by 
dimension and level - Presence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.8.9 
Summary statistics of EQ-5D-3L by 
dimension and level- Absence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.8.10 
Summary statistics of EQ-5D-3L by 
dimension and level 
 
Per Protocol Set 
 
14.2.2.8.11 
Summary statistics of EQ-5D-3L by 
dimension and level - Presence of 
Primary Sjogren 
Per Protocol Set 
 
14.2.2.8.12 
Summary statistics of EQ-5D-3L by 
dimension and level - Absence of 
Primary Sjogren 
Per Protocol Set 
 
14.2.2.8.13 
Shift from baseline of EQ-5D-3L by 
dimension and level 
Full Analysis Set 
 
14.2.2.8.14 
Shift from baseline of EQ-5D-3L by 
dimension and level 
Per Protocol Set 
 
14.2.2.9. 
Proportion and frequency of 
preservative-free artificial tears use 
(n° drops/day) by period  
Full Analysis Set 
 
14.2.2.10. 
Analysis of Change in Schirmer test I 
from Baseline to Week 2 – Eligible 
eye 
Full Analysis Set 
 
14.2.2.11. 
 
Analysis of Change from baseline in 
symptoms questionnaire (SANDE) at 
Week 2 
Full Analysis Set 
 
14.2.2.12. 
Analysis of Change from baseline in 
Corneal and conjunctiva vital 
staining with fluorescein to Week 2 
Full Analysis Set 
 
14.2.2.13. 
Analysis of Change from baseline in 
Tear Film Break up time at week 2 – 
Eligible eye 
Full Analysis Set 
 
14.2.2.14.1 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 2 
Full Analysis Set 
 
14.2.2.14.2 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 2- Presence of 
Primary Sjogren 
Full Analysis Set 
 
14.2.2.14.3 
Number of patients who experienced 
a worsening in symptom scores 
(SANDE) and/or NEI score >= 50% 
assessed at week 2 - Absence of 
Primary Sjogren 
Full Analysis Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
This document is confidential. 
SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
Controlled Document ID: 3903A.01, Effective Date 29-Oct-2018 
Filing requirements: TMF 
Page 52 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.2.2.15.1 
Analysis of Change from baseline in 
goblet cells density – Eligible eye 
Full Analysis Set 
 
14.2.2.15.2. 
Summary of goblet cells density 
(cells/mm²) - Eligible eye 
Full Analysis Set 
 
14.2.2.15.3 
Summary of goblet cells density 
(cells/mm²) - Presence of Primary 
Sjogren – Eligible eye 
Full Analysis Set 
 
14.2.2.15.4 
Summary of goblet cells density 
(cells/mm²) - Absence of Primary 
Sjogren – Eligible eye 
Full Analysis Set 
 
14.3.1.1.1 
Treatment-Emergent Adverse 
Events – Overall Summary 
Safety Set 
Yes 
14.3.1.1.2 
Treatment-Emergent Adverse 
Events – Overall Summary - 
Presence of Primary Sjogren 
Safety Set 
 
14.3.1.1.3 
Treatment-Emergent Adverse 
Events – Overall Summary - 
Absence of Primary Sjogren 
Safety Set 
 
14.3.1.2.1 
Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term 
Safety Set 
 
14.3.1.2.2 
Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Presence of 
Primary Sjogren 
Safety Set 
 
14.3.1.2.3 
Treatment-Emergent Adverse 
Events by System Organ Class and 
Preferred Term - Absence of Primary 
Sjogren 
Safety Set 
 
14.3.1.3.1 
Treatment-Emergent Ocular Adverse 
Events Study Treatment by MedDRA 
System Organ Class and Preferred 
Term 
Safety Set 
 
14.3.1.3.2 
Treatment-Emergent Ocular Adverse 
Events Study Treatment by MedDRA 
System Organ Class and Preferred 
Term - Presence of Primary Sjogren 
Safety Set 
 
14.3.1.3.3 
Treatment-Emergent Ocular Adverse 
Events Study Treatment by MedDRA 
System Organ Class and Preferred 
Term - Absence of Primary Sjogren 
Safety Set 
 
14.3.1.4.1 
Treatment-Emergent Ocular Adverse 
Events Related to Study Treatment 
by MedDRA System Organ Class 
and Preferred Term 
Safety Set 
 
14.3.1.4.2 
Treatment-Emergent Ocular Adverse 
Events Related to Study Treatment 
by MedDRA System Organ Class 
and Preferred Term - Presence of 
Primary Sjogren 
Safety Set 
 
14.3.1.4.3 
Treatment-Emergent Ocular Adverse 
Events Related to Study Treatment 
by MedDRA System Organ Class 
and Preferred Term - Absence of 
Primary Sjogren 
Safety Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 53 of 64 
Table Number 
Name 
Analysis Set 
 
Topline  
14.3.1.5.1 
Treatment-Emergent Adverse 
Events related to study treatment by 
System Organ Class and Preferred 
Term 
Safety Set 
 
14.3.1.5.2 
Treatment-Emergent Adverse 
Events related to study treatment by 
System Organ Class and Preferred 
Term - Presence of Primary Sjogren 
Safety Set 
 
14.3.1.5.3 
Treatment-Emergent Adverse 
Events related to study treatment by 
System Organ Class and Preferred 
Term - Absence of Primary Sjogren 
Safety Set 
 
14.3.1.6.1 
Serious Treatment-Emergent 
Adverse Events by System Organ 
Class and Preferred Term 
Safety Set 
Yes 
14.3.1.6.2 
Serious Treatment-Emergent 
Adverse Events by System Organ 
Class and Preferred Term - 
Presence of Primary Sjogren 
Safety Set 
 
14.3.1.6.3 
Serious Treatment-Emergent 
Adverse Events by System Organ 
Class and Preferred Term - Absence 
of Primary Sjogren 
Safety Set 
 
14.3.1.7.1 
Treatment-Emergent Adverse 
Events Leading to study 
discontinuation by System Organ 
Class and Preferred Term 
Safety Set 
 
14.3.1.7.2 
Treatment-Emergent Adverse 
Events Leading to study 
discontinuation by System Organ 
Class and Preferred Term - 
Presence of Primary Sjogren 
Safety Set 
 
14.3.1.7.3 
Treatment-Emergent Adverse 
Events Leading to study 
discontinuation by System Organ 
Class and Preferred Term - Absence 
of Primary Sjogren 
Safety Set 
 
14.3.1.8.1 
Treatment-Emergent Adverse 
Events of Special Interest by System 
Organ Class and Preferred Term 
Safety Set 
 
14.3.1.8.2 
Treatment-Emergent Adverse 
Events of Special Interest by System 
Organ Class and Preferred Term - 
Presence of Primary Sjogren 
Safety Set 
 
14.3.1.8.3 
Treatment-Emergent Adverse 
Events of Special Interest by System 
Organ Class and Preferred Term - 
Absence of Primary Sjogren 
Safety Set 
 
14.3.1.9.1 
Treatment-Emergent Adverse 
Events by System Organ Class, 
Preferred Term, and Maximum 
Severity 
Safety Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Table Number 
Name 
Analysis Set 
 
Topline  
14.3.1.9.2 
Treatment-Emergent Adverse 
Events by System Organ Class, 
Preferred Term, and Maximum 
Severity - Presence of Primary 
Sjogren 
Safety Set 
 
14.3.1.9.3 
Treatment-Emergent Adverse 
Events by System Organ Class, 
Preferred Term, and Maximum 
Severity - Absence of Primary 
Sjogren 
Safety Set 
 
14.3.2.1 
Deaths, Listing 
Randomized Set 
 
14.3.2.2 
Serious Treatment-Emergent 
Adverse Events, Listing 
Randomized Set 
 
14.3.2.3 
Treatment-Emergent Adverse 
Events Leading to study 
discontinuation, Listing 
Randomized Set 
 
14.3.2.4 
Treatment-Emergent Adverse 
Events of Special Interest, Listing 
Randomized Set 
 
14.3.2.5 
Deaths due to COVID-19, Listing 
Randomized Set 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 55 of 64 
 Index of Figures 
Figure 
Number 
Name 
Analysis Set 
14.2.1.11 
Schirmer test I at each visit by dose 
group  
Full Analysis Set 
14.2.1.12 
Schirmer test I at each visit by dose 
group - Presence of Primary Sjogren 
Full Analysis Set 
14.2.1.13 
Schirmer test I at each visit by dose 
group - Absence of Primary Sjogren 
Full Analysis Set 
14.2.1.14 
Change from baseline of Schirmer test 
I (95% C.I.) by dose group  
Full Analysis Set 
14.2.1.15 
Change from baseline of Schirmer test 
I (95% C.I.) by dose group - Presence 
of Primary Sjogren 
Full Analysis Set 
14.2.1.16 
Change from baseline of Schirmer test 
I (95% C.I.) by dose group 
 - Absence of Primary Sjogren 
Full Analysis Set 
14.2.2.1.11 
SANDE score at each visit by dose 
group  
Full Analysis Set 
14.2.2.1.12 
SANDE score at each visit by dose 
group - Presence of Primary Sjogren 
Full Analysis Set 
14.2.2.1.13 
SANDE score at each visit by dose 
group - Absence of Primary Sjogren 
Full Analysis Set 
14.2.2.1.14 
Change from baseline of SANDE score 
(95% CI) by dose group  
Full Analysis Set 
14.2.2.1.15 
Change from baseline of SANDE score 
(95% CI) by dose group 
 - Presence of Primary Sjogren 
Full Analysis Set 
14.2.2.1.16 
Change from baseline of  
SANDE score (95% CI) by dose group 
- Absence of Primary Sjogren  
Full Analysis Set 
14.2.2.2.11 
Schirmer test II at each visit by dose 
group  
Full Analysis Set 
14.2.2.2.12 
Schirmer test II at each visit by dose 
group - Presence of Primary Sjogren 
Full Analysis Set 
14.2.2.2.13 
Schirmer test II at each visit by dose 
group - Absence of Primary Sjogren 
Full Analysis Set 
14.2.2.2.14 
Change from baseline of Schirmer test 
II (95% CI) by dose group  
Full Analysis Set 
14.2.2.2.15 
Change from baseline of Schirmer test 
II (95% CI) by dose group- Presence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.2.16 
Change from baseline of Schirmer test 
II (95% CI) by dose group- Absence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.3.11 
Corneal and conjunctiva vital staining 
total score at each visit by dose group  
Full Analysis Set 
14.2.2.3.12 
Corneal and conjunctiva vital staining 
total score at each visit by dose group - 
Presence of Primary Sjogren 
Full Analysis Set 
14.2.2.3.13 
Corneal and conjunctiva vital staining 
total score at each visit by dose group - 
Absence of Primary Sjogren 
Full Analysis Set 
14.2.2.3.14 
Change from baseline of Corneal and 
conjunctiva vital staining total score 
(95% CI) by dose group  
Full Analysis Set 


Statistical Analysis Plan for Interventional Studies 
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Figure 
Number 
Name 
Analysis Set 
14.2.2.3.15 
Change from baseline of Corneal and 
conjunctiva vital staining total score 
(95% CI) by dose group- Presence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.3.16 
Change from baseline of Corneal and 
conjunctiva vital staining total score 
(95% CI) by dose group- Absence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.4.11 
Tear film break-up time (TFBUT) at 
each visit by dose group  
Full Analysis Set 
14.2.2.4.12 
Tear film break-up time (TFBUT) at 
each visit by dose group - Presence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.4.13 
Tear film break-up time (TFBUT) at 
each visit by dose group - Absence of 
Primary Sjogren 
Full Analysis Set 
14.2.2.4.14 
Change from baseline  of Tear film 
break-up time (TFBUT) (95% CI) by 
dose group  
Full Analysis Set 
14.2.2.4.15 
Change from baseline  of Tear film 
break-up time (TFBUT) (95% CI) by 
dose group - Presence of Primary 
Sjogren  
Full Analysis Set 
14.2.2.4.16 
Change from baseline  of Tear film 
break-up time (TFBUT) (95% CI) by 
dose group - Absence of Primary 
Sjogren 
Full Analysis Set 
14.2.2.5.7 
Barplot of Number of Patients who 
Experienced a Worsening in Symptom 
Scores (SANDE) and/or NEI Score ≥ 
50% Assessed at Week 4 by dose 
group  
Full Analysis Set 
14.2.2.5.8 
Barplot of Number of Patients who 
Experienced a Worsening in Symptom 
Scores (SANDE) and/or NEI Score ≥ 
50% Assessed at Week 4 by dose 
group - Presence of Primary Sjogren  
Full Analysis Set 
14.2.2.5.9 
Barplot of Number of Patients who 
Experienced a Worsening in Symptom 
Scores (SANDE) and/or NEI Score ≥ 
50% Assessed at Week 4 by dose 
group - Absence of Primary Sjogren  
Full Analysis Set 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
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Page 57 of 64 
 Index of Listings 
 
Listing 
Number 
Name 
Analysis Set 
16.2.1.1 
Patient Disposition – Screen failure 
Enrolled Set 
16.2.1.2 
Patient Disposition – Randomized 
patients 
Randomized Set 
16.2.1.3 
Patients affected by COVID-19 – 
Randomized Set 
Randomized Set 
16.2.2.1 
Protocol Deviations 
Randomized Set  
16.2.2.2 
Protocol Deviations due to COVID-19 
Randomized Set 
16.2.3.1 
Patients Excluded from Analysis Set 
Randomized Set 
16.2.4.1 
Demographics and Baseline 
Characteristics 
Enrolled Set  
16.2.4.2 
Ocular and Systemic Medical History 
Enrolled Set  
16.2.4.3 
Previous Ocular and Systemic 
Medications 
Enrolled Set  
16.2.4.4 
Concomitant Ocular and Systemic 
Medications 
Randomized Set  
16.2.5.1 
Study Drug Administration 
Randomized Set 
16.2.5.2 
Study Drug Compliance 
Randomized Set 
16.2.6.1 
Primary Efficacy Endpoint Schirmer 
test I 
Randomized Set 
16.2.6.2.1 
Symptoms questionnaire (SANDE) 
Randomized Set 
16.2.6.2.2 
Schirmer test II 
Randomized Set 
16.2.6.2.3 
Corneal and conjunctiva vital staining 
with fluorescein (National Eye Institute 
[NEI] scales) 
Randomized Set 
16.2.6.2.4 
Tear Film Break-up Time (TFBUT) 
 
Randomized Set 
16.2.6.2.5.1 
Quality of Life Impact of Dry Eye on 
Everyday Life (IDEEL) Questionnaire –
Daily activities 
Randomized Set 
16.2.6.2.5.2 
Quality of Life Impact of Dry Eye on 
Everyday Life (IDEEL) Questionnaire –
Feelings 
Randomized Set 
16.2.6.2.5.3 
Quality of Life Impact of Dry Eye on 
Everyday Life (IDEEL) Questionnaire –
Work 
Randomized Set 
16.2.6.2.5.4 
Quality of Life Impact of Dry Eye on 
Everyday Life (IDEEL) Questionnaire –
Dry eye treatment satisfaction 
Randomized Set 
16.2.6.2.5.5 
Quality of Life Impact of Dry Eye on 
Everyday Life (IDEEL) Questionnaire – 
Dry eye symptom bothers 
Randomized Set 
16.2.6.2.6 
Patient Global Impression of Change 
(PGIC) 
 
Randomized Set 
16.2.6.2.7 
EQ-5D 3L 
Randomized Set 
16.2.6.2.8 
Preservative-free artificial tears use 
Randomized Set 
16.2.6.2.9 
Goblet Cells Density as per Laser 
Scanning Confocal Microscopy 
Randomized Set 
16.2.6.2.10 
Best Corrected Distance Visual Acuity 
(BCVDA) Test 
Randomized Set 
16.2.6.2.11 
Slit Lamp Biomicroscopy 
Randomized Set 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 58 of 64 
Listing 
Number 
Name 
Analysis Set 
16.2.6.2.12 
Corneal Endothelium and Stroma 
Evaluation as per Confocal Microscopy 
Randomized Set 
16.2.6.2.13 
External ocular examination 
Randomized Set 
16.2.7.1 
Adverse Events (Part 1) 
Randomized Set 
16.2.7.1 
Adverse Events (Part 2) 
Randomized Set 
16.2.8.1 
Urine pregnancy test 
Randomized Set 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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SAP Version: Dompe NGF0118 SAP Text  – Version 1.2 17 Sep 2020 
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Page 59 of 64 
 Appendices 
APPENDIX I SAMPLE SAS CODE IN STATISTICAL ANALYSIS 
 
1) Sample Code for Efficacy Analysis : Schirmer test I 
 
An Analysis of variance will be  used for Schirmer test I, followed by Williams test. An example of the 
SAS code to perform this analysis is below. 
 
************************************************************************  
* SAS Code: GLM (Analysis ofvariance) followed by William test 
* Variables in the model:   
*&var=CHG = Change from baseline in Schirmer test I at week 4 
*&trt=trt01p = treatment planned  
***********************************************************************; 
 
%macro WILLIAMS(dat = , trt = , var = ); 
 
/*####################### WILLIAMS TEST ##############################*/ 
 
/*For Williams Test, We Assume a Monotonic Dose Relationship (i.e. x0 <= x1 <= x2 <=... x7 etc.). If 
this does not occur, then a dose that does not conform (when sorted by dose level) should be 
combined with next closest dose and averaged.Keep doing this until we get conformance. Note that 
this relies on comparing vs x0, so x0 should always be lowest result*/ 
  
%global lsm1 maxdose contmean; 
  
/*Assign a New Dose Number (Consecutive) for Processing*/ 
 
proc sort data = &dat. out = DOSEN (keep = &trt.) nodupkey; 
 
by &trt.; 
run; 
data DOSEN; 
 
set DOSEN; 
 
DOSEN = _N_; 
run; 
data &dat.2; 
 
merge &dat. DOSEN; 
 
by &trt.; 
run; 
 
 
 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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proc glm data = &dat.2 noprint outstat=STAT_(keep = _TYPE_ DF SS where=(_TYPE_="ERROR")); 
 
class DOSEN; 
 
model &var. = DOSEN; 
 
lsmeans DOSEN / pdiff cl; 
 
output out = STAT p=LSMEAN r=resid LCL=LCI UCL=UCI STDP=STDERR; 
run; 
 
proc sort data = STAT out = STAT2 (keep = &trt. DOSEN LSMEAN LCI UCI STDERR) nodupkey; 
 
by DOSEN; 
run; 
 
/*Get Max Dose Level for Processing*/ 
proc sql noprint; 
 
select compress(put(max(DOSEN),best.)) into :MAXDOSE  
 
from STAT2; 
quit; 
%put &maxdose.; 
 
/*Get LSMEAN for Placebo/Control for Processing*/ 
proc sql noprint; 
 
select compress(put(LSMEAN,best.)) into :CONTMEAN  
 
from STAT2(where=(DOSEN=1)); 
quit; 
%put &contmean.; 
 
/*Get Number of Observations and Merge Back on to GLM Output*/ 
proc univariate data = STAT noprint; 
 
by DOSEN; 
 
var RESID; 
 
output out = N N=N; 
run; 
 
data STAT_2 (drop = _TYPE_ SS); 
 
set STAT_; 
 
if nmiss(DF,SS) = 0 then MSE = SS/DF; 
 
do DOSEN = 1 to &maxdose.; 
 
output; 
 
end; 
run; 
 
data STAT2; 
 
merge STAT2(in=a) N STAT_2; 
 
by DOSEN; 
 
if a; 
run; 
 
 
/*Get Dose Level 1 LSMean for Checking Whether Each Dose >= Dose1*/ 
proc sql noprint; 
 
select compress(put(LSMEAN,best.)) into :LSM1  


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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from STAT2(where=(DOSEN=1)); 
quit; 
%put &lsm1.; 
 
/*Output All LSMEANS and N for All Dose Levels Present*/ 
%macro VAR(var = ); 
proc sort data = STAT2; 
 
by MSE DF; 
run; 
proc transpose data = STAT2 out = STAT2_&var.(drop = _NAME_) prefix=&var.; 
 
by MSE DF; 
 
id DOSEN; 
 
var &var.; 
run; 
%mend VAR; 
%VAR(var = LSMEAN); %VAR(var = N); 
 
data STAT3(drop = _LABEL_); 
 
merge STAT2_LSMEAN STAT2_N; 
run; 
 
data STAT4; 
 
set STAT3; 
 
array LSMEAN(&maxdose.); array N(&maxdose.); array DIFF(&maxdose.); array 
DENOM(&maxdose.);  
 
array T(&maxdose.); 
 
CONTROL = LSMEAN(1); 
 
do j = 1 to &maxdose.-1; 
 
 
if LSMEAN(j) > LSMEAN(j+1) then do; 
 
 
 
EN = N(j+1); 
 
 
 
EMEAN = LSMEAN(j+1); 
 
 
 
NMEAN = N(j+1)*LSMEAN(j+1); 
 
 
 
do k = j to 1 by -1; 
 
 
 
 
if EMEAN < LSMEAN(k) then do; 
 
 
 
 
 
EN = EN + N(k); 
 
 
 
 
 
NMEAN = NMEAN + N(k)*LSMEAN(k); 
 
 
 
 
 
*EMEAN = (EMEAN*N(k)/(EN)) + ((N(k)*LSMEAN(k))/(EN)); 
 
 
 
 
 
EMEAN = NMEAN/EN; 
 
 
 
 
 
do r = k to j+1; 
 
 
 
 
 
 
LSMEAN(r) = EMEAN; 
 
 
 
 
 
end; 
 
 
 
 
end; 
 
 
 
end; 
 
 
end; 
 
end; 
 
do j = 2 to &maxdose.; 
 
 
DIFF(j) = (LSMEAN(j)-CONTROL); 
 
 
DENOM(j) = ((MSE*((1/N(j))+(1/N(1))))**0.5); 
 
 
T(j) = DIFF(j)/DENOM(j); 
 
end; 
run; 


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 62 of 64 
 
data STAT5 (drop = EMEAN EN MSE DF j k r DIFF: DENOM:); 
 
set STAT4; 
 
array LSMEAN(&maxdose.); array T(&maxdose.); array p(&maxdose.);  
 
do i = 2 to &maxdose.; 
 
 
p(i) = 1 - probmc("Williams",T(i),.,DF,i-1); 
 
end; 
run; 
 
 
%macro OUT(var2=, dat = , out = ); 
data &out.(keep = DOSE:); 
 
set &dat.; 
 
%do i = 1 %to &maxdose.;  
 
 
rename &var2.&i.=DOSE&i.; 
 
%end; 
run; 
%mend OUT; 
 
%OUT(var2 = LSMEAN, dat = STAT3, out = LSMEAN1); 
%OUT(var2 = LSMEAN, dat = STAT5, out = LSMEAN2);  
%OUT(var2 = N, dat = STAT5, out = N);  
%OUT(var2 = T, dat = STAT5, out = T);  
%OUT(var2 = P, dat = STAT5, out = P); 
 
data WILLIAMS (keep = TYPE DOSE1-DOSE&maxdose.); 
 
retain TYPE DOSE1-DOSE&maxdose.; 
 
length TYPE $50.; 
 
set LSMEAN1(in=a) LSMEAN2(in=b) N(in=c) T(in=d) P(in=e); 
 
if a then TYPE = "LSMeans (Original)"; 
 
if b then TYPE = "MLE"; 
 
if c then TYPE = "No. Obs"; 
 
if d then TYPE = "Williams T Statistic"; 
 
if e then TYPE = "P-Value"; 
run; 
%mend WILLIAMS; 
 
 
 
 
 
 


Statistical Analysis Plan for Interventional Studies 
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Page 63 of 64 
 
2) Sample Code for Efficacy Analysis : Schirmer test I in case of presence of many missing data 
 
For RMM, if SAS mixed model is used, the sample SAS codes will be like the following: 
 
PROC MIXED DATA=SCHIRMERI;  
CLASS usubjid TRT01P visit;  
MODEL chg = TRT01P TRT01P * visit /ddfm=kr;  
repeated visit / sub = usubjid type = un;  
lsmeans TRT01P / cl diff at time = Week4;  
  
3) Sample Code for Exploratory sensitivity Efficacy Analysis : Schirmer test I  
 
 
PROC MIXED DATA=SCHIRMERI;  
CLASS STRATA TRT01P ;  
MODEL chg = TRT01P STRATA STRATA*TRT01P /solution; 
lsmeans STRATA*TRT01P / pdiff cl  at time=Week4; 
 
 
4) Sample Code for Efficacy Analysis : IDEEL and EQ-5D-3L 
 
PROC MIXED DATA=IDEEL;  
CLASS usubjid TRT01P visit;  
MODEL chg = TRT01P  visit TRT01P * visit /ddfm=kr;  
repeated visit / sub = usubjid type = un;  
lsmeans TRT01P*visit / cl pdiff; 
lsmeans TRT01P / cl pdiff; 
 
 
5) Sample Code for Efficacy Analysis:  PGIC 
 
A Wilcoxon rank sum test will be used for PGIC. An example of the SAS code to perform this analysis 
is reported below. 
 
************************************************************************  
* SAS Code: Wilcoxon 
* Variables in the model:   
* aval = value of PGIC 
*trt01pn = treatment planned 
***********************************************************************; 
 
PROC NPAR1WAY  DATA=PGIC WILCOXON; 
WHERE TRT01P  in ( “Placebo” “Dose 1”); 
CLASS TRT01P; 
VAR AVAL; 
RUN; 
 
6) Sample Code for Efficacy Analysis:  Proportion of subjects with worsening in SANDE and/or 
NEI score>=50% 
 
************************************************************************  


Statistical Analysis Plan for Interventional Studies 
Dompé farmaceutici S.p.A - Protocol No.: NGF0118 
 
 
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Page 64 of 64 
* SAS Code: Wilcoxon 
* Variables in the model:   
* aval = worsening in symptom scores (SANDE) and/or NEI score >= 50%  : yes or No 
*trt01pn = treatment planned 
***********************************************************************; 
 
PROC FREQ DATA=Prop;  
WHERE TRT01P  in ( “Placebo” “Dose 1”); 
            TABLES trt01p*aval / chisq;  
             RUN;