A 2 Weeks, Randomized, Double-masked, Controlled Study to Assess Tolerability, Safety, Permanence on the Ocular Surface, Efficacy of Lubricin (20 and 50 μg/ml) vs Sodium Hyaluronate 0.18% in Ocular Discomfort Following Refractive Surgery.
Phase: NA
Conditions: Ocular Discomfort
Sponsor: Dompé Farmaceutici S.p.A

 
 
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+ 
 
 
CLINICAL INVESTIGATIONAL PLAN 
LUB0116MD 
 
Final Version 2.0 – 13 December 2016 
 
A 2 week, randomized, double-masked, controlled, parallel group study to evaluate 
tolerability, safety, permanence on the ocular surface and efficacy of two concentrations of 
Lubricin (20 and 50 μg/mL) eye drops versus sodium hyaluronate (HA) 0.18% eye drops 
(Vismed®) in patients with ocular discomfort following refractive surgery. 
 
 
Study Phase:   Pre-market 
 
Manufacturer/Sponsor: 
Dompé farmaceutici s.p.a.  
Via Santa Lucia, 6 
20122 MILANO 
Italy 
 
Materiovigilance Contact (Serious Adverse Event 
(SAE) reporting): 
Dompé Drug Safety 
Dompé farmaceutici s.p.a. - Milano 
Fax: 
 
 
E-mail: 
 
Medical Monitor/Medical Expert: 
Flavio Mantelli, MD, PhD 
Dompé farmacutici s.p.a. - Milano 
Phone: 
 
e-mail: 
 
CRO: 
  
  
 
 
 
 
CONFIDENTIAL 
This document contains strictly confidential information and cannot be disclosed or used, 
unless authorized in writing by Dompé farmaceutici s.p.a. 
This study will be conducted in compliance with the protocol, attachments VIII and X of  
legislation decree 24 February 1997, n.46 and s.m.i., Declaration of Helsinki, Good Clinical 
Practice (GCP) as set forth in the International Conference on Harmonization (ICH) guidelines 
on GCP (ICH E6), ISO14155-2012  and applicable local regulatory requirements. 
 
 
 
 
PPD
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CLINICAL INVESTIGATION PLAN HISTORY 
CIP No:
Version No: 
Date: 
LUB0116MD 
Final 1.0 
Amendment No: 
Version No.: 
Date: 
|0|1| 
|Final 2.0| 
|1|3| -  |1|2| -  |1|6| 
|__|__| 
|_____________| 
|__|__| -  |__|__| -  |__|__| 
|__|__| 
|_____________| 
|__|__| -  |__|__| -  |__|__| 
NOTICE: Part or all of the information presented in this document may be unpublished 
material and should be treated as confidential information, and not to be disclosed to any 
unauthorized person in any form, including publications and presentations, without the written 
agreement of the sponsor. 
CCI

 
 
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TABLE OF CONTENTS 
 
 
- 
CLINICAL INVESTIGATION PLAN HISTORY  
2 
- 
APPROVALS AND AGREEMENTS 
3 
- 
TERMS AND ABBREVIATIONS 
11 
 
 
 
 
1 
STUDY SUMMARY 
 
 
 
 
13 
 
1.1 
Overall study synopsis 
13 
 
1.2 
Flow chart 
18 
 
 
2. 
IDENTIFICATION 
AND 
DESCRIPTION 
OF 
THE 
INVESTIGATIONAL DEVICE 
19 
2.1 
Investigational Device  
19 
2.1.1. Lubricin 
19 
2.1.2 Pre-clinical Toxicology profile 
20 
2.1.3. Hyaluronic Acid (HA) 
20 
2.2 
Manufacturer 
 
 
 
 
 
 
 
21 
2.3 
Investigational Devices (ID)  
21 
2.3.1 Treatment period (Investigational Medical Devices) 
21 
2.3.2 Follow-Up Period 
25 
2.4 
ID Identification and Traceability 
25 
2.5 
Instructions for Use and Intended Purpose of IDs 
22 
2.5.1. Packaging and Labelling 
22 
 
 
2.6 
Population and Indications 
22 
2.7 
IDs description 
23 
2.8 
Training and Experience on ID use  
23 
2.9 
Methods and Medical Procedures in the Use of ID     
23 
  
 

 
 
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3. 
DESIGN STUDY JUSTIFICATION 
23 
 
3.1 
Relevant Pre-clinical Tests 
24 
 
3.2 
Clinical Data 
25 
 
 
4.  
RISK/BENEFITS 
27 
 
4.1 
Anticipated Clinical Benefits 
27 
 
4.2 
Anticipated Adverse Device Effects 
27 
 
4.3 
Residual Risks from Risk Analysis Report 
27 
 
4.4 
Risks Associated with the Participation in the CI 
27 
 
4.5 
Risks Associated with Concomitant Medical Treatments 
27 
 
4.6 
Risk Control 
27 
 
4.7 
Risk/Benefit Rationale 
28 
 
 
5. 
OBJECTIVES OF THE CLINICAL INVESTIGATION 
28 
 
5.1 
Primary and Secondary Objectives 
28 
 
5.2 
Claims and Intended Performances  
28 
 
5.3 
Risks and anticipated ADE 
28 
 
 
6. 
STUDY DESIGN 
29 
 
6.1 
Clinical Study Design  
29 
 
 
6.1.1  Description and Justification of Study Design 
29 
 
 
6.1.2  Primary and Secondary Endpoints 
29 
 
 
6.1.3 Duration and Timing of the Variable Recording 
29 
 
 
6.1.4  Methods and Equipments for Endpoints Recordings 
34 
 
 
 
6.1.4.1 Ocular Examination 
34 
 
 
6.1.5  Subjects Replacement 
35 
 
6.2.  
ID and Comparators 
36 
 
 
6.2.1 Description and justification of ID/Comparator exposure 
36 
 
 
6.2.2 Justification of the choice of Comparator 
36 
 
 
6.2.3 List of other Medical Device used  
36 
 
6.3. 
Subjects 
36 
 
 
6.3.1  Inclusion Criteria for Subject Selection 
36 
 
 
6.3.2.  Exclusion criteria for Subject Selection 
37 

 
 
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6.3.3   Criteria and procedures for Subject Withdrawal or  
 
 
Discontinuation 
 
 
 
37 
 
 
6.3.4   Point of enrolment 
38 
 
 
6.3.5  Total Expected Duration of the Clinical Investigation 
38 
 
 
6.3.6 Expected duration for Each Subject 
38 
 
 
6.3.7  Total number of Randomized Subjects  
38 
 
 
6.3.8   Total Enrolment Time 
38 
 
6.4. 
Procedures 
39 
 
 
6.4.1 Clinical investigation procedure  
39 
 
 
 
6.4.1.1 Efficacy 
39 
 
 
 
6.4.1.2 Tolerability and Safety 
44 
 
 
 
6.4.1.3 General Procedure 
45 
 
 
6.4.2  CRO activities 
47 
 
 
 
6.4.2.1 Database Management 
47 
 
 
6.4.3  Foreseeable Bias  
47 
 
 
6.4.4  Material Supplied to the clinical Center 
47 
 
6.5. 
Monitoring, Data and Quality Management  
47 
 
 
6.5.1 Monitoring  
47 
 
 
 
6.5.1.1 Clinical Monitoring and identification of the source 
 
 
 
data 
48 
 
 
6.5.2 Audit 
49 
 
 
6.5.3 Inspections 
49 
 
 
7.  
STATISTICS  
49 
 
7.1 
Design, Methods and Analytical Procedures  
49 
 
 
7.1.1 Statistical Methods 
49 
 
 
7.1.2 Definitions 
49 
 
 
7.1.3 Demographics, Baseline and Background Characteristics 
50 
 
 
7.1.4 Tolerability and Safety Evaluation  
50 
 
 
7.1.5 Analysis of the Ophthalmological Evaluations  
50 
 
7.2 
Sample Size 
51 
 
7.3 
Expected Drop-out Date 
51 

 
 
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7.4 
Interim Analysis  
51 
 
7.5 
Statistical Criteria for CI Termination  
51 
 
7.6  
Statistical Plan Deviations 
51 
 
7.7 
Subgroups  
51 
 
7.8 
Missing, Drop-out and All Data Analysis 
51 
 
7.9 
Exclusion of Particular Information 
51 
 
 
7.9.1 Reason for Exclusion from the Full Analysis Set 
51 
 
 
8. 
DATA MANAGEMENT 
52 
 
8.1 
Data Review, Cleaning and Data Queries 
52 
 
8.2 
Electronic Data System 
52 
 
8.3 
Data Retention 
52 
 
8.4 
Data Retention Timing 
52 
 
 
8.4.1 Archiving 
53 
 
8.5 
Quality Assurance 
53 
 
 
8.5.1 Confidentiality and data Protection 
53 
 
 
9. 
AMENDMENTS TO THE CIP 
54 
 
 
10. 
DEVIATIONS FROM THE CIP 
54 
 
10.1 
Investigator Statements 
54 
 
10.2 
Deviation Procedures 
54 
 
10.3  Notification and Timing 
54 
 
10.4 
Corrective/Preventive Actions and Investigators Disqualification 
 
 
Procedures 
54 
 
 
11. 
DEVICE ACCOUNTABILITY 
54 
11.1 
Supply and Storage of the ID and other Materials 
54 
 
11.2 
Responsibilities 
55 
 
11.3 
Control of Occurred Treatments  
55 
 
11.4 
Compliance with ID Administration 
55 
 
 
12. 
STATEMENTS OF COMPLIANCE 
55 

 
 
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12.1 
Declaration of Helsinki 
55 
 
12.2 
International Standard 
55 
 
12.3 
Ethic Committee and Regulatory Authorities Approval 
55 
 
12.4 
Amendments and EC/CA Additional Requirements 
56 
 
12.5 
Insurance Policy 
56 
 
 
12.5.1 Liability Statement  
56 
 
 
13. 
INFORMED CONSENT 
56 
 
13.1 
General Procedures 
56 
 
13.2 
Special Procedures 
57 
 
 
14. 
SAFETY EVALUATION AND REPORTING OF ADVERSE EVENTS; 
SERIOUS ADVERSE EVENT AND DEVICE DEFICIENCES 
57 
 
14.1 
Definitions 
57 
 
14.2 
Management of Adverse Event/Adverse Device effect 
58 
 
14.3 
List of always Serious Adverse Events and rescue procedures  
59 
 
14.4 
Management of Serious Adverse Event/Adverse Device effect 
59 
 
14.5 
Process of Device Deficiencies Reporting 
60 
 
14.6 
Timeframes and contacts for Reporting from the Investigator to 
 
 
the Sponsor/CRO 
61 
 
14.7 
Regulatory Reporting  
61 
 
14.8 
Data Monitoring Information 
62 
 
 
15. 
VULNERABLE POPULATION 
62 
 
15.1 
General Description 
62 
 
15.2 
Specific IC Procedures 
62 
 
15.3 
EC Procedures 
62 
 
15.4 
Special Medical Care 
62 
 
 
16. 
SUSPENSION AND PREMATURE TERMINATION OF CI 
62 
 
16.1 
General Criteria and Site Criteria 
62 
 
 
16.1.1. Removing Subjects from the study  
63 
 
 
16.1.2 .Discontinuation Criteria 
63 

 
 
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16.1.2.1. Primary Reason for Discontinuation 
63 
 
 
16.1.3 Discontinuation Procedures  
64 
 
 
16.1.4 Withdrawal of Subject 
64 
 
16.2 
Breaking Masked Criteria 
64 
16.3 
Follow-up 
65 
 
 
17. 
PUBLICATION POLICY 
65 
 
 
18. 
BIBLIOGRAPHY 
66 

 
 
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TERMS AND ABBREVIATIONS 
 
 
 
 
AE = Adverse Event 
 
ADE = Adverse Device Event 
ANOVA = Analysis of variance 
BCDVA = Best Corrected Distance Visual Acuity 
CPL = Clinical Project Leader 
CDISC = Clinical Data Interchange Standards Consortium 
 
CI = Clinical Investigation 
 
CIMF = Clinical Investigation Master File 
 
CIP = Clinical Investigation Plan 
 
CIR = Clinical Investigation Report 
 
CRF = Case Report Forms 
CRO = Contract Research Organization 
 
DD = Device Deficiencies 
DEWS = Dry Eye WorkShop  
 
DMC = Data Monitoring Committee 
 
EC= Ethics Committee  
 
ETDRS = Early Treatment Diabetic Retinopathy Study 
 
FAS = Full Analysis Set 
GCP = Good Clinical Practice 
GLP = Good Laboratory Practice 
HA = sodium hyaluronate 
IB = Investigation Brochure 
ICF = Informed Consent Form 
ICH = International Conference on Harmonization 
 
ID = Investigational Device 
 
IF = Investigator File 
 
IOP = Intraocular Pressure 
IEC = Independent Ethics Committee  
 
IS = Investigational Site 
 
IV = Intravenous 
 
MedDRA = Medical Dictionary of Regulatory Activities 
 
MD = Medical Device 
 
ml = milliliters 
 
mmHg = millimeters of Mercury 
 
µg = Micrograms 
 
NA = Not Applicable  
NGF = Nerve Growth Factor 
 
NK = Neurotrophic Keratitis 
 
PI = Principal Investigator(s) 
PT = Preferred Term 
PTAE = Pre-Treatment Adverse Event 
PR = Pulse Rate 
TID = Three times per day 
RA = Regulatory Authorities 
 
SAE = Serious Adverse Events 
 
SADE = Serious Device Events 

 
 
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SANDE = Symptom Assessment iN Dry Eye 
 
SAP = Statistical Analysis Plan 
 
SLE = Slit Lamp Examination 
 
s.m.i. = following change and /or additions 
 
SOC = System Organ Class 
 
SOP = Standard Operating Procedure 
 
SDTM = Study Data Tabulation Model 
 
ST = Schirmer’s test 
 
TEAE = Treatment-Emergent Adverse Event 
 
TF = Technical File 
 
TFBUT = Tear Film Break Up Time 
 
VA = Visual Acuity 
 
VAS = Visual Analogical Scale 
 
WHODDE = World Health Organization Drug Dictionary Enhanced  

 
 
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1. 
STUDY SUMMARY 
 
1.1 
OVERALL STUDY SYNOPSIS 
 
CLINICAL STUDY SYNOPSIS: 
Study Number: LUB0116MD 
Title of Study: A 2 week, randomized, double-masked, controlled, parallel group 1 week follow-up 
study to evaluate tolerability, safety, permanence on the ocular surface and efficacy of two 
concentrations of Lubricin (20 and 50 μg/mL) eye drops versus sodium hyaluronate (HA) 0.18% eye 
drops (Vismed®) in patients with ocular discomfort following refractive surgery. 
Study Sites: 1 site in Italy 
Phase of Development: pre-market 
Study Objectives:  
The primary objective of the study is to assess the tolerability and safety of Lubricin (20 and 
50 μg/mL) eye drops solution administered over 2 weeks in patients with ocular discomfort 
following refractive surgery. 
Secondary objectives of the study are aimed at studying efficacy, including ocular surface 
permanence, of Lubricin (20 and 50 μg/mL) eye drops solution administered over 2 weeks 
versus sodium hyaluronate (HA) 0.18% eye drops solution in patients with ocular discomfort 
following refractive surgery. 
Study Design and Methodology:  
A 2 week randomized (1:1:1), controlled, double-masked, parallel group, pre-market study. 
Patients with ocular discomfort following refractive surgery procedure (within 6 months from 
enrollment into the investigation) will be evaluated at baseline (Day 1), at Week 2 (day 152 
days) and at Week 3 follow-up visit (day 22±2, or early exit). 
Number of Patients:  
Thirty (30) patients (10 per arm) randomized 1:1:1 to Lubricin 20 µg/ml eye drops solution or 
Lubricin 50 µg/ml eye drops solution or sodium hyaluronate (HA) 0.18% eye drops solution will be 
enrolled.  
As the primary objective of this study is to evaluate the tolerability and safety of Lubricin (20 and 50 
μg/mL) eye drops solution administered over 2 weeks in patients with ocular discomfort following 
ocular refractive surgery, sample size was calculated based on clinical feasibility and no formal 
sample size calculation has been performed. 

 
 
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Diagnosis and Criteria for Inclusion/Exclusion:  
Adult patients with ocular discomfort (defined as SANDE score ≥ 30 at baseline) following ocular 
refractive surgery (within 6 months from enrollment). 
Inclusion Criteria: 
1. Patients 18 years of age or older. 
2. Patients undergone ocular refractive surgery within 6 months from Day 1 Visit. 
3. Patients with ocular discomfort defined as SANDE score ≥ 30 at baseline. 
4. Average VAS score (dryness, foreign body sensation, burning/stinging, itching, pain, stick 
feeling, blurred vision and photophobia) ≥ 25 mm; 
5. Best corrected distance visual acuity (BCDVA) score ≥ 0.1 decimal units in both eyes at the 
time of study enrolment. 
6. 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 IEC for the 
current study. 
 
Exclusion Criteria: 
1. Patients with a severe Dry Eye condition (severity level 4 according to the Report of the 
International Dry Eye Workshop -DEWS, 2007) 
2. Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye at 
the time of study enrolment 
3. Evidence of an active ocular infection in either eye 
4. History or presence of ocular surface disorders other than ocular discomfort in either eye  
5. Use of any ocular topical medication other than the study medications for the treatment of 
ocular diseases including artificial tears during the study period 
6. Use of topical cyclosporine, topical corticosteroids or any other topical medication for the 
treatment of dry eye in either eye within 30 days of study enrolment 
7. History of any ocular surgery (excluding laser or refractive surgical procedures) in either eye 
within 30 days before study enrolment. Ocular surgery will not be allowed during the study 
treatment period and elective ocular surgery procedures should not be planned during the 
duration of the follow-up period 
8. Known hypersensitivity to one of the components of the study or procedural medications 
9. Participation in another clinical study at the same time as the present study or within 90 days 
of screening/baseline visit 
10. History of drug, medication or alcohol abuse or addiction. 
11. 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 on the urine pregnancy test at the Screening/Baseline Visit or, 
c. intend to become pregnant during the study treatment period or, 
d. are breast-feeding or, 
e. not willing to use highly effective birth control measures, such as:  Hormonal 
contraceptives – oral, implanted, transdermal, or injected and/or mechanical barrier 
methods – spermicide in conjunction with a barrier such as a condom or diaphragm 
or IUD during the entire course of and 30 days after the study treatment periods. 
TEST Investigational Medical Device, Dosage and Mode of Administration:   
Treatment period:  
Sterile isotonic aqueous solution for ocular administration containing Lubricin 20 µg/ml eye drops 
solution or Lubricin 50 µg/ml. In all patients, both eyes will be treated, unless only one eye meets the 
eligibility criteria. If just one eye is treated, that will be the "Study/Primary eye". If both eyes are 

 
 
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treated, the worst one (highest VAS average score) should be chosen as "Study/Primary eye"; in the 
event average VAS score was equal in both eyes, right eye will be chosen as "Study/Primary eye".The 
investigator will administer the morning study dose on Day 1 then patients will self-administer the 
drops at home/site, as applicable. 
Eligible patients will self-administer 1 drop of Lubricin 20 µg/ml or Lubricin 50µg/ml in the eye(s) 
which underwent refractive surgery three times a day (TID) approximately every 6h for 2 weeks. 
No other ocular topical treatments allowed, including artificial tears/lubricants. 
Follow-up period: 
Follow-up period of 7 days, any ocular topical treatments allowed, including other artificial 
tears/lubricants as prescribed by the treating physician. 
Duration of Investigational Device Treatment:  
Treatment duration 14 days (2 weeks) ±2 days (maximum treatment duration 16 days). 
Follow-up period of 7 days, any ocular topical treatments allowed, including other artificial 
tears/lubricants as prescribed by the treating physician. 
REFERENCE Investigational Medical Device, Dosage and Mode of Administration 
Treatment period:  
Sodium hyaluronate (HA) 0.18% eye drops (Vismed®) multidose. In all patients, both eyes will be 
treated, unless only one eye meets the eligibility criteria. If just one eye is treated, that will be the 
"Study/Primary eye". If both eyes are treated, the worst one (highest VAS average score at enrolment 
at enrollment) should be chosen as "Study/Primary eye"; in the event average VAS score was equal in 
both eyes, right eye will be chosen as "Study/Primary eye". The investigator will administer the 
morning study dose on Day 1 then patients will self-administer the drops at home/Site, as applicable. 
Eligible patients will self-administer 1 drop of Sodium hyaluronate (HA) 0.18% in the eye(s) which 
underwent refractive surgery three times a day (TID) approximately every 6h for 2 weeks. 
No other ocular topical treatments allowed, including artificial tears/lubricants. 
Follow-up period: 
Follow-up period of 7 days, any ocular topical treatments allowed, including other artificial 
tears/lubricants as prescribed by the treating physician. 
Study procedures: 
Visit 1 – Day 1 – Baseline – Pre-Dose 
 Explanation to the patient of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number (as S01, S02, etc.) 
 Demographic data 
 Medical and surgical history/current medical conditions 
 Prior/concomitant medications 
 External Ocular Examination 
 AE monitoring 
 Ocular examination in both eyes: 
1. Assessment of ocular tolerability (Visual analogue scale, VAS: dryness, foreign body 
sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) 
2. Assessment by SANDE questionnaire 
3. Assessment of best corrected distance visual acuity 
4. Slit lamp examination (SLE) to assess the Eyelid - Meibomian glands, Eyelid Erythema, 
Eyelid – Oedema, Lashes, Conjunctiva Erythema, Lens, Iris, Anterior Chamber, Corneal 
transparency, Corneal neovascularization 
5. Assessment of central corneal sensitivity by Cochet-Bonnet aesthesiometry 
6. Tear collection for Lubricin dosing (both eyes) using tear wash technique with 40 μL of sterile 

 
 
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saline solution 
At least 10 minutes break 
7. Tear Film Break Up Time (TFBUT) 
8. Corneal fluorescein staining (Oxford score) 
At least 15 minutes break 
9. Schirmer's test (ST) I (without anaesthesia)  
10. Intraocular pressure (IOP) 
 Pregnancy test for female patients. 
 Inclusion/exclusion criteria evaluation 
 Patient eligibility confirmation and randomization number assignment 
Visit 1 – Day 1 - Dose  
 At the completion of the pre-dose assessments, the investigator will administer the study 
product (morning dose) into the eligible eye(s) 
Visit 1 – Day 1 – 15 minutes post-dose 
 Assessment of ocular tolerability (Visual analogue scale, VAS: dryness, foreign body 
sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the right eye 
Visit 1 – Day 1 – 30 minutes post-dose 
 Assessment of ocular tolerability (Visual analogue scale, VAS: dryness, foreign body 
sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the left eye 
 The Investigator will deliver to the patients the investigational medical device for the 
treatment period (15±2 days) 
At home: From Day 1 to Week 2 Visit: 
 Self-administration at home of the Investigational medical device TID approximately 
every 6h into the eligible eye(s) 
Visit 2 – Week 2 ± 2 Days (prior the morning dose) 
 Review of current medical conditions (ocular and systemic: including External Ocular 
Examination) 
 AE and concomitant medications  
 Ocular examination in both eyes, consisting of the assessments detailed for the baseline 
visit (points 1-10), in the same order and with the same intervals 
 Urine Pregnancy test (only female) 
Visit 2 – Week 2 ± 2 Days - Dose  
 At the completion of the pre-dose assessments, the investigator will administer the study 
product (morning dose) into the eligible eye(s) 
Visit 2 – Week 2 ± 2 Days – 15 minutes post-dose 
 Assessment of ocular tolerability (Visual analogue scale, VAS: dryness, foreign body 
sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the right eye 
Visit 2 – Week 2 ± 2 Days – 30 minutes post-dose 
 Assessment of ocular tolerability (Visual analogue scale, VAS: dryness, foreign body 
sensation, burning/stinging, itching, pain, stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the left eye 
Visit 3 – Final Follow-up Visit - 7±2 days after last administration (day 22 ± 2) 
 Review of current medical conditions (ocular and systemic: including External Ocular 
Examination) 

 
 
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 AE and concomitant medications  
 Ocular examination in both eyes, consisting of the assessments detailed for the baseline 
visit (points 1-10), in the same order and with the same intervals 
 Patient discharge 
 
Criteria for Evaluation: 
Evaluation of the clinical tolerability, safety and efficacy of treatment with Lubricin eye drops in 
patients with moderate to severe dry eye, on the basis of the following assessments. 
Primary outcomes: 
 
Tolerability using a Visual analogue scale (VAS) for dryness, foreign body sensation, 
burning/stinging, itching, pain, stick feeling, blurred vision and photophobia  
 
Treatment-emergent adverse events (TEAEs), assessed throughout the study 
Secondary outcomes 
 
Ocular surface vital staining with Fluorescein (Oxford scale) 
 
Schirmer-I test (without anaesthesia); 
 
Permanence of Lubricin on the Ocular Surface Tear film break-up time (TFBUT); 
 
Best corrected distance visual acuity (BCVA); 
 
SANDE questionnaire scores – discomfort improvement entity; 
 
SANDE questionnaire scores – discomfort improvement speed; 
 
Signs evaluated by Slit lamp examination (SLE) (blepharitis, eyelid hyoeremia/oedema, 
lashes, conjunctiva hyperemia) 
 
Intraocular pressure (IOP) 
 
Corneal sensitivity by Cochet-Bonnet aesthesiometry 
Variables will be compared between groups at each time point. 
Statistical Methods: 
The data documented in this study will be listed by patient, dose, eye (left and right, if applicable) and 
evaluation time point. 
Appropriate descriptive statistics will be used according to the nature of the variable. 
Not available data will be evaluated as “missing values”. The statistical analysis will be performed 
using SAS® version 9.3 (TS1M1) for Windows® or higher.  
A statistical analysis plan (SAP) will be issued before database lock. Final statistical analysis models 
will be presented in detail in the SAP. 

 
 
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1.2. 
Study Flow Chart 
 
Visit 1 
Visit 2 
Visit 3 
Final Visit follow-up 
Day 22 ± 2/ETV 
Evaluation 
Day 1 
Baseline 
Day 
15 ± 2 
Informed Consent 
X 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
Pregnancy test for females 
X 
X 
 
Eligibility/Enrolment 
X 
 
 
Demography 
X 
 
 
Medical/Surgical history (ocular &systemic) 
X 
 
 
Review of current medical conditions (ocular & systemic) 
 
X 
X 
Prior and concomitant medications (ocular & systemic) 
X 
X 
X 
External Ocular Examination 
X 
X 
X 
VAS ocular tolerability assessment 
X** 
X** 
X 
SANDE questionnaire 
X 
X 
X 
Best corrected distance visual acuity  
X 
X 
X 
Slit lamp examination (SLE) 
X 
X 
X 
Central corneal sensitivity by Cochet-Bonnet aesthesiometry  
X 
X 
X 
Tear collection for Lubricin dosing 
X*** 
X*** 
X**** 
Tear Film Break Up Time (TFBUT) 
X 
X 
X 
Corneal fluorescein staining (Oxford score) 
X 
X 
X 
Schirmer's test (ST) I without anesthesia 
X 
X 
X 
Intraocular pressure (IOP) 
X 
X 
X 
Self-administration at home 
X* 
X* 
 
First Administration at study site 
X 
X 
 
Compound Dispensing  
X 
 
 
Adverse events 
X 
X 
X 
*Self-administration at home during the study period 
** pre-dose, 15 minutes post–dose, 30 minutes post–dose 
***  pre-dose – in both eyes, 15 minutes post–dose in the right eye, 30 minutes post–dose in the left eye 
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2.   IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
2.1. 
Investigational Devices 
2.1.1. Lubricin  
Lubricin, also called Proteoglycan 4 (PRG4), is a mucin-like glycoprotein originally discovered in 
synovial fluid, as a secreted product of cells that line the joint tissues, which is present at the 
surface of articular cartilage (1,2). 
In vitro studies have shown that lubricin in saline buffer acts as a lubricant between various 
surfaces, as well as in synovial fluid, providing evidence that lubricin is a principal lubricating 
protein in joints. Besides the lubricating property, lubricin has been shown to exert anti-adhesive 
action, strain energy dissipation, anti-bacterial and a protective effect on underlying cells (3-6). 
The lubricating, anti-adhesive, protective and anti-bacterial properties of Lubricin raised interest 
on its roles at the ocular surface, in normal and pathologic conditions such as dry eye (see 
Lubricin Investigator’s Brochure, 
) (7). 
The expression of Lubricin in animal models and in human ocular surface and meibonian gland 
was first described by the team of D. Sullivan (8,9). 
As previously mentioned, lubricin has recently been discovered at the ocular surface, where its 
boundary lubricating properties may play a critical protective role as they do at the articular 
cartilage surface. Specifically, human corneal and conjunctival epithelial cells have been shown to 
express PRG4 mRNA, and PRG4 protein has been observed in human meibomian gland 
secretions via proteomic analysis (8,9) . 
The discovery of this molecule responsible for boundary lubrication at the ocular surface supports 
the hypothesis of Ehlers, who already in 1965 theorized that boundary lubrication must take place 
between the eyelid wiper region and the cornea (10).While a normal tear film containing mucins 
in the acqueous layer surely contributes to the normal hydrodynamic lubrication of the ocular 
surface, in pathologies such as dry eye disease where there is an altered tear film, boundary 
lubrication involving lubricin may be a primary method of friction reduction. Boundary 
lubrication may also be dominant at the cornea–contact lens interface where there is a relative lack 
of aqueous tear (5, 6, 8-11). 
Therefore, the absence of lubricin may also promote ocular surface damage. Supporting this 
hypothesis, a higher fluorescein staining of the ocular surface has been demonstrated in animal 
models lacking lubricin. Since increased fluorescein staining is commonly associated with dry eye 
disease, a reduction in lubricin content may likely increase shear stress at the ocular surface, 
which, in turn may lead to inflammation and accumulation of inflammatory mediators in the tear 
film, triggering the typical symptoms of discomfort observed in dry eye patients. Supporting these 
hypothesis, the team of Sullivan and Schmidt (8) has recently described that the use of exogenous 
lubricin at the ocular surface provides a dramatic friction-lowering effect at the cornea-eyelid 
interface. Furthermore, given the known ability of lubricin to reduce friction on articular cartilage 
in a synergistic manner with hyaluronic acid, the current mainstay in dry eye symptoms' relief, 
and the broad commercial availability of ophthalmic formulations containing hyaluronic acid 
intended to provide lubrication, lubricin may also function synergistically with hyaluronic acid to 
reduce friction at the ocular surface. 
Based on the available preclinical studies lubricin may be an important barrier to the development 
of corneal and conjunctival epitheliopathies in dry eyes and its use as a novel lubricating and anti-
adhesive eye drop is under investigation in this clinical investigation.  
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2.1.2 Preclinical Toxicology Profile 
The following Biocompatibility studies have been performed so far: 
LUBRICIN EYE DROPS has been tested for cytotoxicity by direct contact on BalbC 3T3 monolayer 
cells according to ISO 10993-5:2009 and resulted not cytotoxic. 
Guinea-pig maximixation test was performed according to ISO 10993-10:2010 in order to 
evaluate the possible sensitization effects of LUBRICIN EYE DROPS, according to these results the 
ID was considered not sensitizing  
Ocular irritation test in rabbit was also performed according to ISO 10993-10:2010. Following 
ocular examination with ophthalmoscope after 1, 24, 48 and 72 hours, the test item resulted not 
irritant. Ocular examination included the assessment of cornea, iris and conjunctiva. 
The compatibility of LUBRICIN EYE DROPS with soft contact lens was tested according to ISO 
11981:2009. The results obtained proved that the ID exerts physical compatibility to soft contact 
lens according ISO 11981:2009 
 
Overall the preclinical toxicity data obtained in vitro and in vivo tests indicate a low risk of 
adverse side effects in humans under the circumstanced of the intended clinical plan. 
2.1.3  Hyaluronic acid (HA) 
Hyaluronic acid is a linear polysaccharide found in all living organisms and is a universal 
component of the extracellular matrix of body tissues where it is distributed ubiquitously in all 
tissues (12). It is a molecule with negative charges and can form in the presence of H2O a highly 
viscous solution. HA is a glycosaminoglycan present in the human vitreous and is able to bind a 
large number of water molecules and, therefore, creating a twisting ribbon structure which in 
physiological structure may occupy a very large domain, this also allows an very high swelling 
factor, up to 10.000 (13). The chemical structure of HA is formed by units of D -glucuronic acid 
and N-acetylglucosamine and remains constant throughout the phylogenetic chain. This identity is 
largely used clinically because if injected or administered to human it eliminates theoretically all 
the possible risks of allergic reactions, which instead are potentially present in the use of non-
human natural products, such as non- human collagen (14). From the industrial point of view HA 
can be obtained by extraction from animal tissue, usually cockscomb, for bacterial fermentation 
and recombinant biotechnology. Natural HA has a relatively short half-life (1-2 days) in all 
connective tissues except the vitreous body of the eye (15). 

 
 
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2.2.  
Manufacturers 
Lubricin Eye Drops manufactured by Dompé farmaceutici s.p.a. via Campo di Pile SNC, 
67100 L’Aquila. Produced (bulk and masked packaging) by 
 
 (See Annex A – Lubricin eye drops -Instruction 
for the subjects).  
Sodium hayluronate (HA) 0.18%: (Vismed®) multidose manufactured by 
 
 
 will supply the HA for the Clinical Investigation in masked packing. (See Annex B – 
Vismed® 0.18% - Instruction for the subjects). 
2.3.  
Investigational Devices (ID) 
2.3.1 Treatment Period (Investigational Medical Devices) 
TEST: Lubricin 20 µg/ml or Lubricin 50 µg/ml : is aseptically filled multidose container, suitable 
for products for ocular instillation. Lubricin 20 µg/ml or Lubricin 50 µg/ml will be supplied for 
the Clinical Investigation in masked packing. 
For additional details on Lubricin please refer to Annex A. 
A single multidose container will supply treatment for both weeks of treatment. Instructions for 
use will be provided to the subject during visit 1. 
 
CONTROL: Sodium hyaluronate (HA) 0.18% eye drops (Vismed®) multidose, commercially 
available in Italy will be supplied for the Clinical Investigation in masked packing. 
For additional details on Vismed® please refer to Annex B. 
A single multidose container will supply treatment for both weeks of treatment. Instructions for 
use will be provided to the subject during visit 2. 
2.3.2 Follow-Up Period 
During the follow-up period patients may receive any ocular topical treatments allowed, including 
other artificial tears/lubricants as prescribed by the treating physician. 
 
2.4. ID Identification and Traceability 
Patients will be randomized 1:11 to LUBRICIN EYE DROPS solution (20 µg/ml or 50µg/ml – Drop: 
50µl – 1 µg/drop or 2.5 µg/drop respectively) or sodium hyaluronate (HA) 0.18% (Drop: 50µl - 
90 µg/drop) eye drops solution. The randomization groups will be generated with a computer 
procedure. 
The randomization system will be prepared and implemented by the CRO. 
Individual treatment codes will be provided in a closed envelope to the Investigators and to 
Dompé Materiovigilance Department for safety procedures. 
Each eligible subject will be assigned to a randomization number according to the sequence of 
study entry, from 01 to 30. The Investigational Site (IS) will be delivered in adequate quantity to 
provide treatment for 30 subjects. 
All containers will be also identified by a codified batch to maintain the masked condition and 
ensure traceability.  
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2.5. Instructions for Use and Intended Purpose of IDs 
The instruction for use are reported in Annex A (Lubricin eye drops) and B (Vismed®). 
The intended purpose of Lubricin eye drop is the use as a novel lubricating and anti-adhesive 
agent in patients suffering from ocular discomfort following refractive surgery. 
2.5.1 Packaging and Labelling 
The ID labelling will report all the information requested according to the Annex 13 of the Good 
Manufacturing Practice (published by the Commission in The rules governing medicinal products 
in the European Community, Volume 4) as follows: 
a. Name, address and telephone number of the sponsor, contract research organization or 
investigator (the main contact for information on the product, clinical study and emergency 
un-masked) 
b. ID dosage form, route of administration, quantity of dosage units, and in the case of open 
studies, the name/identifier and strength/potency 
c. The batch and/or code number to identify the contents and packaging operation 
d. CIP reference code allowing identification of the study, site, investigator and sponsor if not 
given elsewhere 
e. The KIT identification number and where relevant, the visit number 
f. The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 
i. The storage conditions 
j. Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
Labels will be in Italian. 
 
2.6.  
Population and Indications 
EYE DROPS are intended to be used in subjects suffering from ocular discomfort following 
refractive surgery in order to contribute to normal hydrodynamic lubrication of the ocular surface 
by boundary lubrication. 
 
Thirty (30) subjects (1:1:1 randomization experimental vs experimental vs control) will be 
randomized in the study.   
To participate in the study, male and female subjects must be 18 or older with ocular discomfort 
(defined as SANDE score ≥ 30 at baseline) following ocular refractive surgery (within 6 months 
from enrollment) 
Subjects must fulfil all of the study inclusion and none of the exclusion criteria.  
 
Recruitment will proceed until the planned number of subjects is randomized. 
2.7. 
IDs Description 

 
 
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As other proteins for ocular use (e.g. sodium hyaluronate acid), recombinant human Lubricin 
(rhLubricin) is produced from fermentative synthesis. 
The protein is produced in mammalian CHO (Chinese hamster ovary) cells by extracellular 
excretion into the media. CHO cell lines have frequently been used as substrates for production 
with no reported safety problems related to viral contamination of the products. For these cell 
lines, endogenous particles have been extensively characterized and clearance has been 
demonstrated.  However, Lubricin Starting Material undergoes viral inactivation and viral 
removal. 
, is expressed by 
transfected Chinese Hamster Ovary cells 
.  
Validations and specifications of production of Lubricin Starting material and the final product are 
reported in IB § 2.4 Summary of Manufacturing Process and Validation. 
 
Sodium hayluronate 0.18%: (Vismed®) multidose, Manufacturer TRB CHEMEDICA AG), 
commercially available in Italy. The instruction for use is reported in Annex B. 
2.8. 
Training and Experience on ID use 
The Investigator/s will ensure that all staff who may participate to the study is adequately 
informed on procedure reported by the CIP, the treatments provided in this study, their functions 
and tasks in the study. The investigator will keep a list of the staff, duly qualified, who has been 
delegated into a significant part of duties related to the study. 
Any particular training for the use of the eye drops is not required considering that it is a very 
common route of administration. 
 
2.9. 
 Methods and Medical Procedures in the Use of ID  
The methods and the medical procedures for a correct use of the Test ID/Control ID are reported 
in detail in the “Instruction for Use” (Annexes A and B). 
 
3. 
STUDY DESIGN JUSTIFICATION 
Laser refractive surgery for the correction of refractive errors has become an affordable and safe 
procedure. However, a large number of patients complain of ocular surface symptoms after 
refractive surgery. In fact, both photorefractive keratectomy (PRK) and laser in situ 
keratomileusis (LASIK) can induce or exacerbate dry eye, that manifests as an increase in degree 
and frequency of symptoms, corneal findings, such as superficial punctate keratopathy, and 
abnormal results of dry eye tests, such as the Schirmer test and tear break-up time. The cause 
mainly involves decreased corneal sensation, resulting in decreased feedback to the lacrimal gland 
and reduced tear production. Other causes may include increased evaporation, inflammation, or 
toxicity of medications. Dry eye symptoms are usually transient, lasting only a few weeks, but in a 
significant percentage of patients these symptoms can last up to 1 year. (17). 
In addition, refractive surgery procedures have been described to exert a neurotrophic damage to 
the cornea, along with other changes in corneal shape, that affect tear dynamics causing ocular 
surface alterations. As a consequence, symptoms of dryness may occur in more than 50% of 
patients after LASIK, with other complications such as fluctuating vision, decreased best 
corrected visual acuity, and severe discomfort occurring in approximately 10% of patients (18). 
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As a consequence of the widespread use of refractive surgery, a safe and non-toxic treatment that 
can improve ocular surface symptoms after the procedures is highly sought after by patients and 
clinicians. 
Lubricin, also called Proteoglycan 4 (PRG4), is a mucin-like glycoprotein originally discovered in 
synovial fluid, as a secreted product of cells that line the joint tissues, which is present at the 
surface of articular cartilage. 
In vitro studies have shown that lubricin in saline buffer acts as a lubricant between various 
surfaces, as well as in synovial fluid, providing evidence that lubricin is a principal lubricating 
protein in joints. Besides the lubricating property, lubricin has been shown to exert anti-adhesive 
action, strain energy dissipation, and a protective effect on underlying cells. 
Lubricin has been investigated on its roles at the ocular surface, in normal and pathologic 
conditions such as dry eye. In fact, Lubricin is a natural human protein with most potent lubricant 
and anti-adhesive properties present on the ocular surface and on meibonian gland. The presence 
of this protein at the ocular surface was first described by the team of Sullivan D. (14,16). 
Based on the available preclinical and clinical investigations Lubricin may be an important barrier 
to the development of corneal and conjunctival epitheliopathies as a consequence of refractive 
surgery procedures. 
Its use as a novel lubricating and anti-adhesive eye drop is under investigation in this clinical 
investigation. During the previous clinical investigations conducted it has been demonstrated that 
a Lubricin 150 µg/ml eye drop formulation is non-inferior to ocular surface lubricant sodium 
hyaluronate 0.13% and sodium hyaluronate 0.18%. 
The objective of this study is to evaluate tolerability, safety, permanence on the ocular surface and 
efficacy of two concentrations of Lubricin (20 and 50 μg/mL) eye drops versus sodium 
hyaluronate (HA) 0.18% eye drops (Vismed®) in patients with ocular discomfort following 
refractive surgery. 
3.1. 
Relevant Pre-Clinical Tests 
The expression of Lubricin in human corneal, conjunctival epithelial cells, along with 
corneoscleral rims, conjuntival tissues, and conjunctival impression cytology samples  in vitro 
was already demonstrated (8). .Expression of Lubricin was also observed in human meibomian 
gland epithelial cells and in other human tissues (uterine, cervical, bladder prostatic samples as 
well as in articular cartilage and synovial membranes). The in vitro test on human cornea-eyelid 
interface showed an effective friction-lowering boundary lubricant activity for Lubricin which 
resulted in statistical significant (P< 0.001-0.05) lower static friction as compared to Aquify (eye 
drops containing 0.1% Hyaluronic acid; CIBA Vision) and saline at all velocities.  
Similar trends were observed from kinetic friction experiments, where the highest values were 
observed in saline which were not statistically different from AQuify at all velocities. Lubricin 
showed lower values as compared to saline at all velocities and only at the lower velocity as 
compared to AQuify (8). 
LUBRICIN EYE DROPS have been tested for cytotoxicity by direct contact on BalbC 3T3 monolayer 
cells according to ISO 10993-5:2009 and resulted not cytotoxic  
Guinea-pig maximization test was performed according to ISO 10993-10:2010 in order to 
evaluate the possible sensitization effects of LUBRICIN EYE DROPS, according to these results the 
ID was considered not sensitizing. 
The compatibility of LUBRICIN EYE DROPS with soft contact lens was tested according to ISO 
11981:2009. The results obtained proved that the ID exerts physical compatibility to soft contact 
lens according ISO 11981:2009. 

 
 
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Other relevant preclinical results are reported in IB §3.1 (Preclinical Testing). 
 
3.2. 
Clinical Data 
3.2.1 LUB0114MD: 
A 
MULTICENTER, 
RANDOMIZED, 
DOUBLE-MASKED, 
CONTROLLED,  
NON-INFERIORITY STUDY TO EVALUATE TOLERABILITY, SAFETY AND EFFICACY OF LUBRICIN EYE 
DROPS VERSUS SODIUM HYALURONATE EYE DROPS (OCUYAL®) ADMINISTERED FOUR TIMES A DAY 
FOR 4 WEEKS AND 1 WEEK FOLLOW-UP IN SUBJECTS WITH MODERATE DRY. 
The study, which enrolled 56 subjects, was a multicentre, randomized (1:1), double-masked, 
controlled, non-inferiority study to evaluate the tolerability, safety and efficacy of Lubricin eye 
drops (monodose; 150µg/mL) versus with a widely used commercial 0.13% sodium hyaluronate 
eye drop formulation administered 4 times a day for 4 weeks in subjects with moderate dry eye 
disease. 
The primary objective of this study was to demonstrate that lubricin 150 µg/mL is non-inferior to 
a widely used commercial 0.13% sodium hyaluronate eye drop formulation in improving signs 
and symptoms in patients with moderate dry eye. 
Since the lubricin effect was expected to be similar to that of hyaluronic acid, it was hypothesised 
that the largest clinically acceptable effect to declare non-inferiority between treatments was a 
change in SANDE questionnaire results (Symptom Assessment iN Dry Eye) overall score 
(primary parameter) of 12 mm, with an estimated standard deviation (SD) of 13 (about 70% of 
mean at 28 days post-treatment). 
Results obtained from this clinical investigation allow claiming the efficacy, the safety and the 
tolerability of use of the test IMD. The investigation results demonstrated the non inferiority of 
lubricin 150 µg/mL eye drops versus the comparator sodium hyaluronate 0.13% eye drops thus 
confirming the use intended for lubricin as ocular surface lubricant. No limitation in the use of 
lubricin 150 µg/mL eye drops, when used according to the recommendations provided, either as 
IMD in future clinical investigations or as marketed medical device, is envisaged as compared to 
sodium hyaluronate 0.13% eye drops. On the basis of the results and the observations done during 
the clinical investigation, the benefit/risk ratio observed for the test IMD did not differ from that 
of the comparator.  
 
3.2.2 LUB0115MD: A 2 WEEK, RANDOMIZED, DOUBLE-MASKED, CONTROLLED, PARALLEL GROUP 
AND 1 WEEK FOLLOW-UP STUDY TO EVALUATE TOLERABILITY, SAFETY AND EFFICACY OF LUBRICIN 
(150 µG/ML) EYE DROPS VERSUS SODIUM HYALURONATE (HA) 0.18% EYE DROPS (VISMED®) IN 
PATIENTS WITH MODERATE DRY EYE (DE). 
The study, which enrolled 40 subjects, was a 2-week, monocentric, randomized (1:1), double-
masked, controlled, study to evaluate tolerability, safety and efficacy of lubricin 150 µg/mL eye 
drops in comparison with a widely used commercial 0.18% sodium hyaluronate eye drop 
formulation in patients with moderate dry eye. 
 
Eligible patients self-administered 1 drop of Lubricin 150 µg/ml in both eyes two times a day 
(BID) every 8h±1h for 1 week and then patients self-administered 1 drop of Lubricin 150 µg/ml in 
both eyes from two to six times a day as needed (PRN) during the second week of the study. 
Results obtained from this clinical investigation allow claiming the efficacy, the safety and the 
tolerability of use of the test device. The investigation results demonstrated the similarity of 
lubricin 150 µg/mL eye drops versus the comparator sodium hyaluronate 0.18% eye drops used 
by patients with dry eye syndrome of moderate intensity thus confirming the use intended for 

 
 
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lubricin as ocular surface lubricant. No limitation in the use of lubricin 150 µg/mL eye drops, 
when used according to the recommendations provided, either as Investigational Medical Device 
(IMD) in future clinical investigations or as marketed medical device is envisaged as compared to 
sodium hyaluronate 0.18% eye drops.  

 
 
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RISK/BENEFITS 
4.1. 
Anticipated Clinical Benefits 
LUBRICIN EYE DROPS are intended to be used in subjects suffering from ocular discomfort 
following refractive surgery in order to contribute to normal hydrodynamic lubrication of the 
ocular surface by boundary lubrication. 
Therefore the primary objective of this study is to evaluate the tolerability and safety of an eye 
drop treatment containing Lubricin 20µg/ml or 50µg/ml as compared with a standard sodium 
hyaluronate (HA) 0.18% eye drop solution in subjects suffering from ocular discomfort following 
refractive surgery.  
4.2. 
Anticipated Adverse Device Effects 
Based on preclinical studies (ISO 10993) there is no evidence of adverse events related to the use 
of the Lubricin eye drops. 
Local or systemic adverse device effects after the use of Lubricin or sodium hyaluronate eye drop 
solutions are not described. However, it could be possible to observe local irritation and/or local 
hypersensitivity reaction to a component of the device. 
Besides, immediately after ocular instillation a transient blurred vision could be experienced. 
4.3. 
Residual Risks from Risk Analysis Report 
The risk analysis according to ISO 14971 has been carried out by a team of experts and the results 
seem to be congruent, in particular 2 possible events located in the intolerable risk area and 6 
possible events located in the Alarp 1 zone (defined between 6 and 11) have been identified and 
adequately commented and managed. For each risk Dompé has identified actions to reduce or 
eliminate the probability that risk is manifested. At the end of the analysis and with the actions 
involved, each risk is considered inside the area of risk broadly acceptable. 
4.4. 
Risks Associated with the Participation in the CI 
The subjects randomized in the CLINICAL INVESTIGATION (CI) are suffering from ocular 
discomfort following refractive surgery and no other associated ocular conditions.  All procedures 
performed during the CI are not invasive and are not associated with risks for the patients. During 
Schirmer test the patient may experience minimal conjunctival discomfort due to the contact with 
the strip. However, these tests are currently performed during routine ocular examination in all the 
dry eye patients, with no concerns. The use of topical fluorescein, which is also routinely done in 
dry eye patients’ visits, may cause transient irritation or allergic reactions, but does not carry any 
additional risk. Therefore no additional risks are expected apart those typical of eye drops 
administrations. 
4.5. 
Risks Associated with Concomitant Medical Treatments 
No risks are known for the concomitant use of Lubricin or sodium hyaluronate eye drop solutions 
and other medications.  
4.6. 
Risk Control 
The risks associated with the CI are those typical of eye drops instillations and will be minimized 
by the involvement of highly specialized medical staff who will specifically train the patients on 
the use of test ID/Control ID. All drug prescriptions and other medical intervention will be 
performed or approved by medical personnel. 
 

 
 
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4.7. 
Risk/Benefit Rationale 
The subjects enrolled in this CI are in the need of dry eye symptoms relief. 
Based on preclinical studies (ISO 10993), the Risk Assessment and the lubricant characteristics of 
Lubricin eye drops, it can be expected that benefit/risk for the investigational Medical Device is 
similar to the one associated to the control. 
5. 
OBJECTIVES OF THE CLINICAL INVESTIGATION 
5.1. 
Primary and Secondary Objectives 
The primary objective of the study is to assess the tolerability and safety of Lubricin (20 and 50 
μg/mL) eye drops solution administered over 2 weeks in patients with ocular discomfort following 
refractive surgery. 
Secondary objectives of the study are aimed at studying efficacy, including ocular surface 
permanence, of Lubricin (20 and 50 μg/mL) eye drops solution administered over 2 weeks versus 
sodium hyaluronate (HA) 0.18% eye drops solution in patients with ocular discomfort following 
refractive surgery. 
5.2. 
Claims and Intended Performances 
Both IDs under study will improve temporarily lubrication of the ocular surface, reducing the 
symptoms, and increasing the tear film stability and ocular surface lubrication. 
The Lubricin eye drops is expected to stabilize the lacrimal film, keeping the ocular surface 
protected and can be used with contact lenses. 
5.3. Risks and Anticipated Adverse Device Events 
Up to now, there are no known anticipated adverse events associated with the use of LUBRICIN 
EYE DROPS, anyway the occurrence of side effects cannot be excluded. 
It must be considered that topical treatment with LUBRICIN EYE DROPS could cause local irritation 
or allergic reactions. There are no known contraindications to the use of LUBRICIN EYE DROPS. 
All examinations and assessments that will be carried out during this study are non-invasive, are 
commonly used in the management of subjects with dry eye and pose no risk to the subjects. 
Subjects might feel a slight discomfort during the execution of Schirmer test and a local allergic 
reaction or irritation from the use of fluorescein may be observed. There are no known 
contraindications to the use of lubricin or sodium hyaluronate eye drops. No data are available 
about the embryo and fetal toxicity, therefore the experimental treatment will not be allowed to 
pregnant women or nursing mothers and women of childbearing potential not using appropriate 
birth control methods. 
Local or systemic adverse device effects after the use of Lubricin or hyaluronic acid eye drop 
solutions are not described. However, it could be possible to observe local irritation and/or local 
hypersensitivity reaction to a component of the device. 
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6. STUDY DESIGN 
6.1. Clinical Study Design 
6.1.1. Description and Justification of Study Design 
This is a 2-week randomized (1:1:1), controlled, double-masked, parallel group study, to evaluate 
tolerability, safety permanence on the ocular surface and efficacy of two concentrations of 
Lubricin (20 and 50 μg/mL) eye drops versus sodium hyaluronate (HA) 0.18% eye drops 
(Vismed®) in patients with ocular discomfort following refractive surgery. 
Enrolled subjects will be randomized at inclusion, 1:1:1 ratio to receive Lubricin 20 µg/ml eye 
drops solution or Lubricin 50 µg/ml eye drops solution or sodium hyaluronate (HA) 0.18% eye 
drops solution. Upon randomization and until the end of the treatment period, subjects will be 
required to not use topical ophthalmic medications except of the study treatments.  
On the Day 1 Visit (Baseline visit) subjects will be dispensed of the study medication and 
instructed to self-administer at home three times a day approximately every 6 hours for 2 weeks. 
Subjects will be evaluated after 2 weeks of treatment and 1 week after end of treatment. 
 
The subjects will be involved in the study for a maximum of 25 days from screening visit to last 
follow-up visit.  
6.1.2 Primary and Secondary Endpoints 
The primary endpoints of the study are: 
1. Tolerability using a Visual analogue scale (VAS) for dryness, foreign body sensation, 
burning/stinging, itching, pain, stick feeling, blurred vision and photophobia  
2. Treatment-emergent adverse events (TEAEs), assessed throughout the study 
 
Secondary outcomes will include:  
1. Ocular surface vital staining with Fluorescein (Oxford scale) 
2. Schirmer-I test (without anaesthesia); 
3. Permanence of Lubricin on the Ocular Surface Tear film break-up time (TBUT); 
4. Best corrected distance visual acuity (BCVA); 
5. SANDE questionnaire scores – discomfort improvement entity; 
6. SANDE questionnaire scores – discomfort improvement speed; 
7. Signs evaluated by Slit lamp examination (SLE) (blepharitis, eyelid hyoeremia/oedema, 
lashes, conjunctiva hyperemia) 
8. Intraocular pressure (IOP) 
9. Corneal sensitivity by Cochet-Bonnet aesthesiometry 
 
Parameters will be evaluated at each visit as reported on par 1.2 – Study Flow Chart.  
The safety of the Test ID/Control ID will be evaluated by reporting and evaluating the eventually 
occurred AE/ADE and SAE/SADE. 
6.1.3. Duration and Timing of the Variable Recording  
A written informed consent will be obtained before any study assessment or procedure. Maximum 
study duration will be 25 days, including all study visits. 
Each study subject will undergo to 3 visits. 

 
 
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The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical site by the 1st 
enrolled subject. The last subject last visit (LSLV) is defined as the last visit performed at the 
clinical site (or the telephonic follow-up, if applicable) by the last subject, i.e. the last visit 
foreseen by the study protocol, independently of the fact that the subject is a completer or a 
withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 
 Interventional phase 
 Visit 1 - Day 1 
 Visit 2 - Day 15 ± 2. 
 
 Follow-up phase 
 Visit 3 - Final Visit follow-up - (Day 22±2) /ETV (Early Termination Visit) in case of 
early discontinuation, discontinued subjects will undergo an early termination visit (ETV).  
 
The procedures/assessments details are summarized hereafter. 
 

 
 
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Day 
Procedures/Assessments 
Visit 1 – Day 1 – Baseline – Pre-Dose 
Day 1  
pre-dose 
 Explanation to the patient of study aims, procedures and 
possible risks 
 Informed consent signature 
 Screening number (as S01, S02, etc.) 
 Demographic data 
 Medical and surgical history/current medical conditions 
 Prior/concomitant medications 
 External Ocular Examination 
 AE monitoring 
 Ocular examination in both eyes: 
1. Assessment of ocular tolerability (Visual analogue scale, VAS: 
dryness, foreign body sensation, burning/stinging, itching, pain, 
stick feeling, blurred vision and photophobia) 
2. Assessment by SANDE questionnaire 
3. Assessment of best corrected distance visual acuity 
4. Slit lamp examination (SLE) to assess the Eyelid - Meibomian 
glands, Eyelid Erythema, Eyelid – Oedema, Lashes, Conjunctiva 
Erythema, Lens, Iris, Anterior Chamber, Corneal transparency, 
Corneal neovascularization 
5. Assessment of central corneal sensitivity by Cochet-Bonnet 
aesthesiometry 
6. Tear collection for Lubricin dosing (both eyes) using tear wash 
technique with 40 μL of sterile saline solution 
At least 10 minutes break 
7. Tear Film Break Up Time (TFBUT) 
8. Corneal fluorescein staining (Oxford score) 
At least 15 minutes break 
9. Schirmer's test (ST) I (without anaesthesia)  
10. Intraocular pressure (IOP) 
 Pregnancy test for female patients. 
 Inclusion/exclusion criteria evaluation 
 Patient eligibility confirmation and randomization number 
assignment 
 At the completion of the pre-dose assessments, the 
investigator will administer the study product (morning 
dose) into the eligible eye(s) 
 
Baseline - 
Visit 1 
Day 1  
15 minutes 
post-dose 
The following procedures will be performed: 
 Assessment of ocular tolerability (Visual analogue scale, VAS: 
dryness, foreign body sensation, burning/stinging, itching, pain, 
stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the right eye 

 
 
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Day 
Procedures/Assessments 
Baseline - Visit 1 
Day 1  
30 minutes 
post-dose 
The following procedures will be performed: 
 Assessment of ocular tolerability (Visual analogue scale, VAS: 
dryness, foreign body sensation, burning/stinging, itching, pain, 
stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the left eye 
 The Investigator will deliver to the patients the investigational 
medical device for the treatment period (15±2 days) 
At home 
From Day 1 
to Week 2± 2 
Days Visit 
 Self-administration at home of the Investigational medical device 
TID approximately every 6h into the eligible eye(s) 
 
Visit 2 
Week 2 ± 
2 Days 
(prior the 
morning 
dose) 
The following procedures will be performed before receiving the first 
eye drop treatment of the day: 
 
 
Review of current medical conditions (ocular and systemic: 
including External Ocular Examination) 
 
AE and concomitant medications  
 
Ocular examination in both eyes, consisting of the assessments 
detailed for the baseline visit (points 1-10), in the same order and 
with the same intervals 
 
Urine Pregnancy test (only female) 
 
At the completion of the pre-dose assessments, the investigator 
will administer the study product (morning dose) into the eligible 
eye(s) 
 
Visit 2 
Week 2 ± 
2 Days  
15 minutes 
post-dose 
The following procedures will be performed: 
 Assessment of ocular tolerability (Visual analogue scale, VAS: 
dryness, foreign body sensation, burning/stinging, itching, pain, 
stick feeling, blurred vision and photophobia) 
 Tear collection for Lubricin dosing in the right eye 
Visit 2 
Week 2 ± 
2 Days  
30 minutes 
post-dose 
The following procedures will be performed: 
 Assessment of ocular tolerability (Visual analogue scale, VAS: 
dryness, foreign body sensation, burning/stinging, itching, pain, 
stick feeling, blurred vision and photophobia) 
Tear collection for Lubricin dosing in the left eye 

 
 
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Day 
Procedures/Assessments 
Visit 3/ETV  
Final Follow-Up Visit 
Days 22±2 
The final visit is defined as the visit performed 7±2 days after last 
administration (day 21 ± 2). In case of study discontinuation subjects 
will undergo an early termination visit. 
 
The following procedures will be performed: 
 Review of current medical conditions (ocular and systemic: 
including External Ocular Examination) 
 AE and concomitant medications  
 Ocular examination in both eyes, consisting of the 
assessments detailed for the baseline visit (points 1-10), in 
the same order and with the same intervals 
 Patient discharge 
 

 
 
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6.1.4. Methods and Equipments for Endpoints Recordings 
6.1.4.1. Ocular evaluations 
Ocular evaluations will be performed on both eyes. The assessments must always be performed 
according the sequence (1 – 10) detailed in § 6.1.3 The assessment will be performed at visit 1 
(day 1), 2 (day 15±2), 3 (day 22±2))/early termination visit. 
The ophthalmological assessment will include: 
 
1. Visual analogue scale (VAS): Local ocular tolerability score: A global ocular discomfort 
score will be determined using a 100 mm VAS  
2. Symptom Assessment in Dry Eye (SANDE): Subjects with SANDE overall score ≥ 30 mm 
are eligible for enrolment\randomization. The SANDE questionnaire is a short questionnaire 
to evaluate both dry eye intensity and frequency by using a 100 mm VAS.  
3. Best corrected distance visual acuity (BCDVA): Subjects with best corrected distance visual 
acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes are eligible for 
enrolment\randomization. Refraction and visual acuity measurements will be performed for all 
subjects by trained vision examiners only.  
 
Equipment: Refraction equipment required includes:  
 Retroilluminated Light box and ETDRS 4 meter distance acuity chart set  
 Trial lens frames 
 Trial lens set with plus or minus cylinder lenses  
 Jackson cross-cylinders of 0.25, 0.50, and 1.00 diopters  
 Pinhole occluder 
 Tissues or eye pads and tape  
 A 1 meter rigid measuring stick 
4. Slit lamp examination (SLE): The slit lamp examination must be performed before the 
instillation of any dilating or anesthetic eye drops or the fluorescein agent.  
The subject will be seated at the slit lamp while being examined. Grading of the eyelids, l 
lashes, conjunctiva, cornea, lens, iris and anterior chamber will be done.  
5. Central corneal sensitivity by Cochet-Bonnet aesthesiometry: The Cochet-Bonnet 
aestheiometer contains a thin, retractable, nylon monofilament that extends up to 6 cm in 
length. Variable pressure can be applied to the cornea by adjusting the monofilament length. 
The monofilament length ranges from 6 to 0.5 cm.  As the monofilament length is decreased 
the pressure increases from 11 mm/gm to 200 mm/gm. 
Corneal sensation will be measured in the affected eye(s) in the central area of the cornea 
using a Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye 
drops.  
Start the procedure by testing the corneal sensitivity within the area (center) of the PED or 
corneal ulcer of the affected eye. 
Steps for using the Cochet Bonnet aesthesiometer:  
1. Extend the filament of the aestheiometer to full length of 6 cm.  Slowly advance the 
monofilament towards the eye until the tip perpendicularly touches the corneal surface. 
Continue to exert a slight pressure until obtaining an inflection deviation of the filament of 
about 4% (i.e. the first visible inflection).  If a positive reaction to the touch of cornea is 
illicited proceed to step 3.  If a positive reaction is not achieved proceed to step 2.  (NOTE:  

 
 
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A positive response is any action indicating corneal sensation whether communicated 
verbally or physically). 
2. Retract the filament incrementally in 0.5 cm and repeat this step until the patient gives a 
positive reaction indicating that the contact of the monofilament on the cornea has been 
sensed.  (NOTE: The shorter filament lengths indicate decreased corneal sensation). 
3. Record the length of the filament in cm at which the patient sensed the contact with the 
cornea.   
4. Repeat steps 1-3 in each of the 4 corneal quadrants (superior nasal, inferior nasal, superior 
temporal and inferior temporal) outside the area of the PED or corneal ulcer in the affected 
eye and in each of the 4 corneal quadrants of the non-affected eye.  
5. To clean the instrument refer to your national standards for devices that contact the eye 
and tears or follow the suggested manufacturer’s recommendations. 
The length of the filament in cm at which the patient corneal sensation was observed for the 
tested area of the cornea will be entered into the eCRF. 
6. Tear collection for Lubricin dosing: tear collection will be performed using tear wash 
technique with 40 μL of sterile saline solution. Dompé farmaceutici s.p.a. will be responsible 
for samples collection and dosing procedure. 
7. Tear Film Break Up Time (TFBUT): TFBUT will be measured by determining the time to 
tear break-up. The TFBUT will be performed after instillation of sodium fluorescein solution 
into the inferior conjunctival cul-de-sac of each eye.  
8. Corneal fluorescein surface staining (Oxford score): The corneal fluorescein staining will be 
graded by using the Oxford scheme to assess cornea and conjunctiva epithelium damage. It will 
be performed after instillation of sodium fluoresce in into the inferior conjunctival cul-de-sac 
of each eye with the aid of a slit lamp at 10X magnification using cobalt blue illumination. 
9. Schirmer's test (ST) I (without anaesthesia): Schirmer strips (Manufacturer: Contactcare 
Ophthalmics &Diagnostics; distributor: Alfa Intes S.r.l., Via Fratelli Bandiera, n.c.c. - 80026 
Casoria (NA), Campania ITALIA) will be used. 
This test will be performed to measure aqueous tear secretion prior to the instillation of any 
dilating or anesthetic eye drops. Both eyes may be tested at the same time.  
This test will be conducted in a dimly lit room.  
10. Intraocular pressure (IOP): IOP may be performed using either Goldmann applanation 
tonometry after the instillation of a topical anesthetic.  
IOP should be measured in both eyes after completion of all other slit lamp examinations to 
avoid potential interference with the other evaluations.  
All examinations and assessments that will be carried out during this study are non-invasive , are 
commonly used in the management of subjects with dry eye and pose no risk to the subjects. 
Subjects might feel a slight discomfort during the execution of the Schirmer test and a local 
allergic reaction or irritation from the use of fluorescein may be observed. 
6.1.5. Subjects Replacement 
Discontinued subjects will not be replaced. Any patient who exits early from the study must 
undergo all procedures outlined in Visit 3. 
6.2.  
ID AND COMPARATORS 

 
 
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6.2.1. Description and Justification of ID/Comparator Exposure 
During the 2 week (15±2 days) double-masked, randomized, controlled treatment period, 
(hereafter, also referred to as the controlled treatment period) enrolled subjects will be randomized 
at baseline in a 1:1:1 ratio to the experimental treatment arm (Lubricin 20 µg/ml or Lubricin 
50µg/ml, one drop TID for two weeks) or the control arm Vismed® 0.18% (sodium hyaluronate 
eye drop solution, one drop TID for two weeks). 
During the follow-up period at the discretion of the treating physician any ocular topical treatment is 
allowed, including other artificial tears/lubricants. 
Investigational Medical Devices will be administered by ocular route according to 1:1:1 
randomization. If the subject forgets to take the study drug, it should be taken as soon as the 
subject remembers. 
The proposed duration of the treatment has been considered as adequate to support local 
tolerability, safety and efficacy of the product in comparison with the selected control. 
6.2.2. Justification of the Choice of Comparator  
HA 0.18% eye drops are one of the most used ocular lubricant for moderate dry eye patients.  
The presentation of the control has been selected to ensure complete masking of the CI. 
6.2.3. Number and Justification of the IDs Used 
The tolerability, safety and efficacy profile of LUBRICIN EYE DROPS will be compared with HA 
0.18% (Vismed® multidose) one of the most used eye drops in relieving eye dry symptoms.  
During the follow-up period at the discretion of the treating physician any ocular topical treatment is 
allowed, including other artificial tears/lubricants. 
Each subjects will receive enough quantity of IDs to complete the study, in case of loss of samples 
by the subject/s, and after an enquiry, Dompé will provide sufficient amount of samples in surplus 
over the minimum required for full treatment. 
6.3. SUBJECTS 
The subject selection criteria will be checked at the Day 1 baseline Visit (Visit 1). 
6.3.1.  Inclusion criteria for Subject Selection 
 
1. Patients 18 years of age or older. 
2. Patients undergone ocular refractive surgery within 6 months from Day 1 Visit. 
3. Patients with ocular discomfort defined as SANDE score ≥ 30 at baseline. 
4. Average VAS score (dryness, foreign body sensation, burning/stinging, itching, pain, stick 
feeling, blurred vision and photophobia) ≥ 25 mm; 
5. Best corrected distance visual acuity (BCDVA) score ≥ 0.1 decimal units in both eyes at 
the time of study enrolment. 
6. 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 IEC for the current study. 

 
 
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6.3.2.  Exclusion criteria for Subject Selection 
1. Patients with a severe Dry Eye condition (severity level 4 according to the Report of the 
International Dry Eye Workshop -DEWS, 2007) 
2. Best corrected distance visual acuity (BCDVA) score of < 0.1 decimal units in either eye 
at the time of study enrolment 
3. Evidence of an active ocular infection in either eye 
4. History or presence of ocular surface disorders other than ocular discomfort in either eye  
5. Use of any ocular topical medication other than the study medications for the treatment of 
ocular diseases including artificial tears during the study period 
6. Use of topical cyclosporine, topical corticosteroids or any other topical medication for the 
treatment of dry eye in either eye within 30 days of study enrolment 
7. History of any ocular surgery (excluding laser or refractive surgical procedures) in either 
eye within 30 days before study enrolment. Ocular surgery will not be allowed during the 
study treatment period and elective ocular surgery procedures should not be planned 
during the duration of the follow-up period 
8. Known hypersensitivity to one of the components of the study or procedural medications 
9. Participation in another clinical study at the same time as the present study or within 90 
days of screening/baseline visit 
10. History of drug, medication or alcohol abuse or addiction. 
11. 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 on the urine pregnancy test at the Screening/Baseline Visit or, 
c. intend to become pregnant during the study treatment period or, 
d. are breast-feeding or, not willing to use highly effective birth control measures, 
such as:  Hormonal contraceptives – oral, implanted, transdermal, or injected 
and/or mechanical barrier methods – spermicide in conjunction with a barrier such 
as a condom or diaphragm or IUD during the entire course of and 30 days after the 
study treatment periods. 
6.3.3.  Criteria and Procedure for Subject Withdrawal or Discontinuation  
A subject should be withdrawn from the trial if, in the opinion of the Investigator, it is medically 
necessary or if it is the wish of the subject. 
The study treatment will be discontinued at any time if any of the following events occur: 
 Adverse event: Any significant adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, please 
refer to § 14. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a patient to follow-up 
 non-compliance with study ID: an indication that a patient has not agreed with or followed 
the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a physician 
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 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in the 
body (uterus), after union of an ovum and spermatozoon, during the period from conception to 
birth  
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by the 
protocol 
 study terminated by Sponsor: an indication that a clinical study was stopped by its Sponsor 
 site terminated by Sponsor: an indication that a clinical site was stopped by the study 
Sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually related 
to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
Any treatment discontinuation must be recorded on the case report form (CRF) by the 
Investigator, who will indicate date and reason(s) for treatment withdrawal. Unless the subject has 
withdrawn consent, the early termination visit assessments should be performed as detailed in 
Section 6.1.3. 
6.3.4.  Point of Enrolment 
Subjects will receive the randomization number before enter in a 2 week double-masked, 
randomized, controlled treatment period, followed by 1 week follow-up. 
6.3.5.Total Expected Duration of the Clinical Investigation  
The study is expected to be completed within 3-4 months. 
The study will be considered completed at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in the CIP. 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 subjects will 
receive doses of the IDs, and subjects already having received a dose of IDs will not receive any 
further doses of the study ID but will undergo all safety assessments scheduled after the last dose 
of ID, up to an including the end of study examination 
6.3.6.  Expected Duration for Each Subject  
Treatment duration 14 days (2 weeks) ± 2 days (maximum total study duration 16 days) and 1 
week (7± 2 days) of follow-up. 
The total maximum duration is expected to be about 25 days. 
6.3.7. Total Number of Randomized Subjects  
30 subjects (10 per arm) will be randomized to 1:1:1 ratio.  
Recruitment will proceed until the planned number of randomized subjects is achieved. 
6.3.8. Total Enrolment Time 
 
The best total enrolment time is estimated to be of 45 days. 

 
 
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6.4. 
PROCEDURES 
 
6.4.1. Clinical Investigation Procedures 
6.4.1.1. Efficacy 
Ocular Evaluations 
Ocular evaluations will be performed on both eyes. The assessments must always be performed 
according the sequence (1 – 10) detailed in § 6.1.3. The assessment will be performed at visit 1 
(day 1), 2 (day 15±2), 3 (day 22±2) /early termination visit.  
The ophthalmological assessment will include: 
 
1. Symptom Assessment in Dry Eye (SANDE): Subjects with SANDE overall score ≥ 30 mm 
are eligible for enrolment. 
The SANDE questionnaire is a short questionnaire to evaluate both dry eye intensity and 
frequency by using a 100 mm VAS. The subject symptoms of ocular dryness and/or irritation 
will be quantified on the scale based on two questions that assess both severity and frequency 
of symptoms. A VAS is a measurement instrument that tries to measure a characteristic or 
attitude that is believed to range across a continuum of values and cannot easily be directly 
measured. For example, the amount of irritation that a subject feels ranges across a continuum 
from none to an extreme amount of irritation. From the subject's perspective this spectrum 
appears continuous (i.e. their irritation does not take discrete jumps, as a categorization of 
none, mild, moderate and severe would suggest). It was to capture this idea of an underlying 
continuum that the VAS was devised.  
For the assessment, the subjects mark on the 100 mm VAS line the point that they feel 
represents their perception of their current state. The VAS score is determined by measuring 
in millimetres from the left hand end of the line to the point that the subject marks. The 
SANDE scores will be then evaluated for the 2 questions severity (0-100) and frequency (0-
100).  
2. Best corrected distance visual acuity (BCDVA): Subjects with best corrected distance visual 
acuity (BCDVA) score of ≥ 0.1 decimal units in both eyes are eligible for enrolment.  
Refraction and visual acuity measurements will be performed for all subjects by trained 
vision examiners only. The name of the vision examiner should be documented in the 
subject’s visual acuity (VA) worksheet (provided by the Sponsor) at each visit. Refraction 
should be conducted prior to visual acuity testing to obtain best-corrected vision as described 
below. Best-corrected visual acuity is measured at all trial visits using standard charts, 
lighting, and procedures. Best correction is determined by careful refraction at that visit 
according to the standard protocol for refraction as described below  
Equipment: Refraction equipment required includes:  
 
Retroilluminated Light box and ETDRS 4 meter distance acuity chart set  
 
Trial lens frames 
 
Trial lens set with plus or minus cylinder lenses  
 
Jackson cross-cylinders of 0.25, 0.50, and 1.00 diopters  
 
Pinhole occluder 
 
Tissues or eye pads and tape  
 
A 1 meter rigid measuring stick 

 
 
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Visual acuity charts: Chart 1 is used for testing the visual acuity of the RIGHT eye; Chart 2 
for testing the LEFT eye; and Chart R (or 3) for refraction only. Subjects should not be 
allowed to see any of the charts before the examination. 
A distance of 4 meters is required between the subject’s eyes and the visual acuity chart. With 
the box light off, not more than 15 foot-candles of light (161.4 Lux) should fall on the centre 
of the chart. To measure the amount of light, the room is set up for visual acuity testing, but 
with the box light off. The light meter is placed at the fourth line from the top of the chart, 
with its back against the chart and the reading is taken. If more than one line available for 
testing visual acuity, the visual acuity of an individual subject should be measured in the 
same line at each visit, if possible. If different lines are used to test visual acuity, they must 
each meet the same standards.  
Retroilluminated ETDRS charts are used in this trial. The illuminator box will be either wall-
mounted or mounted on a stand. The light box should be mounted at a height such that the top 
of the third row letter is 49 + 2 inches from the floor.  
The visual acuity light box is equipped with two General Electric 20-watt fluorescent tubes 
and ballast. Each tube is partly covered by a 14-inch fenestrated sleeve, which is centered on 
the tube and open in the back. This serves as a “baffle” to produce even illumination over the 
testing chart. Because the illumination of fluorescent tubes diminishes by 5 percent during the 
first 100 hours and by another 5 percent during the next 2000 hours, new tubes should be kept 
on for 4 days (96 hours) continuously, and should be replaced once a year 
A sticker should be placed on the back of the light box, indicating the date when the present 
tubes were installed. A spare set of burned in bulbs should be available on site.  
Detailed instructions for VA assessment As a reminder, Charts 1, 2 and R (or 3) are used for 
testing the right eye, left eye, and refraction, respectively. Subjects should not see the charts 
until the test begins. The lens correction from the subjective refraction should be in the trial 
frame worn by the subject.  
All eyes must be tested at 4 meters first, even if the refraction was performed at 1 metre  
The subject should be seated comfortably directly in front of the chart so that the eyes remain 
at the 4 meter distance. Testing always begins with the right eye. The fellow eye should be 
occluded with a folded tissue or eye pad lightly taped over the eye behind the trial frame 
serves as an effective occluder that allows eccentric fixation without inadvertent use of the 
covered eye. After testing the right eye, occlusion of the right eye should be done BEFORE 
Chart 2 is put up for testing the left eye.  
The subject is asked to read the letters slowly, approximately one letter per second. The 
subject should be told that only one chance is given to read each letter, but may change their 
mind before moving to the next letter. If the subject is unsure about the identity of the letter, 
then the subject should be encouraged to guess.  
The subject should begin by reading the top line of the chart and continue reading every letter 
on each smaller line, from left to right on each line. The subject should be encouraged to 
continue reading even if making mistakes. Each letter read is counted. The examiner circles 
every correct letter read and totals each line and the whole column (0 if no letters are correct) 
on the provided VA worksheet. An X is put through letters read incorrectly. Letters, for 
which no guess was attempted, are not marked. When a subject reaches a level where he/she 
cannot guess, the examiner may stop the test, provided that the subject has made errors on 
previous guesses, which is a clear indication that the best visual acuity has been obtained.  
When a subject cannot read at least 20 letters on the chart at 4 meters, the subject is tested at 1 
meter. The distance from the subject to the chart should be measured again using the rigid one 
meter stick. The distance is measured from the outer canthus to the center of the fourth letter 
(right eye) or the second letter (left eye) of the third line of the chart. The spherical correction 

 
 
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in the trial frame should be changed by adding +0.75 to correct for the closer test distance. 
The subject may fixate eccentrically or turn or shake his/her head to improve visual acuity. 
Particular care should be taken to make sure the subject does not move forward when testing 
at 1 metre. The subject should be reminded to blink. 
The examiner should not tell the subject if a letter was identified correctly. The patient may 
be encouraged by neutral comments, such as “good”, “next”, and “OK”.  
The examiner should not stand close to the chart during testing. Attention should be focused 
on the patient and the VA worksheet. If the patient has difficulty locating the next line to 
read, the examiner may go up to the chart and point briefly to the next line to be read, but 
then must move away from the chart.  
When 20 or more letters are read at 4 meters the visual acuity score for that eye is recorded as 
the number of letters correct at 4 meters plus 30 (refer to the VA worksheet). The patient gets 
credit for the 30 letters at 1 meter even though they did not have to read them. Otherwise, the 
visual acuity score is the number of letters read correctly at 1 meter plus the number, if any, 
read at 4 meters. If no letters are read correctly at either 4.0 meters or 1 meter, then the visual 
acuity score is recorded as “0”. 
3. Slit lamp examination (SLE): The slit lamp examination must be performed before the 
instillation of any dilating or anesthetic eye drops or the fluorescein agent. 
The subject will be seated at the slit lamp while being examined. Grading of the eyelids, 
lashes, conjunctiva, cornea, lens, iris and anterior chamber will be done according to the 
following scales:  
Eyelid - Meibomian glands (evaluation of the central ten Meibomian gland openings in the 
mid-portion of the upper eyelid):  
0 = None (none are plugged).  
1 = Mild (1 to 2 glands are plugged).  
2 = Moderate (3 to 4 glands are plugged).  
3 = Severe (All glands are plugged).  
Eyelid - Erythema  
0 = None (normal).  
1 = Mild (redness localized to a small region of the lid(s) margin OR skin).  
2 = Moderate (redness of most or all lid margin OR skin).  
3 = Severe (redness of most or all lid margin AND skin).  
4 = Very severe (marked diffuse redness of both lid margin AND skin).  
Eyelid - Oedema  
0 = None (normal).  
1 = Mild (localized to a small region of the lid).  
2 = Moderate (diffuse, most or all lid but not prominent/protruding).  
3 = Severe (diffuse, most or all lid AND prominent/protruding).  
4 = Very severe (diffuse AND prominent/protruding AND reversion of the lid).  
Lashes  
0 = Normal  
1 = Abnormal (specify)  
Conjunctiva – Erythema  
0 = None (normal).  
1 = Mild (a flush reddish color predominantly confined to the palpebral or bulbar 
conjunctiva).  
2 = Moderate (more prominent red color of the palpebral or bulbar conjunctiva).  
3 = Severe (definite redness of palpebral or bulbar conjunctiva).  

 
 
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Conjunctiva - Oedema  
0 = None (normal).  
1 = Mild (slight localized swelling).  
2 = Moderate (moderate/medium localized swelling or mild diffuse swelling).  
3 = Severe (severe diffuse swelling).  
4 = Very severe (very prominent/protruding diffuse swelling). 
Lens  
0 = No opacification (normal lens).  
1 = Mild lens opacification.  
2 = Moderate lens opacification.  
3 = Severe lens opacification. 
N/A = Subject with artificial lens 
Iris  
0 = Normal  
1 = Abnormal. 
Anterior Chamber Inflammation (Slit beam = 0.3 mm wide, 1.0 mm long)  
0 = None (no Tyndall effect).  
1 = Mild (Tyndall effect barely discernible).  
2 = Moderate (Tyndall beam in the anterior chamber is moderately intense).  
3 = Severe (Tyndall beam in the anterior chamber is severely intense).  
Cornea transparency 
0= completely transparent  
1= mild opacity 
2= moderate opacity (iris details clearly visible) 
3=severe opacity (iris details not clearly visible) 
4=complete cornea opacity (anterior chamber structures not visible) 
Cornea neovascularization 
0= absence of neovascularization 
1= neovascularization in less than 90° 
2= neovascularization between 90° and 180°  
3= neovascularization between 180° and 270°  
4= neovascularization between 270° and 360° 
 
Relevant findings of the SLE will be entered in the CRF.  
4. Central corneal sensitivity by Cochet-Bonnet aesthesiometry: The Cochet-Bonnet 
aestheiometer contains a thin, retractable, nylon monofilament that extends up to 6 cm in 
length. Variable pressure can be applied to the cornea by adjusting the monofilament length. 
The monofilament length ranges from 6 to 0.5 cm.  As the monofilament length is decreased 
the pressure increases from 11 mm/gm to 200 mm/gm. 
Corneal sensation will be measured in the affected eye(s) in the central area of the cornea 
using a Cochet Bonnet aesthesiometer before the instillation of any dilating or anesthetic eye 
drops.  
Start the procedure by testing the corneal sensitivity within the area (center) of the PED or 
corneal ulcer of the affected eye. 
Steps for using the Cochet Bonnet aesthesiometer:  
a) Extend the filament of the aestheiometer to full length of 6 cm.  Slowly advance the 
monofilament towards the eye until the tip perpendicularly touches the corneal surface. 
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about 4% (i.e. the first visible inflection).  If a positive reaction to the touch of cornea is 
illicited proceed to step 3.  If a positive reaction is not achieved proceed to step 2.  (NOTE:  
A positive response is any action indicating corneal sensation whether communicated 
verbally or physically). 
b) Retract the filament incrementally in 0.5 cm and repeat this step until the patient gives a 
positive reaction indicating that the contact of the monofilament on the cornea has been 
sensed.  (NOTE: The shorter filament lengths indicate decreased corneal sensation). 
c) Record the length of the filament in cm at which the patient sensed the contact with the 
cornea.   
d) Repeat steps 1-3 in each of the 4 corneal quadrants (superior nasal, inferior nasal, superior 
temporal and inferior temporal) outside the area of the PED or corneal ulcer in the affected 
eye and in each of the 4 corneal quadrants of the non-affected eye.  
e) To clean the instrument refer to your national standards for devices that contact the eye 
and tears or follow the suggested manufacturer’s recommendations. 
The length of the filament in cm at which the patient corneal sensation was observed for the 
tested area of the cornea will be entered into the eCRF. 
5. Tear collection for Lubricin dosing: tear collection will be performed using tear wash 
technique with 40 μL of sterile saline solution. Dompé farmaceutici s.p.a. will be responsible 
for samples collection and dosing procedure. Samples will be shipped after LPLV 
6. Tear Film Break Up Time (TFBUT):  
TFBUT will be measured by determining the time to tear break-up. The TFBUT will be 
performed after instillation of fluorescein solution into the inferior conjunctival cul-de-sac of 
each eye. The subject will be instructed to blink several times to thoroughly mix the 
fluorescein with the tear film. In order to achieve maximum fluorescence, the examiner 
should wait approximately 30 seconds after instillation before evaluating TFBUT. With the 
aid of a slit lamp at 10X magnification using cobalt blue illumination, the examiner will 
monitor the integrity of the tear film, noting the time it takes to form lacunae (clear spaces in 
the tear film) from the time that the eye is opened after the last blink. This measurement will 
be performed within 10 seconds maximum. The TFBUT will be measured twice during the 
first minute after the instillation of the fluorescein. If the 2 readings differ by more than 2 
seconds a third reading is taken.  
The TFBUT value will be the average of the 2 or 3 measurements. 
Relevant TFBUT findings will be entered in the CRF. 
 
7. Schirmer's test (ST) I (without anaesthesia):  
This test will be performed to measure aqueous tear secretion prior to the instillation of any 
dilating or anesthetic eye drops. Both eyes may be tested at the same time.  
This test will be conducted in a dimly lit room. While the subject looks upwards, the lower lid 
will be drawn gently downwards and temporally. The rounded bent end of a sterile strip will 
be inserted into the lower conjunctival sac over the temporal one-third of the lower eyelid 
margin. The test should be done without touching directly the Schirmer test strip with the 
fingers to avoid contamination of skin oils. The subjects will be instructed to close their eyes 
gently. 
After 5 minutes have elapsed, the Schirmer’s test strip will be removed and the length of the 
tear absorption on the strip will be measured (millimeters/5 minutes).  

 
 
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The wetting distance at 5 minutes for each eye will be recorded in the CRF.  
8. Corneal fluorescein surface staining (Oxford score):  
The corneal fluorescein staining will be graded by using the Oxford scheme to assess cornea 
and conjunctiva epithelium damage. It will be performed after instillation of sodium fluoresce 
in into the inferior conjunctival cul-de-sac of each eye with the aid of a slit lamp at 10X 
magnification using cobalt blue illumination. 
Staining is represented by punctate dots on a series of panels (A-E). Staining ranges from 0-5 
for each panel and 0-15 for the total exposed inter-palpebral conjunctiva and cornea. The dots 
are ordered on a log scale as follow: 
Corneal fluorescein staining will be assessed after the Tear Film Break Up Time (TFBUT) 
examination and will also be graded according to the oxford scheme. 
 
9. 
Intraocular pressure (IOP): IOP may be performed using either Goldmann applanation 
tonometry after the instillation of a topical anesthetic.  
IOP should be measured in both eyes after completion of all other slit lamp examinations 
to avoid potential interference with the other evaluations. The subject and slit lamp should 
be adjusted so that the subject’s head is firmly positioned on the chin rest and against the 
forehead rest without leaning forward or straining.  
Both eyes will be tested, with the right eye preceding the left eye. The same equipment 
must be used throughout the course of the study.  
IOP for each eye in mmHg will be recorded in the CRF.  
6.4.1.2.  Tolerability and Safety 
Adverse Events 
At each visit, after the subject 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?”  

 
 
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AEs should be reported for any clinically relevant change in concomitant medication(s) that is the 
result of an untoward (unfavorable and unintended) change in subject'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 subject’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. 
 
Visual analogue scale (VAS): Local ocular tolerability score: A global ocular discomfort score 
will be determined using a 100 mm VAS on which 0 means no symptoms and 100 means the 
worst possible discomfort. This evaluation is to be performed before any ophthalmic assessment 
at a given study visit. Specific ocular symptoms to be assessed with the VAS include: 
 dryness 
 foreign body sensation, 
 burning/stinging, 
 itching,  
 pain,  
 sticky feeling  
 blurred vision  
 photophobia  
VAS parameters that will be used for the evaluation of tolerability and safety are: . 
The subjects will be instructed to place a vertical mark on the horizontal line indicating his/her 
level of discomfort for that symptom in the eyes. The VAS is expected to take the subject about 5 
minutes to complete. A VAS is a measurement instrument that tries to measure a characteristic or 
attitude that is believed to range across a continuum of values and cannot easily be directly 
measured. 
 
6.4.1.3. General procedure 
Women of childbearing potential are not excluded from the study as long as adequate birth control 
methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are summarized in 
the protocol’s exclusion criteria. 
Prior to enrolment in the clinical trial, female subjects of childbearing potential and their partners 
must be advised of the importance of avoiding pregnancy during the entire course of the study 
treatment and for the 30 days after the study treatment period ends and of the potential risks 
associated with an unintentional pregnancy. During the trial, female subjects are to be instructed 
to contact the Investigator immediately if they suspect they might be pregnant; in the same way, 
male subjects who become aware that the partner might be pregnant, are to be instructed to 
contact the Investigator immediately.  The study Sponsor must be contacted immediately and a 
decision will be made regarding continuation of the pregnant woman in the study based upon the 
circumstances surrounding the pregnancy. Pregnancy is not reportable as an adverse event; 
however, complications may be reportable and will be decided on a case by case basis. A form 

 
 
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prepared by the Sponsor will be utilized to capture all pregnancy-related information until the 
birth of the child for both the subject and the partner during the study treatment period (2 weeks) 
and follow-up period (total 3 weeks). 
Data collection – CRFs 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRFs. He must also check that the data reported in the CRFs correspond to those 
in the subjects’ source documents.  
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-point 
pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be carried out 
by the investigator or a designated member of staff. Incorrect entries must not be covered with 
correcting fluid, or obliterated, or made illegible in any way. A single stroke must be drawn 
through the original entry. Corrections have to be dated and initialed. In the interest of 
completeness of data acquisition, the questions which are repeated in each section of the CRFs 
should be answered in full, even if there are no changes from a previous examination. 
The investigator must provide a reasonable explanation for all missing data. 
The CRFs will be completed, signed by the investigator, sent to the CRO Biometry Unit for data 
management procedures and finally sent to the Sponsor.  
Unique subject identifier 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains of 
the CDISC SDTM model. The unique subject identifier for study site consists of the Sponsor 
study code (i.e. LUB0116MD), the 3-digit screening number (e.g S01, S02, etc.) and, if 
applicable, the 2-digit subject study number (e.g. 01, 02, etc.). 
Study code, screening number and subject study number are separated by slashes (e.g. 
“LUB0116MD/S01/01”). The last 5 digits of the unique subject identifier (randomized subjects), 
corresponding to the subject screening and subject study numbers separated by a slash, or the last 
3 digits of the unique subject identifier (not randomized subjects), corresponding to the subject 
screening number, will appear as subject identifier in the individual listings and figures of the 
clinical study report and will be used to identify the subjects in in-text tables or wording (if 
applicable). 
Coding dictionaries 
Medical/surgical history and underlying diseases, physical examination abnormalities and AEs 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA™). 
Prior and concomitant medications will be coded using the WHO Drug Dictionary Enhanced 
(WHODDE). Version of coding dictionaries will be stated in the study report. 
Concomitant Treatments 
All concomitant therapies taken during the study from screening visit to the follow-up visit must 
be recorded in the specific section of the CRF. 
Allowed/Disallowed treatments  
Use of topical cyclosporine, topical corticosteroids or any other topical medication for the 
treatment of dry eye in either eye is not allowed during the treatment period. 
During the study follow-up period (from day 15±2 to day 22±2), any ocular topical treatments 
allowed, including other artificial tears/lubricants as prescribed by the treating physician. 

 
 
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Hormonal contraceptives for females will be allowed.  
6.4.2. CRO Activities 
CRO shall prepare all the documents on the need for the CI which shall be approved by 
Sponsor/Investigator. CRO shall following and monitoring the entire conduction of the CI up to 
its conclusion. CRO shall prepare all the documents to implement the Technical File of ID (e.g. 
Clinical Investigational Report).  
6.4.2.1. Database management 
Data management of all data captured within the CRF will be performed by the CRO with the 
Clinical Data Management System (CDMS) according to a double data entry with total re-entry of 
data and discrepancy resolution by a third individual. CRO will update and verify the database 
and create the final SAS data sets. The tabulation datasets and analysis datasets created according 
to the standard CDISC (STDM and ADaM) will be provided to the Sponsor with all the other 
study documentation.  
6.4.3. Foreseeable Bias  
In order to minimize the bias the clinical study is design as randomized (1:1:1), controlled, 
double-masked. Subjects will enter in a 2 week double-masked, randomized, controlled treatment 
period. The double-masked technique is used to assure the double blind of the study. 
6.4.4. Material supplied to the clinical centre 
Besides the ID products, the following study material will be supplied to the clinical centre: 
 CIP 
 CRF for each subject plus some spare copies 
 VAS forms and SANDE Questionnaires for each subjects 
 copy of the investigator’s brochure (IB) relative to the ID 
 informed consent forms 
 Urine Pregnancy Test 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
main documents: ICH guidelines, confidentiality agreement (if applicable), CIP amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if applicable), 
confidential subject identification code list form, drug accountability forms, investigator and study 
staff list form other documents will be provided by CRO. 
6.5. 
Monitoring, Data and Quality Management  
6.5.1. Monitoring 
Quality assurance is under Dompé farmaceutici s.p.a.’s responsibility. 
Monitoring activities and responsibilities will be described in detail in a monitoring plan  
Monitoring of the present clinical trial is assigned to CRO that has the responsibility to adequately 
qualify the monitoring staff and assures that the conduct of the Clinical investigation complies 
with the approved CIP, subsequent amendment(s), ISO 14155-2012 and the GCP. 
According to the ISO 14155-2012 and the GCP, a number of measures and procedures aimed to 
guarantee data quality and reliability are to be applied and followed in carrying out this clinical 
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6.5.1.1. Clinical monitoring and identification of source data 
The study will be monitored by regular monitoring visits in compliance with ISO 14155-2012, 
GCP and CRO Standard Operating Procedures (SOPs) to verify data entered and collected on the 
CRF(s). Monitoring will be performed by the CRO. 
The Investigator should agree to receive periodic monitoring visits, based on subjects’ enrolment 
rate or for other reasons, such as to verify SAEs. 
At each visit, the Investigator or a designated member of the study personnel should be available 
to provide direct access to all study-related documentation, including the original subject notes, 
and to make any necessary corrections to the CRF and/or other study documents. Source 
documents should be available to support the data recorded in the CRF, apart from those data for 
which the CRF might be accepted as being the sole source document and that will be identified 
prior to study commencement (physical examination, vital signs biometric measures, pregnancy 
test, external ocular examination, slit lamp examination, TFBUT, corneal fluorescein surface 
staining, Schirmer’s tests I, intraocular pressure). The confidentiality of the subjects’ identities 
shall be well protected consistent with local and national regulations when the source documents 
are subject to direct access. 
The monitor will provide the Investigator with all the study materials before the study starts and, 
during the course of the study, will check at least the following: 
 Full compliance with ISO 14155-2012, ICH-GCP, the study protocol and applicable 
regulatory requirements. 
 Subject recruitment. 
 Subject compliance. 
 Drug accountability. 
 Completeness and accuracy of the CRF data and their consistency with the source 
documents (appropriate source data verification will be conducted on all CRFs). 
 Verification of the facilities. 
 Investigator's Trial Master File. 
The monitor will ensure completeness of CRFs on an ongoing basis. 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a CI necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial. 
6.5.2. Audit 
The Investigator/Institution must allow Dompé farmaceutici s.p.a. and/or independent bodies 
acting on behalf of the Sponsor and CRO to have the right to perform the audits as an integral part 
of the quality assurance system.. The audit is an independent verification, separate from the 
monitoring activity, of the activities and of the documents to ensure that the activities pertinent to 

 
 
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the study were duly carried out and that they were recorded, analyzed and transferred in 
compliance with the protocol, ISO 14155, GCP, relevant SOPs and with applicable legislation. 
6.5.3. Inspections 
The Investigator/Institution must allow national and foreign Regulatory Authorities to conduct 
inspections.  
The Inspection on the part of one or more Regulatory Authorities consists of an official review of 
the documents, facilities, records and any other resource considered by the authorities to be 
connected with the study. 
7.  
STATISTICS  
7.1 
Design, Methods and Analytical Procedures 
7.1.1 Statistical Methods  
The data documented in this study will be listed by subject, treatment, eye (enrolled eye(s), left 
and right) and evaluation time point, i.e Baseline or Day 1 (Visit 1), Day 15 ±2 (Visit 2) and 
follow-up (Visit 3). 
Appropriate descriptive statistics will be used according to the nature of the variable. 
Not available data will be evaluated as “missing values”. The statistical analysis will be performed 
using SAS® version 9.3 (TS1M1) for Windows® (19) or higher.  
7.1.2   Definitions 
A subject will be defined as screened after the signature of the informed consent, regardless of the 
completion of all the screening procedures. 
A subject will be defined as randomized in the study if he/she is assigned to a treatment arm (Test 
1 (20 µg/mL), Test 2 (50 µg/mL) or Control). 
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, baseline 
and background characteristics 
 Full Analysis Set (FAS): all randomized subjects, who receive at least one dose of the ID. 
This analysis set will be used for the efficacy analysis 
 Safety set: all subjects who receive at least one dose of the investigational medicinal 
product(s). This analysis set will be used for tolerability and safety analyses 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Enrolled set, 
FAS and Safety set. Subjects will be evaluated according to the treatment dose they will actually 
receive. 

 
 
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7.1.3  Demographic, Baseline and Background Characteristics 
Standard continuous or categorical variable summaries will be used for demographic and 
population characteristics.Data will be presented for Baseline visit. 
7.1.4 Tolerability and Safety Evaluation 
AEs 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of the ID and not worsening after the first 
dose of the IMD 
 TEAEs: all AEs occurring or worsening after the first dose of the ID 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarized by dose and overall. The number and percentage 
of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and PT, 
seriousness, relationship to treatment and severity.  
A summary of adverse events leading to premature withdrawal will be provided, grouped by body 
system and preferred term. 
Visual analogue scale (VAS) 
Local ocular tolerability score will be performed before any ophthalmic assessment at a given 
study visit. Specific ocular symptoms to be assessed with the VAS include: dryness, foreign body 
sensation; burning/stinging; itching; pain; sticky feeling; blurred vision; photophobia. Time 
profile of treatments will be analized according to analysis of variance for repeated measure 
model.  
7.1.5 Analysis of Ophthalmological Evaluations  
Variables will be presented using descriptive statistics according to the nature of the variable, i.e. 
arithmetic mean, SD, CV (%), minimum, median and maximum values for quantitative variables, 
proportions and frequencies for qualitative variables. 
Considering the design of the study, data will be presented at Baseline, Day 15 and Follow-up 
periods separately. Changes from baseline and Day 15 will also be presented. 
Inferential tests on changes from baseline will be used to estimate potential differences between 
treatments within Day 15 visits separately. 
For the following variables Student t test will be considered: 
Corneal fluorescein surface staining (Oxford score) 
Schirmer's test (ST) I (without anaesthesia) 
Tear Film Break Up Time (TFBUT) 
Best corrected distance visual acuity (BCDVA) 
Assessment of central corneal sensitivity by Cochet-Bonnet aesthesiometry 
Symptom Assessment in Dry Eye (SANDE) 

 
 
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Intraocular pressure (IOP) 
For Slit lamp examination (SLE), grading of the eyelids, lashes, conjunctiva, cornea, lens, iris and 
anterior chamber will be processed separetely using Wilcoxon Rank Sum Test. 
  
7.2  
Sample Size 
As the primary objective of this study is to evaluate the tolerability and safety of Lubricin (20 and 
50 μg/mL) eye drops solution administered over 2 weeks in patients with ocular discomfort 
following ocular refractive surgery, sample size was calculated based on clinical feasibility and no 
formal sample size calculation has been performed. 
7.3 
Expected Drop-out Rate 
An anticipated 10% drop-out of the randomized subjects will be expected 
7.4 
Interim Analysis  
No formal interim analyses will be planned  
7.5 
Statistical criteria for CI Termination  
Since no formal interim analysis is planned, statistical criteria for CI termination is not defined.  
7.6 
Statistical Plan Deviations 
Full details and chages of statistical analyses will be reported and justified in the CIR 
7.7 
Subgroups  
No subgroups are expected in this CI 
7.8 
Missing, Drop-out and All Data Analysis  
Not available data will be evaluated as “missing values”. All data obtained will be used in the 
analysis and no imputation will be carried out for missing data to come from data not recorded in 
the CRF, from withdrawal of subjects from the study or from exclusion of subjects evaluated 
during the blind review meeting. 
7.9 
Exclusion of Particular Information 
7.9.1.  Reasons for Exclusion from the Full Analysis Set 
Reasons for the exclusion from the Full Analysis Set are the following: 
 
failure to take at least one dose of the IDs  
 
lack of any efficacy data post enrolment 
 
failure to satisfy inclusion/exclusion criteria (eligibility violations). Subjects who fail to 
satisfy an inclusion/exclusion criterion may be excluded from the analysis without the 
possibility of introducing bias only under the following circumstances: 
 
the inclusion/exclusion criterion was measured prior to enrolment 
 
the detection of the relevant eligibility violations can be made completely objectively 
 
all detected violations of the particular inclusion/exclusion criterion are excluded 

 
 
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8 
DATA MANAGEMENT 
8.1 
Data Review, Cleaning and Data Queries 
Data management of all data captured within the CRF will be performed by the CRO with the 
Clinical Data Management System (CDMS) according to a double data entry with total re-entry of 
data and discrepancy resolution by a third individual. CRO will update and verify the database 
and create the final SAS data sets. The tabulation datasets and analysis datasets created according 
to the standard CDISC (STDM and ADaM) will be provided to the Sponsor with all the other 
study documentation.  
Missing data will not be entered in any format in the database. Queries will be issued and resolved 
directly between CRO staff personnel and the Investigators through the Monitors.  
8.2 
Electronic Data System 
The statistical analysis will be performed using the qualified software SAS® version 9.3 
(TS1M1)for Windows® (19) or higher.  
 
8.3 
Data Retention  
Essential documents should be retained by Investigator’s, until at least 15 years after study 
conclusion. Investigator’s should maintain Site File (including signed Informed Consent forms 
and copy of Subject Information Sheet for all subjects), subject files, other source data (laboratory 
records, ECGs etc.) and CRF copies for the period of time for as long as possible but not less than 
15 years.  
Investigator must be also requested to inform Sponsor/CRO whenever he/she should leave the 
investigational study site after the termination of the study; this in order to allow undertaking 
measures for the maintenance of the essential documents relevant to the trial. 
No documents related to the study will be destroyed without the prior written consent of Sponsor 
and the investigator/s. 
The originals of all documents and copies of all documentation and correspondence related to the 
study will be added to the Clinical Investigation Master File (CIMF) and will be kept by CRO in a 
safe place in their offices until the end of the study and thereafter by the Sponsor throughout the 
product life. The CIR will be kept by the Sponsor, or any buyers, for at least 5 years after the 
recall of the product.  
8.4 
Data Retention Timing 
No documents related to the study will be destroyed without the prior written consent of Sponsor 
and the investigator/s.  
The investigator and the Sponsor should maintain the study documents as specified in the ISO 
14155-2012 and as required by the applicable regulatory requirement(s).  
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects 
including ophthalmic assessments, insurance contracts, certificate of analysis of the ID(s), ID(s) 
accountability records, signed informed consent forms, confidential subjects identification code, 
CRFs, curricula vitae of the investigator and other participants in the study, study staff lists and 
responsibilities, monitoring reports and final study report. 

 
 
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The investigator and the Sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
Study documents must be retained by the investigator and the Sponsor as long as needed to 
comply with ISO & ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the Sponsor agree to adhere to these requirements. 
 
8.4.1 Archiving 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
The investigator must keep source documents for each subject in the study. All information on the 
CRFs must be traceable to these source documents.   
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
The investigator and the sponsor should maintain the CI documents as specified in the “Essential 
Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP, in the ISO 14155 – Annex  
E and as required by the applicable regulatory requirement(s).  
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the CI and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects, 
insurance contracts, drug accountability records, signed informed consent forms, confidential 
subjects identification code, CRFs, curricula vitae of the investigator and other participants in the 
CI, study staff lists and responsibilities, monitoring reports and final study report. 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP and ISO, national and international regulations. By signing the protocol, 
the investigator and the sponsor agree to adhere to these requirements. 
8.5 
Quality Assurance 
Audit will be made by QAU of Dompé farmaceutici s.p.a. and/or by a delegated third party 
according to GCP and ISO 14155 and Dompé SOPs. 
8.5.1. Confidentiality and data protection 
By signing this protocol, the Investigator(s) agree to keep all the information provided by the 
Sponsor in strict confidentiality and to request similar confidentiality from his/her staff. Study 
documents provided by the Sponsor (protocols, Investigators' brochures, CRFs and other 
materials) will be stored appropriately to ensure their confidentiality. The information provided by 
the Sponsor to the Investigator and to the CRO cannot be disclosed to others without direct 
written authorization from the Sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
Data on subjects collected on the CRFs during the study will be documented in an anonymous 
way. If, as an exception, it becomes necessary to identify a subject for safety or regulatory 
reasons, the monitor, the Sponsor and the investigator will be bound to keep this information 
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9 
AMENDMENTS TO THE CIP 
In order to obtain interpretable results, neither the investigator nor the Sponsor will alter the study 
conditions agreed upon and set out in this CIP. Amendments should be made by mutual 
agreement between the investigator and the Sponsor. Any amendment must be set out in writing, 
giving the reasons, and being signed by all concerned parties. The amendment becomes then part 
of the CIP. 
All amendments will be sent to the EC and concerned Competent Authorities. 
10 
DEVIATIONS FROM THE CIP 
10.1 
Investigator Statements 
As reported in page 4 of this CIP the Investigator’s signed the agreement to conduct the study 
according to this CIP and to comply with its requirements and its ethical and safety 
considerations.  
10.2 
Deviation Procedures 
The investigator/s as soon as possible informs the Sponsor/CRO in the case of repeated violations 
of CIP.  
CIP deviations and their explanations should be provided on the CRF of competenceDeviations 
from the statistical plan will be included in the Final Report and adequately justified.  
10.3 
Notification and Timing 
Any amendments to the CIP will be discussed and approved with the Dompé and, if necessary, 
submitted and approved by the Ethical Committee and Competent Authority (if appropriate). 
10.4 
Corrective/Preventive Actions and Investigator Disqualification Procedures 
The Investigator’s and the Centre/s has been qualified according to Dompé SOP, if during the 
monitoring/auditing visit  arise repeated deviations to the CIP, Dompé might suspend or finish the 
CI (see also Statement agreement of page 4) and disqualify the Investigator’s /Centre according to 
Dompé SOPs. 
11 
DEVICE ACCOUNTABILITY 
The Test ID/Control ID will be supplied by Sponsor to Study Site in quantities sufficient to 
complete the treatment of subjects randomized.  
11.1 
Supply and Storage of the ID and Other Materials 
The ID/Control ID will be sent to the Investigator/s in a quantity sufficient for the randomized 
subjects.  
The Pharmacist and/or Investigator will be responsible for receipt, proper storage and usage of 
IDs.  
Partially used or unused IDs should be destroyed on site (on request of Dompé, and 
documentation of destruction provided to Dompé farmaceutici s.p.a.) or returned to Dompé 
farmaceutici s.p.a., at the end of the study. Adequate record of receipt, use or loss of IDs will be 
retained. 

 
 
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11.2 
Responsibilities 
All product supplies that will be used in the CI must be stored and maintained securely under the 
responsibility of the Investigator/s, or the Hospital Pharmacist, or other trial staff personnel 
designated and authorized by the Investigator/s to store and dispense ID, according to the 
regulations in force.  
IDs shall be dispensed in accordance with CIP requirements and Investigator’s prescription and it 
is the Investigator’s responsibility to ensure that an accurate record of dispensed and returned 
compounds is maintained. 
This will be possible with the regular completion of the CRF section about ID Dispensing and the 
ID Accountability Form which will be part of the IF. 
11.3  Control of Occurred Treatment 
e investigator/s will ensure that the subject has received the Test ID/Control ID at Visit 1; any 
deviations from the fixed dosing will be specifically asked to the subjects at each visit and 
deviations will be included in the CRF. The Investigator should accurately complete all the ID 
Accountability Forms at all visits and check treatment self-administration compliance.  
Any new information about the IDs will be communicated to the subject and the consent modified 
and submitted to the EC for approval. 
12 
STATEMENTS OF COMPLIANCE 
12.1 
Declaration of Helsinki 
The CRO/sponsor and the Investigator’s ensure that all procedures described in this CIP, data 
evaluation and documentation will be produced strictly according to the current version of 
Declaration of Helsinki. 
12.2 
International Standard 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The present clinical study will be also carried out according to Attachments VIII and X del 
legislation decree 24 February 1997, n.46 and s.m.i., the standard ISO14155-2012  and the general 
principles of “ICH Topic E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status 
September 1997 and post Step errata (linguistic corrections), July 2002. 
 
12.3 
Ethic Committee and Regulatory Authority Approvals and Any Additional 
Requirements 
The CIP and essential documents (CRF, ICF, Insurance, etc..) will be approved by the Ethics 
Committees. The approval of the CIP by the relevant Ethics Committee will be obtained before 
the start of the study. 
Study notification to the Competent Authority will be performed according to the Italian current 
regulations on Medical Device. 
It is understood that the study can begin only after full approval by the Ethics Committee, and by 
the Competent Authorities. Products will not be sent to Investigator/s before the Ethics Committee 
and Competent Authorities approvals.  

 
 
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12.4 
Amendments and EC/CA Additional Requirements  
Any amendment to this CIP will be sent to the EC/CA (if required), any amendments that may 
lead to increased risks and/or inconvenience to the subject must first be approved by the EC and 
Competent Authority, if appropriate, and such approval in writing addressed to the Sponsor.  
Copies of all documents must be stored also by the Investigator/s. Any revision of the CIP shall be 
reported on the CRF, if applicable. Any additional EC/CA requirement will be followed as 
appropriate. 
12.5 
Insurance Policy 
An insurance cover has been issued in favor of the subjects participating in this clinical study. The 
insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities 
12.5.1 Liability Statement  
On behalf of the Sponsor, the investigational sites will take out reasonable third-party liability 
insurance cover in accordance with all local legal requirements. The civil liability of the 
investigators, the persons instructed by them and the hospital, practice or institute in which they 
are employed and the liability of the Sponsor in respect of financial loss due to personal injury and 
other damage which may arise as a result of the carrying out of this study are governed by the 
applicable local laws. 
As a precautionary measure, the investigators, the persons instructed by them and the hospital, 
practice or institute are included in such cover in respect of work done by them in carrying out 
this study to the extent that the claims are not covered by their own professional indemnity 
insurance. 
 
13 
INFORMED CONSENT 
 
13.1 
General Procedures 
Before being enrolled into the clinical study, the subjects must have expressed their consent to 
participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in both 
oral and written form. The information sheet and informed consent form will be prepared in the 
local language by Dompé and must be approved by the EC and regulatory authorities. It will 
include all the elements required by law according to the ISO 14155-2012 and ICH-GCP 
recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organized 
 the type of treatment 
 any potential negative effects attributable to the study treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons and 
without jeopardizing their further course of medical treatment  
 the existence of subject insurance cover and obligations following from this cover 

 
 
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Adequate time and opportunity to satisfy questions will be given to the subjects and the time will 
be recorded. 
The investigator will be supplied with an adequate number of blank informed consent forms to be 
used. The forms will be signed and dated by both the investigator and the subjects.  
A copy of the signed form will be given to the subject. 
To ensure medical confidentiality and data protection, the signed informed consent forms will be 
stored in the investigator's study file according to the regulatory requirements. 
The investigator will allow inspection/audit of the forms by authorized representatives of the 
Sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
forms, that informed consent has been obtained. 
In case any new information regarding the IDs will be available during the study the subject will 
be contacted by the Investigator and if the case a new informed consent will be prepared, 
submitted to the EC/CA and after approval proposed to the subject. 
 
13.2 
Special Procedures  
No vulnerable subjects are expected to be enrolled in this CI.  
14 
SAFETY EVALUATION AND REPORTING OF ADVERSE EVENTS, SERIOUS 
ADVERSE EVENTS AND DEVICE DEFICIENCIES  
14.1 
Definitions  
MEDDEV 2.7/3 (Rev 3, May 2015) attached to this CIP (Annex C), provides definitions for 
serious and non-serious Adverse Events (SAE and AE) and Adverse Device Effects (SADE and 
ADE) and for Device Deficiency (DD) and Unanticipated Serious Adverse Device Effect 
(USADE). All serious adverse events must be fully recorded and immediately notified to all 
Competent Authorities of the Member States in which the clinical investigation is being 
performed within the timeframe and format specified in the MEDDEV 2.7/3; all adverse events 
and device deficiencies (related to the identity, quality, durability, reliability, safety or 
performance of an investigational medical device) shall be documented and assessed. 
 
The Flowchart for guidance of adverse event categorization is reported in figures F1 and F2 of 
ISO 14155:2011 (Annex D of this CIP).  

 
 
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The ISO 14155 Adverse Event Categorization is summarized hereafter. 
 
ADVERSE 
EVENTS 
 
 
Non-device-related 
 
Device- or Procedure -Related 
Non-Serious 
 
Adverse Event  
(AE) 
Adverse Device Effects  
(ADE) 
Serious 
Serious 
Adverse 
Event 
(SAE) 
Serious Adverse Device Effects 
(SADE) 
Anticipated 
Unanticipated 
 
 
 
Anticipated 
Serious 
Adverse 
Device 
Effects  
(ASADE) 
 
Unanticipated 
Serious 
Adverse 
Device Effects  
(USADE) 
 
14.2 
Management of adverse event/adverse device effect 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.   
Information on all adverse events should be recorded immediately in the source document, and 
also in the appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms and abnormal diagnostic procedures results should recorded in the source 
document, though should be grouped under one diagnosis. 
 
When an AE/ADE occurs, the Investigator must fill in the appropriate section of the CRF 
recording at least the following information: 
- 
description of the event 
- 
subject’s identification (initials, subject number) 
- 
duration (start date and end date) 
- 
intensity (mild/moderate/severe) 
- 
action taken 
- 
outcome 
- 
assessment of relationship to investigational medical device(s) 
assessment of relationship to the procedure involved (any procedure in the clinical 
investigation plan) 
- 
assessment of seriousness of the AE/ADE.  
 All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution or stabilization. 
 
While filing in the AE information in the CRF, the Investigator shall assess the event and 
evaluate it for the following three criteria: 
- 
Serious: yes/no 
- 
Relationship with study treatment. 
 
An AE shall be considered serious if: 

 
 
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a) led to a death, injury or permanent impairment to a body structure or a body function. 
b) led to a serious deterioration in health of the subject, that either resulted in: 
- a life-threatening illness or injury, or 
- a permanent impairment of a body structure or a body function, or 
- in-patient hospitalization or prolongation of existing hospitalization, or 
- in medical or surgical intervention to prevent life threatening illness 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious adverse 
event. 
 
If the event is assessed as serious, the event shall be treated and processed as SAE/SADE as 
described in Paragraph 14.4. 
 
The relationship between the use of the ID (including the medical - surgical procedure) and the 
occurrence of each adverse event shall be assessed and categorized. Clinical judgement shall be 
used and the relevant documents, such as the Investigator’s Brochure, the Clinical Protocol or the 
Risk Analysis Report shall be consulted when assessing the causality. The presence of 
confounding factors, such as concomitant medication/treatment, the natural history of the 
underlying disease, other concurrent illness or risk factors shall also be considered. 
The above considerations apply also to the serious adverse events occurring in the comparison 
group. 
In line with the MEDDEV 2.7/3 (to be referred to for further information), each SAE will be 
classified according to five different levels of causality. The sponsor and the investigators will use 
the following definitions to assess the relationship of the serious adverse event to the 
investigational medical device or procedures: 
Not related: relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
- the event has no temporal relationship with the use of the investigational device or the 
procedures; 
- the serious event does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible; 
- the discontinuation of medical device application and reintroduction of its use do not impact on 
the serious event; 
- the event involves a body-site or an organ not expected to be affected by the device or 
procedure; 
- the serious event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors); 
- harms to the subject are not clearly due to use error; 

 
 
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In order to establish the non-relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
3) Possible: the relationship with the use of the investigational device is weak but cannot be ruled 
out completely. Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be classified as possible. 
4) Probable: the relationship with the use of the investigational device seems relevant and/or the 
event cannot reasonably be explained by another cause, but additional information may be 
obtained. 
5) Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures; 
- the event has a temporal relationship with investigational device use/application or procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical device (if the response pattern 
is previously known); 
- the discontinuation of medical device application and reintroduction of its use, impact on the 
serious event (when clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an effect 
of another device, drug or treatment) have been adequately ruled out; 
- harm to the subject is due to error in use; 
In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious event. 
 
The Investigator shall notify to the Sponsor and CRO (at the contacts reported at § 1.1) any 
AE/ADE within 30 calendar days from initial awareness. The page of the appropriate 
section in the CRF (AE – Adverse Event page) shall be sent to the Sponsor via e-mail or 
fax. 
 
The Sponsor Materiovigilance Department shall review the Investigator’s assessment of 
all AE/ADEs and determine and document in writing the evaluation of the seriousness and 
relationship to the ID. In case of disagreement between the Sponsor and the Investigator, the 
Sponsor shall communicate the discrepancy to the Investigator. 
The Investigator shall refer to the Dompé medical Expert for any Clinical issue and question (see 
contact at § 1.1). 

 
 
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14.3 
List of always serious adverse events and rescue procedure 
The following adverse events are considered to be of special interest and by default shall be 
reported as SAEs (medically important criteria): 
 
 Adverse Events that caused a decrease in visual acuity of >30 ETDRS letters or > +0.6 
LogMAR (compared with the last assessment of visual acuity at the last visit) lasting >1 hour 
 Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse lasting >1 hour 
 Adverse Events that required surgical intervention (e.g., conventional surgery, vitreous tap or 
biopsy with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to 
prevent permanent loss of sight 
 Adverse Events associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis) 
 Adverse Events that, in the opinion of the investigator, may require medical intervention to 
prevent permanent loss of sight. 
 
All AEs should be followed-up to determine outcome of the reaction. The Investigator should 
follow up the event until resolution or stabilization of the condition at least until 10 days after the 
final visit. It is the Investigator's responsibility to assure that the subjects experiencing an AE 
receive definite treatment for any AE, if required. 
 
The Investigator shall refer to the Dompé Medical Expert for any Clinical issue and question (see 
contact at § 1.1) 
14.4 
Management of Serious adverse event/Serious adverse device effect 
The Investigator must record all SAEs/SADEs, including sight-threatening events, occurring at 
any time during the study regardless of presumed causal relationship, on the Serious Adverse 
Event form.  
Within 24 hours from first knowledge of the SAE, the Investigator shall send the filled in and 
signed SAE form to the Sponsor and the CRO, as described in Paragraph 14.6. 
If assistance is needed with the reporting of a SAE, contact details for the Sponsor and the CRO 
are provided in § 1.1. 
Samples of SAE Reporting forms to be sent to the Sponsor are provided among the study 
documentation.  
The telephone, e-mail address and telefax numbers of the contact person(s) for reporting are listed 
also in the Investigator File provided to the site.  
The investigator must complete the Serious Adverse Event Reporting Form in English. 
If necessary a case narrative, as much exhaustive as possible, will be attached to the SAE 
Reporting Form. A photocopy of all relevant examinations which have been carried out for the 
event (ECG, lab tests…) will also be attached.  
The original copy of the form must be kept with the study documentation at the site.  
Depending on the nature and seriousness of the SAE, the Sponsor may request further 
information, including copies of appropriate medical records of the subject, as well as results of 
laboratory tests performed. If the subject was hospitalized, a copy of the discharge summary 
should be provided to the Sponsor as soon as it is available, if possible.  
In any case, the Investigator shall further follow up each SAE to complete case information till 
resolution of the event, as appropriate, and provide the follow up information to the Sponsor.  

 
 
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Follow-up SAE information should be communicated through a new SAE form duly filled in and 
signed, within 24 hours from awareness, to the same contacts reported below for initial SAE 
reports, whenever becoming aware of new available information regarding the SAE, once the 
condition is resolved or stabilized and when no more information about the event is expected.  
SAEs that are still ongoing at the end of the study period must be followed up to determine the 
final outcome.   
Any SAE that occurs after the study period (defined as 10 days after Follow-up visit) and if 
considered to be possibly related to the study treatment or study participation should be recorded 
and reported immediately to the Sponsor. 
SAE will be managed directly by the Dompé Materiovigilance Department, with the support of 
the Dompé Medical expert who will provide assessment of causality, expectedness and medical 
evaluation and may draft Follow Up requests.  
SAE shall be notified to the Competent Authority by the Sponsor Materiovigilance Department 
(see Paragraph 14.7 for timing and procedure)  
The Investigator will also accomplish to his/her obligations with respect to EC, as per local EC 
rules.    
The Investigator shall refer to the Dompé medical Expert for any Clinical issue and question (see 
contact at § 1.1). 
14.5 
Process of Device Deficiencies Reporting 
The Investigator shall inform the CRO/Sponsor as soon as possible of any Device Deficiencies 
found during the study.  
Device deficiencies should be investigated by the Sponsor Quality Department and if related to 
safety should be assessed also by Sponsor Materiovigilance Department according to internal 
SOPs.  
Device deficiencies that might have led to a SAE, if 
a) suitable action had not been taken 
b) intervention had not been made, or 
c) circumstances had been less fortunate 
shall be reported to the Regulatory Authority within the same timeframe and modalities for SAE 
(see Paragraph 14.7). 
 
14.6 
Timeframes and Contacts for Reporting from Investigator to the Sponsor/CRO  
The Investigator shall report via e-mail or fax as per contact details reported in  § 1.1: 
 
 
AE/ADE 
SAE/SADE 
Device deficiencies 
Deadline from 
awareness 
30 calendar days 
24 hours 
3 calendar days 
Reporting tool 
AE page from CRF 
SAE form  
Description using e-
mail 
Sponsor department   Materiovigilance 
 Medical expert 
 Clinical 
Development 
 Materiovigilance 
 Medical expert 
 Clinical 
Development 
 Quality  
 Materiovigilance 
 Medical expert 
 Clinical 
Development 
CRO 
TBD 
TBD 
TBD 

 
 
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14.7 
Regulatory Reporting  
The following events are considered reportable events in accordance with Annex 7, section 2.3.5 
and Annex X, section 2.3.5 of Directives 90/385/EEC and 93/42/EEC, as described in MEDDEV 
2.7/3: 
- any SAE, 
- any Investigational Medical Device Deficiency that might have led to a SAE if:  
a) suitable action had not been taken or  
b) intervention had not been made or  
c) if circumstances had been less fortunate 
- new findings/updates in relation to already reported events. 
In addition, any device deficiency that led to a SADE (therefore falling under the definition of 
SAE). 
Dompé Materiovigilance Department shall submit reportable events to all National Competent 
Authority/ies (NCA) where the clinical investigation has commenced, using the summary 
tabulation as per MedDev Guideline (MEDDEV 2.7/3 – APPENDIX SUMMARY REPORTING 
FORM) attached to this CIP as Annex C.  
Dompé must report to the NCAs where the clinical investigation has commenced: 
• 
a SAE which indicates an imminent risk of death, serious injury, or serious illness and that 
requires prompt remedial action for other subjects/subjects, users or other persons or a new 
finding to it: immediately, but not later than 2 calendar days after awareness by the sponsor of 
a new reportable event or of new information in relation with an already reported event. 
• 
any other reportable events as described above or a new finding/update to it: immediately, but 
not later than 7 calendar days following the date of awareness by the sponsor of the new 
reportable event or of new information in relation with an already reported event. 
Regulatory reporting is independent from causality assessment (also SAE unrelated to ID shall be 
reported to NCA). 
The Investigator shall ensure reporting to his Ethic Committee of the reportable SAEs or 
Investigational Medical Device Deficiency, within the timeframes and with the form requested by 
the Ethic Committee. 
 
Reporting Form for Regulatory reporting (SAE Reporting Form - MedDev 2.7/3 Rev 3) 
The reporting form template for the summary SAE tabulation is given in the Appendix of 
MEDDEV 2.7/3 Rev 3 (the form will be taken in use from 1 September 2016 at the latest). 
The table gives a cumulative overview of the reportable events per clinical investigation and shall 
be updated and transmitted to participating NCAs each time a new reportable event or a new 
finding to an already reported event is to be reported. More detailed information has to be 
provided on request of an NCA, if so requested by using the individual reporting form.  
New/updated information shall be identified in the status column of the tabular form as: 
a = added = new reportable event; 
m = modified = new finding/update to an already reported event; 
u = unchanged. 
Changes in a line should be highlighted in bold and/or colour in the respective column. 

 
 
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The reporting form is study specific and covers only a given clinical investigation, defined by a 
distinct clinical investigation plan.  
English is the recommended language for the reporting form.  
The report should be sent by email in Excel to the participating NCAs, or an equivalent format 
which allows using the inserted filters. 
Unblinding is not mandatory before regulatory submission of a reportable SAE/ Investigational 
Medical Device Deficiency 
14.8 
Data monitoring information 
No DMC is expected for this CI due to the expected relatively low incidence of AE/SAE and 
ADE/SADE. 
15 
VULNERABLE POPULATION 
15.1 
General Description 
No vulnerable population is expected see also § 13.2 
15.2 
Specific IC Procedures 
No specific ICF are expected see also § 13.2 
15.3 
EC Procedures 
No specific requirements are expected from EC due to what stated in the previous §15.1 
15.4 
Special Medical Care 
No specific medical procedures are expected due to what stated in the previous §15.1 
16 
SUSPENSION AND PREMATURE TERMINATION OF CI 
16.1 
General Criteria and Site Criteria 
According to the Declaration of Helsinki, each subject has the right withdraw from the study at 
any time without giving any justification.  
In absence of relevant CIP violations or medical contraindications the Investigator shall make all 
reasonable efforts to keep the subject in the study. If, however, it becomes necessary to withdraw 
a subject from the study, a complete final evaluation must be performed. All the results of this 
evaluation, together with date of withdrawal and reason(s) for the subject’s exclusion from the 
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16.1.1 Removing Subjects from the Study 
A subject should be withdrawn from the trial if, in the opinion of the Investigator, it is medically 
necessary or if it is the wish of the subject. 
The study treatment will be discontinued at any time if any of the following events occur: 
 Development of AE or unacceptable toxicity, precluding further therapy with the IDs. 
Severe protocol violations, such as an incorrect treatment administration, or a 
concomitant use of not permitted medications. Before removal, these cases should first 
be discussed with Dompé farmaceutici s.p.a. 
 Severe protocol violations, such as an incorrect treatment administration, or a 
concomitant use of not permitted medications. Before removal, these cases should first 
be discussed with Dompé farmaceutici s.p.a. 
 Subject request. 
 Subject has been enrolled, but has not started study treatment e.g. due to onset of AE, 
consent withdrawal etc before treatment could be started. 
 Subject becomes pregnant 
 Treating physician decision in the subject’s best interest. 
 Onset of ocular conditions requiring additional topical treatments (e.g. onset of ocular 
inflammation, infection, hypertension etc) or surgery 
 Request of Dompé farmaceutici s.p.a.  
Any treatment discontinuation must be recorded on the case report form (CRF) by the 
Investigator, who will indicate date and reason(s) for treatment withdrawal. Unless the subject has 
withdrawn consent, the early termination visit assessments should be performed as detailed in 
§ 6.1.3. 
16.1.2 Discontinuation Criteria 
The Investigator or Dompé farmaceutici s.p.a. may decide to terminate the study if in the opinion 
that continuing in the study poses unacceptable risks to the subjects. If such a decision is reached, 
no further subjects will receive study products and the study will stop. The decision will be based 
on an overall assessment of tolerability and safety.  
16.1.2.1  
Primary Reason for Discontinuation 
 Adverse event: Any significant adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, please 
refer to § 14. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a patient to follow-up 
 non-compliance with study ID: an indication that a patient has not agreed with or followed 
the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a physician 
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 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in the 
body (uterus), after union of an ovum and spermatozoon, during the period from conception to 
birth  
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by the 
protocol 
 study terminated by Sponsor: an indication that a clinical study was stopped by its Sponsor 
 site terminated by Sponsor: an indication that a clinical site was stopped by the study 
Sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually related 
to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
16.1.3 Discontinuation Procedures 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions. This examination will verify that all values tested at screening 
have remained within a clinically acceptable range (i.e. not clinically significant changes 
compared to screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 report in the CRF date and time of the last dose administration, and date and primary reason of 
study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
16.1.4 Withdrawal of Subjects 
It will be documented whether or not each subject completed the clinical study. If, for a subject, 
study treatment or observations are discontinued, the primary reason for discontinuation will be 
recorded. 
16.2 
Breaking Masked Criteria 
The randomization list is held by CRO. 
Individual envelopes identified with the subject assignment number have been prepared. Each one 
includes the identity of the treatment assigned to each subject. These envelopes, duly closed and 
sealed, are included into the IF. 
During the study the integrity of the envelopes will be regularly checked by CRO Monitor during 
the visits at site. At the end of the study all the individual envelopes must be returned to Dompé. 
The sealed envelope can only be opened in case of emergency, when knowledge of the ID is 
essential for treating the subject. 
Only in case of real need the Investigator may open the sealed envelope. In case of opening, all 
the details (date, time, reasons….) must be specified into the CRF and the Sponsor must be 
informed within 24 hours. 
If an envelope is opened before the end of the trial, the subject will be excluded from the trial. 
A copy of the Individual envelopes identified with the subject assignment number will be also 
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treatment only for safety reason and will document envelope opening; unblinding is not 
mandatory before regulatory submission of a reportable SAE/ Investigational Medical Device 
Deficiency. 
16.3 
Follow-up 
The CIP provides a follow-up visit and therefore throughout the study the Investigator should 
ensure the follow–up of all AEs, both serious and non-serious, until stable outcome of the event, 
i.e.: recovery, recovery with stable sequelae, death. “Stable” defines a clinical condition to be 
reasonably considered as not evolving, according to investigator’s judgement.For any follow-up 
information on SAEs, a new Serious Adverse Event Reporting form must be sent. Each re-
occurrence, complication, relevant progression or sequelae of the original event should be 
reported as a follow-up to the first event.  
Any SAE/SADE occurred within 10 days after conclusion of subject’s participation in the trial 
should be reported as well.  
Subjects who drop-out from the study due to AE/ADE will be followed at least for the next 10 
days, or until stable outcome of the event. Subjects who drop-out from the study due to a 
SAE/SADE will be followed in any case until stable outcome. 
17 
PUBLICATION POLICY 
The Sponsor agrees that the study results (including negative and inconclusive as well as positive 
results) can be made publicly available by the Investigator publishing in peer reviewed journals; 
presenting results at scientific congresses; and posting information and results on internet-based 
public registers and databases. 
In any case, study results will be communicated in full to the competent Health Authorities by the 
submission of a complete Clinical Investigational  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 investigational 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 
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18  
BIBLIOGRAPHY 
1. 
Schumacher BL, Block JA, Schmid TM, et al. A novel proteoglycan synthesized and 
secreted by chondrocytes of the superficial zone of articular cartilage. Arch Biochem 
Biophys 1994; 311:144–152. 
2. 
Swann DA, Slayter HS, Silver FH. The molecular structure of lubricating glycoprotein-I, 
the boundary lubricant for articular cartilage. J Biol Chem 1981; 256:5921–5925. 
3. 
Jay GD, Tantravahi U, Britt DE, et al. Homology of lubricin and superficial zone protein 
(SZP): Products of megakaryocyte stimulating factor (MSF) gene expression by human 
synovial fibroblasts and articular chondrocyteslocalized to chromosome 1q25. J Orthop 
Res 2001;1 9:677–687. 
4. 
Jay GD, Harris DA, Cha CJ. Boundary lubrication by lubricin is mediated by O-linked 
beta(1–3)Gal-GalNAc  oligosaccharides. Glycoconj J 2001; 18:807-15. 23.  
5. 
Jay GD, Waller KA.The biology of Lubricin: Near frictionless joint motion.Matrix Biol. 
2014 Aug 27 
6. 
Aninwene GE 2nd, Abadian PN, Ravi V, Taylor EN, Hall DM, Mei A, Jay GD, Goluch 
ED, Webster TJ. Lubricin: A novel means to decrease bacterial adhesion and 
proliferation.J Biomed Mater Res A. 2014 Apr 16. doi: 10.1002/jbm.a.35195. [Epub ahead 
of print] 
7. 
LUBRICIN  - FINAL Investigator’s Brochure MD001 – Rev 02 – 15 July 2016 
8. 
Schmidt TA, Sullivan DA, Knop E, Richards SM, Knop N, Liu S, Sahin A, Darabad RR, 
Morrison S, Kam WR, Sullivan BD Transcription, translation, and function of lubricin, a 
boundary lubricant, at the ocular surface. JAMA Ophthalmol. 2013; 131 (6): 766-76 
9. 
Cheriyan T, Schmid TM, Spector M. Presence and distribution of the lubricating protein, 
lubricin, in the meibomian gland in rabbits. Mol Vis. 2011; 17:3055-61. 
10. 
Ehlers N The precorneal film. biomicroscopical, histological and chemical investigations. 
Acta Ophthalmol Suppl. 1965:SUPPL 81:1-134 
11. 
Morrison S, Sullivan DA, Sullivan BD, Sheardown H, Schmidt TA. Dose-dependent and 
synergistic effects of proteoglycan 4 on boundary lubrication at a human cornea-
polydimethylsiloxane biointerface. Eye Contact Lens. 2012;  38 (1):27-35 
12. 
Laurent TC and JRE Fraser. Hyaluronan FASEB J. 1992; 6: 2397-404  
13. 
Schramm C. et al The cross-linked biopolymer hyaluronic acid as an artificial vitreous 
substitute. Ophthalmol Vis Sci 2012; 53:613-21;  
14. 
Liu L. et al Microbial production of hyaluronic acid current state, challenges and 
perstectives. Microbiol Cell Factories,;2011, 1099  
15. 
Frank P and Gendler E. Hyaluronic acid for soft- tissue augmentation Clin Plast Surg. 
2001; 28 (1): 121-6;  
16. 
The definition and classification of dry eye disease: report of the Definition and 
Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 
2007; 5(2): 75-92. 
17. 
Ang RT, Dartt DA, Tsubota K. Dry eye after refractive surgery Curr Opin Ophthalmol. 
2001 Aug;12(4):318-22. 

 
 
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18. 
Ambrósio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye and neurotrophic 
epitheliopathy: pathophysiology and strategies for prevention and treatment J Refract Surg. 
2008 Apr;24(4):396-407. 
19. 
SAS/STAT® User’s Guide, Version 9.3 (TS1M1) for Windows 
 
 

 
 
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ANNEX A 
 
 
LUBRICIN EYE DROPS  
SUBJECT’S INSTRUCTIONS 
(Italian version) 
 

 
 
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FOGLIO ILLUSTRATIVO 
 
LUBRICIN GOCCE OCULARI 
 
Questo documento contiene il testo proposto da Dompé per il foglio illustrativo da 
utilizzare con il dispositivo medico (DM) sperimentale “Lubricina gocce oculari”. 
Al termine della valutazione ai fini della sperimentazione clinica, tale testo potrebbe 
subire delle modifiche. 
 
Si fa anche presente che il nome “Lubricina gocce oculari” non sarà quello proposto 
per la marcatura CE, ma sarà solo utilizzato per identificare il DM stesso durante la 
sperimentazione clinica. 
 
 
 

 
 
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ANNEX B 
 
 
VISMED®  
PATIENT’S INSTRUCTIONS  
(Italian & English version) 
 

 
 
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ANNEX C 
 
 
 
MEDDEV 2.7/3 – Rev 3 - 2015 

 
 
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ANNEX D 
 
 
Flowchart for guidance of adverse event 
and deficiencies categorization 
Figures F.1 and F.2 of ISO 14155 

 
 
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