Phase I Clinical Study, to Evaluate the Safety and Tolerability of the Ophthalmic Gel PRO-165 Versus Artelac® Nightime Gel, on the Ocular Surface of Ophthalmological and Clinically Healthy Subjects
Phase: PHASE1
Conditions: Dry Eye Syndromes
Sponsor: Laboratorios Sophia S.A de C.V.

CONFIDENTIAL 
Creation date: february 2017 
Phase I clinical study to evaluate the safety and 
tolerability of PRO-165 ophthalmic gel versus 
Artelac® Nightime Gel on the ocular surface of 
ophthalmologically and clinically healthy subjects 
Protocol code:SOPH165-0217/I 
Protocol version:4.0 
Version date: 21/Jan/2022 
Clinical Trial ID: NCT04704531 
Sponsor: Laboratorios Sophia, S.A. de C.V. 

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1. Summary
Title of the study: 
Estudio clínico fase I, para evaluar la seguridad y tolerabilidad del gel oftálmico PRO-165 versus 
Artelac® Nightime Gel, en la superficie ocular de sujetos oftalmológica y clínicamente sanos. 
 
Protocol code: 
SOPH165-0217/I 
Creation date: 
February 7, 2017 
Protocol version: 
4.0 
Version date: 
January 21, 2022 
Therapeutic indication: 
Eye lubricant 
Study period: 
4 months 
Development phase: I 
Aim: 
To evaluate the safety and tolerability of the PRO-165 formulation on the ocular surface of 
ophthalmologically and clinically healthy subjects. 
Hypothesis: 
PRO-165 ophthalmic gel presents a safety and tolerability profile similar to Artelac ® Nightime Gel 
in ophthalmologically and clinically healthy subjects. 
Methodology: 
Phase I, controlled, parallel-group, double-blind, randomized, exploratory clinical study. 
Number of patients: 
32 subjects, divided into 2 groups [16 subjects (16 eyes) exposed per group] 
Diagnosis and main inclusion criteria: 
-
Systemically and ophthalmologically healthy subjects
-
Signed informed consent.
-
Age between 18 and 45 years.
-
Both sexes
-
Blood tests [complete blood count ( CBC ), three-element blood chemistry (BC), and liver
function tests (LFTs)] within normal parameters
-
Visual capacity 20/30 or better
Test product, dose and route of administration, 
-
PRO-165 Sodium hyaluronate 0.2% ophthalmic gel. Manufactured by Laboratorios Sophia
, SA de CV, Zapopan, Jalisco, Mexico.
▪
Dosage: One drop of gel, 4 times a day during the waking period, in the
fornix of the right eye.

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▪
Route of administration: ophthalmic
Treatment duration: 10 days 
Reference product, dosage and route of administration: 
1.
Artelac ® Nightime Gel. Carbomer 0.2%, ophthalmic gel. Made in Germany by: Dr.
Gerhard Mann Chem Pharm. Fabrik GmbH Brunsbütteler Damm 165-173 D-13581, Berlin,
Germany . Imported and marketed by: Bausch & Lomb México, SA de CV, Av. Michoacán
No. 20, Warehouse 10, Section F; Renovación Neighborhood; Iztapalapa District, Zip Code
09209; Mexico City
Evaluation criteria: 
Primary safety outcome variables: 
-
Presence of adverse events.
Secondary outcome variables: 
-
Tear film break-up time
-
Vital signs: HR, RR, SBP.
-
Posterior segment
-
Intraocular pressure.
-
Visual capacity.
-
Laboratory tests: BHc , QS and PFH.
-
Ocular surface stains.
Primary tolerability outcome variables: 
-
Eye comfort index
Statistical methodology: 
Data will be expressed using measures of central tendency. Qualitative variables will be presented 
as frequencies, proportions, and/or percentages. Statistical analysis will be performed using the 
Kruskal-Wallis test for quantitative variables. Differences between qualitative variables will be 
analyzed using the X 2 test or Fisher's exact test. An alpha ≤ 0.05 will be considered significant. 

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2. Content
1. SUMMARY
1 
2. CONTENT
3 
3. INDEX OF ABBREVIATIONS
7 
4. ADMINISTRATIVE STRUCTURE OF THE STUDY
9 
5. INTRODUCTION
11 
5.1 THEORETICAL FRAMEWORK  
11 
5.2 BACKGROUND  
15 
5.2.1 SODIUM HYALURONATE  
15 
5.2.1.1 Pharmacokinetics in the eyeball 
16 
5.3 PROBLEM STATEMENT  
16 
5.4 JUSTIFICATION  
16 
5.5 OBJECTIVES AND HYPOTHESES  
17 
5.5.1 GENERAL OBJECTIVE  
17 
5.5.2 SPECIFIC OBJECTIVES  
17 
5.5.3 SECONDARY OBJECTIVES  
17 
5.5.4 HYPOTHESIS  
17 
5.6 STUDY DESIGN AND PLAN  
17 
5.6.1 DISCUSSION OF THE STUDY DESIGN  
17 
6. MATERIALS AND METHODS. PARTICIPANTS, INTERVENTIONS AND VARIABLES
18 
6.1 STUDY CENTER  
18 
6.1.1 ORGANIZATION OF THE CENTER  
18 
6.1.2 DOCUMENTATION TO BE DELIVERED TO THE SPONSOR 
18 
6.1.3 CLOSURE OF THE CENTER  
19 
6.2 ELIGIBILITY CRITERIA  
19 
6.2.1 INCLUSION CRITERIA  
19 
6.2.2 EXCLUSION CRITERIA  
19 
6.2.2.1 General criteria 
19 
6.2.2.2 Medical and therapeutic criteria 
19 
6.2.3 ELIMINATION CRITERIA  
20 
6.2.4 SUBJECT IDENTIFICATION  
20 
6.3 INTERVENTION  
20 
6.3.1 TREATMENTS ADMINISTERED  
20 
6.3.1.1 Treatment under study  
20 
6.3.1.2 Reference treatment  
21 

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6.3.2 STRATEGIES TO IMPROVE ADHERENCE AND PROCEDURE TO MONITOR ADHERENCE  
21 
6.3.2.1 Procedure for monitoring adherence  
22 
6.3.3 CONCOMITANT TREATMENTS AND INTERVENTIONS PERMITTED AND PROHIBITED DURING THE STUDY 
23 
6.3.4 TREATMENT MANAGEMENT  
23 
6.3.4.1 Delivery and reception  
23 
6.3.4.2 Storage  
24 
6.3.4.3 Return  
24 
6.4 OUTCOME VARIABLES  
24 
6.4.1.1 Primary outcome variables  
24 
6.4.1.2 Secondary outcome variables  
24 
6.4.3 METHODS AND SCALES TO BE USED FOR MEASURING VARIABLES  
24 
6.4.3.1 Visual capacity  
26 
6.4.3.2 Eye comfort index  
27 
6.4.3.3 Ocular surface stains  
27 
6.4.3.4 Presence of adverse events  
27 
6.4.3.5 Intraocular pressure  
27 
6.4.3.6 Vital signs  
28 
6.4.3.7 Tear film break-up time  
28 
6.4.3.8 Pregnancy test  
28 
6.4.3.9 Laboratory tests  
28 
6.4.4 MEASUREMENT TIME  
28 
6.5  STUDY SCHEDULE AND DIAGRAM  
30 
6.5.1 PROCEDURES TO BE PERFORMED PER VISIT  
31 
6.5.1.1 Scrutiny visit  
31 
6.5.1.2 Baseline visit  
31 
6.5.1.3 Visit 1  
32 
6.5.1.4 Final Visit  
32 
6.5.1.5 Safety call  
32 
6.5.2 STUDY DIAGRAM  
32 
6.6 SAMPLE SIZE  
33 
6.6.1 SAMPLE SIZE CALCULATION  
33 
6.7 RECRUITMENT  
34 
7. METHODS. INTERVENTION ALLOCATION
34 
7.1 GENERATING THE ASSIGNMENT SEQUENCE 
34 
7.2 BLINDING MECHANISM  
34 
7.3 IMPLEMENTATION  
34 
7.4 BLINDING (MASKING)  
34 
7.4.1 OPENING THE BLIND  
34 
8. METHODS. DATA COLLECTION, MANAGEMENT, AND ANALYSIS
35 
8.1 DATA COLLECTION METHODS  
35 
8.1.1 STRATEGIES FOR COMPLETING THE FOLLOW-UP  
35 
8.2 DATA MANAGEMENT  
35 

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8.3 STATISTICAL METHODOLOGY  
36 
8.3.1 ANALYSIS OF PRIMARY AND SECONDARY OUTCOME VARIABLES 
36 
8.3.2 ADDITIONAL ANALYSES  
37 
8.3.3 POPULATION ANALYSIS AND MISSING DATA HANDLING  
37 
9. METHODS. MONITORING
37 
9.1 DATA MONITORING  
37 
9.2 PRELIMINARY ANALYSES AND EARLY TERMINATION OF THE STUDY 
38 
9.3 ADVERSE EVENTS  
39 
9.3.1 RESEARCHER RESPONSIBILITIES  
39 
9.3.1.1 Recording adverse events on Case Report Form  
39 
9.3.1.2 Monitoring of adverse events  
40 
9.3.1.3 Procedures for a serious adverse event  
41 
9.3.1.4 Causality Assessment  
42 
9.3.2 SPONSOR RESPONSIBILITIES  
44 
9.4 AUDIT  
44 
9.4.1 PRE-STUDY AUDIT  
44 
9.4.2 AUDIT/INSPECTION DURING THE CONDUCT OF THE STUDY  
44 
10. ETHICAL CONSIDERATIONS
44 
10.1 APPROVAL OF COMMITTEES  
44 
10.2 AMENDMENTS TO PROTOCOL  
45 
10.3 CONSENT  
46 
10.3.1 OBTAINING  
46 
10.3.2 SPECIAL CONSIDERATIONS  
46 
10.3.3 MODIFICATION TO INFORMED CONSENT  
46 
10.4 CONFIDENTIALITY  
47 
10.5 DECLARATION OF INTERESTS  
47 
10.6 ACCESS TO INFORMATION  
47 
10.7 ANCILLARY AND POST-STUDY CARE  
47 
10.8 BIOSECURITY ASPECTS  
47 
10.9 FINAL REPORT AND PUBLICATION OF RESULTS 
48 
10.9.1 FINAL REPORT  
48 
10.9.2 COMMUNICATION OF RESULTS  
48 
10.9.3 PUBLICATION OF RESULTS  
48 
11. FINANCING AND INSURANCE
49 
11. 1  COMPENSATION TO STUDY PARTICIPANTS 
49 
11.2  STUDY INSURANCE
49 
12. BIBLIOGRAPHIC REFERENCES
50 

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13. SIGNATURE PAGE
55 
13.1 SIGNATURES OF THE SPONSOR'S REPRESENTATIVES 
55 
13.2 RESEARCHER  
55 
14. ANNEXES
57 
14.1 EYE COMFORT INDEX 
57 
14.2 OXFORD SCALE  
59 
Index of tables and figures 
Table 1. Administrative structure  ....................................................................................................... 9 
Table 2. SDPL classification by severity  ............................................................................................ 14 
Table 3. Treatment recommendations for SDPL  .............................................................................. 15 
Table 4. Qualitative-quantitative formulation of PRO-165  .............................................................. 21 
Table 5. Scales to be used  ................................................................................................................ 26 
Table 6. Karch and Lasagna algorithm modified by Naranjo  ........................................................... 43 
Figure 1. Classification of SDPL by etiology  ...................................................................................... 13 
Figure 2 Minimum organization of the center  ................................................................................. 18 
Figure 3. Diagram of study  ............................................................................................................... 33 
Figure 4. Adverse event care  ............................................................................................................ 41 

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3. Index of abbreviations
ALT 
Alanine transferase 
AST 
A spartate transferase 
BAK 
Benzalkonium Chloride, ( for its acronym in English Benzalkonium chloride .) 
BD 
Direct bilirubin 
BI 
Indirect bilirubin 
BHc 
Complete blood count 
GCP 
Good Clinical Practices 
BT 
Total bilirubin 
CV 
Visual capacity 
ICC 
Informed Consent Letter 
CEI 
Research Ethics Committee 
CI 
Informed consent 
CRF 
Case Report Form Form ) 
DEWS International Workshop on 
Dry Eye Eye Workshop ) 
AE/EAS 
Adverse event/serious adverse event 
FDA  
Food and Drug Administration Administration ) 
FC  
Heart rate 
RR 
Respiratory rate  
GAG 
Glycosaminoglycans 
ICH 
International Conference on Harmonization (ICH) on Harmonization ) 
ICO 
Eye Comfort Index 
IP 
Principal Investigator of the clinical study 
ITF 
International Task Force on Dry Eye Force ) 
PFH 
Liver function tests 
IOP 
Intraocular pressure 
QS 
Blood chemistry 
TAS 
Systemic blood pressure 

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TF 
Fluorescein staining 
TVL 
Lissamine green stain 
ULF 
Functional Lacrimal Unit

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4. Administrative structure of the study
The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia , SA de 
CV is shown in Table 1Administrative structure 
Function 
Name / Contact 
Affiliation ¥ 
Medical Director of 
the study 
Medical and Regulatory Affairs Director 
Operations 
Manager 
Regional Clinical Research Manager 
Studio Director 
Medical Manager 
Clinical 
Development 
Team 
Chief of Medical Affairs Operations 
Clinical 
Development 
Team 
Biostatistics Manager 
¥ Employees of Laboratorios Sophia , SA de CV Av. Paseo del Norte No. 5255, Col. Guadalajara Technology Park,
Guadalajara-Nogales Highway Km13.5 C.P45010 Zapopan, Jalisco, Mexico Tel +52 (33) 3000 4200
Table 1Administrative structure 

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5. Introduction
5.1 Theoretical framework 
Dry eye disease (DED) Eye Eye disease ) is a common ocular condition that significantly diminishes 
quality of life and affects 6–34% of the adult population worldwide.  [1] [2]Although there are no 
formal studies on the prevalence of the disease in Latin American countries, several reports suggest 
a higher prevalence of severe symptoms and clinical diagnosis of DED in the Hispanic population 
compared to the Caucasian population.[2] [3]  
DED is a tear film disorder that results in damage to the ocular surface and is associated with 
symptoms of ocular discomfort. DED has also been called keratoconjunctivitis. sicca (KCS), sicca 
syndrome , xerophthalmia, dry eye syndrome, ocular surface disease, tear film dysfunction 
syndrome (TPDS), or simply dry eye. Strictly speaking, some of these terms are not synonymous, 
since, for example, DED can occur without keratitis, KCS; this protocol will use TPDS as  [4] [5]a 
synonym for DED, assuming that they are interchangeable concepts and adopting the definition of 
the 2007 International Dry Eye Workshop (DEWS). Eye Workshop ): 
Dry eye is a multifactorial disorder of the tear film and ocular surface that 
causes symptoms of discomfort, visual disturbances, and tear film 
instability with potential damage to the ocular surface. It is accompanied 
by increased tear film osmolarity and inflammation of the ocular surface. 
[4] 
LPDS is an alteration of the lacrimal functional unit (LFU), an integral system comprising the lacrimal 
glands, ocular surface (cornea, conjunctiva and meibomian glands), eyelids and the afferent and 
efferent nervous network that interconnects them. [6] 
This LFU controls the main components of the tear film and regulates them in response to 
environmental, endocrinological, and cortical influences. Its main function is to preserve the 
integrity of the tear film, the transparency of the cornea, and the quality of the image projected 
onto the retina. [6] [7] [8] [9] 
Damage or disruption to any component of the UFL can destabilize the tear film and lead to ocular 
surface disease manifested as PLDS. Tear film stability, a hallmark of a normal eye, is threatened 
when interactions between tear film-stabilizing components are compromised by decreased 
secretion, delayed clearance, and altered tear composition. Inflammation is a secondary 
consequence. Reflex tear secretion, in response to irritation, is considered the initial compensatory 
mechanism, but over time, inflammation accompanying secretory dysfunction and decreased 
corneal sensitivity compromises the reflex response and results in further tear film instability. 
Disruption of the UFL is considered to play a critical role in the development of various forms of dry 
eye. [4] 
The tear film is a highly specialized and carefully structured moisturizing layer that covers the cornea 
and conjunctiva. It has been classically described as a trilaminar structure composed of a lipid 
surface layer, an aqueous intermediate layer, and an internal mucinous layer .  [10]Currently, it is 
considered a hydrated gel with a concentration gradient of its components, mucin, 
water/electrolytes, proteins, and other components such as immunoglobulins.  [7]The tear film has 
four main functions: 1) Maintain a regular optical surface, 2) Prevent friction between the structures 
of the ocular surface, 3) Nourish the cornea, and 4) First line of defense against ocular surface 
infections.[11]  

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Based on models of the tear film's "microstructure" and its interface with ocular surface cells, the 
mucin layer should always be present in a healthy tear film.  [10]This layer provides support for the 
rest of the tear film on the ocular surface, helping to keep it moist and lubricated.  [12]The epithelial 
cell layer of the conjunctiva includes goblet cells, which secrete mucin. These cells are the main 
source of mucin for the tear film. [11] 
Within the framework of the DEWS, the etiopathogenic classification of PLDS was established, which 
is summarized in Figure 1This classification aims to provide a more up-to-date understanding of 
PLDS. It is divided into two main classes: aqueous deficiency and evaporative. The aqueous 
deficiency category primarily refers to a failure of tear secretion. The evaporative class has been 
subdivided to distinguish between causes that depend on intrinsic conditions of the eyelids and 
ocular surface and those that arise from extrinsic influences. 
PLDS can begin in either class, but these are not mutually exclusive. It is recognized that a disease 
can begin in one major class and coexist or even lead to events that produce PLDS through a 
mechanism in another class. This is part of a vicious cycle of interactions that can amplify severity. 
An example of this is that all forms of PLDS cause goblet cell loss, which over time will contribute to 
a loss of tear film stability, surface damage, and evaporative water loss. [4] 
Many pathophysiological mechanisms of PLPS stimulate the sensory nerves of the cornea, which is 
why PLPS is described as a "symptomatic disease."  [13] [14] [15]In most patients, there is a 
relationship between symptoms and clinical signs; however, it is also recognized that in some 
patients, the severity of symptoms does not correspond to the clinical signs of the disease.  [14] [16] 
[17] 
Classifying PLPS according to severity is currently challenging, as there is no gold standard for 
determining its severity; however, disease severity is one of the most relevant factors when 
considering therapeutic options for PLPS.  [18]In 2006, a panel of specialists called the Delphi Panel 
issued a severity classification, later adopted by the DEWS. Severity was classified into four levels, 
based on the increasing frequency and intensity of various signs and symptoms.  [18]See Table 2 
There are other systems for classifying the severity of PLDS referred to by other authors, [19] [20] 
[21] [22]including the European Consensus algorithm of the ODISSEY group, which classifies
discordant PLDS cases as severe, which are therefore more difficult to classify. [23]
In addition to the most highly correlated diagnostic methods for PLDS (OSDI, TRL, Schirmer test ), 
conjunctival impression cytology (CIC) has recently been used. CIC is a minimally invasive technique 
that evaluates the characteristics of goblet cells. This technique can be used for diagnostic purposes, 
to elucidate the mechanism of the disease, and to evaluate treatment efficacy. [24] 

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Figure 1Classification of SDPL by etiology 
SDPL
Aqueous deficiency
Sjögren's syndrome
Primary
Secondary
No Sjögren's 
syndrome
Tear deficiency
Obstruction of the 
tear duct
Reflex blocking
Systemic 
medications
Evaporative
Intrinsic
Meibomian 
deficiency
Alterations in eyelid 
opening
Low flicker rate
Drug action 
(Accutane)
Extrinsic
Vitamin A deficiency
Topical medication 
preservatives
Use of contact lenses
Ocular surface 
diseases e.g. allergies

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Table 2Classification of SDPL by severity 
Degree 
1 Light 
2 Moderate 
3 Severe 
4* Disabling 
Discomfort, 
severity 
and 
frequency 
Mild and/or 
episodic; occurs 
under 
environmental 
stress 
Moderate 
episodic or 
chronic, with or 
without stress 
Frequent or constant 
severe without stress 
Severe and/or 
disabling and 
constant 
Visual 
symptoms 
None or mild 
episodic fatigue 
Annoying and/or 
limiting episodic 
Chronic and/or 
constant limiting 
discomfort 
Constant and/or 
possibly disabling 
Conjunctival 
injection 
None to mild 
None to mild 
+ 
+/++ 
Conjunctival 
staining 
None to mild 
Variable 
Moderate to marked 
Marked 
Corneal 
staining 
None to mild 
Variable 
Marked center 
Severe and 
widespread 
punctate erosion 
Tear/corneal 
signs 
None 
Light debris, 
decreased 
meniscus 
Filamentous keratitis, 
mucus aggregation, 
increased debris in 
tears 
Filamentous 
keratitis, mucus 
aggregation, 
increased debris in 
tears, ulcer 
Meibomian 
glands 
/ 
eyelids 
Meibomitis present 
variably 
Meibomitis 
present variably 
Frequent 
Trichiasis , 
keratinization, 
symblepharon 
TRL 
Variable 
≤ 10 
≤ 5 
Immediate 
Schirmer I 
Variable 
≤ 10 
≤ 5 
≤ 2 
*Must have signs and symptoms.
Adapted from Behrens A, Doyle JJ, Stern L, et al.[18]
The treatment currently available for SDPL can be divided into: 
a)
Tear supplements: lubricants.
b)
Tear retention: tear punctum occlusion, contact lenses.
c)
Stimulation of secretion: secretagogues .
d)
Biological substitutes: autologous serum, salivary gland autotransplant.
e)
Anti-inflammatory drugs: cyclosporine, steroids, tetracyclines.
f)
Essential fatty acids
g)
Environmental strategies
Recommended practices in dry eye by the American Academy of Ophthalmology and the Delphi 
Panel of the International Task Force Force , ITF) on the treatment of dry eye, favored, in turn, by 
the DEWS, are based on the severity of the disease See Table 3. The recommendations may be 
modified by the ophthalmologist, based on clinical experience and the individual profile of his 
patient. [18] [25] [26] 

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Table 3Treatment recommendations for LPDS 
Level 1: 
Education and dietary and environmental modifications 
Elimination of systemic medications that alter UFL 
Lubricants 
Eyelid treatment 
Level 2: 
If level 1 treatments are insufficient, add: 
Anti-inflammatories 
Tetracyclines 
Tear plugs 
Secretagogues 
Level 3: 
If level 2 treatments are insufficient, add: 
Autologous serum 
Contact lenses 
Permanent occlusion of tear ducts 
Level 4: 
If level 3 treatments are insufficient, add: 
Systemic anti-inflammatories 
Surgery (tarsorrhaphy, transplantation: mucous membrane, salivary gland, 
amniotic membrane) 
Modified from the ITF [18] 
The primary goal of caring for patients with PLDS is to improve ocular comfort and quality of life, as 
well as to return the ocular surface and tear film to a state of homeostasis. Although symptoms are 
rarely eliminated, they can often be reduced, resulting in improved quality of life. [26] 
Ocular lubricants are the first line of treatment for PLDS and a constant at all treatment levels. They 
are characterized as hypotonic or isotonic solutions containing electrolytes, surfactants, and various 
types of viscosifying agents. The main variables in ocular lubricant formulations relate to the 
selection or concentration of electrolytes, osmolarity, the type of viscopolymer system, and the 
presence or absence of preservatives. [26] 
5.2 Background 
5.2.1 Sodium hyaluronate 
It is a biopolymer, a disaccharide of the GAG family, formed by the alternating sequence of N-acetyl-
D-glucosamine and glucuronate in linear chains. In physiological solvents, they form spirals; their
configuration is determined by their viscosity. It is a constituent of the extracellular matrix,
connective tissue, vitreous humor, umbilical cord, synovial fluid, skin, etc. It can be composed of
more than 10,000 disaccharide pairs. At concentrations above 0.1%, sodium hyaluronate forms a
network. The diffusion rate through the network is inversely related to the size of the polysaccharide
molecules, which are stable. Proteoglycans contribute to providing mechanical and elastic
properties. Numerous authors have reported that HS has a high water-retaining capacity; it has been
established that 1 g of HS can retain up to 6 L of water. [28]
Sodium hyaluronate is synthesized on the inner surface of the plasma membrane as a linear 
polymer, in contrast to other GAGs, which are synthesized by enzymes in the Golgi apparatus. The 

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enzymes responsible for the synthesis of sodium hyaluronate are hyaluronate and 
glucosyltransferases , which coordinately polymerize and translocate sodium hyaluronate outside 
the cell into the extracellular matrix. [29]  
5.2.1.1 Pharmacokinetics in the eyeball 
Route of administration: Ophthalmic. 
Release: immediate. 
Absorption: No absorption of HS through the cornea has been reported when applied to the ocular 
surface. Pharmacokinetic studies conducted in patients with dry eye showed that the HS solution 
reached its maximum concentration within 10 minutes and is widely distributed across the ocular 
surface. 
Metabolism: It is biotransformed by hyaluronidases. 
Elimination: It is eliminated from this compartment through the lacrimal sac and tear duct without 
intraocular absorption, in approximately 45 minutes.  [30]Based on the results of preclinical 
research in rabbits conducted by Laboratorios Sophia SA de CV, the ocular half-life correlates with 
the volume of the formula. 
5.3 Problem Statement 
There are few effective treatments for PLDS. Clinical development of new treatments is slow due to 
the multiple pathogenesis of PLDS and its variable semiotics. The different treatment phases have a 
common denominator: the use of ocular lubricants. 
Although there is a wide variety of topical lubricants, with different viscosifying agents, there is no 
evidence that one is better than another. 
Although ocular lubricants have not been shown to be sufficient to completely resolve the ocular 
surface alteration and inflammation seen in patients with PLDS, they have been shown to provide 
protection to the ocular surface and reduce symptoms and clinical findings. 
Sodium hyaluronate (SHN) is a biopolymer, glycosaminoglycan (GAG), a constituent of the 
extracellular matrix. It provides PRO-165 with viscoelastic and water-retaining properties, enabling 
it to function as an effective lubricant that protects the ocular surface and reconstructs the tear film. 
Formulating it as an ophthalmic gel can provide a longer dwell time, promoting prolonged 
lubrication. Currently, the range of lubricants in ophthalmic gels is not as extensive as that of 
solutions. Therefore, adding a new option to this group of pharmaceutical formulations will 
contribute to improved care for patients with PLDS. 
5.4 Justification 
Patients with LPDS, regardless of its etiology and severity, will need to use ocular lubricants to 
reduce symptoms and improve their quality of life. 
Ocular lubricants are the first-line treatment for ocular symptoms related to tear film dysfunction 
in self-reported healthy subjects, with a prevalence of 5% to 35% in those over 50 years of age. 
[32]If we add to this the number of patients who report occasional symptoms or symptoms that are
dependent on a work or occupational situation and who will use them intermittently throughout
their lives, the population spectrum that will have access to these medications is very broad. It is

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estimated that 50% of patients diagnosed with tear film dysfunction without concomitant diseases 
will use more than two types of ophthalmic solutions in 5 years of treatment. 
PRO-165 is an ophthalmic gel lubricant formulation for which a safety profile must be documented. 
5.5 Objectives and hypotheses 
5.5.1 General Objective 
To evaluate the safety and tolerability of the PRO-165 formulation on the ocular surface of 
ophthalmologically and clinically healthy subjects. 
5.5.2 Specific objectives 
−
To describe the safety of PRO-165 ophthalmic gel by presenting adverse events.
5.5.3 Secondary Objectives 
−
To describe the safety of PRO-165 ophthalmic gel through changes in intraocular pressure.
−
To describe the safety of PRO-165 ophthalmic gel through changes in visual ability.
−
To describe the safety of PRO-165 ophthalmic gel through changes in laboratory testing.
−
To describe the safety of PRO-165 ophthalmic gel when evaluating ocular surface stains
−
To describe the safety of PRO-165 ophthalmic gel through changes in tear break-up time.
−
To describe the safety of PRO-165 ophthalmic gel through changes in vital signs.
−
To describe the tolerability of PRO-165 ophthalmic gel by the presence of the symptoms:
burning, foreign body sensation, and itching.
5.5.4 Hypothesis 
H 0 PRO-165 ophthalmic gel presents a safety and tolerability profile similar to Artelac ® Nightime 
Gel in ophthalmologically and clinically healthy subjects 
H 1 PRO-165 ophthalmic gel presents a different safety and tolerability profile than Artelac ® 
Nightime Gel in ophthalmologically and clinically healthy subjects. 
5.6 Study design and plan 
Phase I, controlled, parallel-group, double-blind, randomized, exploratory clinical trial. 
5.6.1 Discussion of the study design 
The study design (clinical trial) is considered the highest standard of data quality when exploring the 
effect of an intervention. The drug development phase (Phase I) corresponds to the study objective, 
which is to evaluate safety and tolerability. Therefore, the intervention time is short and the 
required sample size is smaller than that of an efficacy clinical trial. The presence of parallel groups 
allows for comparisons between intervention groups on outcome variables. Blinding and 
randomization reduce biases that occur with other designs, e.g., selection bias, assessment bias, 
among others. 
The selection of Artelac ® Nightime Gel was based on the need to compare PRO-165 with a 
treatment with the same formulation and the same indication as PRO-165. Although they do not 
share the same active ingredients, this does not limit their comparability, as no pharmacological 
action is expected from either treatment. Since there is no ophthalmic gel with the same 
concentration of the active ingredient as PRO-165, and since comparison with placebo is not feasible 
due to technical difficulties, Artelac ® Nightime Gel is an option for conducting a comparative Phase 
I study. 

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6. Materials and methods. Participants, interventions, and variables
6.1 Study center 
This study will be conducted in properly equipped and registered ophthalmology offices. Depending 
on the sponsor's needs, these offices may be private or public, attached to a hospital or clinic, or 
independent. 
6.1.1 Organization of the center 
Each study center will have a principal investigator (PI). The PI is the ophthalmology specialist 
leading the clinical study. 
The PI is responsible for forming a multidisciplinary research team to execute the clinical study 
according to the protocol, under his or her scientific guidance. The PI is responsible for designing 
the organization of his or her center and selecting the personnel who will perform these functions. 
However, the minimum organization of the research team requested by the sponsor requires the 
following: a sub-investigator , study coordinator, and pharmacist. (See Figure 2Minimum 
organization of the center.) 
Any person designated by the PI as responsible for monitoring the study (coinvestigator, sub-
investigator, nurse, etc.) or for a specific role in the study (pharmacist, administrative assistant, 
study coordinator, etc. ) must be listed on the “Delegation of Responsibilities” form. 
Figure 2Minimum organization of the center 
The "Delegation of Responsibilities" and the "Center Organizational Chart" must be submitted to 
the sponsor before the start of the study and updated if the members or their responsibilities 
change. 
6.1.2 Documentation to be delivered to the sponsor 
The IP must submit to the sponsor, before the start of the study: 
- Updated curriculum vitae , in Spanish, dated and signed (maximum 10 pages), of the IP and the
staff that make up the center's organizational chart.
- Copy of academic certifications from the IP (degree and specialty diploma in ophthalmology;
federal professional licenses)
- A copy of academic certifications of the highest degree obtained by each member of your research
team, which support their ability to perform the delegated functions.
Principal 
Investigator
Subinvestigator
Pharmacist
Study 
Coordinator

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- Copy of the notice of operation or similar issued by the corresponding regulatory entity (when
applicable)
- A valid certificate of good clinical practice. If the issuing institution does not specify the validity
period in the certificate, the certificate issue date must not be more than one year old.
6.1.3 Closure of the center 
The closure of the center will be agreed upon in advance by the sponsor and the PI, once the last 
visit of the last enrolled subject has been completed. The closure process will be in accordance with 
the sponsor's internal operating procedures. 
It is the sponsor's prerogative to close a study center prematurely; they must inform the IP of the 
reasons for the closure. 
6.2 Eligibility criteria 
6.2.1 Inclusion criteria 
-
Signed informed consent.
-
Systemically and ophthalmologically healthy subjects evaluated during the medical history.
-
Age between 18 and 45 years.
-
Both sexes.
-
Blood tests [complete blood count ( CBC ), three-element blood chemistry (BC), and liver
function tests (LFTs)] within normal parameters specified by the reference laboratory with
a lower and upper margin of 10%.
-
Vital signs are within normal limits. (Resting vital signs: blood pressure ≤ 139/89 mmHg ,
heart rate 60-100 beats per minute, and respiratory rate 12-24 breaths per minute)
-
Visual capacity 20/30 or better, in both eyes.
-
Intraocular pressure ≥11 and ≤ 21 mmHg .
6.2.2 Exclusion criteria 
6.2.2.1 General criteria 
−
Subjects with a history of hypersensitivity to any of the components of the investigational
products.
−
Subjects who are users of topical ophthalmic medications of any pharmacological group.
−
Subjects who use medications by any other route of administration.
−
Pregnant or breastfeeding women.
−
Women with no history of bilateral tubal obstruction , oophorectomy or hysterectomy, who
do not ensure a hormonal contraceptive method or intrauterine device during the study
period.
−
Subjects with participation in clinical research studies 90 days prior to inclusion in this study.
−
Known diagnosis of liver disease
−
Inability to attend or respond to assessments conducted at each visit.
−
Positive smoking (specified as cigarette consumption regardless of quantity and frequency)
−
Positive alcoholism (specified as the consumption of alcoholic beverages, regardless of
quantity and frequency, during the study intervention period).
−
Contact lens wearers.
6.2.2.2 Medical and therapeutic criteria 
−
History of any chronic-degenerative disease.
−
Inflammatory or infectious disease, active at the time of entering the study.

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−
Unresolved injuries or trauma at the time of study entry.
6.2.3 Elimination criteria 
−
Withdrawal of the consent letter under information.
−
Presentation of a serious adverse event.
−
Non-tolerability or hypersensitivity to any of the compounds used during the tests
(fluorescein, lissamine green , tetracaine)
−
Non-tolerability or hypersensitivity to any of the investigational drugs.
−
Adherence < 50% determined by subject's diary.
6.2.4 Subject identification 
Patients in the study will be identified by a number and their initials. 
The initials of the subject of study will be obtained starting with the first letter of the name, followed 
by the first letter of the first surname and the first letter of the second surname, obtaining a 
maximum of three letters. In case the person has two names or a compound surname, the first letter 
will always be used. 
Example: 
1.
Arieh Daniel Mercado Carrizalez
a.
Initials: AMC
2.
Juan De la Torre O Rozco
a.
Initials: JDO
During the screening phase, participants will be assigned a consecutive three-digit number. Once 
the subject has been selected, they will be assigned a number that will identify them throughout 
the study. This code will consist of eight numbers in the following order, from left to right: 
•
three digits of the molecule under study according to the name given by the sponsor.
•
two digits corresponding to the research center number.
•
three digits of the consecutive number assigned to its inclusion in the research center.
Example: 
6.3 Intervention 
6.3.1 Treatments administered 
6.3.1.1 Treatment under study 
-
PRO-165
o
Active ingredients (lubricant): sodium hyaluronate 0.2%
o
Pharmaceutical form: Ophthalmic gel
o
Prepared by: Laboratorios Sophia , SA de CV
o
Dosage: One drop of gel, 4 times a day during the waking period, in the fornix of the
right eye.
165-01-001
Key to the 
molecule 
Center number 
Inclusion number 

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o
Formulation description: Clear gel, free of visible particles.
o
Packaging description: Sterile multi-dose tube, low-density polyethylene and
aluminum polylaminate with high-density polyethylene cap.
Table 4Qualitative -quantitative formulation of PRO -165 
Agent type 
Amount mg/ mL 
Function 
Sodium hyaluronate 
2.0 
Active ingredient 
Chondroitin sulfate 
Not shown 
Viscosant 
Polyoxylated Castor Oil 35 
Not shown 
Solubilizer 
Polyethylene glycol 8000 1 
Not shown 
Cosolvent 
Edetate disodium dihydrate 
Not shown 
Chelating agent 
Cetrimide 
Not shown 
Conservative 
Glycerin 
Not shown 
Osmoregulator 
Sodium hydroxide 
Not shown 
pH adjustment 
Homopolymer carbomer type B 2 
Not shown 
Gelling agent 
Polycarbophil 3 
Not shown 
Gelling agent 
Water 
for 
the 
preparation 
of 
injectables cbp 4 
Not shown 
Vehicle 
Qualitative and quantitative formulation of the investigational product PRO-165. The concentration of the active 
ingredient is shown, as well as the substances that act as additives. (1) Synonym of Carbowax ® (2) Synonym of 
Carbopol® 974P NF Polymer, USP (3) Synonym of Noveon ® AA-1 Polycarbofil , USP (4) as much as is sufficient for 
6.3.1.2 Reference treatment 
o
Artelac ® Nightime Gel
o
Active ingredients: Carbomer 0.2%
o
Pharmaceutical form: Ophthalmic gel
o
Prepared by: Dr. Gerhard Mann Chem Pharm. Fabrik GmbH Brunsbütteler Damm
165-173 D-13581, Berlin, Germany . Imported and marketed by: Bausch & Lomb
México, SA de CV, Av. Michoacán No. 20, Warehouse 10, Section F; Renovación
Neighborhood; Iztapalapa, Zip Code 09209; Mexico City, Mexico City.
o
Dosage : One drop of gel, 4 times a day during the waking period, in the fornix of
the right eye.
o
Solution description: Clear gel, free of visible particles.
o
Packaging description: Sterile multi-dose tube.
o
Characterization: The characterization, stability, and formulation of the comparator
will be supported by its packaging, lot number, and IPP, a copy of which will be kept
in the study's master folder.
6.3.2 Strategies to improve adherence and procedure to monitor adherence 
Adherence to the intervention is essential to achieve the objectives of clinical research. Adherence 
is defined as: "the extent to which people's behavior (including medication intake) corresponds to 

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the instructions of the health service provider."  [33]The safety profile of a product may be under- 
or overvalued due to poor adherence. 
The strategies to be carried out to improve adherence are: 
1.
Direct questioning by the IP regarding the application of the intervention.
2.
At the IP's discretion, reminder messages or calls may be sent.
3.
Delivery of a printed schedule specifying the date of the visit and its activities
4.
Subject's diary.
6.3.2.1 Procedure for monitoring adherence 
For more than four decades, numerous studies have been conducted on the appropriate way to 
measure and quantify medication adherence, but none have reached a consensus that could serve 
as the gold standard, whether in cross-sectional or longitudinal studies. [34] [35] [36] [37] [38] [39] 
[40] [41]
There are different procedures for measuring adherence to pharmacological interventions. The 
most common procedure involves self-reports , which include patient interviews, questionnaires, 
and self-monitoring diaries. Their strengths are speed, flexibility, low cost, and ease of 
implementation; they have a high degree of specificity for non-adherence, but their sensitivity and 
reliability for adherence are low. [41] [42] 
Biochemical measurement of the drug, or its metabolite, is one of the methods that best confirms 
drug use. However, in addition to being costly and impractical, it is of little use in ophthalmic 
applications, as peripheral concentrations may be undetectable; and samples from other tissues 
require more invasive methods that would be inadvisable. [41] 
Medication counting is another way to measure adherence. Classically referred to as "pill counting," 
in ophthalmology it is translated as the weight of the bottle. This is a simple, inexpensive, and 
noninvasive method. The main disadvantages of this method are: 1. It cannot confirm medication 
application (it could have been intentionally dropped or instilled outside the eye), and 2. It depends 
on the subject bringing the medication back. [41] [42] 
A multi-method approach to adherence measurement is recommended. Because there is no ideal 
adherence measure, it is appropriate to use more than one method when aiming to achieve results 
that resemble reality. Selecting two or more methods allows for balancing their strengths and 
weaknesses, thus more accurately capturing adherence levels. [40] 
Adherence assessment will be facilitated by the subject's diary and will be performed as follows: 
𝐴𝑑= (𝐴𝑟)100/𝐴𝑖 
Ad = Adhesion 
A r = Registered applications 
A i = Applications indicated for the intervention 
Final adherence will be determined by the average adherence from each visit. Overall adherence 
(all subjects) will be determined by the average of each subject's final adherence. 
Adherence to the procedure, taking into account weight, will be calculated as follows: the weight of 
the empty tube, the weight of the drop, the weight of the tube with its contents, the total amount 
of gel to be applied during the entire procedure, and the total weight of the gel applied. The 
following simplified formula will be used: 

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𝐴𝑑= (𝑃𝑖−𝑃𝑓)100
𝑃𝑇
Where: 
Ad = adhesion 
𝑃𝑖= weight of the tube delivered to the subject at the start 
𝑃𝑓= weight of the tube returned by the subject 
𝑃𝑇 = weight of the dosage indicated for the intervention 
𝑃𝑇= (𝑃𝑔)𝐺 
Where: 
𝑃𝑔= weight of a drop of the intervention, determined by the research and development department 
G = number of applications indicated for the intervention 
It will not be considered for the calculation of adhesion if the tube does not maintain its physical 
integrity. 
There is no standardized parameter to define adequate adherence; it must be defined and outlined 
by the objectives of the particular research. [41] 
Calculating adhesion by weight is not chosen as the ideal way to monitor adhesion, due to the 
difficulty in standardizing the amount of product per application, due to the characteristics of the 
formulation (gel). 
6.3.3 Concomitant treatments and interventions permitted and prohibited during the study 
The use of concomitant medications by any route of administration will not be permitted during the 
intervention period, except for those specified for the study procedures. The objective of this 
restriction is to avoid drug interactions that could alter the results of the evaluated variables. 
6.3.4 Treatment management 
The interventions will be provided by Laboratorios Sophia , SA de CV, for the research center. They 
will be labeled, reconciled, and weighed beforehand. Treatment management will be the 
responsibility of the researcher or a designated member of their team. 
6.3.4.1 Delivery and receipt 
Delivery will be made in sealed cardboard boxes by courier or directly by sponsor staff to the 
research center's address, according to the study plan. 
Reception will be handled exclusively by the research center team, including the researcher. They 
must verify the condition of the primary packaging (the box). If it shows alterations or defects in its 
integrity that, in their opinion, could have damaged the contents, they must report this to the 
sponsor. If the package shows no significant defects, they will open it. 
Inside, you must locate the receipt acknowledgment document and the temperature and humidity 
data logger . You must verify that the recorded temperature and humidity comply with the 
specifications for transport and storage (see section 6.3.4.2 Storage). You will verify the content 
(interventions) with what is reported in the document. If the document corresponds to the content, 
you will sign the receipt and send it to the sponsor. If not, you will notify the sponsor. 

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At the study center, staff assigned by the PI will administer the appropriate treatment to admitted 
subjects, sufficient for the study period. This treatment will be administered at the baseline visit. 
The center must record the medication administered. 
6.3.4.2 Storage 
The medication must be stored in a secure area with restricted access. 
Storage temperature should be at room temperature, no more than 30º Celsius. 
The research center is required to record the temperature and humidity recorded in the data logger 
, using the format designated by the sponsor . This record must include the current temperature and 
humidity, as well as the minimum and maximum values for each. This must be done at least once a 
day on weekdays. 
These data will be compared by the clinical monitor according to the record in the data logger . 
6.3.4.3 Return 
Research subjects will return their medications to the staff designated by the PI at the center during 
the final visit. The return will be made by the research center upon the sponsor's instructions. Prior 
to return, the research center must conduct a count of the assigned medication and the remaining 
medication to create an inventory that will be used to complete the final medication return form. 
6.4 Outcome variables 
6.4.1.1 Primary outcome variables 
−
Security
o
Presence of adverse events.
−
Tolerability
o
Eye comfort index
6.4.1.2 Secondary outcome variables 
−
Tear film break-up time
−
Vital signs: HR, RR, SBP.
−
Posterior segment
−
Quality questionnaire
−
Intraocular pressure.
−
Visual capacity.
−
Laboratory tests: BHc , QS and PFH.
−
Ocular surface stains.
6.4.3 Methods and scales to be used for measuring the variables 
Variable 
Unit 
Symbol 
Guy 
Measurement 
method 
Normal value 
Age 
Years 
-- 
Continued 
Calculation from the 
date of birth 
NA 
Gender 
Female / Male 
F / M 
Nominal 
Direct questioning 
NA 
Adverse events 
Number of cases 
n 
Discreet 
Counting 
NA 
Intraocular 
pressure 
Millimeters of 
mercury 
mmHg 
Continued 
Goldman applanation 
tonometry 
11 - 21 

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Variable 
Unit 
Symbol 
Guy 
Measurement 
method 
Normal value 
Visual capacity 
Fraction 
Snellen 
Nominal 
Primer 
20/20 
Tear break-up time 
Seconds 
s 
Continued 
Direct count 
> 10
Eye comfort index 
Points 
-- 
Discreet 
Questionnaire 
NA 
Adverse events 
Present / Absent 
-- 
Nominal 
Comprehensive 
assessment 
Absent 
Vital signs 
Heart rate 
Beats per minute 
bpm 
Discreet 
Auscultation 
60 – 100 
Respiratory rate 
Breaths per 
minute 
rpm 
Discreet 
Auscultation 
12 – 24 
Systemic blood 
pressure 
Millimeters of 
mercury 
mmHg 
Continued 
Non-invasive 
auscultatory 
measurement 
< 120 / 80 
Anterior segment 
Ocular surface 
stains 
Degrees 
-- 
Discreet 
Direct observation 
with fluorescein and 
lissamine green 
staining 
Oxford Scale 
Ophthalmological signs and symptoms 
Blood count 1 
Erythrocytes 
M/ uL 
Continued 
Hemoglobin 
Grams per 
deciliter 
g/ dL 
Continued 
Hematocrit 
Percentage 
% 
Continued 
VGM 
Femtoliters 
fL 
Continued 
HCM 
picograms 
pg 
Continued 
CMHbG 
Grams per 
deciliter 
g/ dL 
Continued 
Leukocytes 
Thousands per 
liter units 
Thousand/ 
uL 
Continued 
Platelets 
Thousands per 
liter units 
Thousand/ 
uL 
Continued 
Myelocytes 
Percentage 
% 
Discreet 
Metamyelocytes 
Percentage 
% 
Discreet 
Bands 
Percentage 
% 
Discreet 
Segmented 
Percentage 
% 
Discreet 
Lymphocytes 
Percentage 
% 
Discreet 

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Variable 
Unit 
Symbol 
Guy 
Measurement 
method 
Normal value 
Monocytes 
Percentage 
% 
Discreet 
Eosinophils 
Percentage 
% 
Discreet 
Basophils 
Percentage 
% 
Discreet 
Blastos 
Percentage 
% 
Discreet 
Blood chemistry 1 
Glucose 
Milligrams per 
deciliter 
mg/ dL 
Continued 
Urea 
Milligrams per 
deciliter 
mg/ dL 
Continued 
Creatinine 
Milligrams per 
deciliter 
mg/ dL 
Continued 
Liver function tests 1 
Alanine transferase 
Units per liter 
U/L 
Continued 
Aspartate 
transferase 
Units per liter 
U/L 
Continued 
Total bilirubin 
Milligrams per 
deciliter 
mg/ dL 
Continued 
Direct bilirubin 
Milligrams per 
deciliter 
mg/ dL 
Continued 
Indirect bilirubin 
Milligrams per 
deciliter 
mg/ dL 
Continued 
1 The measurement method and normal values will be designated by the clinical analysis laboratory designated by the sponsor. 
Table 5Scales to be used 
The methods and scales that will be used to measure the variables are described below, which are 
in strict alphabetical order: 
6.4.3.1 Visual capacity 
Visual acuity (VA) is a test of visual function. Spatial visual acuity is the ability to distinguish separate 
elements of an object and identify them as a whole. It is quantified as the minimum angle of 
separation (located at the nodal point of the eye) between two objects that allows them to be 
perceived as separate objects. 
Snellen notation is described as the distance at which the test is performed divided by the distance 
at which the letter is vertically equivalent to 5 minutes of arc. Thus, at 6 meters, a letter 6/6 (20/20) 
is equivalent to 5 minutes of arc, a letter 6/12 (20/40) is equivalent to 10 minutes, and a letter 6/60 
(20/200) is equivalent to 50 minutes. The Snellen fraction can also be expressed as a decimal (i.e., 
20/20 = 1 and 20/40 = 0.5). [43]  
VA will be assessed at baseline, without refractive correction, using the Snellen chart. This chart will 
be placed in a location with adequate natural or artificial lighting and at a distance of 3 m from the 
subject being assessed. Visual acuity will be measured in each eye, starting with the right eye (RE), 

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asking the subject to keep both eyes open and using an occluder to cover the left eye (LE); the 
subject will read aloud the lines indicated by the evaluator. The evaluator will record the smallest 
line of letters visible as the RE VA in the clinical record. The LE is then assessed using the same 
method. 
The subject's best refractive correction will then be performed, and the examination will be 
repeated using the obtained refraction. This result will be reported as CV, entered as a fraction in 
the clinical record and on the Case Report Form (CRF), and will also be entered as a decimal on the 
CRF. By definition, the CV cannot be less than the VA.  
6.4.3.2 Eye comfort index 
This questionnaire is designed to measure ocular surface irritation using Rasch analysis to produce 
estimates on a linear interval scale (scores: 0–100). Similar to the index for ocular surface diseases, 
the Ocular Comfort Index (OCI) assesses symptoms. The OCI contains six items that focus on 
discomfort associated with the ocular surface. Each of these questions has two parts, which 
separately inquire about the frequency and severity of symptoms.  [44]See Appendix 14.1 Eye 
comfort index 
The evaluator will give the questionnaire to the subject and allow them to answer it calmly without 
any pressure or coercion. They will only assist them if they have difficulty understanding any of the 
questions. 
Ocular surface stains 
•
Lissamine green staining .
A drop of topical anesthetic will be instilled into the conjunctival fornix. A second drop will
then be applied to the tip of the lissamine green strip and allowed to run into the fornix. It is
essential to rapidly assess the staining, sequentially, first in the OD and then the OS, so that
the observed patterns are equally bright. [19]See Appendix 14.2 Oxford Scale
•
Fluorescein staining.
A drop of topical anesthetic will be instilled in the conjunctival fornix. A second drop will then
be applied to the tip of the fluorescein strip and allowed to run into the fornix. It is essential
to rapidly assess the staining, sequentially, first in the OD and then the OS, so that the
observed patterns are equally bright. This assessment will be performed using a cobalt blue
filter. [19]See Appendix 14.2 Oxford Scale
For both stains, the value obtained according to the Oxford scale will be recorded in the CRF. 
6.4.3.4 Presence of adverse events  
The management of AEs will be carried out according to what is described in section 9.3 Adverse 
events 
The IP will record any AEs presented by the study subjects in the corresponding section of the CRF, 
in addition to mentioning them in their essential document. 
The IP must perform a complete ophthalmologic examination of the ocular surface, anterior 
segment, and posterior segment. Any pathological changes found must be reported in accordance 
with the AD management guidelines. 
6.4.3.5 Intraocular pressure 
Tonometry is the objective measurement of IOP, based primarily on the force required to flatten 
the cornea or the degree of corneal indentation produced by a fixed force. Goldman tonometry, 
based on the Imbert-Fick principle, is considered the gold standard for IOP measurement. 

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[43]Tonometry is performed after instillation of a drop of topical anesthetic (tetracaine 0.5%),
fluorescein, and the use of a cobalt blue filter (after evaluating corneal surface staining). These
measurements are recorded in the clinical record and on the CRF.
 6.4.3.6 Vital signs 
The vital signs to be assessed (HR, RR and SBP) may be measured by an assistant duly designated in 
the center's organization and the delegation of responsibilities. The technique to be used for HR and 
RR will be counting repetitions in one minute by direct auscultation with a stethoscope. 
SBP should be measured after 5 minutes of rest on the left arm. The instrument may be manual or 
automatic, as the PI deems appropriate. All measurements must be performed under equal 
conditions. Three measurements will be taken, with a minimum interval of 5 minutes between 
measurements, and recorded in the patient record. The average will also be recorded on the grade 
and the CRF. 
6.4.3.7 Tear film break-up time 
One of the first aspects of the tear film to change when there is a change in the ocular surface is its 
stability. In general, if the corneal or conjunctival surface is damaged, it is unlikely that a stable tear 
film can be maintained. 
The most common method for assessing tear film stability is fluorescein-based TRL. Once fluorescein 
is instilled, the patient is asked not to blink using the cobalt blue filter. The fluorescein-stained 
precorneal layer will shift to less fluorescent or non-fluorescent regions. The time elapsed from the 
last blink until these regions appear is the TRL. It is reported in seconds in the clinical record and on 
the CRF. 
6.4.3.8 Pregnancy test 
This refers to the performance of a rapid pregnancy test in all women of childbearing age who wish 
to enter the study. By childbearing age, we mean women who have not experienced menopause. 
For the purposes of this study, menopause is defined as 12 months from the last menstrual period 
in women over 40 years of age or who have undergone a hysterectomy or bilateral oophorectomy. 
Women of childbearing age using contraceptive methods, including bilateral tubal obstruction , 
must undergo a pregnancy test. This test will be performed by the PI or a designated team member 
according to the instructions for the device provided by the sponsor. When applicable, the 
performance, result, and date must be recorded on the CRF. If not applicable, the reason must be 
noted. 
6.4.3.9 Laboratory tests 
The PI will generate the order for the BH, QS, and LFT studies, to be performed by the clinical 
laboratory designated by the sponsor. The clinical laboratory will provide the PI with the results for 
evaluation and recording. The normal parameters to be considered will be the ranges established 
by the laboratory; however , the PI's clinical judgment will prevail in determining whether the results 
are normal or abnormal. 
6.4.4 Time of measurements 
Measurements of the primary and secondary outcome variables will be performed and evaluated 
for each visit, according to the following: 
Baseline Visit / Day 0. 

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Some of these measurements will be performed at the screening visit to complete the eligibility 
criteria (see Study schedule and diagram), at the discretion of the PI, and if no more than 10 days 
have passed, they may be taken to complete the baseline visit data. 
1.
Visual capacity.
2.
Intraocular pressure.
3.
Eye comfort index
4.
Ocular surface evaluation
a.
Includes stains
b.
TRL
5.
Adverse event evaluation.
6.
Vital signs.
7.
Evaluation of laboratory test results
Visit 1 / Day 5.  
It can be done in a period of ± 2 days in relation to day 5 of application. 
1.
Visual capacity.
2.
Intraocular pressure.
3.
Ocular surface evaluation
a.
Includes stains
b.
TRL
4.
Vital signs.
5.
Adverse event evaluation.
Final Visit / Day 11.  
It can be done in a period + 1 day in relation to the 11th day of the start of application, not before 
the 11th day since the 10 days of application would not be met. 
1.
Visual capacity.
2.
Intraocular pressure.
3.
Eye comfort index
4.
Ocular surface evaluation
a.
Includes stains
b.
TRL
5.
Vital signs.
6.
Evaluation of adverse events.
Safety Call / Day 13.  
It can be carried out within a period of ± 1 day in relation to the 13th day from the start of 
application. 
1.
Ask about the presence of any adverse events.
2.
Evaluation of laboratory test results

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6.5 Study schedule and diagram 
Procedures 
Scrutiny 
Baseline 
Visit 
Visit 1 
Final Visit 
Security Call 
Day 0 - X 
to
Day 0 
Day 5 ± 2 
Day 11 at + 
1 
Day 13 ± 1 
CI Signature 
X 
Medical record 
X 
Ophthalmological clinical history 
X 
Laboratory sample collection 
X 
X 
Laboratory Test Review 
X 
X 
Pregnancy test 
X 
X 
Eligibility criteria 
X 
X b 
Assignment 
X 
Delivery of intervention 
X c 
Return of intervention 
X 
Adherence assessment 
X 
X 
Adverse events 
X 
X 
X 
Intraocular pressure 
X 
X 1 
X 
X 
Visual capacity 
X 
X 1 
X 
X 
TRL 
X 
X 1 
X 
X 
Ocular surface stains 
X 
X 1 
X 
X 
Vital signs 
X 
X 1 
X 
X 
Eye Comfort Index 
X 
X 
Submission of the subject's diary 
X 
X 
Return/Evaluation of the Subject's 
Diary 
X 
X 
Return and Evaluation of the 
quality questionnaire 
X 
Subject continuity assessment 
X 
The screening visit may be up to 10 days prior to the baseline visit; if this is exceeded, the subject will not be 
allowed to enter. 
b These criteria will be completed with the results of the laboratory tests and those collected during the 
scrutiny visit. 
c The instruction will be given to start the application the following day. 
1 They can be taken from the screening visit, as long as no more than 10 days have passed; it is the IP's 
prerogative to measure them again at the baseline visit. 

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6.5.1 Procedures to be performed per visit 
6.5.1.1 Scrutiny visit 
▪
Signature of informed consent: refers to the signing of the written informed consent
document. See 10.3 Consent 
▪
General and ophthalmological medical history: refers to the technical, clinical, and legal
document that chronologically records the patient's health conditions, medical procedures,
and other procedures performed on the patient. It includes a comprehensive
ophthalmological history and examination to determine the patient's eligibility, i.e.,
evaluation of both eyes and ocular adnexa, slit-lamp examination of the ocular surface and
anterior segment, and fundoscopy . If the patient is recruited from the study center's
established office, the existing medical history may be used; only one update is required.
▪
Laboratory sampling: see 6.4.3.9 Laboratory tests.
▪
Pregnancy test: see 6.4.3.8 Pregnancy test.
▪
Eligibility criteria: Refers to the PI's review, which verifies that the subject can be included
in the study if they meet the inclusion criteria and do not meet the exclusion criteria. See
6.2 Eligibility criteria
▪
Intraocular pressure: see 6.4.3.5 Intraocular pressure
▪
Visual capacity: see 6.4.3.1 Visual capacity
▪
TRL: see 6.4.3.7 Tear film break-up time
▪
Ocular surface stains: see Ocular surface stains
▪
Vital signs: see 6.4.3.6 Vital signs
6.5.1.2 Baseline visit 
▪
Laboratory Test Review: Refers to the PI's review and analysis of the BHc , QS, and PFH
results. See 6.4.3.9 Laboratory tests.
▪
Eligibility criteria: The laboratory results will determine the subject's profile for inclusion or
exclusion. 
▪
Assignment: This refers to determining the intervention the patient will follow during the
study. This will be done according to section 7. Methods. Intervention allocation . This
assignment will be done at the baseline visit (day 0) and will be accompanied by the
indication to begin the treatment period the following day (day 1).
▪
Delivery of intervention: Refers to the delivery of the investigational product to the study
patient by the research center. This will be carried out in accordance with sections 6.3.1
Treatments administeredand 6.3.4.1 Delivery and receipt.
▪
Variable Assessment: Data from the assessment of the variables listed below may be taken
from the scrutiny visit, as long as it is not taken more than 7 days prior to this visit. It is the
IP's prerogative to decide whether to use the information from the scrutiny visit or repeat
the assessments during this visit.
o
Intraocular pressure
o
Visual capacity
o
TRL
o
Ocular surface stains
o
Vital signs
▪
Eye comfort index: see 6.4.3.2 Eye comfort index
▪
Delivery of the subject's diary: Refers to the delivery by the IP to the subject of the subject's
diary instrument. 

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6.5.1.3 Visit 1 
▪
Adherence assessment: refers to the assessment carried out by the IP in accordance with
section 6.3.2.1 Procedure for monitoring adherence
▪
Adverse events: see 6.4.3.4 Presence of adverse events
▪
Intraocular pressure: see 6.4.3.5 Intraocular pressure
▪
Visual capacity: see 6.4.3.1 Visual capacity
▪
TRL: see 6.4.3.7 Tear film break-up time
▪
Ocular surface stains: see Ocular surface stains
▪
Vital signs: see 6.4.3.6 Vital signs
▪
Submission of the subject's diary: see 6.5.1.2 Baseline visit
▪
Return/Review of Subject Diary: Refers to the subject handing over the subject diary to the
PI. The PI will review the diary to ensure it is complete correctly, assess post-instillation
symptoms , and record the applications.
▪
Subject Continuance Assessment: Refers to the PI's determination of the subject's desire to
continue participating in the study.
6.5.1.4 Final Visit 
▪
Laboratory sampling: see 6.4.3.9 Laboratory tests
▪
Pregnancy test: see 6.4.3.8 Pregnancy test
▪
Return of intervention: see 6.5.1.3 Visit 1.
▪
Adherence assessment: refers to the assessment carried out by the IP in accordance with
section 
▪
Adverse events: see 6.4.3.4 Presence of adverse events
▪
Intraocular pressure: see 6.4.3.5 Intraocular pressure
▪
Visual capacity: see 6.4.3.1 Visual capacity
▪
TRL: see 6.4.3.7 Tear film break-up time
▪
Ocular surface stains: see Ocular surface stains
▪
Vital signs: see 6.4.3.6 Vital signs
▪
Eye comfort index: see 6.4.3.2 Eye comfort index
▪
Subject diary return/evaluation: see 6.5.1.3 Visit 1.
▪
Return/evaluation of the quality questionnaire: refers to the submission of the quality
questionnaire to the IP by the subject. 
6.5.1.5 Safety call 
▪
Adverse events: see 6.4.3.4 Presence of adverse events
▪
Laboratory test review: see 6.5.1.2 Baseline visit
6.5.2 Study diagram 
An enrollment time of 30 days is estimated for the entire sample. 

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Figure 3Study diagram 
6.6 Sample size 
A total size of 32 subjects is estimated, distributed in 2 intervention groups. [16 subjects (16 eyes) 
per group] 
6.6.1 Sample size calculation 
There are no references on the calculation of the sample size in phase I studies, and the formulation 
of Humylub Ofteno® has not reported any adverse events in its periodic safety reports. Therefore, 
it was considered appropriate to base the calculations on previous phase I studies conducted by 
Laboratories . Sophia , SA de CV [45, 46, 47, 48]. 
The calculation was based on the adverse event presentation reported by Christ T., in a randomized, 
single-blind, parallel-group controlled clinical trial evaluating the efficacy and tolerability of a 5% 
dexpanthenol ophthalmic gel versus a 5% panthenol ointment in 48 subjects with corneal erosion, 
UV-induced keratoconjunctivitis, or similar conditions. The intervention consisted of applying 1 cm 
of the gel and ointment for 4 and 3 days, respectively.[49] 
The percentage of good tolerance reported with the gel was 25%, so it is expected that no more 
than 10% of subjects will report poor tolerance with the formulation proposed in this protocol. 
The sample size was calculated using the formula for proportions 
𝑛= 𝑝 (1 −𝑝) (
𝑍1−𝛼+ 𝑍1−𝛽
𝑝−𝑝0 − 𝛿)
2
With a statistical confidence of 95% corresponding to type I error, equal to 1.96, with a power of 
90%, corresponding to type II error, equal to 0.84. 
According to the previous calculation, the result is 26 subjects, which was increased by 20% to 
account for probable losses. The total required sample size is 32 subjects . Therefore, each group 
will consist of 16 subjects, each of whom will contribute an eye to the analysis. 
10 días 
Waiting for 
laboratory 
results 
Artelac® Nightime Gel 
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Day 0 
Baseline 
visit 
Day 5 
Visit 1 
Day 11 
Final 
Visit 
Day 13 
Security 
call 
-1 to -10
days
Scrutiny
Day 1 
Start 
appliction 
Day 10 
End 
appliction.

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6.7 Recruitment 
It is recommended that during the development of this research protocol, the principal investigator 
request approval from the Research Ethics Committee and the Research Committee, as well as 
authorization from the relevant regulatory body, to publish or disseminate in mass media the 
invitation to participate in the study to those individuals who meet the eligibility criteria. 
It is possible to discuss with other health professionals the opportunity for healthy subjects to be 
evaluated by an ophthalmologist at no cost, as well as undergo office examinations that will allow 
for a more precise determination of their clinical ocular status by participating in a clinical research 
protocol sponsored by Laboratorios Sophia SA de CV. 
7. Methods. Intervention allocation
7.1 Generating the assignment sequence 
Two strata will be used for the intervention groups, which will be balanced for each research center. 
The allocation will be 1:1. Data will be generated through a validated electronic system from an 
external provider, previously evaluated and authorized by Laboratorios Sophia SA de CV. 
Information regarding this provider will be found in the study's master folder. 
7.2 Blinding mechanism 
Blinding will be performed by personnel assigned by the Clinical Operations Management of 
Laboratorios Sophia SA de CV. This will consist of identical labeling for both interventions. This will 
prevent the PI, the study subject, and all unauthorized individuals from identifying which 
intervention each container belongs to. 
7.3 Implementation 
The sequence will be generated using an electronic randomization system. This system will be 
contracted by Laboratorios Sophia , SA de CV to a third party. Information about this third party will 
be found in the study's master folder. 
7.4 Blinding (Masking) 
Blinding will be performed on the subject and principal investigator. Furthermore, the statistical 
analysis will be performed blindly for the partial and final analyses. 
Blinding will be carried out using identical labels. These, in compliance with current and applicable 
regulations, must contain at least: 
-
Name, address and telephone number of the sponsor
-
Pharmaceutical form and route of administration
-
Batch number
-
Legend “Exclusively for clinical studies”
-
Expiration date
7.4.1 Opening the blind 
Blinding may be opened in the following cases: 
1.
Presence of a serious adverse event.
2.
Safety alert for the use of the drugs under study.

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3.
In the event that the sponsor determines it for any security reason or other reason that it
deems appropriate.
8. Methods. Data collection, management, and analysis
8.1 Data collection methods 
The sponsor will assign a clinical monitor to the research site, who will be authorized to monitor, 
review, procure, and ensure that the quality of the information obtained from participants is reliable 
and trustworthy. The monitor will schedule periodic visits to the research sites to review source 
documents and corroborate the information captured in the case report form (CRF). The monitor 
will be trained in the study protocol information (objective, visits, procedures, accepted range of 
values, etc.). If the data are not identical between the two records, the clinical monitor will generate 
a discrepancy, which must be resolved by the research site within the timeframe the sponsor deems 
reasonable to meet the objectives of the clinical study. Discrepancies will be corrected in accordance 
with Good Documentation Practices. 
The data recorded in the CRF will be reviewed by Laboratorios Sophia , SA de CV personnel trained 
in ophthalmology, clinical, and pharmacology, who will have the authority to generate discrepancies 
in the event that the data do not adhere to the provisions of the research protocol or put 
participants at risk. 
Once all discrepancies generated by the clinical monitoring team and clinical staff have been 
resolved , the data will be downloaded into an electronic database (Excel spreadsheet) by personnel 
designated by the sponsor. A new review of the data will be conducted to verify its accuracy, and 
new discrepancies may be generated if deemed necessary. 
The generated database will be safeguarded by the sponsor and will only be accessible to designated 
personnel. 
8.1.1 Strategies for completing the follow-up 
•
You will be clearly informed of the importance of the study and the benefits the population
will gain from its results.
•
Transportation assistance will be provided to enable participants to attend their visits.
•
A printed calendar will be provided to remind participants of their appointments and
upcoming activities, as well as their estimated duration.
•
If the participating subject does not attend their appointment, the research site will call to
determine the reason and will attempt to schedule a new appointment within the
established window or an unscheduled appointment. (If an appointment cannot be
scheduled, the presence of adverse events and the reason for discontinuing the study will
be asked as minimum information.)
8.2 Data Management 
The subject's medical record (including clinical notes, examination results, etc. ), as well as the 
subject's diary, and the ICO questionnaire are considered source data. 
The PI or their designated team member will complete the Case Report Form (CRF) as well as all 
other documents provided by the sponsor (e.g., treatment management documents). 

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A CRF was designed to record the data required by the protocol and collected by the researcher at 
each visit. 
In the case of self-assessment questionnaires, the principal investigator or the person responsible 
for completing them is not permitted to modify what was written by the study subject. 
Data entry at the center will be performed by the researcher, or a designated person from their 
team, after completing the Medical Record. The researcher or a designated person from their team 
will be trained in completing the CRF. 
All corrections to the CRF data must be made by the researcher or a designated person on his or her 
team according to the instructions provided. 
To ensure data confidentiality and security, usernames and passwords will be used to restrict system 
access to authorized personnel only. 
The monitor must ensure that all information on the CRF has been completed. After comparing the 
data with the source documents, the monitor will ask the investigator to make any necessary 
corrections or clarifications so that the responses and closure can be completed as quickly as 
possible. 
The Scientific Committee of Laboratorios Sophia , SA de CV will conduct the final medical-scientific 
review and issue guidelines for freezing the database. 
8.3 Statistical methodology 
8.3.1 Analysis of primary and secondary outcome variables 
Statistical analysis will be performed by Sophia Laboratories staff . SPSS version 19 (IBM Corporation 
, Armonk , NY, USA) will be used. 
The designated personnel will be blinded to the intervention groups. Coding will be performed using 
consecutive numbers for each intervention group. 
The data will be collected and organized in an Excel spreadsheet. They will then be exported to the 
SPSS software platform. The variables will be categorized according to their nature. 
The results of continuous quantitative variables will be expressed and presented using measures of 
central tendency and dispersion (mean, standard deviation, and ranges , as appropriate). Nominal 
and ordinal qualitative variables will be presented using frequencies, proportions, and/or 
percentages. See Table 5Scales to be  
Kolmogorov-Smirnov test will be performed to determine whether the distribution is normal in the 
results obtained in each study group [50].  
The statistical analysis of continuous quantitative variables to find significant differences ( p ) will 
be as follows: 
•
Intra-group analysis : will be determined by the Wilcoxon rank test, for quantitative
variables [51]
•
Between-group analysis : Kruskal-Wallis test  [52]. This nonparametric test is used to
determine whether a group of data comes from the same population. Intuitively, it is
identical to ANOVA with the data replaced by categories. For quantitative variables, the
Student t statistic is used .
The level of difference to consider significance will be an alpha of 0.05 or less. 

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The results of the nominal and ordinal qualitative variables will be presented as frequencies, 
proportions, and percentages. See Table 1 (section 6.4.3). 
Statistical analysis to identify significant differences in qualitative variables will be performed by 
creating 2x2 contingency tables and will be carried out as follows: 
•
Intra-group difference : McNemar  [53]'s test . This test is applied to 2x2 contingency tables
with a dichotomous trait, with matched subject pairs, to determine whether the row and
column marginal frequencies are equal (marginal homogeneity).
•
Difference between groups : Pearson's χ 2 test (or Fisher's exact test).
The level of difference to consider significance will be an alpha of 0.05 or less. 
For adverse event reporting, all eyes of participants randomized to an intervention group after the 
baseline visit will be considered. Results will be expressed as the number of cases (eyes). 
The final results report will be displayed in tables or graphs, as appropriate. 
The investigational drug will be considered safe and tolerable when there are no clinical or statistical 
differences in all primary outcome variables compared to its comparators. 
Subjects with an adherence rate greater than 60% will be included in the statistical analysis to meet 
the study objective, based on the subject's diary. However, even if the subject's diary indicates 
adherence greater than 60%, if the adherence calculated by weight is less than 30%, the subject will 
not be included. The minimum dose necessary to obtain a pharmacological effect (lubricant/1 gel 
application per day) and the presence of adverse events (exposure) were considered sufficient to 
meet the overall design objective, in accordance with the pharmacological characteristics of the 
investigational product. 
8.3.2 Additional analyses 
No additional analyses beyond those previously described are planned. However, these may be 
performed if specific safety aspects of an intervention need to be analyzed during the study, 
maintaining blinding until the study's completion. 
8.3.3 Population analysis and missing data handling 
An intention-to-treat analysis will be performed, including data from participants who completed at 
least visit 1. 
9. Methods. Monitoring
9.1 Data Monitoring 
The purpose of monitoring visits is to confirm that studies sponsored by Laboratorios Sophia , SA de 
CV are conducted in accordance with the ethical principles established in the Declaration of Helsinki, 
with Good Clinical Practices, and with applicable regulatory requirements. The site monitor must 
verify compliance with the protocol, amendment(s), review accounting records for the 
investigational product, and verify that the site personnel and facilities are adequate for conducting 
the study. 
The researcher must ensure that sufficient time, space, and qualified personnel are available for 
monitoring visits. 

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In order to conduct the monitoring review, it is mandatory to provide direct access to all source data 
and data related to the study site. The monitor will conduct a review of the CRF and a Source 
Document Verification (SDV). SDV refers to the verification of records in the CRF by comparing them 
with the source data that the researcher will make available for this purpose. 
Regarding the CRF, the monitor will mark the completed and approved screens on each visit if the 
electronic platform is used. 
In accordance with applicable regulations, Good Clinical Practices, and the procedures of 
Laboratorios Sophia , SA de CV, Laboratorios Sophia , SA de CV monitors will contact the site prior 
to the start of the study to review the protocol, regulatory, ethical, and Laboratorios Sophia , SA de 
CV requirements with site personnel. When reviewing procedures for data collection, the discussion 
will also include the identification, agreement, and documentation of individual data for which the 
records in the CRF will serve as source documents. 
Laboratorios Sophia , SA de CV will monitor the study to verify, among other things, that: 
•
The data is authentic, correct and complete.
•
The safety and rights of the subjects are being protected.
•
The study is being conducted in accordance with the currently approved protocol, any other
study agreements, Good Clinical Practices, and all applicable regulatory requirements.
The investigator and the head of the medical institution (when applicable) agree to allow the 
monitor direct access to all relevant documents. 
Study monitoring visits will be conducted at regular intervals, depending on the recruitment rate, 
under arrangements between the investigator and the sponsor. All information related to these 
visits will be treated as strictly confidential. 
Upon premature completion or discontinuation of the study, the monitor will conduct site closure 
activities with the investigator or site personnel, as appropriate, in accordance with applicable 
regulations, Good Clinical Practices, and Laboratorios Sophia , SA de CV procedures. 
After the study is closed, the investigator must maintain all study records on-site in a secure location. 
Records must be maintained to allow for easy and timely retrieval, when necessary (e.g., during an 
audit or inspection). Laboratorios Sophia , SA de CV will inform the investigator/institution of the 
length of time these records must be retained in order to comply with all applicable regulatory 
requirements. However, the investigator/institution must seek written approval from the sponsor 
before disposing of these records. The minimum retention period will satisfy the most stringent 
standard applicable to that study site, as set forth in GCP, any institutional requirements, or 
applicable laws or regulations, or the standards/procedures of Laboratorios Sophia , SA de CV. 
The researcher/institution must notify Laboratorios Sophia , SA de CV of any changes in archiving 
arrangements including, but not limited to, the following: archiving in an off-site facility, transfer of 
ownership of records in the event the researcher leaves the site. 
9.2 Preliminary analysis and early termination of the study 
If a partial analysis is required, as described in section 8.3.2, this will allow the sponsor to make a 
decision about early termination of the study if the safety of the participants is compromised. 
Early termination of the study will be considered in the following cases: 

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1.
Presence of serious adverse events in more than 5% of participants in any intervention
group.
2.
The competent authority (COFEPRIS) considers it as security alerts.
3.
The Sponsor determines this for its convenience or eventualities such as: financial support,
manufacturing errors, etc.
4.
Lower recruitment than expected.
If the decision is to terminate the clinical study early, the research center will be notified within the 
first 24 hours, using the available means of communication. The corresponding authority and the 
Ethics Committees involved will also be informed. 
The research center is required to inform subjects participating in the clinical study within 24 hours 
of receiving the information from the sponsor. All subjects involved in any phase of the study must 
be informed. 
The outcome of the preliminary evaluation will be the responsibility of the Clinical Operations 
Management and the Medical Directorate of Laboratorios Sophia , SA de CV, which will have the 
authority to determine the fate of this protocol, as they deem appropriate. 
9.3 Adverse events 
9.3.1 Researcher Responsibilities 
Conduct adverse event verification through questioning, a relevant physical examination, 
assessment of progress, as well as appropriate medical and pharmacological management, 
resolution or outcome, and final discharge following the definitions established in national and 
international regulations.[54] [55] [56] 
In the event of adverse events or any occurrence that puts the health and well-being of patients at 
risk, appropriate medical care will be provided, either at the research site or by referring the patient 
to the Hospital Center with the highest resolution capacity with which the researcher's site and/or 
the researcher has a medical care agreement. The researcher will notify the sponsor's clinical 
monitor, in accordance with the times established in national and international regulations. In the 
case of serious adverse events, the sponsor will be notified and the corresponding information will 
be recorded in the case report form, and in turn, the Research Ethics Committee and the Research 
Committee will be informed. 
The care of adverse events will be carried out according to the event care diagram (see Figure 
4Adverse event care) 
The final report to be drafted by the Scientific Committee of the Clinical Operations Department of 
Laboratorios Sophia , SA de CV, will include a report on adverse events in compliance with current 
national and international regulations. [55] [54] 
9.3.1.1 Recording adverse events on the Case Report Form 
The adverse event registry considers information concerning the participating patient's 
identification data such as code, age, sex, left eye, right eye. 
Information about the type of adverse event, adverse reaction, or suspected adverse reaction to 
the investigational product or study drug, as applicable. The date on which the adverse event 
occurred is reported, as well as the date on which the Investigator became aware of it, and the date 
of resolution or outcome, as applicable. The clinical diagnosis is indicated. Include among 
concomitant medications the therapy used for the pharmacological management of the adverse 

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event, suspected adverse reaction, or adverse reaction. Record the outcome or resolution of the 
event: patient recovered without sequelae, with sequelae, or not recovered. Patient who died due 
to the adverse reaction/adverse event; patient who died and it is judged that the drug may have 
contributed; patient who died and the death was not related to the investigational product or drug; 
or indicate that the consequence of the event is unknown. 
Record information about the investigational product or drug, or the drug associated with the 
adverse event, adverse reaction, or suspected adverse reaction. As applicable, information 
concerning the generic name, distinctive name, or code of the investigational product and/or 
investigational drug must be recorded, as appropriate according to the methodological design of 
the study. This is relevant in the case of blinded studies or those where placebo is used as a 
comparator, since there are circumstances that justify opening the blind to determine whether the 
adverse event, adverse reaction, or suspected adverse reaction may be attributable to the active 
agent, combination of active agents, or pharmacologically inert substance(s), such as vehicles or 
additives, as appropriate to the phase of clinical research in which the development of the drug is 
located. It will also be necessary to record data concerning the batch number, manufacturing 
laboratory, expiration date, dose, route of administration, start and end dates of administration 
and/or consumption, reason for the prescription; depending on whether it is a product or 
medication under investigation (protocol in which the patient is currently participating) or a 
medication that the subject under investigation consumes for the treatment of concomitant 
underlying diseases or uses for the management of some temporary sign or symptom that does not 
correspond to the Natural History of the pathology that motivated his/her entry into the research 
protocol. 
Record the withdrawal or discontinuation of the drug, investigational product, or investigational 
drug, as appropriate. Indicate whether the adverse event disappears upon withdrawal of the 
investigational product, investigational drug, or suspected drug (of causing the event). Also indicate 
whether a dose adjustment is made, if the event changes in intensity or severity, and if the reaction 
persists. It is important to note that in patients who are re-exposed to the investigational product, 
investigational drug, or drug, which had previously been discontinued, if the adverse reaction or 
event reappears . 
Regarding concomitant pharmacotherapy, indicate the generic name, dose, route of administration, 
start and end dates, and the reason for the prescription, regardless of whether it is in accordance 
with the prescribing information or the data sheet or if it is used outside the regulations or as 
authorized by the local, national, or international regulatory body. 
Regarding relevant clinical history. The analysis of the adverse event, adverse reaction, or suspected 
adverse reaction takes into account the previously described information. However, the clinical 
context in which the adverse event occurs in the participants of the clinical research protocol is of 
special interest. Therefore, information about previous conditions, hypersensitivity or allergy 
symptoms, previous surgical procedures, laboratory tests or examinations performed on the 
participant, etc., that the researcher deems appropriate may be mentioned. If there is not enough 
space in the case report form, the information from the clinical note may be supplemented in the 
clinical record. 
9.3.1.2 Monitoring of adverse events 
The PI will provide care and management of the participant's AE until its resolution, as described in 
the following section. If the participant develops a chronic adverse event during the study, the 
patient will only be monitored for 30 days after the last pharmacological intervention. 

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9.3.1.3 Procedures for a serious adverse event 
The adverse event handling process considers the following stages: 
Figure 4Adverse event care 
A.
During the development and conduct of this clinical research, undesirable harmful events
or adverse reactions of medical significance may occur in the participating patient, which
do not necessarily have a causal relationship with the investigational product or
investigational drug. These harmful phenomena may occur during the use of investigational
drugs, unintentionally, at doses authorized for use in humans by a local, national, or
international regulatory entity, whether for prophylaxis, diagnosis, treatment, or for the
modification of a physiological process. However, it may be suspected that the
investigational product, the investigational drug, or the placebo may cause some unwanted
clinical manifestation. Adverse events, adverse reactions, or suspected adverse reactions to
one or more drugs may occur during the systematic evaluation of participants (on the days
in which the clinical review is scheduled, according to the schedule of activities) or suddenly,
in such a way that,
B.
The researcher must be the first person to whom the patient notifies that he or she has
developed or experienced any harmful clinical phenomenon during his or her participation
in this research protocol.
C.
In accordance with his or her clinical judgment; based on the pertinent physical
examination, questioning, etc., as well as the analysis of the information available in the
medical literature and that referred to in the investigator's manual, Prescribing Information
or the comparator drug's data sheet, the principal investigator determines the appropriate
treatment for the adverse event/reaction; whether
D. at the research site or at the hospital with the highest resolution power (1st, 2nd or 3rd
level of medical care). So that, in case the patient is referred by the Researcher to a hospital,
he/she attends through a referral system, it may be with an identification card that the
patient belongs to the present investigation and there is an office or folio number, which
belongs to the emergency care agreement with the health institution with the highest
resolution power or a medical reference note issued by the principal investigator is given to
the participating patient so that appropriate care is provided. It should be noted that the

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Sponsor of the study, Laboratorios Sophia , SA de CV, will pay the expenses for the medical 
care of the participating patient, only if the adverse event, adverse reaction or suspected 
adverse reaction to a medication is associated or related to the investigational product or 
investigational medication. 
E.
Taking the clinical information collected, either during the care provided at the research site
or that provided by the treating physician(s) at the hospital, the principal investigator
records the adverse event, suspected adverse reaction or adverse reaction to medication in
his/her clinical note in the clinical record, recording the seriousness, intensity (mild,
moderate or severe), relationship with the product or medication under investigation, as
well as:
F.
The migration of relevant data to the case report format and its respective adverse event
section, indicating the pertinent information, already referred to in section 9.3.1.1. This is
because in cases of serious adverse events, which must be reported within 24 hours after
the principal investigator becomes aware of them, the clinical monitor of the study is
informed, so that he or she, in turn, informs the Scientific Committee and the
Pharmacovigilance Department of the sponsor, and subsequently informs the Research
Ethics Committee. Regarding non-serious adverse events, these will be recorded and
appropriately addressed, and the corresponding regulatory entity will be informed about
the safety profile of the investigational product or investigational drug in the final report of
the clinical trial.
G. The recording of the outcome of the adverse event, suspected adverse reaction, or adverse
reaction to medication depends substantially on the principal investigator's monitoring of
the participant, since the majority of adverse phenomena are expected to be ophthalmic in
nature (see the safety profile section in section 5.3 and in the investigator's manual).
However, systemic alterations may exist. Therefore, at the investigator's discretion, the
participant's withdrawal or retention will be considered, in accordance with the provisions
of section 6.2.2 Exclusion criteriaof this research protocol.
9.3.1.4 Causality Assessment 
Causality assessment, the methodology used to estimate the probability of attributing an adverse 
reaction, a suspected adverse reaction, or an observed adverse event to a drug, investigational drug, 
or investigational product, considers probabilistic categories based on the available evidence and 
the quality of the information, in accordance with national pharmacovigilance regulations.  [54]As a 
tool to facilitate the probabilistic categorization of causality, the principal investigator may use the 
Karch and Lasagna algorithm , modified by Naranjo, which rates different items to assign a value to 
the cause-effect relationship between the administration of the drug and the adverse reaction. 
[57]See Table 6Karch and Lasagna algorithm modified by Naranjo
Karch and Lasagna algorithm modified by Naranjo 
No . 
Reagent 
Score 
Yea
h 
No 
1.
There are conclusive previous reports on adverse drug reaction, adverse event or
suspected adverse drug reaction
+1
0 
2.
The adverse event occurred when the suspected drug was administered
+2
-1

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Karch and Lasagna algorithm modified by Naranjo 
No . 
Reagent 
Score 
Yea
h 
No 
3.
The adverse drug reaction, adverse event, or suspected adverse drug reaction
improved upon discontinuation or administration of a specific antagonist
+1
0 
4.
The adverse drug reaction/adverse event/suspected adverse drug reaction recurred
upon administration of the investigational drug/investigational product/investigational
drug
+2
-1
5.
There are alternative causes that can provoke this reaction.
-1
+2
6.
The adverse reaction/adverse event/suspected adverse drug reaction occurred after
placebo administration
-1
+1
7.
The drug was determined in blood or other fluids in toxic concentrations
+1
0 
8.
The intensity of the adverse reaction/adverse event/suspected adverse drug reaction
was greater with higher doses or less with lower doses
+1
0 
9.
The patient has had similar reactions to the investigational drug/product or
investigational drug in the past
+1
0 
10.
The adverse reaction/adverse event/suspected adverse drug reaction was confirmed
with some objective evidence
+1
0 
Total score 
Addition 
Probabilistic category based on the score obtained 
Yo 
The causal relationship is verified 
≥ ,9 
II 
The ADR is likely due to the investigational drug or product 
5 to 8 
III 
The ADR may be due to the investigational drug or product 
1 to 4 
IV 
The causal relationship is doubtful 
0 
The items considered by the Karch and Lasagna algorithm , modified by Naranjo, are shown. Each item 
receives a defined score, and the final sum allows estimating the probabilistic category of the cause-effect 
relationship between the administration of the investigational drug/product/drug and the adverse 
reaction, adverse event, or suspected adverse reaction. Note that if the information is unavailable, a score 
of zero is recorded. 
Table 6Karch and Lasagna algorithm modified by Naranjo 
Thus, the degree of certainty for establishing the investigational product or investigational drug (as 
applicable) as the causal agent of the harmful event occurring to the participating patient may be 
indicated directly by the principal investigator based on their clinical experience or through the 
voluntary application of the aforementioned tool. However, it is important for the investigator to 
consider the following arguments in favor of a causal relationship: 
a)
Strength of association that refers to the number of cases in relation to those exposed.
b)
The consistency of the data, that is, the presence of a common characteristic or pattern.

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c)
The exposure-effect pattern: which determines the relationship with the site of onset, time,
dose and reversibility after suppression.
d)
Biological plausibility: refers to the possible pharmacological or pathophysiological
mechanisms involved in the development or presentation of the adverse event.
e)
Experimental findings: for example, the appearance of anomalous metabolites or high levels
of drug or its biotransformation product.
f)
Analogy: experience acquired with other related drugs, adverse reactions frequently
produced by the same family of pharmacological agents.
g)
Nature and characteristics of the data: objectivity, accuracy and validity of the relevant
documentation. [58]
9.3.2 Sponsor Responsibilities 
The sponsor will be responsible for and cover the costs arising from medical care for adverse events 
related to the investigational product (see section 11. Financing and insurance). 
9.4 Audit 
To ensure compliance with GCP and all applicable regulatory requirements, Laboratorios Sophia , 
SA de CV may conduct a quality assurance audit. Regulatory agencies and research and ethics 
committees may also conduct an inspection of this study. 
9.4.1 Pre-study audit 
The research centers included in the study will be subject to a pre-study visit prior to center 
selection, where they will be verified to meet the minimum requirements indicated by the sponsor. 
9.4.2 Audit/Inspection during the conduct of the study 
They may take place at any time before, during, or after the conclusion of the study. If an audit or 
inspection is conducted, the researcher and the institution must agree to allow the 
auditor/inspector direct access to all relevant documents and must allocate their own and staff time 
to the auditor/inspector to discuss the findings and any pertinent issues. If the audit is conducted 
by a regulatory agency or committee, the researcher must notify the auditor/inspector immediately. 
10. Ethical considerations
10.1 Approval of committees 
This study will be conducted in accordance with the standards of the “Declaration of Helsinki”, 
World Medical Association 2013. “ Nuremberg Code”; Nuremberg Trial by the International Tribunal 
of Nuremberg , 1947. “Belmont Report”, National Commission for the Protection of Subjects of 
Biomedical and Conduct Research, 1979. It will be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicines for human use of the 
“International Conference on Harmonization” ( The International Council for Harmonisation (ICH) 
Guideline for Good Clinical Practice. “International Ethical Guidelines for Biomedical Research 
Involving Human Subjects of the Council for International Organizations of Medical Sciences ” of 
Medical Sciences , CIOMS, 2002). “International Ethical Guidelines” for Epidemiological Studies of 
the Council for International Organizations of Medical Sciences of Medical Sciences , CIOMS, 2008). 
The Research Ethics Committee and the Research Committee will evaluate the protocol before 
conducting the study and will issue their approval or any possible modifications for its 

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implementation. These Committees must be notified of any significant changes to the protocol. In 
addition to the above, the current regulations issued by the Ministry of Health must also be 
complied with. General Health Law, NOM 012 Mexican Official Standard NOM-012-SSA3-2012, 
which establishes the criteria for the execution of health research projects in human beings. The 
study is considered research with greater than minimum risk according to the Regulations of the 
General Health Law on Health Research, Title Two, Chapter I, Article 17, Category III, published in 
the Official Gazette on January 6, 1987. 
The principal investigators, study coordinators or personnel authorized by the sponsor will submit 
for evaluation by the Research Ethics Committees, Research Committees, and when applicable, the 
Biosafety Committee, the essential documentation of the research project: research protocol, 
informed consent letter, researcher's manual, subject diary, as well as those requested, additionally, 
in accordance with the local, national or international requirements applicable by the regulatory 
entities. 
The study will not be initiated at the research site without the confidentiality agreements and 
financial proposals from each of the principal investigators, duly signed, and without having 
previously obtained the favorable opinion and/or approval of the corresponding Research Ethics 
Committees, Research Committees, and, when applicable, the Biosafety Committee. 
The study will not begin without meeting the relevant local, national, or international regulatory 
requirements and obtaining the appropriate health authorization. 
10.2 Amendments to the protocol 
The amendment process will be relevant when there is a need to make any changes to a document 
that is part of the research project or protocol, due to changes in the methodological structure, 
replacement of the principal investigator, or the identification of risks to the research subjects. 
Documents that may be amended include: the protocol, informed consent letter, researcher's 
manual, patient documents, measurement scales, and activity schedule. 
Any amendment must be approved by the sponsor and/or the principal investigator. The amended 
document(s), once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, when applicable, by the Biosafety Committee (entities that issued the initial 
favorable opinion for the conduct of the research), will be sent for authorization by the relevant 
regulatory entity. 
Amendments that substantially modify the protocol or impose additional or different risks on 
research subjects must be approved by the aforementioned Committees. It is the investigator's 
responsibility to take measures in situations requiring immediate action to prevent unnecessary 
harm to study participants. 
The principal investigator is responsible for communicating to the Research Ethics Committee any 
amendments to the protocol that could affect the rights, safety, or well-being of the research 
participants. They must also report any situation or new knowledge that indicates an increased risk 
to the participants, the premature termination or suspension of the study, the reasons for it, and 
the results obtained to that point. They must also report the conclusion of the study upon 
completion of the research protocol. 
The list of amendments, and where necessary, the list of errata issued, will be included in the final 
research report. 

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10.3 Consent 
10.3.1 Obtaining 
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. 
Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice and will be in compliance 
with all applicable laws and regulations. 
The IP will provide the potential participant with all information regarding the characteristics of the 
study, its potential benefits, risks, objectives, and procedures. 
This information will be provided in a language understandable to the subject. The subject will be 
explained that they have the right to discontinue their participation in the study at any stage, 
without affecting their relationship with the researcher and/or their future participation. Informed 
consent will be presented to the potential participant; they must have sufficient time to review each 
and every aspect mentioned above. Any questions they may have will be clarified by the person 
responsible for obtaining informed consent. 
Once the participant agrees to participate in the study, he or she must sign and date the informed 
consent letter in the presence of two witnesses, whether or not related to the study subject. These 
witnesses will participate in the informed consent process and sign, confirming that the process was 
carried out prior to any study procedure, that the study information was clearly explained, and that 
any questions were clarified. 
In the event that a subject is illiterate, acceptance will be with his or her fingerprint, and in the event 
that the subject is not capable of providing adequate written informed consent, a “legally 
authorized” representative of the subject may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The IP must also sign and date this consent. 
Informed consent must be signed in duplicate by all parties involved, and two witnesses. One copy 
will be filed in the subject's file and the other will be given to the participant. The PI must document 
the date the informed consent was signed in the subject's medical record. 
10.3.2 Special considerations  
The auxiliary studies that will be performed during the study (laboratory tests) do not pose an 
additional risk that should be considered apart from the procedures listed in the informed consent. 
10.3.3 Modification to informed consent 
Changes to the “informed consent” constitute an amendment to this document and must be 
submitted for approval to the Research Ethics Committees and, if applicable, to the Competent 
Authorities. 
The amendment shall include a copy of the new version in the language(s) of the country. 
Such amendments may be implemented only after obtaining written approval from the Research 
Ethics Committee and the Regulatory Body (as applicable), except for an amendment that is 
required to eliminate an immediate danger to the study subjects. 

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Each subject affected by the amendment must complete, date, and sign two originals of the new 
version. The subject will be given one signed original of the amendment, and the researcher will 
retain the second original. 
10.4 Confidentiality 
All documents and information provided to the investigator by the sponsor are strictly confidential. 
The investigator expressly agrees that the data regarding his or her professional and clinical 
experience, provided to the sponsor on paper and stored electronically, are solely for use in 
connection with his or her activities with the clinical trial sponsor, in accordance with Good Clinical 
Practice. The investigator agrees that he or she and his or her team members will use the 
information only within the framework of this study, to carry out the protocol. This agreement is 
binding as long as the confidential information has not been publicly disclosed by the sponsor. The 
clinical trial protocol provided to the investigator may be used by the investigator and his or her 
colleagues to obtain informed consent from the subjects for the study. The clinical trial protocol, as 
well as any information derived from it, must not be disclosed to other parties without the sponsor's 
written authorization. 
The researcher will not disclose any information without the prior written consent of Laboratorios 
Sophia , SA de CV, except to representatives of the Competent Authorities, and only at their request. 
In the latter case, the researcher is obligated to inform Laboratorios Sophia , SA de CV before 
disclosing the information to these authorities. 
The researcher will complete and maintain a subject selection record, as well as the identification 
and enrollment list of each subject participating in the study. The researcher agrees to grant on-site 
access to the auditor and/or representatives of the Competent Authorities. The information will be 
treated in compliance with professional secrecy. 
10.5 Declaration of interests 
The IP agrees to declare his or her financial interests and conflicts of interest prior to the start of the 
study. 
10.6 Access to information 
The final study database will be the property of Laboratorios Sophia , SA de CV, and access to it will 
be restricted. The PI will not have access to it except with prior written authorization from the 
sponsor. 
10.7 Ancillary and post-study care 
Once the study is completed and adverse events are closed according to section 9.3 Adverse events, 
the sponsor will not extend care to the research subject. 
10.8 Biosecurity aspects 
NO BIOSECURITY IMPLICATIONS 
The present protocol, entitled: “Phase I clinical study to evaluate the safety and tolerability of PRO-
165 ophthalmic gel versus Artelac ® Nightime Gel, on the ocular surface of ophthalmologically and 
clinically healthy subjects”, and number:SOPH165-0217/I IT HAS NO BIOSECURITY IMPLICATIONS, 
since no infectious-contagious biological material will be used; pathogenic strains of bacteria or 
parasites; viruses of any type; radioactive material of any kind; genetically modified animals and/or 

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cells and/or plants; toxic, hazardous, or explosive substances; or any other material that puts the 
health or physical integrity of the research center staff or research subjects at risk, or affects the 
environment. It is also declared that no cell, tissue, or organ transplant procedures, or cell therapy, 
will be carried out in this project, nor will laboratory, farm, or wildlife animals be used. 
10.9 Final report and publication of results 
10.9.1 Final report 
Once the statistical analysis is completed, a final report will be written with the results obtained, by 
the Scientific Committee of the Clinical Operations Department of Laboratorios Sophia , SA de CV. 
This report will be prepared following the recommendations of the ICH E3 Step 4 Guide. 
10.9.2 Communication of results 
Regardless of the results of the study, Laboratorios Sophia , SA de CV, is committed to 
communicating the final report of the study to the principal investigators and the corresponding 
regulatory entities in the countries with participating research centers. The company maintains at 
all times the rights to publish and disclose the information contained therein. 
10.9.3 Publication of results 
Laboratorios Sophia , SA de CV, acting as the sponsor of the study, assumes full responsibility for its 
role and retains exclusive property rights over the study results, which it may use in any manner it 
deems appropriate. 
The PI agrees not to publish or communicate data collected only in one center or in part of the 
centers before the publication of the complete results of the study, unless there is prior written 
agreement from Laboratorios Sophia , SA de CV. 
Any draft publication and/or communication related to the study and/or the results obtained during 
or after the study's completion must be submitted to the participating physician researchers at least 
30 days in the case of a publication and 15 days in the case of an abstract, before the scheduled 
date for the communication and/or presentation of a publication. The physician researchers must 
comment on the draft within 15 days in the case of a publication and 7 days in the case of an 
abstract, from the date the draft is received. 
However, if the sponsor is in the process of filing a patent application for the results of the study, 
the sponsor may delay publication or communication of the study results until the date of 
registration. 

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11. Financing and insurance
11. 1 Compensation to study participants
Subjects participating in the study will not receive financial compensation for their participation. 
However, subjects will receive travel expenses for each scheduled visit they attend on time. This 
amount, as well as the amount, will be specified in the informed consent form. 
11.2 Study insurance 
In accordance with current local regulations, Laboratorios Sophia SA de CV has contracted a civil 
liability insurance policy to fulfill its responsibility to provide the medical treatment and 
compensation to which a subject would be legally entitled in the event of damages directly caused 
by this research. 
In the event of a medical emergency, the research center must have the personnel, materials, 
equipment, and procedures for its immediate management. 

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13. Signature Page
13.1 Signatures of the sponsor's representatives 
Name: 
Signature 
Qualification: 
Medical Director of the study 
Date 
Name: 
Signature 
Qualification: 
Director of the study 
Date 
Name: 
Signature 
Qualification: 
Developer of the current version of the protocol 
Date 
13.2 Researcher 
I agree to conduct this clinical study according to the design and guidelines of this protocol, adhering 
to the provisions of this protocol. I agree to conduct the study in accordance with accepted 
standards of Good Clinical Practice. I agree to report all information and data in accordance with the 
protocol, particularly any adverse events. I also agree to manage clinical supplies provided by the 
sponsor strictly in accordance with this protocol. I understand that the information that identifies 
me may be used by the sponsor. Because the information contained in this protocol and the 
Investigator's Manual is confidential, I understand that sharing it with any third party not involved 
in the approval, supervision, or conduct of the study is prohibited. I will ensure that necessary 
precautions are taken to protect the information from loss, inadvertent disclosure, or access by 
unauthorized parties. 
Name: 
Signature 
Qualification: 
Date 

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14. Annexes
14.1 Ocular comfort index 
SOPH165-0217-I
/
/
Iniciales del sujeto:
No. de sujeto: 165-______-_______
Indicaciones:
Este cuestionario fue diseñado para calificar el confort de sus ojos.
Para cada pregunta circule su respuesta
Ejemplo:
En la semana pasada, ¿qué tan seguido sus ojos estuvieron rojos?
No existen respuestas correctas o incorrectas. No tome demasiado tiempo en cada pregunta.
1
En la semana pasada, ¿qué tan seguido sus ojos se sintieron secos?
Cuando sus ojos se sentían secos, por lo general, ¿qué tan intensa era la sensación?
2
En la semana pasada, ¿qué tan seguido sus ojos se sintieron arenosos ?
Cuando sus ojos se sentían arenosos , por lo general, ¿qué tan intensa era la sensación?
3
En la semana pasada, ¿qué tan seguido sus ojos sintieron punzadas ?
Cuando sus ojos sentían punzadas , por lo general, ¿qué tan intensa era la sensación?
4
En la semana pasada, ¿qué tan seguido sus ojos se sintieron cansados ?
Cuando sus ojos se sentían cansados , por lo general, ¿qué tan intensa era la sensación?
Hoja 1 de 2
No lo he sentido
Severo
0
1
2
3
4
5
6
No lo he sentido
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
Nunca
Siempre
0
1
2
3
4
5
6
6
Siempre
Severo
0
1
2
3
4
5
0
1
2
3
4
5
6
5
6
Nunca
Siempre
Íne de Confort Ocular
Nunca
No. de estudio
Fecha: 
0
1
2
3
4
Ficha de identificación
Eye Comfort Index 
ldentificatio11 card 
Date: 
tudy No.: SOPH172-0919-1 
Subject's initials: 
Subject No.: 172-__ -__ 
Directions: 
Tifs questionnaire was designed to ra e ttie comfort of your ,eyes . 
For each question, circle your answer. 
Example: 
In tile past week, how often were your eyes red? 
Never 
0 
2 
3 
4 
5 
There are no right or wrong answers. Don't spend too much time on each question. 
1 
In, the past week, how often did: your eyes feel dry ? 
Never 
0 
2 
3 
4 
When your eyes felt dry, how severe was the sensation usually? 
I have.11't feli it 
0 
1 
2 
3 
4 
2 
In, the past week, how often did your eyes feel .gntty ? 
0 
1 
2 
3 
4 
When your eyes felt gritty, ~ icalty, how intense was the sensation? 
I haven't felt it 
0 
2 
3 
4 
3 
In, the past week, how often d'id your eyes feel throbbing ? 
Never 
0 
2 
3 
4 
When your eyes felt like they were stinging, how intense was the sensation usu 
I have11't feli it 
0 
2 
3 
4 
4 In the past week, how olten did your eyes feel tired ? 
Never 
0 
2 
3 
4 
When your eyes felt tired, how intense was tile feeling usualllf? 
I have11't leli it 
0 
1 
2 
3 
4 
5 
6 
Severe 
5 
6 
5 
6 
5 
6 
' ' ' ' 
~ · 
5 
6 
1/? 
Severe 
5 
6 
5 
6 
Severe 
5 
6 
______________________________________________________________________ Sheet 1 of2_. 

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5
En la semana pasada, ¿qué tan seguido sus ojos se sintieron adoloridos ?
Cuando sus ojos se sentían adoloridos , por lo general, ¿qué tan intensa era la sensación?
6
En la semana pasada, ¿qué tan seguido sus ojos sintieron comezón ?
Cuando sus ojos sentían comezón , por lo general, ¿qué tan intensa era la sensación?
Nunca
Siempre
0
1
2
3
4
5
6
Severo
0
1
2
3
4
5
6
No lo he sentido
No lo he sentido
Índice de confort ocular
Hoja 2 de 2
Índice de confort ocular, traducido del Ocular Comfort Index disponible en: http://iovs.arvohournals.org
Severo
0
1
2
3
4
5
6
Nunca
Siempre
0
1
2
3
4
5
6

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14.2 Oxford Scale 
Igual o menor que el panel A 
Igual o menor que el panel B, mayor 
que el A
Igual o menor que el panel C, mayor 
que el B
Igual o menor que el panel D, mayor 
que el C
Igual o menor que el panel E, mayor 
que el D
Mayor que el panel E