Evaluation of the Efficacy and Safety of DM05 Versus Optive™ on the Treatment of Moderate to Severe Ocular Dryness
Phase: NA
Conditions: Dry Eye
Sponsor: Horus Pharma

                                       
 
 
PRM02-F-012_A_V1 
Clinical investigational plan for MD 
 
 
Evaluation of the efficacy and safety of DM05 versus OptiveTM on 
the treatment of moderate to severe ocular dryness 
 
Clinical Investigational Plan for Medical Device according to ISO standard 14155:2011 and its 
updates 
 
Clinical Investigational plan #: 
15E1122 
ANSM registration number: 
2016-A01843-48 
Investigational medical device : 
1. DM05 
Comparative medical device 
2. OptiveTM 
Form : 
1. Sterile emulsion (multidose) 
2. Sterile solution (multidose) 
Application(s) : 
Ocular route 
CRO : 
DERMSCAN - PharmaScan  
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE 
FRANCE 
Coordinating Investigator: 
Pr Christophe BAUDOUIN 
Centre Hospitalier National d'Ophtalmologie des 
Quinze-Vingts 
28 Rue de Charenton 
75012 Paris 
FRANCE 
Sponsor : 
HORUS PHARMA 
148 Avenue G.Guynemer 
Cap Var 
06 700 SAINT LAURENT DU VAR 
FRANCE 
Clinical 
Investigation 
Plan 
date 
and 
version #:  
Final Version 4.0 of 04/09/2017 
 
 

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TABLE OF CONTENTS 
1- 
GENERAL INFORMATION ....................................................................................... 6 
1.1 
Introduction ...................................................................................................................... 6 
1.2 
Identification of the clinical investigation plan (CIP) ................................................... 6 
1.3 
Sponsor ............................................................................................................................. 6 
1.4 
Coordinating Investigator ............................................................................................... 7 
1.5 
Overall synopsis of the clinical investigation ............................................................... 9 
2- 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE ......13 
2.1 
Summary description of the investigational device and its intended purpose ....... 13 
2.2 
Details concerning the manufacturer of the investigational device ......................... 13 
2.3 
Name or number of the model/type ............................................................................. 13 
2.4 
Traceability of the investigational device .................................................................... 13 
2.5 
Intented purpose of the investigational device in the proposed clinical 
investigation ................................................................................................................... 14 
2.6 
populations and indications for which the investigational device is intenDed ...... 14 
2.7 
Description of the investigational device .................................................................... 14 
2.8 
Summary of the training and experience needed to use the investigational device
 14 
2.9 
Description of the specific medical or surgical procedures involved in the use of 
the investigational device ............................................................................................. 15 
3- 
JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION ............15 
3.1 
Summary of the results of the relevant pre-clinical testing/ assessment carried out 
to justify the use of the investigational device in human subjects .......................... 15 
3.2 
Summary of clinical data relevant to the proposed clinical investigation ............... 16 
4- 
RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL 
INVESTIGATION ..............................................................................................................16 
4.1 
Anticipated clinical benefits ......................................................................................... 16 
4.2 
Anticipated adverse device effects .............................................................................. 16 
4.3 
Residual risks associated with the investigational device as identified in the risk 
analysis report ............................................................................................................... 17 
4.4 
Risks associated with participation in the clinical investigation.............................. 17 
4.5 
Potential Interactions with concomitant medical treatments .................................... 17 
4.6 
Steps that will be taken to control or mitigate the risks ............................................ 17 
4.7 
Risk-to-benefit rationale ................................................................................................ 17 
5- 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION .............17 
5.1 
Main objective ................................................................................................................ 17 
5.2 
Secondary objective(s) .................................................................................................. 17 
5.3 
Primary and secondary hypotheses to be accepted or rejected by statistical data 
from the clinical investigation ...................................................................................... 17 
5.4 
Risks and anticipated adverse device effects that are to be assessed ................... 17 
6- 
DESIGN OF THE CLINICAL INVESTIGATION ........................................................18 
6.1 
General information ....................................................................................................... 18 
6.2 
Investigational device(s) and comparator(s) .............................................................. 24 

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6.3 
Studied population ........................................................................................................ 26 
6.4 
Procedures ..................................................................................................................... 27 
6.5 
Monitoring ....................................................................................................................... 28 
7- 
STATISTICAL CONSIDERATIONS .........................................................................29 
7.1 
Statistical design, method and analytical procedures ............................................... 29 
7.2 
Sample size and its statistical justification ................................................................. 31 
7.3 
Level of significance and power of the clinical investigation ................................... 32 
7.4 
Statistical pass/fail criteria to be applied to the results of the clinical investigation
 32 
7.5 
Provision for an interim analysis, where applicable .................................................. 32 
7.6 
Criteria for the termination of the clinical investigation on statistical grounds ..... 32 
7.7 
Procedures for reporting any deviation(s) from the original statistical plan .......... 32 
7.8 
Specification of subgroups for analysis ..................................................................... 32 
7.9 
Procedures that take into account all the data ........................................................... 32 
7.10 
Treatment of missing, unsued or spurious data, including drop-outs and 
withdrawals..................................................................................................................... 32 
7.11 
Exclusion METHOD of particular information from the testing of the hypothesis, if 
relevant ........................................................................................................................... 32 
7.12 
In multicentre investigations, minimum and maximum number of subjects to be 
included BY each centre ............................................................................................... 32 
8- 
DATA MANAGEMENT .............................................................................................33 
8.1 
Procedures used for data review, database cleaning and issuing/resolving data 
queries ............................................................................................................................ 33 
8.2 
Procedures for verification, validation and securing of electronic clinical data 
systems, if applicable .................................................................................................... 34 
8.3 
Procedures for data retention and specifed retention period ................................... 34 
8.4 
Other aspects of clinical quality assurance, as appropriate ..................................... 34 
9- 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ..................................35 
10- DEVIATIONS FROM CLINICAL INVESTIGATION PLAN ........................................35 
10.1 
Statement specifying that the Investigator is not allowed to deviate from the CIP 35 
10.2 
Procedures for recording, reporting and analysing CIP deviations ......................... 35 
10.3 
Notification requirements and time frames ................................................................. 35 
10.4 
Corrective and preventive actions and principal Investigator disqualification 
criteria ............................................................................................................................. 35 
11- DEVICE ACCOUNTABILITY ....................................................................................35 
12- STATEMENTS OF COMPLIANCE ...........................................................................36 
12.1 
Declaration of Helsinki .................................................................................................. 36 
12.2 
ISO 14155 standard and local regulations .................................................................. 36 
12.3 
EC and/or regulatory authorities .................................................................................. 36 
12.4 
Insurance ........................................................................................................................ 36 
13- INFORMED CONSENT PROCESS ..........................................................................36 
13.1 
General process for obtaining informed consent ...................................................... 36 
13.2 
Informed consent process if the subject is unable to give it .................................... 37 

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14- ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES
 
37 
14.1 
Definitions....................................................................................................................... 37 
14.2 
Timelines for reporting .................................................................................................. 39 
14.3 
General process for reporting adverse events and device deficiencies ................. 40 
14.4 
Process for reporting serious adverse events and contact details.......................... 41 
14.5 
Process for reporting a pregnancy .............................................................................. 43 
14.6 
List of foreseeable adverse events and anticipated adverse device effects ........... 43 
14.7 
Information regarding the Data monitoring committee (DMC), if established ........ 43 
15- VULNERABLE POPULATION .................................................................................43 
16- SUSPENSION OR PREMATURE TERMINATION OF THE CLINICAL 
INVESTIGATION ..............................................................................................................43 
16.1 
Criteria and modalities of premature end of treatment or subject exclusion from 
the clinical investigation ............................................................................................... 43 
16.2 
Criteria for access and to breaking the blinding/masking code during the clinical 
investigation ................................................................................................................... 44 
16.3 
Requirements for subject follow-up ............................................................................ 44 
17- PUBLICATION POLICY ...........................................................................................44 
18- BIBLIOGRAPHY ......................................................................................................45 
18.1 
Concerning study rationale .......................................................................................... 45 
18.2 
Ethical aspect ................................................................................................................. 45 
19- CIP SIGNATURES ...................................................................................................46 
 

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ABREVIATION LIST: 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
ANSM 
Agence Française de Sécurité Sanitaire des Produits de Santé 
CA 
Competent Authority 
CIP 
Clinical Investigational Plan 
CNIL 
Commission Nationale Informatique et Libertés 
CPP 
French Ethics Committee - Comité de Protection des Personnes 
CRA 
Clinical Research Assistant 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSP 
Code de la Santé Publique 
D 
Day 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ICH 
International Conference on Harmonisation 
ITT 
Intent To Treat 
MD 
Medical Device 
OSDI 
Ocular Surface Disease Index 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
TBUT 
Tera film Break-Up Time 
 
 
 

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1- GENERAL INFORMATION 
 
1.1 
INTRODUCTION 
 
Dry eye syndrome is a multifactorial disease of the tears and ocular surface that results in symptoms of 
discomfort, visual disturbance and tear film instability, with potential damage to the ocular surface. It 
affects millions of people worldwide. Symptoms of dry eye vary between patients and can include itching, 
gritty feeling, burning, foreign body sensation, dryness, photosensitivity, pain, blurred vision, and contact 
lens intolerance. Dry eye can have an adverse effect on patient quality of life, affecting, in particular, 
reading, computer use, watching television, and driving. The first mainstay for treatment of stage 1 dry 
eye is the use of artificial tears, which are predominantly aqueous-based and do not contain a lipid 
component and probably only provide momentary relief from symptoms and therefore, low patient 
satisfaction. Given the lipid layer is compromised in certain forms of dry eye, it’s often beneficial to add 
lipids to compensate.  
 
DM05 is a medical device of class IIb. It consists in non-preserved single dose eye drops, containing 
sodium hyaluronate and lipids which, due to its physical properties (non-irritant water soluble polymer 
and lipid to avoid evaporation), is used for the moistening and lubrication of the ocular surface. In medical 
practice, DM05 is intended to improve signs and symptoms related to dry eye. 
 
The objective of this study is to compare DM05 with another medical device already commercialized, 
OptiveTM, in terms of improvement of ocular signs and symptoms, on patients with moderate to severe 
ocular dryness and already treated by artificial tears for at least 3 months. Ninety subjects are planned 
to be included (45 subjects using each product), with moderate to severe ocular dryness. The efficacy 
and safety of each product, used between 4 and 6 times per day, will be assessed after 35 and 84 days 
of treatment. 
 
 
1.2 
IDENTIFICATION OF THE CLINICAL INVESTIGATION PLAN (CIP) 
 
TITLE OF THE CIP: Evaluation of the efficacy and safety of DM05 versus OptiveTM on the 
treatment of moderate to severe ocular dryness 
 
CIP #: 15E1122 
 
VERSION AND DATE OF THE CIP: FINAL VERSION 3.0 OF 24/03/2017 
 
SUMMARY OF THE REVISION HISTORY IN THE CASE OF AMENDMENTS: 
 VERSION 4.0 OF 04/09/2017: MODIFICATION OF SAMPLE SIZE CALCULATION AND SUBJECT NUMBER, 
ADDITION OF ONE CENTER IN POLAND AND 2 CENTERS IN SPAIN. 
VERSION 3.0 OF 24/03/2017: SUPPRESSION OF ONE CENTER IN TUNISIA, ADDITION OF ONE CENTER 
IN SPAIN,ADDITION OF ONE CENTER IN FRANCE. 
VERSION 2.0 OF 05/01/2017: ADDITION OF ONE CENTER IN SPAIN AND E-CRF. 
VERSION 1.0 OF 17/11/2016: INITIAL PROTOCOL 
 
 
 
1.3 
SPONSOR 
 
 
Sponsor : 
 
 
HORUS PHARMA 
148 Avenue G.Guynemer 
Cap Var 
Sponsor’s contact: 
 
Chantal COUDERC 
HORUS PHARMA 
148 Avenue G.Guynemer 
Cap Var 

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06 700 SAINT LAURENT DU VAR 
FRANCE 
TEL: +33 (0)4 93 19 54 03 
FAX: +33 (0)4 93 19 54 09 
 
06 700 SAINT LAURENT DU VAR 
FRANCE 
Tel : +33 (0)4 83 32 20 75 
E-mail : chantal.couderc@horus-pharma.fr 
 
 
Contact for medical device vigilance:  
 
Carole GARD 
HORUS PHARMA 
148 Avenue G.Guynemer 
Cap Var 
06 700 SAINT LAURENT DU VAR 
FRANCE 
TEL: +33 (0) 04 93 14 01 42 
FAX: +33 (0) 4 93 19 54 09 
E-mail : carole.gard@horus-pharma.fr 
 
Audrey YAHIYA 
HORUS PHARMA 
148 Avenue Guynemer 
Cap Var 
06 700 SAINT LAURENT DU VAR 
France 
E-mail :audrey.yahiya@horus-pharma.fr 
TEL: +33 (0) 4 93 19 33 74  
FAX: +33 (0) 4 93 19 54 09 
 
 
 
1.4 
COORDINATING INVESTIGATOR 
 
Pr Christophe BAUDOIN 
Centre Hospitalier National d'Ophtalmologie des 
Quinze-Vingts 
28 Rue de Charenton 
75012 Paris 
FRANCE  
Tel: 01 40 02 13 01 
E-mail : cbaudouin@15-20.fr 
 
 
1.5. MAIN INVESTIGATOR FOR POLAND 
 
Dr Ewa PAW 
DERMSCAN Poland Sp. z o.o. 
ul. Kruczkowskiego 12 
80-288 Gdańsk 
POLAND 
Tel : +48 58 732 02 99 
 
 
 
 
 
 

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1.6. 
COORDINATING INVESTIGATOR FOR SPAIN 
 
Pr Margarita Calonge (MD, PhD) 
IOBA, Instituto Universitario de Oftalmobiologia Aplicada 
Paseo de Belén, 17 
47011 Valladolid 
SPAIN 
 
CONTRACT RESEARCH ORGANISATION (CRO) 
 
C.R.O. 
 
DERMSCAN - PharmaScan 
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE  
FRANCE 
Tél.: 04 72 82 36 56  
Fax: 04 78 89 60 48 ou 04 72 82 60 86 
Project Manager 
 
Audrey NATALIZIO 
DERMSCAN - PharmaScan 
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE  
FRANCE 
Tel. : +33 (0) 4 72 82 36 56 
Fax : +33 (0)4 28 29 08 12 
E-mail: ana@dermscan.com 
 
 
 
Clinical Research Assistant: 
 
Nadine BERRY 
DERMSCAN - PharmaScan 
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE  
FRANCE 
Tel. : +33 (0) 4 72 82 36 56 
Fax : +33 (0)4 28 29 08 12 
E-mail: nbe@dermscan.com 
Biostatistician: 
 
Cédric JUNG 
DERMSCAN - PharmaScan 
114 Boulevard du 11 Novembre 1918 
69100 VILLEURBANNE  
FRANCE 
Tel. : +33 (0) 4 72 82 36 56 
Fax : +33 (0)4 28 29 08 12 
E-mail: cju@dermscan.com 
 
 
DATA MANAGEMENT AND STATISTICS 
 
BIOSTATEM 
Parc d’activités Via Domitia 
205 Avenue des Gardians 
34 160 CASTRIES 
FRANCE 
 
 
 

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1.5 
OVERALL SYNOPSIS OF THE CLINICAL INVESTIGATION 
 
ANSM registration #: 
2016-A01843-48 
Clinical investigation #: 
15E1122 
Title of the Clinical Investigation: 
Evaluation of the efficacy and safety of DM05 versus OptiveTM 
on the treatment of moderate to severe ocular dryness 
Sponsor: 
HORUS PHARMA 
148 Avenue G.Guynemer 
Cap Var 
06 700 SAINT LAURENT DU VAR 
FRANCE 
Objectives: 
Main objective: 
To demonstrate the non-inferiority of DM05 in comparison with 
OptiveTM, in terms of cornea and conjunctiva staining (Oxford 
score) on patients with moderate to severe ocular dryness, after 35 
days of treatment. 
 
Secondary objectives 
• To evaluate the efficacy of DM05 in comparison with OptiveTM 
on other signs and symptoms associated to moderate to severe 
ocular dryness, after 35 and 84 days of treatment 
 
• To evaluate the safety of DM05 over 84 days of treatment. 
Design: 
Multicentric, comparative, randomized, investigator-blinded, in 
parallel groups study. 
Planned Sample Size: 
80 subjects included 
Number of centers: 
7 centers in France, 2 in Poland and 4 in Spain 

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Inclusion criteria: 
• 
Sex: male or female.  
• 
Age: more than 18 years. 
• 
Subject with a dry eye syndrome needing artificial tears in 
the 3 months preceding the inclusion. 
• 
Subject having used only artificial tears without preservative 
(NaCl 0.9%, Hydrabak®) during 1 or 2 weeks before 
inclusion (at 3 drops per day). 
• 
Diagnosis of moderate to severe ocular dryness defined by 
a score OSDI (Ocular Surface Disease Index) ≥18. 
• 
Subject with at least one eye with: 
- Global ocular staining (cornea and conjunctiva) ≥4 and ≤9 
(Oxford scale from 0 to 15) 
AND one the following criteria: 
- 
Schirmer test ≥ 3mm/5 min and ≤9mm/ 5 min 
OR 
- 
Sum of 3 measurements of Tear film Break-Up Time 
(TBUT) ≤ 30s. 
• 
Subject, having given freely and expressly his/her informed 
consent. 
• 
Subject who is able to comply with the study requirements, 
as defined in the present protocol, at the Investigator’s 
appreciation. 
• 
In France: subject being affiliated to a health social security 
system. 
• 
Female subjects of childbearing potential should use a 
medically accepted contraceptive regimen since at least 12 
weeks before the beginning of the study, during all the study 
and at least 1 month after the study end. 
Exclusion criteria: 
• 
Pregnant or nursing woman or planning a pregnancy during 
the study. 
• 
Subject deprived of freedom by administrative or legal 
decision. 
• 
Subject in a social or sanitary establishment. 
• 
Major subject who is under guardianship or who is not able 
to express his consent. 
• 
Subject being in an exclusion period for a previous study. 
• 
Subject suspected to be non-compliant according to the 
Investigator’s judgment. 
• 
Subject wearing contact lenses during the study. 
• 
Far best corrected visual acuity < 1/10 
• 
Subject with severe ocular dryness with one of these 
conditions: 
- 
Eyelid or blinking malfunction 
- 
Corneal disorders not related to dry eye syndrome 
- 
Ocular metaplasia 
- 
Filamentous keratitis 
- 
Corneal neovascularization 
• 
Subject with severe meibomian gland dysfunction (MGD) 
• 
Within the last 3 months prior to the inclusion, history of 
ocular trauma, infection or inflammation not related to dry eye 
syndrome. 
• 
Within the last 12 months, history of ocular allergy or ocular 
herpes. 
 

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Exclusion criteria: 
• 
Refractive or cataract surgery within the last 6 months. 
• 
Any laser other than refractive surgery within the last 3 
months. 
• 
Any troubles of the ocular surface not related to dry eye 
syndrome. 
• 
Ocular hypertension or glaucoma needing an hypotonic 
treatment 
• 
Subject having used artificial tears in the 6 hours preceding 
the inclusion visit. 
• 
Use during the month preceding the inclusion or during the 
study of: isotretinoïd, cyclosporine, tacrolimus, sirolimus, 
pimecrolimus, punctual plugs. 
• 
Any not stabilized systemic treatment, which can have an 
effect on performance or safety criteria, at the investigator 
appreciation. 
 
Investigational device: 
Name / code: 
Galenic form: 
 
DM05 
Sterile emulsion (multidose) 
Comparator device: 
Name / code: 
Galenic form: 
 
OptiveTM 
Sterile lotion (multidose) 
Dosage: 
Duration: 
Administration route: 
1 to 2 drops in each eye between 4 and 6 times per day 
84 days 
Ocular route 
Efficacy Parameters: 
Main criterion: 
Evaluation of the non-inferiority of DM05 in comparison with 
OptiveTM, in terms of cornea and conjunctiva staining (Oxford 
score), on worse eye, between D0 and D35. 
 
Secondary criteria:  
• Comparison of D35 versus D0 and D84 versus D0 for each 
product and comparison between products for the following 
parameters: 
- 
Evolution of cornea and conjunctiva staining (Oxford score) 
on worse eye. 
- 
Evolution of OSDI score (Ocular Surface Disease Index). 
- 
Evolution of Van Bijsterveld score (Lissamine green staining) 
in worse eye. 
- 
Evolution of Schirmer test result in worse eye. 
- 
Evolution of Tear film Break-Up Time (TBUT) in worse eye. 
- 
Evolution of ocular dryness severity by evaluation of each 
main symptom by the patient and total score of all symptoms 
- 
Evaluation of treatment performance by the investigator and 
the patient. 
• Evaluation of the average frequency of use during 84 days for 
DM05 and OptiveTM. 
Safety Parameters: 
Collection of adverse events and adverse device effects. 
Study Procedures: 
Selection visit: D-14 to D-7 
Wash-out period: 1 to 2 weeks with preservative-free 0.9% NaCl 
at 3 drops per day (Hydrabak®):  
D0 : inclusion visit 
Follow-up visits: D35, D84 

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Statistics: 
Three population will be defined: 
- Intention to treat (ITT) population corresponding to all patients 
randomized 
- Safety population corresponding to all patients randomized and 
having received at least one dose of treatment. 
- Per protocol (PP) population corresponding to patients of the 
safety population who will not present major protocol deviation 
(decided by the Data Review Committee during a blind review 
process days). 
 
Analysis of the main criterion 
 
Main analysis;  
The main analysis of the main criterion will be conducted on the PP 
population. The hypothesis of non-inferiority of DM05 compared to 
Optive® will be tested by calculating the bilateral 95% CI of the 
difference between groups (DM05 – Optive®) of the change from 
baseline of global ocular staining in the worse eye on Day 35. A two-
way analysis of covariance (ANCOVA) model will be constructed 
using main effects of treatment and baseline score as covariate. 
Adjusted means (least square mean and error standard of the mean) 
by treatment will be presented as well as an estimate of the difference 
between adjusted means.  
 
A 95% two-sided confidence interval, based on the ANCOVA model, 
will be computed for the difference of DM05 minus Optive®.  
 
If the upper bound is no higher than 2 points for the PP population, it 
will be concluded that the null hypothesis can be rejected and that 
DM05 is non-inferior to Optive®. 
 
The p value of non-inferiority will be expressed taking on board the 
predefined margin of non inferiority.  
This analysis will be based on observed cases 
Sensitivity analysis of the main criterion: 
Same analysis will be performed on ITT population with imputation 
of values in case of missing data with LOCF technique (baseline 
value or value in case of withdrawal) and without imputation 
(observed cases).  
 
In case of conclusion of non inferiority of DM05 compared to 
Optive®, the superiority of DM05 compared to Optive® will be 
tested. The superiority analysis carried out on the ITTT population 
will be considered as the main analysis. Results will be also 
provided on the PP population. 
 
Study Duration: 
Clinical investigation beginning : February 2017 
Clinical investigation end: February 2018 
Clinical investigation global duration: 12 months 
Duration by subject: 84 days of treatment + 7 to 14 days of wash-out 
 
 

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2- IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE  
2.1 
SUMMARY DESCRIPTION OF THE INVESTIGATIONAL DEVICE AND ITS INTENDED 
PURPOSE  
 
Identification of the device: DM05. 
 
Device classification: Class IIb according to Rule 5 of Annex IX Directive 93/42/EEC amended by 
Directive 2007/47/EC.  
 
Indication: DM05 is recommended in cases of moderate to severe sensations of dry eyes. 
 
Composition: 
sodium 
hyaluronate 
(0.18%), 
triglycerides 
and 
phospholipids, 
Sodium 
carboxymethylcellulose, sodium citrate, citric acid, sodium chlorure and water. 
 
Properties: 
 
DM05 is an emulsion which stabilizes the tear film by acting on the three layers: lipid layer, aqueous 
layer and mucus layer. It restores the lipid layer thanks to its lipids (triglycerides and phospholipids) to 
improve lubrication and decrease tear film evaporation. It also contains sodium hyaluronate, component 
naturally present in the eye, which contributes to protect and moisturize the ocular surface. Thanks to 
the physical properties of sodium hyaluronate, DM05 has high water retention and viscoelastic 
properties, which allows the creation of a lubricant, homogeneous and protective film on the ocular 
surface. In this way, it has an effect on the aqueous layer to moisturize and protect the ocular surface. 
DM05 is hypo-osmolar to compensate the harmful inflammation induced by the tears hyper-osmolarity 
in case of ocular dryness. Sodium hyaluronate also has mucus-like properties, which allow to stimulate 
tear film integration. It is preservative and surfactant free to optimize local tolerance. 
 
Contra-indications: 
DM05 is contraindicated in case of hypersensitivity to any component. 
 
Adverse effects: 
In some very rare cases, some transitory troubles can appear such as conjunctiva mild irritation, foreign 
body sensation, ocular redness or burning or temporary blurred vision. 
 
 
2.2 
DETAILS CONCERNING THE MANUFACTURER OF THE INVESTIGATIONAL DEVICE  
 
Legal manufacturer: Horus Pharma - 148 Avenue Georges Guynemer, 06700 Saint-Laurent-du-Var. 
 
2.3 
NAME OR NUMBER OF THE MODEL/TYPE 
 
DM05. 
 
2.4 
TRACEABILITY OF THE INVESTIGATIONAL DEVICE 
 
Each product will be assigned a batch number to insure its traceability from its production to destruction. 
During the study, each product will be labelled with a specific label: 
 
The labelling of the products will be realized by DERMSCAN. 
 
Here is presented an example of the labels which will be pasted on each product, in French language: 
 
Primary packaging if applicable: 
• Study number:  
• Treatment number: 
• Product name and batch number:  
• Administration route:  
 
 

Horus Pharma 
CIP #15E1122 
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Secondary packaging: 
 
• Study site (name and address) : 
 
• Principal investigator: 
Dr. xxxxxx 
• Emergency phone number :   
• Study number :  
 
• Treatment number : 
 
• Study period : 
• Administration route:  
• Storage conditions :  
• Expiry date :  
• Product name and batch number:  
• Mention: For clinical use only. External use. Keep out of reach of children 
 
 
2.5 
INTENTED PURPOSE OF THE INVESTIGATIONAL DEVICE IN THE PROPOSED CLINICAL 
INVESTIGATION 
 
The intended purpose of the investigational device in this clinical investigation is to improve ocular signs 
and symptoms related to moderate to severe dryness. 
 
2.6 
POPULATIONS AND INDICATIONS FOR WHICH THE INVESTIGATIONAL DEVICE IS 
INTENDED 
 
This medical device is intended for symptomatic treatment of moderate to severe sensations of dry eye. 
The population that will be included in this clinical investigation will be patients previously treated by 
artificial tears for at least 3 months and with signs and symptoms of moderate to severe ocular dryness 
at the inclusion: Ocular Surface Disease Index (OSDI) ≥18 and tear deficiency as assessed by Schirmer 
test and/or TBUT (Tear film Break-up Time). 
 
 
2.7 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE  
 
Reference 
DM05 
Formula 
Components 
Quantity (%) 
Sodium hyaluronate 
0.18 % 
Medium chain triglycerid - Miglyol 812 
0,10% 
Soy lecithin – Epikuron 170 
0,10% 
Sodium carboxymethylcellulose  
0,10% 
Citrate 3Na 2H2O 
0.0412 % 
Citric acid 
0.021 % 
NaOH (1 N)  
QS pH 6.7 
Water for injection  
qsp 100 ml 
Galenic form 
Hypo-osmolar sterile emulsion 
Route/ mode of 
administration 
Ocular route. 
Instillation in the eyes. 
Always shake the single-dose unit before instillation. 
Packaging 
Multidose 10 ml vials 
Confidentiality procedure 
Commercial packaging 
Storage 
At room temperature (below 25°C) 
 
2.8 
SUMMARY 
OF 
THE 
TRAINING 
AND 
EXPERIENCE 
NEEDED 
TO 
USE 
THE 
INVESTIGATIONAL DEVICE 
 
The use of the investigational device is very simple and doesn’t need a special training or experience, 
as it’s intended to be used by the subjects themselves. The instructions for use are described in 
paragraph 6.2.1.2. 
 

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2.9 
DESCRIPTION OF THE SPECIFIC MEDICAL OR SURGICAL PROCEDURES INVOLVED IN 
THE USE OF THE INVESTIGATIONAL DEVICE 
 
Not applicable. 
 
3- JUSTIFICATION FOR THE DESIGN OF THE CLINICAL INVESTIGATION  
3.1 
SUMMARY OF THE RESULTS OF THE RELEVANT PRE-CLINICAL TESTING/ 
ASSESSMENT CARRIED OUT TO JUSTIFY THE USE OF THE INVESTIGATIONAL DEVICE IN 
HUMAN SUBJECTS 
 
3.1.1 
Cytotoxicity test 
 
The cytotoxicity direct contact test was performed on “DM05” according to ISO 10993-5:2009 in 2014. 
For the cytotoxicity test by direct contact a confluent BalbC 3T3 cell culture in exponential phase of 
growth was used. 
 
 
A qualitative evaluation was performed observing cell culture by an inverted microscope, while a 
quantitative evaluation was performed using the Neutral Red Uptake method (NRU). The NRU is a 
method that allows to measure cell vitality using their capacity to incorporate and to bind a cellular vitality  
“DM05” was applied to the monolayer of BalbC 3T3 and was incubated at 37°C +/- 1°C in CO2 
atmosphere for 24 hours. 
After 24 hours of incubation the cells were observed to microscope (qualitative evaluation) to evaluate 
the biological reaction. 
After 24 hours of contact, in the cell treated with test item no detectable zone around or under specimen 
was observed (reactivity grade 0). 
After the qualitative evaluation cells were treated for 3 hours with the Medium containing the cell vitality 
dye and then with a Desorb Solution that allows to obtain a cell lysate. The optic density was then 
calculated after a 540 nm spectrophotometric reading. 
Cells treated with test sample have shown a cell vitality reduction of 52%. 
On the basis of the results, interpreted according to ISO- 10993-5:2009, the test item “DM05” 
must be considered cytotoxic on this model. This result could be due to the osmolarity of the solution 
(around 150 µosml-1 instead of 300 and lipid in the solution).   
 
A comparison of the corneal healing process under OPTIVE®, OPTIVE Fusion TM, VISMED® Multi and 
“DM05” against 0.01 % BAC as positive control in the Ex Vivo Eye Irritation Test (EVEIT) – long-term 
was performed. 
“DM05” showed a rapid corneal healing on day 2 that was superior to any of the other tested products. 
A minor signs of toxicity was observed at 6 days but are not well understood. Of all listed ingredients in 
the given concentrations only Miglyol® 812 has been shown to cause minor irritation to the conjunctiva 
in an animal model, the Draize test.  However, one drop per hour is used during 6 days (night and day). 
This model is not representative of the usual posology (one to two drops 6 times a day as a maximum) 
In contrast, the safety sheet of the product indicates no ocular toxicity. 
3.1.2 
Sensitization test 
A guinea pig maximization test according to ISO 10993-10:2010 was performed in 2014 on ““DM05”. 
A preliminary test was effected on three guinea pig in order to select the adequate concentration. 
“DM05” was intradermally injected (induction I) and topically applied (induction II) to ten test guinea pig 
in attempt to induce delayed sensitization. A negative control solution of 0,9% NaCl was similarly 
injected and topically applied to five control guinea pigs. Following a recovery period, all the test and 
control animals received a challenge patch.  
All sites were scored at 24 (± 2) and 48 (± 2) hours after patch removal. 
No clinical sign was observed throughout the study. No evidence of sensitization by topical route was 
observed with “DM05” (sensitization grade 0). 
Under the condition of this study, the topical application of “DM05” evaluated at a concentration of 100%, 
according to the ISO 10993-10 standard, did not induce delayed sensitization in the guinea pig (grade 

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0). Based on this results, “DM05” was not considered a sensitizer in the guinea pig maximization 
model. 
 
3.1.3 
Irritation test  
 
An ocular irritation test according to ISO 10993-10:2010 was performed in 2014 on “DM05”. 
Each day during 5 consecutive days, 6 instillations of 0,1 mL of MD19 were instilled into the lower 
conjunctival sac of the left eye of 3 rabbits and 0,1 mL of 0,9 % NaCl solution was instilled into the lower 
conjunctival sac of the right eye (negative control). 
Ocular reaction were evaluated by slit-lamp evaluation daily (before and 1 hour ± 0,1 h after each 
instillation) and 24 (± 2), 48 (± 2) and 72 (± 2) hours after the last instillation and graded according to 
the system for grading ocular lesion. 
The observation of both eye before and after each instillation and 24 (± 2), 48 (± 2) and 72 (± 2) hours 
after the last instillation did not reveal any ocular irritation. 
Under the conditions of this study, “DM05” met the requirement of the eye irritation test 
according to the procedure described in the ISO 10993-10 standard. 
 
3.1.4 
Conclusion on biological safety evaluation 
According to the results of the three above tests, and according to the well-established use of sodium 
hyaluronate and lipids in medicinal product for many years, “DM05” biological safety could be considered 
as acceptable. 
 
3.2 
SUMMARY 
OF 
CLINICAL 
DATA 
RELEVANT 
TO 
THE 
PROPOSED 
CLINICAL 
INVESTIGATION 
 
The tolerance and efficacy of the tested medical device (DM05) was evaluated in a clinical study realized 
in Mauritius in 2015. 
22 subjects were included in the study.  
 
Product DM05 was well tolerated 30 minutes after its first use and after 14 days of use. Some subjects 
reported slight functional signs after product use and 4 subjects had a slight corneal staining after 
instillation on D14. These signs were considered as not relevant by the investigator because they are 
usual after an instillation of a product in the eyes. 
 
At least 85% of the subjects who presented uncomfortable sign on D0 observed an improvement of their 
signs from the first product application and the improvement was even better after 14 days of product 
use. 
The product “DM05” was efficient in reducing ocular dryness after 14 days of use. 
Product “DM05” was very well appreciated by the subjects for its efficacy on eye dryness, after 14 days 
of use. 
 
 
4- RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND CLINICAL 
INVESTIGATION 
4.1 
ANTICIPATED CLINICAL BENEFITS 
 
Improvement of the signs and symptoms associated to ocular dryness. 
 
4.2 
ANTICIPATED ADVERSE DEVICE EFFECTS 
 
In some very rare cases, some transitory troubles can appear such as conjunctiva mild irritation, foreign 
body sensation, ocular redness or burning or temporary blurred vision. 
 

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4.3 
RESIDUAL RISKS ASSOCIATED WITH THE INVESTIGATIONAL DEVICE AS IDENTIFIED 
IN THE RISK ANALYSIS REPORT 
 
DM05 is contraindicated in case of hypersensitivity to any component. 
 
 
4.4 
RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL INVESTIGATION 
 
There will not be additional risks for the patients, associated with their participation in the clinical 
investigation. 
 
4.5 
POTENTIAL INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
 
Maintain a minimum interval of 15 minutes between instillation of another eye drops.  
 
4.6 
STEPS THAT WILL BE TAKEN TO CONTROL OR MITIGATE THE RISKS  
 
In case of adverse reaction to the studied MD, the subjects will be asked to call the investigator who will 
decide if the subject must stop the product use or not. The Investigator can prescribe a rescue treatment 
if needed. 
 
4.7 
RISK-TO-BENEFIT RATIONALE 
 
The benefits for the patients will be a possible improvement of their ocular symptoms and signs 
associated to ocular dryness.  
 
On the other hand, no specific risk has been identified with the use of this medical device, except the 
following events that can also be observed with similar devices: stinging or eye glued sensation related 
to the instillation of the product in the eye. 
 
The balance benefit-risk is then more in favor of the benefits. 
5- OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
5.1 
MAIN OBJECTIVE 
 
To demonstrate the non-inferiority of DM05 in comparison with OptiveTM, in terms of cornea and 
conjunctiva staining (Oxford score) on patients with moderate to severe ocular dryness, after 35 days 
of treatment. 
 
5.2 
SECONDARY OBJECTIVE(S) 
 
• To evaluate the efficacy of DM05 in comparison with OptiveTM on other signs and symptoms 
associated to moderate to severe ocular dryness, after 35 and 84 days of treatment. 
 
• To evaluate the safety of DM05 over 84 days of treatment. 
 
5.3 
PRIMARY AND SECONDARY HYPOTHESES TO BE ACCEPTED OR REJECTED BY 
STATISTICAL DATA FROM THE CLINICAL INVESTIGATION 
 
Non-inferiority of DM05 in comparison with OptiveTM, in terms of cornea and conjunctiva staining (Oxford 
score) after 35 days of treatment on worse eye, with a limit of non-inferiority equal to 2. 
 
 
5.4 
RISKS AND ANTICIPATED ADVERSE DEVICE EFFECTS THAT ARE TO BE ASSESSED 
 
Non applicable. 
 

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6- DESIGN OF THE CLINICAL INVESTIGATION 
6.1 
GENERAL INFORMATION 
6.1.1 
Description of the type of clinical investigation  
 
The clinical investigation will be: 
 single blind (investigator-blinded) 
 randomized 
 in parallel groups, 
 versus comparator, 
 multicentric in France, Poland and Spain, 
 on ambulatory patients. 
6.1.2 
Description of the measures to be taken to minimize or avoid bias 
 
Because the comparator will be in commercial packaging, the blinding of the subject is not possible. 
 
However, the study will be blinded for the investigator: evaluations will be done by an independent 
investigator, different than the person who will distribute the product. Subjects will be identified by a 
patient number. Each patient number will be associated to a treatment number, according to a 
randomization list provided before the beginning of the clinical investigation, and randomized either in 
one of both treatment groups (DM05 or Optive®). 
 
6.1.3 
Primary and secondary endpoints with rationale for their selection and measurement 
 
6.1.3.1 
Primary endpoint 
Evaluation of the non-inferiority of DM05 in comparison with OptiveTM, in terms of cornea and 
conjunctiva staining (Oxford score), on worse eye, between D0 and D35. 
 
6.1.3.2 
Secondary endpoints 
• Comparison of D35 versus D0 and D84 versus D0 for each product and comparison between 
products for the following parameters: 
- 
Evolution of cornea and conjunctiva staining (Oxford score on a scale) on worse eye. 
- 
Evolution of OSDI score (Ocular Surface Disease Index). 
- 
Evolution of Van Bijsterveld score (Lissamine green staining) in worse eye. 
- 
Evolution of Schirmer test result in worse eye. 
- 
Evolution of Tear film Break-Up Time (TBUT) in worse eye. 
- 
Evolution of ocular dryness severity by evaluation of each main symptom by the patient and 
total score of all symptoms 
- 
Evaluation of treatment performance by the investigator and the patient. 
- 
Collection of adverse events and adverse device effects. 
• Evaluation of the average frequency of use during 84 days for DM05 and OptiveTM. 
 
6.1.4 
Methods and timing for assessing, recording and analysing variables 
 
At selection and inclusion visits (D-14 to D-7 and D0), evaluations will be done on both eyes. 
On D0, the worse eye will be defined as follows: 
- 
If only one eye is eligible (i.e., fulfils all ophthalmological inclusion criteria with no ophthalmological 
exclusion criteria), the study eye is the eligible eye.  

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- 
If both eyes are eligible, the worse eye will be the eye with the highest Oxford score. If both eyes 
have the same Oxford score, the worse eye will be the eye with the highest Van Bijsterveld Score. 
If both eyes have the same Van Bijsterveld Score, the worse eye will be the eye with lowest Schirmer 
test result or lowest TBUT, if both eyes have the same scores, the worse eye will be the right eye. 
On D35 and D84, all evaluations except symptoms evaluations (evaluation on average on both eyes) 
will be done only on the worse eye. 
 
6.1.4.1 
Performance criteria 
6.1.4.1.1 Cornea and conjunctiva staining (Oxford score) 
Cornea and conjunctiva staining will be assessed with a slit lamp after instillation of unpreserved 
fluorescein in the examined eye. In order to optimize the fluorescein staining signal without any masking 
by the fluorescence quenching effect, 1 drop of fluorescein will be instilled in the examined eye. 
Cornea and conjunctiva staining is represented by punctate dots on a serie of panels (A-E). Staining 
ranges form 0-5 for each zone and from 0-15 for the total exposed inter-palpebral conjunctiva and 
cornea. The dots are ordered on the log scale (Oxford scale) below: 
 
PANEL 
Grade 
Criteria 
 
 
 
0 
 
 
Equal to or less than panel A 
 
 
I 
 
 
Equal to or less than panel B, 
greater than A 
 
 
II 
 
 
Equal to or less than panel C, 
greater than B 
 
 
III 
 
 
Equal to or less than panel D, 
greater than C 
 
 
IV 
 
 
Equal to or less than panel E, 
greater than D 
 
V 
 
Greater than E 
 
FROM 0-5 
 
FROM 0-5 
 
FROM 0-5 
TOTAL 
SCORE: 
 
FROM 0-15 
 

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6.1.4.1.2 Ocular Surface Disease Index (OSDI) 
The OSDI is assessed on a scale from 0 to 100, with higher scores representing greater disability. 
The patients will be asked the following 12 questions: 
 
Have you experienced any of the following 
during the last week? 
All of the 
time 
Most 
of 
the time 
Half 
of 
the time 
Some of 
the time 
None of 
the time 
1. Eyes that are sensitive to light. 
4 
3 
2 
1 
0 
2. Eyes that feel gritty? 
4 
3 
2 
1 
0 
3. Painful or sore eyes? 
4 
3 
2 
1 
0 
4. Blurred vision? 
4 
3 
2 
1 
0 
5. Poor vision? 
4 
3 
2 
1 
0 
Subtotal score for answers 1 to 5 
A 
 
Have problems with your eyes limited 
you in performing any of the following 
during the last week? 
All 
of 
the 
time 
Most 
of 
the time 
Half of 
the 
time 
Some 
of 
the 
time 
None of 
the time 
NA 
6. Reading? 
4 
3 
2 
1 
0 
NA 
7. Driving at night? 
4 
3 
2 
1 
0 
NA 
8. Working with a computer or bank 
machine (ATM)? 
4 
3 
2 
1 
0 
NA 
9. Watching TV? 
4 
3 
2 
1 
0 
NA 
Subtotal score for answers 6 to 9 
B 
 
Have your eyes felt uncomfortable in 
any of the following situations during 
the last week? 
All 
of 
the 
time 
Most 
of 
the time 
Half of 
the 
time 
Some 
of 
the 
time 
None of 
the time 
NA 
10. Windy condition? 
4 
3 
2 
1 
0 
NA 
11. Places or areas with low humidity 
(very dry)? 
4 
3 
2 
1 
0 
NA 
12. Areas that are air conditioned 
4 
3 
2 
1 
0 
NA 
Subtotal score for answers 10 to 12 
C 
 
Add subtotals A, B and C to obtain D 
(D=sum of scores for all questions answered) 
D 
 
Total number of questions answered 
(do not include questions answered NA) 
E 
 
OSDI is calculated according to the following formula:    OSDI= D x 25/ E 

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6.1.4.1.3 Van Bijsterveld score 
The ophthalmologist will realize a colorimetric test with Lissamine green dye. Lissamine green stains 
dead and degenerate cells, and does not stain healthy epithelial cells.  
The evaluation will be done from 1 to 4 minutes after the staining. 
 
The ophthalmologist will determine the dry eye severity with the following scales (Van Bijsterveld Score 
from 0 to 9 1): 
 
 
Nasal bulbar conjunctiva 
0 
1 
2 
3 
 
 
 
 
No staining 
 
 
 
Confluent staining 
 
 
Temporal bulbar conjunctiva 
0 
1 
2 
3 
 
 
 
 
No staining 
 
 
 
Confluent staining 
 
 
Cornea  
 
0 
 
1 
2 
3 
 
 
 
 
No staining 
 
 
 
Confluent staining 
 
 
Total score: …….. / 9 
 
6.1.4.1.4 Schirmer test 
The Schirmer test is a method used to evaluate aqueous tear production. 
It consists in inserting a strip (measuring 35 by 5 mm), without anaesthesia, over the lower lid margin of 
the eye during 5 minutes and then measuring the length of paper wetting in millimeters. The results is 
expressed in mm/5min. 
 
6.1.4.1.5 Tear Break Up Time (TBUT) 
The Tear Break Up Time (TBUT) is the measurement of the break-up time of lacrymal film. This is the 
time needed by the lacrymal film to cover in an homogeneous and coherent way all the ocular surface. 
TBUT is assessed with slit lamp examination and expressed in seconds. 
To measure TBUT, fluorescein is instilled into the patient's tear film and the patient is asked not to blink 
while the tear film is observed with slit lamp. The TBUT is recorded as the number of seconds that 
elapse between the last blink and the appearance of the first dry spot in the tear film. 
The TBUT will be assessed three times and the sum of these three measurements will be calculated. 
 
 
 

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6.1.4.1.6 Ocular dryness symptoms 
The subjects will score their ocular symptoms (one global score for both eyes) on structured scales 
from 0 to 10. These scales are presented below. 
 
1. Discomfort 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
2. Burning / stinging 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
 
 
 
 
 
 
 
 
 
 
3. Eye dryness sensation 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
4. Itching 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
5. Sandy feeling / Foreign body sensation 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
6. Photophobia 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
7. Blurred vision 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Very 
important 
 
In case of other symptom(s) declared by the patient, it will be also recorded in the CRF (free text). 
The sum of all symptom scores will be calculated to obtain a score from 0 to 70. 

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6.1.4.1.7 Global treatment performance score 
Performance of the treatment will be assessed by the investigator and the patient using the following 
rating scale: 
1. Very satisfactory 
2. Satisfactory 
3. Not very satisfactory 
4. Unsatisfactory 
 
6.1.4.2 
Safety criteria 
All systemic and ocular adverse events (AE) and adverse device effects (ADE) will be collected and 
reported by the investigator (see paragraph 14) throughout the study. A daily-log will be given to the 
subject at each visit in order to write eventual concomitant treatments or adverse events. 
 
6.1.5 
Timing for assessing and recording the variables 
 
 
Procedure 
Visit 1 
Selection visit 
(D-14 to D-7) 
Visit 2 
Day 0 
Visit 3 
Day 35 ± 
3 days 
Visit 4 
Day 84 ± 7 
days 
Wash-out period 
 

Treatment period 
Written informed consent 

 
 
 
Checking of the inclusion and exclusion 
criteria 

 
 
 
Medical history, previous and concomitant 
treatments, demographic data 

 
 
 
Urinary pregnancy test for female subjects 
with childbearing potential 
 



Distribution of Hydrabak® (NaCl 0.9%) 
 



Inclusion and random assignment 




OSDI score 
 

 
 
Global ocular staining (Oxford score) 
 

 
 
Schirmer test 




TBUT 
 

 
 
Van Bijsterveld score 
 

 
 
Symptoms evaluation by the patient 
 

 
 
Treatment performance evaluation by the 
patient and the investigator 
 

 
 
Distribution of treatments by a third person 
 

 
 
Distribution of a daily-log 
 



Adverse events recording 
 



Concomitant medication 
 



 
 
 

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6.1.6 
Equipment to be used for assessing, recording and analysing variables and arrangements for 
monitoring maintenance and calibration 
 
Each investigator will use his own slit lamp. Dyes (Fluoresceine Faure 0.5% SDU, Lissamine green) and 
Schirmer strips will be given by the Sponsor. 
 
6.1.7 
Any procedures for the replacement of subjects 
 
No replacement condition is foreseen. 
Drop-outs will not be replaced as it is foreseen to randomize 80 subjects for having at least 68 subjects 
to be analysed. 
 
6.2 
INVESTIGATIONAL DEVICE(S) AND COMPARATOR(S) 
6.2.1 
Description of the exposure to the investigational device(s) or comparator(s), if used 
 
6.2.1.1 
Dosage 
For both investigational medical device (DM05) and comparator (Optive®), one to two drops will be 
instilled in each eye from 4 to 6 times per day. 
 
6.2.1.2 
Instructions for use 
 
DM05: 
 
Wash hands carefully before application. 
1. For the first application, verify that the cap seal is not broken and unscrew the cap. You will hear the 
tamper-proof ring when it breaks for the first time. 
2. Always shake the vial before application. 
3. Apply 1 to 2 drops from 4 to 6 times per day. With your index finger, draw the lower eyelid gently 
downwards, while looking up, and then squeeze the vial to apply the eye drops. Do not touch the eyes 
or eyelids with the tip of the vial. After application, spontaneous blinking will evenly distribute the 
emulsion over the surface of the eye, creating a transparent and durable film. 
4. Seal the vial with the protective cap after every use. 
 
 
Optive® 
 
Instil one to two drops in each eye from 4 to 6 times per day. 
 
6.2.1.3 
Precautions for use 
DM05: 
- 
For external use only.  
- 
Do not swallow.  
- 
Store at room temperature (below 25°C).  
- 
Wash hands carefully prior to instillation.  
- 
Always shake the vial before application. 
- 
Do not touch the tip of the vial with hands, eyes or eyelids (risk of microbial contamination). 
-  
Replace the protective cap on the tip of the vial after every use (risk of microbial contamination). 

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- 
Do not use if the vial is damaged (risk of microbial contamination). 
- 
Maintain a minimum interval of 15 minutes between administration of two ophthalmic products. 
- 
Do not use after the expiry date stated on the vial and the package (risk of microbial 
contamination). 
- 
Keep out of reach and sight of young children. 
 
Optive® 
- 
Do not use if of you are allergic to one of the constituent. 
- 
Do not swallow. 
- 
To avoid any contamination, ensure that the dropper does not touch any surface and avoid any 
direct contact with the eye. 
- 
Carefully close the bottle after use. 
- 
Do not use after the expiry date stated on the bottle 
- 
Keep out of reach of children. 
- 
Keep at room temperature. 
- 
Do not use the bottle if the inviolability cap on the bottle neck is damaged before the first use of the 
product. 
- 
Respect at least 5 minutes between administration of two ophthalmic products. 
6.2.2 
Justification of the choice of comparator(s)  
Optive®, number two on the French market of medical devices indicated for moderate to severe ocular 
dryness with 28% of market share (source : GERS- May 2016) and part of the European leaders in 
ocular dryness is the chosen comparator. 
 
6.2.3 
 List of any other medical device or medication to be used during the clinical investigation 
 
All patients will be given preservative free artificial tears during the wash-out period. 
• 
Name of the auxiliary product: HYDRABAK® (NaCl 0.9%) 
• 
Composition: 
Name of the ingredients 
Centesimal formula (g): 10 mL vial 
Active ingredient 
 
Sodium chloride 
0.090 g 
Other ingredients 
 
Sodium dihydrogen phosphate dihydrate 
0.0067 g 
Disodium phosphate dodecahydrate 
0.0317 g 
Water for injections  
ad 10 mL 
 
• 
Form: Hydrabak® is unpreserved NaCl 0.9 % eye drops, coming from commercially purchased 
batches. Hydrabak® is to be used within 8 weeks after opening and stored at temperatures 
below 25°C. 
 
• 
Instructions for use 
1 instillation in both eyes  3 times per day. 
Instillation of preservative-free artificial tears should not be performed within the 6 
hours prior to the D0 visit. 
6.2.4 
Number of investigational devices to be used, together with a justification 
 
DM05: Each subject will receive 2 vials of 10 ml. 
Optive: each subject will receive 2 vials of 10 ml 
 

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6.3 
STUDIED POPULATION 
6.3.1 
Inclusion criteria for subject selection 
• 
Sex: male or female.  
• 
Age: more than 18 years. 
• 
Subject with a dry eye syndrome needing artificial tears in the 3 months preceding the inclusion. 
• 
Subject having used only artificial tears without preservative (NaCl 0.9%, Hydrabak®) during 1 to 2 
weeks before inclusion (at 3 drops per day). 
• 
Diagnosis of moderate to severe ocular dryness defined by a score OSDI (Ocular Surface Disease 
Index) ≥18. 
• 
Subject with at least one eye with 
- Global ocular staining (cornea and conjunctiva) ≥4 and ≤9 (Oxford scale from 0 to 15) 
AND one the following criteria: 
- 
Schirmer test ≥ 3mm/5 min and ≤9mm/ 5 min 
OR 
- 
Sum of 3 measurements of Tear film Break-Up Time (TBUT) ≤ 30s. 
• 
Subject, having given freely and expressly his/her informed consent. 
• 
Subject who is able to comply with the study requirements, as defined in the present protocol, at 
the Investigator’s appreciation. 
• 
In France: subject being affiliated to a health social security system. 
• 
Female subjects of childbearing potential should use a medically accepted contraceptive regimen 
since at least 12 weeks before the beginning of the study, during all the study and at least 1 month 
after the study end. 
 
6.3.2 
Exclusion criteria for subject selection  
• 
Pregnant or nursing woman or planning a pregnancy during the study. 
• 
Subject who had been deprived of their freedom by administrative or legal decision. 
• 
Subject in a social or sanitary establishment. 
• 
Major subject who is under guardianship or who is not able to express his consent. 
• 
Subject being in an exclusion period for a previous study. 
• 
Subject suspected to be non-compliant according to the Investigator’s judgment. 
• 
Subject wearing contact lenses during the study. 
• 
Far best corrected visual acuity < 1/10. 
• 
Subject with severe ocular dryness with one of these conditions: 
- 
Eyelid or blinking malfunction 
- 
Corneal disorders not related to dry eye syndrome 
- 
Ocular metaplasia 
- 
Filamentous keratitis 
- 
Corneal neovascularization 
• 
Subject with severe meibomian gland dysfunction (MGD). 
• 
Within the last 3 months prior to the inclusion, history of ocular trauma, infection or inflammation 
not related to dry eye syndrome. 
• 
Within the last 12 months, history of ocular allergy or ocular herpes. 
• 
History of inflammatory corneal ulcer, recurrent corneal erosion, uveitis. 
• 
Refractive or cataract surgery within the last 6 months. 
• 
Any laser other than refractive surgery within the last 3 months. 
• 
Any troubles of the ocular surface not related to dry eye syndrome. 
• 
Ocular hypertension or glaucoma needing an hypotonic treatment 
• 
Subject having used artificial tears in the 6 hours preceding the inclusion visit. 
• 
Use during the month preceding the inclusion or during the study of: isotretinoïd, cyclosporine, 
tacrolimus, sirolimus, pimecrolimus. punctual plugs. 
• 
Any not stabilized systemic treatment, which can have an effect on performance or safety 
criteria, at the investigator appreciation. 
 
 
 

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6.3.3 
Point of enrolment 
 
Estimated date of clinical investigation beginning: February 2017. 
Estimated date of clinical investigation end: February 2018. 
 
6.3.4 
Total expected duration of the clinical investigation 
13 months. 
 
6.3.5 
Expected duration of each subject’s participation 
84 days of treatment + 7 to 14 days of wash-out. 
6.3.6 
Number of subjects required to be included in the clinical investigation 
80 patients are expected to be randomized in the clinical investigation: 40 patients in each group of 
treatment. 
 
6.3.7 
Estimated time needed to select this number in the clinical investigation (enrolment period) 
9 months. 
 
6.4 
PROCEDURES 
 
6.4.1 
Description of all the clinical-investigation-related procedures that patients undergo during the 
clinical investigation 
 
Selection visit (D-14 to D -7) 
 
- The ophthalmologist will propose to his/her patient to participate to the clinical investigation. 
- Information of the patient on study aims and schedule. 
- Signature of information sheet and consent form in two copies by the patient and the investigator. 
- Collection of previous medical and ophthalmological history, previous and actual treatments, 
demographic data. 
- The ophthalmologist will evaluate the Ocular Surface Disease Index, the global ocular staining (Oxford 
score) and will realize the Schirmer test and TBUT. 
- Checking of inclusion and exclusion criteria. 
- If the patient is eligible, distribution of Hydrabak® to be used three times per day in both eyes until the 
inclusion visit, as well as a daily log to write eventual concomitant treatments and adverse events. 
 
Inclusion visit (D0) 
 
- The patient will bring back the Hydrabak® and the daily-log completed. 
- Collection of adverse events and concomitant treatments. 
- The ophthalmologist will evaluate the Ocular Surface Disease Index, the global ocular staining (Oxford 
score) and will realize Schirmer test and TBUT. 
- Checking of inclusion and exclusion criteria. 
- If the patient is eligible, inclusion of the patient and attribution of a randomization number. 
- The ophthalmologist will evaluate the Van Bijsterveld score.  
- The patient will evaluate his/her ocular symptoms. 
- A third person will distribute the treatment according to the randomization list and explain the mode of 
use of the treatment, as well as a daily log to write eventual concomitant treatments and adverse events 
 
D35 
 
- The patient will bring back the treatments (used and non-used) and the daily-log completed. 

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- Collection of adverse events and concomitant treatments. 
- The ophthalmologist will evaluate the Ocular Surface Disease Index, the global ocular staining (Oxford 
score), the Van Bijsterveld score and will realize Schirmer test and TBUT. 
- The patient will evaluate his/her ocular symptoms. 
- The patient and the investigator will evaluate the treatment performance on a 4-point scale. 
- A third person will distribute the treatment according to the randomization list and remain the patient 
about the mode of use, as well as a daily log to write eventual concomitant treatments and adverse 
events. 
 
D84 
 
- The patient will bring back the treatments (used and non-used) and the daily-log completed. 
- Collection of adverse events and concomitant treatments. 
- The ophthalmologist will evaluate the Ocular Surface Disease Index, the global ocular staining (Oxford 
score), the Van Bijsterveld score and will realize Schirmer test and TBUT. 
- The patient will evaluate his/her ocular symptoms. 
- The patient and the investigator will evaluate the treatment performance on a 4-point scale. 
 
6.4.2 
Description of activities performed by Sponsor representatives (excluding monitoring) 
 
The Sponsor has delegated the following activities to the CRO (Dermscan): 
 
- 
Submission of the study files to the EC and competent authority 
- 
Monitoring of the study 
- 
Data management 
- 
Statistical analysis and clinical investigation report writing. 
 
6.4.3 
Any known or foreseeable factors that may compromise the outcome of the clinical investigation 
or the interpretation of results 
 
Not applicable. 
 
6.5 
MONITORING 
 
The monitoring of the study will be done by Dermscan. The monitor has the responsibility to familiarise 
the Investigator(s) and the centre staff involved in the study with all study procedures if necessary. The 
monitor has the responsibility of reviewing the ongoing study with the Investigator(s) to verify adherence 
to the CIP and to deal with data queries as well as any problems that arise during the conduct of the 
study.  
6.5.1 
Monitoring visits 
 
6.5.1.1 
Selection visit 
Before any involvement of a clinical research centre/private practice into the study, the CRA and/or the 
study monitor should perform a selection visit in order to verify: 
- adequate human and technical resources, 
- adequate recruitment capabilities, 
- availability regarding planning constraints. 
 
6.5.1.2 
Initiation visit 
Before any subject’s enrolment, the CRA and/or the study monitor will conduct an initiation visit in order 
to familiarize the centre’s staff with the study CIP and schedule.  
This visit will also be the occasion to review with the center: 
- 
the Investigator file which should contain: 
▪ 
the study CIP, 

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▪ 
the curriculum vitae of the Investigator, 
▪ 
the Authorization as a clinical centre, if applicable, 
▪ 
the insurance certificate, 
▪ 
the favourable opinion of the ethic committee, 
▪ 
the approval of CA, 
▪ 
the Investigator brochure, 
▪ 
the financial agreement between all parts, 
▪ 
all necessary documents for study follow-up, etc. 
- 
the CRF and the way to complete it, 
- 
the information sheet and consent forms and the way to obtain consent, 
- 
the investigational products, 
- 
the study material (pregnancy test, etc.), 
- 
and all other necessary aspects and materials detailed in the study CIP. 
 
6.5.1.3 
Monitoring visits 
For the duration of the study, monitoring visits may be performed by the CRA in order to check the study 
performance in accordance with the study CIP. 
The Clinical Research Associate ensures the coherence and the veracity of the data reported in the 
Case Report Form compared to the source data. He/she verifies that the study is performed according 
to the CIP and that all documentation necessary to ensure a good follow-up of the study is present and 
well completed. 
These visits will also serve to ensure product accountability. 
During these visits, the CRA reserves the right to ask for queries resolution, directly in the document(s) 
concerned or with specific data clarification forms. He/she ensures the completion of the Investigator 
file and retrieves all documents necessary for updating the trial master file. 
When applicable, the CRA may retrieve duplicate of the CRF to be sent to the data management 
department. 
 
6.5.1.4 
Close-out visit 
A close out visit will take place after the study has come to a conclusion. The CRA will retrieve all study 
products, materials, CRFs, consent forms (if applicable) and to confirm the completion of the Investigator 
file, including all study related documents. When necessary, the Sponsor may also ask for the resolution 
of any delayed queries in the CRFs. 
 
6.5.2 
Access to source data  
In accordance with good clinical practices and the standards of the data protection law, data obtained 
in the course of a biomedical research has to be treated confidentially to guarantee the subjects’ privacy.  
 
The Investigator agrees that, subject to local regulations and ethical considerations, the Sponsor 
representatives designee and/or and any regulatory agency have direct access to all study records, 
CRFs, corresponding subject medical records, study drug dispensing records and study drug storage 
area, and any other documents considered source documentation. The Investigator also agrees to assist 
the representative, if required. 
 
7- STATISTICAL CONSIDERATIONS 
 
7.1 
STATISTICAL DESIGN, METHOD AND ANALYTICAL PROCEDURES  
 
A Statistical Analysis Plan (SAP) specifying analyses in detail will be written before blind review and 
locking the database. 
The statistical analysis will be performed after the data has been cleaned and after the database is 
locked. 
No interim analysis is planned. 
 

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7.1.1 
Analysed population  
 
Three populations will be defined: 
- Intention to treat (ITT) population corresponding to all patients randomized 
- Safety population corresponding to all patients randomized and having received at least one dose of 
treatment 
- Per protocol (PP) population corresponding to patients of the safety population who will not present 
major protocol deviation (decided by the Data Review Committee during a blind review process) 
 
7.1.2 
Primary endpoint 
 
7.1.2.1 
Main analysis   
The main analysis of the main criterion will be conducted on the PP population. The hypothesis of non-
inferiority of DM05 compared to Optive® will be tested by calculating the bilateral 95% CI of the 
difference between groups (DM05 – Optive®) of the change from baseline of global ocular staining in 
the worse eye on Day 35. A two-way analysis of covariance (ANCOVA) model will be constructed using 
main effects of treatment and baseline score as covariate. Adjusted means (least square mean and 
error standard of the mean) by treatment will be presented as well as an estimate of the difference 
between adjusted means.  
 
A 95% two-sided confidence interval, based on the ANCOVA model, will be computed for the difference 
of DM05 minus Optive®.  
 
If the upper bound is no higher than 2 points for the PP population, it will be concluded that the null 
hypothesis can be rejected and that DM05 is non-inferior to Optive®. 
 
The p value of non-inferiority will be expressed taking on board the predefined margin of non-
inferiority.  
This analysis will be based on observed cases. 
 
7.1.2.2 
Sensitivity analysis 
Same analysis will be performed on ITT population with imputation of values in case of missing data 
with LOCF technique (baseline value or value in case of withdrawal) and without imputation (observed 
cases).  
 
In case of conclusion of non-inferiority of DM05 compared to Optive®, the superiority of DM05 
compared to Optive® will be tested. The superiority analysis carried out on the ITTT population will be 
considered as the main analysis. Results will be also provided on the PP population. 
7.1.3 
Secondary endpoint(s) 
 
Quantitative data: 
 
Quantitative variables will be summarized by number of patients, mean, median, standard deviation, 
minimum, and maximum for each time point. Changes from baseline will also be calculated and 
tabulated for each time-point (D35-D0 and D84-D0). 
 
A mixed ANOVA model (PROC MIXED) for repeated measures will be fitted to raw data, including the 
factor treatment as fixed (2 levels), time as fixed (3 levels), and product by time interaction, as well as 
the patient effect as random. 
 
From this model, the contrasts of interest will be built on the adjusted means: 
* 
to test whether each change from baseline (D35-D0 and D84-D0). differ significantly from 0 by 
product. 
* 
to test whether the products differ significantly for each change from baseline (D35-D0 and 

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D84-D0).  
 
The underlying assumptions (normality and homoscedasticity) will be checked using Shapiro-Wilk test 
and graphical representations of the residuals. In case of strong deviation, a non-parametric approach 
will be performed. 
 
Qualitative data: 
 
Categorical variables will be summarized with frequency and percentages for each time point. 
 
For the global performance, treatments groups will be compared with a Chi2 test. 
For other qualitative variables, the changes from baseline for each product will be assessed with a 
Wilcoxon signed-rank test. The comparison between the treatments will be assessed with a Mann-
Whitney test for each change from baseline (D35-D0 and D84-D0).  
 
Safety data:  
 
The safety data will be summarised using descriptive statistics by treatment group in the Safety 
population.  
Summary safety assessments include AEs, best-corrected visual acuity, ocular symptoms and the 
global tolerance assessment by the investigator. 
 
The adverse events will be coded using the MedDRA dictionary. The evaluation of the adverse events 
only considers the treatment-emergent AEs (TEAEs) with onset date on or after the day of the first study 
drug instillation. 
The ocular TEAEs and the non-ocular TEAEs will be analysed separately. 
 
The number and percentage of patients experiencing at least one AE will be provided by treatment 
group, by primary SOC and PT, for the following categories of events: 
- All AEs 
- All TEAEs 
- Maximum severity for all events by PT (regardless of causality) 
- Treatment-related AEs 
- Serious AEs 
- AEs that lead to study withdrawal.  
The difference between treatments groups on the incidence rate will be analyzed for each PT using 
Fisher’s exact test.  
The statistical significance level of 5% will be applied for the safety analyses. 
 
• The best-corrected visual acuity will be described in the worse eye and in the contralateral eye, at each 
visit and change from baseline. 
 
• The usual severity and the usual duration of each ocular symptom upon instillation will be described 
at each D35 and D84 visits. 
 
• The global tolerance assessment by the investigator will be described at each D35 and D84 visits. 
 
 
7.2 
SAMPLE SIZE AND ITS STATISTICAL JUSTIFICATION 
 
The primary objective of this study is to confirm the non-inferiority of DM05 in comparison with OptiveTM 
reference for global ocular staining assessed with a 0-15 score (Oxford score). The clinical non-inferiority 
margin was set at 2 points on the Oxford score. Assessing a standard-deviation equal to 2.5, a total of 
68 patients (34 patients in each group) is required to reach a power of 90% to set-up the non-inferiority 
based on a bilateral confidence interval at 95%. 
Assuming a drop-out rate of 15%, 80 patients will be randomized in the study to keep sufficient power 
for main analysis of the primary end point (analysis on PP population).  
 
 
 
 

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7.3 
LEVEL OF SIGNIFICANCE AND POWER OF THE CLINICAL INVESTIGATION 
 
All statistical tests will be assessed at  = 5% level of significance in a bilateral approach.  
 
7.4 
STATISTICAL PASS/FAIL CRITERIA TO BE APPLIED TO THE RESULTS OF THE 
CLINICAL INVESTIGATION 
 
Non-inferiority of DM05 versus Optive with a non-inferiority margin set at 2 points on the Oxford score. 
 
7.5 
PROVISION FOR AN INTERIM ANALYSIS, WHERE APPLICABLE 
 
No interim analysis is foreseen. 
 
7.6 
CRITERIA FOR THE TERMINATION OF THE CLINICAL INVESTIGATION ON STATISTICAL 
GROUNDS  
 
As no intermediary statistical analysis has been planned, no statistical criteria for the termination of the 
clinical investigation has been defined. 
 
7.7 
PROCEDURES 
FOR 
REPORTING 
ANY 
DEVIATION(S) 
FROM 
THE 
ORIGINAL 
STATISTICAL PLAN 
 
Any modification to the statistical analysis plan due to a substantial modification of the CIP will be 
documented as an amendment and will be described in the final study report if applicable. 
 
7.8 
SPECIFICATION OF SUBGROUPS FOR ANALYSIS 
 
Not applicable. 
 
7.9 
PROCEDURES THAT TAKE INTO ACCOUNT ALL THE DATA 
 
Three populations will be defined: 
- Intention to treat (ITT) population corresponding to all patients randomized 
- Safety population corresponding to all patients randomized and having received at least one dose of 
treatment 
- Per protocol (PP) population corresponding to patients of the safety population who will not present 
major protocol deviation (decided by the Data Review Committee during a blind review process). 
 
7.10 
TREATMENT OF MISSING, UNSUED OR SPURIOUS DATA, INCLUDING DROP-OUTS AND 
WITHDRAWALS 
 
In the case of missing values, the last observation carried forward (LOCF) method will be applied 
using at each visit the last observation available for analysis on FAS and PP. 
 
 
7.11 
EXCLUSION METHOD OF PARTICULAR INFORMATION FROM THE TESTING OF THE 
HYPOTHESIS, IF RELEVANT 
 
Not applicable. 
 
7.12 
IN MULTICENTRE INVESTIGATIONS, MINIMUM AND MAXIMUM NUMBER OF SUBJECTS 
TO BE INCLUDED BY EACH CENTRE 
 
The recruitment will be competitive between the different centers. No minimum and maximum number 
of patients will be set for each center.  
 

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8- DATA MANAGEMENT 
8.1 
PROCEDURES 
USED 
FOR 
DATA 
REVIEW, 
DATABASE 
CLEANING 
AND 
ISSUING/RESOLVING DATA QUERIES 
 
8.1.1 
Identification of source data 
 
All clinical data in the CIP and collected by the Investigator will be notified in the source document. 
OSDI questionnaire and daily log completed by the subjects will be considered as source documents. 
 
8.1.2 
Case report Form completion 
e-CRFs will be used for this study.The investigator is responsible for ensuring that data are properly 
recorded on each subject’s eCRFs and related documents. An investigator who has signed the protocol 
signature page or his/her authorized designee is to personally sign the eCRFs (as indicated on the 
eCRF) to 
validate that the observations and findings are recorded on the eCRFs correctly and completely.  
The data reported on the eCRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing. Any change or correction to 
data reported on an eCRF shall be dated, initialed, and explained, if necessary, and shall not obscure 
the original entry (ie, an audit trail shall be maintained); this applies to both written and electronic 
changes or corrections. 
 
8.1.3 
Data management and review 
 
 
8.1.3.1 
Data management 
Data management will consist in the different following steps: 
- 
Redaction of a data management plan and a data validation plan. 
- 
Redaction of e-CRF specifications and completion guidelines for the investigators 
- 
Redaction of annotated CRF 
- 
Programming and validation of consistency controls 
- 
Data Clarifications Forms (DCFs) emission and database correction 
- 
Data listings emission 
- 
MedDRA coding of AE/ADE and WhoDrug for concomitant medications and validation 
of the coding by an expert 
- 
Data Management report 
 
8.1.3.2 
Data Review 
A blind data review will be organised at DERMSCAN – PharmaScan, 114 Boulevard du 11 Novembre 
1918, 69100 VILLEURBANNE – FRANCE or by phone. 
 
Will be present a minima the sponsor, Dermscan project manager, the statistician and the study monitor. 
Study coordinating investigator may be present by phone. 
 
The study review will aim at determining the analysis population by:  
 
• 
reviewing the conditions of study’s realisation, 
• 
determining the populations for the statistical analyses, 
• 
specifing all the protocol’s deviations as major or minor, 
• 
reviewing the statistical analysis plan. 
 
Following the study review, the statistical analysis populations will be defined and a report will be written 
and validated by DERMSCAN and the Sponsor. The data base will thus be corrected and locked. 

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8.1.4 
Preparation and lock of the Database  
 
The database will be locked upon resolution of all queries. A copy of the locked database will be sent to 
the Sponsor. A signed database lock form will be provided. 
After the database will be locked, any change to the database can only be done from database correction 
forms approved by the Project Manager and the Sponsor. If the database will need to be corrected, 
lock/unlock of the database must be clearly documented by the Project Manager in the study file. 
 
8.1.5 
Data unblinding at study end 
 
Unblinding of the assigned treatments will occur after the completion of the following steps:  
 
1. All CRF data are entered into the computer; 
2. All data clarifications, if any, are resolved; 
3. Major deviations or intercurrent events, if any, are defined and identified; 
4. All information necessary to analyze the data is integrated into the data base; 
5. The database is formally locked. 
 
 
8.2 
PROCEDURES FOR VERIFICATION, VALIDATION AND SECURING OF ELECTRONIC 
CLINICAL DATA SYSTEMS, IF APPLICABLE 
 
Not applicable. 
 
 
8.3 
PROCEDURES FOR DATA RETENTION AND SPECIFED RETENTION PERIOD 
 
The Sponsor must archive the CIP, documentation, approvals and all other essential documents related 
to the study, including certificates that satisfactory audit and inspection procedures have been carried 
out, for 15 years Dermscan - PharmaScan will archive all documents concerning the study as detailed 
below: 
- 
All documents must be archived in a secure place and treated as confidential material. 
- 
Paper documents relating to this study are stored maximum during one year on site before to 
be transmitted for archiving to an approved service provider. 
- 
Data will be archived securely as digital and paper version for 15 years from the date of dispatch 
of the final report’s acceptance.  
 
At the end of this period of 15 years, the study archives will be destroyed unless otherwise stipulated in 
writing by the Sponsor. 
 
 
8.4 
OTHER ASPECTS OF CLINICAL QUALITY ASSURANCE, AS APPROPRIATE 
 
In order to ensure the conformity of the studies entrusted to Good Clinical Practices and regulatory 
requirements, DERMSCAN has implemented a quality management system which has been certified 
ISO 9001:2008. This system consists of procedures and quality controls. 
 
 
 

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9- AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
 
Any modification to the CIP will be treated as a substantial or non-substantial modification, according to 
its nature, and will be submitted for opinion/approval to the Ethics Committee and/or Competent 
Authority. 
 
10- DEVIATIONS FROM CLINICAL INVESTIGATION PLAN 
 
10.1 
STATEMENT SPECIFYING THAT THE INVESTIGATOR IS NOT ALLOWED TO DEVIATE 
FROM THE CIP 
 
The Investigators are not allowed to deviate from the CIP, excepted under emergency circumstances, 
to protect the rights, safety and well-being of the subjects. In this case, such deviations shall be 
documented and reported to the Sponsor and the EC as soon as possible. 
 
10.2 
PROCEDURES FOR RECORDING, REPORTING AND ANALYSING CIP DEVIATIONS 
 
All CIP deviations will be managed according to Dermscan SOP. 
 
A priori, subjects having at least a major deviation and subjects with insufficient treatment duration or 
without any evaluation of main criterion will be excluded from PP analysis. 
 
Nevertheless, all observations will be discussed during the « data review » which occurs before data 
analysis. 
 
10.3 
NOTIFICATION REQUIREMENTS AND TIME FRAMES 
 
All deviations observed by the CRA during monitoring visits will be reported to the Sponsor in the 
monitoring report, within maximum 10 days after the visit. 
In case of serious GCP and protocol deviations the CRA should report to the Sponsor by a phone call 
or writing an email within 24 hours. 
 
At the study end, all deviations will be summarized and analyzed in the data review report, sent to the 
Sponsor. 
 
10.4 
CORRECTIVE 
AND 
PREVENTIVE 
ACTIONS 
AND 
PRINCIPAL 
INVESTIGATOR 
DISQUALIFICATION CRITERIA 
 
If major deviations from an investigator are observed during monitoring, the CRA will warn the 
investigator of the importance to respect the CIP. An investigator who continuously violates the CIP 
despite CRA warnings could be excluded from the investigation after agreement of the Sponsor. 
 
11- DEVICE ACCOUNTABILITY 
The IMD should only be dispensed only under the supervision of a physician approved for the study. 
The Investigator (or delegate) is responsible for dispensing the study products to the patients who are 
randomised in the study. The study devices must not be administered to patients who are not 
randomised in the study. 
 
A preprinted accountability form provided by the CRO must be kept current and must identify the subject 
number/the number of the IMD dispensed, and the amount of IMD dispensed to and returned by each 
subject at each visit, with the corresponding dates. 
All IMD supplies (empty containers, as well as partly used and unused IMD) must be available for 
inspection at every monitoring visit. The CRA or Sponsor delegate should verify the investigational site’s 

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products accountability records against record of administrated doses in the CRF. All used and non-
used products will be destructed after signature of the clinical report. 
 
12- STATEMENTS OF COMPLIANCE 
 
12.1 
DECLARATION OF HELSINKI  
 
The investigation will be performed on patients, in accordance with the ethical principles that have their 
origin in the declaration of Helsinki. 
 
The current revision of the Declaration of Helsinki is the accepted basis for clinical study ethics, and 
must be fully followed and respected by all engaged in research on human beings. Any exceptions must 
be justified and stated in the CIP. Independent assurance that subjects are protected can only be 
provided by an ethics committee/institutional review board and freely obtained informed consent.  
It is the responsibility of the Investigator(s) to ensure that the study is conducted in full conformance with 
the principles of the current Revised Version of the Declaration of Helsinki.  
 
 
12.2 
ISO 14155 STANDARD AND LOCAL REGULATIONS 
 
The investigation will be performed according to standard ISO 14155:2011 and its updates, and any 
regional or national regulations. 
 
12.3 
EC AND/OR REGULATORY AUTHORITIES 
 
It is the responsibility of the Sponsor or its legal representative to submit a copy of the CIP and detailed 
patient information sheet and consent form to an ethics committee/institutional review board in order to 
obtain independent approval to conduct the study. Ethics committee/institutional review board approval 
must be obtained before the study is started. The approval of the ethics committee/institutional review 
board must be sent in writing, to the Sponsor or its legal representative. The Ethics Committee approval 
letter must mention the Ethics Committee members and their function. 
In parallel or after the Ethics Committee submission, the Sponsor or its legal representative must 
address an authorization request to the national competent authority, if applicable.  
Any clinical trial cannot been performed without having obtained the agreement of the Ethics Committee 
and the inherent authorization of the national competent authority (if applicable). 
 
12.4 
INSURANCE 
 
The Sponsor has subscribed an insurance contract to cover the liability of the Investigators, the Sponsor 
himself and anyone involved in the study. 
The copy of the insurance certificate is presented separately in the EC and CA submission file. 
 
 
13- INFORMED CONSENT PROCESS 
 
13.1 
GENERAL PROCESS FOR OBTAINING INFORMED CONSENT 
 
It is the responsibility of the Investigator(s) to obtain informed consent from each subject participating in 
the study, after explanation of the aims, methods, benefits and potential hazards of the study. 
It should be completely and unambiguously clear to each subject that she/he is free to refuse to 
participate in the study, or that she/he can withdraw her/his consent at any time and for any reason, 
without incurring any penalty or withholding of treatment on the part of the Investigator. 
 

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The consent obtaining should be done under such conditions that permit to the subject to consider in 
the best way the ratio benefits/ risks associated to his/her participation in the study. 
The Investigator insures that the content of the information and consent form is appropriate to the study 
and that the process for obtaining the consent is in conformity with the applicable regulation. 
 
In the frame of this study, the consent will be obtained before any study-specific procedures were 
performed, and thus in accordance with the Helsinki declaration. 
No subject could be included and/or randomized before having signed the consent form, written in an 
understandable language. 
 
Each subject will receive oral and written information concerning the studied product(s), its nature, the 
duration and the conditions of the study. The consent will be personally signed and dated by the subject 
in two copies and by the person in charge of the consent obtaining. 
Each subject will receive an original of the information sheet and consent form, dated and signed. The 
second original of the signed and dated consent form will be archived in the Investigator file. The 
Investigator will complete and keep a list of subjects having given their consent. No copy of this list will 
be given to the Sponsor. 
 
13.2 
INFORMED CONSENT PROCESS IF THE SUBJECT IS UNABLE TO GIVE IT 
 
Non applicable. 
 
14- ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES 
14.1 
DEFINITIONS 
Table 1 below presents categorization of adverse events 
 
Table 1- Adverse event categorization 
 
 
ADVERSE 
EVENTS 
Non-device-related 
Device- or procedure-related 
 
Non-serious 
Adverse Event (AE)a 
Adverse Device Effect (ADE) 
Serious 
 
Serious 
Adverse 
Event (SAE)b 
Serious Adverse Device Effect (SADE) 
Anticipated 
Unanticipated 
Anticipated Serious 
Adverse Device Effect 
(ASADE) 
Unanticipated 
Serious Adverse 
Device Effect 
(USADE) 
a      Includes all categories 
b      Includes all categories that are serious 
 
The definitions of the different terms are presented below. 
14.1.1 Adverse event (AE) 
 
“Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users, or other persons, whether or not related to the 
investigational medical device”. 

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This definition includes events related to the investigational medical device or comparator and events 
related to the procedures involved except for events in users or other persons, which only include events 
related to investigational medical devices.   
14.1.2 Adverse device effect (ADE) 
 
“Adverse event related to the use of an investigational medical device”. 
This definition includes any adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical 
device as well as any event resulting from use error or from intentional misuse of the investigational 
medical device. 
14.1.3 Device deficiency 
“Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety, or 
performance.” 
 
Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 
14.1.4 Serious adverse event (SAE) 
 
A serious adverse event is defined as an adverse event that: 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal 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 serious adverse event. 
 
14.1.5 Serious adverse device effect (SADE) 
 
“Adverse device effect that has resulted in any of the consequences characteristic of a serious adverse 
event.” 
 
14.1.6 Unanticipated Serious Adverse Device Effect (USADE) 
 
“Any serious adverse device effect which by its nature, incidence, severity, or outcome has not been 
identified in the current version of the risk analysis report.” 

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NOTE: anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, 
severity or outcome has been identified in the risk analysis report. 
 
14.1.7 New fact definition (Article L. 1123-10 du CSP)  
 
Fact concerning the sequence of the research and likely to endanger the subjects security. 
In general it concerns all new information which might lead to a negative re-evaluation of the benefit/risk 
ratio of the research or which might be sufficient for modifications to be envisaged in the administration 
of the experimental product, the line of research, or documents related to the research. 
 
14.1.8 Severity 
 
Severity is a clinical determination of the intensity of an adverse event.  The severity assessment for a 
clinical adverse event is to be completed using the following definitions as guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Incapacitating with inability to work or do usual activity 
 
14.1.9 Relationship to the investigational medical device 
The Investigator must determine the relationship (if any) between an adverse event and the device or 
treatment procedure.  An adverse event could be considered treatment-related when, in the judgment 
of the Investigator, it is reasonable to believe that the event may have been caused by the device or is 
associated with the procedure, such as an event that can be attributed to other products, surgical 
techniques, or medications required specifically for the procedure. 
 
14.2 
TIMELINES FOR REPORTING 
The Investigator must report the different types of adverse events according to the following table: 
 
 

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Table 2- Timelines for reporting  
 
Adverse Event 
Type 
Reporting by the Investigator to 
the Sponsor 
Reporting by the Sponsor to the EC and 
competent authorities 
AES, ADEs 
Record on CRF adverse event 
form upon awareness for review 
by the clinical monitor 
Not reported 
SAEs, SADEs 
Record on Serious Adverse Event 
Form and fax or email to the 
Sponsor within 24 hours of 
awareness 
- SAE associated with an impending risk of 
death, or for an injury or serious disease 
and requiring a quick medical treatment for 
others patients / subjects, users or other 
person or for any new information: 
immediately upon awareness, at the 
latest within 7 days in France, Tunisia, 
Poland and Spain. For Tunisia, when the 
death concerns a subject included in 
Tunisia, this delay is shortened to 48 
hours. 
 
-in other SAE or any related news: 
immediately upon awareness, at the 
latest within 15 days in France, Tunisia 
and Spain and within 7 days in Poland. 
 
 
14.3 
GENERAL PROCESS FOR REPORTING ADVERSE EVENTS AND DEVICE DEFICIENCIES 
 
14.3.1 Documentation 
 
All adverse events shall be documented in a timely manner throughout the clinical investigation in the 
source file and the CRF and shall be reported as specified below. 
All adverse events shall be reported in an interim or final report of the clinical investigation. 
 
All device deficiencies related to the identity, quality, durability, reliability, safety or performance of an 
investigational medical device shall be documented throughout the clinical investigation and 
appropriately managed by the Sponsor. 
Device deficiencies that did not lead to an adverse event but could have led to a medical occurrence: 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
shall be reported as specified below. 
 
14.3.2 Reporting by the Investigator 
 
The principal Investigator shall: 
 
a) record every adverse event and observed device deficiency, together with an assessment, 
 
b) report to the Sponsor, without unjustified delay, all serious adverse events and device deficiencies 
that could have led to a serious adverse device effect; this information shall be promptly followed by 
detailed written reports, 
 
c) report to the EC serious adverse events and device deficiencies that could have led to a serious 
adverse device effect, if required by the national regulations or by the EC, 
 

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d) report to regulatory authorities serious adverse events and device deficiencies that could have led 
to aserious adverse device effect, as required by the national regulations, 
 
e) supply the Sponsor, upon Sponsor's request, with any additional information related to the safety 
reporting of a particular event. 
 
14.3.3 Reporting by the Sponsor 
 
The Sponsor is responsible for the classification of adverse events and ongoing safety evaluation of the 
clinical investigation and shall: 
 
a) review the Investigator's assessment of all adverse events and determine and document in writing 
their seriousness and relationship to the investigational device; in case of disagreement between the 
Sponsor and the principal Investigator(s), the Sponsor shall communicate both opinions to concerned 
parties, as defined in c), d) and e) below, 
 
b) review all device deficiencies and determine and document in writing whether they could have led to 
a serious adverse device effect; in case of disagreement between the Sponsor and the principal 
Investigator(s), the Sponsor shall communicate both opinions to concerned parties, as defined in c), d) 
and e) below, 
 
c) report or ensure the reporting to the EC by the principal Investigator(s), of all serious adverse events 
and device deficiencies that could have led to a serious adverse device effect, if required by national 
regulations or by the EC, 
 
d) report to regulatory authorities, within the required time period, all serious adverse events and device 
deficiencies that could have led to a serious adverse device effect, if required by national regulations or 
the CIP, 
 
e) report all relevant safety information to the DMC, if established, according to written procedures, 
 
f) in the case of a multicentre clinical investigation, inform all principal Investigators in writing of all the 
serious adverse events at all investigation sites that have been reported to the Sponsor, and ensure that 
they are reported to their EC, if required by national regulations or by the EC, whichever is more 
stringent; this information shall be sent to all the principal Investigators within a time frame established 
based on the perceived risk as defined in the risk analysis report, 
 
g) ensure that the EC and the regulatory authorities are informed of significant new information about 
the clinical investigation,  
 
h) in case of serious adverse device effects and device deficiencies that could have led to serious 
adverse device effects, determine whether the risk analysis needs to be updated and assess whether 
corrective or preventive action is required. 
 
14.4 
PROCESS FOR REPORTING SERIOUS ADVERSE EVENTS AND CONTACT DETAILS 
14.4.1 Documentation and declaration of Serious Adverse Event (SAEs, SADEs) by the Investigator to 
the Sponsor 
 
The declaration of Serious Adverse Event (Events, Reactions, or suspicion of Serious Adverse 
Reactions), Adverse Reactions requiring a medical treatment or which seem to have a character of 
seriousness is a legal requirement. 
The Investigator must report all these adverse events in the source file, the “adverse event 
documentation” form in the CRF, and in the SAE notification form. 
 
The Investigator must immediately notify by telephone, fax, or e-mail the Sponsor and DERMSCAN at 
the latest, within 24 hours of the Investigator becoming aware of the event, all SAE except for those 
recorded in the CIP or the Investigator’s brochure as not requiring an immediate notification. 
 

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Materiovigilance Department 
Horus Pharma 
Address 148 avenue G Guynemer Cap Var 06700 
Saint Laurent du Var France  
TEL: +33 (0)4 93 19 54 03 
FAX: +33 (0)4 93 19 54 09 
vigilance@horus-pharma.fr 
 
This first notification is confirmed by sending the form by fax (fax n° indicated in the CIP) or by e-mail 
with an acknowledgement of receipt, to the Sponsor and DERMSCAN within 48 hours of knowledge 
by the Investigator. Without acknowledgement of receipt of fax or e-mail, a letter with 
acknowledgement of receipt is also sent to the Sponsor accompanied by the form. 
As a part of monitoring of serious adverse events, if necessary, this 1st notification will be followed by 
additional detailed written reports. 
 
The Investigator must notify the Sponsor of adverse events and of the results of abnormal analyses 
defined in the CIP as determining factors for the evaluation of the safety of individuals participating in 
biomedical research, in conformance with the notification requirements specified in the CIP and within 
the time constraints also specified in the CIP. 
In notifications, individuals participating in research are identified by a code number. 
 
14.4.2 Declaration of the serious adverse events (SAEs, SADEs) by the Sponsor in France 
In conformance with the French Public Health law 2004-806 of 9 August 2004, its decree of application 
and orders, the Sponsor reports all serious adverse events occurred during the research by electronic 
mail to the Competent Authority and to the Ethics Committee by electronic mail, fax or post mail (all with 
acknowledgement of receipt).  
 
In case of clinical investigation conducted with a blind, the Sponsor lifts the blind prior to reporting a 
Suspected Unanticipated Serious Adverse Device Effect (SUSADE) to the CA and the EC concerned. 
 
The notification deadline to the CA and the EC are: 
-in the event of SAE associated with an impending risk of death, or for an injury or serious disease and 
requiring a quick medical treatment for others patients / subjects, users or other person or for any new 
information: immediately, at the latest within 7 days. 
-in other SAE or any related news: immediately, at the latest within 15 calendar days of the Sponsor 
becoming aware of the event. 
 
14.4.3 Declaration of the serious adverse events (SAEs, SADEs) by the Sponsor in Tunisia, Poland 
and Spain. 
 
The serious adverse events, including the ones related to the study device, shall be reported by the 
Sponsor to the regulatory authorities and EC as required by national regulations applicable for medical 
products. This declaration will be delegated by the Sponsor to Dermscan. 
 
14.4.3.1 Sponsor’s annual report to the Competent Authority and to the Ethics Committee 
Once per year for the duration of the research or on request the sponsor transmits a safety report with 
all the available safety information to the CA and the EC. This report includes notably, the list of all the 
suspected serious adverse reactions and an analysis of the information regarding the safety of 
individuals participating in the research. 
 
 
 
 

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14.5 
PROCESS FOR REPORTING A PREGNANCY 
 
The occurrence of a pregnancy (reported or diagnosed) after screening but before inclusion (first use of 
the investigational product) in the study is not reported to the Sponsor unless severity criteria (like SAE 
related to CIP procedures). If the pregnancy is confirmed, the studied product must not be administrated 
and the subject immediately withdrawn from the study. 
 
If the pregnancy is suspected during products administration phase, the product must be stop 
immediately and until result of the pregnancy test. 
If the pregnancy is confirmed, the product is definitively stopped and the subject withdrawn from the 
study. 
 
The Investigator must immediately notify the Sponsor of the pregnancy using specific form and reports 
it in the “adverse event documentation” of the CRF. 
Women who become pregnant during the study will be followed until the outcome of the pregnancy is 
known, and reported to the Sponsor (baby health). 
 
 
14.6 
LIST OF FORESEEABLE ADVERSE EVENTS AND ANTICIPATED ADVERSE DEVICE 
EFFECTS 
 
In some very rare cases, some transitory troubles can appear such as conjunctiva mild irritation, foreign 
body sensation, ocular redness or burning or temporary blurred vision. 
 
 
14.7 
INFORMATION REGARDING THE DATA MONITORING COMMITTEE (DMC), IF 
ESTABLISHED 
 
Not applicable. 
 
15- VULNERABLE POPULATION 
 
Not applicable. The population studied during the clinical investigation is not considered as a vulnerable 
population 
16- SUSPENSION 
OR 
PREMATURE 
TERMINATION 
OF 
THE 
CLINICAL 
INVESTIGATION 
 
16.1 
CRITERIA AND MODALITIES OF PREMATURE END OF TREATMENT OR SUBJECT 
EXCLUSION FROM THE CLINICAL INVESTIGATION 
 
Subjects will be free to withdraw from the study at any time if they wish so and for any reason, without 
having to provide any justification to the Investigator. 
The Investigator has the right to withdraw a subject for any reason, for subject’s best interests, including 
illness or adverse events.  
The Sponsor may decide to withdraw subjects for major deviation to the CIP, for administrative reasons 
or for any other valuable reason ethically justified. 
 
Subjects may discontinue the study for the following reasons: 
1. Subject consent withdrawal: subjects have the right to exit from the study at any time and for 
any motive, without their right to treatment being affected. 
2. Medical reasons or adverse events: the Investigator has the right to withdraw a subject in case 
of intercurrent illness or adverse events or if in the Investigator’s opinion, continuation in the 
study would be detrimental to the subject's well-being. 
3. Appearance of an exclusion criterion. 

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4. Failure to follow-up: if a subject does not come to the scheduled visits, several attempts have to 
be done to try to contact him/her; to obtain the reasons for non-attendance. 
5. Violations and deviations from the CIP. 
6. Administrative reasons. 
 
16.2 
CRITERIA FOR ACCESS AND TO BREAKING THE BLINDING/MASKING CODE DURING 
THE CLINICAL INVESTIGATION 
 
The Investigator will receive a sealed code envelope for each patient entered in the study, for use in 
emergency. Each envelope will contain the identity of patient's treatment. A set of code envelopes will 
also be retained by the CRO and the Sponsor. 
The code envelopes may only be opened in the case of an emergency, such as a Serious Adverse 
Event, that requires knowledge of the identity of the investigational product in order to manage the 
patient's condition. 
If opened, the time, date and reason for opening the code envelope must be written on the envelopes 
and signed by the Investigator; the Sponsor must be immediately notified in this instance. 
At the end of the study all envelopes (opened and unopened) must be returned to the Sponsor, along 
with the completed case report forms. The envelopes will be checked at each monitoring visit by the 
study monitor/CRA to ensure that the seals are either unbroken, or that any opening is adequately 
accounted for. 
 
16.3 
REQUIREMENTS FOR SUBJECT FOLLOW-UP  
16.3.1 Modalities and calendar of recording data 
 
Withdrawal due to intercurrent disease or adverse event must be fully documented in the case report 
form and should include any available and/or appropriate complementary information. 
 
In all cases, the reason for withdrawal must be recorded in the case report form. The subject must be 
followed up to state the reason for withdrawal and to establish whether the reason is an adverse event. 
Since the moment the Investigator knows the early termination or exclusion, the withdrawal of the 
subject must be formalized by a visit. If possible, all examinations scheduled for the final study day must 
be performed on all subjects who received the investigational product but do not complete the study 
according to CIP. 
The Investigator must make every effort to contact subjects who dropped-out of the study early. In the 
case where no visit is possible, this withdrawing must be recorded by the Investigator in the case report 
form and the source data documentation, and, if necessary, the registered letter with acknowledgement 
of receipt, to the subject. All the documentation concerning that subject must be as complete as possible. 
 
16.3.2 Modalities for replacing these subjects if any 
No replacement condition is foreseen (see paragraph 6.1.7). 
 
16.3.3 Modalities for the follow-up of these subjects  
When the premature exit is due to an adverse device effect, the subject will be followed until the 
resolution or the stabilization of the symptoms. 
 
17- PUBLICATION POLICY 
The Sponsor reserves the right to review all the manuscript(s) and abstract(s) before their submission 
for publication or presentation. Publication of data will be at the discretion of the Sponsor 
 
This is not intended to restrict or hinder publication or presentation, but to allow the Sponsor to protect 
proprietary information and to provide comments based on information that may not yet be available to 
the Investigator(s). 

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18- BIBLIOGRAPHY 
 
18.1 
CONCERNING STUDY RATIONALE 
 
1. 
Van Bijsterveld O.. Diagnostic test s in the sicca syndrome . Arch Ophthalmol 1969;82:10—4. 
 
2. 
Anthony J. Bron, FCOphth, FMedSci et al, Grading of Corneal and Conjunctival Staining in the 
Context of Other Dry Eye Tests. CORNEA. Volume 22, Number 7, October 2003. 
 
3. 
J.L. Gayton. Etiology, prevalence, and treatment of dry eye disease. Clinical Ophthalmology 
2009:3 405–412. 
 
4. 
M. Amrane, C. Creuzot-Garcher. Ocular tolerability and efficacy of a cationic emulsion in 
patients with mild to moderate dry eye disease – A randomized comparative study. Journal 
français d’ophtalmologie (2014) 37. 589-598. 
 
5. 
T. Kaercher,  U. Thelen, G. Brief, R.J. Morgan-Warren, R. Leaback. A prospective, multicenter, 
noninterventional study of Optive Plus in the treatment of patients with dry eye: the prolipid 
study. Clinical Ophthalmology 2014:8 1147–115. 
 
6. 
V. Baeyens, A. Bron, C. Baudouin. Efficacy of 0.18% hypotonic sodium hyaluronate ophthalmic 
solution in the treatment of signs and symptoms of dry eye disease. Journal français 
d’ophtalmologie (2012) 35, 412—419. 
 
 
18.2 
ETHICAL ASPECT 
 
1. 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI/ Ethical Principles for 
Medical Research Involving Human Subjects- Helsinki Declaration (1964) and its successive 
updates 
2. 
ICH TOPIC E6/ Note for guidance on Good Clinical Practice- CPMP / ICH / 135 / 95, January 
1997 
3. 
LOI HURIET SERUSCLAT/ CSP Titre II – Recherches Biomédicales- n°88-138 du 20 décembre 
1988 modifié par la loi française 2004-806 du 9 août 2004, concernant la santé publique 
4. 
LOI "INFORMATIQUE ET LIBERTES"/ Loi n°78-17 du 6 janvier 1978 relative à l’informatique, 
aux fichiers et aux libertés mise à jour par la loi n°2004-801 du 6 août 2004 concernant la 
protection des personnes pour la déclaration à la CNIL 
 
 
 

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19- CIP SIGNATURES  
 
We agree to conduct the study in accordance with the study CIP described in this document and in 
compliance with GCP and applicable regulatory requirements. 
 
 
FOR THE SPONSOR: 
 
 
Chantal COUDERC 
 
 
 ____________________  
 ___________________ 
 
 
 
Date 
Signature 
 
 
 
 

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FOR THE CRO/SMO: 
 
 
 
 
Audrey NATALIZIO 
Project Manager 
 
 ____________________  
 ___________________ 
 
 
 
Date 
Signature 
 
 
 
 
 
 
Cédric JUNG 
Biostatistician 
 
 ____________________  
 ___________________   
 
Date 
Signature 
 
 
 
 

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FOR THE COORDINATING INVESTIGATOR: 
 
 
 
Pr. Christophe BAUDOUIN 
 
 
 
 
 ____________________  
 ___________________ 
 
 
 
 
 
 
 
 
Date 
 
 
 
Signature 
 
 
 
 

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APPENDIX 1 : AE AND SAE forms 
 
SAE form 
 
I. INFORMATION ABOUT THE INVESTIGATOR / INFORMATION SUR L’INVESTIGATEUR 
1. Investigator name:                                     Tel: 
…………….... 
   nom de l’investigateur                                         
                                                                         Fax:  .……………. 
Profession (speciality):                                          
Profession (spécialité) 
 
 Street address: 
 adresse 
 
City/ ville:                                         Zip Code/Postal Code/Zone: 
                                                            code postal 
State/Province:                             
 état/région                                       Country/ pays: 
2. Report                               
2.a Date of this report 
    Rapport                              Date de ce rapport : 
     initial /initial  
     follow-up /  
         complémentaire 
2.b. Notification date 
       date de notification 
 
Reception date 
date de réception 
 
Identification # / N° d’identification  
(1)  
 
II. ADVERSE EVENT INFORMATION / INFORMATION SUR L’EVENEMENT 
3. Birth date / date de naissance du sujet 
3.a. Age / âge 
 
Years-Months(1) / 
ans-mois(1) 
4. Sex / sexe 
 
  1 ♂      2 ♀ 
5.Weight/poids 
 
kg / kg 
6. Height/ taille 
 
cm / cm 
Day / jour 
 
Month / mois 
 
Year / année 
 
7. Serious Event (check the appropriate 
boxes) Evénement grave (cocher les cases 
appropriées) : 
 
1 death / décès 
 date / date : 
 
 
2 life threatening /  
      mise en jeu du pronostic vital 
 
3 lasting or significant incapacity 
      or handicap /  
      incapacité ou handicap  
      important ou durable 
 
4 hospitalization or prolongation of 
      existing hospitalization /  
      hospitalisation ou prolongation  
      d’hospitalisation 
   duration of hospitalization /  
   durée de l’hospitalisation 
                        years, months, days (1) 
                        années, mois, jours (1) 
                        ongoing / en cours 
 
5 congenital anomaly/ birth defect 
      anomalie ou malformation congénitale 
 
6 other, define / autre, préciser : 
……………………………………. 
 
8. Event description (also exams and/or laboratory results) 
      description de l’événement (y compris les éventuels examens et/ou résultats 
     de laboratoire) 
 
 
 
  
 
8.a Place of the serious event / Lieu de survenue de l’évènement grave : 
…………………………………………………………………………………….. 
 9. Severity / 
       sévérité 
    
1 light / 
 Légère 
 
2 moderate /  
Modérée 
 
3 severe /  
sévère 
  
10. Outcome of the subject (complete for a 
follow-up report or SAE end) / issue pour le sujet 
(compléter pour un rapport complémentaire ou à la clôture 
de l’EIG) 
1 completely recovered / guérison complète     
2 condition still present and unchanged / 
   affection toujours présente et inchangée 
3 recovered with sequelae /guérison avec séquelles  
4 condition deteriorating / aggravation de l’affection   
5 condition improving / amélioration de l’affection   
6 death / décès   autopsy / autopsie     1 yes/oui    
                                                                    2 no/non 
7 unknown (lost to follow-up) / évolution inconnue   
11. Event onset date 
(2)       date de début de 
l’événement 
12. Event termination date 
       date de fin de l’événement 
Day 
/ 
jour 
Month/ mois Year/ année 
 
Day/jour 
 
Month/mois Year/année 

Horus Pharma 
CIP #15E1122 
Final Version 4.0 
Date: 04/09/2017 
Confidential 
Page 50/53 
 
 
 
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Clinical investigational plan for MD 
 
(1) delete as appropriate / 
(1 )barrer les mentions inutiles 
 
 ongoing / en cours 
 
 
III. STUDIED PRODUCT(S) INFORMATION / INFORMATION SUR LE(S) PRODUIT(S) A L’ESSAI 
13. Tested product(s) 
 produit(s) testé(s) 
   
13.a.batch # / N° de lot  
14. Dosage / posologie 
15. Administration route               1 oral / orale                           3 transmucous / transmuqueuse    
       voie d’administration               2 parenteral / parentérale        4 cutaneous / cutanée 
        5 other / autre ( to specify / préciser : ……………………………………………………….) 
 
16. Kind of product :        1 cosmetic / cosmétique,    2 drug / médicament,    3 medical device / dispositif médical,   
      Type de produit           4 other / autre (to specify / préciser) : …………………………………………………………..) 
17. Dates of tested product administration 
       Dates d’administration du produit à l’étude 
from /du                                      to /au 
 ongoing / en cours           not applicable / sans objet 
18. Treatment duration                    years, months, days (1) 
      durée du traitement                       années, mois, jours (1) 
  
 not applicable / sans objet 
 ongoing / en cours 
19. Definitive termination of studied product 
       arrêt définitif du produit à l’étude 
     1 yes / oui 
     0 no / non 
19.a. Tempory suspension of the studied product  
         arrêt temporaire du produit à l’étude     
  1 yes / oui     if yes, number of days of stopping 
  0 no / non         si oui, nombre de jours d’arrêt 
20. Event resolved with termination of treatment? 
       Disparition de l’événement après arrêt du traitement ? 
 
0 no / non   1 yes /oui   2 not applicable / sans objet 
21. Event reappeared with reintroduction of treatment? 
       réapparition de l’événement  après réintroduction du  
       traitement ?  
 0 no / non   1 yes /oui   2 not applicable / sans objet 
22. Product administered: was the code blinded out? / produit administré : le code a-t-il été levé ? 
                     0 no / non                1 yes / oui                 2 not applicable / sans objet 
 
IV. ASSOCIATED DRUG(S) AND MEDICAL HISTORY / MEDICAMENT(S) ASSOCIE(S) ET ANTECEDENTS  
23.ASSOCIATED DRUGS (excluding therapy to treat SAE)/MEDICAMENTS ASSOCIES (excepté les traitements ayant servi 
à résoudre l’EIG) 
Drug 
médicament 
Indication 
indication 
Dosage 
posologie 
Administration route 
voie d’administration 
Beginning date 
date de début 
End date 
date de fin 
Event related 
lié à l’EIG 
a. 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
  1 yes / oui 
  0 no / non 
b. 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
  1 yes / oui 
  0 no / non 
c. 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
  1 yes / oui 
  0 no / non 
   
24. RELEVANT MEDICAL HISTORY / ANTECEDENTS MEDICAUX PERTINENTS 
 
 
 
 
 

Horus Pharma 
CIP #15E1122 
Final Version 4.0 
Date: 04/09/2017 
Confidential 
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V. ACTION TAKEN / ACTION ENTREPRISE 
25. Action taken / action entreprise 
       (1) no action taken / aucune action entreprise   
       (2) Concomitant medication taken to treat the event (complete Field 26) / traitement concomitant pris pour 
               traiter l’événement (compléter le champ 26) 
       (3) no drug therapy given (if checked, note therapeutic measures in Field VII) / pas de traitements correcteurs  
              prescrits (si cette case est cochée, donner les mesures thérapeutiques prises au champ VII) 
 
26. DRUG THERAPY GIVEN / MEDICAMENTS AYANT SERVI À TRAITER L’EIG 
Drug 
médicament 
Indication 
indication 
Dosage 
posologie 
Administration route 
voie d’administration 
Beginning date 
date de début 
End date 
date de fin 
 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
 
 
1 oral / orale 
2 parenteral / parentérale 
3 transmucous / transmuqueuse 
4 cutaneous / cutanée 
5 other/autre :……….……. 
 
 
 
 
 
 ongoing /  
      en cours 
 
27. LABORATORY FINDINGS (enter only those findings significant or necessary for SAE diagnosis) /  
       RESULTATS D’EXAMENS (noter uniquement les résultats nécessaires au diagnostic de l’EIG ou significatifs) 
Test / lab name 
test / nom de l’examen 
Unit 
unité 
Value 
valeur 
Date 
date 
Test / lab name 
test / nom de l’examen 
Unit 
unité 
Value 
valeur 
Date 
date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27.a. COMMENTS ON LABORATORY FINDINGS in Field VII / REMARQUES SUR LES RESULTATS D’EXAMENS en VII 
 
VI. CONCLUSION 
According to the investigator, the SAE is linked: 
  selon l’investigateur, L’EIG semble plutôt lié : 
29. According to the sponsor, the SAE is linked: 
     selon le promoteur, l’EIG semble plutôt lié : 
 28a. to the studied product/  
au produit à l’essai 
0 Excluded / exclue                   
1 Unlikely/ douteux 
2 Not clearly attributable/ possible  
3 Likely/ vraisemblable 
4 Very likely / très vraisemblable 
28b.to the study procedures /  
aux procédures de l’essai 
0 Excluded / exclue                   
1 Unlikely/ douteux 
2 Not clearly attributable/ possible  
3 Likely/ vraisemblable 
4 Very likely / très vraisemblable 
 
1 to the studied product / au produit à l’essai 
2 to the study procedures / aux procedures de 
l’essai 
3 other, define / autre, préciser : 
 
0 no relationship / sans relation  
30. If, according to the sponsor, the SAE appears to be related to the studied product, the event is:       1 expected / attendu 
      si selon le promoteur, l’EIG paraît plutôt lié au produit à l’essai, l’événement indésirable est :      0 unexpected / inattendu 
31. Sponsor comments / commentaires du promoteur 
 
 
 
 
 

Horus Pharma 
CIP #15E1122 
Final Version 4.0 
Date: 04/09/2017 
Confidential 
Page 52/53 
 
 
 
PRM02-F-012_A_V1 
Clinical investigational plan for MD 
 
VII. ADDITIONAL INFORMATION / INFORMATIONS COMPLEMENTAIRES 
FOR ADDITIONAL INFORMATION / POUR COMPLEMENT D’INFORMATION: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date of report / Date du rapport : 
 
 
 
 
Signature / Signature : 
 
 
 
 
 

Horus Pharma 
CIP #15E1122 
Final Version 4.0 
Date: 04/09/2017 
Confidential 
Page 53/53 
 
 
 
PRM02-F-012_A_V1 
Clinical investigational plan for MD 
 
AE form 
 
 
PARTIE I : 1ère documentation de l’événement 
                                                                                                              First documentation of the adverse event 
 
 
N°/ # 
_ _ 
 
1. Description de l’événement / Event description 
En cas de réaction cutanée, préciser sa localisation et si elle correspond à la zone d’application du produit testé / In case of cutaneous reaction, specify 
its localisation and if it corresponds to the product application area 
 
 
 
 
 
2. Date de début de l’événement  
    Event onset date 
 
 
3. Sévérité
té / / severity 
 
1 légère / mild 
2 modérée / moderate 
3 sévère / severe 
 
4. Photo des signes cliniques / Pictures of 
clinical signs  
 
0 NON / NO  
1OUI /YES  
3 NA* 
 
 
5. Actions entreprises vis-à-vis du produit 
étudié 
Actions taken with the studied product 
 
0 aucune / none 
1 arrêt définitif  / definitive interruption  
2 arrêt transitoire /temporary interruption 
   Durée / Duration………………………. 
3 diminution de la dose / dose decrease 
 
6. Actions entreprises vis-à-vis de 
l’événement  
Actions taken due to the event 
 
0 aucune / none 
1 traitement correcteur / corrective treatment 
Compléter le tableau des traitements concomitants / 
Complete concomitant treatment form 
2 autre, à spécifier / other, define : 
     ………………… 
 
7. Evénement Indésirable Grave (EIG)
G) 
      Serious Adverse Event (SAE) 
 
 0  NON / NO  
 1  OUI / YES  
Si “OUI”, remplir un formulaire de 
déclaration d’EIG. 
 If “YES”, complete a SAE declaration Form. 
 
8. Délai entre l’évènement et la dernière 
prise/application du produit étudié ? 
Timeframe from the last product taken/application 
 
                 minutes/heures/jours 
                 minutes /hours /days 
 
 NA* 
 
9. 
Relation 
de 
causalité 
avec 
le(s) 
produit(s) étudié(s) 
Event relationship with the study product(s) 
 
0 oui / yes 
1 non / no 
2 possible / possible 
 
 
10. Relation avec les procédures de 
l’étude  
Event relationship with the study methods 
 
0 oui / yes 
1 non / no 
2 possible / possible 
 
 
11. Evolution / Outcome 
 
 Non connue / Unknown 
 
 En cours* / ongoing     * commentaire obligatoire / Compulsory comment  
Remplir la partie II et/ou la partie III à la prochaine cinétique 
 
 Guéri  
 Resolved 
 
Date de guérison                                                        
Event stop date 
 
Durée Duration                     (secondes/minutes/heures/jours)  
                                            Seconds /minutes /hours /days 
 
12. Commentaires / Comments 
(Intensité, antécédents… / Intensity, medical history…) 
 
Si EI en cours, évolution à ce jour / If AE ongoing, evolution  this day:   
1 amélioration / improved 
2 pas de changement / unchanged 
3 aggravation / worsened  
4 perdu de vue / lost to follow-up  
 
 
Date du rapport/ Report Date :                                         Nom et signature / Name and signature : 
 
STOP : REMPLIR LES PARTIES CI-DESSOUS LORS DES PROCHAINES CINETIQUES UNIQUEMENT POUR LES EI EN COURS 
PARTIE II :suivi 
       Follow up 
 
Evolution de l’EI à chaque cinétique (amélioration ou aggravation) /  Evolution of the adverse event 
Dater et parapher chaque commentaire / date and initial each comment. 
REMPLIR LA PARTIE III A LA GUERISON DE L’EI PRECEDEMMENT EN COURS OU A LA FIN DE L‘ETUDE 
PARTIE III : Guérison ou fin
d’étude /Event or study termination 
 
Date de guérison 
Event stop date 
 
 
 
Sujet perdu de vue  
 
Untraceable subject                                     
  
 EI toujours en cours à la fin de l’étude /AE ongoing at the study end 
        Date de fin de l’étude :     
         Study stop date     
 
 L’EI nécessite-t-il un suivi ?   NON / NO   
1          si oui, date prévue pour le suivi ** : 
 Does this AE need a follow up?              OUI **/YES 
2            The predictive date for the follow up 
                                                                                                                          
** Prévenir Immédiatement le  service ARC 
pour garantir le suivi / inform Immediately the CRA service to guarantee the follow up 
Date du rapport / Report Date :                                         Nom et signature / Name and signature : 
 
*NA = Non applicable/ Not applicable                                   Rappel des définitions en fin de CRF/ 
F/ Definitions at the CRF end