A 4-Week, Phase II, Multicenter, Randomized, Double-Masked, Vehicle-Controlled, Parallel Group Study With 4 Weeks of Follow-Up to Evaluate Safety and Efficacy of a New Formulation of Recombinant Human Nerve Growth Factor (rhNGF) Eye Drop Solution at Two Different Concentrations in Patients With Dry Eye Disease
Phase: PHASE2
Conditions: Dry Eye Disease
Sponsor: Dompé Farmaceutici S.p.A

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
          C LI NI C A L T RI A L  
P R O T O C O L  
 
 
F ull Title:  
A 4 -Wee k, P hase II, M ultice nter, Ra n d o mize d, D o u ble -Mas ke d, Ve hicl e - 
C o ntr olle d, Parallel Gr o u p St u d y Wit h 4 Wee ks of F oll o w -U p t o E val uate 
Safet y a n d Efficac y of a ne w f or m ulati o n of Rec o m bi na nt H u ma n Ner ve 
Gr o wt h 
Fact or (r h N G F) 
E y e 
Dr o p 
S ol uti o n 
at t w o 
d iffere nt 
C o nce ntrati o ns i n patie nts wit h Dr y E ye Diseas e  
 
 
Tri al N a me:  
R E D U C O  
 
Tri al N u m ber:  
N G F 0 1 2 3  
 
C o m p o u n d N a me: R ec o m bi na nt H u ma n N er ve G r o wt h F act or (r h N G F)  
 
 
Re g ul at or y A ge nc y I de ntifier N u m bers:  
E U -C T n u m ber: 2 0 2 3 -5 0 7 5 6 1 -2 6 -0 0  
 
 
I N D n u m ber: 1 1 5 8 9 2 
 
I n vesti g ati o n al Pr o d uct:  
Rec o m bi na nt H u ma n Ner ve Gr o wt h Fact or 
(r h N G F)  
 m g/ vial i n a 
 
pre parati o n  
 
Tri al p h ase : 
II 
 
Versi o n : 
     FI N A L  3. 0  
 
A me n d me nt :  
Fi n al 2. 0  
 
A me n d me nt Sc o pe:  
Gl o b al  
 
S p o ns or A p pr o v al D ate:  
1 1 /Marc h / 2 0 24  
 
 
 
S T A T E M E N T O F C O N FI D E N TI A LI T Y  
I nf or m ati o n i n t his pr ot oc ol a n d acc o m p a nyi n g d oc u me nts c o nt ai ns privile ge d or c o nfi de nti al 
i nf or m ati o n t h at is t he pr o perty of D o m pé f ar m ace utici S. p. A. It is u n derst o o d t h at t he i nf or m ati o n 
will n ot be use d, div ul ge d, or p u blis he d wit h o ut pri or writte n c o nse nt of D o m pé f ar m ace utici S. p. A., 
exce pt t o t he exte nt s uc h di scl os ure is re q uire d by a p plic a ble l a ws a n d re g ul ati o ns. 
 
 
 
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 2  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
C O N T A C T I N F O R M A TI O N  
 
S P O N S O R  
D o m pé far m ace utici S. p. A.,  
Via Sa nta L ucia 6 - 2 0 1 2 2 Mila n Ital y  
P h o ne: + 3 9. 0 2. 5 8 3 8 3 1  
Fa x: + 3 9. 0 2. 5 8 3 8 3 3 2 4  
S p o ns or Me dic al E x pert  
S p o ns or Me dic al M o nit or  
S p o ns or De vel o p me nt Direct or  
S p o ns or Cli nic al Tri al M a n a ger  
 
 
 
S p o ns or C o or di n ati n g Pri nci p al 
I n vesti g at or 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 3  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
S p o ns or S A E Re p orti n g  
 
 
 
 
 
 
 
C R O S afet y Re p orti n g  
 
 
 
 
S p o ns or Q u alifie d Pers o n  
 
 
 
 
 
P P D P har mac o vi gila nce  
2 4 -H o ur Safet y H otli ne: + 4 4 1 2 2 3 3 7 4 2 4 0  
Safet y H otli ne Fa x: + 4 4 1 2 2 3 3 7 4 1 0 2  
E mail: 
m ailt o: E M E A A SI A S afet y Ce ntr al. S M @ p p d.c o m  
  
 
P P D
P P D

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 4 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
AMENDMENT DETAILS 
History of Amendments 
A total of 1 prior global amendment has occurred as shown in the table below: 
 
Document 
Sponsor Approval Date 
(dd/mmm/yyyy) 
Approximate {(#/%)} Enrolled 
Amendment 1 
16 November 2023 
0% enrolled globally 
Original Protocol 
13 September 2023 
0 
 
History of Amendments 
 
The table below provides an overview of the current amendment to NGF0123 – REDUCO Protocol 
Final v. 3.0, Amendment 2.0 dated 11 March 2024. 
 
Amendment Number: 
2 
Approximate {%/#} Enrolled: 
6%/ 18 patients.  
 
Reason(s) 
for 
Amendment: 
Primary: 
Regulatory agency (AIFA) 
request to amend. 
Secondary: 
Other (clarification of language) 
 
Summary of Changes in the Current Amendment (Amendment 2.0): 
 
 
Section # and Name 
 
Description of Change 
 
Brief Rationale for 
Change 
1.1 Synopsis, 
Design 
 
The following text was added: 
‘…and will receive commercially available 
preservative free AT, TID, provided by the 
Sponsor.’ 
For further clarification 
of study procedures. 
Summary of the Amendment: 
The primary purpose of the current amendment is to update the 
protocol for study NGF0123 reflecting AIFA’s feedback on 
clarifying an exclusion criterion, update of a repealed Directive, 
rationale for placebo-controlled trial design, and to elaborate 
further on the selection of IMP dosing. 
Is this amendment likely to 
have a substantial impact on 
safety or rights of the 
participants, or 
on the reliability and 
robustness of the data 
generated in the clinical 
trial? 
 No 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 5  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
1. 1  S y n o psis,  
Criteria f or 
I ncl usi o n/ E xcl usi o n 
 
 
T he e xcl usi o n criteri o n ar o u n d oc ular s ur ger y 
was f urt her clarifie d b y a d di n g t he f oll o wi n g 
te xt (e xcl usi o n criteri o n # 4): 
‘4. P ossi bility of t he nee d f or Oc ul ar s ur gery 
at t he ti me of i ncl usi o n i n t he st u dy or 
a ntici p ate d oc ul ar s ur gery ex pecte d d uri n g t he 
p artici p ati o n i n t he st u dy .’ 
F oll o wi n g t he re q uest 
b y AI F A  
1. 2 Sc he d ule of 
Acti vities, Ta ble 1 . 
Sc he d ule of Acti vities 
Pla n ne d D uri n g t he 
Differe nt Visits  
 
 
T he ta ble was m o difie d t o i ncl u de a circ u mfle x 
acce nt a gai nst  
 a n d t he le ge n d of t he 
ta ble was m o difie d t o a d d t he f oll o wi n g 
acc o m pa n yi n g te xt:  
‘ ^ 
 will be a d mi nistere d t o all s u bjects 
b ut c o m plete d o nly by t h ose t h at eit her h ave 
 or h ave fille d t his f or m bef ore.’ 
F or f urt her clarificati o n 
of st u d y pr oce d ures.  
2.  I ntr o d ucti o n 
 
T he re peale d Directi ve was delete d:  
‘Directive 2 0 0 1/ 2 0/ E C of t he E ur o pe a n 
P arli a me nt a n d …’  
    F oll o wi n g t he re q uest 
b y AI F A  
4. 2 Rati o nale f or Trial 
Desi g n  
 
T he f oll o wi n g te xt was a d de d:  
‘ …t o pr ovi de t he mi ni m u m a m o u nt of 
l u bric ati o n nee de d i n D E D p atie nts w hile 
e ns uri n g a p pr o pri ate w as h -o ut fr o m a ny ot her 
previ o us t o pic al tre at me nt effect .’ 
F or f urt her clarificati o n 
of st u d y desi g n.  
4. 2 Rati o nale f or Trial 
Desi g n  
 
T he f oll o wi n g te xt was a d de d t o clarif y t he 
rati o nale f or a place b o-c o ntr olle d trial desi g n:  
‘ …I n a d diti o n t o testi n g t he t w o 
c o nce ntr ati o ns of r h N G F (  mc g/ m L a n d 
mc g/ m L), t his st u dy i nc or p or ates a ve hicle 
c o ntr ol gr o u p. T he ve hicle c o ntr ol gr o u p h as 
bee n i nc or p or ate d i n t his st u dy i n or der t o 
de m o nstr ate effic acy of o ur ne w f or m ul ati o n i n 
i m pr ovi n g sy m pt o ms a n d si g ns i n p atie nts wit h 
dry eye, a dise ase w here it is k n o w n t h at a 
relev a nt pl ace b o effect m ay be ex pecte d a n d 
t he prese nce of a n i n active c o ntr ol gr o u p 
f av ors t he c orrect i nter pret ati o n of a ny 
tre at me nt effect.’ 
F oll o wi n g t he re q uest 
b y AI F A  
5. 2 E xcl usi o n Criteria  
 
T he e xcl usi o n criteri o n ar o u n d oc ular s ur ger y 
was f urt her clarifie d b y a d di n g t he f oll o wi n g 
te xt (e xcl usi o n criteri o n # 4): 
‘4. P ossi bility of t he nee d f or oc ul ar s ur gery at 
t he ti me of i ncl usi o n i n t he st u dy or a ntici p ate d 
oc ul ar s ur gery ex pecte d d uri n g t he 
p artici p ati o n i n t he st u dy .’ 
F oll o wi n g t he re q uest 
b y AI F A  
5. 4 Scree n Fail ures  
T he f oll o wi n g te xt was a d de d t o clarif y re -
scree ni n g criteria: 
‘P atie nts m ay be re -scree ne d o n a c ase-by -c ase 
b asis after revie wi n g it wit h t he S p o ns or.’  
 F or f urt her clarificati o n of 
st u d y pr oce d ures. 
C CI
C CI
C
C
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 7  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
ti mes a da y ( TI D) (a p pr o xi matel y e ver y 6 
h o urs), sta rti n g o n D ay 1 ( B aseli ne visit) a n d 
c o nti n ue t he tre at me nt i n t he m or ni n g w he n 
t hey w ake u p, f or t he ne xt 2 wee ks. De pe n di n g 
o n t he ti me of t he s u bject’s B aseli ne visit, it is 
re as o n a ble a n d p ossi ble t h at all d oses m ay n ot 
be a d mi nistere d o n t his d ay.’  
7. 1. 1 Criteria f or 
Per ma ne nt 
Disc o nti n uati o n of 
Trial I nter ve nti o n  
 
Criteri o n # 2 was a me n de d t o i ncl u de t he 
f oll o wi n g te xt (a d de d te xt i n Italic): 
‘ 2) W orse ni n g of t he cli nical c o n diti o n t hat 
re q uires treat me nt disc o nti n uati o n per 
p h ysicia n decisi o n or oc ul ar s ur gery .’ 
 T o ali g n wit h ot her 
si milar g ui da nce 
pr o vi de d b y AI F A  
7. 1. 1 Criteria f or 
Per ma ne nt 
Disc o nti n uati o n of 
Trial I nter ve nti o n  
T he f oll o w i n g te xt was a d de d: 
‘ …a n d will receive preserv ative free A T, TI D, 
pr ovi de d by t he S p o ns or .’ 
F or f urt her clarificati o n 
of st u d y pr oce d ures  
   8. 2 Trial Visits a n d     
F oll o w -U p Assess me nts  
 Defi niti o n of E n d of Trial ( E o T)/ E n d of St u d y 
( E O S) was a me n de d t o re m o ve a m bi g uit y: 
‘E n d of Tri al ( E o T)/ E n d of St u d y ( E O S): as 
per article 2 ( 2 6)  of t he E ur o pea n Cli nical Trial 
Re g ulati o n ( C T R), E o T/ E n d of St u d y ( E O S) is 
t he last visit of t he last patie nt gl o ball y  or a l ater 
p oi nt as re q uire d by st u dy activities . 
 F oll o wi n g re q uest b y AI F A  
8. 3 Assess me nts a n d 
Cli nical Defi niti o ns,  
Ta ble 6. List of 
Assess me nts  
    
T he f oll o wi n g te xt was a d de d u n der 
 
‘ …T his f or m will be a d mi nistere d t o al l 
s u bjects b ut c o m plete d o nly by t h ose t h at 
eit her h ave  
 or h ave fille d t his f or m 
bef ore .’ 
 F or f urt her clarificati o n 
of st u d y pr oce d ures  
1 1. 1   Re g ulat or y a n d 
Et hical C o nsi derati o ns  
 
T he re peale d Directi ve was delete d u n der t he 
secti o n o n E ur o pe:  
‘ … a n d re pe ali n g  Directive 2 0 0 1/ 2 0/ E C, 
w here a p plic a ble ’ 
F oll o wi n g t he re q uest 
b y AI F A  
1 1. 1 1 Seri o us 
Breac hes Ma na ge me nt  
 
T his secti o n was a me n de d t o reflect t he 
f oll o wi n g c ha n ges: 
‘Pr ocess ( as defi ne d u n der art. 5 2 of E ur o pe a n 
Re g ul ati o n 5 3 6/ 2 0 1 4):  
I nstit uti o ns, C R O, a n d i nvesti g at ors t h at are 
i nv olve d i n t he cli nic al tri al m a n a ge me nt are 
o bli ge d t o n otify t he S p o ns or a b o ut a ny 
Seri o us Bre ac hes a n d s us pecte d Seri o us 
Bre ac h wit hi n 2 4 h o urs fr o m t he i de ntific ati o n 
of s uc h Seri o us Bre ac h at t he f oll o wi n g  e m ail 
a d dress: seri o us bre ac hes. gc p @ d o m pe.c o m  
 
T he S p o ns or will m a n a ge t he eve nt acc or di n g 
t o t he i nter n al pr ocess f or t he m a n a ge me nt a n d 
F or f urt her clari ficati o n 
of st u d y pr oce d ures  
C CI
C CI
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 8 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
notification of the relevant competent 
authority.  
Process (as defined under art. 52 of European 
Regulation 536/2014): 
Institutions, CRO, and investigators involved 
in the clinical trial management must notify the 
Sponsor about any Serious Breaches and 
suspected Serious Breach within 24 hours from 
the identification of such Serious Breach.  
If not otherwise specified in relevant study 
plans, manuals and agreements with the 
contracted CRO, the Sponsor will manage the 
event according to the internal process for the 
management and notification of the relevant 
competent authority.’ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 9 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
Table of Contents 
 
CONTACT INFORMATION 
2 
AMENDMENT DETAILS 
4 
LIST OF TABLES 
12 
LIST OF ABBREVIATIONS/ ACRONYMS/ DEFINITIONS OF TERMS 
13 
1 
PROTOCOL SUMMARY 
16 
1.1 
SYNOPSIS 
16 
1.2 
SCHEDULE OF ACTIVITIES 
33 
1.3 
SCHEMA 
36 
2 
INTRODUCTION 
37 
2.1 
PURPOSE OF TRIAL 
37 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL MEDICINAL PRODUCT 37 
2.3 
RELEVANT NON-CLINICAL STUDIES 
38 
2.3.1 
Efficacy Studies 
38 
2.3.2 
Toxicology Studies 
38 
2.4 
PHARMACOKINETICS AND PRODUCT METABOLISM 
39 
2.4.1 
Biodistribution in Non-clinical Studies 
39 
2.4.2 
Clinical Pharmacokinetics 
39 
2.4.3 
Metabolism 
41 
2.5 
RELEVANT CLINICAL TRIALS 
41 
2.6 
DISEASE REVIEW AND TRIAL RATIONALE 
42 
2.6.1 
Alternative treatments 
42 
2.7 
SUMMARY OF BENEFITS AND RISK 
43 
3 
TRIAL OBJECTIVES AND ENDPOINTS 
45 
3.1 
TRIAL OBJECTIVES, ENDPOINTS AND ESTIMANDS 
46 
3.2 
PRIMARY AND KEY SECONDARY ESTIMANDS 
49 
3.2.1 
Primary Estimand 
49 
3.2.2 
Key Secondary Estimands 
49 
3.3 
ASSESSMENT OF EFFICACY 
51 
4 
TRIAL DESIGN 
52 
4.1 
DESCRIPTION OF TRIAL DESIGN 
52 
4.2 
RATIONALE FOR TRIAL DESIGN 
53 
5 
TRIAL POPULATION 
54 
5.1 
INCLUSION CRITERIA 
54 
5.2 
EXCLUSION CRITERIA 
55 
5.3 
SELECTION OF STUDY EYE 
56 
5.4 
SCREEN FAILURES 
56 
5.5 
LIFESTYLE CONSIDERATIONS 
56 
5.5.1 
Meals and Dietary Restriction 
57 
5.5.2 
Caffeine, Alcohol, Tobacco, and Other Habits 
57 
5.5.3 
Physical Activity 
57 
5.5.4 
Other Activities 
57 
6 
TRIAL INTERVENTION AND CONCOMITANT THERAPY 
58 
6.1 
DESCRIPTION OF TRIAL INTERVENTION, DOSING AND ADMINISTRATION 
58 
6.1.1 
Non-Investigational Medicinal Product 
59 
6.1.2 
Trial Intervention Dose Modification 
59 
6.2 
RATIONALE FOR TRIAL INTERVENTION 
59 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 10 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
6.3 
PREPARATION, HANDLING, STORAGE AND ACCOUNTABILITY 
60 
6.4 
PARTICIPANT ASSIGNMENT, RANDOMISATION AND MASKING 
63 
6.4.1 
Participant Assignment 
63 
6.4.2 
Randomization 
63 
6.4.3 
Masking and Unmasking Procedure 
64 
6.5 
TRIAL INTERVENTION COMPLIANCE 
65 
6.6 
CONCOMITANT THERAPY 
65 
6.6.1 
Prohibited Concomitant Therapy 
65 
6.6.2 
Permitted Concomitant Therapy 
66 
6.6.3 
Rescue Therapy 
66 
6.6.4 
Other Therapy 
66 
7 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT WITHDRAWAL 
FROM TRIAL 
66 
7.1 
CRITERIA FOR DISCONTINUATION OF TRIAL INTERVENTION 
67 
7.1.1 
Criteria for Permanent Discontinuation of Trial Intervention 
67 
7.1.2 
Temporary Discontinuation or Interruption of Trial Intervention 
68 
7.1.3 
Rechallenge 
68 
7.2 
PARTICIPANT WITHDRAWAL FROM THE TRIAL 
68 
7.3 
LOST TO FOLLOW-UP 
68 
7.4 
TRIAL STOPPING RULES 
68 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
69 
8.1 
SCREENING/BASELINE 
69 
8.2 
TRIAL VISITS AND FOLLOW-UP ASSESSMENTS 
71 
8.3 
ASSESSMENTS AND CLINICAL DEFINITIONS 
73 
8.4 
PHARMACOKINETICS 
75 
8.5 
GENETICS 
75 
8.6 
BIOMARKERS 
75 
8.7 
IMMUNOGENICITY ASSESSMENT 
75 
9 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
75 
9.1 
DEFINITIONS 
75 
9.1.1 
Adverse Event 
75 
9.1.2 
Adverse Drug Reaction 
75 
9.1.3 
Serious Adverse Event 
76 
9.1.4 
Unexpected Adverse Events 
76 
9.1.5 
Suspected Unexpected Serious Adverse Reaction 
77 
9.1.6 
Adverse Events (AEs) of Special Interest (Sight-threatening Events) 
77 
9.2 
MONITORING AND REPORTING ADVERSE EVENTS 
77 
9.3 
RECORDING ADVERSE EVENTS 
78 
9.3.1 
Follow-Up of Patients with Adverse Events 
78 
9.3.2 
Relationship of AEs to the Investigational Medicinal Product 
79 
9.3.3 
Severity of AEs 
80 
9.4 
SERIOUS ADVERSE EVENT REPORTING 
80 
9.4.1 
Reporting Procedure for Investigators 
80 
9.4.2 
Conditions that should not be reported as Serious Adverse Events 
82 
9.4.3 
Adverse Events Exemption 
82 
9.4.4 
Reporting Procedure to IRB/IEC and to Regulatory Authorities 
82 
9.4.5 
Periodical Reporting to Regulatory Authorities 
83 
9.5 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY 
84 
9.6 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
84 
9.7 
OVERDOSE 
84 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 11 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
10 
STATISTICS 
85 
10.1 
SAMPLE SIZE 
85 
10.2 
OVERVIEW OF PLANNED STATISTICAL ANALYSIS 
85 
10.3 
INTERIM ANALYSIS 
85 
10.4 
PATIENT POPULATION 
86 
10.4.1 
Screened Population (SCR) 
86 
10.4.2 
Enrolled Population (ENR) 
86 
10.4.3 
Randomized Population (RND) 
86 
10.4.4 
Safety Population (SAF) 
86 
10.4.5 
Full Analysis Set (FAS) 
86 
10.4.6 
Per Protocol Population (PP) 
86 
10.5 
ESTIMANDS 
87 
10.6 
STATISTICAL METHODOLOGY 
87 
10.6.1 
Descriptive Statistics 
87 
10.6.2 
Primary Analysis of Efficacy Variables 
88 
10.6.3 
Sensitivity and Supportive Analyses 
89 
10.6.4 
Secondary and Exploratory Analysis 
91 
10.6.5 
Analysis of Safety Variables 
91 
10.6.6 
Missing Data 
92 
10.6.7 
Intermediate Analyses for the DMC 
92 
10.6.8 
Specification of Subgroups for Analysis 
92 
11 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND TRIAL OVERSIGHT
 
92 
11.1 
REGULATORY AND ETHICAL CONSIDERATIONS 
92 
11.2 
COMMITTEES 
93 
11.3 
INFORMED CONSENT PROCESS 
93 
11.4 
DATA PROTECTION AND CONFIDENTIALITY 
94 
11.5 
EARLY SITE CLOSURE OR TRIAL TERMINATION 
94 
11.6 
QUALITY TOLERANCE LIMITS 
94 
11.7 
DATA QUALITY ASSURANCE 
94 
11.8 
DISSEMINATION OF CLINICAL TRIAL DATA AND PUBLICATION POLICY 
94 
11.9 
MONITORING ACTIVITIES 
95 
11.10 COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 96 
11.11 SERIOUS BREACHES MANAGEMENT 
96 
12 
DATA HANDLING AND RECORD KEEPING 
97 
12.1 
SOURCE DOCUMENTS AND CASE REPORT FORMS 
97 
12.1.1 
Systems Validation 
98 
12.2 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING THE 
TRIAL 98 
12.3 
ESSENTIAL DOCUMENT RETENTION 
99 
12.4 
LONG-TERM SAMPLE RETENTION 
99 
13 
PRIOR PROTOCOL AMENDMENTS 
100 
14 
REFERENCES 
128 
15 
APPENDICES 
129 
APPENDIX 1-SPONSOR APPROVAL PAGE 
129 
APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE 
130 
 
 
 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 12 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
LIST OF TABLES 
 
Table 1: Schedule of activities planned during the different visits ............................................................................ 33 
Table 2: Summary of potential risks for the patients and mitigation strategy ......................................................... 44 
Table 3: Trial objectives and endpoints ........................................................................................................................... 46 
Table 4: Description of treatments ................................................................................................................................... 58 
Table 5: Description of NIMP ........................................................................................................................................... 59 
Table 6: List of assessments............................................................................................................................................... 73 
Table 7: Relationship of the Adverse Event to the IMP ............................................................................................... 79 
Table 8: Severity of the Adverse Event ............................................................................................................................ 80 
 
 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 2 9  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
Visit 3 - Wee k 2 ( D a y 1 3 ± 1) S T U D Y P R O D U C T PI C K -U P VI SI T  
1.  C o nc o mita nt O c ular a n d S yste mic M e dicati o ns U p date  
2.  Rec or d A Es  
3.  C hec k Patie nt Diar y  
4.  C ollect 
u se d/u n use d 
S t u d y Pr o d uct  (t o 
b e c hec ke d 
b y 
i n de pe n de nt pers o n n el), 
5.  St u d y p r o d uct d is pe nsi n g:  Patie nts will be s u p plie d wit h a 
bi wee kl y kit of St u d y P r o d uct s ufficient f or 2 wee ks of treat me nt.  
Visit 4 - Wee k 4 ( D a y 2 8 ± 1): E N D O F T R E A T M E N T VI SI T ( O R 
E A R L Y E XI T VI SI T)  
1.  C o nc o mita nt Oc ular a n d S yste mic Me dicati o ns U p date  
2.  Rec or d A Es  
3.  C hec k t he Patie nt D iar y f or t he treat me nt p eri o d. 
4.  S A N D E q uesti o n naire  
5.  
 
6.  O p ht hal mic E xa mi nati o ns:   
A.  Best -C orrecte d 
Dista nce 
Vis ual 
Ac uit y ( B C D V A) b y 
E T D R S  
B.  E xter nal Oc ul ar E xa mi nati o n  
C.  Assess NI K B U T (at selecte d ce nt ers)  
D.  Sc hir mer -I test wit h o ut a nest hesia.   
E.  Slit La m p E xa mi nati o n ( S L E) of t he a nteri or se g me nt of t he 
e ye (c or nea, c o nj u n cti va, a nteri or c h a m ber, iris, li ds a n d 
las hes)  
F.  Assess b ul bar re d n ess ( V B R 1 0)  
G.  I nstill fl u orescei n a n d wait 3 0 sec o n ds. 
H.  Assess f T B U T .  
I. 
After 2 -5 mi n utes fr o m t he ti me of fl u ores cei n i nstillati o n, 
assess t otal c or neal fl u orescei n stai ni n g sc ore ( N EI scal e, 
sc ore ra n ge 0-1 5).  
J. 
A p pl y lissa mi ne gree n .  
K.  Assess t otal c o nj u ncti val lissa mi ne gree n stai ni n g s c ore ( N EI 
scale, sc ore ra n ge 0-1 8) wit hi n 2 mi n utes of i nstillati o n of 
d ye.  
L.  P erf orm 
 e ye dr o p  
 res p o nse test 
( o nl y i n patie nts wit h 
)  
7.  C ollect use d a n d u n use d S t u d y P r o d ucts (t o be c hec ke d b y 
i n de pe n de nt pers o n n el) 
8.  Retrie ve Patie nt Diar y f or t he treat me nt peri o d . 
9.  Dis pe nse preser vati ve free artifici al tears ( A T) e ye dr o ps t o be 
a d mi nistere d 3 ti mes a d a y . 
1 0.  Deli ver i nstr ucti o ns t o S u bject.  
1 1.  Dis pe nse t he P atie nt Di ar y t o rec or d a d h ere n ce t o t he pres er vati ve 
free artificial tears  ( A T) e ye dr o ps d uri n g t he F oll o w -U p  p eri o d, 
a n y ne w or c ha n g es i n c o nc o mita nt me dicati o ns, a n y u n us ual 
me dical c o n diti o n . 
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 3 7  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
2  
I N T R O D U C TI O N 
 
T he trial will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d its a me n d me nts, i n c o m plia nce wit h 
G C P a n d t he a p plica ble re g ulat or y re q uire me nts i n U S A a n d E ur o pe as i n dicate d i n t he I C H -
G C P E 6 ( R 2) g ui deli ne f or g o o d cli nical practice a n d t h e ot her rel e va nt g ui deli nes f or t h e 
c o n d uct of cli nical tri als . T he cli nical st u d y is re g ulate d b y t he E U C T R Re g ulati o n n o. 
5 3 6/ 2 0 1 4 . 
 
Rec o m bi na nt h u ma n N G F (r h N G F) is t he acti v e pri nci ple of O X E R V A T E ® 0. 0 0 2 % (
 
mc g/ m L) r h N G F o p ht hal mic s ol uti o n a mar kete d me dic i nal pr o d uct alrea d y a p pr o ve d f or 
cli nical use b y t he E M A i n J ul y 2 0 1 7 f or treat me nt of m o derate -t o-se vere ne ur otr o p hi c 
keratitis ( N K), a n d b y t h e F D A i n A u g ust 2 0 1 8 f or t he treat me nt of N K. O ver 1 6 0 0 0 N K 
patie nts ha ve bee n alr ea d y e x p ose d t o O X E R V A T E ® 0. 0 0 2 % r h N G F e y e dr o p f or m ulati o n 
at 
 mc g/ m L at t he rec o m me n de d d ose re gi me n of 1 dr o p/ e y e e ver y 2 h ( 6 ti mes a da y wit hi n 
a 1 2-h o ur peri o d) f or 8 w ee ks ( O X E R V A T E ® U. S. Pac ka ge I nsert). A s u m mar y of t he m ost 
rele va nt cli nical o bs er vati o ns is i ncl u de d i n t his secti o n a n d a list of selecte d scie ntifi c 
refere nces is pr o vi de d at t he e n d of t his d oc u me nt §1 4 .  
 
2. 1  
P U R P O S E O F T RI A L  
 
T he ai m of t he st u d y is t o i n vesti gate t he safet y a n d t he efficac y of a ne w o p ht hal mic 
f or m ulati o n (e ye dr o ps) of t w o  
 c o nce ntrati o ns of rec o m bi na nt h u ma n ner ve gr o wt h 
fact or (r h N G F)  a n d 
 mc g/ m L i n patie nts wit h dr y e ye. T he tr eat me nt is 4 wee ks lo n g a n d 
t he pri mar y e n d p oi nt  is efficac y i n i m pr o vi n g dr y e ye s y m pt o ms, meas ure d 4 wee ks after t he 
c o m pleti o n of t he st u d y treat me nt ( wee k 8).  
 
2. 2  
N A M E A N D D E S C RI P TI O N O F T H E I N V E S TI G A TI O N A L 
M E DI CI N A L 
P R O D U C T  
 
Rec o m bi na nt h N G F, t he acti ve pri n ci ple, has t h e s a me se q u e nce of n ati ve h N G F. T h e c G M P 
gra de i n vesti gati o nal me dici nal pr o d uct (I M P) c o nsists of a  
 pr o d uct c o m prisi n g 
rec o m bi na nt h u m a n ner ve gr o wt h fact or (r h N G F, 
 mc g/ vial), 
 
diss ol ve d i n 1 m L (I M P 2) or 2 m L (I M P 1) of a dil ue nt c o ntai ni n g 
 T he ve hicle s ol uti o n c o ntai ns t he 
sa me 
 pre p arati o n wit h o ut r h N G F, a n d it is diss ol ve d i n 1 m L or 2 m L  of t he sa me 
dil ue nt t o e ns ure t he st u d y mas ki n g. T he rec o nstit uti o n of t he  
 pr o d uct wit h t he 
dil ue nt yiel ds i n all cases a sterile a q ue o us s ol uti o n s uita ble f or o p ht hal mic use (e ye dr o ps).  
F or m ore i nf or mati o n see § 6. 1 . 
T he ve hicle s ol uti o n is use d d uri n g t he R u n -I n peri o d b y all eli gi ble patie nts f or 1 2± 2 da ys, 
as descri be d i n § 6 , a n d t he sa me ve hicle is a d mi nistere d t o t he I M P ( ve hicle) gr o u p f or 4 
wee ks bet w ee n visit 2 a n d visit 4.  I M P 1 is t he o p ht hal mic s ol uti o n c o ntai ni n g  mc g/ m L of 
r h N G F w hile I M P 2 is t he o p ht hal mic s ol uti o n c o ntai ni n g 
 mc g/ m L of r h N G F. T hes e 
s ol uti o ns (a n d t he c o m p o ne nts) are i n dicat e d i n t his st u d y wit h t he ge neral na me of St u d y 
Pr o d uct(s).  
 
C
CI
C
C CI
C
C
C
CI
C CI
C
C CI
C CI
C CI
C CI
C CI
C CI
C
C
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 3 8  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
2. 3  
R E L E V A N T N O N -C LI NI C A L S T U DI E S  
 
N o ncli nical  st u dies were perf or m e d t o assess t he safet y a n d effi cac y of t he pr o p ose d n e w 
o p ht hal mic f or m ulati o n of r h N G F a n d t he ve hicle.  
 
2. 3. 1  Effic ac y St u dies  
 
T he effi cac y of t he ne w f or m ulati o n of r h N G F was i n vesti gate d i n a m o use m o del of 
 (
 
m o del of 
). T h e res ults s h o we d 
 effic ac y of t he ne w f or m ulati o n of r h N G F e y e dr o ps a n d t he refere nce o ne. T he 
t o pical o p ht hal mic a d mi nistrati o n of r h N G F 
 mc g/ m L ne w f or m ulati o n was well t olerate d 
i n t his m o del ( 4 e ye dr o ps / da y f or 1 0 da ys) wit h n o alterati o ns i n c or neal se nsiti vit y or 
e pit helial i nte grit y i n treate d mice.  
 
2. 3. 2  T o xic ol o g y St u dies  
 
T he oc ular t olera nce a n d p ote ntial t o xicit y of t he ne w f or m ulati o n c o ntai ni n g t he test ite m 
r h N G F (rec o m bi na nt h u ma n ner ve gr o wt h fact or) a n d t he ne w e xci pie nt,  
 was 
assesse d f oll o wi n g dail y a d mi nistrati o ns b y t he oc ular t o pical r o ute (e ye dr o ps, 3 ti mes a da y 
i n b ot h e yes, 4-h o ur a part) f or at least 1 3 wee ks i n t he Ne w -Zeal a n d W hite ra b bits a n d t he 
re versi bilit y of a n y fi n di n gs was e val uate d d uri n g a 2 -wee k rec o ver y peri o d. I n a d diti o n,  a 
pr o of of e x p os ure of t he c o m p o u n ds was deter mi ne d.  
 
A ni mals were a d mi nistere d wit h r h N G F at  
 or at 
 µ g/ da y or ve hicl e ( Rec o nstit uti o n 
S ol ve nt c o ntai ni n g  t he ne w e xci pie nt  
 e y e dr o ps, t hree ti mes a da y, i n b ot h e yes f or 
at least 1 3 wee ks. T he f oll o wi n g para met ers a n d e n d p oi nts were e val u ate d: M ortalit y, cli nical 
o bser vati o ns, b o d y w ei g hts a n d b o d y wei g ht gai ns, f o o d c o ns u m pti o n, o p ht hal m ol o g y 
e val uati o n, i ncl u di n g m o difie d Mac D o nal d - S ha d d uc k e x a mi nati o n wit h detaile d o p ht hal mic 
e xa mi nati o n, t o n o metr y a n d est hesi o metr y, cli nical pat h ol o g y para meters ( he mat ol o g y a n d 
cli nical c he mistr y), pr o of of e x p os ure, or ga n 
wei g hts, 
macr osc o pic a n d 
micr osc o pic 
e xa mi nati o ns.  
 
N o r h N G F or  
 le vel was d eter mi ne d i n t he res p ecti ve a nal yze d ser u m sa m ples. T his 
lac k of s yste mic a bs or pti o n after t he t o pical oc ular a d mi nistrati o n of r h N G F was e x pecte d.  
 
D uri n g t he i n -life p hase, r h N G F, f or m ulate d i n  
 di d n ot ca use a n y m ortalit y or 
cli nical si g ns. T here were neit her test ite m -relat e d c ha n ges i n b o d y wei g ht n or i n f o o d 
c o ns u m pti o n. T here were n o r h N G F f or m ulati o n -relate d o p ht hal mic fi n di n gs f or b ot h d ose 
le vels at all e val u ate d e xa mi nati o ns or meas ure me nts d uri n g t he d osi n g p eri o d. N o o p ht hal mic 
fi n di n gs were detect e d i n t he c o ntr ol a ni mals treate d wit h t he f or m ulati o n ve hicle c o ntai ni n g 
 N o treat me nt-relate d c h a n ges i n cli nical pat h ol o g y para meters were o bser ve d. 
 
T he pat h ol o g y e v al uati o n di d n ot re veal a n y test it e m -relat e d c ha n g es i n or ga n wei g ht or t est 
ite m-relate d fi n di n gs at macr osc o pic a n d micr osc o pic e xa mi nati o ns. 
 
I n c o n cl usi o n, u n der t he st u d y e x peri me ntal c o n diti o ns, dail y oc ular t o pical a d mi nistrati o n of 
C CI
C C
C CI
C CI
C CI
C
C CI
C
C
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 3 9  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
r h N G F at  
 or 
 µ g/ d a y t o t he N e w-Z eala n d W hite ra b bit f or at least 1 3 wee ks was well 
t olerate d d uri n g t he i n-life p hase a n d di d n ot ca use cli nical si g ns, cli nical pat h ol o g y a n d or ga n 
wei g hts c ha n g es, gr oss a n d micr osc o pic fi n di n gs. As e x pecte d after oc ul ar a d mi nistrati o n b y 
e ye dr o ps, n o s yste mic e x p os ure t o r h N G F or  
 was detect e d.  
 
2. 4  
P H A R M A C O KI N E TI C S A N D P R O D U C T M E T A B O LI S M  
2. 4. 1  Bi o distri b uti o n i n N o n -cli nic al St u dies  
 
Bi o distri b uti o n st u dies after si n gle  
 a n d re peate d t o pical oc ular a d mi nistrati o n i n 
ra b bits s h o we d t h at w he n a d mi nistere d 
 r h N G F reac h e d b ot h t he reti na a n d o ptic 
ner ve a n d its u pta ke persiste d e ve n after 6 0 da ys fr o m e x p os ure, w hile usi n g e ye dr o ps, t here 
was o nl y a s h ort ti me of resi de nce a n d acc u m ul ati o n le vel, a n d a ne gli gi ble u pta ke was 
o bser ve d f or r h N G F i n b ot h reti na a n d o ptic ner ve.  
 
E ye dr o ps. A distri b uti o n st u d y was perf or me d usi n g triti u m [ 3H]r h N G F a d mi nistere d b y e y e  
dr o ps i n rats. Micr o -a ut ora di o gra p h y of t h e e yes s h o we d t hat [ 3H]r h N G F ca n reac h t he reti n a 
a n d t he o ptic ner ve i n rats. T he distri b uti o n of ra di oacti vit y i n t he e ye balls of male a n d fe mal e 
al bi n o rats was deter mi n e d, s u bjecti vel y, f oll o wi n g oc ular a d mi ni strati o n of [3H]r h N G F at 
n o mi nal d ose le vel of 0. 2 5 or 1. 0 
mc g/e y e/ d ose (act ual d ose le vels 0. 2 4 a n d 1. 3 6 
mc g/e ye/ d ose) usi n g micr o -a ut ora di o gra p h y tec h ni q ues. Tiss ues were h ar veste d at 2, 4, 8, 1 2 
a n d 2 4 h p ost -d ose. At l o w d ose, le vels were detecte d i n t he c or nea, le ns a n d sclera. At hi g h 
d ose, ra di oacti vit y was prese nt i n t he o ptic ner ve, iris, ciliar y b o d y, reti na a n d c h or oi d al beit 
at l o wer le vels t ha n i n t he sclera a n d c or nea. T he s clera a n d c or nea c o ntai ne d m o derate le vels 
at all sa m pli n g ti me.  
 
 I n t he  
 a d mi nistrati o n of r h N G F i n t he ra b bit at asce n di n g d oses, hi g h 
a m o u nts of r h N G F were meas ure d i n t he vitre o us a n d reti na at t he 1 2 0 -h s a m pli n g p oi nt. I n a 
G L P st u d y, r h N G F q u a ntificati o n i n t he ser u m a n d tiss ue bi o distri b u ti o n i n vitre o us, reti na 
a n d o ptic ner ve were carrie d o ut i n ra b bits f oll o wi n g 7  
 a d mi nistrati o ns o ver 3 
m o nt hs. T he le vel of r h N G F i n ser u m was m ostl y u n der t he l o w er li mit of q ua ntificati o n ( 
 
p g/ m L) w he n t he  
 c o nce ntrati o n was a d mi nis tere d (
 mc g/ m L) b ut r h N G F was 
meas ure d d ose -pr o p orti o nall y i n ser u m i n t he mi d a n d hi g h c o nce ntrati o n gr o u ps ( 5 0 a n d 2 5 0 
mc g/ m L). T he le vel of r h N G F i n vitre o us, o ptic ner ve a n d reti na was meas ure d wit h a cert ai n 
varia bilit y b ut rat h er d ose -pr o p orti o nall y. After t he rec o v er y peri o d, r h N G F was still 
detecta ble i n t he reti na of t he 2 5 0 mc g/ m L gr o u p.  
 
2. 4. 2  Cli nic al P h ar m ac o ki netics  
 
I n h u ma ns, p har mac o ki n etics has bee n st u die d i n p hase I ( N G F 0 1 1 2, N G F 0 1 1 7) a n d P has e II 
( N G F 0 2 1 2-R E P A R O) st u dies after e ye dr o ps a d m i nistrati o n. Mi n or c ha n ges ( n ot relat e d t o 
r h N G F d ose) were o bser ve d i n ser u m N G F val ues, b ut t he c ha n ges fr o m baseli ne were 
s p ora dic a n d vari a ble fr o m p ositi ve t o ne gati ve, t h us s u g gesti n g a n i n di vi d ual p h ysi ol o gical 
fl uct uati o n of t he nat ural basal N G F le vels rat her t ha n treat me nt - relate d a bs or pti o n of r h N G F 
e ye dr o ps.  
 
D uri n g t he N G F 0 1 1 2 st u d y i n healt h y v ol u nteers , serial bl o o d sa m ples were c ollecte d pre-
d ose a n d after r h N G F e y e dr o ps. N G F ser u m c o nce ntrati o ns were meas ure d usi n g a vali date d 
C
C
C CI
C CI
C CI
C CI
C CI
C CI
C
C CI
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 4 0  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
E LI S A m et h o d.  
 
Ser u m c o nce ntrati o ns of N G F at all bl o o d sa m pli n g ti mes f or all d ose d s u bjects were f o u n d 
n ot si g nifica ntl y differe nt fr o m basal le vels ( 3 3. 7 5 8 p g/ m L), wit h t he e xce pti o n of si x 
s u bjects. S pecificall y, N G F s er u m le vels were d etecta ble i n o ne s u bject d ose d wit h t he 
 
mc g/ m L c o nce ntrati o n, o ne s u bject d ose d wit h a 6 0 mc g/ m L c o nce ntrati o n, 2 s u bjects d ose d 
wit h 1 8 0 mc g/ m L c o nce ntrati o n, a n d t w o s u bjects u n der ve hicle.  
 
I n t hes e s u bjects wit h q u a ntifia ble ser u m le vels of N G F t he c ha n g es fr o m baseli ne ( Day -1) 
were s p ora dic a n d v arie d fr o m p ositi ve t o n e gati ve val ues t h us s u g gesti n g a n i n di vi d ual 
p h ysi ol o gical fl uct uati o n of t he basal le v els, rat her t ha n a treat me nt -relat e d a bs or pti o n. 
 
T he c o nce ntr ati o n vers us ti me pr ofiles of N G F were als o assess e d fr o m i n di vi d ual ser u m 
sa m ples of Ja pa nese s u bjects ( N G F 0 1 1 7 St u d y). I n t his st u d y vali date d E LI S A tests were use d 
f or P K meas ur e me nts. T he ori gi nal vali date d met h o d was t he sa m e a p plie d t o t he N G F 
deter mi nati o n i n ser u m sa m ples ta ke n fr o m st u dies N G F 0 1 1 2 a n d N G F 0 2 1 2 wit h a L L O Q 
< 3 2 p g/ m L . T he n e w a d diti o nal vali date d E LI S A met h o d i m pr o ve d t h e se nsiti vit y i n t he 
deter mi nati o n of N G F ser u m le vels at < 1 5 p g/ m L.  
 
I n t his st u d y fi ve s u bjects s h o we d ser u m le vels of N G F det ecta ble at Baseli ne ( Da y -1): 3 
(1 5. 0 %) i n t he r h N G F -treate d gr o u p a n d 2 ( 2 0. 0 %) i n t he ve hi cle gr o u p. Ei g ht s u bjects 
s h o we d ser u m le vels of N G F d etect a ble d uri n g t h e st u d y peri o d: 5 treate d wit h r h N G F a n d 3 
treate d wit h ve hicl e.  
 
T he st u d y N G F 0 1 1 7 als o de m o nstrate d t hat t here were n o p h ar mac o ki netics differe nces d ue 
t o et h nicit y. 
 
P har mac o ki netics para m eters w ere als o st u die d i n patie nts wit h m o derate ( Sta ge 2) a n d se vere 
( Sta ge 3) N K ( N G F 0 2 1 2). 
 
Bl o o d sa m ples were c ollecte d at se veral ti me p oi nts fr o m Baseli ne ( Da y 0) t o Wee k 8 d uri n g 
the N G F 0 2 1 2 st u d y t o deter mi ne t he P K pr ofile of r h N G F a n d t o pr o vi de data c o ncer ni n g t h e 
p ossi ble s yste mic e x p os ure of r h N G F i n patie nts wit h Sta ge 2 a n d 3 N K tr eate d wit h r h N G F 
via l ocal a p plicati o n t o t he e ye.  
 
P har mac o ki netic pr ofile of t he patie nts pa rtici pati n g de m o nstrate d t hat t here was n o 
acc u m ulati o n effect of r h N G F. M ost p atie nts ha d a n r h N G F c o nce ntr ati o n bel o w t he L L O Q 
at all meas ure d ti me p oi nts. Fi ve patie nts ( 3 patie nts i n t he r h N G F 
 mc g/ m L gr o u p a n d 2 
patie nts i n t he r h N G F 
 mc g/ m L gr o u p ) ha d r h N G F le vels t hat were a b o v e t he L L O Q. T hese 
o bser vati o ns were li kel y d ue t o fl uct uati o ns ar o u n d a c o nstit uti ve ser u m le vel, i n de pe n de nt 
fr o m t he st u d y treat me nt. 
 
T he res ults of t he p hase II st u d y were c o nsiste nt wit h t he res ults i n healt h y v ol u ntee rs. D ue t o 
t he l o w i nci de nce of s u bj ects wit h detecta ble N G F i n ser u m sa m ples i n pre vi o us st u dies a n d 
t he l o w ma g nit u de of o bser ve d N G F ser u m l e vels, n o f urt her p har mac o ki netic e val u ati o ns 
were perf or m e d i n pre parati o n f or t his cli nical st u d y a n d n o ser u m sa m ples will be c ollecte d 
d uri n g t his st u d y.  
C
CI
C
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 4 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
2. 4. 3  Met a b olis m  
 
r h N G F is a p ol y p e pti de. T he acti vate d r h N G F/ Tr k A c o m ple x ca n b e i nter nalize d a n d r h N G F 
re distri b ute d i n t he tiss ue a n d i nacti vate d b y pr ot e ol ytic pat h wa ys. 
 
2. 5  
R E L E V A N T C LI NI C A L T RI A L S  
 
Treat me nt wit h r h N G F e ye dr o ps s h o we d a g o o d safet y pr ofile i n t w o P hase I st u dies i n 
healt h y v ol u nteers (st u di es N G F 0 1 1 2 a n d N G F 0 1 1 7), a n d i n a P hase I/II st u d y i n patie nts 
wit h N K (st u d y N G F 0 2 1 2 - R E P A R O). T he safet y a n d efficac y of treat me nt wit h r h N G F e ye 
dr o ps i n patie nts wit h N K has bee n de m o nstrate d b y t w o pi v otal ra n d o mize d cli nical trials 
( R C T) i n patie nts wit h N K at sta ge 2 a n d 3 (st u di es N G F 0 2 1 2 a n d N G F 0 2 1 4). F urt h er m ore, 
r h N G F e ye dr o ps h a ve als o bee n e val uat e d i n a P hase I/II st u d y i n pati e nts wit h reti nitis 
pi g me nt osa at c o nce ntr ati o ns of 6 0 mc g/ m L a n d 1 8 0 mc g/ m L ( N G F 0 1 1 3), a n d i n a P hase I/II 
st u d y i n patie nts wit h gla uc o ma at a c o nce ntr ati o n of 6 0 mc g/ m L ( N G F 0 3 1 4).  
 
T he safet y a n d effic ac y of treat me nt wit h r h N G F e ye dr o ps i n patie nts wit h dr y e ye was first 
e val uate d i n a n o pe n -l a bel, u nc o ntr olle d st u d y i n w hic h 4 wee ks of treat me nt wit h r h N G F e y e 
dr o ps at c o nce ntrati o ns of 
 mc g/ m L a n d  mc g/ m L s h o we d t o be safe a n d  effecti ve i n 
i m pr o vi n g s y m pt o ms, c or neal stai ni n g, a n d tear f u ncti o n as c o m pare d t o bas eli ne ( N G F 0 2 1 3). 
T hese res ults pr o m pte d a P hase II R C T i n patie nts wit h dr y e ye disease ( N G F 0 2 1 6) a n d i n 
patie nts wit h oc ular disc o mf ort s y m pt o ms f oll o wi n g refracti ve s ur ger y ( N G F 0 1 1 6), w hic h 
c o nfir me d t h e fa v ora ble t olera bilit y pr ofile of r h N G F e ye dr o ps at a c o nce ntrati o n of 
 
mc g/ m L u p t o 6 ti mes dail y f or 8 w ee ks. A n a d diti o nal P hase II R C T (st u d y N G F 0 1 1 8) 
c o nfir me d t he safet y pr ofile of r h N G F e ye dr o ps at a c o nce nt rati o n of 
 mc g/ m L BI D a n d 
TI D f or 4 wee ks ( o btai n e d b y o n -site dil uti o n of t he 
 mc g/ m L s ol uti o n). Base d o n Sc hir mer 
test I d ata, it s h o we d t hat a hi g her n u m ber of p atie nts res p o n de d t o treat me nt wit h r h N G F BI D 
c o m pare d wit h ve hicl e. T his st u d y als o s h o we d t hat r h N G F TI D treat me nt si g nifica ntl y 
i m pr o ve d f T B U T c o m pare d wit h ve hicle a n d ha d cli nicall y rele va nt b ut dela ye d a n d s ustai ne d 
be neficial effects i n i m pr o vi n g dr y e ye s y m pt o ms ( base d o n S A N D E q uesti o n naire). A p has e 
III R C T i n patie nts wit h m o derate t o se vere Sj o gre n's dr y e ye ( N G F 0 1 2 1 - P R O T E G O -1) 
de m o nstrate d t hat r h N G F e ye dr o ps at a c o nce ntrati o n of
 mc g/ m L i nstille d TI D f or 4 wee ks 
 patie nts’ a q ue o us tear pr o d ucti o n at c o m pleti o n of treat me nt as 
c o m pare d t o v e hicle, w hic h  was s ustai ne d u p till t he e n d of f oll o w -u p at wee k 1 2 ( 8 wee ks 
p ost c o m pleti o n of treat me nt). S y m pt o ms ( S A N D E sc ores) als o s h o we d 
 at 4 w ee ks p ost c o m pleti o n of treat m e nt (wee k 8), w hic h is c o nsiste nt wit h well -
k n o w n 
 f oll o wi n g a n earlier i m pr o ve me nt i n si g ns i n dr y e ye 
disease. H o we v er, t his 
 i n s y m pt o ms was n ot s ustai ne d u ntil t he e n d of f oll o w-
u p.  E ye a n d e yeli d pai n were t he m ost c o m m o n a d verse e v e nts re p orte d wit h r h N G F 
treat me nt. A n ot her P has e III cli nical trial is c urre ntl y o n g oi n g t o e v al uat e t he effi cac y of 
treat me nt wit h r h N G F e y e dr o ps at a c o n ce ntr ati o n of 
 mc g/ m L wit h 3 ti mes dail y d osi n g 
i n patie nts wit h Sj o gre n's S y n dr o me dr y e ye a n d a ut oi m m u ne disease-ass ociate d dr y e ye t hat 
alrea d y recei ve i m m u n o m o d ulat or y treat me nt ( N G F 0 2 2 1, P R O T E G O -2 ). 
 
 
C
C
C
C
C
C
C CI
C CI
C CI
C CI
C CI
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 4 2  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
2. 6  
DI S E A S E R E VI E W A N D T RI A L R A TI O N A L E  
 
Dr y e y e diseas e ( D E D) is a m ultifact orial dise as e of t h e oc ular s urface, c haracteri ze d b y 
i m pair me nt of q ua ntit y of tears a n d/ or q ualit y of t he tear fil m. It is als o acc o m pa nie d b y tear 
fil m h y per os m olarit y, oc ular disc o mf ort s y m pt o ms, oc ular s urface i nfl a m mati o n a n d da ma ge, 
a n d ne ur ose ns or y a b n or malities. D E D ca n bec o m e a c hr o nic pr o gressi ve disease wit h c hr o nic 
disc o mf ort, vis ual dist ur ba nce, tear fil m i nst a bilit y wit h p ote ntial da ma ge t o t he oc ular s urface 
a n d c o nse q ue n ces o n q u alit y of life ( Crai g J P, et al.   2 0 1 7). U ntil n o w, treat me nt has bee n 
li mite d t o t he use of artificial tears or vare nicli ne t o te m p oraril y i m pr o ve l u bricati o n of t he 
oc ular s urface, or t h e us e of t o pical ster oi ds, c y cl os p ori ne A or lifite grast t o decreas e t h e 
i nfla m mat or y reacti o n. T hese treat me nts ha v e bee n ass ociate d wit h patie nt satisfacti o n iss ues 
s uc h as a n o n-fa v ora ble t olera bilit y pr ofile a n d a sl o w o nset of acti o n. 
 
Ner ve gr o w t h fact or ( N G F) bi n ds t o t w o ne ur otr o p hi n rece pt ors p 7 5( N T R) a n d p 1 4 0( Tr k) 
( Tr k A) t o i n d u ce a ut o-p h os p h or ylati o n of t he n e ur otr o p hi n rece pt or, lea di n g t o t he acti vati o n 
of vari o us si g nali n g pat h wa ys, li ke p h os p hati d yli n osit ol 3 -ki nase ( PI 3 K), pr otei n ki nas e B 
( A kt), mit o ge n acti vate d pr otei n ki nase ( M A P K), e xtracell ular si g nal-re g ul ate d ki nase ( Er k). 
T hese pat h wa ys hel p i n re g ulati n g all as pects of oc ular s urface bi ol o g y i ncl u di n g tr o p hic 
s u p p ort t o c or neal cells. r h N G F sti m ulates b ot h oc ular s urface w o u n d h eali n g a n d c or nea 
re pair pr o cesses (L a m bi ase et al 2 0 1 2 ). 
 
E x peri me ntal a n d cli nic al  e vi de nce s u g gests t hat r h N G F ma y affect all t he pat h o ge nic 
mec ha nis ms of dr y e y e, p ote ntiall y rest ori n g o c ular s urface h o me ost asis (L a m bi ase et al 
2 0 1 2 ). S pecificall y, N G F has bee n s h o w n t o sti m ulate tear fil m pr o d ucti o n, pr o m ote c or neal 
e pit helial heali n g, a n d sti m ulate c o nj u ncti val e pit helial differe ntiati o n a n d m uci n sec reti o n 
(C o assi n et al 2 0 0 5 ; Lee et al 2 0 0 6 ; B o ni ni et al 2 0 0 0 ; Ri os et al 2 0 0 7 ). 
 
T he res ults of t he st u dies i n patie nts wit h D E D disc usse d earlier ( N G F 0 1 1 8, N G F 0 1 2 1), as 
well as t he res ults o n refle x te ar secreti o n o btai ne d fr o m t he N K trials ( N G F 0 2 1 2 a n d 
N G F 0 2 1 4), s u g gest e d t hat r h N G F ma y be eff ecti ve f or patie nts wit h a q ue o us deficie nt D E D. 
I n fact, i n pre vi o us st u dies r h N G F a meli orate d t ear f u ncti o n a n d oc ul ar s urface e pit helial 
da ma ge, b ut  
 a n d disc o mf ort were c o m m o nl y o bser ve d o c ular a d v erse e v e nts 
( A Es) d uri n g treat me nt. T heref ore, d ue t o t h e hi g hl y s y m pt o matic nat ure of t his c o n diti o n, i n 
a n eff ort t o 
 e x p erie n ce d b y D E D patie nts d uri n g treat me nt, we pr o p ose t o 
test t w o  
 c o nce ntrati o ns of r h N G F usi n g a ne w  
 r h N G F f or m ulati o n t hat 
all o ws  
 c o n ce ntrati o ns of r h N G F o p ht hal mic s ol uti o ns t o be pre pare d.  
 
Details o n  t he n o n-cli nic al st u dies wit h t his ne w f or m ulati o n of r h N G F ca n be f o u n d i n  § 2. 3 . 
 
T he pr o p ose d cli nical trial is c o n d ucte d i n p atie nts wit h dr y e ye beca use f o ur pre vi o us cli nical 
st u dies ( N G F 0 1 1 8, N G F 0 1 2 1, N G F 0 2 1 2 a n d N G F 0 2 1 4) i n dicat e s o me be nefit i n t his 
p o p ulati o n . T he i n dicati o n “ dr y e ye” is n ot a p pr o v e d as of t o da y b y re g ulat or y a ut h orities.  
 
2. 6. 1  Alter n ati ve tre at me nts  
 
C urre ntl y, t here are a fe w c o m merciall y 
a vaila ble treat me nts f or 
D E D t hat are 
C CI
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 4 3  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
i m m u n o m o d ulat or y, re d uce i nfla m mati o n a n d/ or i m pr o ve tear s ecreti o n fr o m lacri mal gla n ds, 
b ut d o n ot a d dress t h e 
 c o m p o ne nt of D E D. T h ese treat me nts i ncl u de 
R E S T A SI S ™ (c y cl os p ori ne), XII D R A ™ (lifite grast), T Y R V A Y A ™ ( vare nicli ne), a n d 
t o pical 
c ortic oster oi ds 
s uc h 
as 
L O T E M A X ™ a n d 
P R E D F O R T E ™.  MI E B O ™ 
(perfl u or o h e x yl octa n e ) is i nstea d re d u ci n g tear e v a p orati o n. In a d diti o n, t here are n u mer o us 
artificial te ars t hat h el p l u bricate t he oc ular s urface. Ot her treat me nt o pti o ns i ncl u de p u nctal 
pl u gs t o re d uce drai na g e of tears s o  t hat t he tear la ke is mai ntai ne d i n a n eff ort t o i ncrease 
wetti n g of t he oc ular s urfac e.  
 
2. 7  
S U M M A R Y O F B E N E FI T S A N D RI S K  
 
Dr y e y e diseas e ( D E D) is a m ultifact ori al disease a n d r h N G F ( ne w f or m ulati o n –  
 d ose) 
ma y re pres e nt a great be nefit f or all patie nts affecte d, beca use of t he u ni q ue mec ha nis m of 
acti o n bas e d o n t he p h ysi ol o gical r ole of N G F i n t he bi ol o g y of c or nea a n d lacri mal gla n ds. 
T he ne w f or m ulati o n all o ws t he a d mi nistrati o n of a  
 d ose of r h N G F as e ye dr o ps, t hat ca n 
be ke pt at 
° C (
 ° F) wit h i m pr o ve d accessi bilit y t o t he me dicati o n. T he st u d y is 
c o n d ucte d i n m o derate t o se vere dr y e ye beca use f o ur pre vi o us cli nical st u dies s u g gest s o me 
be nefit i n t his p o p ulati o n. T heref ore, s o me p atie nts wit h dr y e y e ma y als o recei v e a be n efit  
fr o m t he a p plicati o n of r h N G F f or 2 8 da ys d uri n g t his st u d y.  
 
T he st u d y is c o nsi dere d a l o w-ris k i nter ve nti o nal trial. It is c o n d ucte d wit h c o nce ntr ati o ns 
(a n d d oses) of r h N G F  
 t ha n t h ose alrea d y teste d i n pre vi o us cli nical st u dies i n dr y e ye 
c o ndit i o n a n d alr ea d y a ut h orize d i n s o me E ur o pea n c o u ntries a n d i n t he U S A f or n e ur otr o p hi c 
keratitis ( N K) tr eat me nt.  
 
F o ur pre vi o us cli nical st u dies were alr ea d y c o n d u cte d i n patie nts wit h dr y e ye de m o nstrati n g 
t hat r h N G F is w ell t olerate d i n t his c o n diti o n. 
 
T he ris k of t his st u d y is f oresee n  as c o m para ble t o t he ris k of t he sta n dar d of care, i n fact t he 
d ose re gi me ns pr o p ose d i n t his pr ot oc ol are  m c g/ m L a n d 
 mc g/ m L t hree dr o ps per d a y 
( b ot h e yes), w hic h is  
 t he d ose a p pr o ve d f or t he tr eat me nt of N K (r h N G F 
 
mc g/ m L si x dr o ps/e ye per da y).  
 
N o partic ular safet y ris ks are f oresee n wit h res p ect t o t he safet y pr ofile of t he mar k ete d 
pr o d uct ( O X E R V A T E ® 
 mc g/ m L) a n d  
 a d verse dr u g reacti o ns ( disc o mf ort pai n) are 
e x pecte d b eca use  of t he  
 d ose s use d i n t his st u d y. 
 
T he f oll o wi n g p ote ntial st u d y ris ks were e v al uate d:  
 
1)  
Partici pa nt  well -bei n g  e. g.- ris k-be nefit bala nce - b ur de n of st u d y visits  
2)  
Lifest yle re q uir e me nts - St u d y s pecific pr oce d ures w hic h carr y ris k -a d diti o nal t o 
sta n dar d care (es: 1 2 ± 2  da ys of R u n -I n, disc o nti n uati o n of pre vi o us o p ht hal mic 
treat me nts) 
3)  
C o m ple xit y of st u d y pr oce d ures  
4)  
E d ucati o n, trai ni n g, e x perie nce , a n d res o urces of a ll i n vesti gat or site staff i n G C P 
a n d st u d y pr oce d ures  
C CI
C C
C C
I
C CI
C CI
C CI
C
C
C CI
C
C
C C
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 49 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
3.2 
PRIMARY AND KEY SECONDARY ESTIMANDS 
 
3.2.1 Primary Estimand 
 
The estimand for the primary objective is defined as follows:  
• Treatment: 4 weeks follow up after 4 weeks of TID administration of rhNGF new 
formulation (two concentrations and vehicle). 
• Population: Male and female patients aged ≥ 18 years with dry eye. Full Analysis Set. 
• Variable: mean change from baseline to week 8 in symptoms of dry eye assessed by 
SANDE Global Score. 
• Intercurrent events (ICEs) and strategies to handle them:  
o Treatment discontinuation: a treatment policy strategy will be applied where all the 
observed values will be used regardless of the occurrence of the ICEs. Missing data 
due to any reason will be handled by using a multiple imputation with a copy-
reference approach (see § 10.6.2 for further details). 
o Use of a prohibited medication, as listed in § 6.6.1, in the week before any 
assessment of SANDE Global Score: a hypothetical strategy will be applied where 
any data collected in the week after the occurrence of the ICE will be discarded. 
Missing data will be imputed by using a multiple imputation with copy-reference 
approach (see § 10.6.2 for further details).  
• Population-level summary: difference in mean change from baseline to week 8 in 
symptoms of dry eye assessed by SANDE Global Score between each concentration 
group of IMP (groups IMP1 and IMP2) and the vehicle group as derived by the Mixed 
Model for repeated measures defined in § 10.6.2. 
 
In summary, the primary estimand is defined as the difference in mean change from baseline 
to week 8 in symptoms of dry eye assessed by SANDE Global Score between treatments in the 
targeted patient population regardless of study treatment discontinuation and had prohibited 
medications not been available to subjects in the week before any study evaluation. 
 
More details are provided in the statistical § 10. 
 
3.2.2 Key Secondary Estimands 
 
Key secondary objective #1 
The estimand for the key secondary objective #1 is defined as follows: 
• Treatment: 4 weeks of TID administration of rhNGF new formulation (two 
concentrations and vehicle). 
• Population: Male and female patients aged ≥ 18 years with dry eye. Full Analysis Set. 
• Variable: proportion of patients improving to Schirmer-I test without anesthesia ≥ 10 
mm/5min in the Study Eye at week 4 (V4). 
• Intercurrent events (ICEs) and strategies to handle them:  
o Treatment discontinuation: a treatment policy strategy will be applied where all the 
observed values will be used regardless of the occurrence of the ICEs. Missing data 
due to any reason will be handled by using a multiple imputation with a copy-

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 50 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
reference approach (see § 10.6.3 for further details). 
o Use of a prohibited medication, as listed in § 6.6.1, in the week before any 
assessment of Schirmer-I score: a hypothetical strategy will be applied where any 
data collected in the week after the occurrence of the ICE will be discarded. Missing 
data for Schirmer-I score will be imputed by using a multiple imputation with copy-
reference approach (see § 10.6.3 for further details), then the proportion of subjects 
with an improvement ≥ 10 mm/5min in the Study Eye will be derived.  
• Population-level summary: difference in proportion of patients improving to Schirmer-
I test without anesthesia ≥ 10 mm/5min in the Study Eye at week 4 (V4) between each 
concentration group of IMP (groups IMP1 and IMP2) and the vehicle group as derived 
by a logistic model defined in § 10.6.3. 
 
In summary, the estimand for the key secondary objective #1 is defined as the difference in 
proportion of patients improving to Schirmer-I test without anesthesia ≥ 10 mm/5min in the 
Study Eye at week 4 (V4) between treatments in the targeted patient population regardless of 
study treatment discontinuation and had prohibited medications not been available to subjects 
in the week before any study evaluation. 
 
Key secondary objective #2 
 
The estimand for the key secondary objective #2 is defined as follows:  
• Treatment: 4 weeks of TID administration of rhNGF new formulation (two 
concentrations and vehicle). 
• Population: Male and female patients aged ≥ 18 years with dry eye. Full Analysis Set. 
• Variable: mean change from baseline in Schirmer-I score without anesthesia in the 
Study Eye at week 4 (V4). 
• Intercurrent events (ICEs) and strategies to handle them:  
o Treatment discontinuation: a treatment policy strategy will be applied where all the 
observed values will be used regardless of the occurrence of the ICEs. Missing data 
due to any reason will be handled by using a multiple imputation with a copy-
reference approach (see § 10.6.3 for further details). 
o Use of a prohibited medication, as listed in § 6.6.1, in the week before any 
assessment of Schirmer-I score: a hypothetical strategy will be applied where any 
data collected in the week after the occurrence of the ICE will be discarded. Missing 
data will be imputed by using a multiple imputation with copy-reference approach 
(see § 10.6.3 for further details).  
• Population-level summary: difference in mean change from baseline to week 4 in 
Schirmer-I score without anesthesia in the Study Eye between each concentration group 
of IMP (groups IMP1 and IMP2) and the vehicle group as derived by an ANCOVA 
model defined in § 10.6.3. 
 
In summary, the estimand for the key secondary objective #2 is defined as the difference in 
mean change from baseline to week 4 in Schirmer-I score without anesthesia in the Study Eye 
between treatments in the targeted patient population regardless of study treatment 
discontinuation and had prohibited medications not been available to subjects in the week 
before any study evaluation. 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 5 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
Key sec o n d ary o bje ctive # 3  
 
T he esti ma n d f or t he ke y sec o n dar y o bjecti ve # 3 is defi ne d as f oll o ws:   
•  
Treat me nt: 4 wee ks of TI D a d mi nistrati o n of r h N G F ne w f or m ulati o n (t w o c o nce ntrati o ns 
a n d ve hicle). 
•  
P o p ulati o n: Male a n d fe male patie nts a ge d ≥ 1 8 years wit h dr y e ye. F ull A nal ysis Set.  
•  
Varia ble: mea n c ha n ge fr o m baseli ne i n t otal c or neal fl u orescei n stai ni n g ( N EI scale) i n t he 
St u d y E ye as assesse d b y t he i n vesti gat or at wee k 4 ( V 4).  
•  
I nterc urre nt e ve nts (I C Es) a n d strate gies t o ha n dle t hem :  
o  Treat me nt disc o n ti n uati o n: a treat me nt p olic y strate g y will be a p plie d w here all t he 
o bser ve d val ues will be use d re gar dless of t he occ urre nce of t he I C Es. Missi n g data d ue 
t o a n y reas o n will be ha n dle d b y usi n g a m ulti ple i m p utati o n wit h a c o p y-refere nce 
a p pr oac h (see §  1 0. 6. 3  f or f urt her details).  
o  Use of a pr o hi bite d me dicati o n liste d i n §  6. 6. 1  i n t he wee k bef ore a n y assess me nt of 
c or neal fl u orescei n stai ni n g: a h y p ot hetical strate g y will be a p plie d w here a n y data 
c ollecte d i n t he wee k after t he occ urre nce of t he I C E will be discar de d. Missi n g data will 
be i m p ute d b y usi n g a m ulti ple i m p utati o n wit h c o p y -refere nce a p pr oac h (see §  1 0. 6. 3  f or 
f urt her details). 
•  
P o p ulati o n -le vel s u m mar y: differe nce i n mea n c ha n ge fr o m baseli ne t o wee k 4 i n t otal 
c or neal fl u orescei n stai ni n g ( N EI scale) i n t he St u d y E ye as assesse d b y t he i n vesti gat or 
bet wee n eac h c o nce ntrati o n gr o u p of I M P ( gr o u ps I M P 1 a n d I M P 2) a n d t he ve hicle gr o u p as 
deri ve d b y a n A N C O V A m o del defi ne d i n §  1 0. 6. 3 . 
 
I n s u m mar y, t he esti ma n d f or t he ke y sec o n dar y o bjecti ve # 3 is defi ne d as t he differe nce i n mea n 
c ha n ge fr o m baseli ne t o wee k 4 i n t otal c or neal fl u orescei n stai ni n g ( N EI scal e) i n t he St u d y E ye as 
assesse d b y t he i n vesti gat or bet wee n treat me nts i n t he tar gete d patie nt p o p ulati o n re gar dless of st u d y 
treat me nt disc o nti n uati o n a n d ha d pr o hi bite d me dicati o ns n ot bee n a vaila ble t o s u bjects i n t he wee k 
bef ore a n y st u d y e val uati o n.  
 
3. 3  
A S S E S S M E N T O F E F FI C A C Y  
 
•  S pecificati o n of t he effic ac y para meters: please see §  1 . 1 a n d 3. 1 . 
•  Met h o ds a n d ti mi n g f or assessi n g, rec or di n g, a n d a nal yzi n g efficac y para me ters: Please 
see § 1. 2 , 3. 1 , 8. 1 , 8. 2  a n d 8. 3 . 
 
T he effic ac y e n d p oi nts i ncl u de d i n t his cli nical st u d y 
were selecte d t o o pti mize t he 
c haracteri zati o n of t he effects of r h N G F i n m o derate t o se vere D E D i n or der t o o btai n r o b ust 
e vi de nce of t he cli nical effic ac y of t he treat me nt a n d its rele va nce f or t he p atie nts. F or t his 
reas o n, s u bjecti ve a n d o bjecti ve meas ures are c ollecte d after 4 wee ks of tr eat me nt a n d at t h e 
e n d of t he F oll o w -U p p eri o d ( wee k 8, V 5). T his st u d y is l o o ki n g at t he effects of r h N G F o n 
m ulti ple mar kers of D E D beca use it is e x pecte d t o see  effi cac y i n meas ures of tear pr o d ucti o n, 
i n meas ures of  
 a n d  
 ge neral D E D s y m pt o ms a n d vis ual ac uit y. T he pre dicti o n 
of effi cac y, t h e st u d y desi g n a n d t he ass oci ate d S A P are base d o n pre vi o us cli nical data 
o btai ne d b y t he S p o ns or t hat ha ve e na bl e d t he pre parati o n of t his trial a n d t he pr o p ose d 
assess me nts. I n partic ular, t he pri mar y e n d p oi nt defi niti o n at wee k 8 ( V 5) (aft er 4 wee ks of 
treat me nt a n d 4 wee ks F oll o w-U p peri o d) is base d o n cli nical o bser vati o ns ma de d uri n g t h e 
st u dies N G F 0 1 1 8 a n d N G F 0 1 2 1  t hat s h o we d a n effect o n t he s y m pt o ms after t he e n d of t h e 
treat me nt peri o d. A c o m bi nati o n of sec o n dar y a n d e x pl orat or y efficac y e n d p oi nts is ma ki n g 
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 5 2  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
s ure t he effect of t he treat me nt is well c haracterize d at wee k 4 ( V 4; 2 8 ± 1 da ys fr o m Baseli ne 
vis it) a n d at wee k 8 ( V 5; 5 6 ± 2 da ys fr o m t he Baseli ne visit - e n d of 4 wee ks of F oll o w -U p).  
 
4  
T RI A L D E SI G N  
 
4. 1  
D E S C RI P TI O N O F T RI A L D E SI G N  
 
T his trial is a 4 -wee ks P hase II, m ulti -ce ntre, ra n d o mize d, d o u ble -mas ke d, ve hicle -c o ntr olle d, 
parallel -gr o u p, d os e -fi n di n g cli nical trial wit h 4 Wee ks of F oll o w-U p t o e val uate safet y a n d 
effic ac y of a n e w f or m ul ati o n of rec o m bi na nt h u ma n Ner ve Gr o wt h Fact or (r h N G F) e y e dr o p 
s ol uti o n at t w o differe nt c o nce ntr ati o ns i n patie nts wit h dr y e ye disease ( D E D).  It is desi g ne d 
as a su p eri orit y cli nic al trial t o assess t he efficac y a n d safet y of a n e w o p ht hal mic f or m ulati o n 
r h N G F as c o m pare d t o a ve hicle i n patie nts wit h dr y e ye dise ase ( D E D). T his is a pr os pecti v e 
P hase II trial f or a ne w f or m ulati o n of t w o c o nce ntrati o ns (  mc g/ m L a n d 
 mc g/ m L) of 
r h N G F e ye dr o ps. T he ne w f or m ulati o n is s pecificall y pre pare d t o all o w t h e a d mi nistrati o n of 
c o nce ntrati o ns of r h N G F e ye dr o p s ol uti o n t o  
 r h N G F i n d uce d  
 
e x perie n ce i n patie nts wit h D E D. T h e ne w f or m ulati o n ca n b e st ore d at 
° C f urt her 
i m pr o vi n g t he c o n diti o ns of st ora ge a n d ma ni p ulati o n of t he dr u g.  
•  T he st u d y is carrie d o ut i n m ulti ple ce nters ( U S A a n d Ital y).  
•  Male or fe male patie nts a ge d ≥1 8 years of a n y race/et h nicit y a n d e ye c ol or will be 
scree n e d f or e nr oll ment t o 
mi ni mize bias i n p o p ulati o n sa m pli n g. All patie nts 
s uccessf ull y e nr olle d will be ra n d o mize d b y I nteracti ve Res p o nse T ec h n ol o g y (I R T); 
b ot h t he i n vesti gat or a n d t he patie nt will be mas ke d t o t he treat me nt ar m assi g ne d. 
Patie nts will be ra n d o mize d 1: 1: 1 t o eit her of t he t w o c o nce ntrati o ns of r h N G F 
f or m ulati o n (
 mc g/ m L or  mc g/ m L) or v e hicl e. T he t otal n u m ber of p atie nts t o be 
e nr olle d i n t he st u d y will be a b o ut 2 9 1 , 9 7  per gr o u p t o tar get 2 7 6  e val ua ble patie nts 
(9 2  per gr o u p). T he t otal n u m ber has be e n o btai n e d c o nsi deri n g a 5 % rat e of patie nts 
n ot e val ua ble f or pri mar y a nal ysis after e nr ol me nt. C o nsi deri n g a scree n fail ure rat e of 
2 0 %, a p pr o xi matel y 3 5 0  s u bjects nee d t o be scree ne d i n or der t o ha ve 2 9 1  patie nts 
e nr olle d a n d at least 2 7 6  patie nts e val ua ble.  
•  T he st u d y is di vi de d i n 4 p hases: Scree ni n g & Start of R u n -I n peri o d ( da y -1 2 ± 2, Visit 
1); R u n -i n Peri o d ( da y -1 2 ± 2/ Scree ni n g Visit 1 t o da y 1/ Baseli ne Visit 2); Treat me nt 
Peri o d ( da y 1/ Baseli ne Visit 2 t o wee k 4/ da y 2 8 ± 1, Visit 4); F oll o w -u p  Peri o d ( E n d 
of Treat me nt visit 4 at wee k 4 t o E n d of F oll o w -u p - E n d of St u d y visit 5 at wee k 8, 
da y 5 6 ± 2). Pr o ce d ures f or i ncl usi o n will be perf or me d at b ot h Visit 1 ( Scree ni n g) a n d 
Visit 2 ( Baseli ne).  
•  At Scree ni n g visit ( Visit 1, da y -1 2 ± 2), eli gi ble p atie nts will be i nstr uct e d t o disc o nti n ue 
all t o pical o p ht hal mic me dicati o ns a n d d uri n g t h e R u n -I n peri o d t he y will o nl y be 
all o we d t o use t he St u d y Pr o d uct ( ve hicl e) o p ht hal mic s ol uti o n pr o vi de d b y t he 
S p o ns or. T his s ol uti o n nee ds t o be pre p are d dail y a n d  a d mi nistere d b y t he patie nt i n 
b ot h e yes as e y e dr o ps s ol uti o n TI D (at a p pr o xi matel y 6 -h o urs i nter vals).  
•  At Visit 2 ( baseli ne visit) a St u d y E ye will be deter mi ne d. Na mel y, t he St u d y E ye is t he 
w orst e ye: ass u mi n g t hat all t he i ncl usi o n/e xcl usi o n criteri a are met i n b ot h e yes, t he 
w orse e ye ( St u d y E ye) will be deter mi ne d at t he Baseli ne visit base d o n t he l o wer 
Sc hir mer I ( wit h o ut a n est hesia) sc ore. If t he Sc hir mer I sc ore of b ot h e y es is i de ntical, 
t he St u d y E ye will be deter mi ne d base d o n t he w orse N EI stai ni n g sc ore f or c or nea a n d 
c o nj u ncti va (first N EI sc ore f or c or nea t he n f or c o nj u ncti va). If b ot h e yes are i de ntical, 
C
C
C
CI
C CI
C CI
C CI
C CI
C
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 5 3  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
t he n si m pl y t he ri g ht e ye will be c o nsi dere d t he St u d y E ye.  
•  T he treat me nt peri o d will start at Baseli ne visit ( Visit 2, da y 1) a n d t he  I M P will be 
a d mi nistere d as a n e y e dr o ps s ol uti o n t o be pre pare d dail y a n d a d mi nistere d b y t he 
patie nt TI D at a p pr o xi m atel y 6 -h i nter vals i n b ot h e yes f or a treat me nt peri o d of 4 
wee ks. D uri n g t he 4 wee ks of mas k e d treat me nt o nl y t he a d mi nistrati o n of I M P  is 
all o we d.  T he use ( n u m ber of dr o ps/ da y) of I M P will be clearl y d oc u me nte d i n a Patie nt 
Diar y a n d i n t he e C R F. Differe nt a d mi nistrati o n fre q ue n cies will be rec or de d a n d 
c o nsi dere d as pr ot oc ol d e viati o n. T he tr eat me nt p eri o d will be c o m plete d at Visit 4 ( da y 
2 8 ± 1) a n d it will be f oll o we d b y a 4 wee ks F oll o w -U p peri o d.  
•  D uri n g t his F oll o w -U p p eri o d patie nts will be re q ueste d t o a d mi nister pres er vati ve free 
artificial tears ( A T) ( NI M P) pr o vi de d b y t he S p o ns or TI D at 6 -h i nter val i n b ot h e yes 
f or a 4-w ee k p eri o d u ntil Visit 5 ( da y 5 6 ± 2, wee k 8). D uri n g t he 4 wee ks of F oll o w -
U p peri o d o nl y t he a d mi nistrati o n of A T pr o vi de d b y t he S p o ns or is all o we d. T he use 
of A T will be clearl y d oc u me nte d i n a Patie nt Diar y a n d i n t he e C R F. Differe nt 
a d mi nistrati o n fre q ue n c ies will be rec or de d a n d c o nsi dere d as pr ot oc ol de viati o n. A n y 
t o pical o p ht hal mic c o nc o mita nt treat me nt i nitiate d d uri n g t he St u d y peri o d ( bet wee n 
Visit 1 a n d Visit 5) m ust be d oc u me nte d o n t h e c o nc o mita nt me dicati o n l o g a n d 
re pres e nts a pr ot oc ol d e viati o n. T he E n d of St u d y Trial visit ( E O S) is e x pecte d at Wee k 
8. T he ma xi m u m t otal st u d y d urati o n will be a b o ut 1 0 wee ks.  
•  Patie nts will be e val uate d at Scree ni n g visit ( da y -1 2 ± 2, V 1) after w hic h t he y will e nter 
a R u n-I n peri o d wit h t he St u d y Pr o d uct ve hicle (fr o m da y -1 2 ± 2 t o da y 1). E val uati o ns 
will c o nti n ue at B aseli ne visit ( da y 1, V 2), wee k 2 ( da y 1 3 ± 1, V 3), wee k 4 ( da y 2 8 ± 1, 
E O T ( V 4)), a n d at w ee k 8 ( da y 5 6 ± 2 f oll o w -u p a n d E O S ( V 5)). At t he i n vesti gat or’s 
discreti o n, a n y patie nt c o ul d be see n f or a n U nsc h e d ule d Visit f or safet y e v al uati o n. A n 
Earl y E xit Visit c o ul d b e d o ne i n case of pre mat ure st u d y disc o nti n uati o n. I n case of 
treat me nt disc o nti n uati o n, patie nts will be as ke d t o c o m plete t he assess me nts at t he 
pla n ne d visits as per Pr ot oc ol. I n cas e of pre m at ure disc o nti n uati o n of t h e st u d y, t he 
s u bject will be re q uire d t o partici pate at t h e E arl y E xit Visit t hat will h a ve t he sa me 
assess me nts of Visit 4 (i n case of earl y treat me nt  a n d st u d y  disc o nti n uati o n bef ore Visit 
4) or t he sa me assess me nts of Visit 5 (i n case t he disc o nti n uati o n fr o m t he st u d y will 
occ ur after t he e n di n g of t he treat me nt b ut bef ore t he e x p ecte d Visit 5). A fl a g will b e 
i nserte d i n t he e C R F t o d efi ne if t he Visit 4 or 5 is a per pr ot oc ol visit or if it is d o ne as 
Earl y E xit Visit.  
•  T he t rial desi g n f oll o ws t he pri nci ples of Q ualit y b y Desi g n ( Q b D) wit h res pect t o 
eli gi bilit y criteria, ra n d o mizati o n, mas ki n g, data q ua ntit y, e n d p oi nts, data i nte grit y, 
I M P ha n dli n g a n d a d mi nistrati o n, site feasi bilit y, safet y re p orti n g, data m o nit ori n g a n d 
d ele gati o n of res p o nsi bilities. Detaile d e val uati o ns a n d ti mi n g are prese nte d i n § 1. 2 , 
1. 3  a n d 8 . 
 
4. 2  
R A TI O N A L E F O R T RI A L D E SI G N  
 
T he st u d y has bee n desi g ne d as a d ose -fi n di n g, s u peri orit y cli nical trial wit h a R u n-I n peri o d usi n g 
ve hicle si nce t his is a ne w f or m ulati o n of r h N G F. D uri n g t he R u n -I n peri o d of 1 2 ± 2 da ys, patie nts 
will o nl y use t he ne w ve hicle f or m ulati o n (t hree ti mes a da y) i n b ot h e yes  t o pr o vi de t he mi ni m u m 
a m o u nt of l u bricati o n nee de d i n D E D patie nts  w hile e ns uri n g a p pr o priate was h -o ut fr o m a n y ot her 
pre vi o us t o pic al treat me nt effect. T his trial tests t w o  
 c o nce ntrati o ns of a ne w  
 r h N G F 
f or m ulati o n (
 mc g/ m L or  mc g/ m L) i n patie nts wit h D E D. T his ne w f or m ulati o n all o ws t he 
C C
C CI
C
C

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 5 5  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
a) S y m pt o ms Assess me nt i n Dr y E ye ( S A N D E) q uesti o n naire  gl o bal sc ore  ≥5 0, a n d  
b)  Sc hir mer -I test wit h o ut a nest hesia > 2 m m a n d < 1 0 m m/ 5 mi n utes, a n d 
c) T otal c or neal fl u orescei n stai ni n g gra de ≥3 ( N EI scale) a n d/ or t otal c o nj u ncti val lissa mi ne  
gree n stai ni n g sc ore ≥3 assesse d b y t he Nati o nal E ye I nstit ute ( N EI) gra di n g s yste m, a n d  
d)  Fl u orescei n Tear Fil m Brea k -U p Ti me (f T B U T) < 1 0 sec o n ds . T he sa me e ye m ust ha ve 
f ulfille d all t he a b o ve criteria. 
4)  Best c orrecte d dista nce vis ual ac uit y ( B C D V A) sc or e o n E T D R S c hart of ≥0. 1 deci mal u nits 
( ≤1. 0 l o g M A R) i n eac h e ye at t he ti me of st u d y e nr oll me nt 
5)  Ne gati ve pre g na nc y test i n fe males of c hil d beari n g p ote ntial.  
6)  O nl y patie nts w h o satisf y all i nf or me d c o nse nt re q uire me nts will be i ncl u de d i n t he st u d y; t he 
pa tie nt a n d/ or his/ her le gal re prese ntati ve m ust ha ve rea d, si g ne d, a n d date d t he i nf or me d 
c o nse nt d oc u me nt bef ore a n y st u d y -relate d pr oce d ures are perf or me d; t he i nf or me d c o nse nt 
f or m si g ne d b y patie nts a n d/ or le gal re prese ntati ves m ust ha ve bee n a p pr o ve d by t he I R B f or 
t he c urre nt st u d y. 
7)  Ha ve t he a bilit y a n d willi n g ness t o c o m pl y wit h st u d y pr oce d ures.  
 
5. 2  
E X C L U SI O N C RI T E RI A  
 
1)  I na bilit y t o s pea k a n d u n dersta n d t he l ocal la n g ua ge s ufficie ntl y t o u n dersta n d t he nat ure of 
t he st u d y, t o pr o vi de writte n i nf or me d c o nse nt, a n d t o all o w t he c o m pleti o n of all st u d y 
assess me nts. 
2)  E vi de nce of a n acti ve oc ular i nfecti o n i n eit her e ye.  
3)  Prese nce of a n y ot her oc ular dis or der or c o n diti o n re q uiri n g t o pical me dicati o n d uri n g t he 
e ntire d urati o n of t he st u d y.  
4)  P ossi bili t y of t he nee d f or oc ular s ur ger y at t he ti me of i ncl usi o n i n t he st u d y or a ntici pate d 
oc ular s ur ger y e x pecte d d uri n g t he partici pati o n i n t he st u d y.  
5)  Hist or y of se vere s yste mic aller g y or se vere oc ular aller g y (i ncl u di n g seas o nal c o nj u ncti vitis, 
A K C, V K C) or c hr o nic c o nj u ncti vitis a n d/ or keratitis ot her t ha n dr y e ye.  
6)  Oc ular scarri n g d ue t o irra diati o n, al kali b ur ns, Ste ve ns -J o h ns o n s y n dr o me a n d oc ular 
cicatricial pe m p hi g oi d.  
7)  Destr ucti o n of c o nj u ncti val g o blet cells s uc h as i n Vita mi n A deficie nc y.  
8)  Se vere bl e p haritis or o b vi o us i nfla m mati o n of t he li d mar gi n.  
9)  I ntra oc ular i nfla m mati o n defi ne d as T y n dall sc ore > 0. 
1 0)  Me dical hist or y of t u m or mali g na nc y i n t he pre vi o us 3 years  
1 1)  S yste mic disease n ot sta bilize d wit hi n 1 m o nt h bef ore t he Scree ni n g visit ( e. g., dia betes wit h 
gl yce mia o ut of ra n ge, t h yr oi d malf u ncti o n) or j u d ge d b y t he i n vesti gat or t o be i nc o m pati ble 
wit h t he st u d y ( e. g., c urre nt s yste mic i nfecti o ns) or wit h a c o n diti o n i nc o m pati ble wit h t he 
fre q ue nt assess me nt re q uire d b y t he st u d y. 
1 2)  Hist or y of a seri o us a d verse reacti o n or si g nifica nt h y perse nsiti vit y t o a n y dr u g or c he micall y 
relate d c o m p o u n ds or ha d a cli nicall y si g nifica nt aller g y t o dr u gs, f o o ds, 
 
e ye dr o p or ot her l ocal a nest hetics or ot her materials, i ncl u di n g oc ular vital d yes, tr o pica mi de 
e ye dr o ps, c o m mercial  artificial tears. 
1 3)  K n o w n or s us pecte d aller g y t o 
 a n d/ or a n y 
ot her c o m p o ne nt of t he ne w r h N G F f or m ulati o n.  
1 4)  Fertile patie nts ( i.e., n ot s ur gicall y sterilize d, or p ost me n o pa usal w o me n f or at least 1 year) 
are e xcl u de d fr o m partici pati o n i n t he st u d y if t he y d o n ot practice a bsti ne nce fr o m 
heter ose x ual i nterc o urse as per us ual a n d c ust o mar y lifest yle, or are u n willi n g t o use a n 
acce pta ble f or m of c o ntrace pti o n s uc h as c o n d o m wit h s per mici dal crea m or jell y f or males, 
or f or fe males if t he y meet a n y o ne of t he f oll o wi n g c o n diti o ns:  
a) C urre ntl y pre g na nt ( p ositi ve uri ne pre g na nc y test at scree ni n g or baseli ne visits) or 
pla n ni n g t o bec o me pre g na nt d uri n g t he d urati o n of t he treat me nt p ha se of t he cli nical 
C CI
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 56 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
trial. 
b) Patient is breastfeeding. 
c) Unwilling to use birth control measures such as 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, or, 
d) Unwilling to continue to use highly effective birth control measures such as hormonal 
contraceptives (oral, implanted, transdermal, or injected) during the entire course of and 
30 days after the study treatment periods. 
15) Any concurrent medical condition that, in the judgment of the principal investigator, might 
interfere with the conduct of the study, confound the interpretation of the study results, or 
endanger the patient’s well-being. 
16) Contact lenses or punctum plug use in either eye during the washout, treatment and follow-up 
phases of the study (previous use is not an exclusion criteria but must be removed and 
discontinued at the Screening visit) 
17) Medical history of drug addiction or alcohol abuse (>1 drink /day for women and >2 drinks 
/day for men following USDA dietary Guidelines 2020-2025). 
18) Any prior ocular surgery including but not limited to amniotic membrane transplant, 
refractive (PTK/LASIK/Epi-LASIK/LASEK/SMILE), palpebral, cataract surgery, 
trabeculectomy, vitrectomy and pan-retinal photocoagulation (PRP) within 90 days before the 
Screening visit. 
19) Participation in a clinical trial with a new active substance, including medical devices, during 
the previous 60 days. 
20) Participation in another clinical trial study at the same time as the present study.  
 
5.3 
SELECTION OF STUDY EYE 
 
At Visit 2 (Baseline visit) a Study Eye will be determined. Namely, the Study Eye is the worst 
eye: assuming that all the inclusion/exclusion criteria are met in both eyes, the worse eye (Study 
Eye) will be determined at the baseline visit based on the lower Schirmer I (without anesthesia) 
score. If the Schirmer I score of both eyes is identical, the Study Eye will be determined based 
on the worse NEI staining score for cornea and conjunctiva (first NEI score for cornea then 
NEI score for conjunctiva). If both eyes are identical, then simply the right eye will be 
considered the Study Eye. 
 
5.4 
SCREEN FAILURES 
 
A patient will be defined as screened after the signature of the informed consent and the 
assignment of a Screening Number. The preparation of an eCRF will be done regardless of the 
completion of all the screening procedures. Patients that will go through screening but will not 
be enrolled will be considered a screen failure. Patients may be re-screened on a case-by-case 
basis after reviewing it with the Sponsor. 
In this study a screen failure rate of about 20% was considered on the basis of the previous 
clinical experience obtained with the NGF0121 - PROTEGO-1 study, which also enrolled 
highly symptomatic dry eye patients. We expect to screen approximately 350 subjects in order 
to have 291 subjects enrolled.  
 
The sample size remains at 291 subjects independent of screen failures. 
 
5.5 
LIFESTYLE CONSIDERATIONS 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 57 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
5.5.1 Meals and Dietary Restriction 
 
No new drastic changes to diet adding fish oil supplements, flaxseed supplements, omega-3 
supplements since they could potentially alter fTBUT. 
 
5.5.2 Caffeine, Alcohol, Tobacco, and Other Habits  
 
Patients should limit smoking tobacco since tobacco smoke is a known eye irritant, it may 
worsen dry eye disease and confound results. Patients should also avoid exposure to second-
hand smoke for prolonged periods. 
 
5.5.3 Physical Activity 
 
No particular restrictions are required. 
 
5.5.4 Other Activities 
 
Avoid heavy use of eye make-up along lash lines like eyeliner and mascara since those could 
artificially alter fTBUT. 
 
 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 6 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
ca uti o n a n d descri be partic ulars a p plica ble t o re g ulat or y re q uire m e nt s (e. g.: kit n u m ber, 
pr ot oc ol n u m ber, st ora g e c o n diti o ns, na me a n d a d dress of t he s p o ns or, state me nt t hat t he 
pr o d uct is f or i n vesti gati o nal use o nl y, etc.). A cli nical la beli n g wit h si milar state me nts will 
be als o pr o vi de d f or t he St u d y Pr o d uct ve hicle t o  be use d d uri n g t he R u n -I n Peri o d. 
 
T he P har macist a n d/ or I n vesti gat or 
will be res p o nsi ble f or recei pt, pr o per st ora ge, 
dis pe nsati o n rec o nciliati o n, usa ge , a n d fi n al dis p osal of re mai ni n g St u d y Pr o d ucts ( w here 
a p plica ble). T he St u d y Pr o d ucts m ust be st ore d at 
° C s heltere d fr o m s u nli g ht a n d heat 
at t he i n vesti gati o nal sites, i n a n a p pr o priate l oc ke d r o o m accessi ble o nl y t o t he p har macist, 
t he I n vesti gat or, or a d ul y desi g nate d p ers o n. A data l o g g er will acc o m pa n y t he St u d y 
Pr o d ucts o n s hi p me nt. It is esse ntial t hat t he i n vesti gati o nal sites verif y t he te m perat ur e 
e xc ursi o n d uri n g s hi p me nt vs. t he acce pta ble st ora ge c o n diti o ns (
° C), i n or der t o 
i de ntif y p ote ntial sta bilit y c o ncer ns d uri n g s hi p me nt. 
T hese 
m ust be i m me diatel y 
c o m m u nicate d t o t he S p o ns or t hat will deci de u p o n a p pr o priate acti o ns t o be ta ke n. A n y 
de viati o n fr o m t he rec o m me n de d pre parati o n, st ora ge a n d ha n dli n g c o n diti o ns of t he St u d y 
Pr o d u cts s h o ul d be i m me diatel y re p orte d b y t he p har macist t o t he S p o ns or a n d t o t he 
I n v esti gat or, a n d t he use of t he St u d y Pr o d uct s h o ul d be s us pe n de d u ntil t he S p o ns or has gi ve n 
a ut h orizati o n f or its c o nti n ue d use. T he St u d y Pr o d uct s u p plies are t o be use d o nl y i n 
acc or da nce wit h t his pr ot oc ol. T he I n vesti gat or will n ot use a n y St u d y Pr o d uct sa m ples f or 
ot her p ur p oses (e. g., treati n g patie nts or de viati n g fr o m t he pr ot oc ol wit h re gar d t o d os e 
re gi me n, d urati o n of treat me nt, etc.). U n der n o circ u msta nces will t he I n vesti gat or gi ve a n y 
St u d y Pr o d uct sa m ples t o a t hir d part y.  
 
U p o n recei pt of t he St u d y Pr o d ucts (i ncl u di n g Ve hicle) a n d NI M P at t he site, t he i n vesti gat or 
will l o g t he recei pt of t he St u d y Pr o d ucts (i ncl u di n g Ve hicle) a n d NI M P a n d st ore as per t he 
st ora ge i nstr ucti o ns pr o vi de d wit h t he St u d y Pr o d ucts (i ncl u di n g Ve hi cle) a n d NI M P kits. 
St u d y Pr o d ucts (i ncl u di n g Ve hicle) a n d NI M P will be dis pe nse d t o t he p atie nts b y q ualifie d 
a n d dele g ate d site staff acc or di n g t o t he st u d y re q uire me nts a n d as liste d i n t h e Sc he d ul e of 
Acti vities ( Ta ble 1 ). T h e site pers o n nel will mai ntai n a n acc o u nta bilit y l o g f or St u d y Pr o d ucts 
(i ncl u di n g Ve hicle), d o c u me nti n g t he recei pt, dis pe nsati o n, ret ur n, a n d destr ucti o n of all 
St u d y Pr o d ucts (i ncl u di n g Ve hicle).  T he site pers o n nel will als o mai ntai n a n acc o u nt a bilit y 
l o g f or NI M P, d oc u me nti n g t he recei pt a n d dis pe nsati o n of NI M P.  
 
T o esta blis h a n d mai ntai n acc o u nta bilit y of St u d y Pr o d ucts (i ncl u di n g Ve hicle) a n d NI M P, 
t he P har macist a n d/ or I n vesti gat or will c o nfir m t he recei pt of t he St u d y Pr o d ucts (i ncl u di n g 
Ve hicle) a n d NI M P s u p pl y i n writi n g b y si g ni n g a n d dati n g sta n dar d dr u g acc o u nta bilit y 
f or ms. T he P har macist a n d/ or I n vesti gat or will kee p a c u m ulati ve i n ve nt or y a n d dis pe nsi n g 
rec or ds a n d will mai ntai n all s u p plies u n der a de q uate sec urit y. A n acc urat e dr u g dis p ositi o n 
rec or d will be ke pt, s pecif yi n g t he date a n d a m o u nt dis pe nse d t o eac h p atie nt. 
 
A de q uate rec or d of recei pt a n d use or l oss of dr u g will be retai ne d. T his i n ve nt or y rec or d kit 
m ust be a vaila ble f or i ns pecti o n b y t he S p o ns or a n d re g ulat or y i ns pecti o n at a n y ti me. C o pies 
of t his rec or d will be pr o vi de d t o t he S p o ns or b y t he C R O t hr o u g h o ut t he d urati o n of t he 
st u d y. 
 
D uri n g t he c o urs e of t he st u d y a n d u ntil its c o ncl usi o n, t he I n vesti gat or will c o m plete t he dr u g 
acc o u nta bilit y f or ms. Partiall y use d or u n use d st u d y dr u g b o xes will be verifie d b y t he C R O 
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 6 2  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
dele gate d M o nit or. T he partiall y use d a n d u n use d st u d y me dicati o n  will be s hi p pe d t o t he 
S p o ns or or  will be destr o ye d after a ut h orizati o n b y t he S p o ns or or b y a n a ut h orize d c o m pa n y 
acc or di n g t o G C P re g ulati o ns.  
 
St u d y Pr o d ucts’ pre parati o n a n d a d mi nistrati o n i nstr ucti o ns will be pr o vi de d se paratel y t o t he 
site a n d t o t he patie nts. 
 
St u d y pr o d ucts will be pr o vi de d t o t he patie nts as a bi wee kl y kit c o ntai ni n g 1 4 dail y b o xes. 
Eac h dail y b o x will c o nt ai n o ne vial of  
 St u d y Pr o d uct a n d o ne vial of dil ue nt 
s ol uti o n. I n t he bi-w ee kl y kit will be als o i ncl u de d a n a p pr o priate n u m b er of vial a d a pter, 
sterile wi pes a n d e m pt y l uer l oc k s yri n ges t o e ns ure pr o d uct rec o nstit uti o n bef ore use a n d 
disi nfecti o n. At ti me of dis pe nsi n g, patie nts will be als o pr o vi de d wit h a se parat e bi wee kl y  
a ncillar y kit c o ntai ni n g sterile wi pes  a n d sterile pi pettes f or dr u g pr o d uct a d mi nistrati o n. 
Patie nts will be pr o vi de d wit h detaile d i nstr ucti o n re p orti n g t he kit c o m p ositi o n a n d 
pr oce d ures f or pr o d uct r ec o nstit uti o n a n d a d mi nistrati o n.  
 
At visit 1 ( Scree ni n g visit) eli gi ble patie nts will be i nstr ucte d b y st u d y pers o n nel h o w t o 
pre pare a n d a d mi nister t h e St u d y Pr o d uct ( ve hicle) e ye dr o p s ol uti o n a n d t h e first e y e dr o p of 
t he St u d y Pr o d uct ( ve hicle) will be a p plie d i n b ot h e yes at t he site b y t he I n v esti gat or. T h e 
I n v esti gat or will d oc u m e nt t he first a d mi nistrati o n of t he St u d y Pr o d uct ( ve hicle) i n t he 
patie nt’s me dical rec or d f oll o wi n g Visit 1 t o c o nfir m t he first a d mi nistrati o n of t he St u d y 
Pr o d uct ( ve hicle). D e pe n di n g o n t he ti me of t he s u bject’s Scree ni n g visit, all d oses ma y n ot 
be a d mi niste re d o n t his da y. At visit 1, t he st u d y pers o n nel will gi ve t he patie nt t he 2-wee kl y 
b o xe d s u p pl y of t he St u d y Pr o d uct ( ve hicle) ( 
 ve hicle wit h dil u e nt); patie nts will 
als o recei ve a se parate a ncillar y a d mi nistrati o n kit c o ntai ni n g sterile pi pett es a n d sterile 
disi nfecta nt wi pes f or pr o d uct rec o nstit uti o n. Patie nts will be i nstr ucte d t o t he n self -
a d mi nister at h o me t he St u d y Pr o d uct ( ve hicle) o ne dr o p 3 ti mes a da y i n b ot h e yes, 
a p pr o xi matel y e ver y 6 h o urs. T he patie nt s h o ul d bri n g t he 2 -wee kl y s u p pl y b o x h o me as s o o n 
as p ossi ble a n d st ore it at 
° C, kee pi n g it a wa y fr o m direct s u nli g ht/ heat.  
 
D uri n g t he R u n -I n peri o d, patie nts will i nstill o ne dr o p of t he s ol uti o n ( ve hicle) i n b ot h e yes 
TI D (a p pr o xi matel y e ver y 6 h o urs), starti n g i n t he m or ni n g w he n t he y wa ke u p, f or a t otal 
d urati o n of 1 2 ± 2 da ys. T he c o nte nts of eac h vial are f or dail y a d mi nistrati o n t o b ot h e yes o nl y 
f or a gi ve n da y. A gitati o n of t he rec o nstit ute d pr o d uct ma y ca us e f oa mi n g, he nce s h o ul d b e 
a v oi de d at a n y ti me. After t he last  a d mi nistrati o n f or t he da y, t he us e d vial s h o ul d be ret ur n e d 
t o t he ori gi nal b o x a n d is n ot t o be re use d. T he use d/ u n use d St u d y Pr o d uct ve hicle vials s h o ul d 
be ret ur n e d t o t he site at t he e n d of t he R u n -I n p eri o d ( V 2). T he p atie nt will bri n g t he m t o t he 
site d uri n g t he Visit 2 a n d t he y will be c h ec ke d b y i n de pe n de nt p ers o n nel n ot directl y i n v ol ve d 
i n st u d y acti vities. T he ve hicle is n ot t o be i nstille d o n t he da y of t he Baseli ne visit ( Visit 2).  
 
At Visit 2 ( baseli ne visit - Da y 1), t he st u d y p ers o n nel will  gi ve t o t he ra n d o mize d patie nt t h e 
bi wee kl y b o xe d s u p pl y of t he St u d y Pr o d uct (I M P or v e hicle,  
 St u d y Pr o d uct wit h 
dil ue nt). T he patie nt s h o ul d bri n g t he I M P, a bi w ee kl y s u p pl y b o x, h o me as s o o n as p ossi ble 
a n d st ore it at 
° C, kee pi n g it awa y fr o m direct s u nli g ht/ heat. At Visit 2 ( Baseli ne) 
patie nts will als o recei v e a s e parate a n cillar y kit c o ntai ni n g sterile pi p ettes a n d sterile 
disi nfecta nt wi pes.  F urt her s pare a ncillar y kit c o m p o ne nts c o ul d b e pr o vi de d t o e ns ure 
pr o d uct a d mi nistrati o n.  I M P o p ht hal mic s ol uti o n pre parati o n a n d i nstillati o n i nstr ucti o ns will 
C CI
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 6 3  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
be pr o vi de d t o t he patie nts.  
 
Patie nts will i nstill o ne dr o p i n b ot h e y es t hree ti mes a da y ( TI D) (a p pr o xi matel y e ver y 6 
h o urs), starti n g o n Da y 1 ( B aseli ne visit) a n d c o nti n ue t he treat me nt f or t he ne xt 2 wee ks. 
De pe n di n g o n t h e ti me of t he s u bject’s Baseli ne visit, it is reas o na ble a n d p ossi ble t hat all 
d oses ma y n ot be a d mi nistere d o n t his da y . T he c o nte nts of eac h vial are f or dail y 
a d mi nistrati o n t o b ot h e y es o nl y f or a gi ve n da y. After t h e last a d mi nistrati o n f or t he d a y, t h e 
use d vial s h o ul d be ret ur ne d t o t he ori gi nal b o x a n d is n ot t o be re use d.  
 
After 2 wee ks d uri n g Visit 3 ( St u d y Pr o d uct pic k -u p visit - Da y 1 3 ± 1) patie nts will ret ur n t h e 
use d/ u n use d st u d y pr o d uct vials t o t he  site t o be c h ec ke d b y i n de pe n d e nt pers o n nel n ot 
directl y i n v ol ve d i n st u d y acti vities. D uri n g t he s a me Visit 3 patie nts will c ollect a sec o n d 
I M P 2-w ee kl y kit a n d a s e parat e a ncillar y kit.  
 
At visit 4 t he use d/ u n use d st u d y pr o d uct vials will be ret ur ne d t o t he site b y t he patie nts t o be 
c hec k e d b y i n de pe n d e nt pers o n nel n ot directl y i n v ol ve d i n st u d y acti vities.  
 
I n s u m mar y, p atie nts will ret ur n t he use d/ u n use d st u d y b o xes/ vials t o t he site pers o n nel i n t his 
or der: St u d y Pr o d uct ( ve hicle) fr o m t h e R u n -I n p eri o d at t he b aseli ne visit ( Visit 2), t he 2-
wee ks st u d y pr o d uct (I M P or ve hicle) at mi d -tr eat me nt visit ( Visit 3), t he sec o n d 2-wee ks 
st u d y pr o d uct (I M P or ve hicle) treat me nt at e n d-of -treat me nt visit ( Visit 4).  
 
At t he sc h e d ule d visits ( Baseli ne, wee ks 2, wee k 4 a n d wee k 8), t h e Pati e nt Diar y will be 
re vie we d b y t he I n v esti gat or wit h t he patie nt f or c o m plete ness a n d a d h ere nce t o tr eat me nt. 
Missi n g i nf or mati o n s h o ul d n ot be pr o vi d e d d uri n g t he Patie nt Diar y c h ec k b ut re p orte d as 
missi n g.  
 
6. 4  
P A R TI CI P A N T A S SI G N M E N T, R A N D O MI S A TI O N A N D M A S KI N G  
 
6. 4. 1  P artici p a nt Assi g n me nt  
 
Eac h patie n t w h o pr o vi des writte n c o nse nt t o partici pate i n t his st u d y will be assi g ne d a u ni q ue 
5 -di git PI D n u m ber ( e. g.,  0 1 -0 0 1) c o nsisti n g of a 2 -di git st u d y ce nter n u m ber f oll o we d b y t he 
3 -di git scree ni n g n u m ber assi g ne d se q u e ntiall y b y eac h st u d y ce nter, fr o m 0 0 1 t o 1 0 0. e C R F 
s h o ul d be c o m plete d f or eac h patie nt t h at si g ne d t he i nf or me d c o ns e nt, i ncl u di n g t he scree ni n g 
fail ures.  
 
6. 4. 2  R a n d o miz ati o n  
 
I nteracti o n Res p o nse T ec h n ol o g y (I R T) will be us e d t o ra n d o mize t h e patie nts i n a 1: 1: 1 rati o 
t o eac h of t he treat me nt ar ms.  
 
Eli gi ble patie nts will be ra n d o mize d i n a 1: 1: 1 rati o t o r h N G F  mc g/ m L TI D (a b o ut 9 7  
patie nts), r h N G F 
 mc g/ m L TI D (a b o ut 9 7  patie nts) or ve hicle o p ht hal mic s ol uti o n TI D 
(a b o ut 9 7  patie nts). Patie nts i n t he ve hicle ar m will be ra n d o ml y assi g ne d 1: 1 t o  t w o differe nt 
ve hicle filli n g v ol u mes t o preser ve mas ki n g. Ne v ert heless, all t he p atie nts ra n d o mize d t o t he 
ve hicle ar m will be a nal y ze d as a si n gle tr eat me nt ar m.  
C
C

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 64 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
Each randomized patient will be allocated with a randomization number, according to the 
stratified randomization list. Drop-outs after randomization will not be replaced. 
 
Randomization will be stratified by site to ensure balanced assignment across treatment 
groups within each site. The stratified permuted block randomization list will be generated 
with a computer procedure by an independent statistician not involved in the conduct of the 
study. 
 
Each Patient kit number will be randomly associated with a treatment group. The 
randomization list will be provided to the facility responsible for IMP packaging/labeling for 
the purpose of IMP preparation.  
 
The enrollment of patients will be scheduled in order to assure an inclusion of approximately 
291 patients to ensure at least 276 evaluable patients assuming up to 5% dropout rate. 
 
6.4.3 Masking and Unmasking Procedure 
 
Appearance, including packaging and labeling, of the study products (IMP or vehicle) will 
not allow recognition of the actual treatment. Masked information on the identity of the 
assigned study products will be provided for each patient.  
 
Unmasking can only occur in case of emergency when knowledge of the treatment identity is 
essential for treating the subject. If the treatment code needs to be broken in the interest of 
patient safety for a medical emergency, the Investigator is allowed to break the treatment code 
for the specific patient, even before informing the Sponsor. The Investigator must always 
notify the Sponsor, so that the reason for any premature unmasking can be documented, by 
means of a communication to CRO/Dompé Global Pharmacovigilance, Safety and 
Surveillance to the contact details in the section “CONTACT INFORMATION” and to 
Dompé Medical Expert. The Investigator will inform the Dompé representative (Dompé 
Medical Expert) if an emergency unmasking was performed without revealing the treatment 
identity, in order to avoid a dissemination of unmasked information. 
 
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety 
Update Report – DSUR) to relevant Regulatory Authorities in the countries concerned, as per 
applicable requirements. 
 
Additionally, Dompé Global Pharmacovigilance, Safety and Surveillance shall unmask the 
patient’s treatment if a reported SAE meets criteria of a Suspected Unexpected Serious 
Adverse Reaction (SUSAR) in order to fulfill expedited regulatory reporting requirements. 
Unmasked information shall not be disclosed to Investigators or to Dompé and CRO Clinical 
Research staff. Specifically, the identity of the IMP treatments will remain unknown to the 
patient, Investigator, site staff, Dompé’s clinical research personnel and CRO staff (apart from 
pharmacovigilance). 
 
Unmasking events will be recorded and reported in the final study report. 
 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 6 5  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
6. 5  
T RI A L I N T E R V E N TI O N C O M P LI A N C E  
 
All patie nts e nr olle d i n t he trial will recei v e a Patie nt Diar y at t he scree ni n g visit ( da y -1 2 ± 2), 
at t he baseli ne visit ( da y 1), a n d at t he e n d -of -treat me nt visit ( wee k 4). T h e patie nts will be 
re q uire d t o fill t hese diaries l o g gi n g t heir use of t h e s u p plie d dr u g ( St u d y Pr o d uct 
ve hicle/I M P/ NI M P). T h ese Patie nt Diaries will be re vie we d b y t he I n v esti gat or wit h t he 
patie nt f or c o m plete n ess at t he sc he d ule d visits ( baseli ne, wee ks 2, 4 a n d 8). T he data fr o m 
t he Patie nt’s Diar y will be e ntere d i n t he e C R F as well.  
 
Starti n g fr o m t he first I M P a d mi nistrati o n d o ne at t he baseli ne visit u ntil t he last e x pecte d 
a d mi nistrati o n (c o nsi deri n g 1 dr o p TI D, i.e. 3 dr o ps per da y), c o m plia nce f or t he st u d y e ye 
will be deri ve d as  t he pr o p orti o n ( %) b et wee n t he act ual n u m ber of dr o ps a d mi nistere d i n t he 
st u d y e ye a n d t he e x p ect e d n u m ber of dr o ps i n th e st u d y e ye as if t he s u bj ects c o m plete d t he 
st u d y (u p t o 8 4 dr o ps  de pe n di n g o n t he date of  treat me nt c o m pleti o n stat us c ollecte d i n t he 
e C R F; f or patie nts w h o pre mat urel y disc o nti n ue t he treat me nt, t he e x pecte d n u m ber is set t o 
8 4 ). F urt her details will be i nserte d i n t he S A P.  
 
Assess me nt of t he I M P acc o u nta bilit y will be m a de b y d eter mi ni n g t he n u m ber of St u d y 
Me dicati o n vials ( 
 pr o d uct) dis pe nse d t o t he patie nt at Baseli ne/ V 2 a n d at Wee k 
2/ V 3 a n d t he n u m ber of u n use d St u d y Me dicati o n vials r et ur ne d at Wee k 4/ V 4 ( E O T). T he 
n u m ber of use d a n d u n use d vials of dil ue nt will als o be c ollecte d.  
 
6. 6  
C O N C O MI T A N T T H E R A P Y  
 
As a g e neral r ule, t he o nl y o p ht hal mic me dicati o ns gi ve n t o t he p atie nts are St u d y Pr o d ucts 
or A T, fr o m t h e Scree ni n g Visit, Da y 1 a n d u ntil all t he fi nal st u d y e val uati o ns ha ve bee n 
c o m plete d at F oll o w -U p Visit, Da y 5 6 ± 2 , i ncl u di n g t he ve hi cle d uri n g t he R u n-I n p hase a n d 
t he preser vati ve free artificial tears ( A T) pr o vi de d b y t he S p o ns or d uri n g t he F oll o w-U p 
peri o d.  
 
T he use ( n u m b er  of dr o ps/ da y) of St u d y Pr o d ucts (I ncl u di n g ve hicl e) a n d A T ( NI M P) will be 
clearl y d oc u m e nte d i n t he Patie nt Diar y a n d e C R F.  
 
6. 6. 1  Pr o hi bite d C o nc o mit a nt T her a p y  
 
D uri n g t he w h ole p eri o d of t he partici pati o n t o t he trial (a b o ut 1 0 wee ks) p atie nts s h o ul d n ot 
use  o p ht hal mic ster oi ds, o p ht hal mic i m m u n o m o d ulat ors s uc h as c ycl os p ori ne 
A a n d 
lifite grast, i ntra nas al te ar-secret a g o g ues s u c h as vare nicli ne, o p ht hal mic t o pical a nti-
hista mi ne, a n y deri v ati ves of ner ve gr o wt h fact or, or a n y me dicati o ns as part of a n ot her 
cli nical trial. T he use of artificial tears - l u bri cati n g e ye dr o ps n ot pr o vi d e d b y t he S p o ns or is 
als o f or bi d de n. Patie nts s h o ul d n ot use p u nctal pl u gs, c o ntact le nses (i ncl u di n g scleral le nses), 
m oist ure g o g gles, war m c o m presses or electr o/ ma g netic sti m ula ti o n de vices o n t he e ye, face 
or scal p. Bef ore t he st u d y u n mas ki n g , a mas k e d re vie w of t he c o n c o mita nt me dicati o n ta ke n 
b y t he patie nts d uri n g t h e st u d y will be d o ne i n or der t o v erif y t he pres e nce of pr o hi bite d 
me dicati o n, t heir fre q ue n c y a n d d osa ge i n or der t o defi ne t he se v erit y of t he de viati o n.  
 
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 66 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
6.6.2 Permitted Concomitant Therapy 
 
During the Run-In period, no ocular topical treatment is allowed, except for Study Product 
vehicle ophthalmic solution, 3 times daily, provided by the Sponsor.  
 
During the treatment period, only the study products (IMP or vehicle) will be allowed for 
topical ocular treatment.  
 
During Follow-Up period, no topical treatment will be allowed except for commercially 
available preservative free AT, TID, provided by the Sponsor. Different administration 
frequencies of study products (including vehicle) and NIMP will be recorded and considered 
as protocol deviation.  
 
During the entire duration of the study, any use of AT not provided by the sponsor will be 
recorded as concomitant medication and considered as protocol deviation.  
 
Patients are encouraged to continue to take any systemic medications that they take as part of 
chronic disease management and not change their medical management as prescribed by their 
treating physician.  
 
Patients are allowed to take over-the-counter painkillers, herbal products, vitamins and 
antacids. All systemic medications, over-the-counter painkillers, 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 drug product name and brand name (especially if 
containing a combination of active principles) 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." 
 
6.6.3 Rescue Therapy 
 
If a patient’s ocular health worsens to an extent that is considered beyond reasonable risk to 
their vision or maintenance of an intact ocular surface, they will be asked to discontinue the 
treatment but to remain in the study for the assessment planned by the protocol until the 
expected end of study. An appropriate treatment could be given by their physician. There will 
be no predefined rescue therapy. It should be checked if the patient still meets all the criteria 
expected to remain in the study. All details should be recorded in the eCRF. 
 
6.6.4 Other Therapy 
 
No other therapy outside of what is outlined in permitted concomitant therapy is allowed 
during the course of this study. 
 
7 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
WITHDRAWAL FROM TRIAL 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 67 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
7.1 
CRITERIA FOR DISCONTINUATION OF TRIAL INTERVENTION 
 
7.1.1 Criteria for Permanent Discontinuation of Trial Intervention 
 
Treatment discontinuation 
 
Patients with tolerability issues, or worsening of symptoms and/or signs may be discontinued 
at any time during the study for the following reasons: 
1) AEs that at Investigator discretion require treatment discontinuation. 
2) Worsening of the clinical condition that requires treatment discontinuation per 
physician decision or ocular surgery. 
3) Violation of study procedures that represent a protocol deviation deemed by the 
Investigator to require treatment discontinuation. 
4) Withdrawal of patient’s consent for any reason. 
5) Patient is lost-to-follow-up notwithstanding all efforts to contact him/her (at least three 
documented attempts by phone and/or email). 
6) Other (e.g., death, pregnancy, planned operation). 
 
Except for items from #4 to #6 of the list reported above that imply also a study 
discontinuation, in case one of the events from #1 to #3 occurs, patients will be asked to 
complete the assessments planned by the protocol regardless the discontinuation of the study 
treatment and will receive preservative free AT, TID, provided by the Sponsor. In case of 
more than one reason, the main one will be reported in eCRF. 
 
Study discontinuation 
 
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 should be discontinued from the study for one of the following reasons: 
1) Withdrawal of patient’s consent for any reason. 
2) AEs, protocol deviations and any other condition for which study procedures may 
compromise the safety and well-being of the patient, as per physician decision. 
3) Patient is lost-to-follow-up notwithstanding all efforts to contact him/her (at least three 
documented attempts by phone and/or email). 
4) Other (e.g., death, pregnancy, planned operation).  
 
In all other situations, including cases where patients should be discontinued from study 
treatment, all efforts will be made to complete study visits and procedures as per protocol. 
 
Before removal, each case should first be discussed with Dompé. 
 
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, patients who 
discontinue the treatment will not be withdrawn from the study by default, but it will be asked 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 68 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
to complete safety and efficacy assessments as per protocol.  
 
The investigator will advise patients who prematurely discontinue any therapies or treatments 
for their condition and refer them for further treatment as appropriate. 
 
7.1.2 Temporary Discontinuation or Interruption of Trial Intervention 
 
Any patient that chooses to discontinue the trial will not be allowed to re-enter or 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. 
 
For any patient discontinuing the study following randomization, the Investigator will: 
• Ask the patient to undergo, as far as possible, the following assessment as planned in 
this protocol. In case the patient withdraws from the study, the patient will be asked 
to undergo, as far as possible, a final medical visit (Early Exit Visit) 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). 
• Arrange for alternative medical care of the withdrawn patient, if necessary. 
• Report in the eCRF date and time of the last dose administration, and date and primary 
reason for study discontinuation. 
• Record in the eCRF any follow-up if the patient is withdrawn for an AE. AE’s should 
be followed until resolution.  
 
7.1.3 Rechallenge 
 
Rechallenge is not permitted in this trial. 
 
7.2 
PARTICIPANT WITHDRAWAL FROM THE TRIAL 
 
There are no criteria for temporary withdrawal from the trial. Any discontinuation or 
withdrawal will result in a permanent discontinuation. The criteria for permanent 
discontinuation from the trial are listed in § 7.1.1. 
 
7.3 
LOST TO FOLLOW-UP 
 
Every effort will be made by the Clinical Trial Manager, CRO Project Team and Investigator 
or their designated staff, to reach patients who are lost to follow-up. Lost to follow-up is 
defined as patients who miss one or more study visits and are not reachable despite every 
reasonable attempt made at contacting them (at least three documented attempts by phone 
and/or email). 
 
7.4 
TRIAL STOPPING RULES 
 
The Sponsor has the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. Reasons for discontinuation have to be documented appropriately. In 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 69 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
this event, no further patients will receive doses of the IMPs, and patients already having 
received a dose of IMP will not receive any further doses of the IMP but will undergo all 
safety assessments scheduled after the last dose of IMP, up to and including the end of study 
examination. 
 
8 
TRIAL ASSESSMENTS AND PROCEDURES 
 
8.1 
SCREENING/BASELINE 
 
Site staff will conduct the following assessments in the order outlined below during each visit. 
 
Visit 1 - Day -12±2:  SCREENING 
1. Informed Consent/HIPAA (only for USA). 
2. Demographics, Ocular and Medical History, Previous and Concomitant Ocular 
and Systemic Medications and Conditions. 
3. Pregnancy Test. 
4. SANDE questionnaire. 
5. Ophthalmic Examinations for each eye:   
A. Best-Corrected Distance Visual Acuity (BCDVA) by ETDRS. 
B. External Ocular Examination. 
C. Schirmer-I test without anesthesia. 
D. Slit Lamp Examination (SLE) of the anterior segment of the eye (cornea, 
conjunctiva, anterior chamber, iris, lids and lashes). 
E. Assess bulbar redness (VBR 10). 
F. Instill fluorescein and wait 30 seconds. 
G. Assess fTBUT. 
H. After 2-5 minutes from the time of fluorescein instillation, assess total corneal 
fluorescein staining score (NEI scale, score range 0-15). 
I. Apply lissamine green. 
J. Assess total conjunctival lissamine green staining score (NEI scale, score 
range 0-18). 
6. Inclusion/Exclusion Criteria Screen the subject for protocol inclusion/exclusion 
criteria. 
7. Dispense IMP (vehicle) eye drops to be instilled; the first drop will be instilled by 
the investigator or delegate and then the IMP (vehicle) will be instilled by the 
patient at home 3 times daily in both eyes for 12 days ±2. 
8. Deliver instructions to patient. 
9. Dispense the Patient Diary to record the administration of Study Product vehicle 
during the Run-In period (vehicle accountability), any new or changes in 
concomitant medications, any unusual medical condition.  
10. Investigator will document the first administration of the Study Product (vehicle) 
in the patient’s medical record following Visit 1 to confirm the first administration 
of the Study Product (vehicle).  
11. AE monitoring and recording, as applicable. 
 
RUN-IN (From Day -12±2 to Day 1):   
Patients at home will proceed with the Run-In of 12 days ± 2 using the dispensed 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 7 0  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
St u d y Pr o d uct ve hicle  e ye dr o ps ( 1 dr o p i n b ot h e yes 3 ti mes a d a y). N o ot her 
o p ht hal mic t o pical a d mi nistrati o ns are per mitte d . 
 
Visit 2 - D a y 1:  B A S E LI N E  
Patie nts will be ra n d o mize d if t he y c o nti n ue t o meet eli gi bilit y criteria at Visit 
2/ Baseli ne.  
 
1.  C o nc o mita nt Oc ular a n d S yste mic Me dicati o ns a n d C o n diti o ns  
2.  A Es m o nit ori n g (rec or di n g a n d e val uati o n, as a p plica ble)  
3.  Pre g na nc y T est  
4.  S A N D E q uesti o n naire  
5.  
6.  O p ht hal mic E xa mi nati o ns i n eac h e y e:   
A.  Best -C orrecte d Dista nce Vis ual Ac uit y ( B C D V A) b y E T D R S  
B.  E xter nal Oc ul ar E xa mi nati o n  
C.  Assess NI K B U T (at selecte d ce nt ers)  
D.  Sc hir mer -I test wit h o ut a nest hesia. 
E.  Slit La m p E xa mi nati o n ( S L E) of t h e a nt eri or s e g me nt of t he e ye (c or nea, 
c o nj u ncti va, a nteri or c ha m ber, iris, li ds a n d las hes)  
F.  Assess b ul bar re d n ess ( V B R 1 0 scale)  
G.  I nstill fl u orescei n a n d wait 3 0 sec o n ds. 
H.  Assess f T B U T  
I. After 2 -5 mi n utes fr o m t he ti me of fl u orescei n i nstillati o n, assess t otal c or neal 
fl u orescei n stai ni n g sc ore ( N EI scale, sc ore ra n g e 0-1 5).  
J.  A p pl y lissa mi ne gree n . 
K.  Assess t otal c o nj u ncti val lissa mi ne gree n stai ni n g sc ore ( N EI scale, sc ore 
ra n ge 0-1 8).  
L.  Perf or m 
 e ye dr o p 
( o nl y i n patie nts 
wit h 
)  
M.  Perf or m s pec ular micr osc o p y t o assess c or neal e n d ot helial cells de nsit y (at 
selecte d sites t hat ha v e a s pec ular micr osc o pe alrea d y a vaila ble).  
N.  I nstill tr o pica mi de e ye dr o p s ol uti o n 1 % after 1 5 mi n utes/ o nce p u pils are 
a de q uatel y dilate d p erf or m f u n d us e xa mi nati o n . 
7.  I n cl usi o n/ E xcl usi o n: Patie nts m ust c o nti n ue t o meet t he Scree ni n g/ E nr oll me nt 
Criteria.  At t he e n d of t he Baseli ne Visit ( Da y 1), it will be deter mi ne d if t he 
s u bject q ualifies f or c o nti n ue d partici pati o n a n d treat me nt i n t he st u d y. 
8.  C ollect use d/ u n use d St u d y Pr o d uct ( ve hicle) of t he R u n -I n p hase (t o be c hec ke d 
b y i n de pe n de nt pers o n n el)  
9.  Retrie ve t he Patie nt Diar y f or t he r u n -i n p eri o d. 
1 0.  Ra n d o mizati o n  
1 1.  St u d y Pr o d uct dis pe nsi n g:  eli gi ble patie nts will be s u p plie d wit h a bi -wee kl y kit 
of St u d y pr o d uct (I M P or ve hicle) after ra n d o mizati o n, s ufficie nt f or 2 wee ks of 
treat me nt per visit. 
1 2.  Deli ver i nstr ucti o n t o S u bjects . 
1 3.  Dis pe nse Patie nt Diar y t o rec or d a d here nce t o t h e a d mi nistrati o n of I M Ps d uri n g 
t he treat me nt peri o d, a n y ne w or c h a n ges i n c o nc o mita nt me dicati o ns, a n y u n us ual 
me dical c o n diti o ns . 
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 7 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
1 4.  A Es m o nit ori n g a n d re p orti n g, as a p plica ble.  
 
8. 2  
T RI A L VI SI T S A N D F O L L O W -U P A S S E S S M E N T S  
 
Site staff will c o n d uct t he f oll o wi n g a ssess me nts i n t he or der o utli ne d bel o w d uri n g eac h visit.   
 
Visit 3 - Wee k 2 ( D a y 1 3 ± 1) S T U D Y P R O D U C T PI C K -U P VI SI T  
1.  C o nc o mita nt Oc ular a n d S yste mic Me dicati o ns U p date.  
2.  A Es m o nit ori n g (rec or di n g a n d e val uati o n, as a p plica ble). 
3.  C hec k t he Patie nt Diar y.  
4.  C ollect 
Use d/ U n use d St u d y Pr o d ucts (I M P or ve hicle;  t o be c h ec k e d b y 
i n de pe n de nt pers o n n el). 
5.  St u d y Pr o d uct Dis pe nsi n g: Patie nts will be s u p plie d wit h a bi wee kl y kit of St u d y 
pr o d uct (I M P or ve hi cle) s ufficie nt f or 2 wee ks of treat me nt.  
 
Visit 4 - We e k 4 ( D a y 2 8 ± 1 ): E N D O F  T R E A T M E N T VI SI T or  E A R L Y E XI T 
VI SI T   
1.  C o nc o mita nt Oc ular a n d S yste mic Me dicati o ns U p date.  
2.  A E s m o nit ori n g (rec or di n g e val uati o n, as a p plica ble). 
3.  C hec k t he Patie nt Diar y of t he treat me nt p eri o d.  
4.  S A N D E q uesti o n naire.  
5.  
6.  O p ht hal mic E xa mi nati o ns:   
A.  Best -C orrecte d Dista nce Vis ual Ac uit y ( B C D V A) b y E T D R S.  
B.  E xter nal Oc ul ar E xa mi nati o n.  
C.  Assess NI K B U T (at selecte d ce nt ers).  
D.  Sc hir mer -I test wit h o ut a nest hesia.   
E.  Slit La m p E xa mi nati o n ( S L E) of t h e a nt eri or s e g me nt of t he e ye (c or nea, 
c o nj u ncti va, a nteri or c ha m ber, iris, li ds a n d las hes).  
F.  Assess b ul bar re d n ess ( V B R 1 0 scale).  
G.  I nstill fl u orescei n a n d wait 3 0 sec o n ds. 
H.  Assess f T B U T.  
I. After 2 -5 mi n u tes fr o m t he ti me of fl u orescei n i nstillati o n, assess t otal c or neal 
fl u orescei n stai ni n g sc ore ( N EI, sc ore ra n ge 0-1 5).  
J.  A p pl y lissa mi ne gree n.  
K.  Assess t otal c o nj u ncti val lissa mi ne gree n stai ni n g sc ore ([ N EI, sc ore ra n ge 0 -
1 8).  
L.  Perf or m 
 e yedr o p 
 ( o nl y i n patie nts 
wit h 
) 
7.  C ollect use d a n d u n use d St u d y Pr o d uct (t o be c hec ke d b y i n de pe n d e nt pers o n nel)  
8.  Retrie ve Patie nt’s Diar y f or t he treat me nt peri o d.  
9.  Dis pe nse preser vati ve free artificial tears ( A T) e ye dr o ps t o be a d mi nistere d 3 
ti mes dail y. 
1 0.  Deli ver i nstr ucti o n t o Patie nt.  
1 1.  Dis pe nse Patie nt Diar y t o rec or d a d here n ce t o preser vati ve free A T e ye dr o ps 
d uri n g t he F U peri o d, a n y ne w or c h a n ges i n c o nc o mita nt me dicati o ns, a n y 
u n us ual me dical c o n diti o n s. 
C CI
C CI
C CI
C CI

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 7 2  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
Visit 5 - Wee k 8 ( d a y 5 6 ± 2) F O L L O W -U P & E N D O F S T U D Y VI SI T o r E A R L Y 
E XI T VI SI T *  
1.  C o nc o mita nt Oc ular a n d S yste mic Me dicati o ns U p date.  
2.  A Es m o nit ori n g (rec or di n g e val uati o n, as a p plica ble).  
3.  C hec k t he Patie nt’s Diar y of t he F oll o w -U p peri o d.  
4.  S A N D E q uesti o n naire.  
5.  
 
6.  O p ht hal mic E xa mi nati o ns:   
A.  Best -C orrecte d Dista nce Vis ual Ac uit y ( B C D V A) b y E T D R S.  
B.  E xter nal Oc ul ar E xa mi nati o n.  
C.  Assess NI K B U T (at selecte d ce nt ers).  
D.  Sc hir mer -I test wit h o ut a nest hesia. 
E.  Slit La m p E xa mi nati o n ( S L E) of t h e a nt eri or s e g me nt of t he e ye (c or nea, 
c o nj u ncti va, a nteri or c ha m ber, iris, li ds a n d las hes).  
F.  Assess b ul bar re d n ess ( V B R 1 0 scale).  
G.  I nstill fl u orescei n a n d wait 3 0 sec o n ds. 
H.  Assess f T B U T.  
I. After 2 -5 mi n utes fr o m t he ti me of fl u orescei n i nstillati o n, assess t otal c or neal 
fl u orescei n stai ni n g sc ore ( N EI scale, sc ore ra n g e 0-1 5).  
J.  A p pl y lissa mi ne gree n.  
K.  Assess t otal c o nj u ncti val lissa mi ne gree n stai ni n g sc ore ( N EI scale, sc ore 
ra n ge 0-1 8).  
L.  Perf or m s pec ular micr osc o p y t o assess c or neal e n d ot h elial cells de nsit y (at 
selecte d sites t hat ha v e a s pec ular micr osc o pe alrea d y a vaila ble).  
M.  I nstill tr o pica mi de e y e dr o p s ol uti o n 1 %. 
N.  After 1 5 
mi n utes/ o nce p u pils are a de q u atel y dilate d perf or m f u n d us 
e xa mi nati o n i n b ot h e yes.  
7.  Retrie ve t he Patie nt’s Di ar y f or t he F oll o w -U p peri o d.  
 
E n d of Tri al  ( E o T)/ E n d of St u d y ( E O S): as per article 2 ( 2 6)  of t he E ur o p ea n C li nical T rial 
R e g ulati o n ( C T R) , E o T/ E n d of St u d y ( E O S) is t he last visit of t he last patie nt gl o ball y . 
 
At t he i n vesti gat or’s discreti o n, a n y patie nt c o ul d be see n f or a n U ns c he d ul e d Visit f or safet y 
e val uati o n.  
 
Pre m at ure Disc o nti n u ati o n a n d E arl y E xit Visit:  ( *) I n case of pre m at ur e disc o nti n uati o n 
of t he st u d y, t he patie nt will be re q uire d t o perf or m t he Earl y E xit Visit t hat will ha ve t he 
sa me ass ess me nts of Visit 4 (i n case of earl y treat me nt disc o nti n uati o n bef ore Visit 4) or t he 
sa me assess me nts of Visit 5 (i n case t he disc o nti n uati o n fr o m t he st u d y will occ ur after t he 
e n di n g of t h e treat me nt b ut bef ore t he e x pecte d Visit 5). A fla g will b e i nserte d i n t he e C R F 
t o defi ne if t he Visit 4 or Visit 5 is a per pr ot oc ol visit or if it is d o ne as Earl y E xit Visit. 
 
 
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 75 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
8.4 
PHARMACOKINETICS 
 
No samples for pharmacokinetic evaluations will be collected during the study.  
 
8.5 
GENETICS 
 
No sample for genetic analyses will be collected during the study.  
 
8.6 
BIOMARKERS 
 
No sample for Biomarker assessment will be collected during the study.  
 
8.7 
IMMUNOGENICITY ASSESSMENT 
 
No sample for immunogenicity assessment will be collected during the study.  
 
9 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
 
9.1 
DEFINITIONS 
 
9.1.1 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 unfavorable 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.  
 
9.1.2 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 also covers medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product. For the purposes of regulatory 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 § 9.3.2, is none or 
unlikely; whereas any AE reported in the study having a possible, probable or highly probable 
relationship to study drug will be considered as an ADR.  
 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 76 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
9.1.3 Serious Adverse Event 
 
A Serious Adverse Event (SAE) is defined as any adverse experience that, in the view of 
either the Investigator or Sponsor, meets any of the following criteria: 
• results in death, 
• 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), 
• requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: In general, hospitalization means that the individual remained at the hospital or 
emergency ward for observation and/or treatment (usually involving an overnight stay) 
that would not have been appropriate in the physician's office or an outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt 
as to whether “hospitalization” occurred, the event should be considered serious. 
• results in persistent or significant disability/incapacity. 
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained ankle) which may 
interfere or prevent everyday life functions, but do not constitute a substantial 
disruption. 
• is a congenital anomaly/birth defect, 
• is an important medical event. 
NOTE: An important medical event is an event that may not result in death, be life 
threatening, or require hospitalization, but may be considered a SAE when, based upon 
appropriate medical judgment, it may jeopardize the patient’s 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 § 9.4.2). 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. 
 
9.1.4 Unexpected Adverse Events 
 
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 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 77 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
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. The determination of expectedness is made by 
the Sponsor on the basis of the IB Reference Safety Information (RSI) section. 
 
9.1.5 Suspected Unexpected Serious Adverse Reaction 
 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an adverse 
reaction that is both unexpected (not consistent with the applicable reference safety 
information) and also meets the definition of a Serious ADR. 
 
9.1.6 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): 
⮚ 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 
⮚ AEs that caused a decrease in visual acuity to the level of light perception or worse 
lasting >1 hour 
⮚ 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. 
⮚ AEs associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis) 
⮚ AEs that can cause retinal vascular occlusion such as intraocular pressure > 40 mmHg. 
⮚ AEs that, in the opinion of the Investigator, may require medical intervention to prevent 
permanent loss of sight. 
 
9.2 
MONITORING AND REPORTING ADVERSE EVENTS 
 
Following study informed consent form signature, at each visit, after the patient has had the 
opportunity to spontaneously mention any problems, the Investigator or appropriate designee 
should inquire about AEs by asking the standard questions:  
• “Have you had any health problems since your last study visit?” 
• “Have there been any changes in the medicines you take since your last study visit?”  
 
AEs should be reported for any clinically relevant change in concomitant 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. 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 78 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
All AEs should be followed-up to determine the 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. 
 
9.3 
RECORDING ADVERSE EVENTS 
 
AE data should be obtained through observation of the patient, from any information 
volunteered by the patient, and 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 the last follow-up visit (week 8). 
 
When possible, signs and symptoms indicating a common underlying pathology should be 
documented as one comprehensive event. For each recorded event, the AE documentation must 
include the onset date, outcome, resolution date (if event is resolved), intensity (i.e., severity), 
any action with study treatment taken as a result of the event, and an assessment of the adverse 
event relationship to the study treatment. 
 
Serious Adverse Events: 
 
The Investigator must record all SAEs, including sight-threatening events, occurring at any 
time during the study (after signature of the informed consent) 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). 
 
9.3.1 Follow-Up of Patients with Adverse Events 
 
The Investigator is responsible for adequate and safe medical care of patients during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the trial. All AEs should be followed-up to determine outcome of the reaction 
or until 10 days after the final visit (EOS or Early Exit 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 a patient was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded 
to Dompé as soon as it becomes available. In addition, a letter from the Investigator that 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 8 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
D o m pé Cli nical O perati o ns  
 
I n a d diti o n t o re p orti n g t he S A E t o D o m pé, t h e I n vesti gat or m ust als o c o m pl y wit h t he 
re q uire me nts r elate d t o t he re p orti n g of S A Es t o t he I R B/I E C w hic h a p pr o ve d t he st u d y. T he 
re q uireme nts of I R Bs/I E Cs var y fr o m o ne I R B/I E C t o a n ot her; h o we ver, as a mi ni m u m 
re q uire me nt, t h e I n v esti gat ors m ust pr o m ptl y re p ort all s us pecte d u ne x p ect e d seri o us a d vers e 
reacti o n ( S U S A R) t o t heir I R B/I E C. 
 
If assista n ce is n ee d e d wit h t he re p orti n g of a S A E, C R O/ D o m pé ma y b e c o ntacte d at t he 
a d dresses pr o vi de d  a b o v e.  
 
S A Es will be ma na ge d directl y b y t he D o m pé P har mac o vi gila nce, Safet y a n d S ur veilla nce 
de part me nt, wit h C R O s u p p ort f or f oll o w -u p re q uests.  
 
T he i n vesti gat or s h o ul d als o re p ort i nf or mati o n o n S A Es t hat c o nti n ue after t he patie nt has 
c o m plete d his/ her partici pati o n i n t he st u d y ( w het her st u d y c o m pleti o n or wit h dra wal ) u nless 
t he patie nt has wit h dra w n his/ her c o nse nt. 
 
F oll o w -u p re p orts (as m a n y as re q uire d) s h o ul d be c o m plete d a n d fa x e d/e maile d f oll o wi n g 
t he sa me pr oce d ure  a b o v e, mar ki n g t he S A E f or m as “f oll o w -u p N u m b er X X”.  
 
W he ne v e r m ore t ha n o ne S A E is o bser ve d, t he I n v esti gat or s h o ul d i de ntif y w hic h is t he 
pri mar y a d v erse e v e nt, i. e., t he m ost rele va nt o ne. If ot her e v e nts are liste d i n t he same re p ort, 
t he I n v esti gat or, al o n g wit h t heir relate d ness t o t he I M P, s h o ul d i de ntif y w hic h A Es are 
seri o us a n d w hic h  are n o n -seri o us. I n a n y cas e, t he I n v esti gat or is re q ueste d t o rec or d his/ her 
o pi ni o n a b o ut t he relate d ness of t he o bser ve d e v e nt(s) wit h t he I M P. 
 
A n assess me nt of e x pect e d ness a n d ca usalit y of eac h S A E will be perf or me d case b y case b y 
D o m pé  P har mac o vi gila n ce . F or S A E re p orte d b y t he I n vesti gat or as n ot relate d t hat is 
s u bse q ue ntl y assess e d t o be relate d b y D o m pé, t he I n v esti gat or will recei ve a n otificati o n. 
De pe n di n g o n t he n at ure a n d seri o us ness of t he A E, f urt her i nf or mati o n, i ncl u di n g c o pies of 
a p pr o priate me dical rec or ds of t he patie nt, as well as res ults of la b orat or y tests perf or me d will 
nee d t o be i ncl u de d i n t he patie nt’s c hart. If t he patie nt was h os pitalize d, a c o p y of t he 
disc har ge s u m mar y s h o ul d be a vaila ble, if p ossi ble.  
 
I n li ne wit h C T 3 Detaile d G ui da nce a n d I C H E 2 A pr o visi o ns, alt h o u g h t he I n vesti gat or d o es 
n ot us uall y  nee d t o acti vel y m o nit or patie nts f or A Es o nce t he trial has e n de d, if t he 
I n v esti gat or bec o mes a w are of a S A E o cc urri n g t o a patie nt after t hat p atie nt has e n de d his/ her 
P P D
P P D

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 82 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
participation in the study (whether study completion or withdrawal), the SAE should be 
reported by the Investigator to the Dompé 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.  
 
9.4.2 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: 
• Hospitalizations planned before entry into the clinical study which is part of the 
normal treatment or monitoring of the studied indication and not associated with any 
deterioration in condition.  
• Hospitalization for routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition. 
• Hospitalization for treatments, which was elective or pre-planned, for a pre-existing 
condition that is unrelated to the indication under study and did not worsen. 
• Hospitalization for general care not associated with any deterioration in condition.  
• Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of SAEs given above and not resulting in hospital admission.  
 
In addition, the following situation shall not be considered SAE: 
• Abnormal test results that do not induce clinical signs and/or symptoms and do not 
require intervention/therapy, i.e., are not clinically significant. 
 
9.4.3 Adverse Events Exemption 
 
There are no adverse event exemptions for this study. 
 
9.4.4 Reporting Procedure to IRB/IEC and to Regulatory Authorities 
 
During the course of the clinical trial, the Sponsor shall report any SUSAR to the concerned 
Regulatory Authority(ies) and IRBs/IEC(s), as soon as possible and in no event later than:  
a) seven calendar days after becoming aware of the information if the event is fatal or 
life threatening; to be followed by any relevant information within eight days.  
b) fifteen calendar days after becoming aware of the information if the event is neither 
fatal nor life threatening.  
Follow-up information shall be reported within the same timelines.  
 
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 SUSAR 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 unmasked by Sponsor Pharmacovigilance prior to regulatory submission 
of a SUSAR to Regulatory Authorities and IRBs/IECs and only cases referred to active 
treatment will be considered expeditable for regulatory reporting, in line with law 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 83 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
requirements.  
 
The Sponsor shall also inform worldwide Regulatory Authorities of SUSARs, as applicable 
(cross reporting). 
 
Dompé shall also notify FDA in an IND safety report of potential serious risks, from clinical 
trials or any other source, as soon as possible after Dompé determines that the information 
qualifies for reporting, in particular shall notify of: 
• any suspected adverse reaction that is both serious and unexpected. Dompé must 
report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event. 
• findings from other studies that suggest a significant risk in humans exposed to the 
drug. Such a finding would result in a safety-related change in the overall conduct of 
the clinical investigation. 
• findings from animal or in vitro testing that suggest a significant risk in humans 
exposed to the drug. 
• increased rate of occurrence of serious suspected adverse reactions. 
 
In line with provisions set forth in 21CFR312, Dompé shall notify all participating US 
Investigators in an IND safety report of any SUSAR and of potential serious risks, from 
clinical trials or any other source, as soon as possible, but in no case later than: 
• Seven calendar days after becoming aware of the information if the event is fatal or 
life threatening; to be followed by any relevant information within eight days. 
• Fifteen calendar days after becoming aware of the information if the event is serious 
but neither fatal nor life threatening. 
 
The Investigators in turn shall notify their IRB/IEC.  
 
Copies of all correspondence relating to reporting of any SAEs to the IRB/IEC should be 
maintained in the Investigator’s Files. 
 
According to US regulations, the Investigators will be informed in an unmasked manner: 
Dompé will open the masking and report only SUSAR referred to rhNGF ophthalmic solution. 
 
EU Investigators shall be informed periodically, in a masked fashion, in line with applicable 
requirements. 
 
As part of periodical information, the Sponsor shall notify the Investigator on a six-monthly 
basis of any serious ADRs (maintaining the masked condition) that occur during ongoing 
clinical trials. 
 
9.4.5 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 in the countries concerned, as per 
applicable requirements. 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 84 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
9.5 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY 
 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are 
summarized in the protocol’s exclusion criteria. 
 
Prior to enrollment in the clinical trial, female 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 CRO/Dompé Pharmacovigilance, Safety 
and Surveillance contacts reported at § 9.4.1, 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 (e.g., if the mother is hospitalized for dehydration), 
in addition to the pregnancy report form, a separate SAE report form must be filed as 
described in § 9.4 with the appropriate serious criterion (e.g., hospitalization) indicated on the 
SAE report form. Miscarriage, stillbirth, and any malformation/disease must be reported as a 
SAE. Any pregnancy leads to the immediate cessation of the study treatment.  
 
9.6 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and 
reasoned in the eCRF, and the patient must be followed up until the resolution of the AE or 
as instructed by the medical monitor. 
 
9.7 
OVERDOSE 
 
Overdose (accidental or intentional) of Study Products (including vehicle) which may or may 
not result in serious adverse reactions, shall be reported to Sponsor Global 
Pharmacovigilance, Safety and Surveillance /CRO 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 intake through different routes (e.g., ingestion) or with suicidal 
intentions and consequent drug overdose. 
 
Since in the preclinical toxicology studies in animals and in the multiple ascending dose study 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 85 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
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. 
 
The Medical Expert should be contacted to discuss corrective treatment, if necessary. 
 
10 
STATISTICS 
 
10.1 
SAMPLE SIZE 
 
The sample size of the study is calculated based on results from the previous study NGF0118 
using the subgroup of patients with baseline SANDE Global Score > 50. Expecting a mean 
difference of about 11 points (with unequal standard deviations in the active and vehicle 
groups: observed mean changes (SD) were -28.2 (26.36) and -17.4 (20.29) for IMP and 
vehicle, respectively) in improvement of SANDE Global Score from baseline to Week 8 in 
favor of rhNGF ophthalmic (eye drop) formulation, a total sample size of 276 evaluable 
patients (92 per group) is needed. This will allow to achieve an overall power of 80% for 
demonstrating superiority of at least one concentration of rhNGF ophthalmic formulation over 
vehicle in the improvement of SANDE Global Score from baseline to week 8, with an overall 
one-sided alpha of 0.025.  
 
The sample size calculation takes into consideration a Bonferroni correction for two 
comparisons (2 concentration groups versus vehicle), i.e., the alpha level has been set to 
0.0125 one-sided for each comparison.  
 
Assuming a 5% rate of patients not evaluable for primary analysis after enrollment, the total 
number of patients to be enrolled in the study will be about 291 (97 per group). Enrollment 
will be competitive. 
 
In Dompé previous studies, a screen failure rate of about 20% has been observed (NGF0121 
- PROTEGO-1). This fact implies that approximately 350 subjects will need to be screened 
in order to have 291 patients enrolled and at least 276evaluable. In any case, the screen 
procedures should be interrupted when the expected sample size of 291 subjects has been 
reached. 
 
10.2 
OVERVIEW OF PLANNED STATISTICAL ANALYSIS 
 
The study plans only a final analysis: this analysis will be conducted when all randomized 
subjects have completed the study [treatment at week 4 (V4) and follow-up at week 8 (V5)] 
and the study database has been locked and unmasked.  
 
10.3 
INTERIM ANALYSIS 
 
No interim analyses are foreseen. 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 86 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
10.4 
PATIENT POPULATION 
 
10.4.1 Screened Population (SCR) 
 
A patient will be defined as screened after the signature of the informed consent, the 
assignment of a Screening number and regardless of the completion of all the screening 
procedures. eCRF should be completed for each patient that signed the informed consent, 
including the screening failures.  
 
10.4.2 Enrolled Population (ENR) 
 
A patient in the SCR population will be defined as enrolled if meets all the inclusion criteria 
and no one of the exclusion criteria at the end of the screening procedure at Visit 1 (Day -
12±2) and Visit 2 (Day 1). Patients in the SCR population but not included in the ENR 
population will be defined as screen failures.  
 
10.4.3 Randomized Population (RND) 
 
The Randomized Population will consist of all patients in the ENR Population who were 
assigned a randomization number. 
 
10.4.4 Safety Population (SAF) 
 
The Safety (SAF) population will consist of all Patients in the RND population who received 
at least one dose of the IMP. Safety population will be analyzed according to the actual 
treatment received. The SAF population will be used to present results on safety data. 
 
10.4.5 Full Analysis Set (FAS) 
 
The Full Analysis Set (FAS) will consist of all Participants in the RND Population who took 
at least one dose of IMP. The FAS will be analyzed according to the intention-to-treat (ITT) 
principle, i.e., by treatment allocation. The FAS population will be used for the primary 
analysis of the study and to present results on efficacy data. 
 
10.4.6 Per Protocol Population (PP) 
 
The Per Protocol (PP) Population will consist of all patients in the FAS population who do 
not have major protocol deviations. Primary efficacy analysis will be conducted on the FAS 
population while SAF and PP populations will be used for safety and sensitivity analysis, 
respectively.  
 
Reasons for the exclusion from the PP population will be determined in the masked Data 
Review Meeting (DRM). A non-exhaustive list of possible reasons for exclusion from the PP 
can be the following: 
• Lack of compliance with IMP and NIMP administration. (§1.1, §4.1, §9.7, §11.6) 
• Missing of any efficacy data post randomization. 
• Intake of prohibited medications. (§4.1, §6.6.1) 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 87 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
10.5 
ESTIMANDS 
 
The estimands for the primary and key secondary objectives are defined in §s 3.2.1 and 3.2.2, 
respectively.  
 
10.6 
STATISTICAL METHODOLOGY 
 
Statistical analysis will be performed by the CRO appointed by Dompé.  
 
10.6.1 Descriptive Statistics 
 
Appropriate descriptive statistics will be produced by treatment arms according to the nature 
of the variable. For continuous data, the number of observations, mean, standard deviation, 
median (25th and 75th percentile) and range (minimum and maximum) will be presented. For 
qualitative data, frequency distributions and percentages per category will be presented. If 
appropriate, confidence intervals around the mean or the proportion will be presented. The 
number of subjects with missing data will be presented under the “Missing” category. Missing 
values will not be included in the denominator count when computing percentages. When 
continuous data will be summarized, only the non-missing values will be evaluated for 
computing summary statistics. Any exception will be declared.  
 
For the purpose of efficacy analysis in this trial, the statistical analysis (both descriptive and 
inferential) will be done on the Study Eye. Details will be provided in the statistical analysis 
outputs as notes. In case analysis involves both eyes, it will be clearly declared. 
 
The significance level used for primary analysis will be 0.0125 one-sided for each active arm 
versus vehicle and will be determined in accordance with the Hochberg approach (Hochberg 
Y. 1988) for the key secondary endpoints (in order to preserve an overall 0.025 one-sided). 
Unless otherwise specified, the significance level used for other statistical testing will be 0.05 
and two-sided tests will be used. All patient data collected on the eCRF will be listed by 
patient and center. 
 
Data transformation (e.g., log transformation) might be used in order to satisfy the assumption 
of normality requested by parametric statistical tests and models. In case such assumptions 
are not met even on the transformed data, non-parametric counterpart tests will be used. In 
case of log transformation, also a back transformation of the results will be provided in order 
to facilitate the clinical interpretation.  
 
The Statistical Analysis Plan (SAP) will be issued before database lock with more technical 
and detailed elaboration of the principal features of statistical analyses. Additional post-hoc 
analysis may be produced to further allow comparison between treatment and control, 
according to the results obtained. Any deviation from the original statistical plan (including 
unplanned analyses) will be documented in the Clinical Study Report.  
 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 89 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
of observations that come from the Vehicle group are used to derive the imputation 
model.  
2) For each imputed dataset, the change from baseline at Week 4 and Week 8 is derived. 
3) The change from baseline at Week 4 and Week 8 will then be used in a MMRM as 
described above with change from baseline as dependent variable and baseline value, 
treatment arm, visit and treatment by visit interaction as independent variable. Subject 
will be considered as cluster variable and an unstructured covariance matrix will be 
set to model the within-subject correlation.  
4) Results obtained on each imputed dataset will be combined using Rubin’s rule to draw 
inference. 
 
The adjusted estimated treatment difference between each concentration of the rhNGF new 
formulation and vehicle will be displayed together with the corresponding two-sided 95% 
confidence interval (CI) and one-sided p-value. 
 
In case both concentrations of rhNGF differ from placebo, the choice between the two 
concentrations will be based on the size of the effect (and corresponding CI), on the results of 
secondary endpoints and on safety data. 
 
10.6.3 Sensitivity and Supportive Analyses  
 
In case at least one of the two primary comparisons is statistically significant, a sensitivity 
analysis will be conducted (on the statistically significant comparison(s)).  
 
The following sensitivity analyses are defined to assess the robustness of results on the 
primary endpoint versus assumptions used in the statistical model for the main estimators. 
They will be done after having applied the hypothetical strategy for ICEs, when expected (i.e., 
after having set to missing the observed values collected in the week after the use of a 
prohibited medication): 
• The comparison between treatment and control will be performed in the FAS 
population by means of MI under the missing at random (MAR) instead of the MNAR 
assumption.  
• A tipping point strategy will be used as a sensitivity analysis for missing data for 
assessment of superiority (if shown) of rhNGF. Tipping point will assess how 
departures from MI under MNAR assumptions must be in order to overturn 
conclusions from the primary superiority analysis. Tipping point will be based on 
iterative application of MI described in § 10.6.2, where the imputed values for each 
rhNGF arms are shifted at a constant Δ to represent a worse effect in each iteration. 
The tipping points are the smallest Δs at which no statistical significance is shown 
(one-sided p≥0.0125) for each arm. Tipping point analysis will be run only if the 
superiority has been proven for at least one of the two concentrations of the rhNGF. 
The tipping point will be firstly searched in the values defined by ±SD. If not found, 
the range will be enlarged to ±2SD. 
• Analysis on complete cases only (i.e., without considering patients with missing 
primary endpoint for any reason and after having discarded any observed case after 
the ICEs under the hypothetical strategy). 
• Analysis on all observed cases (i.e., without considering patients with missing primary 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 90 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
endpoint for any reason and including data discarded due to ICEs handled under the 
hypothetical strategy). 
• Analysis on the PP set instead of FAS. 
 
Moreover, the following two supportive analyses by changing the strategies used in the 
primary estimand (therefore changing the estimand) will be done: 
• Modified strategy #1 to handle ICEs for primary estimand: 
o Treatment discontinuation: a treatment policy strategy will be applied where 
all the observed values will be used regardless of the occurrence of the ICEs. 
Missing data due to any reason will be handled by using a multiple imputation 
with a copy-reference approach (see § 10.6.2 for further details). 
o Use of a prohibited medication listed in § 6.6.1 at any time during the study: a 
hypothetical strategy will be applied where any data collected after the first 
administration of a prohibited medication will be discarded. Missing data will 
be imputed by using a multiple imputation with copy-reference approach (see 
§ 10.6.2 for further details).  
• Modified strategy #2 to handle ICEs for primary estimand: 
o Treatment discontinuation: a treatment policy strategy will be applied where 
all the observed values will be used regardless of the occurrence of the ICEs. 
Missing data due to any reason will be handled by using a multiple imputation 
with a copy-reference approach (see § 10.6.2 for further details). 
o Use of a prohibited medication listed in § 6.6.1 in the week before any 
assessment of SANDE: a composite strategy will be applied where any data 
collected in the week after the occurrence of the ICE (if present) will be 
replaced by a value worse than all values observed for SANDE at week 8.  
 
The modified estimand #1 will be analysed as described for the primary estimand. 
 
For the modified estimand #2, the trimmed approach by Permutt and Li (Permutt T and Feng 
L. 2017) will be used. This method provides an exact test that does not require any modeling 
assumption. The estimand of the primary analysis is the difference between treatment groups 
in mean SANDE change from baseline to week 8 in the FAS population, including all patients 
who have no SANDE measurement at week 8 for any reason. The exact imputed value does 
not matter, as long as it is worse than all values observed in patients with SANDE 
measurements at week 8. The only requirement for this method is that it must be reasonable 
to consider the outcome of dropouts as worse than the highest SANDE Global Score of the 
completers. 
 
The estimand is the between group difference in mean change from baseline in the percentage 
k subpopulation with the best SANDE values at week 8 (i.e., with lowest values, since for 
SANDE questionnaire lower values are better). For this analysis k=50%, 70%, and 90% will 
be used. The method is based on an exact permutation test for the null hypothesis that the 
treatment distributions for the considered outcome at week 8 are equal. 
 
Further details on sensitivity and supportive analyses will be provided in the SAP.  
 
 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 9 1  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
 
1 0. 6. 4  Sec o n d ar y a n d E x pl or at or y A n al ysis  
 
If t he pri mar y a nal ysis of pri mar y e n d p oi nt lea ds t o rejecti o n of t he n ull h y p ot heses, ke y 
sec o n dar y e n d p oi nts will be teste d b y usi n g t he H oc h ber g a p pr oac h  (H oc h ber g Y. 1 9 8 8 ) t o 
s h o w s u peri orit y of eac h c o nce ntrati o n f or w hi c h s u peri orit y vs. v e hicle h as bee n pr o ve n i n 
t he pri mar y a n al ysis. 
 
T his test strate g y pr otects t he fa mil y -wise false p ositi ve err or rate at t he o verall o ne -si de d 
0. 0 1 2 5  le vel f or eac h c o nce ntrati o n vs. ve hicle. Wit h 9 2 s u bjects  e val ua ble  per treat me nt 
gr o u p, t he st u d y w o ul d ha ve a p pr o xi matel y a p o wer of 6 7 %  t o test t he e n d p oi nt wit h t he 
s mallest p-val ue i n t he w orst -cas e sce n ari o w here t he first 2  e n d p oi nt s teste d are n ot 
statisticall y si g nifica nt (i.e., wit h a n a dj uste d al p ha le vel of 0. 0 0 4 1 7 ). 
 
Ke y sec o n dar y e n d p oi nts will be a nal yze d wit h t he sa me strate g y descri be d f or t he pri mar y 
e n d p oi nt f or t he m ulti ple i m p utati o n . M ulti ple i m p utati o n f or Sc hir mer -I t est will be d o n e 
o nce f or b ot h c o nti n u o us a n d dic h ot o m o us e n d p oi nts t hat will be d eri ve d ( i.e., c ha n g e fr o m 
baseli ne a n d i m pr o ve me nt ≥ 1 0 m m/ 5 mi n will be deri ve d after t he i m p utati o n of t he 
c o nti n u o us val ues).  A n A N C O V A m o del wit h treat me nt a n d baseli ne v al ue will be us e d 
i nstea d of t he M M R M f or t he t w o c o nti n u o us e n d p oi nt s si nce t hese are e val uate d  at Wee k 4. 
F or t he s a me reas o n, o nl y baseli ne a n d wee k 4 d ata will be use d i n t he m ulti ple i m p utati o n 
descri be d i n §  1 0. 6. 2 . T h e bi nar y ke y s ec o n da r y e n d p oi nt will be a nal yze d i n a nal o g y wit h 
t he ot her ke y sec o n dar y e n d p oi nts, b ut a l o gistic m o del will be use d i nstea d of a n A N C O V A 
m o del  wit h baseli ne val u e a n d treat me nt as c o v ari ates.  
 
I n cas e of n ot rej ecti o n of t he n ull h y p ot h esis ( or f or t he c o nce ntrati o n f or w hi c h t he 
s u peri orit y is n ot s h o w n), t he a b o ve t esti n g strate g y will n ot be perf or me d. I nst ea d, 
i n de pe n de ntl y of res ults o n pri mar y e n d p oi nt, descri pti ve i n nat ure a nal yses will be perf or me d 
o n all ke y sec o n d ar y a n d sec o n dar y e n d p oi nts at  eac h a vaila ble ti me p oi nt b y mea ns of 
descri pti ve statistics a n d b y a p pr o priate para m etri c or n o n -para metri c tests de pe n di n g o n t he 
distri b uti o n of eac h p ara meter. C ha n ge fr o m b aseli ne val ues a n d s hift ta bl es vers us b aseli ne 
ma y be s u m marize d f or all a vail a ble p ost-baseli ne visits.  
 
F urt her details will be pr o vi de d i n t he S A P.  
 
Details o n t he statistical met h o ds t hat will be use d f or t he a d diti o nal o bjecti ve ( i.e., t he 
vali dati o n of t he Italia n v ersi o n of t he 
) will be pr o vi de d i n t he S A P.  
 
1 0. 6. 5  A n al ysis of S afet y V ari a bles  
 
A d verse e v e nts ( A Es) will be c o de d b y S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T), 
usi n g t he Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A).  
 
Treat me nt -e mer ge nt A Es ( T E A Es) are all e ve nts occ urri n g or w orse ni n g  after t he first d os e 
of t he I M P. T E A Es will be prese nte d b y treat me nt ar m i n ter ms of n u m ber of A Es a n d t heir 
i nci de nce b y S yste m Or g a n Class ( S O C) a n d Preferre d Ter ms ( P T) usi n g Me d D R A. A nal yses 
will be pr o vi de d als o b y seri o us ness, relati o ns hi p t o treat me nt, se verit y , a n d st u d y peri o d 
C CI

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 92 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
(treatment or follow-up). 
 
Individual AEs will be listed in patient data listings. 
 
10.6.6 Missing Data 
 
All reasonable efforts will be made to reduce the rate of missing data by encouraging the 
patients to attend the scheduled visits, even if they have interrupted the study treatment. 
Investigators will be trained about the importance of patient retention and full data capture. 
Also, all reasonable attempts should be made by the Investigators to emphasize continued 
subject’s participation for the full duration of the trial. However, in order to minimize missing 
data, if a patient cannot refer to the site for a planned visit, the Investigator will try to obtain 
any relevant information from the patients, including documents results available from local 
medical care. 
 
10.6.7 Intermediate Analyses for the DMC 
 
Not applicable.  
 
10.6.8 Specification of Subgroups for Analysis 
 
Subgroup analyses of primary and secondary endpoints will be performed on the following 
subgroups of baseline characteristics: 
• Age class (≤Median, >Median) 
• Race/ethnicity 
• Gender 
• Region (EU, US) 
• Etiology of dry eye 
• Medical history 
• Concomitant medication 
 
Statistical details and potential new subgroups definitions will be reported in the SAP. 
 
11 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND TRIAL 
OVERSIGHT 
 
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. 
 
11.1 
REGULATORY AND ETHICAL CONSIDERATIONS 
 
United States. Approval by the Institutional Review Board (IRB) before the start of the study 
will be the responsibility of the Principal Investigator (PI). A copy of the approval letter will 
be supplied to the Sponsor, along with a roster of IRB members or the US Department of 
Health and Human Services (DHHS) general assurance number. During the course of the 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 93 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
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. For institutions/PIs that also utilize the study central IRB, the main study protocol 
and other main study related materials will be submitted to the study central IRB by the 
Sponsor/CRO on behalf of the PI. All documents that are site-specific will be submitted by 
the PI directly to the central IRB and local IRB, as applicable. 
 
Europe. This study will be carried out in full compliance with the guidelines of the 
independent ethics committee (IEC) and government agencies of each respective country as 
well as Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 
April 2014 on clinical trials on medicinal products for human use. Before the study begins, 
the Sponsor will require approval from an IEC and Regulatory agency. During the course of 
the study, the Sponsor or authorized contract research organization (CRO) representative will 
provide timely and accurate reports to the IEC on the progress of the study, at intervals not 
exceeding 1 year (or as appropriate) and will notify the IEC of SUSARs or other significant 
safety findings. The study Protocol, eCRF sample, ICF, information sheet advertisements, and 
amendments (if any) will be approved by the EC in conformance with the EU Regulation 
(EU) No 536/2014), and local regulations.  
 
11.2 
COMMITTEES 
 
Data Monitoring Committee (DMC)/ Data Safety Monitoring Board (DSMB) and Data Safe 
Monitoring Board (DSMB) are not required for this trial considering the following points: 
• The drug under investigation is well characterized and known for not harming patients. 
• This clinical trial does not foresee an interim analysis. 
• The study design is not complex and already performed in other clinical trial in DED. 
• The study does not have a long duration. 
 
11.3 
INFORMED CONSENT PROCESS 
 
Patients, after being given adequate information and explanation related to the study, will give 
voluntary and written informed consent before participating in any study-related procedures.  
 
The informed consent statement contains all the elements of informed consent and contains 
all the core elements and mandatory statements as defined in the Code of Federal Regulation 
(CFR). Signed copy of the ICF and the Patient Information Sheet will be given to the patient, 
and both signed documents will be placed in the Investigator’s Site File. A unique Patient 
identification (PID) number will be assigned according to § 6.4 of the Protocol at the time the 
patient signs the ICF.  
 
Each patient will read or be read (if he/she cannot read or write), assent understanding of, and 
sign or thumbprint an instrument of informed consent, after having had an opportunity to 
discuss them with the Investigator before signing. 
 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 94 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
Patients have the right to choose to stop their participation in the clinical trial at any time 
during the study.  
 
11.4 
DATA PROTECTION AND 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 eCRFs, Questionnaires or Patient Diary, patients will be identified ONLY by the 
assigned patient number.  
 
If patient names are included on copies of documents submitted to Dompé or CRO, 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. 
 
11.5 
EARLY SITE CLOSURE OR TRIAL TERMINATION 
 
Dompé reserves the right to terminate the study in its entirety or at a specific study center at 
any time on the basis of new information regarding safety or efficacy, or if study progress is 
unsatisfactory (poor/ no patient recruitment, inadequate research staffing, site quality issues, 
lack of adherence to protocol etc.), or for other valid administrative reasons. 
 
11.6 
QUALITY TOLERANCE LIMITS 
 
Gross noncompliance (see § 6.5 for derivation of compliance by using the number of drops 
collected in the diary) will be defined as compliance lower than 80% or greater than 120% 
and in case of gross noncompliance the patient will be excluded from the Per Protocol dataset.  
Quality tolerance limits are indicated in the centralized monitoring plan. 
 
11.7 
DATA QUALITY ASSURANCE 
 
The study site may be audited by CRO on behalf of the Dompé or inspected by a Regulatory 
Agency on one or more occasions. The Investigator may be informed in advance of such a 
visit. 
 
11.8 
DISSEMINATION OF CLINICAL TRIAL DATA AND PUBLICATION 
POLICY 
 
All data generated in this study will be the property of Dompé.  
 
The study results will be communicated in full to the related competent authorities for the 
countries involved by the submission of a complete Clinical Study Report. On an exceptional 
basis, Dompé may temporarily delay registration of certain data elements (e.g., compound, 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 95 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
name, outcome, measures etc.) to seek necessary intellectual property protection. This is 
because early disclosure of such data could, in some circumstances, prevent or negatively 
impact patentability. 
 
Publication of the results by the PI will be subject to mutual agreement between the PI and 
Dompé. 
 
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. 
 
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). 
 
11.9 
MONITORING ACTIVITIES 
 
Before any patient enters the study, a representative of Dompé/CRO, 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 progress of the study will be periodically monitored by the Dompé 
representative, a monitor (CRA), 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, the source 
documents, the 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/Data Management 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.  
 
The CRA will visit the study site on a regular basis to perform Source Data Verification (SDV) 
and/or will perform remote checks to ensure that the study is conducted and documented in 
accordance with this protocol, ICH GCP guidelines, regulatory requirements, and any study 
specific documents such as eCRF completion guidelines. 
 
Monitoring visits or remote monitoring will be conducted to confirm that e.g.: 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 96 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
• The investigational team is adhering to the study Protocol. 
• Informed consent has been adequately obtained from all participants prior to study 
specific procedures being performed. 
• AEs have been reported and followed up as required and any SAEs have been reported 
according to the requirements. 
• Data are being accurately recorded in the eCRFs in a timely manner. 
• The Investigator’s Site File is being adequately maintained. 
• Facilities and staffing resources are, and remain, acceptable and sufficient throughout 
the study. 
• The Investigator and the site are receiving sufficient information and support 
throughout the study. 
 
Moreover, during on-site monitoring visits the data recorded in the eCRFs, source documents 
and other study-related records will be compared against each other in order to ensure accurate 
data that reflect the actual existence of the subject in the study i.e. source data verification. 
 
Monitoring procedures are described in the concerned Standard Procedural Documents of the 
CRO in charge and in the Monitoring Plan, which also encompasses situational changes, e.g., 
intermediate switch to remote monitoring only if site visits are not possible; details concerning 
the nature and extent of SDV are also provided in the Monitoring Plan. 
 
11.10 
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. 
 
11.11 
SERIOUS BREACHES MANAGEMENT  
 
Process (as defined under art. 52 of European Regulation 536/2014):  
 
Institutions, CRO, and investigators involved in the clinical trial management must notify the 
Sponsor about any Serious Breaches and suspected Serious Breach within 24 hours from the 
identification of such Serious Breach.  
If not otherwise specified in relevant study plans, manuals and agreements with the contracted 
CRO, the Sponsor will manage the event according to the internal process for the management 
and notification of the relevant competent authority. 
 
Definitions:  
Serious Breach: a breach likely to affect to a significant degree the safety and rights of a 
subject, or the reliability and robustness of the data generated in the clinical trial.  
 
Suspected Serious Breach: an incident, which at the time of communication from the 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 97 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
investigators or from the service providers to the Sponsor, has not yet been assessed by the 
Sponsor to be a Serious Breach. 
 
12 
DATA HANDLING AND RECORD KEEPING 
 
The Investigator will allow designated Sponsor representatives, including staff from the CRO, 
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 
all related information to substantiate the integrity of the data collected during the trial. 
 
12.1 
SOURCE DOCUMENTS AND CASE REPORT FORMS 
 
Main Data Management activities and procedures will be accurately described in the Data 
management Plan (DMP), created by CRO and approved by Dompé.  
 
All data relating to the study will be recorded on eCRFs to be provided by the CRO, through 
the EDC system. eCRF data are the sole property of Dompé and should not be made available 
in any form to third parties, except for authorized Dompé designee or representatives of 
appropriate Health/Regulatory Authorities, without written permission from Dompé. 
 
Data collection will involve the use of an EDC system, to which only authorized personnel 
will have access. In addition to periodic monitoring occurring within the system by 
Dompé/CRO monitors, programmatic edit checks will be used to review the data for 
completeness, logic, and adherence to study protocol (following the Data Validation Plan). 
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. 
Reconciliation of study data and SAEs between Clinical and Drug Safety database will be 
performed by the CRO on an ongoing basis and before the database lock. Procedure will be 
detailed in the DMP. 
 
Encoding of specific data will be carried out by the CRO. For this trial, Medical History, 
Adverse Events and Concomitant Medication will be coded; Medical Dictionary for 
Regulatory Activities (MedDRA) and World Health Organisation (WHO)-DRUG Enhanced 
dictionaries will be used, version number of each dictionary will be documented in the DMP. 
Dictionary version numbers will not be changed during the study.  
 
eCRF is required and should be completed for each patient that signed the informed consent, 
including the screening failures. Source documents should be available to support all the data 
recorded in the eCRF; location of source documents, including those for which the eCRF 
might be accepted as being the sole source document, will be specified and listed at the Site 
Initiation Visit. 
 
All data collected in the context of this study will be stored and evaluated per regulatory 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 98 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
requirements and applicable guidance 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 site, along with adequate source 
documentation, according to ICH requirements. All study records must be available for audit 
by Dompé; its authorized representatives; and Regulatory Inspection by Regulatory 
Authority. 
 
The investigator/institution should maintain adequate and accurate source documents and trial 
records that include all pertinent observations on each of the site’s trial subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, complete, consistent, 
enduring and available. Changes to source data should be traceable, should not obscure the 
original entry, and should be explained, if necessary, via an audit trail. 
 
12.1.1 Systems Validation 
 
Please refer to the Data Management Plan (DMP) created by the CRO and approved by the 
Sponsor. 
 
12.2 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE TRIAL  
 
The following documents will be required from the Investigator prior to the site Initiation 
Visit: 
• Current, signed, and dated Curriculum Vitae of Principal Investigator and any Sub-
Investigators/Site Study Staff. Document updates should be provided at least every 
two years. 
• A signed page of the final protocol and any amendments. 
• A signed copy of the study Financial Agreement/Clinical Study Agreement with the 
CRO, 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 for US and on the Declaration of Interest (DoI) 
for EU. If applicable, the PI will provide an updated financial disclosure agreement to 
the Sponsor 1 year after the completion of the study. 
• IRB/EC approval to conduct the study, including IRB/EC approval of protocol and 
any amendment, ICF, and any patient facing material. 
• Documents of GCP training for PI and all Sub-Investigators listed on the Form FDA 
1572 and according to ICH E6 (R2) for GCP. 
• Other documents may be required and will be described in the essential document 
checklist outlined in the CRO Procedural Manual for site initiation and activation. 
 
A copy of the IRB/IEC approval will be sent to Dompé along with relevant correspondence 
with the IRB/IEC, a roster of IRB/IEC members or the US Department of Health and Human 
Services general assurance number. The study will not be started until full written approval 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 99 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
has been obtained from the appropriate IRB/IEC. The letter of approval should be dated and 
should specify the study references (e.g., protocol number) and the date of the documents 
which were reviewed and approved. 
 
The CRO appointed by Dompé, or the PI will submit any future amendment to the Protocol 
to the IRB/IEC which granted the original approval. Any amendment will be implemented 
only when full approval has been obtained from the appropriate IRB/IEC, except for those 
amendments which involve only logistical or administrative aspects of the study. 
 
The current version of the Investigator brochure.is also required to be submitted to IRB/IEC 
prior to trial initiation. The CRO appointed by Dompé, or the PI will also send to the IRB/IEC 
any updated Investigator’s Brochure. 
The CRO appointed by Dompé, or the PI will also submit to the IRB/IEC which approved the 
protocol, at least annually, any required progress reports and study update, and will inform 
the IRB/IEC of the termination of the study. The CRO appointed by Dompé, or the PI will 
report to the IRB/EC any serious ADRs, life-threatening problems or deaths occurred at other 
sites participating to this clinical trial and/or in other clinical studies. 
 
12.3 
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 (e.g., in Europe 25 years). 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 ICFs from all patients who consented, hospital records and other source documents, 
and all other documentation included in the Investigator’s Site File and Pharmacy/Dispensing 
File.  
 
The Investigator will inform Dompé of the storage location of these essential documents and 
must contact Dompé before disposing of any. If the Investigator wishes to assign the files to 
someone else or to remove them to another location, he/she should consult with Dompé about 
this change.  
 
No records may be transferred to another location or party without written notification to the 
Sponsor. 
 
Dompé will inform the Investigator in writing when these documents no longer need to be 
retained. 
 
12.4 
LONG-TERM SAMPLE RETENTION 
 
We will not acquire any biological samples as part of this study. 

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 128 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
14 
REFERENCES 
 
1) Levi-Montalcini R. The nerve growth factor 35 years later. Science (New York, N.Y.). 
1987; 237: 1154-62.  
2) Lambiase A, Mantelli F, Sacchetti M, Rossi S, Aloe L, Bonini S. Clinical applications 
of NGF in ocular diseases. Arch Ital Biol. 2011;149:283-92. 
3) Craig JP, et al. TFOS DEWS II Definition and Classification Report. Ocul. Surf. 
2017;15: 276–83. 
4) Lambiase A, Sacchetti M, Bonini S. Nerve growth factor therapy for corneal disease. 
Curr Opin Ophthalmol. 2012;23:296-302.  
5) Coassin M, Lambiase A, Costa N, De Gregorio A, Sgrulletta R, Sacchetti M, Aloe L, 
Bonini S. Efficacy of topical nerve growth factor treatment in dogs affected by dry 
eye. Graefe’s Arch Clin Exp Ophthalmol 2005;243:151-5. 
6) Lee HK, Ryu IH, Seo KY, Hong S, Kim HC, Kim EK. Topical 0.1% prednisolone 
lowers nerve growth factor expression in keratoconjunctivitis sicca patients. 
Ophthalmology. 2006;113:198-205. 
7) Bonini S, Lambiase A, Rama P, Caprioglio G, Aloe L. Topical treatment with nerve 
growth factor for neurotrophic keratitis. Ophthalmology 2000;107:1347-51. 
8) Ríos JD, Ghinelli E, Gu J, Hodges RR, Dartt DA Role of neurotrophins and 
neurotrophin receptors in rat conjunctival goblet cell secretion and proliferation. 
Invest. Ophthalmol. Vis. Sci. 2007; 48:1543–51. 
9) OXERVATE ™ US package insert. Boston, MA: Dompe’ U.S. Inc; 2018 
10) Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988;75:800-2. 
11) Permutt T and Feng L. Trimmed means for symptom trials with dropouts. 
Pharmaceuticals Statistics. 2017;16:20-28. 
 
 
 
 

 
 
 
 
 
 
 
Pr ot oc ol N G F 0 1 2 3   
 
 
P a ge 1 2 9  of 1 3 0  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
FI N A L v. 3. 0  A me n d me nt 2. 0  1 1/ M A R/ 2 0 2 4                                                               C O N FI D E N TI A L  
 
1 5  
A P P E N DI C E S  
 
A P P E N DI X 1 -S P O N S O R A P P R O V A L P A G E  
 
A 4 -Wee k, P hase II, M ultice nter, Ra n d o mize d, 
D o u ble -Mas ke d, Ve hicle - C o ntr olle d, Parallel 
Gr o u p St u d y Wit h 4 Wee ks of F oll o w -U p t o E val uate Safet y a n d Efficac y of a ne w f or m ulati o n 
of Rec o m bi na nt H u ma n Ner ve Gr o wt h Fact or (r h N G F) E ye Dr o p S ol uti o n at t w o differe nt 
C o nce ntrati o ns i n patie nts wit h Dr y E ye Diseas e  
 
 
 
 
 
 
Si g nat ure  
 
 
 
 
 
 
Date ( d d/ m m m/ y y y y)  
 
 
 
 
Si g nat ure  
 
 
 
 
 
 
Date ( d d/ m m m/ y y y y)  
 
 
 
 
Si g nat ure  
 
 
 
 
 
 
Date ( d d/ m m m/ y y y y)  
 
 
 
 
Si g nat ure  
 
 
 
 
 
Date ( d d/ m m m/ y y y y)  
 
 
 
P P D
P P D
P P D
P P D

 
 
 
 
 
 
 
Protocol NGF0123  
 
 
Page 130 of 130 
_________________________________________________________________________________ 
 
FINAL v.3.0 Amendment 2.0 11/MAR/2024                                                              CONFIDENTIAL 
 
 
APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE 
 
 
Investigator’s Statement 
 
I have read trial protocol (NGF0123: A 4-Week, Phase II, Multicenter, Randomized, Double-
Masked, Vehicle- Controlled, Parallel Group Study With 4 Weeks of Follow-Up to Evaluate 
Safety and Efficacy of a new formulation of Recombinant Human Nerve Growth Factor 
(rhNGF) Eye Drops Solution at two different Concentrations in patients with Dry Eye 
Disease) and agree to conduct the trial as outlined in the Protocol, and in accordance with the 
Declaration of Helsinki, ICH-GCP and any local regulations, being responsible for personally 
supervise the trial conduct and ensure trial staff complies with Protocol requirement. 
 
 
Name of Principal Investigator: _______________________________________ 
 
 
 
(Block letters)  
 
 
Signature:  ____________________________________     Date: _____________ 
 
 
 
dd/mmm/yyyy