Comparison of the Performance and Safety of T2769 Versus Hylo-Forte® in the Treatment of Moderate to Severe Dry Eye Syndrome.
Phase: NA
Conditions: Dry Eye Syndrome
Sponsor: Laboratoires Thea

CIP N# LT2769-004 
Laboratoires THÉA 
Confidential  
Version 2.0 – 09-APR-2024 
1/109 
 
 
 
1 
GENERAL 
1.1 
IDENTIFICATION OF THE CLINICAL INVESTIGATION PLAN 
1.1.1 
Clinical Investigation References 
 
 
CLINICAL INVESTIGATION PLAN 
 
Investigation No. LT2769-004 
 
 
 
 
Date of the initial Clinical Investigation Plan: 
09-APR-2024  
 
Version of the initial Clinical Investigation Plan: 2.0 
 
 
 
 
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1.1.2 
CIP Amendments 
Amendment N#: NA 
Version of the Amended CIP: NA 
Section 
number 
Section Name 
Changes description 
Rationale or justifications 
NA 
NA 
NA 
NA 
 
 
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TITLE: Comparison of the performance and safety of T2769 versus Hylo-Forte® in the 
 
treatment of moderate to severe Dry Eye Syndrome. 
 
LABORATOIRES THÉA 
 
Clinical Investigation Plan (CIP) No.: 
LT2769-004 
 
 
Investigational Medical Device (IMD): 
T2769 
 
 
Intended purpose:  
Moderate to severe dry eye syndrome 
 
 
Sponsor’s Medical Expert: 
 
 
This confidential clinical investigation plan is the property of Laboratoires THÉA. No unpublished information contained herein may 
be disclosed without prior written approval of Laboratoires THÉA. 
 
 
 
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1.1.3 
Abbreviations and Acronyms 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ALCOACCEA 
Attributable, Legible, Contemporaneous, Original, Accurate, Complete, 
Consistent, Enduring and Available 
 
 
ASADE 
Anticipated Serious Adverse Device Effect 
ATC 
Anatomic Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
CA 
Competent Authority 
CI 
Confidence Interval 
CIP 
Clinical Investigational Plan 
CIR  
Clinical Investigation Report 
 
 
CMP 
Clinical Monitoring Plan 
CNIL 
Commission Nationale de l’Informatique et des Libertés 
CRO 
Contract Research Organisation 
CSP 
Code de la Santé Publique 
DD 
Device Deficiency 
 
 
DED 
Dry Eye Disease 
DES 
Dry Eye Syndrome 
DMP 
Data Management Plan 
e-CRF
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EU 
European Union 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GMP 
Good Manufacturing Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IMD 
Investigational Medical Device 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis Sicca 
LFU 
Lacrimal Functional Unit 
 
 
MAR 
Missing At Random 
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MDR 
Medical Device Regulation 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MMRM 
Mixed Model for Repeated Measures 
NA 
Not Applicable 
NRS 
Numeric Rating Scale 
OSDI 
Ocular Surface Disease Index 
PI 
Principal Investigator 
PP 
Per Protocol  
PT 
Preferred Term 
QoL 
Quality of Life 
Q1 
First Quartile 
Q3 
Third Quartile 
 
 
RM 
Rescue Medication 
RMP 
Risk Management Plan 
RMR 
Risk Management Report 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
 
 
SDR 
Source Data Review 
SDV 
Source Data Verification 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBUT 
Tear Break Up Time 
TEAE 
Treatment Emergent Adverse Event 
USADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual Analogue Scale 
 
 
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1.2 
SPONSOR 
Laboratoires THÉA 
 
 
 
 
 
 
Sponsor contact: Laboratoires THÉA 
 
First Name - Name/function 
Details 
 
Clinical Affairs Director 
Email: 
 
 
Medical Development Director 
Email: 
 
 
Clinical Operation Manager 
Email: 
 
 
Biometrics Manager 
Email: 
 
 
Clinical Project Leader 
Email: 
 
 
Safety Manager 
Email: 
 
 
Safety Specialist 
Email: 
 
 
 
 
 
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1.3 
PRINCIPAL INVESTIGATOR AND INVESTIGATION SITE(S) 
1.3.1 
Investigators Details 
The Sponsor will maintain an updated list of Principal Investigators (PIs), and investigation sites, 
separately from this CIP, throughout the duration of the clinical investigation. The definitive list will 
be provided with the Clinical Investigation Report (CIR). 
Roles, responsibilities, and qualifications of investigators are detailed in the CIP. 
1.3.2 
External Organisations Details 
Name and Functions 
Details 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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STATEMENT OF THE SPONSOR 
 
Comparison of the performance and safety of T2769 versus Hylo-Forte® in the 
treatment of moderate to severe Dry Eye Syndrome 
 
The information contained in this CIP is consistent with: 
 The current risk-benefit evaluation of the IMD 
 The moral, ethical, and scientific principles governing clinical research as set out in the Declaration 
of Helsinki - October 2013, Good Clinical Practice (GCP) as described in the ISO14155 current 
version. 
The investigator will be supplied with details of any significant or new findings, including adverse 
events (AEs), relating to treatment with the IMD. 
 
 
 
SPONSOR: LABORATOIRES THÉA  
 
Clinical Affairs Director 
 
__________________ 
________
 
Date (dd-MMM-yyyy)
signature
 
 
Medical Development Director 
 
__________________ 
________
 
Date (dd-MMM-yyyy)
signature
 
 
Biometrics Manager 
 
__________________ 
________
 
Date (dd-MMM-yyyy) 
signature
 
 
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INVESTIGATOR SIGNATURE PAGE 
 
Comparison of the performance and safety of T2769 versus Hylo-Forte® in the treatment of 
moderate to severe Dry Eye Syndrome 
 
The signature below: 
 Confirms my agreement to conduct the investigation in compliance with GCP – ISO 14155 
current version, Medical Device Regulation (MDR 2017/745), other applicable regulatory, 
and the CIP requirement(s). 
 Confirms my agreement to comply with procedures for data recording/reporting. 
 Confirms my agreement to permit monitoring, auditing, and regulatory inspection. 
 Confirms my agreement to retain the essential documents of this clinical investigation in the 
investigator files until Laboratoires THÉA informs me that these documents are no longer 
needed (i.e. at least 10 years after the last T2769 device has been placed on the market). 
 Ensure that all people assisting with the clinical investigation are adequately informed about 
the CIP, the IMD(s) and their trial-related duties and functions. 
 Confirms that I have read this CIP and that I agree to comply with all parts or items. 
 
All information regarding this CIP and the IMD(s) will be treated as strictly confidential. 
 
INVESTIGATIONAL SITE 
 
Principal Investigator 
 
SPONSOR: LABORATOIRES THÉA  
 
Clinical Project Leader  
 
 
_________________ 
_______
 
First Name - Name 
date (dd-MMM-yyyy) 
signatur
 
 
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TABLE OF CONTENTS 
 
1
GENERAL ................................................................................................................................... 1
1.1
Identification of the Clinical Investigation Plan .................................................................. 1
1.1.1
Clinical Investigation References .................................................................................... 1
1.1.2
CIP Amendments .............................................................................................................. 2
1.1.3
Abbreviations and Acronyms .......................................................................................... 4
1.2
Sponsor ................................................................................................................................... 6
1.3
Principal Investigator and Investigation Site(s) .................................................................. 7
1.3.1
Investigators Details ......................................................................................................... 7
1.3.2
External Organisations Details ........................................................................................ 7
2
IDENTIFICATION AND DESCRIPTION OF THE IMD ................................................... 28
2.1
Summary Description of the IMD and its Intended Purpose .......................................... 28
2.2
Details Concerning the Manufacturer of the IMD............................................................ 28
2.3
Name or Number of Model/Type, included Software Version and Accessories, 
if applicable, allowing a Full Identification ....................................................................... 28
2.4
Packaging and Labelling ..................................................................................................... 28
2.4.1
Packaging ......................................................................................................................... 28
2.4.2
Labelling .......................................................................................................................... 30
2.5
Intended Purpose of the IMD in the Proposed Clinical Investigation ............................ 30
2.6
The Populations and Indications for which the IMD is Intended ................................... 30
2.7
Description of the IMD ........................................................................................................ 30
2.8
Storage Conditions and Indications of Use ........................................................................ 31
2.9
Description of the Specific Medical or Surgical Procedures Involved in the Use 
of the IMD ............................................................................................................................. 31
2.10
Investigator Brochure (IB) and Indication For Use (ifu) ................................................. 31
2.11
Description of Comparative Device .................................................................................... 32
3
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ............ 32
3.4
Description of the Clinical Development Stage ................................................................. 35
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4
BENEFITS AND RISKS OF THE IMD, CLINICAL PROCEDURE AND 
CLINICAL INVESTIGATION............................................................................................... 35
4.1
Anticipated Clinical Benefits............................................................................................... 35
4.3
Risks Associated with Participation in the Clinical Investigation................................... 36
4.4
Possible Interactions with Concomitant Medical Treatments......................................... 36
5
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ............... 38
5.1
Claims for Clinical Performance, Effectiveness or Safety of the IMD............................ 38
5.2
Objectives, Primary 
38
5.3
Scientific Justification and Clinical Relevance for Effect Sizes, Non-Inferiority 
Margins or Equivalence Limits .......................................................................................... 38
5.5
Risks and Anticipated Adverse Device Effects.................................................................. 39
6
DESIGN OF THE CLINICAL INVESTIGATION............................................................... 39
6.1
General.................................................................................................................................. 39
6.1.1
Justification of the Investigation Design....................................................................... 39
6.1.2
Description of the Measures to be Taken to Minimize or Avoid Bias........................ 41
Randomisation ................................................................................................................. 41
Concealment of Allocation .............................................................................................. 41
Masking and Code Breaking........................................................................................... 41
Management of potential confounding factors............................................................... 42
Dispensing........................................................................................................................ 42
Primary Performance Endpoint...................................................................................... 43
Safety Endpoints .............................................................................................................. 44
6.1.5
Methods and Timing for Assessing, Recording, and Analysing Variables................ 45
Screening Period.............................................................................................................. 46
Treatment Period ............................................................................................................. 47
Additional/Optional Visit(s) during the clinical investigation ....................................... 50
Premature Discontinuation Visit during the clinical investigation ............................... 50
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Additional Follow-Up Visit(s) (after the end of the treatment)...................................... 50
Adaptive Follow-Up of Patients Prematurely Withdrawn due to an 
Exceptional Circumstance (e.g. COVID-19 pandemic).................................................. 50
6.1.6
Equipment to be used for Assessing the Clinical Investigation Variables 
and Arrangements for Monitoring Maintenance and Calibration............................. 51
6.1.7
Procedures for the Replacement of Patients................................................................. 51
6.1.8
Investigation Sites ........................................................................................................... 51
6.1.9
Definition of Completion of the Clinical Investigation................................................ 52
6.2
IMD(s) and Comparator(s) ................................................................................................. 52
6.2.1
Description of the Exposure to the IMD....................................................................... 52
6.2.2
List of any Other Medical Device or Medication to be Used during the 
Clinical Investigation...................................................................................................... 52
Run-in Treatment............................................................................................................. 52
Auxiliary Products ........................................................................................................... 53
6.2.3
Number of IMD to be Used, Together with a Justification......................................... 53
6.3
Patients.................................................................................................................................. 53
6.3.1
Inclusion Criteria............................................................................................................ 53
6.3.2
Exclusion Criteria........................................................................................................... 54
6.3.3
Criteria and Procedures for Treatment/Investigation Withdrawal or 
Discontinuation ............................................................................................................... 58
6.3.4
Point of Enrolment.......................................................................................................... 59
6.3.5
Point of Randomisation.................................................................................................. 59
6.3.6
Total Expected Duration of the Clinical Investigation................................................ 59
6.3.7
Expected Duration of each Patient's Participation...................................................... 59
6.3.8
Number of Patients Required to be Randomised in the Clinical 
Investigation .................................................................................................................... 59
6.3.9
Estimated Time Needed to Select this Number (i.e. enrolment period)..................... 59
6.3.11
Information on Vulnerable, Pregnant, and Breastfeeding Population...................... 59
6.4
Procedures ............................................................................................................................ 60
6.4.1
Description of all the Clinical-Investigation-Related Procedures that 
Patients Undergo during the Clinical Investigation..................................................... 60
Demographics and Screening Characteristics................................................................ 60
Performance Measures.................................................................................................... 60
Safety measures................................................................................................................ 63
Prior and Concomitant Therapy...................................................................................... 64
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Permitted Treatments....................................................................................................... 64
Prohibited Prior and Concomitant Medications or Treatments..................................... 65
6.4.2
Description of those Activities Performed by Sponsor Representatives 
(excluding monitoring) ................................................................................................... 65
6.4.3
Any Known or Foreseeable Factors that may Compromise the Outcome of 
the Clinical Investigation or the Interpretation of Results ......................................... 65
6.4.4
Methods for Addressing these Factors in the Clinical Investigation.......................... 65
6.4.5
Description of the Follow-Up Period............................................................................. 65
6.4.6
Appropriate Specific Medical Care Address after the Clinical Investigation........... 66
6.4.7
Recommended Follow-Up Address after the Clinical Investigation .......................... 66
6.4.8
Final Disposition or Potential Future Use of Samples obtained from 
Patients Address.............................................................................................................. 66
6.5.1
Source Documents........................................................................................................... 67
6.5.2
Source Data Verification................................................................................................ 68
6.5.3
Case Report Forms ......................................................................................................... 69
7
STATISTICAL DESIGN AND ANALYSIS........................................................................... 70
7.1
Analysis Population and Procedures.................................................................................. 70
7.2
Statistical anaLysis............................................................................................................... 70
7.2.1
Performance Analyses .................................................................................................... 71
7.2.2
Safety Analyses................................................................................................................ 73
7.3
Analytical Procedures.......................................................................................................... 74
 
7.5
Sample Size Calculation and Justification......................................................................... 74
7.6
Rationale for the Number of Procedures to be Performed by a Single User as 
part of the Learning Curve and how these Data are to be Analysed .............................. 75
7.8
Interim Analysis, CRITERIA FOR THE TERMINATION OF THE 
CLINICAL INVESTIGATION ON STATISTICAL GROUNDS .................................. 75
7.9
Management of Bias and, when Randomisation, Matching or Blinding are 
Applied, Plan for Assessment of Success thereof. ............................................................. 75
7.10
Management of Potential Confounding Factors ............................................................... 75
 
7.12
Specification of Subgroups.................................................................................................. 75
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7.15
Procedures for Reporting any Deviation(s) from the Original Statistical Plan ............. 76

7.17
Define a strategy for pooling data, if applicable................................................................ 76
8
DATA MANAGEMENT .......................................................................................................... 76
8.1
Methods for Data Entry and Collection ............................................................................. 76
8.2
Procedures Used for Data Review, Database Cleaning, and Issuing and 
Resolving Data Queries ....................................................................................................... 77
8.3
Procedures for Verification, Validation and Securing of Electronic Clinical 
Data Systems......................................................................................................................... 78
8.4
Procedures to Maintain and Protect Patient Privacy ....................................................... 78
8.5
Methods for Database Locking at the Start of the Analysis and Storage upon 
Completion of the Clinical Investigation ........................................................................... 79
8.6
Confidentiality ...................................................................................................................... 79
8.7
Data Retention Procedures and specified retention priod ............................................... 79
8.8
Other Aspects of Clinical Quality Assurance .................................................................... 79
8.8.1
Monitoring/Data Audits ................................................................................................. 79
8.8.2
On-site Audits/Regulatory Inspection ........................................................................... 80
9
APPROVAL OF THE CLINICAL INVESTIGATION AND AMENDMENTS ................ 80
10
DEVIATIONS FROM CIP ...................................................................................................... 81
11
IMD ACCOUNTABILITY ...................................................................................................... 81
11.1
Description of the Procedures FOR THE Accountability OF IMD ................................ 81
11.2
Procedures and Particular Materials and Instructions for the Safe Return of 
imd, including those that are Potentially Hazardous ........................................................ 81
12
STATEMENTS OF COMPLIANCE ...................................................................................... 82
13
INFORMED CONSENT PROCESS ....................................................................................... 82
14
ADVERSE EVENTS, AND INCIDENTS ............................................................................... 83
14.1
Definition of Adverse Event (AE) ....................................................................................... 83
14.2
Definition of incident/FIELD SAFETY CORRECTIVE ACTION ................................ 84
14.3
definition of a serious incident ............................................................................................ 84
14.4
Definition of a Serious Adverse Event (SAE) .................................................................... 84
14.4.1
Definition of the Severity of an Adverse Event ............................................................ 84
14.4.2
Causality Relatedness to the IMD ................................................................................. 85
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14.5
Recording AEs ...................................................................................................................... 86
14.6
Reporting of INCIDENT ..................................................................................................... 87
14.7
Follow-Up of Patient after AE ............................................................................................ 88
14.8
Management of Pregnancy .................................................................................................. 88
14.9
List of Foreseeable AEs Together with their Likely Incidence, Mitigation or 
Treatment ............................................................................................................................. 89
14.10
List of Non-Reportable Adverse Events ............................................................................. 89
14.11
Information Regarding the IDMC ..................................................................................... 89
15
VULNERABLE POPULATION ............................................................................................. 89
16
SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION .................................................................................................................... 89
16.1
Temporary Halt of the clinical Investigation .................................................................... 89
16.2
Early Termination of the clinical Investigation................................................................. 90
16.3
Requirements for Patient Follow-Up and Continued Care .............................................. 91
17
PUBLICATION POLICY ........................................................................................................ 92
18
BIBLIOGRAPHY ..................................................................................................................... 93
 
 
 
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2 
IDENTIFICATION AND DESCRIPTION OF THE IMD 
2.1 
SUMMARY DESCRIPTION OF THE IMD AND ITS INTENDED 
PURPOSE 
The patient will be trained for the correct instillation technique of IMD. The patient will be 
provided with an information on the informed consent form, on the labels on the IMD boxes 
and with some reminders about storage and administration in the patient diary. 
Test device: T2769 (Thealoz® Total) 
T2769 is a sterile, phosphate-free and pH neutral solution. It contains Trehalose, Sodium 
Hyaluronate (SH) and Naaga.  
T2769 device is presented in the ABAK® III multi-dose bottle (10 mL).  
As per Instructions for Use (IFU), T2769 is indicated for the treatment of moderate to severe 
dry eye syndrome. 
Comparative device: Hylo Forte® 
HYLO-FORTE® is a sterile, phosphate and preservative-free solution for ocular use containing 
sodium hyaluronate, citric acid anhydrous, sodium citrate and sorbitol. It is presented in a 
COMOD® multi-dose application system (10 mL). 
HYLO-FORTE® is an eye drop for the intensive and therapeutic lubrication of the ocular 
surface in more severe and persistent dry eye sensation including treatment after surgical 
procedures. 
2.2 
DETAILS CONCERNING THE MANUFACTURER OF THE IMD 
The legal manufacturer of T2769 according to the EU Medical Device Regulation (MDR) 
2017/745 is Laboratoires THÉA. 
2.4 
PACKAGING AND LABELLING 
2.4.1 
Packaging  
The IMD will be packaged by approved contractor in accordance with ISO 14155 current 
version and EU MDR 2017/745. The IMDs will be prepared according to the packaging list 
provided by the CRO responsible for biometry (see Section 6.1.2.1). 
T2769 is packaged in a multidose white polyethylene ABAK® III system bottle. The dispenser 
is already used in several currently marketed eye drops. This innovative and patented device 
provides eye drops through a 0.2 μm filter, preventing any bacterial contamination of the 
solution without the use of any preservatives: 
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HYLO-FORTE® is presented in a COMOD® multi-dose application system (10 mL). 
The complete treatment for one patient and for the complete investigation duration will be as 
following: 
Packaging 
Run-in 
treatment: 
Hydrabak® 
T2769 or Hylo Forte® 
Visit #2 
Period 
Visit #2 - D1 to Visit #3 - D15 
Visit #3 
Period 
Visit #3 - D15 to Visit #4 - D36 
Primary (I) 
1 vial 
2 vials 
2 vials 
Final 
1cardboard 
box 
1cardboard carton 
1 cardboard carton 
Each patient will receive 1 preservative-free multidose bottle of Hydrabak® during the run-in 
period and 4 preservative-free multidose bottles of the IMD during the clinical investigation. 
Hydrabak® is supplied in the ABAK® multi-dose bottle. This innovative and patented device 
provides eye drops through a 0.2 μm filter, preventing any bacterial contamination of the 
solution without the use of any preservatives. 
 
 
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2.4.2 
Labelling 
All labels will be written in the local language. The content of the labelling is in accordance 
with ISO 14155 current version and EU MDR 2017/745 specifications and requirements. 
Each vial of run-in treatment and IMD will carry one label. 
The cardboard carton of IMD will also carry a detachable label (flag label) bearing at least the 
CIP number and IMD kit number. This label will be torn off by the person dispensing the IMD 
to the patient and will be stuck in the space provided in the IMD allocation form to record the 
dispensing procedure. 
2.5 
INTENDED PURPOSE OF THE IMD IN THE PROPOSED CLINICAL 
INVESTIGATION 
T2769 is intended to hydrate and soothe itchy, red or irritated eyes in case of moderate to severe 
dry eye syndrome. 
2.6 
THE POPULATIONS AND INDICATIONS FOR WHICH THE IMD IS 
INTENDED 
T2769 is indicated in moderate to severe dry eye syndrome.  
T2769 is suitable for adults (patients over or equal than 18 years excluding pregnant or 
breastfeeding women, see Sections 6.3.1 and 6.3.2). 
2.7 
DESCRIPTION OF THE IMD 
T2769 is an ophthalmic solution composed of trehalose (3%), sodium hyaluronate (0.15%), N-
Acetyl Aspartyl Glutamic Acid Sodium salt (Naaga, 2.45%), 
 
 
The solution is supplied in the ABAK® III multi-dose bottle. This innovative and patented 
device provides eye drops through a 0.2 μm filter, preventing any bacterial contamination of 
the solution without the use of any preservatives. 
The product can be used until 3 months after first opening.  
Table 4 Investigational Medical Device T2769 
Names of ingredients 
Percentage 
formula 
(g/100 ml) 
Function 
Reference to 
standards 
Trehalose dihydrate* 
3.00* 
Lubricating, 
hydrating agent 
Current Eur. Ph. [2297] 
N-acetyl aspartyl glutamic acid, 
sodium salt (NAAGA, Na)* 
2.45* 
Soothing agent 
Internal monograph 
Sodium hyaluronate** 
0.15* 
Lubricating, 
hydrating agent 
Current Eur. Ph. [1472] 
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* 
The quantity of the ingredient (Trehalose dihydrate and Naaga Na) is adjusted as a 
function of its titre and water content 
** The quantity of this ingredient is adjusted as a function of its water content 
The excipients of the T2769 eye-drops 
 are well-
known and commonly used in ophthalmic formulations. 
Batch number and expiry dates will be provided in the certificate of analysis and will be 
specified on the packaging. 
2.8 
STORAGE CONDITIONS AND INDICATIONS OF USE 
All IMD should be stored in its original packaging, protected from light and moisture, at a 
temperature between 8°C and 25°C and the expiry date refers to the last day of that month as 
long as the packaging is intact, and it has been stored correctly. 
The IMD must not be used if the vial is damaged and must not be refrigerated or frozen. 
Until dispensed to the patient, products should be kept in a secure area with restricted access. 
The investigator, the hospital pharmacist or other personnel allowed to store and dispense 
IMD(s) will be responsible for ensuring that the IMD(s) are securely maintained as specified 
by the Sponsor and in accordance with the applicable regulatory requirements. 
The IMD should not be used after the expiry date indicated on the outer cardboard box. The 
expiry date refers to the intact correctly stored packaging. 
The product can be used until 3 months after first opening.  
If significant changes and/or update on labelling, handling and storage are required during the 
clinical investigation, the corresponding sections will be updated by notifying or submitting to 
Competent Authorities (CAs) concerned accordingly. All investigators’ sites will be 
immediately informed about any change by the Sponsor. Investigator or a delegate will inform 
the patient, if any. 
Accordingly, the Sponsor may decide to halt temporarily the recruitment (see Section 16.1). In 
any way, the reasons and the procedures for any changes will be justified and described by the 
Sponsor. 
2.9 
DESCRIPTION OF THE SPECIFIC MEDICAL OR SURGICAL 
PROCEDURES INVOLVED IN THE USE OF THE IMD 
NA. 
2.10 
INVESTIGATOR BROCHURE (IB) AND INDICATION FOR USE 
(IFU) 
All details concerning the IMD are specified in the IB and the IFU. These documents will be 
updated whenever necessary and all applicable versions will be provided to each investigation 
site throughout the clinical investigation. 
At time of CIP writing, validated and applicable version are: 
- 
For the IB: V4, MAR-2024, 
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- 
For the IFU: Ver. 9-07/2023. 
2.11 
DESCRIPTION OF COMPARATIVE DEVICE 
Hylo Forte® is purchased from Scope Ophthalmics. It is a sterile, phosphate and preservative-
free solution for ocular use. 
Packaging and labelling are provided in Sections 2.1 and 2.4, batch number and expiry dates 
will be specified on the packaging. 
Storage conditions are specified in Section 2.8. 
One ml of HYLO-FORTE® contains 2 mg sodium hyaluronate, citric acid anhydrous, sodium 
citrate, sorbitol and water for injections.
 
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3.4 
DESCRIPTION OF THE CLINICAL DEVELOPMENT STAGE 
The investigation is defined as a post-market stage (refer to ISO 14155:2020). The clinical 
investigation design is confirmatory. 
4 
BENEFITS AND RISKS OF THE IMD, CLINICAL PROCEDURE 
AND CLINICAL INVESTIGATION 
4.1 
ANTICIPATED CLINICAL BENEFITS 
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4.3 
RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL 
INVESTIGATION 
Laboratoires THÉA performed a risk analysis according to the current ISO 14971 standard. 
All risks identified in Laboratoires THÉA’s risk analysis were mitigated. The remaining 
residual risks were considered to be of negligible or acceptable levels. This is fully described 
in the Risk Management Report (RMR). The risks mitigated to this latter risk level (acceptable) 
are described in section 4.5.  
All the possible warnings have been put in place in the instructions for use as well as on the 
secondary and primary packaging if possible.  
These hazards cannot arise in the normal conditions of use. 
4.4 
POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL 
TREATMENTS 
To avoid possible interactions with a concomitant treatment, patients will be asked to wait at 
least 15 minutes between use of the IMD and any other eye product. 
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5 
OBJECTIVES 
AND 
HYPOTHESES 
OF 
THE 
CLINICAL 
INVESTIGATION 
5.1 
CLAIMS FOR CLINICAL PERFORMANCE, EFFECTIVENESS OR 
SAFETY OF THE IMD 
There is no claim concerning the clinical performance of THEALOZ TOTAL in the IFU. 
However, the following clinical performances support the claimed clinical benefits: 
- 
THEALOZ TOTAL reduces ocular surface damages. 
- 
THEALOZ TOTAL increases tear film stability/quantity. 
As per the IFU, the claim on clinical safety is: 
- 
THEALOZ TOTAL is well tolerated on the ocular surface. 
As per the IFU, the clinical benefits of THEALOZ TOTAL are:  
- 
THEALOZ TOTAL relieves from the symptoms of dry eyes. 
- 
THEALOZ TOTAL soothes the eyes from itchiness and irritation. 
- 
THEALOZ TOTAL reduces the redness of the eyes. 
As per Laboratoires THÉA, other clinical benefit of THEALOZ TOTAL is improvement of 
(global) ocular comfort. 
5.2 
OBJECTIVES, PRIMARY 
 
The primary objective of the investigation is to demonstrate the non-inferiority of T2769 
compared to Hylo-Forte® in terms of total ocular surface staining (Oxford score) in patients 
with moderate to severe DES. 
 
5.3 
SCIENTIFIC JUSTIFICATION AND CLINICAL RELEVANCE FOR 
EFFECT SIZES, NON-INFERIORITY MARGINS OR EQUIVALENCE 
LIMITS 
Estimation of the standard deviation and determination of the non-inferiority limit are based 
upon data of previous studies and literature. 
Concerning the non-inferiority limit, according to clinicians, a variation not exceeding 2 points 
in the total Oxford grade is considered as not clinically significant (Labetoulle et al. 2022; 
Chiambaretta et al. 2017; Baudouin et al. 2012). 
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5.5 
RISKS AND ANTICIPATED ADVERSE DEVICE EFFECTS  
There are no specific risks and ADE to be assessed during this clinical investigation. 
6 
DESIGN OF THE CLINICAL INVESTIGATION 
6.1 
GENERAL 
6.1.1 
Justification of the Investigation Design 
Methodology: a 5-week, international, multicentre, randomised, investigator-masked, 2 parallel 
groups (T2769 versus Hylo-Forte®) investigation. 
- 
Multicentre  
The investigation will be performed in different sites in EU. 
A multicentre (and multi-investigator) design will provide the possibility of recruiting the 
patients from a wider population than a single-centre design and of using the device in a broader 
range of clinical settings, thus presenting an experimental situation that is more typical of future 
use. In this case, the involvement of a number of investigators also gives the potential for a 
wider range of clinical judgments concerning the value of the therapeutic intervention. In 
addition, it is also a practical means of accruing sufficient patients to satisfy the investigation 
objective.       
- 
Randomised 
At the randomisation visit on Day 1, a patient fulfilling all eligible criteria will be randomly 
assigned to 1 of the 2 treatment groups (T2769 or Hylo-Forte®). Randomisation ensures the 
investigator remains masked to product assignment for DES treatment. It is generally 
considered the most reliable method for evaluating the effects of interventions.  
- 
Choice of run-in period 
Patients meeting the screening criteria will undergo a 7-10-days run-in period. During this 
period, all patients will substitute their current dry eye treatment with Hydrabak®, ophthalmic 
solution containing NaCl 0.9%. Patients will instill 1 drop in each eye, from 3 to 6 times daily. 
 
 
 
(Baudouin et al. 2017; Chiambaretta et al. 2017; Labetoulle et al. 2018; Holland et al. 
2019). 
 
 
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- 
Investigator-masked  
A double-masked investigation design is not possible due to different commercial packaging 
between T2769 – Hylo-Forte®. 
However, the identity of the IMD given to each patient will not be known for the masked 
investigator who is independently in charge of the ophthalmic examination.  
To this aim, the masked investigator will differ from the person who will record the used/unused 
IMDs. The recording will be delegated either to the hospital pharmacy or to a trained 
collaborator (trained by the masked investigator; hereafter referred to as unmasked 
collaborator). Therefore, the masked investigator should not receive the returned IMDs from 
the patients and returned IMD must be stored in a different place from the IMD that have not 
yet been dispensed. Patients will also be trained to not report any information that could lead to 
unblinding in the diary and to the masked investigator.  
If the masked investigator become unmasked, then the patient continues the clinical 
investigation. The patient data will be handled accordingly for the analysis. 
- 
Choice of the comparator group  
 
 
 
  
 
- 
Choice of the investigation population  
 
 
. 
- 
Scheme of administration 
The dose regimen recommended is 1 drop in each eye, from 3 to 6 times daily. 
- 
Choice of the treatment period 
A 5-week treatment period may allow to evaluate the therapeutic effect and to observe any 
potential safety issues.  
A period of 1 month is usually the minimum time required to demonstrate the therapeutic effect 
of a product. 
- 
Choice of primary endpoint 
 
The primary 
endpoint  of this clinical investigation (total ocular surface staining 
(Oxford scale), 
 
 
 (Jones et al. 2017; Aragona et al. 2019; 
Fariselli et al. 2018; Mateo Orobia et al. 2017; Nasser et al. 2018; Pinto-Bonilla et al. 2015; 
Chiambaretta et al. 2017; Novack et al., 2017; Wolffsohn et al., 2017; Begley et al., 2019; 
Nichols et al., 2021; Begley et al., 2022). Consequently, these endpoints are clinically relevant, 
clearly defined and assessed at specified time points in order to provide clinical evidence on the 
efficacy 
 of T2769 in its intended use (i.e., improvement of the ocular signs and 
symptoms in DED patients). 
 
 
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-
Symptom assessment 
Ocular symptoms (except symptoms immediately after drop instillation, not assessed at 
inclusion) as well as AEs will be assessed at all investigation visits.
6.1.2
Description of the Measures to be Taken to Minimize or Avoid Bias
Randomisation
The use of randomisation attempts to mitigate accidental bias (such as selection bias), 
promoting comparability of the study groups and serves as a basis for statistical inference for 
quantitative evaluation of the treatment effect.
The randomisation code list stratified by site and lists of IMDs kit numbers for the packaging
is generated by the CRO responsible for biometry. Patients will be randomised on a 1:1 basis 
to T2769 or Hylo-Forte® respectively.
Randomisation list(s) and lists of IMD numbers for the packaging are to be kept securely by 
the editor according to their procedures.
The IMD packaging list is to be kept by the company responsible for manufacturing and 
labelling of the treatment kits.
The randomisation and the IMD kit number will be allocated to the patients according to 
randomisation list using an Interactive Response Technology (IRT).
Randomisation will occur at Randomisation Visit (Visit #2 - D1) after all procedures have been 
performed and eligibility for the clinical investigation confirmed. The patient who meets the 
eligibility criteria will be randomly assigned to treatment and associated to a randomisation 
number.
Concealment of Allocation
Concealment of allocation will be ensured using an IRT system to perform IMD kit number
allocation so that it’s not possible for the investigators to know the allocation sequence in 
advance.
Masking and Code Breaking
Serious biases may occur in a clinical investigation including investigator bias (which may arise 
due to knowledge by the investigator of treatment allocated to a particular patient), evaluator 
bias and placebo effects. To protect an investigation against these potential biases, masking will 
be used.
This will be an investigator-masked clinical investigation.
The masked investigator will remain masked to the IMD (T2769 – Hylo-Forte®). He/she will 
not receive the returned IMD from the patients.
The following-up and the number of returned IMDs will be recorded by unmasked 
collaborator throughout the clinical investigation.
The unmasked collaborator will also be in charge of incidents reporting as it may include 
information that could lead to unblinding.
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Masking will be achieved by coding the interventions, providing each product unit with 
identical cardboard box and by identifying it by an IMD kit number.
The code should not be broken except:
•
in case of medical emergency (where knowledge of the IMD received would affect 
the treatment of the emergency),
•
or when it is a regulatory requirement (e.g., for serious incident).
The investigator is responsible for accessing the IRT System to obtain the name of the IMD 
received by the patient.
If an emergency code breaking becomes necessary, the investigator should notify the Sponsor.
When a code is broken, the date, time and reason must be recorded in the patient’s Source and 
in any associated AE report. The identity of the IMD should not be disclosed in these 
documents.
The incident form must be completed by unmasked staff. Further to a serious incident 
assessment by the Global Drug Safety & Medical Information Department, the code might be 
broken for reporting purposes. The relevant Laboratoires THÉA, Contract Research 
Organization (CRO), masked investigator and masked staff remain unaware of the 
identification of the IMD as per the above-mentioned process.
The overall randomisation list will be broken for data analysis after database lock.
Management of potential confounding factors
NA
Dispensing 
IMD will be dispensed by the masked collaborator and/or pharmacist or authorised person 
delegated by the investigator and according to the local regulations. Each dispensing of IMDs
will be recorded in the appropriate documentation.
During the whole investigation treatment period, the masked investigator and/or delegate will 
remain masked to the IMD (T2769 – Hylo-Forte®). He/she will not receive the returned IMD
from the patients.
All information regarding the use of the IMDs will be contained in the package given to patients.
The IMDs must be dispensed only to patients in accordance with the CIP and the randomisation.
As soon as the patient has signed the Informed Consent, he/she will receive a patient number 
in the Electronic Case Report Form (e-CRF).
Once all screening criteria have been checked, the patient will receive a box including Run-in 
Hydrabak® treatment for the run-in period.
At the randomisation visit (Visit #2 - D1), once inclusion and exclusion criteria have been 
checked and once the patient is eligible, the randomisation will be performed and the IRT will 
provide the IMD kit number allocated to the patient.
At the other visit (Visit #3 - D15) with dispensation, the IRT will provide the IMD kit number 
allocated to the patient.
Two dispensations will be performed as follows:
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At randomisation (Visit #2 - D1): one box containing enough bottles for the treatment 
period Day 1 to Day 15 ± 1 day will be provided by the investigator (or delegate) or 
pharmacist with the number assigned by the IRT.
-
At Visit #3 - D15: one box containing enough bottles for the treatment period Day 15± 
1 day to Day 36 ± 3 days will be provided by the investigator (or delegate) or pharmacist 
with the number assigned by the IRT.
The site team member will instruct patient on the method of instilling the doses and will train 
his / her patient to not disclose the IMD characteristics neither during the visit not when 
reporting / discussing AE / Device Deficiency (DD). If the IMD is dispensed by a masked 
investigator, he must not open the IMD kit in order to avoid unblinding.
 
Primary Performance Endpoint
The primary performance endpoint is the change from baselinea (D1) in total ocular surface 
staining grade according to Oxford 0-15 grading schemeb at D36 in the study eyec.
It is the most commonly used endpoint in clinical trials with DED patients. It is performed to 
detect ocular damage surface, which is considered as a hallmark sign of DED.
As per literature, 1 month is a standard approach, commonly considered enough to assess a
product performance in dry eye. In addition, in the previous clinical investigation on T2769
conducted by Laboratoires THÉA (CIR LT2769-001/17E1044), the improvement was rapidly 
observed after 14 days of treatment (see Section 3.3).
Thus, the change from baseline (D1) in total ocular surface staining grade according to Oxford 
0-15 grading schemeb (corneal staining by fluorescein and conjunctival staining by fluorescein
with a yellow filter at D36 in the study eyec) was set as the primary performance endpoint to 
evaluate the performance of the treatment.
Different ocular surface staining scales have been developed and despite common usage, a 
universally accepted “gold standard” grading scale does not exist for corneal and conjunctival 
staining. This investigation will use the Oxford scale, a widely used and standardised grading 
scale. International regulatory agencies such as the Food and Drug Administration (FDA) rely 
on corneal and conjunctival staining measurement as a primary endpoint in clinical trials of 
commercially registered dry eye treatments (Begley et al. 2019).
abaseline is defined as the assessment at randomisation visit before the first IMD instillation. Missing value at 
randomisation visit will not be replaced.
bthe analysis will be performed following original oxford scale 
cdefined in the statistical considerations section (see Section 7.2).
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Safety Endpoints
The following safety 
 endpoints will be assessed:
x
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred 
Term (separately for ocular and systemic TEAE).
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6.1.5 
Methods and Timing for Assessing, Recording, and Analysing 
Variables 
Four visits are scheduled during the course of the clinical investigation as presented below: 
Visit#1 (Screening Visit): Day 1-10 to Day 1-7 (Run-in Period) 
Visit#2 – D1 (Randomisation Visit): Day 1 
Visit#3 – D15: Day 15 (±1 day) 
Visit#4 – D36 (Final Visit): Day 36 (±3 days) or Premature Discontinuation Visit. 
Visits should be performed at the same hour (±2 hours) in the morning. 
 
 
 
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Screening Period
Visit#1: Screening Visit (Day 1-10 to /Day 1-7)
Visit#1 will consist of the following procedures and examinations by the investigator or authorised
delegate who will perform the ophthalmologic examination during all the visits and according to 
the following order in each eye.
By the masked investigator or authorised delegate (according to local requirements, the
investigator may delegate tasks to collaborator).
x
Information for the patient and signature of the informed consent (can be done before this visit, 
see Section 13).
x
Demography
x
History of the dry eye
x
Questioning about ocular and systemic medical, and surgical history (other than dry eye)
x
Questioning about previous and concomitant ocular and non-ocular treatments
x
Urine pregnancy testing (if applicable)
x
Measurement of far BCVA*
x
Slit lamp examination*
x
Verification of inclusion and exclusion criteria
x
Status of the patient (start of run-in period or not)
x
Run-in treatment dispensation
x
Patient diary dispensation.
x
The following instructions will be given to the patient:
The next visit must be scheduled within 7 to 10 days later at the same hour, in the morning (± 
2 hours).
Site staff must remind the patients:
Ͳ how to complete the patient diary,
Ͳ to bring the patient diary back at Visit #2,
Ͳ how to instil Hydrabak® and to respect the posology of 1 drop in each eye, from 3 to 6 
times daily,
Ͳ that no preservative-free artificial tears (Hydrabak®) must be instilled for at least 6 hours 
before Visit#2,
Ͳ to bring back used preservative-free artificial tears (Hydrabak®) for compliance check at 
Visit#2.
The run-in period duration will be calculated based on the start and end dates of Hydrabak®. The 
start and end dates of run-in period will be the start date of Hydrabak® and the end of run-in period 
will be the end date of Hydrabak®.
*Ophthalmological examinations and assessments MUST be performed by the SAME masked investigator for all 
the visits and using the same slit lamp.
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Treatment Period
Visit#2: Randomisation Visit (Day 1)
Visit#2 will consist of the following procedures and examinations by the investigator or 
authorised delegate who will perform the ophthalmologic examination during all the visits and 
according to the following order in each eye.
By the masked investigator or authorised delegate, the same as the screening visit (according 
to local requirements, the investigator may delegate tasks to collaborator).
x
Questioning about previous and concomitant ocular and non-ocular treatments
x
OSDI Questionnaire
x
DEAL questionnaire
x
Ocular discomfort (VAS)
x
Questioning about dry eye related ocular symptoms within the last 48 hours
x
Measurement of Far BCVA*
x
Tear Sampling for IL6 and IL8 concentration assessment**
x
Slit lamp examination* for measuring:
-
Measurement of conjunctival hyperaemia*
 
-
 Oxford 0-15 grading scheme* (corneal staining by fluorescein and 
conjunctival staining by fluorescein with yellow filter),
-
TBUT*
x
Schirmer test* (without anaesthesia)
x
AE reporting
x
Verification of inclusion and exclusion criteria
x
Randomisation (IRT system)
x
IMD dispensation
x
Questioning about Run-in treatment compliance
x
Check of the patient diary completion with the patient
x
Status of the patient (Screen failure or randomised)
By the unmasked collaborator:
x
Incidents reporting
The next visit must be scheduled 15 days after Visit #2 (±1 day) at the same hour (± 2 hours).
Site staff must remind the patients:
Ͳ how to complete the patient diary, 
Ͳ to not report any information that could lead to unblinding in the diary,
Ͳ to not report any information that could lead to unblinding to the masked investigator,
Ͳ to bring the patient diary back at Visit #3,
Ͳ how to instil IMD and to respect posology of 1 drop in each eye, from 3 to 6 times daily,
Ͳ that no IMD must be instilled for at least 2 hours before Visit#3.
*Ophthalmological examinations and assessments MUST be performed by the SAME masked investigator for all 
the visits and using the same slit lamp.
**It’s necessary to wait at least 15 minutes after tear sampling to perform the next ophthalmic assessment.
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Visit#3: Day 15 (± 1 day) 
Visit#3 will consist of the following procedures and examinations by the investigator or 
authorised delegate who will perform the ophthalmologic examination during all the visits and 
according to the following order in each eye. 
By the masked investigator or authorised delegate (the same as the screening visit) (according 
to local requirements, the investigator may delegate tasks to collaborator). 
x Questioning about previous and concomitant ocular and non-ocular treatments 
x OSDI Questionnaire 
x DEAL questionnaire  
x Ocular discomfort (VAS) 
x Questioning about ocular symptoms immediately after drop instillation,  
x Questioning about dry eye related ocular symptoms within the last 48 hours 
x Assessment of global performance by the patient 
x Assessment of the ocular tolerance by the patient 
x Measurement of Far BCVA* 
x Tear Sampling for IL6 and IL8 concentration assessment** 
x Slit lamp examination* for measuring: 
- Measurement of conjunctival hyperaemia* 
 
 
- 
 Oxford 0-15 grading scheme* (corneal and conjunctival staining by 
fluorescein with yellow filter) 
- TBUT* 
x Schirmer test* (without anaesthesia) 
x AE reporting 
x Assessment of the ocular tolerance by the investigator 
x Assessment of the performance by the investigator 
x IMD dispensation 
x Questioning about IMD compliance  
x Check of the patient diary completion with the patient 
 
 
 
 
 
 
 
 
 
 
 
*Ophthalmological examinations and assessments MUST be performed by the SAME masked investigator for all 
the visits and using the same slit lamp. 
**It’s necessary to wait at least 15 minutes after tear sampling to perform the next ophthalmic assessment. 
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By the unmasked collaborator: 
x 
Recording the number of returned used and unused IMD in source document (the 
accountability is expected for the quantity of bottles) and transfer this information to masked 
investigator for compliance assessment. 
x 
Incidents reporting 
The next visit must be scheduled 36 days after Visit #2 (±3 days) at the same hour (± 2 hours). 
Site staff must remind the patients: 
Ͳ how to complete the patient diary, 
Ͳ to not report any information that could lead to unblinding in the diary, 
Ͳ to not report any information that could lead to unblinding to the masked investigator, 
Ͳ to bring the patient diary back at Visit #4. 
Ͳ how to instil IMD and to respect the posology of 1 drop in each eye, from 3 to 6 times 
daily, 
Ͳ that no IMD must be instilled for at least 2 hours before Visit#4. 
Visit#4: Day 36 (± 3 days) 
Visit#4 will consist of the following procedures and examinations by the investigator or 
authorised delegate who will perform the ophthalmologic examination during all the visits and 
according to the following order in each eye. 
By the masked investigator or authorised delegate (the same as the screening visit) (according 
to local requirements, the investigator may delegate tasks to collaborator). 
x Questioning about previous and concomitant ocular and non-ocular treatments 
x OSDI Questionnaire 
x DEAL questionnaire 
x Ocular discomfort (VAS) 
x Questioning about ocular symptoms immediately after drop instillation, 
x Questioning about dry eye related ocular symptoms within the last 48 hours 
x Assessment of global performance by the patient 
x Assessment of the ocular tolerance by the patient 
x Measurement of far BCVA* 
x Tear Sampling for IL6 and IL8 concentration assessment** 
x Slit lamp examination* for measuring: 
- Measurement of conjunctival hyperaemia* 
 
 
- 
Oxford 0-15 grading scheme* (corneal and conjunctival staining by 
fluorescein with yellow filter) 
- TBUT* 
x Schirmer test* (without anaesthesia) 
x Urine pregnancy testing  
x AE reporting 
 
*Ophthalmological examinations and assessments MUST be performed by the SAME masked investigator for all 
the visits and using the same slit lamp. 
**It’s necessary to wait at least 15 minutes after tear sampling to perform the next ophthalmic assessment. 
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x
Assessment of the ocular tolerance by the investigator
x
Assessment of the performance by the investigator
x
Questioning about IMD compliance
x
Check of the patient diary completion with the patient
By the unmasked collaborator:
x
Recording the number of returned used and unused IMD in document source (the 
accountability is expected for the quantity of bottles) and transfer this information to masked 
investigator for compliance assessment.
x
Incidents reporting
Additional/Optional Visit(s) during the clinical investigation
NA
Premature Discontinuation Visit during the clinical investigation
A patient who prematurely discontinues from the clinical investigation should have, if 
possible, a Premature Discontinuation Visit. This last site visit should take place as soon as 
possible after the patient stops taking IMD. All follow-up procedures and examinations 
scheduled to be performed at the final visit should be performed at the patient’s premature 
discontinuation visit.
If the patient is tested COVID-19 positive during the course of the clinical investigation, the 
patient has to inform the investigator. Either the patient may continue the clinical
investigation when he/she can follow the CIP requirements safely and in accordance with 
the national/regional recommendations or the patient may be withdrawn from the clinical 
investigation.
Additional Follow-Up Visit(s) (after the end of the treatment)
NA
Adaptive Follow-Up of Patients Prematurely Withdrawn due to an 
Exceptional Circumstance (e.g. COVID-19 pandemic)
The benefit/risk ratio will be evaluated both by the Sponsor at global level (regulatory
requirement) and by the investigator regarding the situation and local regulatory requirements
in his/her country/region and in his/her own investigational site.
If the patient withdrew from the investigation due to an exceptional circumstance, and if an 
onsite visit was not authorised, a premature discontinuation visit by phone is required. 
-
Premature discontinuation phone call
-
Check the IMD compliance with the patient.
-
Instruct the subject to stop the IMD and keep used and unused IMD for later return.
-
Ensure the continuity of artificial tears medication as per routine clinical practice.
-
Collect AE/Serious Adverse Event (SAE), incidents and any changes in concomitant 
treatments.
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- 
Plan a safety onsite visit 4 weeks later (±7 days) and ensure that the patient understands all 
recommendations.  
- 
Record the phone call and all information collected in the patient medical record. 
-  Safety Follow-up visit on site 
During the onsite follow-up visit done 4 weeks (±7 days) after the premature discontinuation 
phone call, the following procedures are required: 
- 
Ensure that dry eye is well controlled. 
- 
Check the IMD compliance with the patient.  
- 
Record the number of the returned used and unused IMD (by the authorised 
unmasked delegate). 
- 
Check that the patient had stopped the IMD and takes the new treatment, collect 
start and end dates of these medications. 
- 
Collect AE/SAE, incidents and any changes in treatments. 
- 
Record the visit and all information collected in the patient medical record. 
If a safety onsite visit is still not possible, the follow-up will be done by phone or online video 
consultation and the patient is asked to return the used and unused investigation products later, 
when the situation improves or the pickup of the IMD directly from the patient will be organised. 
The compliance will be checked with the number of the returned used and unused IMD. 
6.1.6 
Equipment to be used for Assessing the Clinical Investigation 
Variables and Arrangements for Monitoring Maintenance and 
Calibration 
A slit lamp will be used to measure the total ocular surface staining grade according to 
 
Oxford 0-15 grading scheme. 
During the Site Qualification Visit and the Site Initiation Visit, the site must prove that he has 
a maintenance certificate for the slit lamp. During the clinical investigation, the monitor should 
verify that the maintenance is performed (cf. manufacturer guidelines). 
During the clinical investigation, the same slit lamp must be used for the same patient at each 
visit.  
6.1.7 
Procedures for the Replacement of Patients  
The number of screened patients will be followed to obtain 74 randomised patients. 
A screen-failed patient (i.e. patient who consent to participate in the clinical investigation and 
undergo Visit#1 but not subsequently randomised) may be rescreened one time. 
Randomised patients who withdraw will not be replaced by another patient. The patient number 
and associated randomisation number of the withdrawn patient must not be reassigned to a 
different patient. 
6.1.8 
Investigation Sites 
Patients will be enrolled in approximately 4 investigational sites in EU. 
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The Sponsor will maintain an updated list of PIs and investigation sites, separately from this 
CIP, throughout the duration of the clinical investigation. The definitive list will be provided 
with the CIR.
6.1.9
Definition of Completion of the Clinical Investigation
The clinical investigation completion is defined with the last visit of the last patient.
In the case of early termination of the clinical investigation (see Section 16.2), the date of the 
early termination shall be deemed to be the date of the clinical investigation completion.
6.2
IMD(S) AND COMPARATOR(S)
6.2.1
Description of the Exposure to the IMD
IMD will be administered by the patient every day from D1 until Visit 4 (included), one drop 
in each eye 3 to 6 times daily into the lower conjunctival sac of each eye.
No IMD instillation must be done at least 2 hours before Visit#3 and 4. However, the first 
instillation can be done any time after the patient has completed the randomisation visit.
There will be two treatment groups:
• T2769 (test device)
• Hylo-Forte® (comparative device)
A detailed description of T2769 and of Hylo-Forte® is available in Section 0.
6.2.2
List of any Other Medical Device or Medication to be Used during 
the Clinical Investigation
Run-in Treatment
Once all screening criteria have been checked, the patient will receive a box containing 1 bottle
of Hydrabak® treatment for the run-in period between Day-10/Day-7 to Day 1. The patient will 
instil 1 drop in each eye 3 to 6 times daily.
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Auxiliary Products
An auxiliary product is defined as a product used for the needs of a clinical investigation 
as described in the CIP, but not as an IMD.
Fluorescein 
a small amount (micro instillation) of fluorescein will be 
applied in the upper bulbar conjunctiva of each eye by the investigator at visits 2, 3 and 4 to 
perform the slit lamp examination: TBUT and corneal/conjunctival staining with Oxford 0-15 
grading scheme. Conjunctival staining is assessed with a yellow filter.
Yellow filter: it is used for the assessment of the conjunctival staining with fluorescein. The 
filter is placed between the slit lamp objective and the patient eye to enhance contrast. 
Petri dishes and inoculation loops: they are used to perform the fluorescein micro instillation. 
Some drops of fluorescein are put in a petri dish and a small amount of fluorescein is collected 
with an inoculation loop.
Schirmer-Plus: while the patient looks upwards, the lower lid will be drawn gently downwards
and temporally. The rounded bent end of a sterile Schirmer test strip will be hooked in the lower
conjunctival sac over the temporal one-third of the lower eyelid margin. After five minutes, the
moistened paper is removed and the length of the tear absorption on the strip will be measured
(in millimeters).
Urine pregnancy test: each childbearing potential woman will perform a urine pregnancy test 
at Visit#1 and Visit#4.
6.2.3
Number of IMD to be Used, Together with a Justification
During the clinical investigation, each patient will receive 1 bottle of Hydrabak® and the IMD
(4 bottles of T2769 or Hylo-Forte®) to cover run-in and active treatment period.
6.3
PATIENTS
6.3.1
Inclusion Criteria
x
At screening visit
1.1. Informed consent signed and dated (obtained prior to initiating any procedures).
1.2. Patient aged ≥18 years old. 
1.3. Persistence of dry eye syndrome, despite artificial tears use in the previous month prior 
to the screening visit.
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6.3.2 
Exclusion Criteria 
Patient will NOT be eligible if ONE OR MORE of the following criteria is met at both screening 
and randomisation visits. 
Ophthalmic Exclusion Criteria in AT LEAST ONE EYE [2.1] 
2.1.1 Far best-corrected visual acuity (BCVA) ≥+0.7 LogMar (e.g., ≤0.2  
in 
decimal 
value or ≤20/100 Snellen equivalent or ≤50 (ETDRS). 
 
 
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Patient with previous or current ophthalmic condition as defined in the following table:  
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6.3.3 
Criteria and Procedures for Treatment/Investigation Withdrawal or 
Discontinuation 
There are no pre-defined criteria for temporary or permanent treatment discontinuation apart 
from those listed below. 
The patient may voluntarily withdraw from the clinical investigation at any time without 
penalty and for any reason without prejudice to his/her future medical care (Declaration of 
Helsinki). 
The patient must be withdrawn from the clinical investigation if, in the opinion of the 
investigator, there is any situation or condition which puts the patient at significant risk, 
especially in case of: 
- 
Any safety reason(s)/AEs necessitating discontinuation from the investigation, 
- 
Any abnormality with IMD, 
- 
Lack of performance: if the patient or the investigator does not feel that the IMD has 
sufficiently controlled the pathology/has adequately relieved his/her symptoms, 
- 
Patient compliance, 
- 
Patient’s request, 
- 
Any exceptional circumstance (e.g., COVID-19 pandemic), 
- 
Other reasons. 
If a patient has received a prohibited medication, the investigator may withdraw the patient 
from the clinical investigation if it can interfere with the patient safety or data integrity. If no 
risk is identified, the patient may continue the clinical investigation. This will be recorded as a 
protocol deviation and managed accordingly. The Sponsor may also make the decision to 
withdraw a patient if a risk is suspected. 
If a patient prematurely stops the IMD or should/wants to prematurely withdraw from the 
clinical investigation for any reason, the investigator (or delegated assessor) must make every 
effort to perform all the evaluations described for the Final Visit (Visit#4) as soon as possible.  
The investigator (or delegated assessor if physician) will prescribe the best appropriate 
treatment to the patient. 
Additionally, Sponsor can terminate the clinical investigation per reasons discussed in Section 
16.2. 
In all cases, the reason(s) for withdrawal, must be recorded on the patient files (source 
documentation) and the primary reason, must be recorded on the e-CRF.  
The patient discontinued for AE(s) will be followed-up after discontinuation until the event is 
resolved or considered medically stable by the investigator. 
If a patient is lost-to-follow-up, the investigator must do his/her best to contact the patient 
initially by phone, then by letter, and finally by certified mail. If no response is obtained from 
the patient, the investigator is encouraged to contact one of the patient’s relatives or his/her 
general practitioner. The evidence of these contacts must be recorded in the patient files. 
Screen failures are defined as patient who consent to participate in the clinical investigation and 
undergo Visit#1 but are not subsequently randomised in the clinical investigation. 
If a patient is screen-failed, all reasons of screen-failure must be documented in the Source 
document. The screen-failed patient may be rescreened one time. 
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The Procedures for the replacement of patients is described in section 6.1.7. 
Adaptive follow-up in the case of an exceptional circumstance (e.g. COVID-19 pandemic) 
is described in section 0.0 
6.3.4 
Point of Enrolment 
The point of enrolment corresponds to the time at which a patient signs and dates his/her consent 
form. Patients are to be enrolled at about 4 investigational sites in EU. 
6.3.5 
Point of Randomisation 
The point of randomisation corresponds to the time at which a patient is assigned with a 
randomisation number. This randomisation number will be allocated when all Inclusion / 
Exclusion criteria are verified.  
6.3.6 
Total Expected Duration of the Clinical Investigation 
This investigation is planned to start in August 2024 and to be completed in April 2025. 
6.3.7 
Expected Duration of each Patient's Participation 
The treatment period for each patient is 36 ± 3 days for a total maximum investigation duration 
of 49 days (maximum days comprising the run-in, treatment period). 
6.3.8 
Number of Patients Required to be Randomised in the Clinical 
Investigation 
It is planned to randomise 74 patients in order to have 68 evaluable patients (34 per group) for 
the FAS analysis. 
Evaluable patients will be defined as randomised patients having received at least one dose of 
IMD and with at least one performance endpoint post-randomisation visit. 
6.3.9 
Estimated Time Needed to Select this Number (i.e. enrolment period) 
The enrolment period is estimated at about 6 months. 
6.3.11 Information on Vulnerable, Pregnant, and Breastfeeding Population 
This clinical investigation will not be conducted in vulnerable populations as children, pregnant 
or breastfeeding women. A urine pregnancy testing will be performed at Visit#1 and Visit#4 
(See Section 15). 
 
 
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6.4
PROCEDURES
Some procedures must be performed by the same masked investigator or the same authorized
assessor/delegate throughout the clinical investigation (Far BCVA, Slit Lamp Examination, 
Schirmer test, tolerance/performance assessment by investigator).
6.4.1
Description of all the Clinical-Investigation-Related Procedures that 
Patients Undergo during the Clinical Investigation.
Demographics and Screening Characteristics
The following characteristics will be collected:
Ͳ
Age (in years),
Ͳ
Sex,
Ͳ
Previous and concomitant ocular and non-ocular medications,
Ͳ
Result of the urinary pregnancy test (only for women of childbearing potential),
Ͳ
History of the investigated disease,
Ͳ
Ocular medical and surgical history with relevant diagnosis other than the investigated 
disease,
Ͳ
Systemic medical and surgical history with relevant diagnosis
Performance Measures
Ocular Surface Disease Index (OSDI) Questionnaire
The OSDI questionnaire (Schiffman et al., 2000; Miller et al., 2010) must be completed by the 
patient at the beginning of a visit before medical history information is collected or any 
investigation assessments are performed. The total OSDI score range on a scale from 0 to 100
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Ocular discomfort (VAS)
Ocular discomfort (global evaluation for both eyes) will be assessed by the patient at D1, D15 
and D36 visits according to the following: 
“Please mark a vertical line (not a cross) on the horizontal line, indicating your level of ocular 
discomfort due to ocular dryness within the last 48 hours”. VAS will be a 100 mm line: 0 mm 
= No discomfort, 100 mm = Maximal discomfort.
0
100
No discomfort
Maximal discomfort
Dry eye related ocular symptoms throughout the day within 
the last 48 hours
Patient will be asked: “How do you judge the severity of the following ocular symptoms 
throughout the day within the last 48 hours, excluding the symptoms you felt immediately after 
instillation?”
The severity of the following ocular symptoms will be assessed: burning/irritation, stinging/eye 
pain, light sensitivity, itching/pruritus, eye dryness feeling, tearing, foreign body sensation as 
follows:
0 = Absent 
1 = Mild, present but not disturbing 
2 = Moderate, disturbing, but not limiting with daily activities 
3 = Severe, very distressing and interfering with daily activities 
The ocular symptoms will be assessed in global for both eyes at D1, D15 and D36 visits. The 
value at D1 will be the baseline value.
x
Conjunctival hyperaemia
The level of severity of conjunctival hyperaemia will be scored 
 
 in each eye and at D1, D15 and D36 visits (see Section 19.4).
x
Tear Break-Up Time (TBUT)
The tear film stability will be measured 3 times after the instillation of fluorescein. TBUT will 
be rapidly assessed and expressed in seconds. The sum of the 3 measures will also be expressed 
in seconds. TBUT will be measured in each eye and at D1, D15 and D36 visits.
x
Ocular surface staining (
Oxford scale)
The total ocular staining grade using 
 Oxford 0-15 grading scheme will be assessed at 
D1, D15 and D36 visits by staining in corneal area by fluorescein and conjunctival areas 
(temporal and nasal) by fluorescein with a yellow filter.
Cornea and conjunctiva staining is represented by punctate dots on a series of panels (A-E). 
Staining ranges form 0-5 for each zone and from 0-15 for the total exposed inter-palpebral 
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conjunctiva and cornea. The dots are ordered on the log scale (
Oxford scale) (see
Section 19.5).
The score for each area will be recorded for each eye. The global score (sum of score reported 
for each area: corneal + conjunctival) will be used for statistical analysis. The statistical analysis 
will be performed following original oxford scale 
TBUT and ocular surface staining will be assessed after micro instillation of fluorescein. Some 
drops of fluorescein are put in a petri dish and a small amount of fluorescein is collected with 
an inoculation loop and then applied to the upper bulbar conjunctiva. This process will be 
detailed in a specific guide provided to investigation sites.
A slit lamp examination will also be performed at Visit #1 (Screening visit) for evaluation of 
the prohibited ophthalmic conditions in order to verify the ocular eligibility.
The Schirmer test will be performed without anaesthesia (Test I). The test should be done 
without touching directly the strip with the finger to avoid contamination of skin lipids. 
The strip should be placed in the temporal part to avoid any contact with the cornea. The patient 
should keep the eyes closed. Values should be measured just at the end of the 5 minutes.
The Schirmer test will be measured in mm/5 min in each eye and at D1, D15 and D36 visits.
Performance Assessment by the investigator
The investigator must answer to the following question at the end of the patient examination at 
D15 and D36:
“Do you consider the IMD performance as:
-
Very satisfactory 
-
Satisfactory 
-
Not very satisfactory 
-
Unsatisfactory”
Global performance by patient
The global performance is assessed by the patient using a vocal NRS scale. The investigator 
must ask the following question in local language:
“In a scale from 0 to 10, where 0 is COMPLETELY UNSATISFIED and 10 is COMPLETELY 
SATISFIED, indicate the number which corresponds the best to your overall satisfaction with 
the efficacy of the study product in treating your dry eye” (see Section 19.7).
The patient must answer the question verbally.
Tear level of inflammatory cytokines (IL-6 and IL-8)
A tear sampling of at least 5 μL will be performed at D1, D15 and D36 in the study eye using 
a method which is defined in a specific guide. The sample will be analysed by central laboratory 
in order to assess the level of inflammatory cytokines in tears. The Tear sampling will be done 
after answer to patients’ questionnaires and before ocular examinations.
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To prevent the tear sampling from interfering with other ocular assessments, it will be required 
to wait at least 15 minutes after the sampling is performed to continue with the next ocular 
assessment.
Safety measures
Adverse Events
Ocular and systemic AEs will be collected by the investigator (or authorised assessor/delegate) 
at each visit. In case of appearance of a new clinically significant sign or symptom, it should be 
reported as an AE. In case of clinically significant worsening of a pre-existing sign or symptom, 
it should be reported as an AE.
The handling of AEs is detailed in Section 0.
Incidents
Incidents will be collected by the unmasked investigator (or authorised assessor/delegate) at 
D1, D15 and D36 visits.
Ocular Symptoms immediately after drop instillation
The severity of ocular symptoms immediately after drop instillation will be assessed by the 
patient.
“Since the last visit, have you felt any unusual ocular sensation immediately after drop
instillation(s)?
The following symptoms will be evaluated:
-
Burning/Irritation 
-
Stinging/Eye Pain
-
Itching/pruritus
-
Eye dryness feeling
-
Foreign body sensation
-
Severity will be assessed based on a 4-point scale:
0 = 
Absent,
1 = 
Mild - Present but not disturbing,
2 = 
Moderate - Disturbing
3 = 
Severe - Very disturbing.
The translation of these terms will be provided to the site.
Visual Acuity 
Far BCVA will be assessed in each eye at each visit using the same chart (for example a Snellen 
chart) throughout the clinical investigation. It can be expressed using units as /10, decimal 
notation, MAR, logMAR, ETDRS or Snellen notation. It will be analysed after conversion in 
LogMar. (see Section 19.6).
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Ocular Tolerance Assessment by the investigator
The investigator must answer to the following question in local language:
“How do you consider the IMD ocular tolerance? 
-
Very satisfactory
-
Satisfactory
-
Not very satisfactory
-
Unsatisfactory”
Ocular Tolerance Assessment by the Patient
The investigator must ask the patient the following question in local language: 
“How do you consider the study treatment ocular tolerance? 
-
Very satisfactory
-
Satisfactory
-
Not very satisfactory
-
Unsatisfactory”
Treatment Compliance Evaluation
Patient will return all investigational products (IMDs and Hydrabak®), whether used or unused.
For Hydrabak® and IMD (T2769 or Hylo-Forte®), the patient will also have to report 
information about his/her compliance on a paper patient diary during the run-in and the 
treatment period. Each day the patient will enter the date and number of instillations* per day. 
Moreover, it will be asked to add the date and hour of last instillation before the beginning of 
each visit. 
In addition, compliance will be assessed by questioning the patient during the visit (e.g. if there 
was any treatment interruption or missed instillation), by checking on paper patient diary and 
by cross-checking with IMD accountability information provided by unmasked collaborator.
* one instillation = 1 drop in each eye
Prior and Concomitant Therapy 
At screening visit, patient will be asked what treatment he/she has taken within the last 3 
months; this will be recorded on the patient medical record and on the e-CRF documenting 
product details, dose and treatment duration.
Concomitant treatment means any medications or non-medicinal therapies given concurrently 
with the IMD. Any other local or systemic treatment necessary for the patient's welfare has also 
to be recorded on the patient medical record and on the e-CRF documenting product details, 
dose and treatment duration. In case of premature discontinuation, the new treatment for dry 
eye with the start date and dosing must also be collected.
Permitted Treatments
Auxiliary products are permitted (see Section 0). Systemic medication not listed in Table 2 are 
permitted ONLY if there has been no modification of the dosage in the month preceding the 
inclusion visit and if no modification is planned throughout the duration of the study.
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Prohibited Prior and Concomitant Medications or Treatments
Rescue Medications (RMs)
NA.
Prohibited Treatments other than Rescue Medications 
(RMs)
Prohibited treatments as well as prohibited modifications during the clinical investigation are 
presented in the summary in the exclusion criteria and in Table 2.
6.4.2
Description of those Activities Performed by Sponsor 
Representatives (excluding monitoring)
Laboratoires THÉA through CROs is responsible for selecting the investigator(s). Each 
investigator should be qualified by training and experience and should have adequate resources 
to properly conduct the clinical investigation.
Laboratoires THÉA /representatives of Laboratoires THÉA will remind the investigator upon 
his/her responsibilities and procedures for ensuring adequate and correct documentation.
Laboratoires THÉA will inform the investigator, directly or through CRO in charge of 
monitoring, prior to the commencement of the clinical investigation of all relevant chemical, 
toxicological and clinical information required for the proper planning and conduct of the 
clinical investigation and will update this as often as may be necessary during the course of the 
clinical investigation. However, this obligation shall not require Laboratoires THÉA to provide 
information which is already available in published material or of which the investigator could 
reasonably be expected to have knowledge in view of his/her professional training.
Laboratoires THÉA or CROs will nominate a suitably trained person or persons to monitor the 
clinical investigation and to liaise with the investigator.
Laboratoires THÉA/representatives of Laboratoires THÉA, will also be responsible for 
complying with the local regulations applicable to clinical investigation.
6.4.3
Any Known or Foreseeable Factors that may Compromise the 
Outcome of the Clinical Investigation or the Interpretation of Results
The population will be selected according to the inclusion and exclusion criteria to have a 
homogenous population.
A run-in period with Hydrabak® is scheduled to have patient with the same treatment at the 
baseline visit.
6.4.4
Methods for Addressing these Factors in the Clinical Investigation
To not compromise the outcome of the clinical investigation, the patient will be randomly 
assigned to 1 of the 2 treatment groups during the randomisation visit.
6.4.5
Description of the Follow-Up Period
NA
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6.4.6 
Appropriate Specific Medical Care Address after the Clinical 
Investigation 
NA 
6.4.7 
Recommended Follow-Up Address after the Clinical Investigation 
NA 
6.4.8 
Final Disposition or Potential Future Use of Samples obtained from 
Patients Address 
All biological samples (tear samplings) that have already been collected may be retained and 
analysed at a later date, per local regulations (e.g. for potential post study genomic analysis). 
 
 
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6.5.1 
Source Documents 
Each participating investigational site will maintain appropriate medical and research records 
in compliance with GCP (ISO 14155 current version) and any other regulatory and institutional 
requirements for the protection of patient’s confidentiality. 
Source data are all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical investigation necessary for the 
reconstruction and evaluation of the clinical investigation. Source data are contained in source 
documents. 
Source documents are any original documents, data and records. These may include, but are 
not limited to, patient medical records, hospital charts if any, clinic charts, laboratory notes, 
patient’s questionnaires, patient’s diaries if any, the investigator’s files, pharmacy dispensing 
records and recorded data from automated instruments. 
Some specific medical data gathered during routine medical practice visits prior to the 
participation can be used in screening visit and before informed consent form on the patient 
best care interest. 
All following patient’s assessments will be collected via a paper diary and paper questionnaire 
and will be considered as source data: 
- 
Run-in treatment compliance: number of instillations/day 
- 
IMD compliance: number of instillations/day 
- 
OSDI questionnaire 
- 
DEAL questionnaire 
- 
VAS 
The following information should be entered into the patient’s medical record: 
- 
Patient’s name, date of birth, gender 
- 
Patient’s contact information 
- 
The date the patient entered the clinical investigation and patient’s number 
- 
The study title and/or the clinical investigation number 
- 
A statement that informed consent was obtained (including the date) and patient’s card 
was provided to the patient; data protection consent or other country and local patient 
privacy required documentation for this investigation have been obtained (including the 
date) 
- 
Date of all patient’s visits 
- 
Investigated disease history: 
o Diagnosis of DES for each eye 
o Date of onset of the diagnosis in each eye (months/year) 
o Previous use of artificial tears 
- 
Ocular and systemic medical and surgery history (other than dry eye) 
For systemic medical history, the information could be collected via patient interview. For 
ophthalmic medical history of referred patient’s, a letter from the referring ophthalmologist is 
strongly recommended. 
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- 
Prior and concomitant medications (list all prescription and non-prescription 
medications being taken at the time of enrolment and within 3 months before screening 
visit). At each subsequent visit, changes to the list of medications should be recorded. 
- 
Name/initials and signature of the persons who perform assessments 
- 
Visual acuity values (standard BCVA value with used chart name) 
- 
Slit-lamp examination results with score of ocular signs, conjunctival hyperaemia, 
corneal staining by fluorescein and conjunctival staining by fluorescein with a yellow 
filter and TBUT 
- 
Shirmer test results for both eyes 
- 
Occurrence and status of any AEs 
- 
Occurrence and status of any incident 
- 
Review of inclusion/exclusion criteria and patient’s status (confirmation of patient 
eligibility or not, reason for screen failure if applicable) 
- 
Ocular tolerance and performance assessment by Investigator 
- 
Tolerance and performance assessment by the patient 
- 
Information on diary dispensation to the patient and instructions correctly provided 
- 
Information on Run-in treatment dispensation, instruction for use and kit number 
provided to patient 
- 
Information on IMD dispensation, including kit number assignment with IRT 
notification 
- 
Run-in treatment compliance collected by reviewing patient’s diary and interview and 
checked against returned kit 
- 
IMD compliance collected by reviewing patient’s diary and interview and checked 
against returned IMD 
- 
Information on used/unused IMD by patient, assessed by unmasked collaborator 
- 
The date of the patient exited the clinical investigation and a notation as to whether the 
patient completed the clinical investigation or reason for discontinuation. 
6.5.2 
Source Data Verification 
One of the primary responsibilities of monitoring is the Source Data Review (SDR) to check 
quality of source, review CIP compliance, ensure the critical processes and source 
documentation are adequate, to ascertain Investigator involvement and appropriate delegation 
and assess compliance to other areas (e;g; SOPs, GCP, ISO 14155 current version). This will 
require direct access to all source documents, any original documents, data and records of each 
patient. 
It will be verified that informed consent documentation is filed for all screened patients whether 
or not they were randomised into the clinical investigation and that the information is listed in 
the source documents. 
Source Data Verification (SDV) will be recorded in e-CRF and SAE/pregnancy related 
documents, consisting in a comparison of the source documentation and other records relevant 
to the clinical investigation/ with the e-CRF. This will require direct access to all source 
documents, any original documents, data, and records of each patient.  
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The SDV will ensure the data are Attributable, Legible, Contemporaneous, Original, 
Accurate, Complete, Consistent, Enduring and Available (ALCOACCEA guiding principles). 
Source Data Monitoring combines: 
9 Site Monitor review of the source data for a patient in order to confirm that the site is 
compliant with ICH GCP, ISO 14155 current version and the CIP. 
9 Evaluation of the conformity of the data presented in e-CRF, or other Sponsor-provided 
documents, with the available Source Data. 
SDR can be done alone, but SDV cannot be done without prior SDR, since validating data 
transcription is not useful if CIP and GCP, ISO 14155 current version compliance have not 
been confirmed first. 
6.5.3 
Case Report Forms 
The patients will be monitored throughout the clinical investigation and all results of 
evaluations will be recorded in an e-CRF. 
The e-CRF completion guidelines will be provided and introduced to the investigation staff 
before the start of the clinical investigation. 
The investigator and authorised delegate(s) will have secured access to enter the data in the 
appropriate sections of the e-CRF and to IRT. 
The e-CRF must be completed for each patient screened in the clinical investigation, including 
screening failure patients. It should be completed as soon as possible after the patient visit.  
The investigator is required to prepare and maintain adequate and accurate ocular and systemic 
history designed to record all observations and other data pertinent to the investigation for each 
patient.  
The investigator is responsible for ensuring that data are properly recorded on each patient’s e-
CRF and related documents.  
The investigator will be responsible for the punctuality, completeness, consistency and 
accuracy of e-CRF. E-CRF and source data will be retained by the investigator for data 
verification at each scheduled monitoring visit. 
The principal investigator or delegate(s) should personally electronically validate and sign e-
CRFs to ensure that the observations and findings are correctly and completely recorded on the 
e-CRFs.  
All information recorded on the e-CRFs for this clinical investigation must be consistent with 
the patients’ source documentation (i.e., medical records). 
A copy of completed e-CRFs pages and incident forms will be stored in the investigator's 
archives for at least 10 years after the last T2769 device has been placed on the market. 
 
 
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7 
STATISTICAL DESIGN AND ANALYSIS 
The Statistical Analysis Plan (SAP) will provide, before locking the database and breaking the 
blind, detailed methods for the analyses outlined below.  
Any changes from the planned analyses will be described and justified in the final CIR. 
7.1 
ANALYSIS POPULATION AND PROCEDURES  
The following analysis sets will be considered: 
x Safety set: 
All enrolled patients, having received at least one dose of IMD. Patients will be analysed 
according to the treatment received. 
Safety set will be the primary population for safety analysis. 
x Intent-to-Treat (ITT) set: 
All randomised patients. Patients will be analysed according to the treatment they were 
assigned to at randomisation.  
x Full Analysis Set (FAS):  
All randomised patients having received at least one dose of IMD, with at least one baseline 
and one post-randomisation performance assessment. Patients will be analysed according to the 
treatment they were assigned to at randomisation. 
x Per protocol (PP) set: 
Subset of the FAS including patients without any major CIP violations likely to seriously 
affect the primary outcome of the study. Patients will be analysed according to the treatment 
received. 
 
 
   
 
The FAS will be the primary population for performance analysis. The PP set will be considered 
as the secondary population and will be used for sensitivity analyses of the primary 
 
performance endpoint  
7.2 
STATISTICAL ANALYSIS 
Statistical descriptions will be performed by treatment groups. For disposition and demography 
description will also be presented overall. 
Variables recorded for each eye will be described separately for the study eye and for the 
contralateral eye (if applicable). 
Baseline is defined as the assessment at D1 visit before the first IMD instillation. Missing values 
at randomisation visit will not be replaced. 
For endpoints defined as change from baseline, the descriptive statistics by visit (Screening, 
D1, D15 and D36) and the change from baseline at D15 and D36 will be presented.
 
 
 
 
 
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Disposition, demographics, exposure, history of dry eye, medical/surgical history (by System 
Organ Class [SOC] and PT separately for ocular and systemic history), will be summarised by 
treatment group and overall, for the FAS, PP set and Safety set 
 
 Disposition and demographics will also be presented for the ITT. Previous 
and concomitant ocular/non-ocular treatments will be listed. 
7.2.1 
Performance Analyses 
Primary 
 performance endpoint  will be primarily analysed on the FAS. 
Sensitivity analysis of the primary 
performance endpoint will be performed on 
the PP.  
The detailed analysis methods for primary and each secondary performance variables will be 
discussed further in the SAP. 
Primary performance endpoint  
The primary performance endpoint is the change from baseline (D1) in total ocular surface 
staining grade according to Oxford 0-15 grading scheme at D36 in the study eye. The analysis 
will be performed following original Oxford scale 
 
 
 
The inferential analyses of the primary performance endpoint will aim to assess the non-
inferiority of T2769 to Hylo-Forte®. The hypothesis of non-inferiority will be tested by 
calculating the bilateral 95% CI around the difference between groups (T2769 – Hylo-Forte®) 
in mean change from baseline in the total ocular surface staining (Oxford score) to D36 in the 
study eye. If the upper bound is no higher than +2 points, it will be concluded that the null 
hypothesis can be rejected and that the performance of T2769 is non-inferior to that of Hylo-
Forte®.  
The non-inferiority will be primarily tested using a Mixed Model for Repeated Measures 
(MMRM) approach. The model will include treatment and scheduled visit time points (D15 and 
D36) as fixed factors, patient as random factor, and baseline total ocular surface staining 
(Oxford score) as continuous covariate Treatment by scheduled visit time point and baseline 
total ocular surface staining (Oxford score) by scheduled visit time point will be included as an 
interaction term in the model. 
 
 
 
 
 
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Descriptive tables will also be produced presenting data for total ocular surface staining values 
and change from baseline at each visit. 
  
 
 
 
 
 
 
 
 
 
  
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7.2.2 
Safety Analyses 
Safety endpoints will be analysed on the Safety set. 
Ocular and systemic adverse events (AEs) 
Ocular and systemic AE reported during the investigation will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA dictionary). 
Summary tables will be performed on Treatment-Emergent AEs (TEAEs).  
Ocular and systemic TEAEs will be analysed separately on the basis of the localisation and 
System Organ Class (SOC). 
TEAEs are AEs that occurred after the first IMP instillation. For the AEs that occurred the day 
of the first IMP instillation, a question on the eCRF will establish the timing compared to the 
first instillation. .  
Separate descriptions of ocular (for both, study and contralateral eye together) and systemic 
TEAEs will be performed by treatment group: 
• 
An overall summary of the number and percentage of patients experiencing at least 
one AE, SAE, IMD-related AE, IMD-related SAE and AE leading to premature 
investigation IMD discontinuation. 
• 
Number and percentage of patients experiencing at least one AE, as well as the 
number of AEs, by SOC and Preferred Term (PT). The summaries will be performed 
for AEs leading to premature IMD discontinuation.  
• 
Number and percentage of patients with AEs, by SOC, PT and severity. 
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• Number and percentage of patients with AEs, by SOC, PT and relationship to IMD. 
Documented list of individual data concerning TEAEs will be performed.  
 
 
 
 
 
 
 
 
 
 
7.3 
ANALYTICAL PROCEDURES 
Quantitative variables (Continuous data) will be summarised in summary tables indicating the 
number of non-missing/missing observations (n), mean, SD, median, first quartile (Q1), third 
quartile (Q3), minimum and maximum, and 95% Confidence Interval (CI) of the mean/median.  
Qualitative variables (Categorical data) will be summarised in summary tables indicating the 
number of non-missing/missing observations (n), count and percentage of each modality, and 
95% CI. 
 
 
7.5 
SAMPLE SIZE CALCULATION AND JUSTIFICATION 
The sample size is driven by the statistical hypothesis on the primary objective: to demonstrate 
the non-inferiority of T2769 compared to Hylo-Forte® in terms of the change from baseline 
(D1) in total ocular surface staining score assessed on Oxford 0-15 scale, in the study eye at the 
D36 visit. 
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7.6 
RATIONALE FOR THE NUMBER OF PROCEDURES TO BE 
PERFORMED BY A SINGLE USER AS PART OF THE LEARNING 
CURVE AND HOW THESE DATA ARE TO BE ANALYSED 
  
 
7.8 
INTERIM ANALYSIS, CRITERIA FOR THE TERMINATION OF THE 
CLINICAL INVESTIGATION ON STATISTICAL GROUNDS 
NA.  
7.9 
MANAGEMENT 
OF 
BIAS 
AND, 
WHEN 
RANDOMISATION, 
MATCHING 
OR 
BLINDING 
ARE 
APPLIED, 
PLAN 
FOR 
ASSESSMENT OF SUCCESS THEREOF. 
The use of randomisation attempts to mitigate accidental bias (such as selection bias), 
promoting comparability of the study groups and serves as a basis for statistical inference for 
quantitative evaluation of the treatment effect. 
Masking will be achieved by providing each product unit with identical cardboard box and by 
identifying it by an IMD kit number. 
7.10 
MANAGEMENT OF POTENTIAL CONFOUNDING FACTORS  
Baseline value will be included in all MMRM models (if applicable) as covariate.  
Other covariates will be explored and detailed in the SAP. 
7.12 
SPECIFICATION OF SUBGROUPS  
NA.  
 
 
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7.15 
PROCEDURES FOR REPORTING ANY DEVIATION(S) FROM THE 
ORIGINAL STATISTICAL PLAN 
Any changes from the planned analyses will be described and justified in the SAP and the final 
CIR. 
7.17 
DEFINE A STRATEGY FOR POOLING DATA, IF APPLICABLE. 
NA. 
8 
DATA MANAGEMENT 
8.1 
METHODS FOR DATA ENTRY AND COLLECTION 
Each participating site will maintain appropriate medical and research records for this clinical 
investigation in compliance with GCP - ISO 14155:2020 sections 3.47, 3.48 and 7.8.1 and any 
other regulatory and institutional requirements for the protection of patient’s confidentiality. 
Data will be reported in an electronic data capture (EDC) system for collection of electronic 
Case Report Forms. CRO is responsible for the set-up and maintenance of the EDC. The EDC 
will be compliant with FDA 21 CFR Part 11 and EU Annex 11. 
The eCRFs will be completed by the PI or delegates within the investigational sites. Entries in 
the eCRF shall be made complete, correct and in a timely manner. 
 
 
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8.2 
PROCEDURES USED FOR DATA REVIEW, DATABASE CLEANING, 
AND ISSUING AND RESOLVING DATA QUERIES 
Data Management activities will be performed by Laboratoires THÉA Data Manager and/or the 
CRO in charge of Data Management and will be defined in the Data Management Plan (DMP). 
x Management of queries 
The sponsor or representative will ensure that the reported data are consistent and complete. 
Data clarifications requests, also called queries or edit checks, will be generated in the EDC by 
a data manager or the site’s CRA.  
The CRAs affected to the site can open queries for source data verification mismatch, deviation 
verification, safety clarifications, and when data inconsistencies are detected. The CRAs will 
follow and close the queries that they posted. 
The Data management department will create queries based on the data validation plan as 
detailed in the DMP. The purpose of the clarifications will be, but not limited to, data 
completion request, data inconsistencies, verification of possible deviations, clarification 
requests on safety events. The Data management team will follow and close the queries that 
they posted. 
The investigational sites will have to answer directly in the EDC by giving a comment and 
making the necessary corrections to the reported data until the query is considered as resolved 
by the query creator or affiliate. 
No self-evident corrections will be made by the sponsor. 
x Coding of events 
Diagnosis for AEs and medical and surgical history will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). Whodrug Anatomic Therapeutic Chemical (ATC) code will 
be used for previous and concomitant treatment coding. Versioning will be specified in the 
DMP. 
x Management of external data 
o The clinical database and the IRT database will be periodically reconciled to 
ensure that the information reported in both databases are matching.  
o The results of the Tear level of inflammatory cytokines will be sent by the central 
laboratory to the data management department and included in the clinical 
database. The clinical and laboratory databases will be reconciled as detailed in 
the DMP.  
The investigator will cooperate with Laboratoires THÉA and any person nominated by 
Laboratoires THÉA to monitor or supervise the conduct of the investigation. 
The investigator and authorised delegate(s) will ensure that proper data for the clinical 
investigation are collected and accurately documented in the appropriate sections of eCRFs. 
 
 
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8.3 
PROCEDURES 
FOR 
VERIFICATION, 
VALIDATION 
AND 
SECURING OF ELECTRONIC CLINICAL DATA SYSTEMS 
Laboratoire Théa will verify that the EDC provider is able to demonstrate the validity and 
security of the electronic tools used during the study. If necessary, security tests will be 
performed. 
The access to the electronic data systems will be individual and protected by a personalized 
password. 
All data entry and modifications will be stored in an audit’s trail indicating who performed the 
action and when. 
8.4 
PROCEDURES TO MAINTAIN AND PROTECT PATIENT PRIVACY 
Laboratoires THÉA, as Sponsor of the clinical investigation, acting as data controller and is 
committed to protecting the privacy and security of personal data processed for the purposes of 
the clinical investigation under the conditions define below: 
x Compliance with the General Data Protection Regulation (GDPR) and other 
applicable law or regulation: 
Laboratoires THÉA is committed to comply with the Regulation (EU) 2016/679 of the 
European Parliament and of the Council of 27 April 2016 on the protection of natural persons 
with regard to the processing of personal data and on the free movement of such data, and 
repealing Directive 95/46/EC (hereinafter the General Data Protection Regulation “GDPR”) 
and any other applicable law or regulation related to the protection of personal data.  
It is specified that for the clinical investigation, Laboratoires THÉA also comply with the 
applicable guidelines of the French supervisory authority (“Commission Nationale de 
l’Informatique et des Libertés” hereinafter the “CNIL”) as defined in the deliberation n°2019-
153 of 3 May 2019 of the CNIL, also called the “MR-001”.  
x Data subjects information on the processing of their personal data 
The data subjects namely the patients and the investigator, including the personnel working 
with the investigator, are informed of the collection and processing of their personal data for 
the realisation of the clinical investigation.  
In particular, the patients are informed by the investigator during the delivery of the Informed 
Consent Form (ICF) where all the mandatory information of Article 13 of the GDPR are 
provided.   
x Data subjects exercise of their rights on their data 
The data subjects, namely the patients and the investigator, including the personnel working 
with the investigator, have the right, under the conditions and within the limits provided by the 
regulations, to access, rectify, delete or determine guidelines as to the use of their personal data 
after their death, as well as the right to oppose or request the limitation of processing. 
In addition, and according with article L1111-7 of the French Public Health Code, the patients 
can access to their personal data by asking to the investigator. 
For all requests concerning the rights of the patients regarding their personal data, they are 
advised to contact the investigator who will in turn contact Laboratoires THÉA. Otherwise, 
Laboratoires THÉA named a Data Protection Officer who can be contacted by the patients.  
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The data patients, namely the patients and the investigator, including the personnel working 
with the investigator, have the right to bring a complaint with the supervisory authority, namely 
the CNIL in France and/or local equivalent of CNIL. 
8.5 
METHODS FOR DATABASE LOCKING AT THE START OF THE 
ANALYSIS AND STORAGE UPON COMPLETION OF THE 
CLINICAL INVESTIGATION 
The database lock consists in the removal or changing of user access for database to prevent 
any further changes to the data. The database lock enables data collected to be used for formal 
analysis or submission to a regulatory authority. Database lock occurs following the conduct of 
the clinical investigation. 
Database will be locked when all data will be entered and clean. Data Management CRO 
coordinates the activities around Database Lock, including completing the Database Lock 
Checklist, managing Database Lock Form, and ensuring archival activities are complete. 
8.6 
CONFIDENTIALITY 
All information concerning the product as well as any matter concerning the operation of the 
Sponsor, such as clinical indications for the IMD, its formula, methods of manufacture and 
other scientific data relating to it, that have been provided by the Sponsor and are unpublished, 
are confidential and must remain the sole property of the Sponsor. The investigator will agree 
to use the information only for the purposes of carrying out this clinical investigation and for 
no other purpose unless prior written permission from the Sponsor is obtained. 
Laboratoires THÉA has full ownership of the original e-CRFs completed as part of the clinical 
investigation. 
8.7 
DATA RETENTION PROCEDURES AND SPECIFIED RETENTION 
PRIOD 
The investigator must retain the patient identification codes for at least 10 years after the last 
T2769 device has been placed on the market. Patient files and other source data must be kept 
for the maximum period of time permitted by the hospital, institution or private practice, but 
not less than 10 years after the last T2769 device has been placed on the market, to meet the 
Sponsor local regulatory requirements. The investigator must produce investigation 
documentation or supply copies thereof to Sponsor, its designee or to CAs upon request, while 
ensuring patient confidentiality at all times. 
8.8 
OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE 
8.8.1 
Monitoring/Data Audits 
Laboratoires THÉA/representatives of Laboratoires THÉA shall be permitted to audit any 
proposed investigational site prior to commencement and during the course of the clinical 
investigation to ensure that the investigational site is suitable and has the suitable facilities, staff 
and capacity for the conduct of the clinical investigation. 
The e-CRFs should be available for review by the clinical monitor or auditor or national 
regulatory inspectors. The investigator is required to give access to all source documents and 
investigation data, all relevant documentation to the clinical investigation, site facilities and 
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materials/equipments used in the clinical investigation. Laboratoires THÉA and CROs will not 
require the investigator or any member of their staff to take any action or be a party to any 
action which is contrary to the laws of the country in which the clinical investigation is being 
carried out or to medical ethics. 
8.8.2 
On-site Audits/Regulatory Inspection 
CAs, Independent Ethics Committees/ Institutional Review Boards (IECs/IRBs), and/or 
Laboratoires THÉA’s Clinical Quality Assurance Group may carry out on-site audits and/or 
on-site audit inspections. Direct access to source data will be required for these inspections and 
audits; they will be carried out giving due consideration to data protection and medical 
confidentiality. The investigator assures the Sponsor of the necessary support at all times. 
The clinical investigation may be subjected to auditing by representatives of the Sponsor and/or 
to inspection(s) by authorized representatives of local and/or foreign CAs. In case of an audit 
or inspection, the investigator will be informed in advance. The investigator must inform the 
Sponsor as soon as he/she receives the notification of inspection. 
9 
APPROVAL 
OF 
THE 
CLINICAL 
INVESTIGATION 
AND 
AMENDMENTS 
Prior to starting the clinical investigation, the CIP and other relevant documents will be 
submitted and approved by the IEC/IRB and/or CAs, in accordance with regional/local 
regulatory requirements. The Sponsor must ensure that all ethical and legal requirements have 
been met before the first patient is enrolled in the clinical investigation. 
Full compliance with this CIP must be sought. To alter the CIP, amendments must be written, 
approved by the appropriate personnel, and by IEC/IRB/CAs prior to implementation. 
All amendments will be distributed to all CIP recipients, with appropriate instructions. 
By signing the CIP, the investigator confirms that he/she agrees to perform the clinical 
investigation as outlined in the CIP.  
The CIP is the binding document for the investigator, the Sponsor and its designee; 
modifications are only valid if agreed upon by the Sponsor and its designee. Modifications must 
be documented in a signed amended CIP.  
The Sponsor will promptly report the following for review or information to the Ethics 
Committee(s) and the CA for: 
x Substantial CIP modifications 
x Administrative changes 
x Deviations to the CIP implemented to eliminate immediate hazards to the trial patients 
x New information that may affect adversely the safety of the patients or the conduct of 
the clinical investigation. The IEC and the CA must be informed and approve all CIP 
amendments, in accordance with local legal requirements before implementation. 
Amendments must be evaluated to determine whether formal approval must be sought 
and whether the informed consent document should also be revised.  
The written signed approval of the CIP amendment must contain specific identification of the 
document (e.g., the investigator's name and the CIP title and number). 
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10 DEVIATIONS FROM CIP 
The investigator will conduct the clinical investigation in accordance with this CIP, all 
relevant local laws, regulations or guidelines and in accordance with the principles of GCP – 
ISO 14155 current version. The investigator should not initiate the clinical investigation before:  
x The CIP is signed;  
x Written approval from the appropriate IEC and Clinical Trial Authorization from CA 
are received; 
x The site is initiated by Laboratoires THÉA or the CRO designated by Laboratoires 
THÉA.  
During the clinical investigation, in case of important deviations observed in an investigational 
site, (such as deviations related to inclusion and/or exclusion criteria, deviations that may put a 
patient at risk), the Sponsor could decide to stop the enrolment in this site.  
At the end of the clinical investigation, CIP deviations will be reviewed and classified as minor 
or major during a blind data review meeting that will be held before database lock. The 
exclusion of patients from the analysis sets (see details of analysis sets in section 0) will be 
discussed during the blind data review meeting. 
11 IMD ACCOUNTABILITY 
11.1 
DESCRIPTION 
OF 
THE 
PROCEDURES 
FOR 
THE 
ACCOUNTABILITY OF IMD 
Patients will return used and unused IMDs to the site at D15 and D36 visits. 
The unmasked collaborator or pharmacist counts the number of IMDs remaining in the returned 
pack, completes and validates the “Treatment Tracking Form” (used, not used, not returned 
IMD) and the Drug Accountability Module and Return Form in IWRS (if applicable). 
The masked investigator will remain masked to the IMD. He/she will not retrieve the product 
from any patient. IMD returned by patient will have to be stored in a different place from the 
ones that have not yet been dispensed. 
All IMDs will be retained for inspection by the study monitor. The monitor will, upon 
completion of drug count and validation of the return section of the “Treatment Tracking 
Form”, collect used/unused/broken containers of the supplied investigational products and these 
will be returned as instructed by Laboratoires THÉA. 
11.2 
PROCEDURES 
AND 
PARTICULAR 
MATERIALS 
AND 
INSTRUCTIONS FOR THE SAFE RETURN OF IMD, INCLUDING 
THOSE THAT ARE POTENTIALLY HAZARDOUS 
The IMD used and unused will be returned to the depot in France for destruction. 
This return will be prepared by the site team with the help of monitor. The return request will 
be sent to the packaging/labelling CRO. At receipt, the packaging/labelling CRO has to confirm 
the Good Receipt to the site team and monitor.  
All details regarding return of used and unused IMD will be recorded in the Drug accountability 
return module in IRT (if applicable). 
The return will be stored in the depot in waiting the authorization of destruction by the Sponsor. 
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12 STATEMENTS OF COMPLIANCE 
This clinical investigation will be conducted in accordance with the ethical principles of the 
Declaration of Helsinki of October 2013, with GCP as described in the International Standards 
ISO 14155 current version and with the local regulations. 
Prior to commencement of the clinical investigation, the Sponsor or his legal representative in 
the community must submit a valid application, with the same version of the documentation, to 
the IEC and the CA (see Section 9).  
Before the clinical investigation starts, the clinical monitor must ensure that all relevant 
documents are available and that IEC/IRB/CAs authorisation(s) and approval(s) have been 
obtained. Only then, arrangements for shipment of the clinical supplies can be made and 
recruitment can begin. 
The Sponsor or his legal representative will report any amendments (see Section 9) and safety-
related events (see Sections 14.5 and 14.6) according to the local regulations. 
The Sponsor will notify each IEC/IRB/CAs concerned of the end of a clinical investigation in 
all countries in which the clinical investigation has been conducted. That notification will be 
made within 15 days from the end of the clinical investigation in the last country in which the 
clinical investigation has been conducted/in accordance with the local regulations. 
If the clinical investigation has terminated prematurely, the reason for the termination must be 
given (see Section 16). 
When a temporarily halted clinical investigation is resumed the Sponsor will inform all 
involved investigators and must notify IEC/IRB/CA concerned through the EU portal and/or 
another way within 15 days from the restart of the temporarily halted clinical investigation in 
all country concerned.  
The Sponsor will take out reasonable third-party liability insurance cover in accordance with 
all local legal requirements. The civil liability of the investigator, the persons instructed by 
him/her and the hospital, practice or institute in which they are employed and the liability of 
the Sponsor with respect to financial loss due to personal injury and other damage that may 
arise as a result of the carrying out of this clinical investigation are governed by the applicable 
law. 
The Sponsor will arrange for patients participating in this clinical investigation to be insured 
against financial loss due to personal injury caused by the products being tested or by medical 
steps taken in the course of the clinical investigation. 
When required, a hospital specific indemnity agreement and/or an investigator specific 
agreement will be used. 
13 INFORMED CONSENT PROCESS 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s) and adhere to the International Standards ISO 14155 on 
GCP for medical devices and the requirements in the Declaration of Helsinki – October 2013. 
Prior to any investigation-related activity or any discontinuation of current medication, the 
investigator must give the patient oral and written information about the aims, methods, 
anticipated benefits, potential risks and inconveniences of the clinical investigation. The 
measures taken to safeguard the patient’s privacy and the protection of personnel data should 
also be described in the informed consent. The patients must be informed about their right to 
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abstain from participating in the clinical investigation and to withdraw their consent at any time 
without affecting their medical care.  
Before informed consent may be obtained, the investigator should provide the patient ample 
time and opportunity to inquire about details of the clinical investigation and to decide whether 
or not to participate in the clinical investigation. All questions about the clinical investigation 
should be answered to the satisfaction of the patient. The patient must be given the opportunity 
to ask questions and have reasonable time for reflection before giving his/her informed consent. 
Written informed consent must be obtained prior to initiation of any investigational procedures 
or any discontinuation of current medication. No measures whatsoever described in the CIP 
shall be undertaken without such consent indicating that the patient has been given both verbal 
and written information about the investigation and the IMD.  
If the patient is illiterate, oral information regarding the investigation will be provided to the 
patient using the ICF. A witness will be present during the entire informed consent discussion. 
The witness will personally sign and date the ICF to confirm that the information was accurately 
explained to the patient, and apparently understood, and that consent was freely given. 
The ICF is signed and personally dated by the patient or by a patient’s legally acceptable 
representative and by the investigator designee responsible for obtaining the ICF (as per 
ISO14155 and local regulations). 
Once signed, the original ICF is filed in the Investigator Site Binder and a copy is provided to 
the patient (according to the local regulations). 
As soon as the patient has signed the Informed Consent, he/she will receive a patient number.  
The information/consent form may be revised during the clinical investigation whenever 
important new information becomes available. The amended ICF will be submitted for approval 
to the IEC and/or CAs as appropriate (see Section 9). Once approved, informed consent of the 
already enrolled patients will be documented as described above i.e., in the same way as the 
initial informed consent. 
14 ADVERSE EVENTS, AND INCIDENTS 
14.1 
DEFINITION OF ADVERSE EVENT (AE)  
Adverse Event (AE): Any untoward medical occurrence, unintended disease or injury or 
untoward clinical signs (including abnormal laboratory finding) in subjects, users or other 
persons whether or not related to the IMD. 
NOTE: 
x This definition includes events related to the IMD or the comparator 
x This definition includes events related to the procedures involved 
x For users or other persons, this definition is restricted to events related to the use of the 
IMD or comparator. 
NOTE:  
x Adverse event is an incident. 
.Treatment-Emergent AE (TEAE): AE that occurs or that worsens in severity after at least 
one dose of IMD has been administered/applied.   
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14.2 
DEFINITION 
OF 
INCIDENT/FIELD 
SAFETY 
CORRECTIVE 
ACTION 
Incident: any malfunction or deterioration in the characteristics or performance of a device 
made available on the market, including use-error due to ergonomic features, as well as any 
inadequacy in the information supplied by the manufacturer and any undesirable side-effect. 
Field safety corrective action: corrective action taken by a manufacturer for technical or 
medical reasons to prevent or reduce the risk of a serious incident in relation to a device made 
available on the market. 
14.3 
DEFINITION OF A SERIOUS INCIDENT 
Serious incident: any incident that directly or indirectly led, might have led or might lead to 
any of the following: 
x the death of a patient, user or other person,  
x the temporary or permanent serious deterioration of a patient's, user's or other person's 
state of health,  
x a serious public health threat: an event which could result in imminent risk of death, 
serious deterioration in a person's state of health, or serious illness, that may require 
prompt remedial action, and that may cause significant morbidity or mortality in 
humans, or that is unusual or unexpected for the given place and time. 
14.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE)  
A Serious Adverse Event (SAE) is an AE that: 
x Led to death 
x Led to serious deterioration in the health of the subject, that either resulted in  
9 A life-threatening illness or injury, or  
9 A permanent impairment of a body structure or a body function, or  
9 In-patient or prolonged hospitalization, or  
9 Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function or 
9 Chronic disease 
x Led to foetal distress, foetal death or a congenital abnormality or birth defect. 
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by 
the CIP, without serious deterioration in health, is not considered a SAE. 
14.4.1 Definition of the Severity of an Adverse Event  
The intensity of each AE must be assessed by the investigator using one of the following 
categories, and recorded in the e-CRF and incident form 
 
1 = MILD: Event results in mild or transient discomfort, not requiring intervention or 
treatment and does not interfere with the patient daily activities; 
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2 = MODERATE: Event results in sufficient discomfort, may require an additional 
treatment, but does not interfere with the patient’s daily activities; 
3 = SEVERE: Event results in significant symptoms, may require an additional treatment, 
or a modification of this treatment (or hospitalisation) and may interfere with the 
patient’s daily activities. 
Caution: The term “severe” is used to describe the intensity (severity) of the event. This means 
it is not the same as “serious” used to describe the seriousness of SAE which is based on patient 
event outcome or action criteria usually associated with events that pose a threat to a patient’s 
life or functioning (see Section 14.4 for having the definition of a SAE). 
14.4.2 Causality Relatedness to the IMD  
The investigator will assess the causality/relationship between the IMD and the AE and record 
that assessment in the e-CRF and incident form based on the following definitions (only one 
answer possible): 
Each AE will be classified according to four different levels of causality:  
1. Not related  
2. Possible  
3. Probable  
4. Causal relationship  
The sponsor and the investigators will use the following definitions to assess the relationship 
of the adverse event to the investigational device or the investigation procedures. 
1. Not related: Relationship to the device or procedures can be excluded when:  
Ͳ 
the event has no temporal relationship with the use of the device or investigation 
procedures;  
Ͳ 
the adverse event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible;  
Ͳ 
the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the adverse event;  
Ͳ 
the event involves a body-site or an organ that cannot be affected by the device or 
procedures;  
Ͳ 
the adverse 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);  
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 adverse event.  
2. Possible: The relationship with the use of the investigational device or the relationship with 
procedures, 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 where relatedness cannot be assessed, or no information has been 
obtained should also be classified as possible.  
 
3. Probable: The relationship with the use of the investigational device or the relationship with 
procedures, seems relevant and/or the event cannot be reasonably explained by another cause.  
 
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4. Causal relationship: the adverse event is associated with the investigational device or with 
procedures beyond reasonable doubt when:  
Ͳ 
the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures;  
Ͳ 
the event has a temporal relationship with investigational device use/application or 
procedures;  
Ͳ 
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;  
Ͳ 
the adverse event follows a known response pattern to the medical device (if the 
response pattern is previously known);  
Ͳ 
the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the adverse event (when clinically feasible);  
Ͳ 
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;  
Ͳ 
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 adverse event.  
The sponsor and the investigators will distinguish between the adverse events related to the 
investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational 
device.  
Complications caused by concomitant treatments, not imposed by the clinical investigation 
plan, are considered not related. If routine procedures are not imposed by the clinical 
investigation plan, complications caused by them are also considered not related.  
In some particular cases the event may not be adequately assessed because information is 
insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor 
and the investigators will make the maximum effort to define and categorize the event and avoid 
these situations. Where an investigator assessment is not available and/or the sponsor remains 
uncertain about classifying the adverse event, the sponsor should not exclude the relatedness; 
the event should be classified as “possible” and the reporting is not delayed.  
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
events. The occurrence of unanticipated events related could suggest that the clinical 
investigation places subjects at increased risk of harm than was to be expected beforehand. 
14.5 
RECORDING AES 
AEs recording and reporting will extend from signing of informed consent until the final visit. 
If the investigator is aware of an AE occurring within one month after final investigation visit 
and that he/she considers there is a causal relationship with the IMD, the AE should be recorded 
in the e-CRF. An incident form must also be recorded by the unmasked collaborator.  
The investigator shall: 
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a) Record all AEs, regardless of the relationship to IMD and seriousness, in the e-CRF 
together with an assessment. For each AE, a corresponding incident form must also be 
recorded by the masked collaborator. 
b) Supply the Sponsor, upon Sponsor's request, with any additional information related to 
the safety reporting of a particular event. 
All AE reports should contain: a brief description of the event (diagnosis, localisation …), date 
and time of onset (if needed), duration (hours or days), intensity of symptoms (severity), 
treatment required, relationship with IMD and CIP procedure, action taken with the IMD, 
outcome, date and time of resolution and whether the event is classified as serious. 
If there is a worsening of a medical condition that was present before starting the clinical 
investigation, this should be considered as a new AE and a complete evaluation should be 
recorded. 
14.6 
REPORTING OF INCIDENT 
Reporting by the investigator to the sponsor 
If the investigator or masked collaborator observe any incident, the unmasked collaborator must 
report to Laboratoires THÉA within 24 hours of being aware of it using the incident form 
by email to 
 
If the incident is an AE, the investigator or authorised delegated person must also complete the 
e-CFR page. 
Laboratoires THÉA must:  
- 
review all incidents, determine and document in writing whether they meet serious 
incident criteria for reporting to competent authorities; in case of disagreement between 
the Sponsor and the PI(s), the Sponsor shall communicate both opinions to concerned 
parties. 
- 
report to regulatory authorities/IEC/investigators, within the required time period, any 
serious incident.  
Once made aware of any serious incident, Laboratoires THÉA will take the appropriate decision 
to maintain the security/safety of patients by considering field safety corrective action. Any 
field safety corrective action taken by Laboratoires THEA will be reported to competent 
authorities. 
 
Reporting by Laboratoires THEA to Competent Authorities/Ethics Committees 
Laboratoires THEA must report to the National CAs where the clinical investigation has 
commenced:  
- 
in the context of vigilance  
o a serious incident, that has a causal relationship or that the causal relationship is 
reasonable possible with the investigational device; or a field safety corrective 
action, must be reported not later than 15 days  
 notwithstanding related to a serious public health threat must be reported 
immediately or not later than 2 days 
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 notwithstanding related to death or an unanticipated serious deterioration 
in the person state of health must be reported immediately or not later 
than 10 days. 
- 
in the context of clinical investigation 
o a SAE/device deficiency that might have led to a SAE that has a causal 
relationship with the investigational procedure: which indicates an imminent 
risk of death, serious injury or serious illness and that requires action for other 
patients, users or other persons or a new finding to it: must be reported 
immediately, but not later than 2 calendar days after. 
o any other SAE/device deficiency that might have led to a SAE that has a causal 
relationship with the investigational procedure: must be reported 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. 
14.7 
FOLLOW-UP OF PATIENT AFTER AE 
The investigator is responsible for ensuring the follow-up of any patient who experiences an 
AE during the clinical investigation.  
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the event has resolved, any abnormal laboratory values have returned to baseline or 
stabilised at a level acceptable to the investigator and Medical Expert, until there is a 
satisfactory explanation for the changes observed. 
In case of SAE, the investigator or an appropriate qualified physician must re-examine the 
patient at regular intervals until the event has resolved or stabilised at a level acceptable to the 
investigator and Medical Expert and/or until completion of the “Last Patient Last Visit”.  
Further follow up information will be reported to Laboratoires THÉA. 
14.8 
MANAGEMENT OF PREGNANCY  
In case of the investigator or an appropriate qualified physician is informed that a patient 
becomes pregnant while taking IMDs, she will be immediately withdrawn from the clinical 
investigation and she will be followed until the outcome of the birth is available.  
A communication will be sent by the investigator to Laboratoires THÉA as soon as he/she has 
knowledge of the normal outcome. Conversely, if the outcome of the pregnancy meets the 
criteria of SAE (e.g spontaneous or therapeutic abortion, stillbirth, neonatal death, congenital 
abnormality, birth defect), the investigator should follow the procedure for reporting of 
AE/incident. 
Handling of a pregnancy occurring throughout the investigation follows the same reporting 
procedure as per an AE/incident notification. 
Upon medically confirmed pregnancy during the clinical investigation the investigator must: 
Ͳ 
Report immediately (maximum 24 hours) the pregnancy status to Laboratoires THÉA 
by sending the incident form to 
 
 The investigator must also complete the corresponding 
AE e-CRF page.  
Ͳ 
Discontinue the IMD 
Ͳ 
Perform / ensure assessment until delivery of a thorough investigation of the fetus 
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Ͳ 
Remain responsible for any medical advice he/she might sought thus making 
appropriate decision upon pregnancy 
Ͳ 
Report to Laboratoires THÉA Follow-Up data / update(s) using the incident form. 
14.9 
LIST OF FORESEEABLE AES TOGETHER WITH THEIR LIKELY 
INCIDENCE, MITIGATION OR TREATMENT 
According to the IMD leaflets, the following side effects are known: rare possibility of mild 
eye irritation and ocular redness. 
When you use eye drops, you might experience disturbing symptoms such as burning sensation, 
stinging sensation, foreign body sensation in the eye and blurred vision for a short time. 
14.10 
LIST OF NON-REPORTABLE ADVERSE EVENTS  
NA. 
14.11 
INFORMATION REGARDING THE IDMC 
NA. 
15 VULNERABLE POPULATION 
This clinical investigation will not be conducted in children, or in any other vulnerable 
populations. 
If the patient is not capable of giving consent, the written consent of the patient̓s legal 
representative will be required before participation in the clinical investigation (see section 13). 
16 SUSPENSION 
OR PREMATURE TERMINATION OF THE 
CLINICAL INVESTIGATION 
16.1 
TEMPORARY HALT OF THE CLINICAL INVESTIGATION 
The Sponsor may suspend the clinical investigation for any safety, ethical or administrative 
reason at any time. The investigator, IEC or CA may suspend or prematurely terminate 
participation at the investigational sites for which they are responsible. 
As required by the Clinical Trials legislation, in the case of temporary halt of the clinical 
investigation: 
- 
The Sponsor shall notify each country in which that clinical investigation has been 
temporarily halted within 15 days from the temporary halt of the clinical investigation 
with a justification.  
- 
For safety concerns, the Sponsor shall notify all the country(ies) in which that clinical 
investigation is being conducted thereof within 24 hours. 
- 
For an exceptional circumstance (e.g. COVID-19 pandemic), the Sponsor will follow 
the CAs’ recommendations.  
In case of restart after temporarily halted study, a notification will be made to the CA. In case 
of temporarily halt on safety grounds, this notification should be submitted as a substantial 
modification. 
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The communication of the relevant information should take place via the respective national 
procedures applicable to clinical investigations (until EU portal is fully functional). 
16.2 
EARLY TERMINATION OF THE CLINICAL INVESTIGATION 
The Sponsor or the investigator has the right to terminate the clinical investigation for any 
safety, ethical or administrative reason at any time. As far as possible, this should occur after 
mutual consultation. 
As required by the Clinical Trials legislation, in the case of early termination of the clinical 
investigation: 
- 
The Sponsor shall notify each country in which that clinical investigation has been 
temporarily halted within 15 days from the temporary halt of the clinical investigation 
with a justification. 
- 
For safety concerns, the Sponsor shall notify all the country(ies) in which that clinical 
investigation is being conducted thereof within 24 hours. 
The communication of the relevant information should take place via the respective national 
procedures applicable to clinical investigations (until EU portal is fully functional). 
The investigator, IEC or CA may prematurely terminate participation at the investigational sites 
for which they are responsible. 
Should the clinical investigation be terminated prematurely, all investigational materials 
(IMDs, completed, partially completed, etc.) must be returned to the Sponsor or the Sponsor’s 
representative as if the clinical investigation had been completed. 
Laboratoires THÉA shall have the right to terminate the clinical investigation at any time on written 
notice to the investigator. Without in any way limiting this right, Laboratoires THÉA would 
normally only terminate the clinical investigation in the following circumstances:  
Ͳ 
Occurrence of  
x new events related to the conduct of an investigation or the development of an IMD 
likely to affect the safety of patients, such as:  
o a SAE which could be associated with the investigation procedures and 
which could modify the conduct of the clinical investigation, 
o a significant hazard to the patient population such as lack of performance 
of an IMD used for the treatment of a life-threatening disease, 
o a 
major 
safety 
finding 
from 
a 
newly 
completed 
animal 
study/investigation (such as carcinogenicity), 
x a temporary halt of an investigation for safety reasons if the clinical investigation is 
conducted with the same IMDs in another country by the same Sponsor. 
Ͳ 
If severe and/or serious AEs with the IMD in human or animal studies should indicate 
discontinuation of the clinical investigation.  
Ͳ 
If Laboratoires THÉA should wish to discontinue the clinical investigation for 
commercial reasons.  
Ͳ 
If Laboratoires THÉA had reasons to believe that the clinical investigation could not be 
satisfactorily completed, including, but not limited to, the reason that inadequate 
numbers of patients could be enrolled or insufficient investigational sites found within 
the necessary time.  
 
 
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16.3 
REQUIREMENTS FOR PATIENT FOLLOW-UP AND CONTINUED 
CARE 
In the case of temporary halt or early termination of the clinical investigation, the 
requirements for patient follow-up will depend on the circumstance of the temporary halt or 
early termination: 
- 
For reasons not affecting the benefit-risk balance, according to the Sponsor 
recommendations, the investigator could decide if the patient may continue the clinical 
investigation as planned or if the patient should be withdrawn from the clinical 
investigation. 
- 
For reasons of a change of the benefit-risk balance, the patient should be withdrawn 
from the clinical investigation and the IMD must be discontinued. 
- 
For an exceptional reason (e.g. COVID-19 pandemic), each investigator has to decide 
whether the patient continued the clinical investigation when able to follow the CIP 
requirements safely or to withdraw the patient from the clinical investigation, based on 
his/her assessment of the benefit/risk ratio regarding the COVID-19 pandemic situation 
in his/her country/region and own investigational site, in accordance with the 
national/regional recommendations. 
This concerns all patients still on-going in the clinical investigation at the time of temporary 
halt or early termination. 
If a patient is prematurely stopping the IMD or should prematurely withdraw from the clinical 
investigation, the investigator must perform at least one premature discontinuation visit 
followed by one/several follow-up visits as decided by the Sponsor and according to the 
circumstances.  
If possible and depending the circumstance, the premature discontinuation visit will be realized 
on site and the follow-visit(s) could be performed by phone. 
If it is not possible, the premature discontinuation visit will be performed by phone-call and/or 
online video consultation. In this case and if current circumstances are favorable, at least one 
of follow-up safety visit should be performed onsite. 
During the premature discontinuation visit/phone-call, the investigator has to: 
- 
Collect AE/incident,  
- 
Check the IMD compliance, 
- 
Check the number of returned used and unused IMD, 
- 
Instruct the patient to stop or to continue the IMD (depending on the reason as described 
above), 
- 
Ensure the continuity of investigational disease medication (if appropriate), 
- 
Perform evaluations described for the premature investigation discontinuation/final visit 
if possible (onsite visit), 
- 
Prescribe to the patient the best appropriate treatment if needed, 
- 
Collect information on concomitant medications changes.  
 
If some follow-up visit(s) are required or if the premature discontinuation visit could not be 
realized on site, the investigator will have to schedule these phone-calls/visits. During this/these 
visit(s), the investigator has to: 
- 
Collect AE/incident,  
- 
Collect information on concomitant medications changes, 
- 
Check the IMD compliance, if applicable, 
- 
Check the number of returned used and unused IMD, if applicable, 
- 
Perform evaluations described for the premature investigation discontinuation/final visit 
if not done at the premature discontinuation visit, 
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- 
Prescribe to the patient the best appropriate treatment if needed. 
In any case, the requirements for patient follow-up will be described in more details in specific 
guidelines which will be provided to each involved persons (investigators, Investigational team, 
Hospitals etc…) and to Institutions if necessary (IEC, CA etc...). This could be done by 
submitting a notification (in case of emergency) and/or a substantial modification. 
17 PUBLICATION POLICY 
By signing the CIP, the investigator agrees that the results of the clinical investigation may be 
used for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals. If necessary, the CAs will be notified of the 
investigator's name, address, qualifications, and extent of involvement. 
The data resulting from this clinical investigation will be the proprietary information of 
Sponsor. An investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with Laboratoires THÉA in advance. 
At the end of the clinical investigation, Laboratoires THÉA will prepare a Clinical 
Investigation Report. 
For any manuscript for publication prepared by Laboratoires THÉA, Laboratoires THÉA 
reserves the right to select the investigators who will be the authors to review the manuscript. 
Laboratoires THÉA will allow the selected investigators sufficient time for full review of the 
manuscript before publication.  
 
 
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18 BIBLIOGRAPHY 
 
Aragona, Pasquale; Simmons, Peter A.; Wang, Hongpeng; Wang, Tao (2019) Physicochemical 
Properties of Hyaluronic Acid-Based Lubricant Eye Drops. In : Translational vision science & 
technology, vol. 8, n° 6, p. 2. DOI: 10.1167/tvst.8.6.2. 
Baudouin, Christophe; Aragona, Pasquale; Messmer, Elisabeth M.; Tomlinson, Alan; Calonge, 
Margarita; Boboridis, Kostas G. et al. (2013) Role of hyperosmolarity in the pathogenesis and 
management of dry eye disease: proceedings of the OCEAN group meeting. In : The ocular 
surface, vol. 11, n° 4, p. 246–258. DOI: 10.1016/j.jtos.2013.07.003. 
Baudouin, Christophe; Figueiredo, Francisco C.; Messmer, Elisabeth M.; Ismail, Dahlia; 
Amrane, Mourad; Garrigue, Jean-Sébastien et al. (2017) A randomized study of the efficacy 
and safety of 0.1% cyclosporine A cationic emulsion in treatment of moderate to severe dry 
eye. 
In : European 
journal 
of 
ophthalmology, 
vol. 27, 
n° 5, 
p. 520–530. 
DOI: 
10.5301/ejo.5000952. 
Begley, Carolyn; Caffery, Barbara; Chalmers, Robin; Situ, Ping; Simpson, Trefford; Nelson, J. 
Daniel (2019) Review and analysis of grading scales for ocular surface staining. In : The ocular 
surface, vol. 17, n° 2, p. 208–220. DOI: 10.1016/j.jtos.2019.01.004. 
Chiambaretta, Frédéric; Doan, Serge; Labetoulle, Marc; Rocher, Nicolas; Fekih, Lamia El; 
Messaoud, Riadh et al. (2017) A randomized, controlled study of the efficacy and safety of a 
new eyedrop formulation for moderate to severe dry eye syndrome. In : European journal of 
ophthalmology, vol. 27, n° 1, p. 1–9. DOI: 10.5301/ejo.5000836. 
Craig, Jennifer P.; Nichols, Kelly K.; Akpek, Esen K.; Caffery, Barbara; Dua, Harminder S.; 
Joo, Choun-Ki et al. (2017) TFOS DEWS II Definition and Classification Report. In : The 
ocular surface, vol. 15, n° 3, p. 276–283. DOI: 10.1016/j.jtos.2017.05.008. 
Fariselli, Chiara; Giannaccare, Giuseppe; Fresina, Michela; Versura, Piera (2018) 
Trehalose/hyaluronate eyedrop effects on ocular surface inflammatory markers and mucin 
expression in dry eye patients. In : Clinical ophthalmology (Auckland, N.Z.), vol. 12, p. 1293–
1300. DOI: 10.2147/OPTH.S174290. 
Holland, Edward J.; Darvish, Mahshad; Nichols, Kelly K.; Jones, Lyndon; Karpecki, Paul M. 
(2019) Efficacy of topical ophthalmic drugs in the treatment of dry eye disease: A systematic 
literature 
review. 
In : The 
ocular 
surface, 
vol. 17, 
n° 3, 
p. 412–423. 
DOI: 
10.1016/j.jtos.2019.02.012. 
Jones, Lyndon; Downie, Laura E.; Korb, Donald; Benitez-Del-Castillo, Jose M.; Dana, Reza; 
Deng, Sophie X. et al. (2017) TFOS DEWS II Management and Therapy Report. In : The ocular 
surface, vol. 15, n° 3, p. 575–628. DOI: 10.1016/j.jtos.2017.05.006. 
Labetoulle, Marc; Schmickler, Stefanie; Galarreta, David; Böhringer, Daniel; Ogundele, 
Abayomi; Guillon, Michel; Baudouin, Christophe (2018) Efficacy and safety of dual-polymer 
hydroxypropyl guar- and hyaluronic acid-containing lubricant eyedrops for the management of 
dry-eye disease: a randomized double-masked clinical study. In : Clinical ophthalmology 
(Auckland, N.Z.), vol. 12, p. 2499–2508. DOI: 10.2147/OPTH.S177176. 
Mateo Orobia, A. J.; Casas Pascual, P.; Perez Pascual, P.; Cristobal Bescos, J. A.; Perez Garcia, 
D.; Peiro Embid, C. et al. (2017) Effects of 3% trehalose as an adjuvant treatment after lasik. 
In : Clinical 
ophthalmology 
(Auckland, 
N.Z.), 
vol. 11, 
p. 347–353. 
DOI: 
10.2147/opth.s125203. 
Nasser, Linda; Rozycka, Malgorzata; Gomez Rendon, Gabriela; Navas, Alejandro (2018) Real-
life results of switching from preserved to preservative-free artificial tears containing 
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hyaluronate in patients with dry eye disease. In : Clinical ophthalmology (Auckland, N.Z.), 
vol. 12, p. 1519–1525. DOI: 10.2147/OPTH.S160053. 
Pinto-Bonilla, Juan Carlos; Del Olmo-Jimeno, Alberto; Llovet-Osuna, Fernando; Hernández-
Galilea, Emiliano (2015) A randomized crossover study comparing trehalose/hyaluronate 
eyedrops and standard treatment: patient satisfaction in the treatment of dry eye syndrome. 
In : Therapeutics 
and 
clinical 
risk 
management, 
vol. 11, 
p. 595–603. 
DOI: 
10.2147/TCRM.S77091. 
Pucker, Andrew D.; Ng, Sueko M.; Nichols, Jason J. (2016) Over the counter (OTC) artificial 
tear drops for dry eye syndrome. In : The Cochrane database of systematic reviews, vol. 2, 
CD009729. DOI: 10.1002/14651858.CD009729.pub2. 
Schmidl, Doreen; Schmetterer, Leopold; Witkowska, Katarzyna J.; Unterhuber, Angelika; dos 
Santos, Valentin Aranha; Kaya, Semira et al. (2015) Tear film thickness after treatment with 
artificial tears in patients with moderate dry eye disease. In : Cornea, vol. 34, n° 4, p. 421–426. 
DOI: 10.1097/ICO.0000000000000358. 
Stapleton, Fiona; Alves, Monica; Bunya, Vatinee Y.; Jalbert, Isabelle; Lekhanont, Kaevalin; 
Malet, Florence et al. (2017) TFOS DEWS II Epidemiology Report. In : The ocular surface, 
vol. 15, n° 3, p. 334–365. DOI: 10.1016/j.jtos.2017.05.003. 
Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in 
dysfunctional tear syndrome. Am J Ophthalmol. 2009 Feb;147(2):198-205. 
Novack et al., 2017; Wolffsohn et al., 2017; Begley et al., 2019; Nichols et al., 2021; Begley et 
al., 2022 
Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, Gupta PK, Karpecki 
P, Lazreg S, Pult H, Sullivan BD, Tomlinson A, Tong L, Villani E, Yoon KC, Jones L, Craig 
JP. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017 Jul;15(3):539-574. 
Nichols KK, Evans DG, Karpecki PM. A Comprehensive Review of the Clinical Trials 
Conducted for Dry Eye Disease and the Impact of the Vehicle Comparators in These Trials. 
Curr Eye Res. 2021 May;46(5):609-614. 
Begley C, Caffery B, Chalmers R, Situ P, Simpson T, Nelson JD. Review and analysis of 
grading scales for ocular surface staining. Ocul Surf. 2019 Apr;17(2):208-220. 
Begley CG, Caffery B, Nelson JD, Situ P. The effect of time on grading corneal fluorescein and 
conjunctival lissamine green staining. Ocul Surf. 2022 Jul;25:65-70. 
Labetoulle M, Mortemousque B; CBL-101 Study Group. Performance and Safety of a Sodium 
Hyaluronate Tear Substitute with Polyethylene Glycol in Dry Eye Disease: A Multicenter, 
Investigator-Masked, Randomized, Noninferiority Trial. J Ocul Pharmacol Ther. 2022 
Nov;38(9):607-616 
Baudouin C, Cochener B, Pisella PJ, Girard B, Pouliquen P, Cooper H, Creuzot-Garcher C. 
Randomized, phase III study comparing osmoprotective carboxymethylcellulose with sodium 
hyaluronate in dry eye disease. Eur J Ophthalmol. 2012 Sep-Oct;22(5):751-61. 
Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of 
the Ocular Surface Disease Index. Arch Ophthalmol. 2000 May;118(5):615-21. doi: 
10.1001/archopht.118.5.615. PMID: 10815152. 
Kimberly L. Miller, PhD; John G. Walt, MBA; David R. Mink, MS; Sacha Satram-Hoang,PhD; 
Steven E. Wilson, MD; Henry D. Perry, MD; Penny A. Asbell, MD, MBA; Stephen C. 
Pflugfelder, MD. Minimal Clinically Important Difference for the Ocular Surface Disease 
Index. Arch Ophthalmol. 2010;128(1):94-101 
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Thomas Kaercher, Elisabeth M Messmer, Thomas Berninger, Klaudia K Huber-van der Velden, 
Raphaela 
Geiger, 
Pauline 
Cipriano-Bonvin, 
Christina 
Jacobi. 
Topical 
Omega-3 
Polyunsaturated Fatty Acids for the Treatment of Dry Eye – Results from a Pilot Randomized 
Controlled Masked-Observer Study. Clinical Ophthalmology 2022:16 4021–4031 
Duracinsky M, Gryparis A, Chassany O. Impact of Dry Eye on Daily Life and Patient 
Satisfaction Using Eye Drops. Psychometrics Properties of a New Scale. ISPOR Europe, 
Vienna, 
October 
2022. 
Value 
in 
Health 
2022 
(Suppl.); 
12: 
S415. 
DOI: 
10.1016/j.jval.2022.09.2062. 
US Food and Drug Administration. (2009). Guidance for industry patient-reported outcome 
measures: Use in medical product development to support labeling claims. Food and Drug 
Administration. Retrieved August 2023, from https://www.fda.gov/media/77832/download 
 
 
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