Conditions: Dry Eye
Keywords: Sjorgen's dry eye
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 104
Healthy volunteers: no

Brief summary:
Primary objectives

* To compare the efficacy of cenegermin vs vehicle in Schirmer I test (without anaesthesia) \>10mm/5min at Week 4 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Symptom Assessment in Dry Eye questionnaire (SANDE) global score at Week 12 by testing the superiority.

Secondary objectives

* To compare the efficacy of cenegermin vs vehicle in Schirmer I test at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute \[NEI\] scales) at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in Tear Film Break-Up Time (TFBUT) at Week 4, 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in SANDE scores at Week 8, 12 and 16 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in worsening in symptom scores (SANDE) and/or NEI score at Week 4 by testing the superiority.
* To compare the efficacy of cenegermin vs vehicle in impact of dry eye on everyday life (IDEEL) questionnaire at Week 4, 8, 12 and 16 by testing the superiority.

Detailed description:
This is a 4 week phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy of cenegermin ophthalmic solution at 20 mcg/mL solution versus vehicle, in patients with severe Sjogren's dry eye disease.

During the screening all procedures for inclusion and exclusion were performed. From the day of screening the patients stopped any kind of further treatment, except commercially available preservative free artificial tears provided by Sponsor.

At the end of the wash out period, patients meeting the entry criteria for this study were randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL TID or vehicle TID.

During the 4 weeks of masked treatment only the administration of IMP was allowed.

During the follow up period, the patient could administer additional artificial tear eye drops, provided by Sponsor, only if strictly needed, and should document in the patient's diary the number of additional drops administered for each eye.

Patients were then followed up for efficacy and safety endpoints until week 16 and for safety endpoints until week 24.

The total duration of the study was 25 weeks including 1 week of screening.

Arms:
arm 1: One drop of cenegermin 20 mcg/mL (rhNGF 20 mcg/mL) in the pharmaceutical form of ophthalmic sterile solution was instilled in both eyes three times daily (TID), every six hours. arm 2: One drop of vehicle ophthalmic solution was instilled in both eyes TID (every six hours).

Interventions: intervention 1: Oxervate intervention 2: Vehicle
Intervention descriptions: intervention 1: Oxervate®, an ophthalmic solution containing cenegermin 20 mcg/mL, which is a recombinant human Nerve Growth Factor (rhNGF); one drop of the test product will be instilled in both eyes three times daily (TID). intervention 2: Vehicle will be instilled with the same scheme of the test product

Protocol document:
Prot_000.pdf: 
 
 
 
 
Study Protocol: NGF0121 
 
 
Version No. 6.0 – Final 26/JAN/2022 
 
 
 
 
Page 1 of 81 
 
 
CLINICAL STUDY PROTOCOL 
 
Title: A 4-week, Phase III, multicenter, double-masked, vehicle-controlled clinical study to evaluate safety 
and efficacy of Oxervate® (cenegermin) 20 mcg/mL ophthalmic solution versus vehicle, in patients with 
severe Sjogren’s dry eye disease (PROTEGO-1 study) 
 
 
Study Number: 
NGF0121  
 
Study Name:  
PROTEGO-1 
 
IND: 
115892 
 
EUDRACT:                                    2021-003346-21 
 
Investigational Product: 
Cenegermin  
 
Phase of the study: 
 III 
 
 
Protocol Version - Date: 
Version No. 6.0 – 26/JAN/2022 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential information 
that is the property of Dompé farmaceutici s.p.a. It is understood that the information will not be used, 
divulged, or published without prior written consent of Dompé farmaceutici s.p.a., except to the extent such 
disclosure is required by applicable laws and regulations. 
 
 
 
 




 
 
 
 
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TABLE OF CONTENTS 
CONTACT INFORMATION ............................................................................................................... 2 
Table of Contents ................................................................................................................................... 3 
List of Abbreviations and Definitions of Terms   ................................................................................ 7 
1. 
STUDY SYNOPSIS ........................................................................................................... 9 
2. 
SCHEDULE OF EVALUATIONS ................................................................................. 16 
2.1. 
BACKGROUND INFORMATION .................................................................................. 17 
2.1.1. 
Nerve Growth Factor - Overview ...................................................................................... 17 
2.1.2. 
Chemical And Formulation Data ....................................................................................... 18 
2.1.3. 
Rationale for cenegermin (rhNGF) therapy in patients with dry eye ................................ 18 
2.2. 
A SUMMARY OF CLINICAL DATA ............................................................................. 20 
2.3. 
STUDY RATIONALE ...................................................................................................... 21 
2.3.1. 
Risk assessment/benefit evaluation.................................................................................... 22 
2.3.2. 
Description of the Investigational Product ........................................................................ 22 
3. 
OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN ............................ 23 
3.1. 
STUDY OBJECTIVES ...................................................................................................... 23 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE ................................................................... 23 
3.3. 
OVERALL STUDY DESIGN ........................................................................................... 23 
3.3.1. 
Rationale for Selection of dose, control group and treatment schedule in the study ......... 24 
4. 
SELECTION OF STUDY POPULATION ................................................................... 26 
4.1. 
INCLUSION CRITERIA .................................................................................................. 26 
4.2. 
ELIGIBLE EYE ................................................................................................................. 29 
4.3. 
ASSIGNMENT OF PATIENT NUMBER ........................................................................ 29 
4.4. 
RANDOMIZATION ......................................................................................................... 29 
4.5. 
MASKING ......................................................................................................................... 29 
5. 
STUDY MEDICATION .................................................................................................. 31 
5.1. 
DESCRIPTION OF PRODUCT ........................................................................................ 31 
5.1.1. 
Presentation of Non Investigational Medicinal Product (NIMP) ....................................... 31 
5.1.2. 
Presentation of Investigational Medicinal Product ............................................................ 31 


 
 
 
 
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5.2. 
FORMULATION AND PACKAGING ............................................................................ 32 
5.3. 
STORAGE AND HANDLING OF IMP ........................................................................... 34 
5.4. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION ................................ 35 
5.4.1. 
Administration route .......................................................................................................... 35 
5.4.2. 
Dose regimen ..................................................................................................................... 35 
5.5. 
ACCOUNTABILITY OF THE IMP ................................................................................. 35 
5.6. 
CONCOMITANT MEDICATION .................................................................................... 36 
6. 
STUDY PROCEDURE AND ASSESSMENTS ............................................................ 37 
6.1. 
SCREENING AND RANDOMIZATION VISITS ........................................................... 38 
6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS .................................................. 40 
6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT ................................ 47 
6.3.1. 
Primary Reason For Discontinuation From The Study ...................................................... 47 
6.3.2. 
Discontinuation procedures ............................................................................................... 48 
6.3.3. 
Replacement procedure ...................................................................................................... 48 
6.4. 
END OF STUDY ............................................................................................................... 49 
7. 
ENDPOINTS .................................................................................................................... 50 
7.1. 
STUDY ENDPOINTS ....................................................................................................... 50 
7.1.1. 
Co-Primary endpoints ........................................................................................................ 50 
7.1.2. 
Secondary endpoints .......................................................................................................... 50 
7.1.3. 
Exploratory endpoint ......................................................................................................... 50 
7.1.4. 
Safety endpoint .................................................................................................................. 51 
8. 
EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION ............ 52 
8.1. 
DEFINITIONS................................................................................................................... 52 
8.2. 
ADVERSE EVENT (AE) MONITORING ....................................................................... 54 
8.3. 
RECORDING .................................................................................................................... 54 
8.3.1. 
Relationship of AEs to the Investigational Product ........................................................... 55 
8.3.2. 
Severity of AEs .................................................................................................................. 55 
8.4. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 56 
8.4.1. 
Reporting Procedure for Investigators to Dompé and CRO .............................................. 56 
8.4.2. 
Conditions that should not be reported as serious adverse events ..................................... 57 
8.4.3. 
Reporting Procedure to EC/IRB and to Regulatory Authorities ........................................ 57 
8.4.4. 
Periodical Reporting to Regulatory Authorities ................................................................ 58 
8.5. 
UNMASKING OF THE STUDY TREATMENT ............................................................. 59 
8.6. 
FOLLOW-UP OF PATIENTS WITH ADVERSE EVENTS (AES) ................................ 59 
8.7. 
PREGNANCY IN THE CLINICAL TRIAL ..................................................................... 60 


 
 
 
 
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8.8. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ....................... 60 
8.9. 
OVERDOSE ...................................................................................................................... 60 
9. 
STATISTICS .................................................................................................................... 61 
9.1. 
SAMPLE SIZE .................................................................................................................. 61 
9.2. 
ANALYSIS POPULATION .............................................................................................. 61 
9.3. 
OVERVIEW OF PLANNED STATISTICAL ANALYSES ............................................ 61 
9.4. 
STATISTICAL METHODOLOGY .................................................................................. 62 
9.4.1. 
General Considerations ...................................................................................................... 62 
9.4.2. 
Primary Estimand .............................................................................................................. 62 
9.4.3. 
Analysis of efficacy variables ............................................................................................ 62 
9.4.4. 
Analysis of 
variables ...................................................................................... 66 
9.4.5. 
Analysis of safety variables ............................................................................................... 66 
9.4.6. 
Subgroup analysis .............................................................................................................. 66 
9.4.7. 
Missing data ....................................................................................................................... 67 
10. 
ETHICAL CONSIDERATIONS .................................................................................... 68 
10.1. 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE 68 
10.2. 
ETHICAL CONDUCT OF THE STUDY ......................................................................... 68 
10.3. 
DATA MONITORING COMMITTEE ............................................................................. 68 
10.4. 
PATIENT INFORMATION AND CONSENT ................................................................. 69 
10.5. 
CONFIDENTIALITY ....................................................................................................... 69 
10.6. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION69 
11. 
DATA HANDLING AND RECORD KEEPING .......................................................... 70 
11.1. 
CASE REPORT FORMS .................................................................................................. 70 
11.2. 
DATA MANAGEMENT .................................................................................................. 70 
11.3. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING THE 
STUDY .............................................................................................................................. 71 
11.4. 
ESSENTIAL DOCUMENT RETENTION ....................................................................... 72 
12. 
STUDY MANAGEMENT ............................................................................................... 73 
12.1. 
REGULATORY BODY APPROVAL .............................................................................. 73 
12.2. 
MONITORING .................................................................................................................. 73 
12.3. 
ACCESS TO RECORDS ................................................................................................... 74 
12.4. 
AUDIT AND INSPECTION ............................................................................................. 74 
12.5. 
PROTOCOL AMENDMENTS ......................................................................................... 74 
CCI


 
 
 
 
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12.6. 
DISCONTINUATION OF THE STUDY ......................................................................... 74 
12.7. 
PUBLICATIONS............................................................................................................... 75 
13. 
REFERENCE ................................................................................................................... 76 
14 
APPENDICES .................................................................................................................. 78 
14.1 APPENDIX 1-SPONSOR APPROVAL PAGE ............................................................................ 78 
14.2 APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE ............................................................ 79 
14.3 APPENDIX 3 AMERICAN-EUROPEAN CONSENSUS CRITERIA FOR SJÖGREN’S 
SYNDROME ..................................................................................................................... 80 
 
 


 
 
 
 
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List of Abbreviations and Definitions of Terms 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
BCDVA 
Best Corrected Distance Visual Acuity  
BID 
Bis in die (twice a day) 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
RC 
Reading Center 
CRO 
Contract Research Organization 
DE 
Dry Eye 
DED  
Dry Eye Disease 
DHHS 
Department of Health and Human Services 
DNA 
Deoxyribonucleic acid 
DSUR 
Development Safety Update Report 
e-CRF/CRF 
Electronic/Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
ETV 
Early Termination Visit 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPI 
First Patient In 
FPFV 
First Patient First Visit 
FU 
Follow Up 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDEEL 
Impact of Dry Eye on Everyday Life 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUD 
Intra Uterine Device 
LNGFR 
Low-affinity nerve growth factor receptor 


 
 
 
 
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LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for regulatory activities 
mcg/mL 
micrograms/millilitre 
NEI 
National Eye Institute 
NIMP 
Non-Investigational Medicinal Product 
NGF 
Nerve Growth Factor 
NK 
Neurotrophic Keratitis  
PI 
Principal Investigator 
PID 
Patient Identification number 
PP 
Per Protocol Population 
PT 
Preferred Term  
p75NTR 
p75 Neurotrophin Receptor 
rhNGF 
recombinant human Nerve Growth Factor 
RP 
Retinitis Pigmentosa  
SAE 
Serious Adverse Event 
SAF 
Safety population 
SANDE 
Symptom Assessment iN Dry Eye 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
 
 
SLE 
Slit-Lamp Examination 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TFBUT 
Tear Film Break-Up Time  
TID 
Ter in die (thrice a day) 
TrkA 
Tropomyosin receptor kinase A 
USA 
United States of America 
Vs 
Versus 
§ 
Section 


 
 
 
 
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1. STUDY SYNOPSIS  
 
CLINICAL STUDY SYNOPSIS:  
Study Number  
NGF0121 
Title of Study  
A 4-week, Phase III, multicenter, double-masked, vehicle-
controlled clinical study to evaluate safety and efficacy of 
Oxervate® (cenegermin) 20 mcg/mL ophthalmic solution 
versus vehicle, in patients with severe Sjogren’s dry eye 
disease (PROTEGO-1 study) 
Study Name 
PROTEGO-1 
IND N° 
115892 
EUDRACT:                                 2021-003346-21 
Study Centers (Country)  
Approximately 10 study sites in Europe and USA 
Development Phase  
Phase III 
Objective  
The primary objective of this study is to assess the efficacy 
and safety of cenegermin ophthalmic solution at 20 mcg/mL 
concentration administered three times daily for 4 weeks in 
patients with severe Sjogren’s dry eye disease. 
Study Design and 
Methodology  
This is a phase III,  multicenter, double-masked, parallel-
arm, vehicle-controlled trial. 
Number of Patients  
Randomization 1:1 of 90 patients to cenegermin ophthalmic 
solution 20 mcg/mL TID or vehicle ophthalmic solution TID 
for 4 weeks. Assuming a dropout rate of 10%, up to 100 
patients are expected to be enrolled. 
Main Inclusion criteria  
1. Male or female aged ≥ 18 years 
2. Patients with a confirmed diagnosis of Sjogren’s syndrome or other autoimmune disease 
known to induce Sjogren’s Dry Eye Disease (DED). 
3. Patients with severe Sjogren’s dry eye disease characterized by the following clinical 
features: 
a. Corneal and/or conjunctival staining with fluorescein using National Eye 
Institute (NEI) grading system ≥3 
b. SANDE questionnaire global score >25 mm 
c. Schirmer test I (without anaesthesia) ≥2 ≤5mm/5min  
4. The same eye (eligible eye) must fulfill all the above criteria 
5. Diagnosis of severe Sjogren’s dry eye disease at least 3 months before enrollment (current 
use or recommended use of artificial tears for the treatment of Sjogren’s related Dry Eye) 
6. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 
Snellen value) in each eye at the time of study enrolment 
7. If a female of childbearing potential, have a negative urine pregnancy test and use a highly 
effective method to avoid pregnancy for the duration of the trial and 30 days after the 


 
 
 
 
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study treatment period. Males of reproductive potential should use effective contraception 
during treatment and 30 days after the study treatment period 
8. Only patients who satisfy all Informed Consent requirements may be included in the 
study. The patient and/or his/her legal representative must read, sign and date the 
Informed Consent document before any study-related procedures are performed. The 
Informed Consent Form signed by patients and/or legal representative must have been 
approved by the IRB/IEC for the current study 
9. Patients must have the ability and willingness to comply with study procedures. 
 
Main exclusion criteria 
1. Inability to speak and understand the local language sufficiently to understand the nature 
of the study, to provide written informed consent, and to allow the completion of all study 
assessments  
2. Evidence of an active ocular infection, in either eye  
3. Presence of any other ocular disorder or condition requiring topical medication during the 
entire duration of study in either eye 
4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) 
or chronic conjunctivitis and/or keratitis other than dry eye 
5. Intraocular inflammation defined as Tyndall score >0 
6. History of malignancy in the last 5 years 
7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with 
glycemia out of range, thyroid malfunction) or judged by the investigator to be 
incompatible with the study (e.g. current systemic infections) or with a condition 
incompatible with the frequent assessment required by the study 
8. Patient with a history of serious adverse reaction or significant hypersensitivity to any 
drug or chemically related compounds or clinically significant allergy to drugs, foods, 
amide local anesthetics or other materials including commercial artificial tears (in the 
opinion of the investigator) 
9. Females of childbearing potential (those who are not surgically sterilized or post-
menopausal for at least 1 year) are excluded from participation in the study if they meet 
any one of the following conditions:  
a. 
are currently pregnant or,  
b. 
have a positive result at the urine pregnancy test (Baseline/Day 1) or,  
c. 
intend to become pregnant during the study treatment period or,  
d. 
are breast-feeding or, 
e. 
are not willing to use highly effective birth control measures, such as: 
combined (estrogen and progesterone containing) hormonal contraceptives 
associated with inhibition of ovulation (oral, intravaginal, transdermal), 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, implantable, injectable), intrauterine device (IUD), 
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomised partner, sexual abstinence during the entire course of and 30 
days after the study treatment period 


 
 
 
 
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10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the 
conduct of the study, confound the interpretation of the study results, or endanger the 
patient’s well-being  
11. Use of topical cyclosporine, or topical ophthalmic treatments of the same class, within 14 
days of screening visit (day -8). 
12. Use of topical corticosteroids, lifitegrast, autologous serum tears in either eye during the 
study (previous use not an exclusion criteria but must be discontinued at the screening 
visit) 
13. Contact lenses, TrueTear device, moisture goggles, sutureless amniotic membrane or 
punctum plug use during the study (previous use not an exclusion criteria but must be 
discontinued at the screening visit) 
14. History of drug addiction or alcohol abuse within the last year 
15. Any prior ocular surgery (including refractive, palpebral and cataract surgery) if within 
90 days before the screening visit 
16. Participation in a clinical trial with a new active substance during the past 3 months prior 
to screening 
17. Participation in another clinical trial study at the same time as the present study 
 
Test/Reference Product, 
Dosage and Mode of 
Administration  
 Oxervate®, an ophthalmic solution containing cenegermin 20 
mcg/mL, which is a recombinant human Nerve Growth 
Factor (rhNGF); reference product is vehicle. Test and 
reference will be instilled in both eyes according to the 
following scheme:  
Group 1: one drop of cenegermin 20 mcg/mL will be instilled 
in both eyes three times daily (every 6 hours, e.g. 
7:00 am, 01:00 pm; 07:00 pm).  
Group 2: vehicle eye one drop will be instilled in both eyes 
three times daily (every 6 hours, e.g. 7:00 am, 
01:00 pm; 07:00 pm). 
The IMP will be provided in a monthly box containing 28 
daily vials. Together with the IMP monthly box, patients will 
be provided with a sufficient number of pipettes and adaptors 
for the administration of the IMP. 
Duration of Study 
Patients will be evaluated at screening visit (day -8), baseline 
(day 1+2), week 2 (day 14±2), week 4 (day 28±2) or early 
exit, week 8 (day 56±2),  week 12 (day 84±4), and week 16 
(day 112±7) of follow-up. Safety evaluations will also be 
continued in follow-up until week 24 (day 168 ±7)  
Screening Visit (day -8): all procedures for assessment of 
eligibility will be performed.  


 
 
 
 
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Wash-out period (from day -8 to baseline): 8 (+2) days with 
no 
further 
treatment 
except 
commercially 
available 
preservative free artificial tears if strictly needed, provided by 
the Sponsor. The use of artificial tears will be tracked in the 
patient’s diary. 
Treatment: eligible patients will be randomized 1:1 and 
treated for 4 weeks with either cenegermin ophthalmic 
solution 20 mcg/mL or vehicle.  
Only the experimental IMP is allowed during the treatment 
period however, if strictly needed, the patient may use 
commercially available preservative free artificial tears 
provided by the Sponsor. The use of artificial tears will be 
tracked in the patient’s diary. 
Follow up: Initially 8 weeks (from week 5 to week 12) post 
treatment with no further topical ocular treatment except 
commercially available preservative-free artificial tears 
provided by the Sponsor administered three times daily. 
Furthermore, the patient can administer additional artificial 
tear eye drops provided by the Sponsor only if strictly needed, 
and must document in the patient’s diary the number of 
additional drops administered for each eye. 
Patients will then be followed up for efficacy and safety 
endpoints until week 16 and for safety endpoints until week 
24.  
During the follow up period (from week 13 to week 24) other 
topical treatments will be allowed at discretion of the treating 
physician. Such treatments will be recorded by the 
investigators. 
 
Patients can continue any systemic treatment as required to 
control their autoimmune disease throughout the study; any 
change in systemic treatments must be recorded by the 
investigators. 
Maximum total study duration: 112±7 days for efficacy 
evaluations plus an additional 56±7 days for safety 
evaluations. 
Study population 
Patients with severe Sjogren’s dry eye disease will be 
included. A total of 100 patients will be enrolled assuming a 
10% drop out rate to yield 90 eligible patients.  
 
Co- Primary Efficacy 
Endpoint 
• 
Schirmer I test (without anesthesia) >10mm/5min at 
week 4 in the eligible eye.  
• 
Change from baseline in Symptoms questionnaire 
(SANDE) global score at week 12.  




 
 
 
 
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Statistical Methods 
The sample size of the study is calculated based on results 
from previous studies. Expecting a difference of 30% in 
Schirmer I rate of responders (defined as patients reaching a 
value >10mm/5min) at Week 4 and 15 points in Global 
SANDE score improvement at Week 12, a total sample size of 
90 evaluable patients (100 pts considering 10% drop-out rate) 
allows to achieve an overall power of 90% to show superiority 
of cenegermin ophthalmic solution vs vehicle in terms of both 
co-primary endpoints, considering a one-sided alpha of 0.025. 
Summary statistics are defined for quantitative variables 
(number of observations, mean, standard deviation, median, 
minimum and maximum) and qualitative variables (number 
and percentage per category). If appropriate, confidence 
intervals around the mean or the proportions will be presented. 
The proportion of patients reaching a value of Schirmer I test 
(without anesthesia) >10mm/5min at week 4 will be analyzed 
by means of logistic regression. The change from baseline in 
SANDE global score at week 12 will be analyzed by means of 
an adjusted ANCOVA procedure. 
If the primary analysis of primary endpoint leads to rejection 
of the null hypotheses, key secondary endpoints will be tested 
in a conditional sequential manner to show superiority of 
cenegermin versus placebo vehicle according to the pre-
defined ranking sequence. Independently of the results on 
primary endpoints, all secondary endpoints will be analysed at 
each available time point by means of descriptive statistics and 
by appropriate parametric tests. Data record in the 
questionnaires of quality of life will be presented with 
appropriate descriptive statistics and processed with 
appropriate inferential test. Change from baseline value and 
shift tables versus baseline may be summarized for all 
available post-baseline visits.  
 will be descriptively summarized at 
each available time point. Any statistical testing will be 
descriptive in nature. Correlation between sign and symptom 
scores will be assessed.  
AEs will be coded by System Organ Class (SOC) and 
Preferred Term (PT), using the Medical Dictionary for 
Regulatory Activities (MedDRA). Individual AEs will be 
listed in patient data listings. TEAEs will be presented in terms 
of the number of AEs and incidence by treatment, seriousness, 
CCI


 
 
 
 
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relationship to treatment, severity, and study period (treatment 
or follow-up).  
The Safety (SAF) and the Full Analysis Set (FAS) population 
will consist of all patients who will be randomized and 
received at least one dose of the investigational product. Safety 
population will be analyzed according to the actual treatment 
received; Full Analysis Set population will be analyzed 
according to ITT principle, i.e. by treatment allocation. The 
Per Protocol (PP) population will consist of all patients in the 
FAS population who do not have Major Protocol Deviations. 
Primary and secondary efficacy analyses will be conducted on 
the FAS population while SAF and PP populations will be 
used for safety and sensitivity analyses, respectively. 
The Statistical Analysis Plan (SAP) will be issued before 
database lock with more technical and detailed elaboration of 
the principal features of statistical analyses. Any deviation 
from the original statistical plan will be described in the 
Clinical Study Report.  
 
 




 
 
 
 
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Study procedures 
Screening 
(Day-8) 
Visit 1 
Baseline* 
(Day 1 + 2 
days) 
Visit 
2 
Week 
2 a 
(Day 
14 +/- 
2 
days) 
  Visit 3 
End of 
treatment 
Week 4a 
(Day 28 
+/- 2 days) 
Visit 4 
follow-
up 
Week 
8a 
(Day 
56 +/- 2 
days) 
Visit 5 
follow-
up 
Week 
12b 
(Day 
84 +/- 
4 days) 
 
Visit 6 
follow-
up 
Week 
16c 
(Day 
112 +/- 
7 days) 
 
Visit 7 
follow-
up 
Week 
24c 
(Day 
168 +/- 
7 days) 
 
Verify patient study 
medication dosing 
compliance 
 
 
 
X 
 
 
 
 
Concomitant 
Ocular And 
Systemic 
Medications 
 
 
X 
X 
X 
X 
X 
X 
Frequency of 
preservative free 
artificial tears use 
(n° drops/day) 
 
X 
Xe 
Xe 
Xf 
Xf 
X 
 
X 
 
Dispensation, 
check and retrieval 
of patient’s diary 
Xg 
X 
Xh 
X 
Xh 
X 
Xh 
 
Xi 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
*) visit window of +2 days;  a) Visit window of ± 2 days; b) Visit window of ± 4 days; c) Visit window of  ± 7 days; d) 
a monthly box will be given to the patients;  e) During the treatment period patients can use, if strictly needed, the 
preservative free artificial tears provided by the Sponsor; f) During the follow up period it is allowed to use the 
preservative free artificial tears provided by the Sponsor; g) At screening visit only dispensation; h) During the visit 2 - 
week 2, visit 4 - week 8 and visit 6 – week 16, the PI or a delegate must only check if the patient has correctly completed 
the diary; i) At Visit 7 – week 24 only check and retival. 
 
2.1. 
BACKGROUND INFORMATION 
2.1.1. 
Nerve Growth Factor - Overview  
 
Nerve growth factor (NGF) is a polypeptide essential for the survival and growth of sympathetic and sensory 
neurons, and for differentiation of neurons in the central nervous system. It binds with at least two classes of 
receptors: high-affinity tropomyosin receptor kinase A (TrkA), a transmembrane tyrosine kinase, and low-
affinity NGF receptor (LNGFR), also known as p75 neurotrophin receptor (p75NTR).  
NGF and TrkA are expressed in the anterior segment of the eye (iris, ciliary body, lens, cornea and 
conjunctiva), and NGF is released in the aqueous humor. Several pieces of experimental evidence suggest that 
NGF affects all tissues of the anterior ocular segments, playing a crucial role in the physiopathology of several 
anterior ocular segment diseases.  


 
 
 
 
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2.1.2. 
Chemical And Formulation Data  
 
As recombinant human NGF (rhNGF) production in mammalian cells does not achieve adequate yields, a 
manufacturing process based on the use of recombinant Escherichia coli (E. coli) has been developed. 
However, because the biological activity of NGF relies on the formation of three disulfide bonds, and because 
disulfide bonds cannot occur in the reducing cytosol, the purification and renaturation of NGF produced in E. 
coli is problematic. Based on the knowledge that the prosequence increases the yield and rate of refolding of 
NGF, we have developed a manufacturing process starting from proNGF. After expression of proNGF in E. 
coli, the insoluble protein is isolated in the form of insoluble inactive aggregates (inclusion bodies), solubilized 
in a strong denaturing agent and subsequently converted into the natural conformation, which is determined 
by the disulfide bridges present in the natural NGF. Biologically active rhNGF is finally obtained by splitting 
off the prosequence by enzymatic cleavage. The deoxyribonucleic acid (DNA) sequence of human proNGF 
has been optimized for E coli expression (codon adjustment) and two changes in the furin cleavage site, R101V 
and K103A, have been introduced. These two changes are important to ensure a homogeneous rhNGF 
preparation during the process with the mature protein starting with serine 105.  
Oxervate® ophthalmic solution contains cenegermin, a recombinant form of human nerve growth factor 
produced in Escherichia coli. 
2.1.3. 
Rationale for cenegermin (rhNGF) therapy in patients with dry eye 
 
Dry eye is a chronic condition of the ocular surface with severe symptoms and visual impairment, leading to 
worse efficiency to perform duties for an average of 184 work days and resulting in an average loss of 
productivity estimated in 5,000USD per year per patient1.  
Dry eye results from systemic diseases (Sjögren's syndrome, rheumatoid arthritis, systemic lupus 
erythematosus, Stevens-Johnson syndrome, thyroid disease), ocular conditions (meibomian gland dysfunction, 
blepharitis, ocular rosacea, corneal dystrophies), elective surgeries (refractive surgery, blepharoplasty), eyelid 
conditions (lagophthalmos, entropion/ectropion), cranial surgeries, side effects of drugs (antihistamines, 
diuretics, beta-blockers), ocular injuries and burns, chemotherapy and radiation, aging, menopause2. 
Dry eye pathogenesis is multifactorial however, a number of common mechanisms can be identified: (i) 
chronic inflammation of the conjunctiva; (ii) decrease of ocular surface sensitivity; (iii) impairment of quantity 
of tears and/or quality of the tear film, including tear film hyperosmolarity; (iv) changes of conjunctival 
epithelium with squamous metaplasia and decrease of goblet cell density; (v) corneal epithelium damage2. 
Until now, treatment has been limited to the use of artificial tears to temporarily improve lubrication of the 
ocular surface, immunomodulation to increase tear production and decrease inflammation (Cyclosporine, 
Lifitegrast), or the use of topical steroids to decrease the inflammatory reaction acutely. However, chronic use 
of steroids is associated with several complications such as cataract development and increasing intraocular 
pressure2. Cyclosporine is topical immunomodulator indicated to increase tear production in patients whose 
tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis 
sicca. Lifitegrast ophthalmic solution is a lymphocyte function-associated antigen-1 (LFA-1) antagonist 


 
 
 
 
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indicated for the treatment of the signs and symptoms of dry eye disease. On the other hand, experimental and 
clinical evidence suggests that NGF may affect all the pathogenic mechanisms of dry eye, potentially restoring 
ocular surface homeostasis3. Human corneal epithelium, keratocytes, and endothelium produce NGF, and 
express its high affinity tyrosine kinase receptor A (TrkA), and experimental studies demonstrated that the 
activation of TrkA receptors by NGF plays a key role in corneal sensory nerve survival4. 
Indeed, several studies have shown that NGF is involved in the regulation of tear film production. In fact, 
NGF, TrkA and p75, as well as other neurotrophins (NTs) and related receptors, are expressed by the rat 
lacrimal gland tissue; moreover, NGF has been quantified in human tears, indicating that NGF is basally 
released by the lacrimal gland5–7. These data suggest that NGF may play a role in the maintenance of the tear 
film and in its alterations in drying ocular surface diseases. Specifically, considering that NGF potentially 
affects all the components of the ocular surface (cornea, conjunctiva, lacrimal gland, and sensory innervation), 
it might play an important role during dry eye disease. In line with this hypothesis:  NGF topical administration 
in a dog experimental model of dry eye has been shown to increase tear production, conjunctival goblet cell 
density and corneal transparency2,8; an increased tear concentration of NGF has been reported in patients 
affected by keratoconjuctivitis sicca9,10; NGF stimulates glycoconjugate secretion by conjunctival goblet cells, 
without affecting cell proliferation11. 
In several systemic autoimmune conditions, including Sjogren syndrome, the lacrimal gland can be attacked 
by the immune system resulting in an ocular manifestation of aqueous deficient DE (ADDE)12. In fact, the 
leading cause of ADDE in dogs is immune-mediated lacrimal gland dysfunction comparable to Sjogren 
syndrome in humans13. In addition, NGF was found to increase secretory mucin MUC5AC secretion by 
conjunctival goblet cells, without affecting cell proliferation11. The major secretory gel forming mucin 
MUC5AC plays a crucial role in the maintenance of a wet-surfaced ocular surface phenotype, in the clearance 
of debris from the ocular surface epithelia (including pathogens and allergens), and in the stability of the tear 
film, contributing to preventing its premature evaporation14,15. The underlying tear film dysfunction discussed 
thus far encompasses alterations in one, or all, of its layers (i.e. the aqueous, mucin, and lipid layer). Tear 
production is controlled by the lacrimal functional unit (LFU) consisting of the cornea, conjunctiva, lacrimal 
glands, meibomian glands, and the neuronal network that connects them14. When corneal nerves are stimulated, 
afferent signals are triggered through the ophthalmic branch of the trigeminal nerve (V). In turn, efferent 
secretomotor nerve endings stimulate lacrimal glands, meibomian glands and conjunctival goblet cells to 
secrete aqueous, lipids and mucin contents of the tear film, respectively14–16. Likewise, when corneal sensory 
nerves are stimulated, they release neuromediators that provide trophic support for the corneal epithelium and 
keratocytes. These corneal epithelial cells and keratocytes release neuropeptides, neurotrophins and growth 
factors (e.g. NGF) that influence survival, differentiation, and maturation of nerve fibers17. Thus, neurosensory 
abnormalities play a key etiological role in DE that remains largely unaddressed by current approved 
therapeutics.  
Specifically, considering that NGF potentially affects all the components of the ocular surface (cornea, 
conjunctiva and goblet cells, lacrimal gland, and sensory innervation), it may play an important role in 
Sjogren’s DE disease. In addition, considering the mechanism of action of NGF on improving ocular surface 
sensory nerve function, which will induce in turn an improvement in reflex tear secretion and blink rate, it is 
expected that the effects on both signs and symptoms of DE may be long-lasting.  
 
 


 
 
 
 
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2.2. 
A SUMMARY OF CLINICAL DATA  
Cenegermin has been already studied in healthy volunteers and in different subject populations.  
In the completed Phase I study in healthy volunteers (
), a total of 58 subjects (out of 74 
enrolled) were treated with single and multiple doses of different concentrations of cenegermin ophthalmic 
solution showing a good safety profile.  
Furthermore, a Phase I/II multicenter, double-masked, vehicle-controlled study evaluating the safety and 
efficacy of cenegermin at 10 and 20 mcg/mL six times a day in 174 patients with stage 2 and 3 of Neurotrophic 
Keratitis  (study 
) was completed in 2015; the study demonstrated that cenegermin was 
very well tolerated and effective in patients with NK. A successful confirmatory study (
) was 
completed in 2016 and marketing authorization for cenegermin 20 mcg/mL ophthalmic solution was granted 
by the EMA in July 2017 for treatment of moderate to severe NK. While in the US cenegermin was approved 
by FDA in 2018 for all stages of Neurotrophic Keratitis. Cenegermin is distributed under the trade name 
Oxervate® 20 mcg/mL ophthalmic solution. 
In addition to NK, cenegermin ophthalmic solution has been evaluated in a Phase I/II study in retinitis 
pigmentosa (RP) patients at  60 and 180 mcg/mL dosages 
), and in a phase I/II study in glaucoma 
at a dose of 60 mcg/mL 
). An open label, uncontrolled study showed that 4 weeks treatment with 
cenegermin ophthalmic solution at 20 mcg/mL and 4 mcg/mL concentrations was safe and effective in 
improving symptoms, corneal staining and tear production in patients with  dry eye disease 
). These 
results prompted  two additional phase II RCTs in patients with dry eye disease (
) and in those with 
ocular discomfort symptoms following refractive surgery 
); these also confirmed the favourable 
tolerability profile of cenegermin ophthalmic solution at a concentration of 20 mcg/mL when used up to 6 
times daily for 8 weeks.  
In the double-masked vehicle-controlled Phase II study 
 no major differences were observed in  
efficacy when comparing the two administration regimens (6 vs. 2 times/day) and treatment durations (8 weeks 
vs. 4 weeks) in a subset of patients with similar characteristics (hyposecretive dry eye with Schirmer test 
<10mm/5min).  
 
An additional phase II study (
) was specifically designed to further prove this hypothesis. It was a 4 
week, Phase 2, multicenter, randomized, double-masked, vehicle-controlled, parallel group study with 12 
weeks of follow-up to evaluate safety and efficacy of cenegermin ophthalmic solution versus vehicle, in 
patients with moderate to severe dry eye, started in 2018 in patients with hyposecretive dry eye (with or without 
an evaporative component caused by the reduced tear film), including patients diagnosed with primary Sjogren 
syndrome. 
In this phase II trial a total of 261 patients were randomized 1:1:1 to receive either cenegermin TID (i.e. 3 
times/day), or cenegermin BID (i.e. 2 times/day), or vehicle.  
The primary endpoint of the study was the change from baseline in Schirmer I test (without anaesthesia), while 
key secondary endpoints included change from baseline in SANDE scores for severity and frequency, cornea 
and conjunctiva vital staining, TFBUT and quality of life.  Despite the primary endpoint at p<0.025 was not 
reached in the overall population, the study has clearly shown a superior efficacy of both cenegermin arms 
versus placebo, especially considering that due to the Covid-19 emergency recruitment was interrupted when 
only 261 (the minimum number required) out of the 300 patients initially planned were randomized. However, 
when analyzing the percentage of patients achieving more than 10 mm in Schirmer I test scores at the end of 
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treatment, as pre-specified in the statistical analysis plan (SAP), the difference between both cenegermin dose 
regimens vs. placebo was statistically significant for both study groups (p=0.028 for cenegermin TID and 
p=0.007 for cenegermin BID [P-value versus Vehicle TID based on Fisher’s exact test]). It is notewhorty that, 
while no clear dose ranging effect was observed on the tear function endpoints,  symptoms recorded by the 
DE-specific and validated SANDE questionnaire showed a significant persistence of the beneficial effect of 
the higher dose-regimen (TID) over time and up to the full 16 weeks after the end of the 4 weeks treatment 
cycle. In fact, statistical significance vs. vehicle was reached at all follow-up timepoints for the TID with best 
result at week 12 (p=0.002 based on t-test; missing data imputed by LOCF).  In addition, no difference was 
observed in the safety and tolerability profile of the experimental treatment. Specifically, up to 3 instillations 
per day of cenegermin ophthalmic solution in both eyes confirmed to be safe and well tolerated. The two 
cenegermin study groups have shown a similar tolerability. No serious adverse events were reported in the 
study. Adverse reactions were mild and transient, and occurred only during the 4-weeks treatment period of 
the 16-weeks cycle. 
 
The results of these three randomized controlled studies in dry eye disease patients, as well as the results on 
reflex tear secretion obtained in the neurotrophic keratitis trials 
 and 
, suggests that  
cenegermin may be a safe and effective treatment option for patients with hyposecretive/aqueous tear-deficient 
dry eye disease. In all studies rhNGF was well tolerated and the reported ocular AEs were generally transient 
and mostly mild and moderate in intensity during the controlled treatment period and the follow-up period. 
 
In the Phase I, randomized, double-masked, placebo-controlled study to evaluate the safety, tolerability and 
pharmacokinetics of rhNGF eye drops in healthy volunteers of Japanese ethnicity (
), a total of 
30 subjects were enrolled. Twenty subjects were treated with a single dose of cenegermin ophthalmic solution 
at a 20 mcg/mL concentration and a total of 10 subjects were treated with vehicle. On day 1 patients received 
only one dose of cenegermin, then the remainder of the trial they received one drop six times a day. Both the 
single and multiple doses of cenegermin delivered topically as ophthalmic solution were safe and well tolerated 
by healthy subjects of Japanese ethnicity. No clinically important changes in ECG were observed after dosing 
with cenegermin. There was no apparent relationship between treatment and plasma cenegermin levels, and 
this study did not give any indication for an immunogenic potential of cenegermin in humans after ophthalmic 
treatment. 
2.3. 
STUDY RATIONALE 
The data reported above, together with the evidence of cenegermin ophthalmic solution effectiveness in the 
treatment of patients affected by corneal epithelial defects and ulcers, and moderate to severe dry eye make 
cenegermin a strong candidate for the treatment of severe Sjogren’s dry eye disease4,10,18. 
As part of the development plan, the present study was designed in order to evaluate the safety and efficacy of 
Oxervate® (cenegermin ophthalmic solution, rhNGF) versus vehicle in patients with severe Sjogren’s dry eye 
disease. For additional information regarding the development of rhNGF, please consult the current IB. 
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2.3.1. 
Risk assessment/benefit evaluation 
This study is considered a low-risk interventional trial. It is conducted with a previously tested dose of 
medicinal product already authorized and commercialized for the treatment of NK in Europe, US and China.  
The proposed study is conducted in patients with severe Sjogren’s dry eye disease, an indication for which 
Oxervate® (cenegermin) ophthalmic solution is not yet approved, however two preliminary clinical studies 
were already conducted in patients with dry eye demonstrating that cenegermin is well tolerated in this 
condition. 
The risk of this study is comparable to the risk of the standard of care, in fact the dose proposed in this protocol 
is cenegermin 20 mcg/mL three drops per day instilled in each eye, which is well below the dose approved for 
the treatment of NK (cenegermin 20 mcg/mL six drops/eye per day). 
Considering what is discussed above, no particular safety risks are foreseen with respect to the safety profile 
of the marketed product Oxervate® (cenegermin 20 mcg/mL ophthalmic solution). 
 
The patients with severe Sjogren’s dry eye disease participating in this study may potentially benefit from the 
application of cenegermin for 28 days (4 weeks).  
 
 
Any possible risk derived from the administration of cenegermin in the specific population involved in this 
study will be minimized by integrated monitoring which includes clinical observations, Ocular examination, 
laboratory tests. 
2.3.2. 
Description of the Investigational Product 
 
The investigational medicinal product (IMP) consists of a sterile isotonic solution for ophthalmic 
administration, containing cenegermin 20 mcg/mL as drug substance. 
The matching placebo vehicle consists of a sterile isotonic solution. 
Further information is  given in section 5. 


 
 
 
 
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3. OVERALL STUDY DESIGN AND INVESTIGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES  
The study objective is to assess the efficacy and safety of cenegermin (rhNGF) ophthalmic solution at 20 
mcg/mL concentration administered three times daily for 4 weeks in patients with severe Sjogren’s dry eye 
disease. 
3.2. 
STUDY ADMINISTRATIVE STRUCTURE 
This study will be performed at approximately 10 study centers located in the USA and Europe.  At each study 
center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted 
according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.  
The PI at each study center will be responsible for the management of the study, which will consist of 
maintaining the study file and the patient records, corresponding with the IRB, and completing the case 
report forms (eCRFs) and reporting SAEs within 24 hours of initial awareness.  
The PI is responsible for supervising any individual or party to whom the investigator delegates trial related 
duties and functions conducted at the trial site. 
If the investigator/institution retains the services of any individual or party to perform trial-related duties and 
functions, the investigator/institution should ensure this individual or party is qualified to perform those trial-
related duties and functions and should implement procedures to ensure the integrity of the trial-related duties 
and functions performed and any data generated. 
3.3. 
OVERALL STUDY DESIGN  
 
This is a 4 week phase III, multicenter, double-masked, vehicle-controlled study to evaluate safety and efficacy 
of cenegermin ophthalmic solution at 20 mcg/mL solution versus vehicle, in patients with severe Sjogren’s dry 
eye disease  
Patients will be evaluated as per Section 2 “SCHEDULE OF EVALUATIONS”. 
 
 
During the screening (day-8) all procedures for inclusion will be performed. From the day of screening the 
patients will stop any kind of further treatment, except commercially available preservative free artificial tears 
provided by Sponsor for a period of 8 days and 10 days as maximum: day -8 until the baseline visit (day 1+2), 
Figure 1. At the end of the wash out period (day -8 to baseline), patients meeting the entry criteria for this 
study will be randomized 1:1 and treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL 
TID or vehicle TID.  
During the 4 weeks of masked treatment only the administration of IMP is allowed. Nevertheless, if strictly 
needed, the patient can take  preservative free artificial tears (provided by the Sponsor). The use (n° drops/day) 
of preservative free artificial tears will be clearly documented in a patient’s diary and in the eCRF.  




 
 
 
 
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Cenegermin 20 mcg/mL administered two times daily, demonstrated to be safe and well tolerated 
  
will also ensure the lubrification of the ocular surface in the present study where the use of artificial tears will 
be not allowed during the treatment period.  
Higher doses of rhNGF (up to 180 mcg/mL) were administrated to patients with diseases of the back of the 
eye, such as 
 (Study 
) for up to 168 days. 
 
The 20 mcg/mL concentration of cenegermin is well sustained by the current manufacturing process and is 
used in a commercial formulation.  
A dose regimen of 3 drops per day of cenegermin ophthalmic solution and a treatment duration of 4 weeks has 
been selected based on the results of the previous clinical trials described above. 
The administration of a total of 3 drops per day for all the study arms has been chosen to guarantee to patients 
randomized to the vehicle arm to have the minimum amount of lubrication that is compatible with symptoms’ 
relief. A double-blind study design was adopted to minimize systematic bias. Randomization is expected to 
minimize patient selection bias and increase baseline comparability between treatment groups. The use of 
placebo control is critical to the study design for providing an accurate estimate of the additive benefit of 
pharmacotherapy.   
The use of the drug’s vehicle as placebo helps in making the latter as indistinguishable from the cenegermin 
solution. 
Patients with insufficient therapeutic response, tolerability issues, or worsening of symptoms may be 
discontinued at any time during the study. 
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4. SELECTION OF STUDY POPULATION 
 
Patients ≥ 18 years with severe Sjögren's dry eye will be included. A total of 100 patients will be enrolled.  
The safety and efficacy of cenegermin ophthalmic solution will be investigated in these patients.   
 
4.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria: 
1. Male or female aged ≥ 18 years 
2. Patients with a confirmed diagnosis of  Sjögren's syndrome or other autoimmune disease known to 
induce Sjögren’s Dry Eye Disease (DED). 
3. Patients with severe Sjögren’s dry eye disease characterized by the following clinical feautures: 
a. Corneal and/or conjunctival staining with fluorescein using National Eye Institute (NEI) 
grading system ≥3 
b. SANDE questionnaire >25 mm 
c. Schirmer test I (without anaesthesia) ≥2 ≤5mm/5min  
4. The same eye (eligible eye) must fulfill all the above criteria 
5. Patients diagnosed with severe Sjögren’s dry eye disease at least 3 months before enrolment (current 
use or recommended use of artificial tears for the treatment of Sjogren’s related Dry Eye) 
6. Best corrected distance visual acuity (BCDVA) score of ≥ 0.1 decimal units (20/200 Snellen value) in 
each eye at the time of study enrolment 
7. If a female of childbearing potential, have a negative urine pregnancy test and use a highly effective 
method to avoid pregnancy for the duration of the trial and 30 days after the study treatment period  . 
Males of reproductive potential should use effective contraception during treatment and 30 days after 
the study treatment period. 
8. Only patients who satisfy all Informed Consent requirements may be included in the study. The patient 
and/or his/her legal representative must read, sign and date the Informed Consent document before 
any study-related procedures are performed. The Informed Consent form signed by patients and/or 
legal representative must have been approved by the IRB/IEC for the current study 
9. Patients must have the ability and willingness to comply with study procedures 
 
EXCLUSION CRITERIA 
 
1. Inability to speak and understand the local language sufficiently to understand the nature of the study, 
to provide written informed consent, and to allow the completion of all study assessments  
2. Evidence of an active ocular infection, in either eye  
3. Presence of any other ocular disorder or condition requiring topical medication during the entire 
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4. History of severe systemic allergy or of ocular allergy (including seasonal conjunctivitis) or chronic 
conjunctivitis and/or keratitis other than dry eye 
5. Intraocular inflammation defined as Tyndall score >0 
6. History of malignancy in the last 5 years 
7. Systemic disease not stabilized within 1 month before Screening Visit (e.g. diabetes with glycemia out 
of range, thyroid malfunction) or judged by the investigator to be incompatible with the study (e.g. 
current systemic infections) or with a condition incompatible with the frequent assessment required 
by the study 
8. Patient had a serious adverse reaction or significant hypersensitivity to any drug or chemically related 
compounds or had a clinically significant allergy to drugs, foods, amide local anesthetics or other 
materials including commercial artificial tears (in the opinion of the investigator) 
9. Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at 
least 1 year) are excluded from participation in the study if they meet any one of the following 
conditions:  
a. are currently pregnant or,  
b. have a positive result at the urine pregnancy test (Baseline/Day 1) or,  
c. intend to become pregnant during the study treatment period or,  
d. are breast-feeding or, 
e. are not willing to use highly effective birth control measures, such as: combined (estrogen 
and progesterone containing) hormonal contraceptives associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, implantable, injectable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised 
partner, sexual abstinence  during the entire course of and 30 days after the study treatment 
period. 
10. Any concurrent medical condition, that in the judgment of the PI, might interfere with the conduct of 
the study, confound the interpretation of the study results, or endanger the patient’s well-being  
11.  Use of topical cyclosporine, , or topical ophthalmic treatments of the same class, within 14 days of 
screening visit (day -8) 
12. Use of topical corticosteroids, lifitegrast, autologous serum tears in either eye during the study 
(previous use not an exclusion criteria but must be discontinued at the screening visit) 
13. Contact lenses, True Tear device, moisture goggles, sutureless amniotic membrane or punctum plug 
use during the study (previous use not an exclusion criteria but must be discontinued at the screening 
visit) 
14. History of drug addiction or alcohol abuse in the last 2 years 
15. Any prior ocular surgery (including refractive, palpebral and cataract surgery) if within 90 days before 
the screening visit 


 
 
 
 
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16. Participation in a clinical trial with a new active substance during the past 3 months 
17. Participation in another clinical trial study at the same time as the present study. 
 
 
 


 
 
 
 
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4.2. 
ELIGIBLE EYE 
Assuming that all the inclusion/exclusion criteria are met in both eyes, the worse eye (eligible eye) will be 
determined at the baseline visit using a stepladder approach, as follows: 
1. Schirmer’s Test (since this is the primary endpoint)-Worse eye determined as eye with lower 
Schirmer I score.  
2. NEI score (cornea+conjunctival staining) - If Schirmer I score is the same in both eyes, worse eye 
will be determined by NEI score (cornea+conjunctival staining). 
 
If all of the above are identical, determination of the worse eye will be based on the Investigator’s judgement, 
otherwise simply use the right eye as the eligible eye. 
4.3. 
ASSIGNMENT OF PATIENT NUMBER 
Each patient who provides written consent to participate in this study will be assigned a unique 5-digit PID 
number (e.g. 01-001) consisting of a 2-digit study center number followed by the 3-digit screening number 
assigned sequentially by each study center, from 001 to 100.  
4.4. 
RANDOMIZATION 
Eligible patients will be randomized in a 1:1 ratio to either cenegermin ophthalmic solution 20 mcg/mL TID 
(⁓50 patients) or vehicle ophthalmic solution TID (⁓50patients). 
Each randomized patient will be allocated with 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. 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. 
Randomization will be performed through IRS. 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/labelling 
for the purpose of IMP preparation. Each randomized patient will be allocated with randomization number 
according to the stratified randomization list. Dropouts after randomization will not be replaced  
The enrollment of patients will be scheduled in order to assure an inclusion of approximately 100 patients to 
ensure at least 90 patients assuming up to 10% dropout rate. 
4.5. 
MASKING 
The identity of the treatments will remain unknown to the patient, Investigator, site staff and Sponsor’s clinical 
research personnel until the completion of the study (after full data base lock) except in case of specific events 
that will require unmasking of the patient. 


 
 
 
 
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The vials containing cenegermin (20 mcg/mL) or vehicle will be identical in appearance, and the contents of 
the vials will be indistinguishable. All staff directly involved in the analysis of study results will remain masked 
to treatment assignments while the study is in progress. 
A list of sequential kit numbers will be generated by an independent statistician not involved in the conduct of 
the study. Each kit number will be randomly associated with a treatment group. Patients will be assigned to 
treatment in numerical order. A tear-off label from the kit box, with the kit number, will be attached to the 
investigational product dispensing log. 
The investigator will be provided with a protected access to the randomization list so only in case of a medical 
emergency the Investigator can open the treatment allocation for a specific patient.  
Also Dompé’s Pharmacovigilance contact person will be provided with a protected access to randomization 
list , so if required by the Pharmacovigilance activities the Pharmacovigilance contact person can open the 
treatment allocation for a specific Patient. 
 
In the event of a medical emergency where the knowledge of patient treatment is required to provide the patient 
with appropriate care, Investigators will have the possibility to unmask the treatment assignment for a specific 
patient. The Investigators are encouraged to contact the CRO staff before becoming unmasked if there is 
sufficient time. 
If the Investigator becomes unmasked for any reason, this information will be recorded on source data and in 
the eCRF of the study, specifying the date and the reason.  
 
Unmasking events will be recorded and reported in the final study report. 
 


 
 
 
 
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5. STUDY MEDICATION 
5.1. 
DESCRIPTION OF PRODUCT 
5.1.1. 
Presentation of Non Investigational Medicinal Product (NIMP) 
TEST PRODUCT 
 
NIMP 
 
Blink® Tears or equivalent preservative-free artificial tears 
Pharmaceutical form 
 
Lubricating Eye Drops 
Administration 
 
One drop of Blink® Tears or equivalent will be instilled in both 
eyes during the screening week, only if strictly needed by the 
patient. The patient must document in the patient’s diary the n° of 
additional drops administered for each eye. 
One drop of Blink® Tears or equivalent will be instilled in both 
eyes during the 4 weeks of masked treatment, only if strictly 
needed by the patient. The patient must document in the patient’s 
diary the n° of additional drops administered for each eye. 
One drop of Blink® Tears or equivalent will be instilled in both 
eye TID (morning, afternoon and evening) during the initially 8 
weeks of follow up. The patient, only if strictly needed, can 
administer additional drops and must document in the patient’s 
diary the n° of additional drops administered for each eye. 
Administration route 
 
 
 
Ocular  
 
 
 
 
 
 
5.1.2. 
Presentation of Investigational Medicinal Product 
 
TEST PRODUCT 
 
IMP 
Cenegermin (rhNGF  
20 mcg/mL) and/or Placebo vehicle (Vehicle vials). 
 
Manufacturer active 
substance 
 
Dompé Farmaceutici S.p.A., Italy 




 
 
 
 
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2. Put the pipette on adapter inlet 
3. Draw the solution contained in the vial with the pipette until this reaches its capacity 
4. Remove the pipette and use it as a dropper to administer one drop of IMP into each eye. 


 
 
 
 
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5.3. 
STORAGE AND HANDLING OF IMP 
The Pharmacist and/or Investigator will be responsible for receipt, proper storage, and usage of study drug, as 
well as for the IMP distribution, collection of used and unused vials and final disposal of the remaining IMP.  
The investigational product must be stored at -20 ± 5 °C at the investigational sites, in an appropriate locked 
room accessible only to the pharmacist, the Investigator, or a duly designated person.  
A temperature probe and data logger will accompany the drug on shipment. It is essential that the 
investigational sites will verify the temperature excursion during shipment vs. the acceptable storage 
conditions, in order to identify potential stability concerns during shipment. These must be immediately 
communicated to the Sponsor that will decide upon appropriate actions to be taken. The IMP will be stored in 
a locked place, sheltered from light. The vials will be not shaken since agitation of vials may cause foaming 
and/or particle formation.  
On Day 1 (baseline visit), the study personnel will give to the patient the monthly boxes containing the study 
medications 
Patient should bring the study medication, one monthly box, at home as soon as possible and immediately 
store it in a freezer at -20 ± 5 °C. 
The weekly box must be kept at 2-8°C for 7 days protected from light; the daily vial can be kept at room 
temperature,  before the patient will use the single vial for each instillation (both eyes) as long as 12 hours are 
not exceeded. Agitation of vials may cause foaming and/or particle formation. Drug preparation and 
administration instructions will be provided separately to the site and to the patients.  
 
Together with the IMP monthly box, the patient will also receive a separate administration kit of vial adapters 
(one per vial), pipettes (3 per vial) and disinfectant wipes (3 per vial); some spare samples could be provided 
to ensure product administration. 
IMP ophthalmic solution instruction will be provided to patients.  
Patients will use one vial to instill one drop in both eyes (group 1: cenegermin TID; group 2: vehicle TID) 
three times a day (approximately every 6 hours), starting in the morning when they wake up, for a total duration 
of 4 weeks".. 
The contents of each vial are for the daily administration to both eyes only. After the last administration the 
used vial should be returned to the original medication box and is not to be reused. 
Any deviations from the recommended storage conditions should be immediately reported by the pharmacist 
to the Sponsor and Investigator, and the use of the drug should be suspended until they have given authorization 
for its continued use. The IMP supplies are to be used only in accordance with this protocol. The Investigator 
will not use any drug samples for other purposes (e.g., treating patients or deviating from the protocol with 
regard to dose regimen, duration of treatment, etc.). Under no circumstances will the Investigator give any 
drug samples to a third party. 


 
 
 
 
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5.4. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
5.4.1. Administration route 
The Administration route is topical ophthalmic application.  
 
5.4.2. Dose regimen 
In all patients both eyes will be treated for a period of 4 weeks. 
 
The dosing scheme of the different study groups is summarized below: 
 
Group 1: one drop of cenegermin 20 mcg/mL will be instilled in both eyes three times daily (every 6 hours, 
e.g. 7:00 am, 01:00 pm; 07:00 pm).  
  
Group 2: one vehicle drop will be instilled in both eyes three times daily (every 6 hours, e.g. 7:00 am, 01:00 
pm; 07:00 pm). 
 
During the 4 weeks of masked treatment only the administration of IMP  is allowed. Nevertheless, if strictly 
needed, the patient can take a preservative free artificial tears (provided by the Sponsor). The use (n° drops/day) 
of preservative free artificial tears will be clearly documented in a patient’s diary and in the eCRF.  
Both the patients and the investigator will be masked to the study treatment. 
Information about the study drug administration, and comments, will be recorded on the appropriate page of 
the eCRF. 
 
5.5. 
ACCOUNTABILITY OF THE IMP 
The Pharmacist and/or Investigator will confirm the receipt of the IMP supply in writing by signing and dating 
standard drug accountability forms. 
At the week 4 (end of treatment visit) the patient will return the used or unused study boxes/vials to the 
Investigator.  
The Pharmacist and/or Investigator will keep a cumulative inventory and dispensing records, and will maintain 
all supplies under adequate security.  
An accurate drug disposition record will be kept, specifying the date and amount dispensed to each patient.  
Adequate record of receipt and use or loss of drug will be retained. This inventory record must be available 
for inspection by the Sponsor and regulatory inspection at any time. Copies of this record will be provided to 
the Sponsor by the CRO throughout the duration of the study. 


 
 
 
 
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At the scheduled visit, the patient diary should be reviewed by the Investigator with the patient for 
completeness. Missing information should not be provided during the diary check but reported as missing. 
During the course of the study and until its conclusion, the Investigator will complete the drug accountability 
forms. Partially used or unused study drug boxes will be verified by the Investigator and  within one month 
after completion of the trial the partially used and unused study medication will be shipped to the Sponsor or 
will be destroyed after authorization by the Sponsor or by an authorized company according to GCP 
regulations. 
5.6. 
CONCOMITANT MEDICATION 
 
As a general rule, no ophthalmic medication other than study drug will be given to the patient from the 
screening day until all of the final study evaluations have been completed, except for preservative free artificial 
tears provided by the Sponsor.  
 
The preservative free artificial tears will be provided by the Sponsor and can be used according to the following 
scheme: 
1) During the 4 weeks of masked treatment, only if strictly needed, the patient will instill one drop in 
both eyes. 
2) During the 8 weeks of Follow-up period post-treatment one drop will be instilled in both eyes TID 
(morning, afternoon and evening).  
The use (n° drops/day) of preservative free artificial tears will be clearly documented in the patient’s diary and 
eCRF.  
 
All medications (including over-the-counter drugs, herbal products, vitamins, and antacids) taken within 4 
weeks prior to the start of and throughout the study will be clearly documented on the Concomitant 
Medications eCRF page. 
Medication entries should be specific to product name (if a combination drug product) and spelled correctly. 
The dose, unit, frequency, route of administration, start date, discontinuation date, and indication should also 
be recorded. For medications administered only one time, the frequency column may reflect "once." 


 
 
 
 
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6. STUDY PROCEDURE AND ASSESSMENTS 
 
The first patient first visit (FPFV) is defined as the 1st visit performed at one of the clinical centers by the 1st 
screened patient. The last patient, last visit (LPLV) is defined as the last visit performed at one of the clinical 
centers by the last patient (i.e., the last visit foreseen by the study protocol), independently of whether the 
patient completed or withdrew from the study. The First Patient In (FPI) is defined as the first randomized 
patient at one of the clinical centers.  
Patients will be evaluated according to the following scheme: 
 
Interventional phase 
 Screening visit (day -8),  
 Baseline (day 1+2),  
 Week 2 (day 14±2 ), 
 Week 4 (day 28±2 ) or early exit 
 
Follow up visits 
 Week 8   (day 56±2) 
 Week 12 (day 84±4) 
 Week 16 (day 112±7)  
 Week 24 (day 168±7)  
 
The schedule of study procedures and assessments is tabulated by visit in the Schedule of Evaluations in § 2.0.  
The descriptions of the procedures to be performed at each visit are provided below. 
 
 


 
 
 
 
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6.1. 
SCREENING AND RANDOMIZATION VISITS 
During the screening visit (day -8) all procedures for will be performed. From the day of screening the patients 
will stop any kind of further ophthalmic treatment, until all of the final study evaluations have been completed, 
except preservative free artificial tears (wash out period from day -8 to baseline, Day 1 +2). The wash out 
period should not be less than 8 days and more than 10 days.  
At the end of the screening period, patients meeting the entry criteria for this study will be randomized 1:1 and 
treated for 4 weeks with either cenegermin ophthalmic solution 20 mcg/mL TID or vehicle TID. 
 
Slit lamp examination and the fluorescein staining (Corneal and/or Conjunctival staining with Fluorescein) 
will be performed at different time-points, as specified in the section 2 of “SCHEDULE OF EVALUATIONS” 
and procedure will be detailed on the informed consent form. 
An independent Blinded Reading Center (RC) will also be used to assess the images collected at protocol-
specified time points and sent to the RC as specified in the RC procedure manual. 
The RC will provide instructions for the slit lamp photography and the fluorescein staining procedures. 
 


 
 
 
 
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Day 
Procedures/Assessments 
Screening visit  
Day -8 
The following procedures will be performed (order below is mandatory): 
 Explanation to the patient of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number allocation  
 Patient eligibility: Inclusion/exclusion criteria evaluation 
 Pregnancy test for female patients of childbirth potential 
 Demographic data 
 Ocular and systemic medical history 
 Previous ocular and systemic medications (prior to start the study) 
 Ocular examination of both eyes, to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia)  
• Slit-lamp examination (SLE) to assess the eyelid (Meibomian glands), eyelid 
(erythema), eyelid (edema), lashes, conjunctiva erythema, lens, iris, anterior 
chamber, corneal horizontal diameter 
• TFBUT 
• Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining)  
•  
 
 AE collection 
 Preservative free artificial tears dispensation 
 
The Investigator will dispense to the patients the preservative free artificial tears (Blink® 
Tears or equivalent), provided by Sponsor, to be used only if strictly needed by the 
patient (the patient must follow the instruction in the product leaflet). 
The patients will be instructed to enter information of self-administration of Blink® 
Tears or equivalent (if the administration has been occur per eye) and AE occurrence 
into the diary.  
The diary will be given from the PI or delegate during this visit. 
At home 
Day -8 – 
Day 1+2 
(baseline) 
 Recording any unusual medical conditions - AE monitoring (diary) 
 Artificial tears use during the wash-out period (diary) 
Data will be recorded by the patient on the patient’s diary. 
 
 
 
Day 
Procedures/Assessments 


 
 
 
 
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Visit 1 Baseline 
Day 1 +2 
 
The following procedures will be performed (order below is mandatory): 
 
 Pregnancy test for female patients of childbirth potential 
 Previous ocular and systemic medications (prior to start the treatment) 
 Ocular examination of both eyes to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia)  
• Slit-lamp examination (SLE) to assess the eyelid (Meibomian glands), eyelid 
(erythema), eyelid (edema), lashes, conjunctiva erythema, lens, iris, anterior 
chamber, corneal horizontal diameter 
• TFBUT 
• Ocular surface staining (NEI score – corneal and conjunctival fluorescein 
staining  ) 
• Schirmer test II (with Anesthesia) 
 
 Patient eligibility: Inclusion/exclusion criteria evaluation 
 Randomization 
 Study drug dispensation 
 Preservative free artificial tears dispensation  
 AE collection 
 
During visit 1, Day 1+2 or baseline, PI or delegate must check and collect the patient’s 
diary concerning the screening period and provide a new diary for the treatment period. 
The PI or a delegate must check if patient has correctly completed the diary. If not, the 
site staff must retrain the patient.  
The Investigator will dispense to the patients their monthly box containing the study 
drug for the following 4 weeks together with an adequate number of adapters and 
pipettes.  
The Investigator will dispense to the patients the preservative free artificial tears 
(Blink® Tears or equivalent), provided by Sponsor, to be used only if strictly needed 
by the patient (the patient must follow the instruction in the product leaflet ).  
After completing baseline evaluation patients will be administered, by PI, with the 
study treatment as per instructions, and will self-administer at home the subsequent 
doses. Patients will return to the clinical site on Day 14 (±2)  (Week 2, visit 2). 
 
 
6.2. 
STUDY VISITS AND FOLLOW-UP ASSESSMENTS 
After the first two weeks of treatment the patient will undergo a medical assessment during the visit 2 (week 2). 
Following the completion of the double-blind treatment (visit 3, week 4), patients will be followed up for 
efficacy until visit 6 (week 16) and safety assessments until vist 7 (week 24). During the follow-up period until 


 
 
 
 
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week 12 patients will not use further ophthalmic treatment except preservative free artificial tears, provided by 
Sponsor, one drop instilled in both eyes three times daily (morning, afternoon and evening). The patient, only 
if strictly needed, can administer additional drops and must document in the patient’s diary the n° of additional 
drops administered for each eye. After week 12 (visit 5), patients will be followed-up for additional 12 weeks 
until the end of the study (visit 7, week 24) during which patients can use others artificial tears different from 
the artificial tears provided by the Sponsor.  
Slit lamp examination and the fluorescein staining (Corneal and/or Conjunctival staining with Fluorescein) 
will be performed at different time-points, as specified in the section 2 of “SCHEDULE OF EVALUATIONS” 
and procedure will be detailed on the informed consent form. 
An independent Blinded Reading Center will also be used to assess the images collected, as described in the 
previous paragraph. 
 
 
Day 
Procedures/Assessments 
At home 
Days 1-14 
±2 
 Self-administration at home of the IMP, three times daily every 6 h for both eyes 
(diary) 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
 Recording possible use of preservative free artificial tears (diary). 
Data will be recorded by the patient in the patient’s diary. 


 
 
 
 
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Day 
Procedures/Assessments 
Visiti 2 Week 2 
Day 14±2 
The following procedures will be performed (order below is mandatory): 
 
 Ocular examination of both eyes to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia)  
• Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
• TFBUT  
• Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
•  
 
 Concomitant ocular and systemic medications 
 Frequency of patient’s  artificial tear use during first 2  weeks of treatment (to 
be reported in eCRF) 
 AE monitoring 
 
During the visit 2, week 2, the patient must bring the diary assigned during the previous 
visit. The PI or a delegate must check if patient has correctly completed the diary. If 
not, the site staff must retrain the patient.  
At completion of the assessment the patient will be discharged and will be asked to 
return for the end of treatment visit on day 28±2 (Visit 3 week 4). 
The Investigator will dispense to the patients the preservative free artificial tears 
(Blink® Tears or equivalent), provided by Sponsor, to be used only if strictly needed 
by the patient (the patient must follow the instruction in the product leaflet ).  
At home  
Days 14 ±2– 
28 ± 2 
 Self-administration at home of the IMP, three times daily every 6 h for both eyes 
(diary) 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
 Recording possible use of preservative free artificial tears (diary). 
Data will be recorded by the patient on the patient’s diary. 


 
 
 
 
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Day 
Procedures/Assessments 
Visit 3  week 4  
Day 28±2  
  
The following procedures will be performed (the below order is  mandatory): 
 
 Pregnancy test for female patients of childbirth potential 
 Ocular examination of both eyes to be performed by the physician investigator: 
• 
Assessment by SANDE questionnaire 
• 
Assessment by IDEEL questionnaire 
• 
Assessment of best corrected distance visual acuity (BCDVA) 
• 
External Ocular Examination 
• 
Schirmer test  I (without anesthesia)  
• 
Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, Anterior 
Chamber, Corneal Horizontal Diameter 
• 
TFBUT 
• 
Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
• 
Schirmer Test II (with Anesthesia) 
 
 Assessment of compliance to treatment (from patient diary and IMP reconciliation 
from returned weekly boxes) 
 Concomitant ocular and systemic medications 
 Frequency of patient’s artificial tear use during the last 2 weeks of treatment  (to 
be reported in eCRF). 
 AE monitoring 
 Verify patient study medication dosing compliance 
 
 
During visit 3, week 4, PI or delegate must check and collect the patient’s diary 
concerning the treatment period and provide a new diary for the follow up period.  
At completion of the assessment the patient will be discharged and will be asked to 
return for the follow up visit on day 56±2 (Visit 4 week 8). 
The Investigator will dispense to the patients the preservative free artificial tears 
(Blink® Tears or equivalent), provided by Sponsor, to be self-administered three times 
daily, one drop in both eyes during the first 4 weeks of  Follow up. The PI or delegate 
has to explain to the patients that, only if strictly needed, they can administer an 
additional numbers of drops of Blink® Tears or equivalent, by documenting all 
information in the patient’s diary.  
At home 
Days 28 ±2– 
56 ± 2 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
 Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 


 
 
 
 
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Day 
Procedures/Assessments 
Visit 4 Follow up week 8 
 
Day 56± 2 
The following procedures will be performed (the below order is  mandatory): 
 
 Ocular examination of both eyes to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia)  
• Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
• TFBUT 
• Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
 
 Concomitant ocular and systemic medications 
 Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF). 
 AE monitoring 
 
During visit 4, week 8, PI or delegate must check the patient’s diary concerning the  
follow up period. 
The Investigator will dispense to the patient the preservative free artificial tears (Blink® 
Tears or equivalent), provided by Sponsor, to be self-administered three times daily, 
one drop in both eyes during the second 4 weeks of  Follow up. The PI or delegate has 
to explain to the patients that, only if strictly needed, they can administer an additional 
numbers of drops of Blink® Tears or equivalent, by documenting all information in the 
patient’s diary.  
 
At home  
Days 56 ±2– 
84 ± 4 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
 Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 


 
 
 
 
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Day 
Procedures/Assessments 
Visit 5 Follow up week 12  
 
Day 84 ± 4 
 
The following procedures will be performed (the below order is  mandatory): 
 
 Ocular examination of both eyes to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia)  
• Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
• TFBUT 
• Ocular surface staining (NEI score - corneal and conjunctival fluoresce 
instaining) 
 
 Concomitant ocular and systemic medications 
 Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF). 
 AE monitoring 
 
During visit 5, week 12, PI or delegate must check and collect the  patient’s diary 
concerning the follow up period and provide a new diary for the second follow up 
period. 
The Investigator will instruct the patient that during the follow up period (from week 
13 to week 24) other topical treatments will be allowed at discretion of the treating 
physician. Such treatments will be recorded by the investigators. 
The patient has to register the use other preservative free artificial tears in the patient’s 
diary. 
 
At home  
Days 84 ± 4– 
168 ± 7 
 Recording any new or changes in concomitant medications (diary) 
 Recording any unusual medical conditions  - AE monitoring (diary) 
 Artificial tears use during 4 weeks of FU (diary) 
Data will be recorded by the patient on the patient’s diary. 


 
 
 
 
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Day 
Procedures/Assessments 
Visit 6  Follow up week 16 
 
Days 112 ± 7 
 
 
The following procedures will be performed (the below order is  mandatory): 
 
 Pregnancy test for female patients of childbirth potential 
 Ocular examination of both eyes to be performed by the physician investigator: 
• Assessment by SANDE questionnaire 
• Assessment by IDEEL questionnaire 
• Assessment of best corrected distance visual acuity (BCDVA) 
• External Ocular Examination 
• Schirmer test  I (without anesthesia) 
• Slit-lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid 
– Erythema, Eyelid - Edema Lashes, Conjunctiva Erythema, Lens, Iris, 
Anterior Chamber, Corneal Horizontal Diameter 
• TFBUT 
• Ocular surface staining (NEI score - corneal and conjunctival fluorescein 
staining) 
•  
 
 Concomitant ocular and systemic medication 
 Frequency of patient’s artificial tear use during 4 weeks of FU (to be reported in 
eCRF) 
 AE monitoring 
 
PI or delegate must check the patient’s diary concerning the previous follow up 
period. 
 
 
 
 
 


 
 
 
 
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Visit 7 Follow up week 24 
Final visit or early termination visit (ETV) 
Days 168 ± 
7 
The End of Study (EoS)  visit is defined as the last follow-up at week 24. In case of 
premature study discontinuation, patients will undergo an Early Termination Visit 
(ETV). 
 
 
 Concomitant ocular and systemic medication 
 Frequency of patient’s artificial tear use during 8 weeks of FU (to be reported in 
eCRF) 
 AE monitoring 
 
PI or delegate must check and collect the patient’s diary concerning the last follow up 
period. 
 
 
 
6.3. 
EARLY WITHDRAWAL FROM THERAPY OR ASSESSMENT 
6.3.1. 
Primary Reason For Discontinuation From The Study 
A premature discontinuation will occur when a patient who signed the ICF ceases participation in the study, 
regardless of circumstances, before the completion of the study protocol procedures. Patients can be 
prematurely discontinued from the study for one of the following reasons:  
 
 Adverse event (AE): Any significant AE that, in the opinion of the Investigator or concerned patient,  is 
not compatible with study continuation. 
 Disease progression or worsening, that according to the opinion of the Investigator is not compatible 
with study continuation.. 
 Death. 
 Lost to follow-up (Every effort must be made to contact the patient; a registered letter must be sent). 
 Non-compliance with study drug: an indication that a patient has not agreed with or followed the 
instructions related to the study medication. 
 Severe Protocol violation: an event or decision that stands in contrast to the guidelines set out by the 
protocol. 


 
 
 
 
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 Study terminated by the Sponsor: an indication that a clinical study was stopped by Sponsor. 
 Withdrawal of consent: study discontinuation requested by a patient for whatever reason. 
 Other reasons, such as administrative reasons or pregnancy.  
 
Before removal, each case should first be discussed with Dompé farmaceutici S.p.A. 
The reasons for premature discontinuation from the study will be reflected on the Study Termination Record 
of the eCRF. Unless the patient has withdrawn consent, the follow up visit assessments should be performed 
as detailed in § 6. 
 
The investigator should advise patients that prematurely discontinue on any therapies or treatments for their 
condition and refer them for further treatment as appropriate 
6.3.2. 
Discontinuation procedures 
Treatment discontinuation 
Patients who discontinue the treatment will not be withdrawn from the study by default, but will be asked to 
complete safety and efficacy observations as per the protocol, unless otherwise they withdraw their consent.  
 
Study discontinuation 
For any patient discontinuing the study following randomization, the Investigator will:  
 
 ask the patient to undergo, as far as possible, a final medical visit (Early Termination Visit - ETV) to 
examine the patient's health conditions. This examination will verify that all values tested at screening 
have remained within a clinically acceptable range (i.e., not clinically significant changes compared to 
screening). 
 arrange for alternative medical care of the withdrawn patient, if necessary. 
 report in the eCRF date and time of the last dose administration, and date and primary reason of study 
discontinuation. 
 record in the eCRF any follow-up if the patient is withdrawn for an AE. AE’s should be followed until 
resolution. 
 
 
6.3.3. Replacement procedure 
Patients in this study who prematurely discontinue treatment will not be replaced. 
 
It will be documented whether or not each patient completed the clinical study. If, for a patient, study 
treatment or observations are discontinued, the primary reason for discontinuation will be recorded. 


 
 
 
 
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6.4. 
END OF STUDY 
Patients completing the double-blind treatment and follow-up (Visits 1 Baseline to Visit 7 Follow up) will 
be considered completers.  
For the purpose of this trial, the End of Study is defined as the date of the last visit of the last patient. The 
Investigator and the Sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. Reasons for 
discontinuation have to be documented appropriately. In this event, no further patients will receive doses of 
the study drugs, and patients already having received a dose of study drug will not receive any further doses 
of the study IMP but will undergo all safety assessments scheduled after the last dose of study drug, up to an 
including the end of study examination. 


 
 
 
 
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7. ENDPOINTS 
7.1. 
STUDY ENDPOINTS 
The study objective is to assess the efficacy and safety of cenegermin when administered as ophthalmic 
solution to patients with moderate to severe dry eye. 
Evaluation of the clinical efficacy and safety during and at the end of treatment with cenegermin, will be 
performed on the basis of the following assessments at each time point. 
Evaluations will be performed on day -8 (screening), day 1+2 (visit baseline), day 14±2 (week 2), day 28±2   
(week 4 End of treatment), day 56±2 (week 8 Visit 4 FU), day 84±4 (week 12 Visit 5 FU), day 112±7 (week 
16 Visit 6 FU) and day 168±7 (Week 24 Visit 7 FU), according to the schedule of evaluation (§ 2) 
7.1.1. 
Co-Primary endpoints 
• Schirmer I test (without anesthesia) >10mm/5min at week 4.  
• Change from baseline in Symptoms questionnaire (SANDE) global score at week 12 
7.1.2. 
Secondary endpoints 
• Change from baseline in Schirmer I test (without anesthesia) [Time frame: week 4, 8, 12 and 16]; 
• Change from baseline in Cornea and conjunctiva vital staining with fluorescein (National Eye Institute 
[NEI] scales) [Time frame: week 4, 8, 12 and 16]; 
•  Change from baseline in Tear Film Break-Up Time (TFBUT) [Time frame: week 4, 8, 12 and 16];  
• Change from baseline in Symptoms questionnaire (SANDE) scores for severity and frequency [Time 
frame: week 8, 12 and 16];  
• Number of patients experienced  a worsening in symptom scores (SANDE) and/or NEI score ≥ 50% 
assessed at week 4; 
• Quality of life (IDEEL) questionnaire [Time frame: week 4, 8, 12 and 16].  
7.1.3. 
Exploratory endpoint 
• 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
CCI


 
 
 
 
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assessed at  week 2; 
•
 
 
 
7.1.4. 
Safety endpoint 
• 
Incidence and frequency of Treatment-emergent adverse events (TEAEs), assessed throughout the study. 
CCI


 
 
 
 
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8. EVALUATION OF ADVERSE EVENTS AND SAFETY INFORMATION 
8.1. 
DEFINITIONS  
Adverse Event 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related 
to the medicinal product.  
Adverse Drug Reaction  
An Adverse Drug Reaction (ADR) is defined as any noxious and unintended response to a medicinal product 
related to any dose. Any responses to a medicinal product means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
The definition covers also medication errors and uses outside what is foreseen in the protocol, including misuse 
and abuse of the product. For the purposes of 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 
§ 8.3.1,  is none or unlikely; whereas any AE reported in the study having a possible, probable or highly 
probable relationship to study drug will be considered as an ADR.  
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 


 
 
 
 
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• 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 Par. 8.4.2).  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. 
Unexpected Adverse Event/Reaction 
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure or is not listed at the 
specificity or severity that has been observed and listed in the Investigator Brochure. Events that are mentioned 
in the Investigator Brochure (section Reference Safety Information)  as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation are considered unexpected. The determination of expectedness is 
made by the Sponsor on the basis of the IB Reference Safety Information (RSI) section. 
Suspected serious unexpected adverse reaction 
A suspected serious unexpected adverse reaction (SUSAR) is defined as an adverse reaction that is both 
unexpected (not consistent with the applicable RSI) and also meets the definition of a Serious Adverse 
Reaction. 
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, in the opinion of the Investigator, may require medical intervention to prevent permanent loss of 
sight. 


 
 
 
 
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8.2. 
ADVERSE EVENT (AE) MONITORING 
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. 
All AEs should be followed-up to determine outcome of the reaction.  
In order to collect as complete as possible information in the clinical study database, all ADRs and SAEs 
ongoing at the time the subject’s study participation ends should be evaluated within 10 days after the final 
visit. After this period, all unresolved ADRs and SAEs will be reported as “ongoing” in the eCRF. 
8.3. 
RECORDING 
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 last Follow Up visit (week 24). 
When possible, signs and symptoms indicating a common underlying pathology should be documented as one 
comprehensive event. For each recorded event, the AE documentation must include the onset date, outcome, 
resolution date (if event is resolved), intensity (i.e., severity),any action with study treatment taken as a result 
of the event, and an assessment of the adverseevent relationship to the study treatment. 
Serious Adverse Events: 
The Investigator must record all SAEs, including sight-threatening events, occurring at any time during the 
study (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). 
 
 


 
 
 
 
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8.3.1. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the relationship between the AE and the investigational medication, according to 
the criteria in Table below: 
Relationship of the Adverse Event to the IMP 
None 
(Intercurrent 
Event) 
An event that is not and cannot be related to the Investigational Product, e.g. patient is a 
passenger in a road traffic accident or surgical intervention performed during the study, 
but planned before patient enrolment into the study 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality with 
temporal relationship to drug administration which makes a causal relationship 
improbable and in which other drugs, chemicals or underlying disease provide more 
plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s condition or 
treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational Product and 
cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational Product and, 
if applicable, re-appears upon repeat exposure 
 
An ADR is defined as an adverse experience which is reasonably likely to have been caused by the drug. 
Events considered “Possible”, “Probable” and “Highly Probable” related to the IMP treatment and implying a 
reasonable possibility, if considered unexpected, will be reported to appropriate regulatory authorities by the 
Sponsor. 
8.3.2. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below. For each episode, 
the highest severity grade attained should be reported. 
Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of symptoms or 
signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough discomfort to 
interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to work or to do 
usual activities [unacceptable]) 
 
 




 
 
 
 
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An assessment of expectedness and causality of each serious adverse event will be performed case by case by 
Dompé Pharmacovigilance. For SAE reported by the Investigator as not related that is subsequently assessed 
to be related by Dompé, the Investigator will receive a notification. Depending on the nature and seriousness 
of the AE, further information, including copies of appropriate medical records of the patient, as well as results 
of laboratory tests performed will need to be included in the patients chart. If the patient was hospitalized, a 
copy of the discharge summary should be available, if possible. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually need 
to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of a SAE 
occurring to a patient after that patient has ended his/her participation in the study (whether study completion 
or withdrawal), the SAE should be reported by the Investigator to the  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.  
8.4.2. 
Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be SAE and 
shall not be reported as such, but only need to be recorded in the eCRF: 
• 
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 require 
intervention/therapy, i.e. are not clinically significant. 
 
8.4.3. 
Reporting Procedure to EC/IRB and to Regulatory Authorities 
In addition to reporting the SAE to Dompé, the Investigator must also comply with the requirements related to 
the reporting of SAEs to the EC/IRB which approved the study. The requirements of IRBs vary from one IRB 
to another; however, as a minimum requirement, the Investigators must promptly report all suspected 
unexpected serious adverse reaction (SUSAR) to their IRB. 
In line with provisions set forth in 21CFR312, Dompé shall notify all participating 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:  


 
 
 
 
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• 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.  
According to US regulations, the Investigators will be informed in an unblinded fashion: Dompé will open the 
blind and report only SUSAR referred to Oxervate® (cenegermin) ophthalmic solution. 
EU Investigators shall be informed periodically, in a blinded fashion, in line with applicable requirements. 
If the results of an investigation show that an ADR not initially determined to be reportable is reclassified as 
reportable, the Sponsor shall report such reaction in a written safety report as soon as possible, but in no event 
later than 7/15 calendar days after the determination is made. 
Treatment will be unblinded by Dompé Drug Safety Pharmacovigilance prior to submission of a SUSAR to 
Regulatory Authorities and only cases referred to active treatment will be considered expeditable for regulatory 
reporting, in line with law requirements. 
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in the 
Investigator’s Files. 
Dompé shall report SUSAR to the Regulatory Authorities in the EU and to ECs, as per applicable requirements, 
within 7/15 calendar days.  
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. 
8.4.4. 
Periodical Reporting to Regulatory Authorities 
Dompé shall be responsible to prepare and submit annual safety reports (Development Safety Update Report 
– DSUR) to relevant Regulatory Authorities.  


 
 
 
 
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8.5. 
UNMASKING OF THE STUDY TREATMENT 
Masked information on the identity of the assigned investigational product will be provided for each patient. 
Unblinding 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 Drug Safety 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.. 
Additionally, Dompé Drug Safety shall unmask the patient’s treatment if the reported SAE meets criteria of a 
Suspected Unexpected Serious Adverse Reaction (SUSAR) in order to fulfil expedited regulatory reporting 
requirements. Unmasked information shall not be disclosed to Investigators. 
The identity of the treatments will remain unknown to the patient, Investigator, site staff and Dompé’s clinical 
research personnel and 
staff (apart from pharmacovigilance). 
8.6. 
FOLLOW-UP OF PATIENTS WITH ADVERSE EVENTS (AES) 
The Investigator is responsible for adequate and safe medical care of patients during the trial and for ensuring 
that appropriate medical care and relevant follow-up procedures are maintained after the trial. All AEs should 
be followed-up to determine outcome of the reaction or until 10 days after the final visit. The Investigator 
should follow-up the event until resolution or stabilization of the condition. It is the Investigator's responsibility 
to assure that the patients experiencing AEs receive definite treatment for any AE, if required. 
If patient was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to 
/Dompé 
as soon as it becomes available. In addition, a letter from the Investigator that summarizes the events related 
to the case as well as results of any relevant laboratory tests also may be requested. Further, depending upon 
the nature of the SAE, Dompé may request copies of applicable segments of the patient’s medical records. 
For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as completely and 
practically as possible their nature and/or causality until resolution of all queries, clinical recovery is complete, 
laboratory results have returned to normal, stable condition is reached or the subject is lost to follow-up. 
Follow-up may therefore continue until after the subject has left the study up to  10 days after his/her 
discontinuation from the study for unrelated SAEs, and without timelines for related SAEs, unless the patient 
denies consent. 
 
 
PPD
PPD


 
 
 
 
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8.7. 
PREGNANCY IN THE CLINICAL TRIAL 
Women of childbearing potential are not excluded from the study as long as adequate birth control methods 
are being utilized. Women of childbearing potential are defined as all women physiologically capable of 
becoming pregnant. Adequate birth control methods are summarized in the protocol’s exclusion criteria. 
Prior to enrollment in the clinical trial, female patients of childbearing potential and their partners must be 
advised of the importance of avoiding pregnancy during the entire course of the study treatment and for the 30 
days after the study treatment period ends and of the potential risks associated with an unintentional pregnancy. 
During the trial (during the study treatment period and during the follow up), female patients are to be 
instructed to contact the Investigator immediately if they suspect they might be pregnant; in the same way, 
male patients who become aware that the partner might be pregnant, are to be instructed to contact the 
Investigator immediately.  
The Investigator must report every pregnancy on a pregnancy report form as soon as possible (within 24 
hours of learning of the pregnancy) to 
/Dompé Drug Safety contacts reported at Paragraph 8.4.1, even if 
no AE has occurred, and follow it to term.  
The pregnancy form will be utilized to capture all pregnancy-related information until the birth of the child 
for both the patient and the partner.  
If the pregnancy is associated with a SAE (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 § 8.4 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.  
8.8. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned in 
the eCRF, and the patient must be followed up until the resolution of the AE or as instructed by the medical 
monitor. 
8.9. 
OVERDOSE  
Overdose (accidental or intentional) which may or may not result in serious adverse reactions, shall be reported 
to Sponsor Drug Safety/
 by email or fax, following the same procedure for SAE, within 24 hours from the 
Investigator’s knowledge of its occurrence. This includes reports related to drug intake through different routes 
(e.g. ingestion) or with suicidal intentions and consequent drug overdose. 
An overdose of Oxervate®20 mcg/mL of cenegermin ophthalmic solution is defined as the administration of 
50% or more additional drops on any given treatment day. 
 
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. 
PPD
PPD


 
 
 
 
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9. 
STATISTICS 
9.1. 
SAMPLE SIZE 
The sample size of the study is calculated based on results from previous studies. 
Considering a randomization ratio 1:1 and a one-sided alpha of 0.025, a total of 90 evaluable patients will 
allow to achieve an overall power of 90% to show superiority of cenegermin 20 mcg/mL ophthalmic solution 
vs vehicle in terms of both co-primary endpoints, expecting a difference of 30% in Schirmer I rate of 
responders in favour of cenegermin 20 mcg/mL ophthalmic solution treatment at Week 4 and a 15 points 
Global SANDE score improvement at Week 12 (with a SD of 20 points). 
Since both endpoints must be met in order to claim superiority, no multiplicity correction of alpha is required 
Assuming that 10% of subjects will not be evaluable for primary analysis, a total of approximately 100 subjects 
is expected to be enrolled.  
9.2. 
ANALYSIS POPULATION 
The following population will be defined: 
• 
The Safety (SAF) population will consist of all randomized patients who received at least one dose of the 
investigational product. Safety population will be analyzed according to the actual treatment received. The 
SAF population will be used to present results on safety data. 
• 
The Full Analysis Set (FAS) population will consist of all randomized patients who received at least one 
dose of the investigational product. FAS population will be analyzed according to ITT principle, i.e. by 
treatment allocation. The FAS population will be used for the primary analyses of the study and to present 
results on efficacy data. 
• 
The Per Protocol (PP) population will consist of all randomized patients who received at least one dose of 
the investigational product and do not have Major Protocol Deviations. The PP population will be used for 
sensitivity analyses. 
9.3. 
OVERVIEW OF PLANNED STATISTICAL ANALYSES 
The study plans for the following statistical analyses: 
• 
Final analysis: this analysis will be conducted when all enrolled subjects have completed the treatment 
at week 4 and FU at week 12. After data up to week 12 have been locked, results will be provided in 
an aggregate way without unblinding the investigators and study personnel about treatment codes. 
• 
Addendum to final analysis: this additional analysis will be conducted when all enrolled subjects have 
completed the FU at week 24, and the study database has been locked and unblinded. A dedicated 
addendum to the CSR will be created. 


 
 
 
 
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9.4. 
STATISTICAL METHODOLOGY 
9.4.1. 
General Considerations 
Appropriate descriptive statistics will be produced by treatment arms according to the nature of the variable.  
For continuous data, number of observations, mean, standard deviation, median 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 proportions 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) of 
some endpoints will be done on the eligible eye when applicable. Details will be provided in the statistical 
analysis outputs as notes. 
Unless otherwise specified, the significance level used for statistical testing will be 0.05 and two-sided tests 
will be used. All patient data collected on the CRF will be listed by patient and centre.  
The Statistical Analysis Plan 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 deviations from the original 
statistical plan (including unplanned analyses) will be documented in the Clinical Study Report.   
9.4.2. 
Primary Estimand 
A Treatment Policy Estimand is defined by the following:  
• 
Population: Subjects in the FAS population (section 9.2); 
• 
Variable: both signs (Schirmer I test) and symptoms (SANDE global score) endpoints at week 4 and 12, 
respectively; 
• 
Intercurrent event: The occurrence of an intercurrent event is irrelevant. All observed values will be used 
regardless of occurrence of an intercurrent event. Retrieved drop-outs will be used for data imputation of 
missing data; 
• 
Population-level summary: proportion of patients reaching a value of Schirmer I test (without anesthesia) 
>10mm/5min at week 4, and change from baseline in the global SANDE score at week 12.  
9.4.3. 
Analysis of efficacy variables 
9.4.3.1. 
Primary analyses 
The following null hypothesis is defined on the first primary endpoint: the proportion of patients reaching a 
value of Schirmer I test (without anesthesia) >10mm/5min at week 4 in cenegermin (rhNGF) is lower or equal 
than control: 


 
 
 
 
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H01: TrhNGF ≤ TCONTROL 
H11: TrhNGF > TCONTROL 
where TrhNGF and TCONTROL are the proportion of patients reaching a value of Schirmer I test (without 
anesthesia) >10mm/5min at week 4 for cenegermin and control groups, respectively. The null hypothesis H01 
will be rejected if the associated primary analysis p-value will be lower than 0.025. 
This primary endpoint will be analyzed by means of a logistic regression adjusting by pre-defined baseline 
factors (site, gender, age class, baseline Schirmer I test value) and a one-sided test will be used to test for 
differences between treatment groups.  
Similarly, the following null hypothesis is defined on the co-primary endpoint: the change from baseline in the 
global SANDE score at week 12 in cenegermin is lower or equal than control: 
H02: µrhNGF ≤ µCONTROL 
H12: µrhNGF > µCONTROL 
where µrhNGF and µCONTROL are the change from baseline in the global SANDE score at week 12 for cenegermin 
and control groups, respectively. The null hypothesis H02 will be rejected if the associated primary analysis p-
value will be lower than 0.025. 
This coprimary endpoint will be analyzed by means of an ANCOVA model adjusting by pre-defined baseline 
factors (site, gender, age class, baseline global SANDE score) and a one-sided test will be used to test for 
differences between treatment groups.  
Both null hypotheses H01 and H02 must be rejected in order to claim superiority of cenegermin over control. 
Consequently, no multiplicity correction of type I error will be applied on primary endpoints analysis. 
Since patients who discontinue the treatment with the IMP will not be withdrawn from the study but will be 
asked to complete safety and efficacy assessments as per the protocol, missing data under treatment policy 
strategy will be addressed by modeling patients with missing data after retrieved drop-outs (based on 
assumption of missing data would have been like retrieved drop-outs if they were assessed). Retrieved drop-
out patients are defined as patients who discontinue study treatment and decide to remain in the study by 
following the schedule of assessments and continuing to adhere to protocol requirements.  
If enough retrieved drop-out data are available to allow convergence of a regression model, a Multiple 
Imputation model based on retrieved drop-outs (MI-RD) will be used for analysis. Specifically, MI will be 
performed based on the subjects’ allocated treatment arm and observed values (baseline and intermediate) as 
covariates in a regression model using data from subjects that discontinued the treatment but have the primary 
endpoint measurement with gender, and age class as covariates. For each co-primary endpoint, MI-RD will be 
implemented into different steps: 
• 
Intermittent missing data up to primary time point (Week 4 for Schirmer I test, and Week 12 for 
SANDE) will be imputed using MCMC methods assuming missing at random (MAR) data;  
• 
The remaining missing values with a monotone missing data pattern will be imputed based on observed 
data of retrieve dropouts;  


 
 
 
 
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• 
the fully imputed datasets will be analyzed and results will be combined using Rubin’s to draw 
inference.  
If not enough data was retrieved after study treatment discontinuation for assure the convergence of the MI-
RD regression model (the final decision will be done at the time of the analysis and reported in the CSR; 
different approaches might be used for the two coprimary endpoint), the same model will be fit using data from 
subjects of control group, washing-out the effect of treatment; this approach does not assume benefits for 
cenegermin in case of discontinuation and limits a post-discontinuation clinical effect to that of vehicle. 
Specifically, wash-out approach will be implemented in this way: 
• 
Intermittent missing data up to primary time point (Week 4 for Schirmer I test, and Week 12 for 
SANDE) will be imputed using MCMC methods assuming MAR;  
• 
The remaining missing values in the vehicle group with a monotone missing data pattern will be 
imputed based on observed data of the control patients with available endpoint, while the remaining 
missing values in the treatment  group with a monotone missing data pattern will be imputed based on 
observed and imputed data of the control patients;  
• 
All imputed data will be pooled and analyzed, and results will be combined using Rubin’s to draw 
inference.  
Whether for MI-RD or wash-out approach, the adjusted estimated treatment differences between cenegermin 
and vehicle (difference in proportions for Schirmer’s test and differences in means for SANDE) will be 
displayed together with the corresponding two-side 95% confidence intervals and p-values. 
 
9.4.3.2. 
Sensitivity analyses 
The following sensitivity analyses are defined to assess the robustness of results on each primary endpoint 
versus assumptions used in the statistical model for the main estimators : 
• 
The comparison between treatment and control will be performed in the FAS population by means of 
MI under MAR assumption instead of missing not at random (MNAR). MI will be implemented in 
two steps:  
o Intermittent missing data up to primary time point (Week 4 for Schirmer I test, and Week 12 
for SANDE) will be imputed using MCMC methods assuming MAR. A separate imputation 
model will be used for each treatment arm. The imputation models will include the observed 
values (baseline and intermediate), gender, and age class as covariates. In case of non-
convergence or non-estimability issues, a single model will be considered with treatment arm 
added as explanatory variable to the model;  
o The remaining missing values with a monotone missing data pattern will be imputed based on 
data of corresponding treatment group.  
Each imputed dataset will be analyzed using observed and imputed as described in section 9.4.3.1. 
Rubin’s rule will be used for combining results to draw inference. The adjusted estimated treatment 
differences between cenegermin and vehicle (difference in proportions for Schirmer’s test and 


 
 
 
 
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differences in means for SANDE) will be displayed together with the corresponding two-side 95% 
confidence intervals and p-values.  
 
• 
A tipping point strategy will be used as a sensitivity analysis for missing data for assessment of 
superiority (if shown) of cenegermin. For each coprimary endpoint, 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-RD (or MI 
under wash-out approach), where the imputed values for the cenegermin arm 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 (p≥0.025).  
  
In addition, for each primary endpoint, the regression models detailed in section 9.4.3.1 will be performed for 
supportive purposes: 
• 
by considering complete cases only (i.e. without considering patients with missing primary endpoint);  
• 
on the PP set instead of FAS. 
Details on sensitivity and supportive analyses will be provided in the SAP. 
 
9.4.3.3. 
Secondary analyses 
In case analysis of the primary endpoints leads to rejection of null hypotheses, the following key secondary 
endpoints will be tested in a conditional sequential manner to show superiority of cenegermin versus control 
(at alpha one-sided 0.025) according to the following ranking: 
 
1. Change from baseline in Schirmer I test (without anesthesia) at week 8;  
2. Change from baseline in SANDE scores for severity at week 12; 
3. Change from baseline in SANDE scores for frequency at week 12;  
4. IDEEL modules (Quality of Life [27 questions], Dry eye Treatment satisfaction & Bother [10 
questions], and Dry eye Symptom bother [20 questions]) at week 12 and at week 4 (in this order);  
5. Change from baseline in Cornea and conjunctiva vital staining with fluorescein NEI scales at week 4, 
week 8 and at week 12 (in this order); 
6. Change from baseline in TFBUT at week 4, week 8 and at week 12 (in this order). 
This hierarchical test strategy protects the family-wise false positive error rate at the overall one-sided 0.025 
level.  
Key secondary endpoints 1., 2., and 3. will be analyzed as detailed in section 9.4.3.1. 
Changes from baseline in each IDEEL modules scale score will be analyzed using an mixed model for repeated 
measures (MMRM). The analyses will include the fixed, categorical effects of treatment, visit (4 levels: Weeks 


 
 
 
 
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4, 8, 12, 16) and treatment by visit interaction. Subject will be considered as a random effect. The covariance 
matrix used will be "unstructured". Comparisons versus vehicle TID will be provided using least square means 
at each visit and overall. Missing data will be imputed according to the questionnaire manuals. 
Changes from baseline in TFBUT and Fluorescein staining (NEI scale) will be analyzed by means of an 
ANCOVA model adjusting by pre-defined baseline factors (site, gender, age class, corresponding baseline 
value). Missing data will be imputed according to MI-RD (or wash-out approach, see section 9.4.3.1). 
In case of not rejection of null hypotheses, the above test strategy will not be performed. Instead, independently 
of results on primary endpoints, descriptive in nature analyses will be performed on all secondary endpoints at 
each available timepoints by means of descriptive statistics and by appropriate parametric tests depending on 
the nature of the variable and its distribution. Data transformation might be used in order to satisfy the 
assumption of normality requested by parametric statistical tests. In case such assumptions are not met, non-
parametric counterpart tests will be used. Change from baseline value (for continuous variables) and shift 
tables versus baseline (for categorical variables) will also be summarized for all post-baseline visits. 
Further details will be provided in the SAP. 
9.4.4. 
Analysis of 
variables 
In addition to descriptive statistics at each available time point, 
 variables will be analyzed by means 
of inferential tests depending on their nature and distribution (all confidence intervals and statistical tests on 
 endpoints are of descriptive nature). Change from baseline value (for continuous variables) and 
shift tables versus baseline (for categorical variables) might be reported for all post-baseline visits. 
Correlation between sign and symptom scores at different time points will be assessed.  
9.4.5. 
Analysis of safety variables 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs (TEAEs) are all events occurring or worsening after the first dose of the IMP. TEAEs 
will be presented by treatment arm in terms of number of AEs and their incidence by System Organ Class 
(SOC) and Preferred Terms (PT) using MedDRA. Analyses will be provided also by seriousness, relationship 
to treatment, severity and study period (treatment or follow-up). 
Individual AEs will be listed in patient data listings. 
9.4.6. 
Subgroup analysis 
Subgroup analyses of primary and secondary endpoints will be performed on the following subgroups of 
baseline characteristics: 
• 
Age class (≤Median, >Median), 
• 
Race, 
• 
Ethnicity. 
CCI
CCI
CCI


 
 
 
 
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Statistical tests for interaction (between subgroup variable and treatment arm) will be performed before 
investigate further subgroups: analyses will be performed if interaction tests between treatment and variable is 
statistically significant at 15% nominal level. Variables that may be evaluated after test for interaction are: 
• 
Region (EU, US), 
• 
Sjögren's syndrome (primary, secondary), 
• 
Medical history, 
• 
Concomitant medication. 
Statistical details and potential new subgroups definitions will be reported in the SAP. 
9.4.7. 
Missing data 
All reasonable efforts will be made to reduce the rate of missing data. Investigators will be trained about the 
importance of patient retention and full data capture. Also, any 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 follow-up visit, the Investigator will 
try to obtain any relevant information from the patients, including documents/laboratory results available from 
local medical care. 
 


 
 
 
 
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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INSTITUTIONAL REVIEW BOARD AND INDEPENDENT ETHICS COMMITTEE 
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 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.  
Europe 
This study will be carried out in full compliance with the guidelines of ethics committee (EC) and government 
agencies of each respective country as well as the European Union (EU) Clinical Trial Directive (Directive 
2001/20/EC), where applicable. Before the study begins, the Sponsor will require approval from an EC 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 EC on the progress of the study, at 
intervals not exceeding 1 year (or as appropriate), and will notify the EC of SAEs or other significant safety 
findings. The study protocol, ICF, information sheet advertisements, and amendments (if any) will be approved 
by the EC at the study centers in conformance with the EU Clinical trial directive (Directive 2001/20/EC), and 
local regulations.  
10.2. 
ETHICAL CONDUCT OF THE STUDY  
The study will be conducted in full compliance with applicable legislation, FDA, EMA and ICH guidelines 
for good clinical practice (GCP) and in accordance with the ethical principles that have their origins in the 
Declaration of Helsinki and 21 CFR § 312.120.  
10.3. 
DATA MONITORING COMMITTEE 
A Data Monitoring Committee is not required for this trial considering the following point: 
• 
The drug under investigation is well characterized and known for not harming patients 
• 
The study design is not complex and already performed in other clinical trial in DED 
• 
The study does not have a long duration. 


 
 
 
 
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10.4. 
PATIENT INFORMATION AND CONSENT  
Eligible patients can take part in the study only after providing the written informed consent approved by the 
EC/IRB. Informed consent must be obtained before starting any procedure pertaining to the study (i.e. all the 
procedures described in the protocol). A Patient Information Sheet and Informed Consent Form, which meet 
regulatory requirements and are appropriate for this study, will be provided to the patient. 
 
Each patient will read or be read (if he or she cannot read or write), assent understanding of, and sign or 
thumbprint an instrument of informed consent and after having had an opportunity to discuss them with the PI 
before signing; each patient will be made aware that he or she may withdraw from the study at any time.   
The informed consent statement contains all the elements of informed consent and contains all the core 
elements and mandatory statements as defined in the CFR. Signed copies of the ICF and Patient Information 
Sheet will be given to the patient, and both documents will be placed in the Investigator’s site files. A unique 
patient identification (PID) number will be assigned according to § 4.3 of the protocol at the time the patient 
signs the ICF.  
10.5. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential. An agreement for 
disclosure will be obtained in writing by the patient and will be included in the ICF. Patient’s data collected 
during the study will be handled in accordance with applicable data protection laws and regulations.  
On the CRFs, or Diary,patients will be identified ONLY by the assigned patient number. If patient names are 
included on copies of documents submitted to Dompé farmaceutici s.p.a. or 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. 
10.6. 
COMPENSATION FOR MEDICINE-INDUCED INJURY AND INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance contract according to national 
laws for patients/Investigators/Institutions participating in the clinical trial.   
In case of questions about medical care, cost for medical care or insurance, patients can talk to their 
Investigator. Contact details will be given in the Patient Informed Consent Document. 
 


 
 
 
 
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11. 
DATA HANDLING AND RECORD KEEPING  
11.1. 
CASE REPORT FORMS 
All data relating to the study will be recorded on eCRFs to be provided by theCRO, 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. 
A eCRF is required and should be completed for each patient that signed the informed consent, including the 
screening failure. 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 center Initiation Visit. 
The eCRF must be available for review to designated Dompé’s representatives at each scheduled 
monitoring/audit visit.The PI is responsible for verifying that all data entries in the eCRFs are accurate and 
correct. The PI must sign the completed eCRF before database lock and its submission to the Sponsor.  
Patient’s diary 
The patient will report in the Diary the details of self-administration at home of the IMP, as well as any new 
or changes in concomitant medications, any unusual medical conditions and the use of artificial tears. It is 
responsibility of the Investigator to explain to each patient how to enter the data in the Diary and to check the 
data inserted in the Diary to ensure correct completion as well as correct administration of the IMP. 
The information collected in the Diary will be part of the patient’s data collected. 
Data reported on Diary is 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. 
11.2. 
DATA MANAGEMENT  
Main Data Management activities and procedures will be accurately described in the DMP, created by 
 
and approved by Dompè.  
Data collection will involve the use of an EDC system , to which only authorized personnel will have access. 
In addition to periodic monitoring occurring within the system by Sponsor/CRO Monitors, programmatic edit 
checks will be used to review the data for completeness, logic, and adherence to study protocol (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 
PPD


 
 
 
 
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or her patients’ data, will be collected. . Reconciliation of study data and SAEs between Clinical and Drug 
Safety database will be performed by 
 in ongoing basis and the before database lock. Procedure will be 
detailed in the DMP. 
Encoding of specific data will be carried out by 
. 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. 
All data collected in the context of this study will be stored and evaluated per regulatory requirements and 
applicable guidances for electronic records. Also, data will be stored and evaluated in such a way as to 
guarantee patient confidentiality in accordance with the legal stipulations applying to confidentiality of data. 
Study records (e.g., copies of eCRFs, regulatory documents) will be retained at the study center, along with 
adequate source documentation, according to CA and ICH requirements. All study records must be available 
for audit  by Dompé farmaceutici S.p.A.; its authorized representatives; and Regulatory Inspection by 
Regulatory Authority.  
The investigator/institution should maintain adequate and accurate source documents and trial records that 
include all pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be traceable, should not 
obscure the original entry, and should be explained if necessary via an audit trail. 
11.3. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING THE 
STUDY 
The following documents will be required from the Investigator prior to the initiation visit: 
- 
Current, 
signed 
and 
dated 
Curriculum 
Vitae 
of 
Principal 
Investigator 
and 
any 
Sub-Investigators/co-workers. Updates should be provided at least every two years. 
- 
A signed page of the final protocol and any amendments. 
- 
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. If applicable, the PI will provide an updated financial disclosure agreement to the 
Sponsor 1 year after the completion of the study. 
 
PPD
PPD


 
 
 
 
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11.4. 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP E6 R2) until at least 
2 years after the last approval of a marketing application in an ICH region, and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the Investigational Product. These documents should be retained 
for a longer period however if required by the applicable regulatory requirements. The Investigator should take 
measures to prevent accidental or premature destruction of these documents. 
The essential documents include at least: the signed protocol, copies of the completed eCRFs, signed Patient 
Informed Consent Forms from all patients who consented, hospital records and other source documents, and 
all other documentation included in the Investigator Site File and Pharmacy/Dispensing File. 
 
The Investigator will inform the CRO of the storage location of these essential documents and must contact 
the Sponsor 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 the Sponsor. about this change. 
Dompé farmaceutici S.p.A. will inform the Investigator in writing when these documents no longer need to be 
retained. 


 
 
 
 
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12. 
STUDY MANAGEMENT 
 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA General 
Assembly, Fortaleza, Brazil, October 2013) and ICH Harmonised Tripartite Guideline for Good Clinical 
Practice (ICH-GCP E6-R2) and any local regulations. 
12.1. 
REGULATORY BODY APPROVAL  
 
Dompé or the CRO or other consultant appointed by Dompé will obtain the necessary approval from the 
Competent Authorities, as needed, prior to initiation of the study. The study will not be started until written 
approval from the relevant Competent Authorities (or no objection within the timeframe set by the local 
regulation, as applicable) has been received by Dompé. 
Where appropriate, any amendments to the Protocol will be sent to the Competent Authority/FDA. 
12.2. 
MONITORING 
Before any patient enters the study, a representative of Sponsor/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 CRFs 
using the electronic data capture (EDC) system. After the first patient is enrolled, the progress of the study will 
be periodically monitored by the Sponsor representative, a monitor,conducting on-site visits. This CRA will 
also be able to review query statuses remotely, possibly warranting more frequent communication with the PI 
and his or her staff. The PI will make available to the CRA the eCRFs, source documents, signed consent 
forms, and all other study-related documents. The PI and his or her staff will be responsible for reviewing 
eCRFs, resolving data queries generated by the CRA via the system, providing missing or corrected data, 
approving all changes performed on his or her data, and endorsing the patient data within the EDC system. 
This approval method will include applying an electronic signature, a uniquely assigned username and 
password that together will represent a traditional handwritten signature.  
The monitor 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.: 
• 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 


 
 
 
 
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• 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 Source Data 
Verification are also provided in the Monitoring Plan. 
12.3. 
ACCESS TO RECORDS 
The Investigator will allow designated Dompé farmaceutici S.p.a. 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 substantiate the integrity of the 
data collected during the trial. 
12.4. 
AUDIT AND INSPECTION 
The study site may be audited by Sponsor or delegate or inspected by a regulatory agency on one or more 
occasions. The Investigator may be informed in advance of such a visit.  
12.5. 
PROTOCOL AMENDMENTS 
Any amendment to this protocol will be provided to the PI in writing by Dompé farmaceutici s.p.a. No protocol 
amendment may be implemented (with the exceptions noted below) before it has been approved by the 
IRB/IEC and the signature page, signed by the PI, has been received by Dompé farmaceutici s.p.a. If the 
protocol is amended to eliminate or reduce the risk to patients, the amendment may be implemented before 
IRB/IEC review and approval. However, the IRB/IEC must be informed in writing of such an amendment, and 
approval must be obtained within reasonable time limits. Deviating from the protocol is permitted only if 
absolutely necessary for the safety or clinical management of the patients and must immediately be reported 
to Dompé farmaceutici s.p.a. 
12.6. 
DISCONTINUATION OF THE STUDY 
Dompé farmaceutici S.p.A. reserves the right to terminate the study in its entirety or at a specific study center 
at any time on the basis of new information regarding safety or efficacy, or if study progress is unsatisfactory 
for whatever reason (including epidemics), or for other valid administrative reasons. 


 
 
 
 
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12.7. 
PUBLICATIONS 
All data generated in this study will be the property of Dompé farmaceutici S.p.A. Publication of the results 
by the PI will be subject to mutual agreement between the PI and Dompé farmaceutici S.p.A. 
The Sponsor agrees that the study results (including negative and inconclusive as well as positive results) can 
be made publicly available by the Investigator publishing in peer reviewed journals; presenting results at 
scientific congresses; and posting information and results on internet-based public registers and databases. 
In any case, study results will be communicated in full to the related competent authorithies for the countries 
involved by the submission of a complete Clinical Study Report. 
As the Sponsor agrees that the study results can be published by the Investigator(s), the Investigator agrees to 
submit any manuscript (abstract, publication, paper etc.) to the Sponsor before any public disclosure. 
This will be done in order to ensure that clinical trial results are reported in an objective, accurate and balanced 
manner. The Sponsor reviews proposed manuscripts prior to submission within a reasonable period of time 
(30-90 business days in relation with the complexity of the work). 
The Investigator(s) will also be provided by the Sponsor with the clinical study report and the results of any 
additional analysis, tables, figures etc undertaken for the purposes of the article, in order to take responsibility 
for the content of the publication(s). 
On an exceptional basis, the Sponsor may temporarily delay registration of certain data elements (e.g. 
compound, name, outcome, measures etc.) to seek necessary intellectual property protection. This is because 
early disclosure of such a data could, in some circumstances, prevent or negatively impact patentability. 
 


 
 
 
 
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13. 
REFERENCES 
 
1. Pflugfelder, S. C. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am. J. Manag. Care 
14, S102-106 (2008). 
2. Craig, J. P. et al. TFOS DEWS II Definition and Classification Report. Ocul. Surf. 15, 276–283 (2017). 
3. Lambiase, A., Sacchetti, M. & Bonini, S. Nerve growth factor therapy for corneal disease. Curr. Opin. 
Ophthalmol. 23, 296–302 (2012). 
4. Lambiase, A., Bonini, S., Aloe, L., Rama, P. & Bonini, S. Anti-inflammatory and healing properties of 
nerve growth factor in immune corneal ulcers with stromal melting. Arch. Ophthalmol. Chic. Ill 1960 
118, 1446–1449 (2000). 
5. Nguyen, D. H., Beuerman, R. W., Thompson, H. W. & DiLoreto, D. A. Growth factor and neurotrophic 
factor mRNA in human lacrimal gland. Cornea 16, 192–199 (1997). 
6. Ghinelli, E. et al. Presence and localization of neurotrophins and neurotrophin receptors in rat lacrimal 
gland. Invest. Ophthalmol. Vis. Sci. 44, 3352–3357 (2003). 
7. Vesaluoma, M. et al. Effects of oleoresin capsicum pepper spray on human corneal morphology and 
sensitivity. Invest. Ophthalmol. Vis. Sci. 41, 2138–2147 (2000). 
8. Coassin, M. et al. Efficacy of topical nerve growth factor treatment in dogs affected by dry eye. Graefes 
Arch. Clin. Exp. Ophthalmol. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 243, 151–155 (2005). 
9. Lee, H. K. et al. Topical 0.1% prednisolone lowers nerve growth factor expression in 
keratoconjunctivitis sicca patients. Ophthalmology 113, 198–205 (2006). 
10. Bonini, S., Lambiase, A., Rama, P., Caprioglio, G. & Aloe, L. Topical treatment with nerve growth 
factor for neurotrophic keratitis. Ophthalmology 107, 1347–1351; discussion 1351-1352 (2000). 


 
 
 
 
Study Protocol: NGF0121 
 
 
Version No. 6.0 – Final 26/JAN/2022 
 
 
 
 
Page 77 of 81 
 
 
11. Ríos, J. D., Ghinelli, E., Gu, J., Hodges, R. R. & Dartt, D. A. Role of neurotrophins and neurotrophin 
receptors in rat conjunctival goblet cell secretion and proliferation. Invest. Ophthalmol. Vis. Sci. 48, 
1543–1551 (2007). 
12. McMonnies, C. W. Aqueous deficiency is a contributor to evaporation-related dry eye disease. Eye Vis. 
7, 6 (2020). 
13. Leonard, B. C. et al. Comprehensive Clinical, Diagnostic, and Advanced Imaging Characterization of 
the Ocular Surface in Spontaneous Aqueous Deficient Dry Eye Disease in Dogs. Cornea 38, 1568–1575 
(2019). 
14. Stern, M. E. & Pflugfelder, S. C. Inflammation in dry eye. Ocul. Surf. 2, 124–130 (2004). 
15. Pflugfelder, S. C. Antiinflammatory therapy for dry eye. Am. J. Ophthalmol. 137, 337–342 (2004). 
16. Labetoulle, M. et al. Role of corneal nerves in ocular surface homeostasis and disease. Acta Ophthalmol. 
(Copenh.) 97, 137–145 (2019). 
17. Mastropasqua, L., Massaro-Giordano, G., Nubile, M. & Sacchetti, M. Understanding the Pathogenesis of 
Neurotrophic Keratitis: The Role of Corneal Nerves. J. Cell. Physiol. 232, 717–724 (2017). 
18. Lambiase, A., Rama, P., Bonini, S., Caprioglio, G. & Aloe, L. Topical treatment with nerve growth 
factor for corneal neurotrophic ulcers. N. Engl. J. Med. 338, 1174–1180 (1998). 
19. Vitali, C. et al. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria 
proposed by the American-European Consensus Group. Ann. Rheum. Dis. 61, 554–558 (2002). 
 


 
 
 
 
Study Protocol: NGF0121 
 
 
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Page 78 of 81 
 
 
14 APPENDICES 
14.1 APPENDIX 1-SPONSOR APPROVAL PAGE 
 
NGF0121 (PROTEGO-1 study): A 4-week, Phase III, multicenter, double-masked, vehicle-controlled clinical 
study to evaluate safety and efficacy of Oxervate® (cenegermin) 20 mcg/mL ophthalmic solution versus 
vehicle, in patients with severe Sjogren’s dry eye disease  
 
 
Sponsor Medical Expert:         
______Date: ____/_____/_____ 
 
 
 
 
 
 
Sponsor Chief Medical Officer
_______Date: _____/____/_____ 
Flavio Mantelli, Chief Medical Officer 
 
 
 
 
 
 
Sponsor Clinical Trial Manager:
_____________Date: _____/____/____ 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
 
 
 
Study Protocol: NGF0121 
 
 
Version No. 6.0 – Final 26/JAN/2022 
 
 
 
 
Page 79 of 81 
 
 
14.2 APPENDIX 2-INVESTIGATOR’S SIGNATURE PAGE 
 
Investigator’s Statement 
 
I have read study protocol NGF0121 (PROTEGO-1) from the title “A 4-week, Phase III, multicenter, double-
masked, vehicle-controlled clinical study to evaluate safety and efficacy of Oxervate® (cenegermin) 20 
mcg/mL ophthalmic solution versus vehicle, in patients with severe Sjogren’s dry eye disease (PROTEGO-1 
study)” and agree to conduct the study as outlined in the protocol, and in accordance with the Declaration of 
Helsinki, ICH-GCP E6 (R2) and any local regulations, being responsible for personally supervise the study 
conduct and ensure study staff complies with protocol requirement. 
 
 
Name of Principal Investigator (block letters):____________________________________________ 
 
 
 
Signature:  _______________________________  
Date: 
 _________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
Study Protocol: NGF0121 
 
 
Version No. 6.0 – Final 26/JAN/2022 
 
 
 
 
Page 80 of 81 
 
 
14.3 APPENDIX 3 AMERICAN-EUROPEAN CONSENSUS CRITERIA FOR SJÖGREN’S 
SYNDROME 
 
Reference:  Vitali C, et al. Classification criteria for Sjogren’s syndrome: a revised version of the European 
criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61:554-55819. 
In order to make a diagnosis of Sjögren’s syndrome, the following criteria must be met: 
I. Ocular Symptoms (at least one) 
• 
Symptoms of dry eyes for at least 3 months 
• 
A foreign body sensation in the eyes 
• 
Use of artificial tears 3 or more times per day 
II. Oral Symptoms (at least one) 
• 
Symptoms of dry mouth for at least 3 months 
• 
Recurrent or persistently swollen salivary glands 
• 
Need for liquids to swallow dry foods 
III. Ocular Signs (at least one) 
• 
Abnormal Schirmer’s test, (without anesthesia; ≤5 mm/5 minutes) 
• 
Positive vital dye staining of the eye surface 
IV. Histopathology 
• 
Lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm2) 
V. Oral Signs (at least one) 
• 
Unstimulated whole salivary flow (≤1.5 mL in 15 minutes) 
• 
Abnormal parotid sialography 
• 
Abnormal salivary scintigraphy 
VI. Autoantibodies (at least one) 
• 
Anti-SSA (Ro) or Anti-SSB (La), or both 
For a primary Sjögren’s syndrome diagnosis: 
• 
Any 4 of the 6 criteria, must include either item IV (Histopathology) or VI (Autoantibodies) 
• 
Any 3 of the 4 objective criteria (III, IV, V, VI)  
 
For a secondary Sjögren’s syndrome diagnosis: 
• 
In patients with another well-defined major connective tissue disease, the presence of one symptom 
(I or II) plus 2 of the 3 objective criteria (III, IV and V) is indicative of secondary SS. 


 
 
 
 
Study Protocol: NGF0121 
 
 
Version No. 6.0 – Final 26/JAN/2022 
 
 
 
 
Page 81 of 81 
 
 
Exclusion Criteria 
• 
Past head and neck radiation treatment 
• 
Hepatitis C infection 
• 
Acquired immunodeficiency syndrome (AIDS) 
• 
Pre-existing lymphoma 
• 
Sarcoidosis 
• 
Graft versus host disease 
• 
Current use of anticholinergic drugs 
 
 

SAP_001.pdf: 
 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  1  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
 
S T A TI S TI C A L A N A L Y SI S P L A N  
 
P R O T O C O L: N G F 0 1 2 1  
A 4 -w e e k, P h a s e III, m ulti c e nt e r, d o u bl e -m a s k e d, v e hi cl e -
c o nt r oll e d st u d y t o e v al u at e s af et y a n d effi c a c y of O x e r v at e ®  
( c e n e g e r mi n) 2 0 m c g / m L o p ht h al mi c s ol uti o n v e r s u s v e hi cl e, i n 
p ati e nt s wit h s e v e r e Sj o g r e n ’s d r y e y e di s e a s e  (P R O T E G O -1 
st u d y) . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 
 
 
 




 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  3  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
 
C o nte nts  
A P P R O V A L P A G E  ............................................................................................................................ 2  
A b bre viati o ns  ...................................................................................................................................... 7  
1.  
Re visi o n Hist or y  ...................................................................................................................... 8  
2.  
I ntr o d u cti o n ............................................................................................................................. 9  
3.  
St u d y Desi g n  ............................................................................................................................ 9  
3. 1  
Ge neral desi g n a n d pla n  ................................................................................................... 9  
3. 2  
St u d y O bjecti ves e n d e n d p oi nt  ......................................................................................... 9  
3. 2. 1  
Pri mar y  ......................................................................................................................... 9  
3. 2. 2  
Sec o n dar y  ..................................................................................................................... 9  
3. 2. 3  
E x p l orati ve .................................................................................................................. 1 0  
3. 2. 4  
Safet y  .......................................................................................................................... 1 1  
3. 3  
Sc he d ule of e v al uati o ns  .................................................................................................. 1 1  
4.  
Ge neral defi niti o ns  ................................................................................................................ 1 2  
4. 1  
I n v esti gati o nal dr u g a n d stu d y treat me nt  ....................................................................... 1 2  
4. 2  
Date of first a n d last a d mi nistrati o n of st u d y dr u g  ......................................................... 1 2  
4. 3  
St u d y da y  ........................................................................................................................ 1 2  
4. 4  
Visit Sc he d ule a n d Visit Wi n d o ws  ................................................................................. 1 3  
4. 5  
Baseli ne  .......................................................................................................................... 1 3  
4. 6  
P ost -baseli ne  ................................................................................................................... 1 3  
4. 7  
Eli gi ble e ye  ..................................................................................................................... 1 3  
5.  
Sa m ple size j ustificati o n  ........................................................................................................ 1 4  
6.  
Ra n d o mizati o n a n d bli n di n g  .................................................................................................. 1 4  
6. 1. 1  
Ra n d o mizati o n  ............................................................................................................ 1 4  
6. 1. 2  
U n bli n di n g  .................................................................................................................. 1 4  
6. 2  
O ver vie w of pla n ne d statistical a nal yses  ....................................................................... 1 5  
7.  
Statis tical A nal ysis ................................................................................................................ 1 5  
7. 1  
Ge neral  ........................................................................................................................... 1 5  
7. 2  
A nal ysis sets  ................................................................................................................... 1 6  
7. 2. 1  
Scree ne d s et  ................................................................................................................ 1 6  
7. 2. 2  
E nr olle d set ( E N R)  ..................................................................................................... 1 6  
7. 2. 3  
Ra n d o mize d set ( R N D)  .............................................................................................. 1 6  
7. 2. 4  
F ull A nal ysis set ( F A S)  .............................................................................................. 1 6  


 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  4  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
7. 2. 5  
Safet y set ( S A F)  .......................................................................................................... 1 6  
7. 2. 6  
Per Pr ot oc ol set ( P P)  ................................................................................................... 1 6  
7. 3  
Pri mar y esti ma n d  ............................................................................................................ 1 6  
7. 4  
Usa ge of a nal ysis sets  ..................................................................................................... 1 7  
7. 5  
S u b -gr o u p a nal yses  ........................................................................................................ 1 7  
7. 6  
I nteri m a nal ysis .............................................................................................................. 1 8  
7. 7  
Data M o nit ori n g C o m mittee  .......................................................................................... 1 8  
7. 8  
Ha n dli n g of missi n g a n d i nc o m plete data  ...................................................................... 1 8  
7. 9  
C ha n ges i n t he pla n ne d a nal ysis  ..................................................................................... 1 9  
7. 1 0  
Bli n d Data R e vie w Meeti n g ( B D R M)  ........................................................................... 2 0  
7. 1 1  
S oft ware  ......................................................................................................................... 2 0  
8.  
E val uati o n of De m o gr a p hic a n d Baseli ne C haract eristics  .................................................... 2 0  
8. 1  
S u bject e nr ol me nt a n d dis p ositi o n  ................................................................................. 2 0  
8. 2  
Pr ot oc ol de viati o ns  ......................................................................................................... 2 0  
8. 3  
St u d y disc o nti n uati o ns  ................................................................................................... 2 0  
8. 4  
De m o gra p hics a n d baseli ne c haracteristics  .................................................................... 2 1  
8. 5  
Oc ular a n d s yst e mic Me dical Hist or y a n d C o nc o mita nt Diseases  ................................. 2 1  
8. 6  
Pri or a n d c o nc o mita nt m e dicati o ns  ................................................................................ 2 2  
8. 7  
Dr y E ye His t or y ............................................................................................................. 2 2  
8. 8  
Ot her baseli ne c haracteristics  ......................................................................................... 2 2  
8. 8. 1  
Eli gi ble e ye  ................................................................................................................. 2 2  
8. 8. 2  
S A N D E  ....................................................................................................................... 2 2  
8. 8. 3  
I D E E L ......................................................................................................................... 2 2  
8. 8. 4  
B C D V A  ...................................................................................................................... 2 3  
8. 8. 5  
E xter nal oc ular e xa mi nati o n  ....................................................................................... 2 3  
8. 8. 6  
Sc hir mer test I a n d Sc hir mer test II  ............................................................................ 2 3  
8. 8. 7  
Slit La m p O p ht hal mic E xa m  ...................................................................................... 2 3  
8. 8. 8  
Fl u orescei n Stai ni n g ( N EI Scale)  ............................................................................... 2 3  
8. 8. 9  
Tear Fil m Brea k -u p Ti m e ( T F B U T)  ........................................................................... 2 4  
9.  
E val uati o n o f Treat me nt C o m plia nce a n d E x p os ure ............................................................. 2 4  
9. 1  
C o m plia nce t o I M P  ........................................................................................................ 2 4  
9. 2  
E x p os ure t o I M P  ............................................................................................................. 2 4  
9. 3  
Use of preser vati ve free artificial tears ........................................................................... 2 4  
1 0.  
E va l uati o n of Efficac y ........................................................................................................... 2 5  


 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  5  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
1 0. 1  
A nal ysis of pri mar y effic ac y e n d p oi nt  ........................................................................... 2 5  
1 0. 1. 1  Testi n g strate g y a n d m ulti plicit y a dj ust me nt  .............................................................. 2 5  
1 0. 1. 2  A nal ysis details  ........................................................................................................... 2 5  
1 0. 1. 3  Se nsiti vit y a nal yses  ..................................................................................................... 2 7  
1 0. 1. 4  S u p p orti ve a nal yses  .................................................................................................... 2 8  
1 0. 2  
A nal ysis of sec o n dar y efficac y e n d p oi nts  ...................................................................... 2 8  
1 0. 2. 1  Testi n g strate g y a n d m ulti plicit y a dj ust me nt  .............................................................. 2 8  
1 0. 2. 2  A nal ysis details  ........................................................................................................... 2 8  
1 0. 2. 3  Descri pti ve A n al ysis  ................................................................................................... 3 1  
1 1.  
E val uati o n of Safet y  .............................................................................................................. 3 3  
1 1. 1  
A d verse e ve nts  ............................................................................................................... 3 3  
1 2.  
Deri vati o ns  a n d dat e c o n ve nti o ns  .......................................................................................... 3 5  
1 2. 1  
Varia ble d eri vati o n  ......................................................................................................... 3 5  
1 2. 2  
S A N D E deri vati o n  ......................................................................................................... 3 8  
1 2. 3  
I D E E L deri v ati o n ........................................................................................................... 3 8  
1 2. 4  
C or neal a n d C o nj u ncti va Vi tal Stai ni n g wit h Fl u orescei n ( N EI scale) ......................... 4 1  
1 2. 5  
Partial date c o n ve nti o ns  ................................................................................................. 4 1  
1 3.  
Ta bles, Fi g ur es a n d Listi n gs  .................................................................................................. 4 4  
1 3. 1  
Ta ble C o n ve nti o ns  .......................................................................................................... 4 4  
1 3. 2  
Listi n g C o n ve nti o ns  ....................................................................................................... 4 4  
1 4.  
Refere n ces  ............................................................................................................................. 4 4  
1 5.  
A p pe n dices  ............................................................................................................................ 4 5  
1 5. 1  
Ta bles  ............................................................................................................................. 4 5  
1 5. 2  
Listi n gs  ........................................................................................................................... 5 1  
1 5. 3  
Fi g ures  ............................................................................................................................ 5 2  
1 5. 5  
S A S C o de f or t he pri mar y a nal ysis  ................................................................................ 5 3  
1 5. 5. 1  Sc hir mer I test > 1 0 m m/ 5 mi n at wee k 4 ...................................................................... 5 3  
1 5. 5. 2  C ha n ge fr o m bas eli ne i n t he gl o bal S A N D E sc ore at wee k 1 2  .................................. 5 5  
 
 
 
 


 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  6  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
I n d e x of Ta bl es 
Ta ble 1: Re visi o n hist or y  .................................................................................................................... 8  
Ta ble 2: Usa ge of a nal ysis set  .......................................................................................................... 1 7  
Ta ble 3: Vari a ble deri v ati o n r ules  .................................................................................................... 3 5  
Ta ble 4: Calc ulati o n of I D E E L di me nsi o n sc ores  ............................................................................ 3 9  
Ta ble 5: S u m mar y of di me nsi o ns a n d cl usters of ite ms of t he I D E E L q uesti o n naire  ...................... 4 0  
Ta ble 6: Al g orit h m f or Treat me nt E mer ge nce of A d verse E v e nts  ................................................... 4 1  
Ta ble 7: Al g orit h m f or Pri or/ C o nc o mita nt me dicati o ns  ................................................................... 4 3  


 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  7  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
A b bre vi ati o ns  
A D R  
A d verse Dr u g Reacti o n  
A E  
A d verse E ve nt  
A N C O V A  
A nal ysis of C o varia nce  
A T C  
A nat o mical T hera pe utic C he mical  
B C D V A  
Best C orrecte d Dista nce Vis ual Ac uit y  
B D R M  
Bli n d Data Re vie w Meeti n g  
C S R  
Cli nical St u d y Re p ort  
e C R F  
electr o nic Case Re p ort F or m  
E N R  
E nr olle d set  
E U  
E ur o pea n U ni o n  
F A S  
F ull A nal ysis set  
K F R  
Ke y First efficac y Res ults  
I D E E L 
I m pact of dr y e ye o n e ver y da y life 
I M P 
I n vesti gati o nal Me dic i nal Pr o d uct  
M A R  
Missi n g at Ra n d o m  
M C M C  
Mar k o v c hai n M o nte Carl o  
Me d D R A  
Me dical Dicti o nar y f or re g ulat or y acti vities  
MI  
M ulti ple I m p utati o n  
MI -R D  
M ulti ple I m p utati o n usi n g retrie ve dr o p o uts  
M M R M  
Mi xe d M o del f or Re peate d Meas ure me nts  
M N A R  
Missi n g N ot at Ra n d o m  
N EI  
Nati o nal E ye I nstit ute  
P P  
Per pr ot oc ol set  
P T  
Preferre d Ter m  
r h N G F 
rec o m bi na nt h u ma n Ner ve Gr o wt h Fact or 
R N D  
Ra n d o mize d set  
S A E  
Seri o us A d verse E ve nt  
S A F  
Safet y set  
S A N D E  
S y m pt o m Assess me nt i n Dr y E ye  
S A P  
Statistical A nal ysis Pla n  
S E M  
Sta n dar d err or of t he mea n  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt  
T F B U T  
Tear Fil m Brea k -U p Ti me  
TI D  
Ter i n die (t hree ti mes a da y)  
U S  
U nite d States  
 
 
 










 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  1 2  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
Fi g ure 1 : St u d y d ur ati o n  
 
 
4.  Ge ner al defi niti o ns  
4. 1  
I n vesti g ati o n al dr u g a n d st u d y tre at me nt 
O xer vate ® , a n o p ht hal mic s ol uti o n c o ntai ni n g ce ne ger mi n 2 0 mc g/ m L, w hic h is a rec o m bi na nt 
h u ma n Ner ve Gr o wt h Fact or (r h N G F); refere nce pr o d uct is ve hicle. Test a n d refere nce will be 
i nstille d i n b ot h e yes acc or di n g t o t he f oll o wi n g sc he me:  
•  Gr o u p 1: o ne dr o p of ce n e ger mi n 2 0 mc g/ m L will be i nstille d i n b ot h e yes t hree ti mes dail y 
(e ver y 6 h o urs, e. g. 7: 0 0 a m, 0 2: 0 0 p m; 0 9: 0 0 p m).  
•  Gr o u p 2: v e hicle e ye o ne dr o p will b e i nstille d i n b ot h e yes t hree ti mes dail y (e ver y 6 h o urs, 
e. g. 7: 0 0 a m, 0 2: 0 0 p m; 0 9: 0 0 p m).  
T he I M P  will be pr o vi d e d i n a m o nt hl y b o x c o ntai ni n g 2 8 dail y vials. T o get h er wit h t he I M P m o nt hl y 
b o x, patie nts will be pr o vi de d wit h e n o u g h pi pettes a n d a da pt ors f or t he a d mi nistrati o n of t he I M P.  
4. 2  
D ate of first a n d l ast a d mi nistr ati o n of st u d y dr u g  
T he date of first a d mi nistrati o n of st u d y dr u g is defi ne d as t he date of  first a d mi nistrati o n of I M P as 
per I M P A d mi nistrati o n e C R F f or m (i nf or mati o n tra nscri be d fr o m Patie nt Di ar y). 
T he date/ti me of last a d mi nistrati o n  of st u d y dr u g is defi ne d as t he Date of last treat me nt 
a d mi nistrati o n  as per E n d of treat me nt  e C R F f or m. T his val ue has t o be c o nsiste nt wit h  I M P 
A d mi nistrati o n i nf or mati o n rec or de d o n t he c orres p o n di n g e C R F f or ms. I n case of differe nt dates, 
t he latest will be use d as treat me nt e n d. 
4. 3  
St u d y d a y  
T he st u d y da y descri bes t he da y of t he e ve nt or assess me nt date, relati ve t o t he refere nce start date 
w hic h is t he date of Visit 1 - Baseli ne.  
T he st u d y da y is defi ne d as:  


 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  1 3  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
•  T he date of t he e ve nt ( visit date, o nset dat e of a n e ve nt, assess me nt dat e etc.) –  refere nce start 
date + 1 if e v e nt is o n or after t he refere n ce start date.  
•  T he date of t he e ve nt ( visit date, o nset dat e of a n e ve nt, assess me nt dat e etc.) –  refere nce start 
date if e ve nt prece des t he refere nce start dat e.  
4. 4  
Visit Sc he d ule a n d Visit Wi n d o ws  
Assess m e nts a n d st u d y visits will be perf or m e d as liste d i n Para gra p h n o. 2 (“Sc he d ule of 
e val uati o ns ”) a n d i n Para gra p hs  n o.  6  ( “St u d y Pr oce d ure a n d Assess me nts ”) o f t he St u d y Pr ot oc ol  
[1 ] c o ntai ni n g a d diti o nal details a b o ut sc he d ule d visits a n d ti me wi n d o ws.   
Sc he d ule d visits a n d ti me wi n d o ws are:  
•  Scree ni n g ( Da y  -8)  
•  Visit 1 - Baseli ne ( Da y 1 + 2 da ys)  
•  Visit 2 - Wee k 2  ( Da y 1 4 ±  2 da ys)  
•  Visit 3  - E n d of treat me nt  Wee k 4  ( Da y 2 8 ±  2 da ys)  
•  Visit 4  - f oll o w-u p  Wee k 8  ( Da y 5 6 ±  2 da ys)  
•  Visit 5  - f oll o w-u p  Wee k 1 2  ( Da y 8 4 ±  4 da ys)  
•  Visit 6  - f oll o w-u p  Wee k 1 6  ( Da y 1 1 2 ±  7 da ys)  
•  Visit 7  - f oll o w-u p  Wee k 2 4  ( Da y 1 6 8 ±  7 da ys)  
F or effi cac y a n d safet y e n d p oi nts, data will be e val uate d acc or di n g t o t he Visit at w hic h t he y ha ve 
bee n c ollecte d . 
4. 5  
B aseli ne  
Baseli ne is defi n e d as t he last visit pri or t o a n d i ncl u di n g date of t he ra n d o mizati o n visit  ( Visit 1). 
U nless ot her wise s pecifi e d, bas eli ne val ues are defi ne d as t he meas ure me nts ta ke n d uri n g t his visit.  
I n cas e of m ulti ple meas ure me nts d uri n g b aseli n e visit, t he last ass ess me nt will be c o nsi dere d as 
baseli ne e val u ati o n bef ore start of treat me nt.  
4. 6  
P ost -b aseli ne  
F or safet y a n d effi cac y e val uati o ns all assess me nts after t h e first a d mi nistrati o n of st u d y dr u g are 
c o nsi dere d as “p ost -bas eli ne ” assess me nt.  
4. 7  
Eli gi ble e ye  
Ass u mi n g t hat all t he i ncl usi o n/e xcl usi o n criteria are met i n b ot h e yes, t he w orse e y e (eli gi ble e ye) 
will be  deter mi ne d at t he baseli ne visit usi n g a ste pla d der a p pr oac h, as f oll o ws:  
1.  Sc hir mer’s Test : wors e e ye deter mi ne d as e ye wit h l o wer  Sc hir mer I sc ore. 
2.  N EI sc ore : if Sc hir mer I s c ore is t he s a me i n b ot h e yes, w ors e e y e will b e d eter mi ne d  b y N EI 
sc ore (c or nea +  c o nj u ncti val stai ni n g).  
If all t he a b o ve are i d e ntical, deter mi nati o n of t he w orse e ye will be base d o n t he in vesti gat or’s 
j u d ge me nt, ot her wise t he ri g ht e ye will be use d as t he eli gi ble e ye.  


 
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5.  S a m ple size j ustific ati o n  
T he sa m ple siz e of t he st u d y is calc ulate d bas e d o n res ults fr o m pre vi o us st u dies.  
Sa m ple size was calc ulat e d acc or di n g t o t he f oll o wi n g ass u m pti o ns:  
•  ra n d o mizati o n rati o 1: 1.  
•  a differe n ce of 3 0 % i n Sc hir mer I rate of res p o n ders ( val ue > 1 0 m m/ 5 mi n at wee k 4. ) i n fa v or 
of  r h N G F treat me nt at Wee k 4, wit h a res p o n der rate of 5 % f or ve hicl e.  
•  1 5 p oi nts i n Gl o bal S A N D E sc ore i m pr o ve me nt at Wee k 1 2, wit h  a sta n dar d de viati o n of 2 0 
p oi nts . 
Base d o n t hese ass u m pti o ns, a  t otal sa m ple siz e of 9 0 e v al ua ble p atie nts ( 1 0 0 pts c o nsi deri n g 1 0 % 
of patie nts n ot e v al ua bl e aft er e nr oll me nt ) all o ws t o ac hie ve a n o verall p o wer of 9 0 % t o s h o w 
s u peri orit y of r h N G F e ye dr o ps s ol uti o n vs ve hicle i n ter ms of b ot h c o -pri mar y e n d p oi nts, 
c o nsi deri n g a o ne-si de d al p ha of 0. 0 2 5. S pecificall y:  
•  A p o wer of 9 5. 8 % is ac hi e ve d f or Sc hir m er I pri mar y e n d p oi nt.  
•  A p o wer of 9 4. 0 % is ac hi e ve d f or S A N D E pri mar y e n d p oi nt.  
6.  R a n d o miz ati o n a n d bli n di n g  
6. 1. 1  Ra n d o mizati o n  
Eli gi ble patie nts will be ra n d o mize d i n a 1: 1 rati o t o eit her ce ne ger mi n o p ht hal mic s ol uti o n 2 0 
mc g/ m L TI D or ve hicl e o p ht hal mic  s ol uti o n TI D. 
Ra n d o mizati o n will be stratifie d b y site t o e ns ure bala nce d assi g n me nt acr oss treat me nt gr o u ps. T h e 
stratifie d per m ute d bl oc k ra n d o mizati o n list will be ge nerate d wit h a c o m p uter pr oce d ure b y a n 
i n de pe n de nt statisticia n n ot i n v ol ve d i n t he c o n d uct of t he st u d y. 
Ra n d o mizati o n will be perf or me d t hr o u g h I R S. Eac h Patie nt Kit n u m ber will be ra n d o ml y ass ociate d 
wit h a treat me nt gr o u p. T he ra n d o mizati o n list will be pr o vi de d t o t he facilit y res p o nsi ble f or I M P 
pac ka gi n g/la belli n g f or t he p ur p ose of I M P pre parati o n. Eac h ra n d o mize d patie nt will be all ocate d 
wit h ra n d o mizati o n n u m ber acc or di n g t o t he stratifie d ra n d o mizati o n list. 
Dr o p o uts after 
ra n d o mizati o n will n ot be re pla ce d  
T he e nr oll me nt of patie nts will be sc he d ule d i n or der t o ass ure a n i ncl usi o n of a p pr o xi matel y 1 0 0 
patie nts t o e ns ure at least 9 0 patie nts ass u mi n g u p t o 1 0 % of patie nts n ot e val ua ble after e nr oll me nt . 
6. 1. 2  U n b li n di n g 
T he i de ntit y of t he treat me nts will re mai n u n k n o w n t o t he patie nt, i n vesti gat or, site staff a n d 
S p o ns or’s cli nical researc h pers o n nel u n til t he c o m pleti o n of t he st u d y (after f ull data base l oc k) 
e xce pt i n case of s pecific e ve nts t hat will re q uire u n mas ki n g of t he patie nt.  
T he vials c o ntai ni n g ce n e ger mi n ( 2 0 mc g/ m L) or ve hicle will be i de ntical i n a p peara n ce, a n d t he 
c o nte nts of t he vials will be i n disti n g uis ha ble. All staff directl y i n v ol ve d i n t he a nal ysis of st u d y 
res ults will re mai n mas ke d t o treat me nt assi g n me nts w hile t he st u d y is i n pr o gress. 
T he i n vesti gat or will be pr o vi de d wit h a pr otecte d access t o t he ra n d o mizati o n list s o o nl y i n case of 
a me dical e mer ge n c y t he i n vesti gat or ca n o pe n t h e treat me nt all ocati o n f or a s pecific p atie nt.  


 
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Als o D o m pé’s  P har mac o vi gila nce c o ntact pers o n will be pr o vi de d wit h a pr otecte d access t o 
ra n d o mizati o n list, s o if re q uire d b y t he P har mac o vi gila nce acti vities t he P har mac o vi gila nce c o ntact 
pers o n ca n o p e n t he treat me nt all ocati o n f or a s p ecific Patie nt.  
I n t h e e ve nt of a me di cal e mer ge n c y w here t he k n o wle d ge of p atie nt treat m e nt is re q uire d t o pr o vi de 
t he patie nt wit h a p pr o priate care, i n vesti gat ors will ha ve t he p ossi bilit y t o u n mas k t he treat me nt 
assi g n me nt f or a s pecific patie nt. T he i n vesti gat ors are e n c o ura g e d t o c o nt act t he C o ntract Researc h 
Or ga nizati o n  staff bef ore bec o mi n g u n mas ke d if t h ere is s uffici e nt ti me. 
If t he i n vesti gat or bec o mes u n ma s ke d f or a n y reas o n, t his i nf or mati o n will be rec or de d o n s o urce 
data a n d i n t he e C R F of t he st u d y, s pecif yi n g t he date a n d t he reas o n.  
U n mas ki n g e ve nts will be rec or de d a n d re p orte d i n t he fi nal st u d y re p ort.  
6. 2  
O ver vie w of pl a n ne d st atistic al a n al yses  
A nal yses will be c o n d u cte d w he n all e nr olle d s u bjects ha ve c o m plete d t he st u d y a n d t he st u d y 
data base h as bee n l oc k e d a n d u n bli n de d . Ke y first efficac y res ults  ( K F R) will be pr o vi de d cl ose t o 
t he data base cl os ure i n or der to  i de ntif y efficac y fi n di n g s i n a s h ort ti mefra me.  
T he list of ta bles, listi n gs, a n d fi g ures t o be pr o vi de d at eac h a n al ysis is re p orte d i n  a p pe n di x  1 5.  
7.  St atistic al A n al ysis  
7. 1  
Ge ner al  
All patie nt data c ollecte d d uri n g t he st u d y will be liste d b y patie nt  a n d site.  
A p pr o priate descri pti ve statistics will be pr o d uce d b y treat me nt ar ms acc or di n g t o t he nat ure of t he 
varia ble.  
F or c o nti n u o us data, n u m ber of o bs er vati o ns, m ea n, sta n d ar d d e viati o n, me dia n , ra n g e ( mi ni m u m 
a n d ma xi m u m) a n d 9 5 % c o nfi de nce i nter vals  will be prese nt e d.  
F or cate g ori cal  dat a, fre q ue nc y distri b uti o ns a n d p erce nt a ges wit h 9 5 % c o nfi de nce i nter val s ( Wils o n 
met h o d) per cate g or y will be prese nte d.  
F or pri mar y a nal ysis, t he t hres h ol d f or clai mi n g statistical si g nifica nce will 0. 0 2 5 o ne-si de d. F or 
ot her a n al ysis, u nless ot her wise s p ecifie d, t he si g nifica nce le vel f or statistical testi n g will be 0. 0 5 
a n d t w o-si de d tests.  
T he statistical a n al yses ( b ot h descri pti ve a n d i nf ere nti al) of s o me e n d p oi nts will be d o ne o n t h e 
eli gi ble e ye w he n a p plica ble. Details will be pr o vi de d i n t he statistical a nal ysis o ut p uts as n otes.  
A d diti o nal p ost -h oc a nal ysis ma y be pr o d uce d t o f urt her all o w c o m paris o n bet wee n treat me nt a n d 
c o ntr ol, acc or di n g  t o t he res ults o btai ne d. A n y de viati o ns fr o m t he ori gi nal statistical pla n (i ncl u di n g 
u n pla n ne d a nal yses) will be d oc u me nte d i n t he C S R . 
 
 


 
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7. 2  
A n al ysis sets  
7. 2. 1  Scree ne d s et 
T he Scree ne d set will c o nsist of all patie nts wit h si g ne d writte n i nf or me d c o nse nt.  
7. 2. 2  E nr olle d set ( E N R)  
T he E N R  set will c o nsist of all patie nts wit h si g ne d writte n i nf or me d c o nse nt a n d f ulfill me nt of 
eli gi bilit y criteria ( i.e., n ot re p orte d as s cree ni n g f ail ure).  
7. 2. 3  Ra n d o mize d  set ( R N D) 
T he R N D  set will c o nsist of all patie nts i n t he E N R  set w h o are ra n d o mize d t o t he st u d y, re gar dless 
of w het her t h e y recei ve  t he I M P or n ot.  
7. 2. 4  F ull A nal ysis set  ( F A S) 
T he F A S  p o p ulati o n will c o nsist of all ra n d o mize d patie nts w h o recei ve d at least o ne d os e of t he 
i nvesti gati o nal pr o d uct. F A S p o p ulati o n will be a nal yze d acc or di n g t o i nte nti o n-t o-treat (I T T) 
pri nci ple, i.e. b y treat me nt all ocati o n re g ar dless h a p pe ni n g of i nterc urre nt e ve nts (treat me nt p olic y 
strate g y). T he F A S p o p ulati o n will be use d f or t he pri mar y a nal ysis of t he st u d y a n d t o prese nt res ults 
o n effic ac y dat a.  
7. 2. 5  Safet y set ( S A F)  
T he S A F  set will c o nsist of all ra n d o mize d p atie nts w h o recei ve d at least o ne d ose of t he 
i n vesti gati o nal pr o d uct. S A F set  will be a nal yze d acc or di n g t o t he act ual treat me nt rece i ve d. T he 
S A F p o p ulati o n will be use d t o prese nt r es ults o n safet y data.  
7. 2. 6  Per Pr ot oc ol set  ( P P) 
T he P P set  will c o nsist of all ra n d o mize d patie nts w h o recei ve d at least o ne d ose of t h e i n vesti gati o nal 
pr o d uct a n d d o n ot ha ve Maj or Pr ot oc ol De viati o ns. T he P P p o p ulati o n will be use d f or se nsiti vit y 
a nal yses. 
7. 3  
Pri m ar y esti m a n d  
T he pri mar y e n d p oi nt s will be a nal yze d usi n g treat me nt p olic y esti ma n d s, defi ne d b y t he f oll o wi n g: 
Pri mar y e n d p oi nt:  
•  P o p ulati o n: S u bjects i n t he F A S p o p ulati o n.  
•  Varia ble: Sc hir mer I test at wee k 4 . 
•  I nterc urre nt e ve nt: T h e o cc urre nce of a n i nterc urre nt e ve nt is irrele va nt. All o bser ve d val ues 
will be use d re gar dless of occ urre nce of a n i nterc urre nt e ve nt. Retrie ve d dr o p o uts  will be use d 
f or data i m p utati o n of missi n g data. 
•  P o p ulati o n -le vel s u m mar y: differe nce i n pr o p orti o n of p atie nts r eac hi n g a v al ue of Sc hir mer 
I test ( wit h o ut a nest hesia) > 1 0 m m/ 5 mi n at wee k 4 .  
C o pri mar y e n d p oi nt:  




 
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•  S A N D E gl o bal, fre q u e nc y a n d se verit y sc ores. 
•  N EI scale . 
•  T F B U T.  
•  I D E E L q uesti o n nair e . 
at eac h a vaila ble ti me p oi nts b y mea ns of descri pti ve statistics.  
I n cas e of c o nti n u o us me as ures, a nal yses will be pr o vi de d f or bas eli ne visit, eac h p ost-bas eli ne visit, 
a n d t heir c h a n ge fr o m b aseli ne. C o m paris o ns bet wee n treat me nts will be perf or me d usi n g t w o -
sa m ple t-test (ass u mi n g u ne q ual varia nces) or, if t he re q uire d ass u m pti o ns are n ot met, t he t w o-
sa m ple Ma n n– W hit ne y U test will be use d. Ass u m pti o n of n or mal distri b uti o n of e n d p oi nts f or 
c o nti n u o us data will be assesse d b y a vis ual i ns pecti o n of distri b uti o n.  
I n cas e of cate g oric al varia bles, t he Fis her’s E x act test will be pr o vi de d i n a d diti o n t o s u m mar y 
descri pti o n . 
Statistical tests f or i nteracti o n ( bet wee n s u b gr o u p varia ble a n d treat me nt ar m) will be perf or me d 
bef ore i n vesti gati n g furt her s u b gr o u ps: a nal yses of pri mar y e n d p oi n ts will be perf or me d  usi n g 
re gressi o n m o del s i ncl u di n g treat me nt, s u b gr o u p varia ble a n d t heir i nteracti o n as c o variate. If t he 
i nteracti o n bet wee n s u b gr o u p varia ble a n d treat me nt ar m is statisticall y si g nifica nt at 1 5 % n o mi nal 
le vel i n at least o ne re gressi o n m o del, t he n s u b gr o u p a nal ysis will be perf or me d. Varia bles t h at ma y 
be e val uat e d after test f or i nteracti o n are:  
Varia bles t hat ma y b e e v al uate d aft er test f or i nteracti o n are:  
•  Re gi o n ( E U, U S),  
•  Sj ö gre n's s y n dr o me ( pri mar y, sec o n d ar y),  w her e “ p ri m ary”  is defi ne d as a c o nfir me d 
di a g n osis of Sj ö gre n's sy n dr o me w hile “ sec o n d ary”  as ot her a ut oi m m u ne dise ase k n o w n t o 
i n d uce Sj ö gre n’s Dry Eye Dise ase, 
•  Me dical hist or y,  
•  C o nc o mita nt me dicati o n.  
S u b gr o u p le vels ma y be p o ole d t o ha ve a n a de q uate n u m ber of  s u bjects per strata t o perf or m t he 
a nal ysis. Decisi o n o n p o oli n g will be ta ke n d uri n g t he Bli n d Data Re vie w Meeti n g ( B D R M), bef ore 
data base l oc k.   
7. 6  
I nteri m a n al ysis 
N o i nteri m a nal ysis is pla n ne d.  
7. 7  
D at a M o nit ori n g C o m mittee  
N o Data M o nit ori n g C o m mittee has bee n esta blis he d.  
7. 8  
H a n dli n g of missi n g a n d i nc o m plete d at a  
All reas o na bl e eff orts will be ma de t o re d uce t he rate of missi n g data. I n v esti gat ors will be trai ne d 
a b o ut t he i m p orta nce of patie nt rete nti o n a n d f ull data ca pt ure. Als o, a n y reas o na ble atte m pts s h o ul d 
be ma de b y t he i n vesti gat ors t o e m p hasize c o nti n ue d s u bject’s partici pati o n f or t he f ull d urati o n of 
t he trial.  


 
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Patie nts w h o disc o nti n ue t he treat me nt will n ot be wit h dra w n fr o m t he st u d y b y defa ult b ut  will be 
as ke d t o c o m plete safet y a n d effi cac y o bs er vati o ns as per t he pr ot oc ol, u nless ot her wise t he y 
wit h dra w t heir c o nse nt. Patie nts w h o disc o nti n ue st u d y treat me nt a n d d eci de t o re mai n i n t he st u d y 
b y f oll o wi n g t he sc he d ule of ass ess me nts a n d c o nti n ui n g t o a d here t o pr ot oc ol re q uir e me nts are 
defi ne d as “retri e ve d dr o p -o ut” patie nts.  
F or t he pri mar y  a n d ke y sec o n dar y  a nal yses, missi n g data will be ha n dle d b y mea ns of M ulti ple 
I m p utati o n usi n g retri e ve dr o p o uts ( MI-R D) , as d etailed i n secti o n s 1 0. 1. 2  a n d 1 0. 2. 2 .  
I n a d diti o n, t o f urt her mi ni mize missi n g data, if a patie nt ca n n ot refer t o t he site f or a pla n ne d f oll o w -
u p visit, t he i n vesti gat or will tr y t o o btai n a n y rele va nt i nf or mati o n fr o m t he patie nts, i ncl u di n g 
d oc u me nts/la b orat or y res ults a vaila ble fr o m l ocal me dical care.  
T he n u m ber of s u bjects wit h missi n g data will be prese nte d u n der t he “ Missi n g” cate g or y. Missi n g 
val ues will n ot be i ncl u de d i n t he de n o mi nat or c o u nt w he n c o m p uti n g perce nta ges. W he n c o nti n u o us 
data will be s u m marize d, o nl y t he n o n -missi n g val ues wil l be e val uate d f or c o m p uti n g s u m mar y 
statistics. 
F or t he a nal ys es of para meters f or w hic h  a n i n de pe n de nt bli n de d rea di n g ce nter  ma y be i n v ol ve d p er 
pr ot oc ol, t he f oll o wi n g r ules will be use d: 
1.  If ass ess me nt fr o m bli n de d rea di n g ce nter  is a vaila ble, s uc h val ue will be use d f or t h e 
a nal ysis . 
2.  If assess me nt  f or m bli n de d rea di n g ce nter  is n ot a vaila ble, t he c orres p o n di n g e val uati o n (if 
a n y) fr o m t he site i n vesti gat or will be use d . 
3.  If b ot h assess me nts  (bli n de d rea di n g ce nter  a n d site i n vesti gat or) are n ot a vail a ble, a statistical 
i m p utati o n met h o d will be a p plie d as des cri be d i n t his S A P.  
R ules f or ha n dli n g missi n g data of  I D E E L q uesti o n naire are re p orte d i n s ecti o n 1 2. 3 , acc or di n g t o 
t he de dicate d ma n ual.  
7. 9  
C h a n ges i n t he pl a n ne d a n al ysis  
T he f oll o wi n g c ha n g es ha ve bee n i ncl u de d, c o m p are d t o t he pr ot o c ol  [1 ]: 
•  I n t he sec o n d ar y e n d p oi nt o n S A N D E,  t he gl o bal sc ore has bee n i ncl u de d (secti o n 3. 2. 2 ) i n 
a d diti o n t o se verit y a n d fre q ue nc y s c ores . 
•  I n t he e x pl orati ve e n d p oi nt o n S A N D E,  t he gl o bal sc ore has b ee n i ncl u de d (secti o n 3. 2. 3 ) i n 
a d diti o n  t o se verit y a n d fre q ue nc y s c ores. 
•  A clarificati o n o n t he use of data  fr o m bli n de d rea di n g ce nter  a n d site i n vesti gat or has bee n 
a d de d i n secti o n 7. 8 . 
•  T he first ke y sec o n dar y e n d p oi nt i n secti o n 1 0. 2. 1  has bee n re w or d e d i n ali g n me nt wit h t he 
defi niti o n of t he Sc hir mer I test  pri mar y  e n d p oi nt . 
•  A clarificati o n o n t he use of a Mi xe d M o del f or Re peate d Meas ure me nts  (M M R M ), e xte nsi o n 
of A N C O V A f or re peate d meas ure me nts , after i m p utati o n t hr o u g h MI -R D f or I D E E L, N EI 
scale a n d T F B U T e n d p oi nts has bee n a d de d i n s ecti o n  1 0. 2. 2 , i n ali g n me nt wit h treat me nt 
p olic y esti ma n d  use d f or pri mar y e n d p oi nt.  
•  C o nsi deri n g t he pr o gress of dat a c ollecti o n, t he o ver vie w of pla n ne d statistical a nal yses 
(secti o n 6. 2) has bee n u p date d. A si n gle dat a bas e l oc k will be p erf or me d at t he e n d of t h e 
st u d y (i nstea d of t w o l oc ks), f oll o we d b y t he release of t he K F R a n d b y t he fi nal a nal yses. 
T his decisi o n re pres e nts a c o nser vati ve c h oice i n f a v or of t he i nte grit y of t h e st u d y.  
 


 
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7. 1 0  Bli n d D at a Re vie w Meeti n g  ( B D R M) 
B D R M s will be hel d bef ore D B  l oc ks. A n y ot her details will be pr o vi de d i n t he B D R M 
d oc u me ntati o n ( Pre -A n al ysis Re vie w) . 
7. 1 1  S oft w are  
All statistical a nal yses a n d data pr ocessi n g will be perf or m e d usi n g Statistical A nal ysis S yste ms 
( S A S ®) S oft ware (rele as e 9. 4  or later ). 
8.  E v al u ati o n of De m o gr a p hic a n d B aseli ne C h ar acteristi cs  
8. 1  
S u bject e nr ol m e nt a n d dis p ositi o n  
All prese ntati o ns o f s u bject dis p ositi o n will be b y treat me nt gr o u p, a n d o v erall.  
F or des cri bi n g t he s u bject dis p ositi o n, t he f oll o wi n g p o p u lati o ns will be s u m marize d:  
1.  S u bjects scree n e d  o verall  (N ).  
2.  S u bjects e nr olle d o verall (N, 1 0 0 % ).  
3.  S u bjects e nr olle d b ut n ot ra n d o mize d a n d reas o n s f or n o n-all ocati o n o verall (N, % ).  
4.  S u bjects ra n d o mize d  b y treat me nt gr o u p, a n d o verall ( N, % ).  
5.  S u bjects ra n d o mize d b ut n ot treate d  b y treat me nt gr o u p, a n d o verall ( N, % ). 
6.  S u bjects i n eac h a nal ysis set  ( F A S, S A F, P P) a n d reas o ns  f or e x cl usi o n  b y treat me nt gr o u p, 
a n d o verall ( N, % ). 
F or  p oi nts 1 - 3 , t he percenta ge de n o mi nat or will be t he n u m ber of E N R  s u bjects; f or p oi nts 4 - 6 , 
t he perce nta ge d e n o mi nat or will be t he n u m ber of ra n d o mize d s u bjects wit hi n eac h ar m. 
Listi n gs will be pr o vi de d base d o n E N R set.  
8. 2  
Pr ot oc ol de vi ati o ns  
All t he pr ot oc ol de viati o ns will b e disc usse d case b y case bef ore u n bli n di n g of t he treat me nt c o d e 
wit h t he cli nical tea m d uri n g t he B D R M  a n d des cri be d i n t he B D R M  Re p ort.  A n y d e viati o n fr o m 
t hese pr ot oc ol pr oce d ures will be re p orte d i n t he st u d y-s pecific Pr ot oc ol D e viati o n f or m. 
N u m ber of occ urre nces a n d of s u bjects wit h at least o ne m aj or a n d mi n or pr ot oc ol de viati o n will be 
s u m marize d f or eac h treat me nt a n d o verall . 
8. 3  
St u d y disc o nti n u ati o ns  
T he f oll o wi n g i nf or mati o n will be s u m mari ze d f or t he ra n d o mize d patie nts b y treat me nt a n d o v erall: 
•  Trial c o m pleters.  
•  S u bjects w h o disc o nti n ue d t he trial pre mat urel y (a n d reas o n s). 
•  N u m ber of s u bje cts w h o c o m plete d eac h pla n ne d visit.  


 
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•  S u bjects w h o disc o nti n ue d t he I M P  (a n d reas o ns). 
•  S u bjects w h o disc o nti n ue d t he I M P b ut c o m plete d  t he st u d y. 
•  S u bjects w h o disc o nti n ue d t he I M P a n d dis c o nti n ue d t he trial pre mat urel y.  
•  Br o ke n ra n d o mizati o n c o de (a n d reas o n s). 
If m ore t h a n 3 0 % of ra n d o mize d s u bjects disc o nti n ue t he st u d y pre mat urel y, t he distri b uti o n of t he 
ti me fr o m ra n d o mizati o n t o disc o nti n uati o n will be s u m marize d usi n g t h e Ka pla n-Meier met h o d. 
T he de gree of u ncertai nt y will be e x presse d wit h 9 5 % c o nfi de n ce li mits (calc ulate d p er t he m et h o d 
pr o p ose d b y Gree n w o o d). C o m paris o n of c ur ves a m o n g ar ms will be perf or me d wit h t he l o g -ra n k 
test. Ka pla n -M eier gra p hs will be prese nte d al o n g wit h t he n u m ber of patie nt -at-ris k at e x act ti me 
p oi nts. S u bjects w h o ha ve n ot pre mat urel y disc o nti n ue d t he trial will be ce ns ore d at st u d y 
ter mi nati o n. 
8. 4  
De m o gr a p hics a n d b aseli ne c h ar acteristi cs  
T he bas eli ne de m o gra p hi c c h aracteristics will be s u m marize d b y treat me nt a n d o verall,  b y mea ns of 
descri pti ve statistics.  N o statistical testi n g will be carri e d o ut.  
T he f oll o wi n g de m o gra p hic a n d baseli ne c haracteristics will be re p orte d:  
•  Ge o gra p hic re gi o n of t he site ( E U , U S) , 
•  Site , 
•  A ge ( years) , 
•  Se x  ( Male, Fe male), 
•  Race,  
•  Et h nicit y,  
•  P ote ntial c hil d beari n g  
•  C o ntrace pti o n met h o d  
•  Pre g na nc y test perf or me d a n d res ult a n d reas o ns f or n o pre g na n c y test. 
8. 5  
Oc ul ar a n d s yste mic Me dic al Hist or y  a n d C o nc o mit a nt Dise ases  
A disease is d efi n e d: 
•  “Pre vi o us  disease”  if it is n ot o n g oi n g at scree ni n g visit (“ o n g oi n g” b o x is tic ke d as “ N o”). 
•  “C o nc o mita nt  disease” if  it is o n g oi n g at scree ni n g visit (“ o n g oi n g” b o x is tic ke d as “ Yes”). 
P re vi o us a n d/ or c o nc o mita nt diseases will be c o de d usi n g 
Me dical Dicti o nar y f or re g ul at or y 
acti vities ( Me d D R A) dicti o nar y  a n d re p orte d i n se parat e ta b ulati o ns. Fre q ue nc y distri b uti o ns a n d 
perce nt a ges will be s u m marize d b y tr eat me nt, t y pe ( O p ht hal mic a n d N o n-O p ht hal mic) , b y S yste m 
Or ga n Class ( S O C) a n d Preferre d Ter m ( P T).  
C o u nts will be gi ve n f or b ot h S O C a n d P T b y s u bject. S u bjects e x p erie nci n g m or e t ha n o n e 
pre vi o us /c o nc o mita nt disease e v e nt will be c o u nte d o nl y o nce wit hi n eac h S O C a n d P T. 
S u bjects e x peri e nci n g m ore t ha n o ne disease cl assifie d i n t he sa me cate g or y will be c o u nte d o nl y 
o nce.  
 
 


 
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8. 6  
Pri or a n d c o nc o mit a nt me dic ati o ns  
A me dicati o n is defi ne d:  
•  “Pri or  me dicati o n ” if ta k e n a n d st o p pe d pri or t o first d ose of st u d y treat me nt. 
•  “C o nc o mita nt  me dicati o n” if ta ke n after t he first d ose of st u d y treat me nt. 
acc or di n g t o t he a v aila bl e parts of t he m e dicati o n dates (see  Ta bl e 7 ). I n case of missi n g i nf or mati o n 
n ot directl y all o wi n g all ocati o n t o eit her of t he t w o a b o ve cat e g ories of me dicati o ns, the me dicati o n 
will be c o nsi dere d as c o n c o mita nt.  
Pri or a n d/ or c o n c o mita nt me dicati o ns will be c o de d usi n g 
W orl d Healt h Or g a nizati o n Dr u g 
Dicti o nar y  a n d re p orte d i n se parate ta b ulati o ns. Fre q u e nc y distri b uti o ns a n d perce nta ges will b e 
s u m marize d b y treat me nt, t y pe ( O p ht hal mic a n d N o n-O p ht hal mic), b y A nat o mical Mai n Gr o u p ( 1st 
le vel of t he A nat o mical T hera p e utic C he mical ( A T C) classificati o n), C he mical S u b gr o up ( 4t h le vel 
of t he A T C classificati o n) a n d Preferre d Na me.  
S u bjects ta ki n g m ore t ha n o ne me dicati o n classifie d i n t he sa me cate g or y will be c o u nte d o nl y o nce.  
8. 7  
Dr y E ye Hist or y  
T he dr y e y e hist or y  c haracteristics will be s u m marize d b y tr eat me nt a n d o verall,  b y mea ns of 
descri pti ve statistics. N o statistical testi n g will b e carrie d o ut.  T h e f oll o wi n g i nf or mati o n will b e 
re p orte d: 
•  E ye affecte d b y Dr y E ye . 
•  Ti me si nce first dia g n osis of Dr y E ye .  
•  Has t he patie nt r ecei ve d pri or treat me nt f or dr y e y e?  
•  E ye  dia g n ose d wit h Se vere Sj ö gre n's Dr y E y e . 
•  Ti me si nce first dia g n osis of Se vere Sj ö gre n's Dr y E ye . 
8. 8  
Ot her b aseli ne c h ar acteristics  
N o statistical testi n g will be carrie d o ut  f or c o m pari n g baseli ne c haracteristics. 
8. 8. 1  Eli gi ble e ye  
E ye w hic h is d efi ne d as eli gi ble e ye a n d t he us e d criteria (I E, W orst Sc hir mer’s  test, W orst N EI 
sc ore, i n vesti gat or’s j u d g e me nt, ri g ht as per pr ot oc ol r ule) will be re p orte d.  
8. 8. 2  S A N D E  
Baseli ne S A N D E sc ores  (fre q ue n c y, se verit y, a n d o verall) will be descri pti vel y s u m marize d b y 
treat me nt a n d o v erall  as a c o nti n u o us  vari a ble . I nf or mati o n o n t he S A N D E assess me nt ( d o ne/ n ot 
d o ne)  will b e re p orte d, wit h reas o ns i n cas e of n ot e xec uti o n.  R ules f or deri vati o n of S A N D E  sc ores 
are re p orte d i n secti o n  1 2. 2 . 
8. 8. 3  I D E E L 


 
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Baseli ne I D E E L s c ores will be descri pti vel y s u m marize d b y tr eat me nt a n d o verall as a c o nti n u o us 
varia ble. I nf or mati o n o n t he I D E E L assess me nt ( d o ne/ n ot d o ne) will be re p orte d, wit h reas o ns i n 
case of n ot e xec uti o n.  R ules f or deri v ati o n of I D E E L sc ores are re p orte d i n secti o n 1 2. 3 . 
8. 8. 4  B C D V A  
Baseli ne S N E L L E N e q ui vale nt sc ores will be s u m marize d b y treat me nt a n d o verall as a n  or di nal 
varia ble f or t he ri g ht e y e, t he left e y e a n d eli gi ble e ye . I nf or mati o n o n t he B C D V A assess ment 
( d o ne/ n ot d o ne) will be re p orte d, wit h reas o ns i n case of n ot e xec uti o n. 
8. 8. 5  E xter nal oc ular e xa mi nati o n  
T he res ults of t he e xter nal oc ular e xa mi nati o n  will be s u m marize d b y treat me nt a n d o verall, b y mea ns 
of descri pti ve statistics.  I nf or mati o n o n t he assess me nt ( d o ne/ n ot d o ne) will be re p orte d, wit h reas o ns 
i n case of n ot e x ec uti o n. T he f oll o wi n g i nf or mati o n will be re p orte d  f or t he eli gi ble e ye : 
•  A n y cli nicall y si g nifica nt a b n or malities a n d t y pes. 
•  A n y e vi de nce of p u nct ual occl usi o n.  
o  if yes, b y w hat mec h a nis m was t his see n. 
•  A n y cli nicall y si g nifica nt a b n or malities i n t he f u ncti o n of t he e yeli d m uscles.  
o  if yes, s pecificati o n. 
•  A n y a b n or malities i n t he c o nj u ncti va a n d t y pes.  
T he sa me i nf or m ati o n will be pr o vi de d, i n a se parate ta b ulati o n, f or t he n o n-eli gi ble e ye.  
8. 8. 6  Sc hir mer test I  a n d Sc hir mer test II  
Baseli ne Sc hir mer test I a n d Sc hir mer test II will be descri pti vel y s u m marize d b y treat me nt a n d 
o verall as c o nti n u o us varia ble s. I nf or m ati o n o n t he assess me nts ( d o ne/ n ot d o ne) will be re p ort e d, 
wit h reas o ns i n cas e of n ot e xec uti o n . 
8. 8. 7  Slit La m p O p ht hal mic E xa m  
T he res ults of t he Slit La m p O p ht hal mic E xa m will be s u m marize d b y treat me nt a n d o verall, b y 
mea ns of descri pti ve statistics. I nf or m ati o n o n t he assess me nt ( d o ne/ n ot d o ne) will be re p orte d, wit h 
reas o ns i n cas e of n ot e x ec uti o n. T he f oll o wi n g i nf or mati o n w ill be re p ort e d f or t he eli gi ble e y e: 
•  E val uati o n.   
o  if A b n or mal, c o m me nts. 
•  H oriz o ntal dia meter of t h e c or nea ( m m) . 
8. 8. 8  Fl u orescei n Stai ni n g ( N EI Scale)  
T he res ults of t he Fl u orescei n Stai ni n g will be s u m marize d b y treat me nt a n d o verall, b y mea ns of 
descri pti ve statistics. I nf or mati o n o n t he assess me nt ( d o ne/ n ot d o ne) will be re p orte d, wit h reas o ns 
i n case of n ot e x ec uti o n. T he f oll o wi n g i nf or mati o n will b e re p orte d f or t he eli gi ble e ye:  
•  Has Oc ular s urface stai ni n g perf or me d ?  
•  C or nea –  Res ult . 
•  C o nj u ncti va –  Res ult . 
•  T otal C or nea Sc ore . 
•  T otal C o nj u ncti va Sc ore . 


 
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R ules f or deri vati o n of N EI  s c ores are re p ort e d i n secti o n 1 2. 4 . 
8. 8. 9  Tear Fil m Brea k -u p Ti m e ( T F B U T)  
Baseli ne T F B U T res ults will be s u m marize d b y treat me nt a n d o verall as a c o nti n u o us varia ble f or 
t he ri g ht e ye, t he left e ye a n d eli gi ble e ye. I nf or m ati o n o n t he T F B U T assess me nt ( d o ne/ n ot d o ne) 
will be re p orte d, wit h r eas o ns i n case of n ot e xec uti o n.  
9.  E v al u ati o n of Tre at me nt C o m pli a nce a n d E x p os ure  
9. 1  
C o m pli a nce t o I M P 
T he assess me nt of patie nts’ c o m plia nce t o t he I M P will be ma de b y deter mi ni n g t he n u m ber of dr o ps 
a d mi nistere d t o t he eli gi ble e ye. O n a per patie nt b asis, t he e val uati o n of t he c o m plia nce will be d o n e 
usi n g t he f oll o wi n g f or m ula:  
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (% ) =  
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑟𝑜𝑝𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑒𝑙𝑖𝑔𝑖𝑏𝑙𝑒 𝑒𝑦𝑒 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑟𝑜𝑝𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑒𝑙𝑖𝑔𝑖𝑏𝑙𝑒 𝑒𝑦𝑒 𝑠𝑐ℎ𝑒𝑑𝑢𝑙𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 ×  1 0 0  
W here  deri v ati o ns r ules f or  “t ot al n u m ber of dr o ps i n t he eli gi ble eye  t ake n d uri n g t he tre at me nt 
peri o d ” a n d f or “t ot al n u m ber of dr o ps i n t h e eli gi ble eye  sc h e d ule d d uri n g t he tre at me nt p eri o d ” are 
pr o vi de d  i n Ta ble 3 . 
C o m plia nce will be s u m marize d b y treat me nt  a n d o verall,  b y mea ns of s u m mar y statistics.  I n 
a d diti o n, c o m plia nce t o I M P will als o be prese nte d f or t he f oll o wi n g cate g ories: < 8 0 %, 8 0 % -1 2 0 %, 
> 1 2 0 % . 
9. 2  
E x p os ure t o I M P 
T he e xte nt of e x p os ure t o I M P i n da ys  will be s u m marize d wit h descri pti ve statistics b y treat me nt 
gr o u p  a n d o v erall . T h e e xte nt of e x p os ure ( da ys ) will be calc ulate d usi n g t he f or m ula re p orte d i n 
Ta ble 3 . 
9. 3  
Use of pres er v ati ve free artifici al te a rs  
T he use ( n° dr o ps/ d a y)  of preser vati ve free artificial tears will be s u m marize d wit h des cri pti ve 
statistics b y treat me nt gr o u p a n d o verall , b y st u d y peri o d (treat me nt / f oll o w-u p) a n d o verall  
acc or di n g t o t he f oll o wi n g f or m ulas:  
𝑈𝑠𝑒 𝑇𝑅𝐸𝐴𝑇=  𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑟𝑜𝑝𝑠 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑟𝑒𝑠𝑒𝑟𝑣𝑎𝑡𝑖𝑣𝑒 𝑓𝑟𝑒𝑒 𝑎𝑟𝑡𝑖𝑓𝑖𝑐𝑖𝑎𝑙 𝑡𝑒𝑎𝑟𝑠 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 tr e at m e nt 𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑜𝑓 𝑡ℎ𝑒 tr e at m e nt 𝑝𝑒𝑟𝑖𝑜𝑑
 ×  1 0 0  
𝑈𝑠𝑒 𝐹−𝑈𝑃=  𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑟𝑜𝑝𝑠 𝑜𝑓 𝑡ℎ𝑒 𝑝𝑟𝑒𝑠𝑒𝑟𝑣𝑎𝑡𝑖𝑣𝑒 𝑓𝑟𝑒𝑒 𝑎𝑟𝑡𝑖𝑓𝑖𝑐𝑖𝑎𝑙 𝑡𝑒𝑎𝑟𝑠 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 f oll o w −u p  𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑜𝑓 𝑡ℎ𝑒 f oll o w −u p  𝑝𝑒𝑟𝑖𝑜𝑑
 ×  1 0 0  
Details are pr o vi de d i n  Ta ble 3 . 
 
 


 
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1 0.  
E v al u ati o n of Effic ac y  
1 0. 1  A n al ysis of pri m ar y effic ac y e n d p oi nt  
1 0. 1. 1  Testi n g strate g y a n d m ulti plicit y a dj ust me nt  
T he f oll o wi n g n ull h y p ot hesis is defi ne d o n t he first pri mar y e n d p oi nt:  t he pr o p orti o n of patie nts 
reac hi n g a val u e of Sc hir mer I test ( wit h o ut a n est hesia) > 1 0 m m/ 5 mi n at wee k 4 i n ce n e ger mi n 
(r h N G F) is l o wer or e q ual t ha n c o ntr ol: 
H 0 1: Tr h N G F ≤ T C O N T R O L  
H 1 1: Tr h N G F > T C O N T R O L  
w here T r h N G F a n d T C O N T R O L  are t he pr o p orti o n of p atie nts reac hi n g a v al ue of Sc hir mer I test ( wit h o ut 
a nest hesia) > 1 0 m m/ 5 mi n at wee k 4 f or ce ne ger mi n a n d c o ntr ol gr o u ps, res pecti vel y. T he n ull 
h y p ot hesis H 0 1 will be rejecte d if t he ass ociate d pri mar y a nal ysis p -val u e will be l o wer  t ha n 0. 0 2 5. 
Si milarl y, t he f oll o wi n g n ull h y p ot hesis is defi ne d o n t he c o -pri mar y e n d p oi nt: t he c ha n ge fr o m 
baseli ne  (re d u cti o n) i n t he gl o bal S A N D E s c ore at wee k 1 2 i n ce ne g er mi n is l o wer or e q u al t ha n 
c o ntr ol:  
H 0 2: µr h N G F ≤ µ C O N T R O L  
H 1 2: µr h N G F > µ C O N T R O L  
w here µ r h N G F a n d µ C O N T R O L  are t he c ha n ge fr o m baseli ne  (re d u cti o n) i n t he gl o bal S A N D E sc ore at 
wee k 1 2 f or ce n e ger mi n a n d c o ntr ol gr o u ps, res p ecti vel y. T he n ull h y p ot hesis H 0 2 will be rejecte d if 
t he ass ociate d pri mar y a n al ysis p-val ue will be l o wer t h a n 0. 0 2 5.  
B ot h n ull h y p ot heses H 0 1 a n d H 0 2 m ust be rejecte d t o clai m s u peri orit y of ce ne g er mi n o ver c o ntr ol. 
C o nse q ue ntl y, n o m ulti plicit y c orrecti o n of t y pe I err or will be a p plie d o n pri mar y e n d p oi nts a n al ysis.  
1 0. 1. 2  A nal ysis details  
B ot h c o-pri mar y e n d p oi nts will be a nal ysed  b y mea ns of MI -R D t o ha n dle missi n g data. Retrie ve d 
dr o p -o ut patie nts are defi ne d as patie nts w h o disc o nti n ue st u d y treat me nt a n d deci de t o re mai n i n t he 
st u d y b y f oll o wi n g t he sc he d ule of assess me nts a n d c o nti n ui n g t o a d here t o pr ot oc ol r e q uire m e nts. 
C o nse q ue ntl y, f or eac h pri mar y e n d p oi nt, MI will be perf or me d base d o n t he s u bjects’ all ocate d 
treat me nt ar m a n d o bser ve d val ues ( baseli ne a n d i nter me diate) as c o v ariates i n a re gressi o n m o del 
usi n g data fr o m Retrie ve d dr o p -o ut patie nts t hat h a ve t he pri mar y e n d p oi nt assess me nt d o ne .  
1 0. 1. 2. 1  Sc hir mer I test > 1 0 m m/ 5 mi n at week 4  
T his  pri mar y e n d p oi nt will be a nal yze d b y mea ns of a l o gistic re gressi o n m o del a dj usti n g b y pre-
defi ne d bas eli ne fact ors ( ge n der, a ge class, bas eli ne Sc hir mer I test val ue  as fi xe d effects a n d site as 
ra n d o m effect) a n d a o n e-si de d test will be use d t o test f or differe nces bet w ee n treat me nt gr o u ps.  
F or t he i m p utati o n of missi n g data  of Sc hir mer I test , a re gressi o n m o del will be creat e d b y i ncl u di n g 
t he baseli ne Sc hir mer I test val ue, ge n der, a ge class, a n d Sc hir mer I test at wee k 2. T w o h u n dre d data 
sets will be ge nerate d,  a n d t he ra n d o m see d n u m b er will be 8 2 0 5 2 0 . MI will be i m ple me nte d i n t he 
f oll o wi n g ste ps:  
1.  P artial i m p utati o n ass u mi n g  Missi n g at Ra n d o m  (M A R ) will be ca rrie d o ut t o i m p ute 
i nter mitte nt ( n o n-m o n ot o ne) missi n g data of Sc hir mer I test u p t o wee k 4 base d o n a 


 
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m ulti variate j oi nt Ga ussi a n i m p utati o n m o del usi n g t he Mar k o v c h ai n M o nt e Carl o ( M C M C) 
met h o d. A se parate i m p utati o n m o del will be use d f or eac h tr eat me nt ar m. I n case of n o n -
c o n ver ge n ce or n o n -esti ma bilit y iss ues, a si n gle i m p utati o n m o del will be c o nsi dere d ( wit h 
treat me nt ar m a d de d as e x pla nat or y vari a ble t o t he m o del). A t otal of 2 0 0 datasets will be 
creat e d. T hese d atasets will be utilize d i n Ste p # 2 . 
2.  T he re mai ni n g m o n ot o ne missi n g data will be i m p ute d usi n g a MI re gressi o n i ncl u d i n g t he 
sa me e x pla n at or y varia bl es of t he pre vi o us ste p. Acc or di n g t o MI -R D a p pr oac h, o nl y n o n -
missi n g val ues fr o m retri e ve dr o p o uts will be use d t o i nf or m t he re gressi o n m o d el. 
3.  Eac h of t he 2 0 0  i m p ute d datasets will be a nal yze d  usi n g o bser ve d a n d i m p ute d data. R u bi n’s 
r ule will be use d f or c o m bi ni n g res ults t o dra w i nfere nce.  
If t here are n ot e n o u g h retrie ve d dr o p o uts f or c o n v er ge nce of MI-R D re gressi o n m o del, a refere nce -
bas e d M ulti ple Im p utati o n  ( MI) a p pr oac h will be a d o pte d t o c o nsi der a missi n g n ot at ra n d o m 
( M N A R) mec h a nis m f or missi n g data: i m p utati o n of val ues i n t he r h N G F ar m (a b o ve ste p # 2) will 
be d o ne usi n g t he n o n -missi n g val ues fr o m t he c o ntr ol gr o u p  (t his a p pr oach will be referre d as “ C o p y 
Refere n ce”) . T his a p pr oac h d oes n ot ass u me be nefits f or r h N G F i n case of disc o nti n uati o n a n d li mits 
a p ost -disc o nti n uati o n cli nical effect t o t hat of ve hicle . T he fi nal decisi o n o n t he use of t he MI -R D 
vs C o p y -Refere nce  f or t his e n d p oi nt  will be d o ne at t he ti me of t he a nal ysis a n d re p orte d i n t he C S R.  
W het her f or MI -R D or C o p y -Refere n ce a p pr oac h, t he a dj uste d esti mate d treat me nt differe nces i n 
pr o p orti o n s bet wee n ce ne ger mi n a n d ve hi cle at wee k 4 will b e dis pl a ye d t o get h er wit h t he 
c orres p o n di n g t w o -si d e 9 5 % c o nfi de n ce i nter vals a n d p-val ue.  
1 0. 1. 2. 2  C h a n ge fr o m b aseli ne i n t he gl o b al S A N D E sc ore at week 1 2  
T his c o -pri mar y e n d p oi nt will be a nal yze d b y mea ns of a n  A nal ysis of C o varia nce  (A N C O V A ) 
a dj usti n g b y pre -defi ne d basel i ne fact ors ( ge n d er, a ge class, bas eli ne gl o bal S A N D E s c ore as fi xe d 
effects a n d site as ra n d o m effect ) a n d a o ne-si de d test will be use d t o test f or differe nces bet wee n 
treat me nt gr o u ps. R ules f or deri vati o n of S A N D E sc ores are re p orte d i n secti o n 1 2. 2 . 
F or t he i m p utati o n of missi n g data, a re gressi o n m o del will be creat e d b y i ncl u di n g t he baseli ne 
gl o bal S A N D E sc ore , ge n der, a g e class, a n d i nter me diate gl o bal S A N D E s c ores u p t o wee k 1 2 . T w o 
h u n dre d data sets will be ge nerat e d,  a n d t he ra n d o m see d n u m ber will be 3 7 1 0 3 9 3 9 . MI will be 
i m ple me nte d i n t he f oll o wi n g ste ps:  
1.  Partial i m p utati o n ass u mi n g M A R will be carrie d o ut t o i m p ute i nter mitte nt ( n o n -m o n ot o ne) 
missi n g data of gl o bal S A N D E sc ore b ase d o n a m ulti variate j oi nt Ga ussia n i m p utati o n m o del 
usi n g t he M C M C met h o d. A se parate i m p utati o n m o del will be use d f or eac h treat me nt ar m. 
I n case of n o n-c o n ver ge nce or n o n -esti ma bilit y iss ues, a si n gle i m p utati o n m o del will be 
c o nsi dere d ( wit h treat me nt ar m a d d e d as e x pla nat or y vari a ble t o t he m o del). A t otal of 2 0 0 
datasets will be create d. T hese datas ets will be utilize d i n Ste p # 2.  
2.  T he re mai ni n g m o n ot o ne missi n g data will be i m p ute d usi n g a MI re gressi o n i ncl u di n g t he 
sa me e x pla n at or y varia bl es of t he pre vi o us ste p. Acc or di n g t o MI -R D a p pr oac h, o nl y n o n -
missi n g val ues fr o m retri e ve dr o p o uts will be use d t o i nf or m t he re gressi o n m o del.  
3.  Eac h of t he 2 0 0 i m p ute d datasets will be a nal yze d  usi n g o bser ve d a n d i m p ute d  data. R u bi n’s 
r ule will be use d f or c o m bi ni n g res ults t o dra w i nfere nce.  
If t here are n ot e n o u g h retrie ve d dr o p o uts f or c o n ver ge nce of MI-R D re gressi o n m o del, a C o p y 
Refere n ce  a p pr oac h  will be a d o pte d t o c o nsi der a M N A R  mec ha nis m f or missi n g data. T he fi nal 
decisi o n o n t he use of t he MI -R D vs C o p y -Refere n ce f or t his e n d p oi nt will be d o ne at t he ti me of t he 
a nal ysis a n d re p orte d i n t he  C S R . 


 
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W het her f or MI -R D or C o p y -Refere n ce a p pr oac h, t he a dj uste d esti mate d treat me nt differe nces i n 
mea ns f or gl o bal S A N D E sc ore bet w ee n ce n e ger mi n a n d v e hicle  at wee k 1 2  will be dis pla ye d 
t o get her wit h t he c orres p o n di n g t w o-si de 9 5 % c o nfi de nce i nter vals a n d p-val ue.  
1 0. 1. 3  Se nsiti vit y a nal yses  
T he f oll o wi n g s e nsiti vit y a nal yses are d efi ne d t o assess t he r o b ust ness of res ults o n eac h pri mar y 
e n d p oi nt vers us ass u m pti o ns use d i n t he statistical m o del f or t he mai n esti mat ors:  
•  T he c o m paris o n bet w ee n treat me nt a n d c o ntr ol will be perf or me d b y m ea ns of MI u n der  
M A R ass u m pti o n i nstea d of M N A R. MI will be i m ple me nte d i n t w o ste ps:  
o  I nter mitte nt missi n g data u p t o pri mar y ti me p oi nt ( Wee k 4 f or Sc hir mer I test, a n d 
Wee k 1 2 f or S A N D E) will be i m p ute d usi n g M C M C met h o ds ass u mi n g M A R. A 
se parat e i m p utati o n m o del will be use d f or eac h treat me nt ar m. T he i m p utati o n 
m o dels will i ncl u de t he o bser ve d val u es ( baseli ne a n d i nter me diate), ge n der, a n d a g e 
class as c o v ariates. I n case of n o n -c o n v er ge nce or n o n -esti ma bilit y iss ues, a si n gle 
m o del will be c o nsi dere d wit h treat me nt  ar m a d de d as e x pla nat or y vari a ble t o t he 
m o del.   
o  T he re mai ni n g missi n g val ues wit h a m o n ot o ne missi n g data patter n will b e i m p ute d 
base d o n data of c orres p o n di n g treat me nt gr o u p.  
o  Eac h i m p ute d dataset will be a nal yze d usi n g o bser ve d a n d i m p ute d data . R u bin’s r ule 
will be use d f or c o m bi ni n g res ults t o dra w i nfere nce. T he a dj uste d esti mate d treat me nt 
differe n ces bet w ee n ce ne ger mi n a n d ve hicle ( differe nce i n pr o p orti o ns f or Sc hir mer’s 
test a n d differe n ces i n mea ns f or S A N D E) will be dis pla ye d t o get h er wit h t he 
c orres p o n di n g t w o -si d e 9 5 % c o nfi de n ce i nter vals a n d p-val ues.  
•  A ti p pi n g p oi nt strate g y will be use d as a se nsiti vit y a nal ysis f or missi n g data f or assess me nt 
of s u peri orit y (if s h o w n) of r h N G F f or eac h e n d p oi nt. Ti p pi n g p oi nt a nal ysis will assess h o w 
de part ures fr o m MI u n d er M N A R ass u m pti o ns m ust be t o o vert ur n c o n cl usi o ns fr o m t he 
pri mar y s u peri orit y a nal ysis. Ti p pi n g p oi nt will be base d o n iterati ve a p plicati o n of MI. I n 
t he first iterati o n, MI-R D met h o d is ass u me d as descri be d i n secti o n  1 0. 1. 2 . I n s uccessi ve 
iterati o ns, t he i m p ute d val ues f or t he r h N G F ar m are s hifte d b y a c o nsta nt t o re pres e nt a w orse 
effect i n eac h iterati o n. T his ca n b e ac hie ve d b y usi n g t he N c o m plete d datasets  o btai ne d 
u n der MI -R D a n d s hift t h e i m p ute d val ues. T h e ti p pi n g p oi nt is t he s hift at w hic h t he p -v al ue 
bec o mes n o n -si g nifica nt. O utli ne of ti p pi n g p oi nt: 
o  Use MI -R D t o i m p ute missi n g val ues.  
o  Ass u mi n g t hat t he ti p pi n g p oi nt is bet wee n -1 0  a n d 0, t he f oll o wi n g acti o ns will be 
perf or me d f or Δ = 0, -0. 1, -0. 2, -0. 3, …, -1 0 : 
▪ A d d Δ t o t he i m p ute d val ues at t he r h N G F ar m.  
▪ A nal yze t he c o m plete d data sets usi n g t he sa me met h o d o utli ne d i n secti o n 
1 0. 1. 2 . 
▪ t he pl ot of all p-val ues f or Δ bet wee n -1 0  a n d 0  will be creat e d . 
o  base d o n t he pl ot, t he a p pr o xi mate val ue of t he ti p pi n g p oi nt T p a p pr o x is i de ntifie d 
c o nsi deri n g a t hres h ol d f or t he p -val ues  of 0. 0 2 5 0 0 . 
o  after i de ntificati o n of T p a p pr o x, fi nest researc h of t he ti p pi n g p oi nt will be perf or me d 
i n t he ra n ge T pa p pr o x ± 1 b y i ncre me nti n g Δ of 0. 0 1 a n d f oll o wi n g t he us ual ste ps:  
▪ A d d Δ t o t he i m p ute d val ues at t he r h N G F ar m. 
▪ A nal yze t he c o m plete d dat a sets usi n g t he sa me met h o d o utli ne d i n secti o n 
1 0. 1. 2 . 
o  T he ti p pi n g p oi nt is t he s mallest Δ at w hic h p -val ue ≥ 0. 0 2 5 0 0.  


 
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1 0. 1. 4  S u p p orti ve a nal yses  
F or  eac h pri mar y e n d p oi nt, t he re gressi o n m o dels detaile d i n secti o n 1 0. 1. 2  will be perf or me d f or 
s u p p orti ve p ur p oses: 
•  b y c o nsi deri n g c o m plete cases o nl y (i.e. wit h o ut c o nsi deri n g patie nts wit h missi n g pri mar y 
e n d p oi nt).  
•  o n t he P P set i nstea d of F A S.  
1 0. 2  A n al ysis of sec o n d ar y effic ac y e n d p oi nts  
1 0. 2. 1  Testi n g strate g y a n d m ulti plicit y a dj ust me nt  
I n cas e t he a nal ysis of t he pri mar y e n d p oi nts lea ds t o rejecti o n of n ull h y p ot hesis, t he f oll o wi n g ke y 
sec o n dar y e n d p oi nts will be teste d i n a c o n ditio nal se q ue ntial ma n ner t o s h o w s u peri orit y of 
ce ne g er mi n vers us c o ntr ol (at al p ha o ne -si de d 0. 0 2 5) acc or di n g t o t he f oll o wi n g ra n ki n g: 
1.  P r o p orti o n of patie nts reac hi n g a val ue of Sc hir mer I test ( wit h o ut a nest hesia) > 1 0 m m/ 5 mi n 
at wee k 8.   
2.  C ha n ge fr o m bas eli ne i n S A N D E sc ores f or se v erit y at wee k 1 2.  
3.  C ha n ge fr o m bas eli ne i n S A N D E sc ores f or fre q u e nc y at w ee k 1 2.   
4.  C ha n ge fr o m bas eli ne i n I D E E L m o d ules ( Q u alit y of Life [ 2 7 q u esti o ns], Dr y e y e Treat me nt 
satisfacti o n & B ot her [ 1 0 q uesti o ns], a n d Dr y e y e S y m pt o m bot her [ 2 0 q uesti o ns]) at wee k 
1 2 a n d at wee k 4 (i n t his or der ).  
5.  C ha n ge fr o m baseli ne i n C or nea a n d c o nj u ncti va vital stai ni n g wit h fl u orescei n N EI scal e  at 
wee k 4, w ee k 8 a n d at w ee k 1 2 (i n t his or der ). 
6.  C ha n ge fr o m bas eli ne i n T F B U T at w ee k 4, wee k 8 a n d at wee k 1 2 (i n t his or der).  
T his hierarc hic al 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 2 5 le vel.  
1 0. 2. 2  A nal ysis details  
A nal ysis of ke y sec o n dar y e n d p oi nts are detaile d bel o w i n secti o ns  1 0. 2. 2. 1  - 1 0. 2. 2. 6  a n d p-val ues 
t o be e val uate d f or c o m p aris o n bet wee n treat me nts i n a se q ue ntial or der are t he f oll o wi n g: 
1.  
P -val ue of treat me nt varia ble fr o m l o gistic re gressi o n m o del o n pr o p orti o n of patie nts 
reac hi n g a val ue of Sc hir mer I test ( wit h o ut a nest hesia) > 1 0 m m/ 5 mi n at wee k 8 (secti o n  
1 0. 2. 2. 1 ), 
2.  
P -val ue of treat me nt vari a ble fr o m A N C O V A re gressi o n m o del o n c ha n g e fr o m baseli ne i n 
S A N D E sc ore f or se v erit y at wee k 1 2 (s ecti o n 1 0. 2. 2. 2 ), 
3.  
P -val ue of treat me nt vari a ble fr o m A N C O V A re gressi o n m o del o n c ha n g e fr o m baseli ne i n 
S A N D E sc ore f or fre q ue nc y at wee k 1 2 (secti o n 1 0. 2. 2. 3 ), 
4. 1  P -val ue of treat me nt varia ble fr o m M M R M  re gressi o n m o del o n I D E E L Q ualit y of Life 
m o d ule at wee k 1 2 (s ecti o n 1 0. 2. 2. 4 ), 
4. 2  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n I D E E L Dr y e ye Treat me nt 
satisfacti o n & B ot her m o d ule at wee k 1 2 (secti o n 1 0. 2. 2. 4 ), 
4. 3  P -val ue of treat me nt varia ble fr o m M M R M  re gressi o n m o del o n I D E E L Dr y e ye S y m pt o m 
b ot her m o d ule at wee k 1 2 (secti o n 1 0. 2. 2. 4 ), 


 
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4. 4  P -val ue of treat me n t varia ble fr o m M M R M  re gressi o n m o del o n I D E E L Q ualit y of Life 
m o d ule at wee k 4 (s ecti o n 1 0. 2. 2. 4 ), 
4. 5  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n I D E E L Dr y e ye Treat me nt 
satisfacti o n & B ot her m o d ule at wee k 4 (secti o n 1 0. 2. 2. 4 ), 
4. 6  P -val ue of treat me nt varia ble fr o m M M R M  re gressi o n m o del o n I D E E L Dr y e ye S y m pt o m 
b ot her m o d ule at wee k 4 (secti o n 1 0. 2. 2. 4 ), 
5. 1  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
C or nea a n d c o nj u n cti va vital stai ni n g wit h fl u orescei n N EI scale at wee k 4 (secti o n 1 0. 2. 2. 5 ), 
5. 2  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
C or nea a n d c o nj u n cti va vital stai ni n g wit h fl u orescei n N EI scale at wee k 8 (secti o n 1 0. 2. 2. 5 ), 
5. 3  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
C or nea a n d c o nj u ncti va vital stai ni n g wit h fl u orescei n N EI s cale at wee k 1 2 (secti o n 
1 0. 2. 2. 5 ), 
6. 1  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
T F B U T val ues at wee k 4 (secti o n 1 0. 2. 2. 6 ), 
6. 2  P -val ue of treat me nt va ri a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
T F B U T val ues at wee k 8 (secti o n 1 0. 2. 2. 6 ), 
6. 3  P -val ue of treat me nt vari a ble fr o m M M R M  re gressi o n m o del o n C ha n ge fr o m baseli ne i n 
T F B U T val ues at wee k 1 2 (secti o n 1 0. 2. 2. 6 ). 
1 0. 2. 2. 1  Sc hir mer I test > 1 0 m m / 5 mi n at week 8 
T he pr o p orti o n of patie nts reac hi n g a v al ue of Sc hir mer I t est ( wit h o ut a n est hesia) > 1 0 m m/ 5 mi n at 
wee k 8 will be a n al yze d as descri be d i n s ecti o n 1 0. 1. 2. 1  f or t he pri mar y efficac y e n d p oi nts.  
1 0. 2. 2. 2  C h a n ge fr o m b aseli ne i n S A N D E sc ore f or severity at week 1 2  
T he c h a n ge fr o m bas eli ne i n S A N D E s c ore  f or se verit y at wee k 1 2  will be a nal yze d as descri be d i n 
secti o n 1 0. 1. 2. 2  f or t he pri mar y efficac y e n d p oi nts.  
1 0. 2. 2. 3  C h a n ge fr o m b aseli ne i n S A N D E sc ores f or fre q ue ncy at week 1 2  
T he c ha n ge fr o m baseli ne i n S A N D E sc ore f or fre q ue nc y at wee k 1 2 will be a nal yze d as des cri be d 
i n secti o n 1 0. 1. 2. 2  f or t he pri mar y effic ac y e n d p oi nts.  
1 0. 2. 2. 4  C h a n ge fr o m b aseli ne i n I D E E L m o d ules ( Q u ality of Life, Dry eye Tre at me nt s atisf acti o n 
& B ot her, a n d Dry eye S y m pt o m b ot her) at week 1 2 a n d at week 4  
R ules f or deri vati o n of I D E E L sc ores are re p orte d i n secti o n 1 2. 3 . T he c ha n ge fr o m baseli ne of e ac h 
I D E E L m o d ule will be a nal yze d b y mea ns of an M M R M a dj usti n g b y pre-defi ne d fact ors ( ge n der, 
a ge class, I D E E L m o d ul e baseli ne val ue , treat me nt, visit, a nd treat me nt b y visit i nteracti o n; s u bject 
will be c o nsi dere d as a ra n d o m effect ). T h e c o varia n ce matri x use d will be " u nstr uct ure d". 
C o m paris o ns vers us ve hicle TI D will be pr o vi de d usi n g least s q uare mea ns at eac h visit a n d o verall 
a n d a o ne-si d e d test will be use d t o test f or differe nces bet wee n treat me nt gr o u ps. 
F or t he i m p utati o n of missi n g data, a re gressi o n m o del will be creat e d b y i ncl u di n g t he baseli ne 
val ue , ge n d er, a ge class, a n d i nter m e diate s c ores u p t o wee k 1 2. T w o h u n dre d dat a sets will be 


 
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ge nerat e d,  a n d t he ra n d o m see d n u m ber will be 2 2 5 6 7 0 . MI will be i m ple me nte d i n t he f oll o wi n g 
ste ps:  
1.  Partial i m p utati o n ass u mi n g M A R will be carrie d o ut t o i m p ute i nter mitte nt ( n o n -m o n ot o ne) 
missi n g data of I D E E L m o d ule sc ore b ase d o n a m ulti variate j oi nt Ga ussia n i m p utati o n m o del 
usi n g t he M C M C met h o d. A se parate i m p utati o n m o del will be use d f or eac h treat me nt ar m. 
I n case of n o n-c o n ver ge nce or n o n -esti ma bilit y iss ues, a si n gle i m p utati o n m o del will be 
c o nsi dere d ( wit h treat me nt ar m a d d e d as e x pla nat or y vari a ble t o t he m o del). A t otal of 2 0 0 
datasets will be create d. T hese datas ets will b e utilize d i n Ste p # 2.  
2.  T he re mai ni n g m o n ot o ne missi n g data will be i m p ute d usi n g a MI re gressi o n i ncl u di n g t he 
sa me e x pla n at or y varia bl es of t he pre vi o us ste p. Acc or di n g t o MI -R D a p pr oac h, o nl y n o n -
missi n g val ues fr o m retri e ve dr o p o uts will be use d t o i nf o r m t he re gressi o n m o del. 
3.  Eac h of t he 2 0 0 i m p ute d datasets will be a nal yze d  usi n g o bser ve d a n d i m p ute d data. R u bi n’s 
r ule will be use d f or c o m bi ni n g res ults t o dra w i nfere nce.  
If t here are n ot e n o u g h retrie ve d dr o p o uts f or c o n ver ge nce of MI-R D re gressi o n m o del, a C o p y 
Refere n ce a p pr oac h will be a d o pte d t o c o nsi der a M N A R mec ha nis m f or missi n g data. T he fi nal 
decisi o n o n t he use of t he MI -R D vs C o p y -Refere n ce f or t his e n d p oi nt will be d o ne at t he ti me of t he 
a nal ysis a n d re p orte d i n t he C S R.  
W het her f or MI -R D or C o p y -Refere n ce a p pr oac h, t he a dj uste d esti mate d treat me nt differe nces i n 
mea ns f or I D E E L m o d ule sc ores bet wee n ce ne g er mi n a n d ve hicle at eac h a vaila ble ti me p oi nt will 
be dis pla ye d t o get her wit h t he c orres p o n di n g t w o -si de 9 5 % c o nfi de n ce i nter vals a n d p-val u e.  
1 0. 2. 2. 5  C h a n ge fr o m b aseli ne i n C or ne a a n d c o nj u nctiv a vit al st ai ni n g wit h fl u orescei n N EI sc al e  
at week 4, week 8 a n d at week 1 2  
R ules f or deri v ati o n of N EI  sc ores are re p orte d i n secti o n 1 2. 4 . T he c ha n ge fr o m baseli ne i n C or nea 
a n d c o nj u ncti va vital stai ni n g wit h fl u orescei n N EI scale will be a nal yze d b y mea ns of a n M M R M 
a dj usti n g b y pre-defi ne d fact ors ( ge n der, a ge class, N EI s cale bas eli ne val ue , treat me nt, visit, a n d 
treat me nt b y visit i nteracti o n; s u bject will be c o nsi dere d as a ra n d o m effect). T he c o varia nce matri x 
use d will be " u nstr uct ure d". C o m paris o ns vers us ve hic le TI D will be pr o vi de d usi n g least s q uare 
mea ns at eac h visit a n d o verall a n d a o ne-si d e d test will be use d t o test f or differe n ces bet w ee n 
treat me nt gr o u ps. 
F or t he i m p utati o n of missi n g data, a re gressi o n m o del will be creat e d b y i ncl u di n g t he baseli ne 
val ue, ge n d er, a ge class, a n d i nter m e diate s c ores u p t o wee k 1 2. T w o h u n dre d dat a sets will be 
ge nerat e d,  a n d t he ra n d o m see d n u m ber will be 2 4 0 5 5 0 . MI will be i m ple me nte d i n t he f oll o wi n g 
ste ps:  
1.  Partial i m p utati o n ass u mi n g M A R will be carrie d o ut t o i m p u te i nter mitte nt ( n o n-m o n ot o ne) 
missi n g data of N EI scale  sc ore b ase d o n a m ulti variate j oi nt Ga ussia n i m p utati o n m o del 
usi n g t he M C M C met h o d. A se parate i m p utati o n m o del will be use d f or eac h treat me nt ar m. 
I n case of n o n-c o n ver ge nce or n o n -esti ma bilit y is s ues, a si n gle i m p utati o n m o del will be 
c o nsi dere d ( wit h treat me nt ar m a d d e d as e x pla nat or y vari a ble t o t he m o del). A t otal of 2 0 0 
datasets will be create d. T hese datas ets will be utilize d i n Ste p # 2.  
2.  T he re mai ni n g m o n ot o ne missi n g data will be i m p ute d usi n g a MI re gressi o n i ncl u di n g t he 
sa me e x pla n at or y varia bl es of t he pre vi o us ste p. Acc or di n g t o MI -R D a p pr oac h, o nl y n o n -
missi n g val ues fr o m retri e ve dr o p o uts will be use d t o i nf or m t he re gressi o n m o del.  
3.  Eac h of t he 2 0 0 i m p ute d datasets will be a nal yze d  usi n g o bser ve d a n d i m p ute d data. R u bi n’s 
r ule will be use d f or c o m bi ni n g res ults t o dra w i nfere nce.  


 
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If t here are n ot e n o u g h retrie ve d dr o p o uts f or c o n ver ge nce of MI-R D re gressi o n m o del, a C o p y 
Refere n ce a p pr oac h will be a d o pte d t o c o nsi der a M N A R mec ha nis m f or missi n g data. T he fi nal 
decisi o n o n t he use of t he MI -R D vs C o p y -Refere n ce f or t his e n d p oi nt will be d o ne at t he ti me of t he 
a nal ysis a n d re p orte d i n t he C S R.  
W het her f or MI -R D or C o p y -Refere n ce a p pr oac h, t he a dj uste d esti mate d treat me nt differe nces i n 
mea ns f or N EI scale  sc ores bet wee n ce ne ger mi n a n d ve hicle at eac h a vaila ble ti me p oi nt will be 
dis pla ye d t o get her wit h t he c orres p o n di n g t w o -si d e 9 5 % c o nfi d e nce i nter vals a n d p-val ue.  
1 0. 2. 2. 6  C h a n ge fr o m b aseli ne i n T F B U T at week 4, week 8 a n d at week 1 2  
T he c ha n g e  fr o m b aseli ne i n T F B U T val u es will be a nal yze d b y mea ns of a M M R M a dj usti n g b y 
pre -defi ne d fact ors ( ge n d er, a ge class, T F B U T bas eli ne val ue , treat me nt, visit, a n d treat me nt b y visit 
i nteracti o n; s u bject will be c o nsi dere d as a ra n d o m effect). T he c o v aria n ce matri x use d will be 
" u nstr uct ure d". C o m paris o ns vers us ve hicle TI D will be pr o vi de d usi n g least s q uare mea ns at eac h 
visit a n d o verall a n d a o n e-si de d test will be use d t o test f or differe nces bet wee n treat me nt gr o u ps.  
F or t he i m p utati o n of missi n g data , a re gressi o n m o del will be creat e d b y i ncl u di n g t he baseli ne 
val ue, ge n d er, a ge class, a n d i nter m e diate s c ores u p t o wee k 1 2. T w o h u n dre d dat a sets will be 
ge nerat e d,  a n d t he ra n d o m see d n u m ber will be 1 0 1 1 4 9 . MI will be i m ple me nte d i n t he f oll o wi n g 
ste ps:  
1.  Partial i m p utati o n ass u mi n g M A R will be carrie d o ut t o i m p ute i nter mitte nt ( n o n -m o n ot o ne) 
missi n g data of T F B U T val ues base d o n a m ulti variate j oi nt Ga ussia n i m p utati o n m o del usi n g 
t he M C M C met h o d. A se parate i m p utati o n m o del will be use d f or eac h treat me nt ar m. I n cas e 
of n o n -c o n ver ge nce or n o n -esti ma bilit y iss ues, a si n gle i m p utati o n m o del will be c o nsi dere d 
( wit h treat me nt ar m a d de d as e x pla nat or y vari a ble t o t he m o del). A t otal of 2 0 0 datasets will 
be create d. T h ese datas ets will be utilize d i n Ste p  # 2.  
2.  T he re mai ni n g m o n ot o ne missi n g data will be i m p ute d usi n g a MI re gressi o n i ncl u di n g t he 
sa me e x pla n at or y varia bl es of t he pre vi o us ste p. Acc or di n g t o MI -R D a p pr oac h, o nl y n o n -
missi n g val ues fr o m retri e ve dr o p o uts will be use d t o i nf or m t he re gressi o n m o del.  
3.  Eac h of t he 2 0 0 i m p ute d datasets will be a nal yze d  usi n g o bser ve d a n d i m p ute d data. R u bi n’s 
r ule will be use d f or c o m bi ni n g res ults t o dra w i nfere nce.  
If t here are n ot e n o u g h retrie ve d dr o p o uts f or c o n ver ge nce of MI-R D re gressi o n m o del, a C o p y 
Refere n ce a p pr oac h will be a d o pte d t o c o nsi der a M N A R mec ha ni s m f or missi n g data. T he fi nal 
decisi o n o n t he use of t he MI -R D vs C o p y -Refere n ce f or t his e n d p oi nt will be d o ne at t he ti me of t he 
a nal ysis a n d re p orte d i n t he C S R.  
W het her f or MI -R D or C o p y -Refere n ce a p pr oac h, t he a dj uste d esti mate d treat me nt differe nces  i n 
mea ns f or N EI scale sc ores bet wee n ce ne ger mi n a n d ve hicle at eac h a vaila ble ti me p oi nt will be 
dis pla ye d t o get her wit h t he c orres p o n di n g t w o -si d e 9 5 % c o nfi d e nce i nter vals a n d p-val ue.  
1 0. 2. 3  Descri pti ve A n al ysis  
I n d e pe n de ntl y of res ults o n pri mar y a n d ke y sec o n dar y e n d p oi nts, descri pti ve i n nat ure a nal yses will 
be perf or me d o n all sec o n dar y e n d p oi nts (secti o n 3. 2. 2 ) at eac h a vaila ble ti me p oi nts b y mea ns of 
descri pti ve statistics.  
I n cas e of c o nti n u o us me as ures, a nal yses will be pr o vi de d f or bas eli ne visit, eac h p ost-bas eli ne visit, 
a n d t heir c h a n ge fr o m b aseli ne. C o m paris o ns bet wee n treat me nts will be perf or me d usi n g t w o -
sa m ple t-test (ass u mi n g u ne q ual varia nces) or, if t he re q uire d ass u m pti o ns are n ot met, t he t w o-


 
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sa m ple Ma n n– W hit ne y U test will be use d. Ass u m pti o n of n or mal distri b uti o n of e n d p oi nts f or 
c o nti n u o us data will be assesse d b y a vis ual i ns pecti o n of distri b uti o n.  
I n cas e of cate g oric al varia bles, s hift ta bles vers us baseli ne will be s u m marize d f or all p ost-b aseli ne 
visits, a n d t he Fis her’s E xact test will be perf or me d.  
T he f oll o wi n g gra p hic al re pres e ntati o ns will be pr o vi de d b y treat me nt : 
•  Sc hir mer I test O bser ve d Mea n ( ± S E M) a n d M ea n c ha n ge fr o m b aseli n e ( ± S E M) at eac h 
ti me p oi nt. 
•  O bser ve d p erce nta ge of patie nts wit h Sc hir mer I t est > 1 0 m m/ 5 mi n at eac h ti me p oi nt.  
•  S A N D E gl o bal sc ore O bser ve d M ea n ( ± S E M) a n d Mea n c ha n ge fr o m b as eli ne ( ± S E M) at 
eac h ti me p oi nt.  
•  C or nea a n d c o nj u ncti va vital stai ni n g t otal sc ore O bser ve d Mea n ( ± S E M) a n d Mea n c ha n g e 
fr o m baseli ne ( ± S E M) at eac h ti me p oi nt.  
•  T F B U T O bser ve d Mea n ( ± S E M) a n d Mea n c ha n g e fr o m baseli ne ( ± S E M) at eac h ti me p oi nt.  
 
 


 
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1 1.  
E v al u ati o n of S afet y  
1 1. 1  A d verse e v e nts  
A d verse E ve nts ( A Es ) st arte d b ef ore a d mi nistrati o n of st u d y tr eat me nt will be c o nsi dere d as p re-
treat me nt; a ny  A E start e d o n or after t h e date of t he first d ose of st u d y  me dicati o n or starte d pri or t o 
first d ose a n d w ors e ne d i n se verit y after t he first d ose will be c o nsi dere d  as Treat me nt -E mer ge nt 
A d verse E v e nt ( T E A E).  
I n case of missi n g or i nc o m plete dates n ot all o wi n g a direct all ocati o n t o a n y of t he t w o cate g ories 
of A Es  ( pre-treat me nt/ T E A E), an  all ocati o n will be d o ne acc or di n g t o t he a vaila ble parts of t he o nset 
a n d t he e n d dat es  (see Ta ble 6 ). I n case of T E A E, t he e ve nt ca n be f urt her classifie d as:  
•  O n Treat me nt p eri o d, or  
•  O n F oll o w -u p peri o d  
acc or di n g t o t he a vaila bl e parts of t he o ns et a n d t he e n d dates (see T a ble 6 ). 
All A Es will be c o de d b y S O C a n d P T  acc or di n g t o Me d D R A  t hesa ur us. I n a d diti o n, eac h A E will 
be gra de d t o ca pt ur e t he relati o ns hi p t o I M P a n d se verit y (see pr ot oc ol f or d etails).  
Pre -treat me nt A Es will be prese nt e d i n t he listi n gs o nl y. 
T E A E s u m maries will be prese nte d, dis pla yi n g fre q ue nci es a n d perce nta ges of patie nts re p orti n g 
A Es wit hi n eac h S O C i n decreasi n g or der of t otal fre q ue n c y. Al o n g wit h A Es, n u m ber of e ve nts  will 
be re p ort e d. O n eac h of t hese s u m maries, p atie nts will be c o u nte d o nl y o n ce per S O C  a n d, wit hi n g 
eac h S O C, p atie nts will be c o u nte d o nl y  o nce per P T . 
“P ossi ble ”, “Pr o ba ble ” a n d “Hi g hl y Pr o ba ble ” or missi n g relati o ns hi ps will  be c o nsi dere d as relate d 
t o st u d y dr u g ( A D R –  A d verse Dr u g Reacti o n ) f or t he s u m mar y ta bl es. “ N o ne” a n d “ u nli kel y” 
relati o ns hi ps will  be c o nsi dere d n ot rel ate d t o st u d y dr u g.  
T he f oll o wi n g ta ble will be prese nt e d  b y treat me nt gr o u p  a n d o verall : 
•  A  s u m mar y o ver vie w ( patie nt wit h at least o ne e ve nt, perce nta ge, a n d n u m b er of ev e nts) of:  
o  T E A E s, 
o  O p ht hal mic T E A E s,  
o  N o n -O p ht hal mic T E A E s,  
o  se vere T E A Es, 
o  se vere O p ht hal mic T E A Es,  
o  se vere N o n-O p ht hal mic T E A E s,  
o  seri o us T E A Es,  
o  seri o us O p ht hal mic T E A Es,  
o  seri o us N o n-O p ht hal mic T E A E s,  
o  n o n -seri o us T E A Es,  
o  A D R s,  
o  O p ht hal mic A D R s,  
o  N o n - O p ht hal mic A D R s,  
o  seri o us A D Rs,  
o  T E A E s lea di n g t o disc o nti n uati o n of I M P,  
o  T E A E s lea di n g t o disc o nti n uati o n of st u dy ,  
o  T E A E s lea di n g t o deat h.  
 
 


 
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T he f oll o wi n g ta bles will be prese nt e d b y treat me nt gr o u p:  
•  S u m mar y of O p ht hal mic T E A Es b y pri mar y S O C a n d P T  a n d b y st u d y peri o d ( o n 
treat me nt/f oll o w-u p a n d o verall ). 
•  S u m mar y of N o n -O p ht hal mic T E A Es b y pri mar y S O C a n d P T  a n d b y st u d y peri o d ( o n 
treat me nt/f oll o w-u p a n d o verall ). 
•  S u m mar y of T E A Es b y pri mar y S O C , P T  a n d Se verit y.  
•  S u m mar y of Seri o us T E A Es b y Pri mar y S O C a n d P T  a n d b y st u d y peri o d ( o n 
treat me nt/f oll o w-u p a n d o verall ). 
•  S u m mar y of A D Rs b y Pri mar y S O C a n d P T  a n d b y st u d y peri o d ( o n treat me nt/f oll o w -u p a n d 
o verall ). 
•  S u m mar y of A D Rs b y Pri mar y S O C a n d P T  a n d Se verit y.  
•  S u m mar y of T E A Es lea di n g t o I M P Disc o nti n uati o n b y Pri mar y S O C a n d P T  a n d b y st u d y 
peri o d ( o n treat me nt/f oll o w -u p a n d o verall ). 
•  S u m mar y of T E A Es lea di n g t o st u d y Disc o nti n uati o n b y Pri mar y S O C a n d P T  a n d b y st u d y 
peri o d ( o n treat me nt/f oll o w -u p a n d o verall ). 
•  S u m mar y of T E A Es lea di n g t o Deat h b y Pri mar y S O C a n d P T.  
•  Listi n g of Deat hs . 








 
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1 2. 2  S A N D E deri v ati o n  
T he S A N D E q uesti o n naire is c o m prise d of t w o q u esti o ns:  
•  H o w ofte n d o y o ur e yes f eel dr y a n d/ or irritate d?  
•  H o w se vere y o u feel y o ur s y m pt o ms of dr y ness a n d/ or irritati o n are?  
T his q uesti o n naire uses a 1 0 0 m m h oriz o ntal li ne f or eac h q uesti o n t o assess oc ular disc o mf ort a n d/ or dr y ness e x p erie nce d b y t he patie nts. I n t he 
S A N D E q uesti o n nair e, fre q ue nc y of s y m pt o ms ra n ges fr o m “rarel y ” t o “all of t he ti me” a n d t he se verit y of s y m pt o ms ra n g es fr o m “ v er y mil d” t o 
“ ver y se v ere”. Patie nts are as ke d t o place a mar k o n t he t w o gi ve n li nes bas e d o n t he e xte nt of t heir s y m pt o ms.  
T he l ocati o ns of t he mar ks ma de b y t he patie nts o n t he 1 0 0 m m h oriz o ntal li nes will be meas ure d i n m m fr o m left t o ri g ht a n d rec or de d as fre q u e nc y 
a n d se verit y sc ore, res pecti vel y.  
T he gl o bal S A N D E sc ore will be calc ulat e d b y m ulti pl yi n g t he fre q ue nc y sc ore b y t he s e verit y sc ore a n d o btai ni n g t he s q uare r o ot.  
1 2. 3  I D E E L deri v ati o n 
I D E E L is a 5 7-ite m q uesti o n naire de vel ope d b y A betz et al.  [3 ], t hat t hat assess t he i m pact of dr y e ye s y m pt o ms o n e ver y da y life. T he p ossi ble 
ra n ge of eac h I D E E L s c ore was 0 (c o m plete disa bilit y) t o 1 0 0 ( n o disa bilit y). T his q uesti o n naire c o nsists of 3 m o d ules:  
•  Dr y e ye Treat me nt s atisfacti o n & B ot her ( 1 0 q uesti o ns) c o m prisi n g t w o secti o ns: “ Treat me nt –  I n Ge neral” a n d “ Treat me nt- E ye dr o ps”.  
•  Dr y e ye Q ualit y of Life ( 2 7 q uesti o ns) c o m prisi n g t hree secti o n s: “ Dail y acti vities”, “ Feeli n gs” a n d “ W or k”.  
•  Dr y e ye S y m pt o m B ot her ( 2 0 q uesti o ns).  
R ules f or t he cal c ulati o n of t he I D E E L di me nsi o n sc ores are re p orte d i n Ta ble 4  a n d Ta ble 5 . 
 
 












 
N G F 0 1 2 1  Statistical A nal ysis Pla n  
Pa ge  4 4  of 5 6  
 
 
 
Ver. Fi nal 3. 0  –  1 4 N o ve m ber 2 0 2 2  
 
 
1 3.  
T a bles, Fi g ures a n d Listi n gs  
1 3. 1  T a ble C o n ve nti o ns  
•  If t he cate g ories of a p ara meter are or dere d, t h e n all cate g ories bet w ee n t h e ma xi m u m a n d 
mi ni m u m cate g or y are prese nte d i n t he ta ble e ve n i n case of fre q u e nc y e q u al t o 0.  
•  If t he cate g ories are n ot or dere d (e. g., Me dical Hist or y), t he n o nl y t h ose cate g ories f or w hic h 
t here is at least 1 s u bje ct re pres e nte d i n 1 or m ore gr o u ps are i ncl u d e d. 
•  U nless ot her wise s pecifie d, t he esti mate d mea n a n d me dia n f or a set of v al ues are pri nte d o ut 
t o 1 m ore si g nifica nt di git t ha n t he ori gi nal val ues, a n d sta n dar d de viati o ns. 
•  Missi n g descri pti ve statistics or p -val ues w hic h ca n n ot be esti mate d are re p orte d a s “-”.  
1 3. 2  Listi n g C o n ve nti o ns  
•  Listi n gs will be s orte d f or prese ntati o n i n or der of s u bject n u m ber, treat me nt gr o u ps  
( pla n ne d), a n d visit. 
•  All listi n gs will c o ntai n t he pla n ne d a n d act ual tr eat me nt.  
•  
Dates are pri nte d i n S A S D A T E 9.f or mat (“ d d M M M y y y y”: 0 1J U L 2 0 0 0 ). Missi n g p orti o ns of 
dates are re prese nte d o n s u bject listi n gs as das hes ( --J U L 2 0 0 0). 
1 4.  
Refere nces  
1.  N G F 0 1 2 1  Cli nical S t u d y P r ot oc ol “A 4 wee k, P has e III, m ultice nter, d o u ble -mas ke d, ve hicle -
c o ntr olle d st u d y t o e val uate safet y a n d  efficac y of O xer vate ® (ce n e ger mi n) 2 0 mc g/ m L 
o p ht hal mic s ol uti o n vers us ve hicle, i n patie nts wit h  se vere Sj o gre n’s dr y e y e disease” Versi o n 
N o. 6. 0 –  2 6 Ja n uar y 2 0 2 2 . 
2.  Case Re p ort F or m Versi o n M S C 0 0 7 –  1 3 Oct o be 2 0 2 2 . 
3.  A betz L, Raja g o pala n K, Mertza nis P, Be gle y C, Bar nes R, C hal mers R; I m pact of Dr y E ye 
o n E ver y da y Life (I D E E L) St u d y Gr o u p. De vel o p me nt a n d vali dati o n of t he i m pact of dr y 
e ye o n e ver y da y life (I D E E L) q uesti o n naire, a patie nt -re p orte d o utc o mes ( P R O) meas ure f or 
t he assess me nt of t he b ur de n of dr y e y e o n patie nts. Healt h Q ual Life O utc o mes. 2 0 1 1 Dec 
8; 9: 1 1 1. d oi: 1 0. 1 1 8 6/ 1 4 7 7 -7 5 2 5 -9 -1 1 1. P MI D: 2 2 1 5 2 1 2 5; P M CI D: P M C 3 2 6 9 3 8 7.