Conditions: Dry Eye Syndromes Lubricant Allergy Tear Disorder
Keywords: Humylub PF artificial tears Ophthalmic lubricant Chondroitin sulfate Sodium hyaluronate
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
Phase I clinical study, to evaluate the safety and tolerability of the preservative-free ophthalmic solution PRO-087 versus Xyel Ofteno® and Systane Ultra®, on the ocular surface of ophthalmological and clinically healthy subjects.

Objective: To evaluate the safety and tolerability of the preservative-free formulation PRO-087 manufactured by Laboratorios Sophia S.A. of C.V. on the ocular surface of clinically healthy subjects.

Hypothesis:

The ophthalmic solution PRO-087 presents a profile of safety and tolerability similar to comparators in healthy subjects

Methodology:

Phase I clinical trial, controlled, of parallel groups, double blind, randomized, exploratory.

Detailed description:
Phase I clinical study, to evaluate the safety and tolerability of the preservative-free ophthalmic solution PRO-087 versus Xyel Ofteno® and Systane Ultra®, on the ocular surface of ophthalmological and clinically healthy subjects.

Objective: To evaluate the safety and tolerability of the preservative-free formulation PRO-087 manufactured by Laboratorios Sophia S.A. of C.V. on the ocular surface of clinically healthy subjects.

Hypothesis:

The ophthalmic solution PRO-087 presents a profile of safety and tolerability similar to comparators in healthy subjects

Methodology:

Phase I clinical trial, controlled, of parallel groups, double blind, randomized, exploratory.

Study period:

3 to 4 months

treatment duration: 10 days

Number of patients:

30 subjects, divided into 3 groups,10 subjects (20 eyes) exposed by group.

Diagnosis and main inclusion criteria:

* Systemically and ophthalmologically healthy subjects
* Signed informed consent.
* Age between 18 to 40 years
* Both genders
* Blood tests complete, blood count (BHC), three element blood chemistry (QS) and liver function tests, within normal parameters
* Visual capacity 20/30 or better

Test product, dose and route of administration:

\- PRO-087. Chondroitin sulfate 0.18% / 0.1% sodium hyaluronate, ophthalmic solution preservative free. made by Laboratorios Sophia, S.A. of C.V., Zapopan, Jalisco, Mexico.

Dosage: 1 drop 4 times a day during the waking period, both eyes Route of administration: topical ophthalmic.

Reference product, dose and route of administration:

1. Xyel Ofteno®. Xanthan gum 0.09% / Chondroitin sulfate 0.1% / preservative-free ophthalmic solution. made by Laboratorios Sophia, S.A. of C.V., Zapopan, Jalisco, Mexico.

   Dosage: 1 drop 4 times a day during the waking period, both eyes Route of administration: topical ophthalmic.
2. Systane Ultra®. Polyethylene glycol 400 0.4%, propylene glycol 0.3%. made by Alcon Laboratories, Inc.

Dosage: 1 drop 4 times a day during the waking period, both eyes Route of administration: topical ophthalmic.

Evaluation criteria:

Primary security outcome variables:

* Goblet cells density .
* Presence of adverse events.
* Intraocular pressure.
* Visual ability
* Laboratory tests
* Epithelial defects in cornea and conjunctiva.
* Ophthalmological signs: conjunctival hyperemia, chemosis.

Secondary outcome variables:

* Tear film rupture time
* Life signs: heart rate, respiratory frequency systemic blood pressure.
* Subsequent segment

Primary outcome variables of tolerability:

* Burning
* Foreign body sensation
* Itching
* Eye comfort index

Statistical methodology:

The data will be expressed with measures of central tendency: mean and standard deviation for the quantitative variables. The qualitative variables will be presented in frequencies and percentages. The statistical analysis will be carried out through the Kruskal-Wallis test for quantitative variables. The difference between the qualitative variables will be analyzed by means of chi square (Chi2). An alpha ≤ 0.05 will be considered significant.

Arms:
arm 1: Dosage: 1 drop in both eyes, 4 times a day during the waking period per 10 days Active principles: chondroitin sulfate 0.18%, sodium hyaluronate 0.1% ophthalmic solution made by Laboratorios Sophia, S.A. de C.V., transparent solution, free of visible particles in a sterile multi-dose bottle. arm 2: Dosage: 1 drop in both eyes, 4 times a day during the waking period per 10 days, Active principles: Xanthan gum 0.9 mg, sodium chondroitin sulfate 1.0 ophthalmic solution made by Laboratorios Sophia, S.A. de C.V., transparent solution, free of visible particles in a sterile multi-dose bottle. arm 3: Dosage: 1 drop in both eyes, 4 times a day during the waking period per 10 days Active principles: Polyethylene glycol 400 0.4%, propyleneglycol 0.3%, Ophthalmic solution, multi-dose dropper bottle, made by Alcon Laboratories, Inc.

Interventions: intervention 1: PRO-087 intervention 2: Systane Ultra intervention 3: Xyel Ofteno
Intervention descriptions: intervention 1: The intervention period consists of a therapy with PRO-087administered 4 times a day in the waking period for 10 days. with a security call to day 13. intervention 2: The intervention period with active comparator drug consists of a therapy with systane administered 4 times a day in the waking period for 10 days. with a security call to day 13. intervention 3: The intervention period with active comparator drug consists of a therapy with Xyel administered 4 times a day in the waking period for 10 days. with a security call to day 13.

Protocol document:
Prot_SAP_000.pdf: 
CONFIDENCIAL 
 
 
 
 
 
 
Creation date: july de 2016 
Phase I clinical study, to evaluate the safety and 
tolerability of the preservative-free ophthalmic 
solution PRO-087 versus Xyel Ofteno® and Systane 
Ultra®, 
on 
the 
ocular 
surface 
of 
ophthalmologically and clinically healthy subjects 
Protocol code:SOPH087-0616/I 
Protocol version: 1.0 
Date of the version: 29/06/2016 
Registry: 173301410A0014/2017 
Sponsor:  Sophia Laboratories, S.A. of C.V.  
 


 
 
 
 
 


PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
Sophia Laboratories, S.A. of C.V. 
Page 1 of 67 
 
1. Summary 
Title of the study: 
Phase I clinical study, to evaluate the safety and tolerability of the preservative-free ophthalmic 
solution PRO-087 versus Xyel Ofteno® and Systane Ultra®, on the ocular surface of 
ophthalmological and clinically healthy subjects. 
 Protocol code: 
SOPH087-0616/I 
Creation date: 
29/06/2016 
 Protocol version: 
1.0 
Date of the version: 
29/06/2016 
Therapeutic Indication: 
Eye lubricant 
Study period:  
3 to 4 months 
Development phase: I 
Goals: 
To evaluate the safety and tolerability of the preservative-free formulation PRO-087 
manufactured by Sophia Laboratories, S.A. of C.V. on the ocular surface of clinically healthy 
subjects. 
Hypothesis: 
To evaluate the safety and tolerability of the preservative-free formulation PRO-087 
manufactured by Sophia Laboratories, S.A. of C.V. on the ocular surface of clinically healthy 
subjects. 
Methodology: 
Phase I clinical trial, controlled, of parallel groups, double blind, randomized, exploratory. 
Number of patients: 
30 subjects, divided into 3 groups [10 subjects (20 eyes) exposed by group] 
Diagnosis and main inclusion criteria: 
 
Systemically and ophthalmologically healthy subjects 
- Signed informed consent. 
- Age between 18 to 40 years. 
-Both genders 
- Blood tests [complete blood count (BHC), three element blood chemistry (QS) and liver 
function tests (PFH)] within normal parameters 
- Visual capacity 20/30 or better 
 


PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
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Sophia Laboratories, S.A. of C.V. 
Page 2 of 67 
 
Test product, dose and route of administration, lot number: 
- 
PRO-087. Chondroitin sulfate 0.18% / 0.1% sodium hyaluronate, ophthalmic solution free 
of preservatives. Prepared by Sophia Laboratories, S.A. of C.V., Zapopan, Jalisco, Mexico. 
 
▪ 
Dosage: 1 drop 4 times a day during the waking period, both eyes 
▪ 
 Route of administration: topical ophthalmic 
Duration of treatment: 10 days 
Reference product, dose and route of administration, lot: 
1. Xyel Ofteno®. Xantana gum 0.09% / Chondroitin sulfate 0.1% / preservative-free 
ophthalmic solution. Prepared by Sophia Laboratories, S.A. of C.V., Zapopan, Jalisco, 
Mexico. 
a. Dosage: 1 drop 4 times a day during the waking period, both eyes 
b. Route of administration: topical ophthalmic 
2. Systane Ultra®. Polyethylene glycol 400 0.4%, propylene glycol 0.3%. Prepared by Alcon 
Laboratories, Inc. 
a. Dosage: 1 drop 4 times a day during the waking period, both eyes 
b. Route of administration: topical ophthalmic 
Evaluation criteria: 
Primary security outcome variables: 
- 
Density of goblet cells. 
- 
Presence of adverse events. 
- 
Intraocular pressure. 
- 
Visual ability 
- 
Laboratory tests: BHc, QS and PFH. 
- 
Epithelial defects in cornea and conjunctiva. 
- 
Ophthalmological signs: conjunctival hyperemia, chemosis.  
Secondary outcome variables: 
- 
Rupture time of the tear film 
- 
Life signs: FC, FR, TAS. 
- 
Subsequent segment  
Primary outcome variables of tolerability: 
- 
Burning 
- 
Foreign body sensation 
- 
Itching 
- 
Eye comfort index 
Statistical methodology: 
The data will be expressed with measures of central tendency: mean and standard deviation for 
the quantitative variables. The qualitative variables will be presented in frequencies and 
percentages. The statistical analysis will be carried out through the Kruskal-Wallis test for 
quantitative variables. The difference between the qualitative variables will be analyzed by means 
of X2 (Chi2). An alpha ≤ 0.05 will be considered significant. 


PRO-087 
 
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2. Content 
1. SUMMARY 
1 
2. CONTENT 
3 
3. ABBREVIATIONS INDEX 
7 
4. ADMINISTRATIVE STRUCTURE OF THE STUDY 
9 
5. INTRODUCTION 
11 
5.1 THEORETICAL FRAMEWORK 
11 
5.2 DEFINITION OF THE PROBLEM AND FUNDAMENTAL REASON 
15 
5.3 BACKGROUND 
16 
5.3.1 SODIUM HYALURONATE 
16 
5.3.1.1 Eyeball pharmacokinetics 
16 
5.3.2  SULFATE CONDROITÍN 
16 
5.3.2.1 Farmacokinetics in the eyeball 
17 
5.3.3 USE OF CONSERVATIVES 
17 
5.4 JUSTIFICATION 
17 
5.5 OBJECTIVES AND HYPOTHESIS 
18 
5.5.1 GENERAL OBJECTIVE 
18 
5.5.2 SPECIFIC OBJECTIVES 
18 
5.5.3 HYPOTHESIS 
18 
5.6  DESIGN AND STUDY PLAN 
18 
5.6.1 DISCUSSION OF THE STUDY DESIGN 
18 
6. MATERIAL AND METHODS. PARTICIPANTS, INTERVENTIONS AND VARIABLES 
19 
6.1 STUDY CENTER 
19 
6.1.1 ORGANIZATION OF THE CENTER 
19 
6.1.2 DOCUMENTATION TO BE DELIVERED TO THE SPONSOR 
20 
6.1.3 CLOSURE OF THE CENTER 
20 
6.2 ELEGIBILITY CRITERIA 
20 
6.2.1 INCLUSION CRITERIA 
20 
6.2.2 EXCLUSON CRITERIA 
21 
6.2.2.1 General criteria 
21 
6.2.2.2 Medical and therapeutic criteria 
21 
6.2.3 ELIMINATION CRITERIA 
21 
6.2.4 IDENTIFICATION OF THE SUBJECT 
21 
6.3 INTERVENTION 
22 
6.3.1 ADMINISTRATED THREATMENTS 
22 


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6.3.1.1 Treatment under study 
22 
6.3.1.2 Reference treatment 
22 
6.3.2 STRATEGIES TO IMPROVE THE ADHERENCE AND PROCEDURE TO MONITOR ADHERENCE 
23 
6.3.2.1 Procedure to monitor adherence 
23 
6.3.3 TREATMENTS AND COMMITTED INTERVENTIONS ALLOWED AND PROHIBITED DURING THE 
STUDY 
24 
6.3.4 MANAGEMENTO OF TREATMENT 
24 
6.3.4.1 Delivery and reception 
24 
6.3.4.2 Storage 
25 
6.3.4.3 Return 
25 
6.4 DISARMING VARIABLES 
25 
6.4.1 SECURITY VARIABLES 
25 
6.4.1.1 Primary outcome variables 
25 
6.4.1.2 Variables of primary outcome of tolerability 
25 
6.4.1.3 Secondary outcome variables 
26 
6.4.2  EFFECTIVENESS VARIABLES 
26 
6.4.2.1 Primary outcome variables 
26 
6.4.2.2 Secondary outcome variables 
26 
6.4.3  METHODS AND SCALES TO BE USED FOR THE MEASUREMENT OF VARIABLES 
26 
6.4.3.1 Visual capacity 
29 
6.4.3.2 Goblet cell density (Cytology per impression) 
29 
6.4.3.3 Eye comfort index 
30 
6.4.3.4 Eye Surface Integrity: 
31 
6.4.3.5 Presence of adverse events 
31 
6.4.3.6 Intraocular pressure 
32 
6.4.3.7 Subsequent segment 
32 
6.4.3.8 Life signs 
32 
6.4.3.9 Ocular Symptomatology 
32 
6.4.3.10 Rupture time of the tear film 
32 
6.4.3.11 Pregnancy test 
33 
6.4.3.12 Laboratory tests 
33 
6.4.4 TIME OF MEASUREMENTS 
33 
6.5 CHRONOGRAM AND STUDY DIAGRAM 
35 
6.5.1 PROCEDURES TO BE CARRIED OUT BY VISIT 
36 
6.5.1.1 Scrutiny visit 
36 
6.5.1.2 Basal Visit 
36 
6.5.1.3 Visit 1 
37 
6.5.1.4 Visit 2 
37 
6.5.1.5 Final  
37 
6.5.1.6 Security call 
38 
6.5.2 STUDY DIAGRAM 
39 
6.6 SAMPLE SIZE 
39 
6.6.1 CALCULATION OF SAMPLE SIZE 
39 
6.7 RECRUITMENT 
40 
7. METHODS. ALLOCATION OF THE INTERVENTION 
40 


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7.1 GENERATION OF THE ASSIGMENT SEQUENCE 
40 
7.2 BLINDING MECHANISM 
40 
7.3 IMPLEMENTATION 
40 
7.4 BLINDING (MASKING) 
41 
7.4.1BLINDING OPENING 
41 
8. METHODS. COLLECTION, ADMINISTRATION AND DATA ANALYSIS 
41 
8.1 METHODS OF DATA COLLECTION 
41 
8.1.1 STRATEGIES TO COMPLETE FOLLOW-UP 
42 
8.2 ADMINISTRATION OF DATA 
42 
8.3 STATISTICAL METHODOLOGY 
42 
8.3.1ANALYSIS OF PRIMARY AND SECONDARY DISOLVEMENT VARIABLES 
42 
8.3.2 ADDITIONAL ANALYSIS 
43 
8.3.3 POPULATION ANALYSIS AND HANDLING OF MISLEADING DATA 
43 
9. METHODS. MONITORING 
44 
9.1 DATA MONITORING 
44 
9.2PRELIMINARY ANALYSIS AND EARLY TERMINATION OF THE STUDY 
45 
9.3 ADVERSE EVENTS 
45 
9.3.1 RESPONSABILITIES OF THE INVESTIGATOR 
45 
9.3.1.1 Record of adverse events in the Case Report Form 
46 
9.3.1.2 Follow-up of adverse events 
47 
9.3.1.3 Procedures for a serious adverse event 
47 
9.3.1.4 Evaluation of casuality 
49 
9.3.2 SPONSORSHIP RESPONSIBILITES 
50 
9.4 AUDIT 
51 
9.4.1 AUDIT PRIOR TO STUDY 
51 
9.4.2 AUDIT/INSPECTION DURING STUDY DRIVING 
51 
10. ETHICAL CONSIDERATIONS 
51 
10.1 APPROVAL OF THE COMITTEES 
51 
10.2AMENDMENTS TO THE PROTOCOL 
52 
10.3 CONSENT (ASSIGNMENT) 
52 
10.3.1 OBTEINMENT 
52 
10.3.2 SPECIAL CONSIDERATIONS 
53 
10.3.3 MODIFICATION TO INFORMED CONSENT 
53 
10.4 CONFIDENTIALITY 
53 
10.5 DECLARATION OF INTEREST 
54 
10.6 ACCESS TO INFORMATION 
54 
10.7AUXILIARY CARE AND SUBSEQUENT TO THE COMPLETION OF THE STUDY 
54 
10.8BIOSECURITY ASPECTS 
54 
10.9  FINAL REPORT AND PUBLICATION OF RESULTS 
54 


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Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
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Page 6 of 67 
 
10.9.1 FINAL REPORT 
54 
10.9.2 COMUNICATION OF RESULTS 
55 
10.9.3 PUBLICATION OF RESULTS 
55 
11.BIBLIOGRAPHICAL REFERENCES 
56 
12. SIGNATURE PAGE 
61 
13. ANNEXES 
63 
13.1 EYE CONFORT INDEX 
63 
13.2 EFRON SCALE FOR CONJUNCTIVE HYPEREMIA 
64 
13.3 OXFORD  SCALE 
64 
 
 
 
Index of tables and figures 
 
 
Table 1. Administrative structure ...................................................................................................... 9 
Table 2. Classification of SDPL by severity  ...................................................................................... 14 
Table 3. Treatment recommendations for the SDPL ....................................................................... 15 
Table 4. Quali-quantitative formulation of PRO-087 ...................................................................... 22 
Table 5. Scales to be used ................................................................................................................ 28 
Table 6. Nelson classification ........................................................................................................... 30 
Table 7. Algorithm of Karch and Lasagna modified by Naranjo ..................................................... 35 
 
Figure 1. Classification of SDPL by etiology ..................................................................................... 13 
Figure 2 Minimum organization of the center................................................................................. 20 
Figure 3. Diagram of the study ......................................................................................................... 39 
Figure 4. Attention to the adverse event ........................................... ¡Error! Marcador no definido. 
 


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Clinical study protocol: SOPH087-0616/I  
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Page 7 of 67 
 
3. Index of abbreviations 
 
 
 
ALT 
 
 
Alanino transferase 
AST  
 
 
Aspartate transferase 
BAK 
 
 
Benzalkonium chloride 
BD  
 
 
Bilirubin direct 
BI  
 
 
Bilirubin indirect 
BHc  
 
 
Complete blood count 
BPC 
 
 
Good clinical practices 
BT  
 
 
Total Bilirubin 
CV  
 
 
Visual capacity 
CCI  
 
 
informed consent letter 
CIC 
 
 
 Cytology by conjunctival impression 
IEC 
 
 
 Research Ethics Committee 
CI  
 
 
Informed Consent 
CRF 
 
 
 Case Report Form (Case Report Form) 
EA / EAS  
 
Adverse event / serious adverse event 
FDA  
 
 
Food and Drug Administration (Food and Drug Administration) 
FC 
 
 
 Heart rate 
FR 
 
 
 Respiratory frequency 
GAG  
 
 
Glycosaminoglycans 
ICH  
 
 
International Conference on Harmonization  
ICO 
 
 
 Eye comfort index 
IP  
 
 
Principal investigator of the clinical study 
PFH 
 
 
 Liver function tests 
IOP 
 
 
 intraocular pressure 
TAS  
 
 
Systemic blood pressure 
 
 
 
 


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TF  
 
 
Fluorescein staining 
TVL 
 
 
 Green lysine stain 
QS  
 
 
Blood chemistry 
TVL  
Green lysine stain 
QS  
 
 
Blood chemistry 


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4. Administrative structure of the study 
The administrative structure of the sponsoring party, corresponding to Sophia Laboratories, S.A. of 
C.V. is shown in Table 1. Administrative structure 
Function 
Contact/name 
Affiliation ¥ 
Medical responsible 
for the study 
Dr. Leopoldo Martín Baiza Durán 
leopoldo.baiza@sophia.com.mx 
Medical Director and Regulatory Affairs 
Director of the study 
Dr. Aldo Arturo Oregón Miranda 
aldo.oregon@sophia.com.mx 
Clinical Operations Manager 
Scientific Comittee 
Dr. Oscar Olvera Montaño 
oscar.olvera@sophia.com.mx 
Ophthalmologist Investigator 
Scientific Comittee 
Dr. en C. Arieh Roldán Mercado Sesma 
arieh.mercado@sophia.com.mx 
Medical Editor 
Coordinator of 
regulatory 
procedures 
LN. Ana Isabel Alcaraz Ledón 
ana.alcaraz@sophia.com.mx 
Specialist in the beginning of clinical 
studies 
Monitoring 
coordinator 
QFB Virginia Manuela Villa Félix 
virgina.villa@sophia.com.mx 
Monitor coordinator 
International 
monitor 
M. en F. Sandra Carolina Gómez Méndez 
sandra.gomez@sophia.com.mx 
Senior Monitor 
Monitor 
QFB Jessica Lizette Mejía Gutiérrez 
jessica.mejia@sophia.com.mx 
Senior Monitor 
Monitor 
LP María Angela González Ávila 
maria.gonzalez@sophia.com.mx 
Junior Monitor 
Monitor 
QFB Lizeth de Jesús Pérez Lerma 
lizeth.perez@sophia.com.mx 
Junior Monitor 
Monitor 
LN Pilar Carolina Castro Mata 
pilar.castro@sophia.com.mx 
Junior Monitor 
Administrative 
Assistant 
LAET Maira Alejandra Ramírez Velazco 
alejandra.ramirez@sophia.com.mx 
Clinical Operations Assistant 
¥ Employees of Sophia Laboratories, S.A. of C.V Av. Paseo del Norte No.5255, Col. Guadalajara Technology Park, 
Carretera Guadalajara-Nogales Km13.5 C.P45010 Zapopan, Jalisco, Mexico Tel +52 (33) 3000 4200 
 
 
 
Table 1. Administrative structure 
 
 
 
 


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PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
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Page 11 of 67 
 
5. Introduction 
5.1 Theoretical framework 
Dry eye disease (DED) is a frequent ocular condition that significantly decreases quality of life and 
affects 6-34% of the world's adult population.  [1] [2] Although there is no formal study on the 
prevalence of the disease in Latin American countries, several reports agree that there is a higher 
prevalence of severe symptoms and clinical diagnosis of DED in the Hispanic population when 
compared with the Caucasian population. [2] [3]  
DED is an alteration of the tear film that results in damage to the ocular surface and is associated 
with symptoms of ocular discomfort. The DED has also been called keratoconjunctivitis sicca (KCS), 
sicca syndrome, xerophtalmia, dry eye syndrome, ocular surface disease, tear film dysfunction 
syndrome (SDPL) or simply dry eye. [4] [5] Strictly some of these terms are not synonymous, since 
for example, the DED can be presented without keratitis, KCS; This protocol will be used as a 
synonym of the DED to the SDPL, assuming they are interchangeable concepts and adopting the 
definition of the International Dry Eye Seminar 2007 (DEWS, for its acronym in English of 
International Dry Eye Workshop): 
Multifactorial disease of the tear and the ocular surface that results in 
symptoms of discomfort, visual alterations and instability of the tear film 
with potential damage to the ocular surface. It is accompanied by an 
increase in the osmolarity of the tear film and inflammation of the ocular 
surface. [4] 
 
The SDPL is an alteration of the functional lacrimal unit (ULF), an integral system comprised of 
lacrimal glands, ocular surface (cornea, conjunctiva and Meibomian glands), eyelids and the sensory 
motor nerves that interconnect them. [6] 
This ULF 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] 
The damage or alteration to any component of the ULF can destabilize the tear film and lead to an 
eye surface disease that is expressed as SDPL. The stability of the tear film, distinctive of a normal 
eye, is threatened when the interactions between the stabilizing constituents of the tear film are 
compromised by decreased secretion, delayed clearance and an altered tear composition. 
Inflammation is a secondary consequence. The reflex tear secretion, in response to irritation, is 
considered to be the initial compensatory mechanism, but, over time, the inflammation that 
accompanies secretory dysfunction and decreased corneal sensitivity compromises the reflex 
response and results in instability of the even bigger tear film. It is considered that the disturbance 
of the UFL plays a very important role in the evolution of different forms of dry eye. [4] 
The tear film is a highly specialized and carefully structured moisturizing layer that covers the cornea 
and the conjunctiva. It is classically described as a trilaminar structure composed of a lipid surface 
layer, an aqueous intermediate layer and a mucinous inner layer. [10] The tear film has four main 
functions: 1) Maintain a regular optical surface, 2) Do not allow friction between structures of the 


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ocular surface, 3) Nourish the cornea and 4) First line of defense against ocular surface 
infections.[11]  
Based on the models of the "microstructure" of the tear film and its interface with the cells of the 
ocular surface, the mucin layer should always be present in a healthy tear film. [10] This layer 
provides support to the rest of the tear film on the ocular surface, helping to keep it moisturized 
and lubricated. [12] The epithelial cell layer of the conjunctiva includes the goblet cells, which are 
mucin excretors. The main source of mucin for the tear film are these cells. [11] 
Within the framework of the DEWS, the etiopathogenic classification of the SDPL was established, 
which is summarized. This classification aims to provide a more up-to-date understanding of the 
SDPL. It is divided into two main classes: aqueous and evaporative deficiency. The category of 
aqueous deficiency refers mainly to a lack of tear secretion. The evaporative class has been 
subdivided to distinguish from causes that depend on intrinsic conditions of the eyelids and ocular 
surface and those that arise from extrinsic influences. 
The SDPL can start in either of the two classes, but these are not mutually exclusive. It is recognized 
that a disease can start in a main class and coexist or even lead to events that produce SDPL by a 
mechanism of another kind. This is part of a vicious cycle of interactions that can amplify the 
severity. An example of this may be that all forms of SDPL cause loss of goblet cells, which over time 
will contribute to a loss of tear film stability, surface damage and evaporative water loss. [4] 
Many pathophysiological mechanisms of the SDPL stimulate the sensory nerves of the cornea, so 
the SDPL is described as a "symptomatic disease". [13] [14] [15] In most patients there is a 
relationship between symptoms and clinical signs, nevertheless it is also recognized that in some 
patients the severity of the symptoms does not correspond to the clinical signs of the disease. [16] 
[14] [17] 
The classification of the SDPL according to its severity currently represents a challenge, since there 
is no gold standard to determine it; notwithstanding, the severity of the disease is one of the most 
relevant factors when considering the therapeutic options for the SDPL. [18] In 2006 a panel of 
specialists, called the Delphi Panel, issued a classification of severity later adopted by the DEWS. The 
severity was classified into four levels, based on the increase in frequency and intensity of various 
signs and symptoms. [18] See ¡Error! No se encuentra el origen de la referencia. 
There are other systems to classify the SDPL severity referred by other authors,[19] [20] [21] [22]  
among them the algorithm of the European consensus of the ODISSEY group which was designed to 
classify as severe patients with discordant SDPL and therefore, more complex to classify. [23]  
In addition to the evaluation parameters of the SDPL, among which a greater correlation has been 
found, OSDI, TRL, and Schirmer's test, cytology by conjunctive impression (CIC) has been used 
recently, which is a minimally invasive technique that allows the analysis of the disease in a clinical 
setting by evaluating mainly the characteristics of goblet cells. CIC can be used for diagnostic 
purposes, to understand the mechanism of the disease and to evaluate the effectiveness of a 
treatment. [24] 
 


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Figure 1. Classification of SDPL by etiology.
 
 
 
SDPL
Aqueous deficiency
Sjögren Syndrome
Primary
Secundary
No sjögren syndrome
Lacrimal Deficiency
Obstruction of the 
lacrimal gland duct
Reflex blockage
Systemic medications
Evaporative
Intrinsic
Meibomian deficiency
Alterations of the 
opening of the eyelid
Low index of blinking
Action of medicines 
(Accutane)
Extrinsic
Deficiency of vitamin A
Preservatives of topical 
medications
Use of contact lenses
Diseases of the ocular 
surface ex. allergies


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Table 2. Classification of the SDPL by severity 
Grade 
1 Mild 
2 Moderate 
3 Severate 
4* Incapacitator 
Discomfort, 
severity 
and 
frequency 
Occurs mildly and / 
or episodically; 
under conditions of 
environmental 
stress 
Occurs chronically 
or episodically, 
with or without 
environmental 
stress 
Occurs frequently and 
/ or constantly without 
stress 
Is constant 
Visual 
symptoms 
None or episodic 
mild fatigue 
Disturbances, 
activity limitation 
in an episodic 
manner 
Disturbances, activity 
limitations in a chronic 
and / or constant way 
Constant and / or 
disabling 
Conjunctival 
injection 
None to mild 
None to mild 
+ 
+/++ 
Conjunctival 
stain 
None to mild 
Variable 
Moderate to marked 
Marked 
Corneal 
staining 
None to mild 
Variable 
Central marking 
Severe and 
disseminated dot 
erosion 
Lacrimal 
/ 
corneal signs 
None 
Mild debris, 
meniscus 
diminution 
Filamentous keratitis, 
lacrimal debris and 
mucinous 
accumulations 
Filamentous 
keratitis, lacrimal 
debris, mucinous 
accumulations, ulcer 
Meibomian 
glands 
/ 
eyelids 
Meibomitis present 
in a variable way 
Meibomitis 
present in a 
variable way 
Frequent 
Trichiasis, 
keratinization, 
simblefaron 
TRL 
Variable 
≤ 10 
≤ 5 
Immediate 
Schirmer I 
Variable 
≤ 10 
≤ 5 
≤ 2 
* It must have signs and symptoms. 
Adapted from Behrens A, Doyle JJ, Stern L, et al.[18] 
 
The treatment currently available for the SDPL can be divided into: 
a) Lacrimal supplements: lubricants. 
b) Tears retention: lacrimal dot occlusion, contact lenses. 
c) Secretion stimulation: secretagogues. 
d) Biological substitutes: autologous serum, autologous salivary gland. 
e) Anti-inflammatories: cyclosporine, steroids, tetracyclines. 
f) Essential fatty acids 
g) Environmental strategies 
 
The treatment recommendations of the American Academy of Ophthalmology and the Guidelines 
for the Dry Eye of the International Working Group, favored by the DEWS, are based on severity See 
¡Error! No se encuentra el origen de la referencia.. The recommendations can be modified by the 
ophthalmologist, based on the clinical experience and the individual profile of your patient. [18] [25] 
[26] 
 


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Table 3. Treatment recommendations for the SDPL 
Level 1: 
Education and dietary and environmental modifications 
Elimination of systemic medications that alter the UFL 
Lubricants 
Eyelid treatment 
Level 2: 
If the treatments of level 1 are insufficient, add: 
Anti-inflammatories 
Tetracyclines 
Closing the puncta with silicone tips 
Secretagogues 
Level 3: 
If the treatments of level 2 are insufficient, add: 
Autologous serum 
Contact lenses 
Permanent closure of the lacrimal dots 
Level 4: 
If level 3 treatments are insufficient, add: 
Systemic anti-inflammatories 
Surgery (tarsorraphy, transplantation: mucous membrane, salivary gland, 
amniotic membrane) 
Modified from the Guidelines for the Dry Eye of the International Working Group  [18] 
 
The main objective in the care of patients with SDPL is to improve the patient's ocular comfort and 
quality of life, in addition to returning the ocular surface and the tear film to its state of homeostasis. 
Although the symptoms are rarely eliminated, they can often be diminished, resulting in an 
improvement in the quality of life. [26] 
Ocular lubricants are the first line of management for the SDPL and a constant in all levels of 
treatment. They are characterized by hypotonic or isotonic solutions, which contain electrolytes, 
surfactants and various types of viscous agents. The main variables in the formulations of ocular 
lubricants are in relation to the selection or concentration of electrolytes, the osmolarity, the type 
of visco-polymeric system, the presence or absence of preservatives. [26] 
 5.2 Definition of the problem and fundamental reason 
There are few effective treatments for the treatment of SDPL. The clinical development of new 
treatments is slow because the pathogenesis of SDPL is multiple and its semiotics variable. The 
different phases of treatment have as a common denominator the use of ocular lubricants. 
Although there is a great variety of topical lubricants, with different viscous agents, there is no 
evidence that one is better than another. The elimination of preservatives, mainly benzalkonium 
chloride (BAK, for its acronym in English benzalkonium chloride) or the development of new less 
toxic preservatives have made eye lubricants more tolerable. 
Although ocular lubricants have not been shown to be sufficient to completely resolve the alteration 
of the ocular surface and the inflammation seen in patients with SDPL, they have been shown to 
provide protection to the ocular surface and to diminish the symptomatology and clinical findings. 


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The combination of sodium hyaluronate (HS) and chondroitin sulfate (CS), which are biopolymers, 
glycosaminoglycans (GAG), constituents of the extracellular matrix, contributes to PRO-087 the 
viscoelastic and water retention properties, to function as a lubricant effective that protects the 
ocular surface and reconstitutes the tear film. 
5.3 Background 
In Mexico and other South American countries, Humylub Ofteno® is available, which is the 
association of HS and CS itself that contains PRO-087, but with BAK as conservative. Humylub 
Ofteno® has been registered in Mexico since July 2007 and there have been no reports of adverse 
reactions associated with the use of Humylub Ofteno®, maintaining a good safety profile. [27]  
5.3.1 Sodium hyaluronate 
It is a biopolymer, disaccharide of the GAG family, formed by the alternating sequence of N-acetyl-
D-glucosamine and glucuronate in linear chains. In physiological solvents it forms spirals; 
configuration determined by its viscosity. It is a constituent of the extracellular matrix, connective 
tissue, vitreous humor, umbilical cord, synovial fluid, skin, etc. It can be constituted by more than 
10,000 pairs of disaccharides. At concentrations above 0.1% sodium hyaluronate constitutes a 
network. The diffusion rate through the network is inversely related to the size of the polysaccharide 
molecules, which are stable. Proteoglycans contribute to mechanical and elastic properties. 
Numerous authors have reported that the HS has a high capacity to retain water, it has been 
established that 1 gr of HS can retain up to 6L of water. [28]  
Sodium hyaluronate is synthesized on the inner side of the plasma membrane as a linear polymer, 
in contrast to other GAGs which are synthesized by enzymes in the Golgi apparatus. The enzymes 
for the synthesis of sodium hyaluronate are hyaluronate and glucosyltranferases, which 
coordinately polymerize and translocate sodium hyaluronate out of the cell into the extracellular 
matrix. [29]  
5.3.1.1 Eyeball pharmacokinetics 
Route of administration: Ophthalmic. 
Release: immediate. 
Absorption: HS absorption through the cornea has not been reported when applied to the ocular 
surface. Pharmacokinetic studies performed in patients with dry eyes showed that the HS solution 
reached its maximum concentration in 10 minutes and is widely distributed on the ocular surface. 
Metabolism: it is biotransformed by hyaluronidases. 
Elimination: it is eliminated from this compartment through the lacrimal sac and the lacrimal duct 
without intraocular absorption, in approximately 45 minutes. [30] Based on the results of preclinical 
research in rabbits developed by Laboratorios Sophia SA de CV, the ocular half-life correlates with 
the volume of the formula. 
5.3.2 Chondroitin sulfate 
It is part of the group of GAGs, like sodium hyaluronate, is a mucopolysaccharide found in the 
extracellular matrix of connective tissues, including the vitreous, cornea and aqueous humor. GAGs 
are high molecular weight aggregates called proteoglycans. These proteoglycans contribute to 
provide mechanical and elastic properties to products containing CS. The CS monomer is a 


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disaccharide compound of N-Acetylgalactosamine and N-glucuronic acid. The sulfate group is fixed 
in galactosamine, in position 4 and 6, which explains the existence of 2 isomers of CS. [31]  
5.3.2.1 Eyeball pharmacokinetics 
Route of administration: ophthalmic. 
 
Release: immediate. 
Distribution: on the ocular surface and nasal epithelium through the nasolacrimal duct. 
Absorption: from the formulation administered topically, it has been determined that there is no 
absorption through the cornea. 
 
Metabolism: by phase I biotransformation reactions, oxidation and reduction. 
Elimination: through the tear system. 
 
5.3.3 Use of conservators 
The preservatives are used in order to inhibit microbial growth and suppress biodegradation inside 
medicines. [32] A great variety of conservatives have been used throughout history. The chronic use 
of drugs has been linked to irritation and alterations of the ocular surface, it has been established 
that the conservatives themselves have adverse events, which are attached to those of the active 
principle that preserve. [33] 
The preservatives are classified into detergents and oxidants, and a more recent version of oxidants 
called buffered by ions. [32] The BAK is the most historically used preservative, belongs to the class 
of detergents. The reasons for its popularity include its broad spectrum of action and its familiarity 
with the formulator industry.  
Although its effectiveness is well recognized, there are numerous studies documenting the harmful 
effects of BAK. BAK at concentrations of 0.05-0.1% induces necrosis and concentrations of 0.01% 
apoptosis. Its effects are cumulative and become more severe at higher concentration and with 
more frequent exposures. [32] [34] [35] It has been postulated that the presence of BAK is 
responsible for changes in the conjunctival surface identified by cytology by impression, such as the 
decrease in the density of goblet cells. [36] [37] 
5.4 Justification 
Patients who attend SDPL independently of its etiology and degree of severity will have to use ocular 
lubricants to reduce symptoms and improve their quality of life. 
Ocular lubricants are the first line of drugs for eye symptoms related to tear film dysfunction in 
healthy subjects, with a prevalence of 25 to 35% in people over 60 years of age and 6% in those over 
40 years. If we add to this those who mention occasional symptoms or who depend on a work or 
occupational situation and who use it for intermittent periods throughout their lives, the spectrum 
of population that will have access to these medications is very extensive. It is estimated that 50% 
of patients diagnosed with lacrimal film dysfunction without concomitant diseases will use more 
than 2 ophthalmic solutions in 5 years of treatment. 
Taking into account the observation of the cumulative effect of conservatives such as BAK and that 
their adverse events are directly linked to the amount instilled and their repetitions, it is imperative 
to provide options that do not have aggravating inflammation secondary to the use of conservatives. 


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PRO-087 is a preservative-free formulation that requires the documentation of your safety profile. 
5.5 Objectives and hypothesis 
5.5.1 General Objective 
To evaluate the safety and tolerability of the preservative-free ophthalmic solution PRO-087 on the 
ocular surface. 
5.5.2 Specific Objectives 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of the 
density of goblet cells 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in intraocular pressure. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in ocular surface stains. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 through changes 
in laboratory tests. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in vital signs. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in visual capacity. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in the tear-rupture time. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in the ocular comfort index. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in the posterior segment. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 by means of 
changes in ophthalmological signs and symptoms. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 when assessing 
the integrity of the anterior segment by means of fluorescein staining.  
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 when evaluating 
the integrity of the anterior segment by means of the green lysine stain. 
 
Describe the safety of the preservative-free ophthalmic solution PRO-087 through the 
presentation of adverse events. 
 
5.5.3 Hypothesis 
Ha  The ophthalmic solution PRO-087 presents a safety and tolerability profile similar to comparators 
in healthy subjects 
Ho The ophthalmic solution PRO-087 presents a different safety and tolerability profile compared to 
comparators in healthy subjects. 
 
5.6 Design and study plan 
Clinical trial, phase I, controlled, parallel groups, double blind randomization, exploratory. 
5.6.1 Discussion of the study design 
 


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The design of the study (clinical trial) is considered the highest quality standard in the data when it 
is sought to explore the effect of an intervention. The phase of pharmacological development (phase 
I) corresponds to the objective of the study which is to assess safety and tolerability, so that the 
intervention time is short and the sample size required is less than that of a clinical efficacy trial. The 
presence of parallel groups allows the comparison between the intervention groups on the outcome 
variables. Blinding and randomisation allow to reduce biases that are incurred with other designs, 
eg. Selection bias, evaluation bias, among others. 
 
6. Material and methods. Participants, interventions and variables 
 
6.1 Center of the study 
 
The present study will be performed in ophthalmology offices duly equipped and registered for their 
proper functioning. According to the needs of the sponsor, these may be private or public, be 
attached to a hospital or clinic or be independent. 
 
6.1.1 Organization of the center 
 
Each study center will have a principal investigator (PI). The PI is the ophthalmology specialist in the 
clinical study.  
The PI is responsible for forming a multidisciplinary research team to carry out the clinical study 
according to protocol, under its scientific guidance. It is the prerogative of the IP the design of the 
organization of its center and the selection of the personnel that will perform the functions. 
Nevertheless, the minimum organization of the research team requested by the sponsor requires 
the figure of sub-researcher, study coordinator and pharmacist. (See Figure 1 ) 
 
 
Any person to whom the PI designates, under his / her responsibility, a part of the follow-up of the 
study (co-investigator, under-researcher, nurse, etc.) or a specific function of participation in the 
study (pharmacist, administrative assistant, study coordinator, etc.) should appear in the 
"Delegation of Responsibilities" format. 
 
 


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Figure 1 Minimum organization of the center 
The "Delegation of Responsibilities" and the "Organizational Chart of the Center" must be delivered 
to the sponsor before the start of the study and updated if the members or their responsibilities are 
changed. 
6.1.2 Documentation to be delivered to the sponsor 
The PI must deliver to the sponsor, before the start of the study: 
- Curriculum vitae updated, in Spanish, dated and signed (maximum 10 pages), of the IP and the 
staff that integrates its organizational chart of the center.  
- Copy of IP academic certifications (degree certificate and specialty diploma in ophthalmology, 
federal professional certificates) 
- Copy of academic certifications of the maximum degree obtained, from each one of the members 
of your research team, that cover their capacity to perform the delegated functions. 
- Copy of operation notice or similar issued by corresponding regulatory entity (When applicable) 
- Certificate of good clinical practice in force. If the issuing institution does not specify the validity 
period in the certificate, the date of issue of the certificate must not exceed one year 
6.1.3 Closure of the center 
The closing of the center will be carried out once the last visit of the last included subject previously 
agreed between the sponsor and the IP has been made. The closing process will be according to the 
internal operating procedures of the sponsor. 
It is the prerogative of the sponsor to prematurely close a study center, it must inform the IP 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 clinical history. 
- 
Age between 18 to 40 years. 
- 
Both genders. 
- 
Blood tests [complete blood count (BHc), three-element blood chemistry (QS) and liver 
function tests (PFH)] within normal parameters specified by the reference laboratory with 
a lower and upper margin of 10%. 
 
Principal
Investigator
Subinvestigator
Pharmacist
Study
coordinator


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- 
Vital signs within normal parameters.  
- 
Visual ability 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 research 
products. 
 
Subject users of topical ophthalmic medications of any pharmacological group.  
 
Subject users of medication by any other route of administration. 
 
Pregnant or lactating women. 
 
Women without a history of hysterectomy, 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 the 
present study. 
 
Diagnosis of liver disease or triple the normal upper value of any of the following liver 
enzymes: aspartate transferase (AST), alanine transferase (ALT) or bilirubin. 
 
Inability to attend or answer the evaluations made in each of the visits. 
 
Positive tobacco use (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 users. 
6.2.2.2 Medical and therapeutic criteria 
6.2.3 Elimination criteria 
 
Withdrawal of the consent letter under information. 
 
Presentation of serious adverse event. 
 
No tolerability or hypersensitivity to any of the compounds used during the tests 
(fluorescein, green lysine, tetracaine) 
 
No tolerability or hypersensitivity to any of the investigational drugs. 
 
Adherence <50% determined by the diary of the subject or by the weight of the bottle, of 
the established dose of the pharmacological intervention in any of the visits. 
6.2.4 Identification of the subject 
 
The patients of the study will be identified by a number and the initials of their name. 
 
The initials of the study subject 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 maximum 
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 


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a. Initials: AMC 
2. Juan De la Torre Orozco 
a. Initials: JDO 
In the counting stage, the participant number will be assigned consecutively, using 3 consecutive 
digits. Once the subject has been selected, he will be assigned a number with which he will be 
identified throughout the study. Said code will be composed of eight numbers in the following order 
from left to right: 
• 
Three digits of the molecule under study according to the denomination by the sponsor. 
• 
Two digits corresponding to the research center number. 
• 
Three digits of the number consecutive to its inclusion assigned to the research center. 
Example: 
 
6.3 Intervention 
6.3.1 Managed treatments 
6.3.1.1 Treatment in study. 
- 
PRO-087  
o Active ingredients (lubricant): chondroitin sulfate 0.18%, sodium hyaluronate 
0.1% 
o Pharmaceutical form: 
o Prepared by: Sophia Laboratories, S.A. of C.V. 
o Dosage: 1 drop in both eyes, 4 times a day during the waking period 
o Description of the solution: transparent solution, free of visible particles. 
o Description of container: sterile multi-dose bottle 
Table 4. Quali-quantitative formulation of PRO-087 
Type of agent 
Quantity mg/mL 
Function 
Chondroitin sulfate 
1.8 
Active principle (lubricant) 
Sodium hyaluronate 
1 
Active principle (lubricant) 
Boric acid 
2.00 
Active principle 
Sodium borate decahydrate 
Without showing 
Additive 
Polysorbate 80 
Without showing 
Additive 
Sorbitol 
Without showing 
Additive 
Potassium chloride 
Without showing 
Additive 
Sodium chloride 
Without showing 
Additive 
087-01-001 
Molecule key 
Center number 
Inclusion number 


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Type of agent 
Quantity mg/mL 
Function 
Magnesium 
chloride 
hexahydrate 
Without showing 
Additive 
Water for the preparation of 
injectables c.b.p. 
1.00 
Vehicle 
Quali-quantitative formulation of the product under investigation PRO-087. The concentration of the active principles 
is shown, as well as the substances that act as a buffer additive. 
6.3.1.2 Reference treatment 
- 
Xyel Ofteno® 
o  Active principles: 
o  Pharmaceutical form: Ophthalmic solution 
o  Prepared by: Sophia Laboratories, S.A. of C.V. 
o  Dosage: 1 drop in both eyes, 4 times a day during the waking period 
o  Description of the solution: transparent solution, free of visible particles. 
o  Description of container: sterile multi-dose bottle  
- 
Systane Ultra®  
o  Active ingredients:): Polyethylene glycol 400 0.4%, propylene glycol 0.3% 
o  Pharmaceutical form: Ophthalmic solution 
o  Presentation: multi-dose dropper bottle 
o  Prepared by: Alcon Laboratories, Inc. 
o  Dosage: 1 drop in both eyes, 4 times a day during the waking period. 
6.3.2 Strategies to improve adherence and procedure to monitor adherence 
1. Each visit the research subject will return the assigned bottle in order to evaluate the 
adherence by weight. 
2. Direct questioning by the IP about the application of the intervention. 
3. At the IP criteria, messages can be sent or reminder calls can be made. 
4. Delivery of printed chronogram specifying the date of the visit and its activities 
5. Journal of the subject.  
6.3.2.1 Procedure to monitor adherence 
Before delivering the medication to the research subject, the pharmacist must carry out the 
weighing of the bottles to be delivered. After the return of the medication by the subject will also 
carry out the weighing. Guidelines to follow for weighing: 
o The pharmacist will use the scale provided by the sponsor 
o Place the bottle in the center of the scale. You will get the result of the 
measurement. 
o Remove the jar from the balance and put it back in, confirming that the 
measurement is the same. If it is different, it will weigh one more time and take the 
average of the 3 measurements 
o Record the result in the log and the CRF provided by the sponsor  
The adhesion will be calculated considering: the weight of the empty bottle, the weight of the drop, 
the weight of the bottle with the content, the calculation of the total of drops to be applied during 
the entire time of intervention and the total weight of the drops applied. The following simplified 
formula will be used: 


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𝐴𝑑= (𝑃𝑖−𝑃𝑓)100
𝑃𝑇
 
Where: 
Ad = Adhesion 
𝑃𝑖 = weight of the bottle delivered to the subject at the start 
𝑃𝑓 = weight of the bottle returned by the subject 
𝑃𝑇 = weight of the posology indicated for the intervention 
 
𝑃𝑇= (𝑃𝑔)𝐺 
Where: 
𝑃𝑔= weight of the intervention drop, determined by the research and development department 
G = number of drops indicated for the intervention 
Adherence will be estimated at each visit where the research subject returns the intervention. Only 
those bottles without apparent physical damage will be considered for the calculation. This result 
will allow the PI to determine if the subject continues in the study according to the stipulations of 
the elimination criteria.  
The evaluation of the adherence by means of the diary of the subject will be carried out in the 
following way: 
 
𝐴𝑑= (𝐴𝑟)100/𝐴𝑖 
Ad = Adherence 
Ar = Registered applications 
Ai = Applications indicated for the intervention 
The final (overall) adhesion will be determined by the average of the adherence of each of the visits. 
It will not be considered for the calculation of final adherence if the subject did not return the bottle 
in two subsequent visits. 
 
6.3.3 Treatments and concomitant interventions allowed and prohibited during the study. 
The use of concomitant medications by any route of administration during the intervention period 
will not be allowed. Except those specified for the study procedures. The objective of this restriction 
is to avoid pharmacological interactions that could alter the results of the evaluated variables. 
6.3.4 Treatment management. 
The interventions will be provided by Sophia Laboratories, S.A. of C.V., for each research center. 
They will be labeled, reconciled and weighed previously. The handling of the treatment will be under 
the responsibility of the researcher or a designated member of his team.  
6.3.4.1 Delivery and reception. 
Delivery will be made in closed cardboard boxes by means of a courier service or directly by the 
sponsor's staff to the home of the research center according to the study plan. 
  


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The reception will be exclusively carried out by the research center team, including the researcher. 
You must check the good condition of the primary packaging (box). In the event that it shows 
alterations or defects in its integrity that from its judgment could have damaged the content, it 
should report it to the sponsor. If the package does not show significant defects, it will proceed to 
open it. 
Inside you must locate the acknowledgment document and the logger (data logger) of temperature 
and humidity. You should check that the registered temperature and humidity comply with the 
specifications for transport and shelter (see section 6.3.4.2 Storage). Verify the content 
(interventions) with what is reported in the document. In case the document corresponds to the 
content, it will sign the receipt and send it to the sponsor. Otherwise, notify the sponsor.  
In the study center, the personnel assigned by the PI will deliver the corresponding treatment to the 
subjects admitted, sufficient for the period to be covered. The delivery will be made in stages, 
medication will be delivered at the baseline visit, on visits 1 and 2. The center must register the 
medication delivered. 
6.3.4.2 Storage. 
The medication must be stored in a secure area with restricted access. 
The storage temperature should be <30 ° Celsius. 
The research center has the obligation to record, in the format designated by the sponsor, the 
temperature and humidity registered in the data logger. This record should include the current 
temperature and humidity, as well as the minimum and maximum of each of these. It must be done 
at least once a day, on business days. 
Said data will be compared by the clinical monitor according to the registration in the data logger.    
6.3.4.3 Return. 
The research subjects will return to the personnel indicated by the IP in the center their treatments 
in visits 1, 2 and final. The refund will be made by the research center when the sponsor indicates 
it. Prior to the return the research center must make a count of the assigned medication and the 
remaining medication, with the aim of creating an inventory which serves for the final filling of the 
medication return form. 
6.4 Outcome variables. 
6.4.1 Security variables. 
6.4.1.1 Primary outcome variables. 
 
Density of goblet cells 
 
Presence of adverse events. 
 
Intraocular pressure. 
 
Visual ability 
 
Laboratory tests: BHc, QS and PFH. 
 
Epithelial defects in cornea and conjunctiva. 
 
Ophthalmological signs: conjunctival hyperemia, chemosis. 
6.4.1.2 Primary outcome variables of tolerability. 
 
Burning 
 
Foreign body sensation 


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-Itching 
-Eye comfort index 
6.4.1.3 Secondary outcome variables. 
 
Rupture time of the tear film 
 
Life signs: FC, FR, TAS. 
 
Subsequent segment 
 
Quality questionnaire. 
6.4.2 Efficacy variables. 
6.4.2.1 Primary outcome variables. 
Does not apply because it is a phase I study. 
6.4.2.2 Secondary outcome variables.   
Does not apply because it is a phase I study. 
 
6.4.3 Methods and scales to be used for the measurement of the variables 
Variable 
Unity 
Symbol 
Type 
Method of measurement 
Normal value 
Age 
Years 
-- 
Continuous 
Calculation from the 
date of birth 
NA 
Gender 
Female Male 
F / M 
Nominal 
Direct questioning 
NA 
Adverse events 
Number of cases 
n 
Discreet 
Count 
NA 
Intraocular pressure 
Milimeters 
of 
mercury 
mmHg 
Continuous 
Goldman´s 
applanation 
tonometry 
11 - 21 
Visual ability 
Fraction 
Snellen 
Nominal 
Primer 
 
Tear rupture time 
Seconds 
s 
Continuous 
Direct count 
> 10   
Eye comfort index 
points 
-- 
Discreet 
Questionnaire 
 
Adverse events 
Present / Absent 
-- 
Nominal 
Comprehensive 
valuation 
Absent 
Goblet cell density 
Cells per square 
millimeter 
Cel/mm2 
Continuous 
Cytology by 
impression 
> 500 cel/mm2 
Vital signs 
Heart rate 
Beats per minute 
lpm 
Discreet 
Auscultation 
60 – 100 
Breathing frequency 
Breaths per 
minute 
rpm 
Discreet 
Auscultation 
12 – 24 
Systemic 
blood 
pressure 
Milimeters of 
mercury 
mmHg 
Continuous 
Non-invasive 
auscultatory 
measurement 
< 120 / 80 
Previous segment 
Epithelial defects 
Degrees 
-- 
Discreet 
Direct observation 
with fluorescein and 
green lysamin stain 
Oxford Scale 


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Variable 
Unity 
Symbol 
Type 
Method of measurement 
Normal value 
Ophthalmologic signs and symptoms  
 
 
Conjunctival 
hyperemia 
Normal / Very 
Light / Mild / 
Moderate / 
Severe 
-- 
Ordinal 
Direct observation. 
Classification of Efron. 
Normal 
Chemosis 
Present / Absent 
 
-- 
Nominal 
Direct observation 
Absent 
Burning 
Severity: Absent, 
very mild, mild, 
moderate and 
severe 
 
-- 
Nominal 
Direct questioning 
Absent 
Foreign body sensation 
Severity: Absent, 
very mild, mild, 
moderate and 
severe 
 
 
-- 
Nominal 
Direct questioning 
Absent 
Pruritus 
Frequency: At all 
times, almost at 
all times, 50% of 
the time, almost 
in no time, at any 
time 
 
-- 
Nominal 
Direct questioning 
Absent 
Postinstilation symptoms 
 
Burning 
Present / Absent 
 
-- 
Nominal 
Journal of the subject 
Absent 
Foreign body sensation 
Present / Absent 
 
-- 
Nominal 
Journal of the subject 
Absent 
Pruritus 
Present / Absent 
 
-- 
Nominal 
Journal of the subject 
Absent 
Red eye (symptom) 
Present / Away 
 
-- 
Nominal 
Journal of the subject 
Absent 
 


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Variable 
Unity 
Symbol 
Type 
Method of measurement 
Normal value 
 
Posterior segment 
Macula 
Normal / 
Abnormal 
-- 
Nominal 
Observación directa 
Normal 
Optical disk 
integrity 
Normal / 
Abnormal 
-- 
Nominal 
Observación directa 
Normal 
Blood count 
Erythrocytes 
 
M/uL 
Continuous 
 
 
Hemoglobin 
Grams over 
deciliter 
g/dL 
Continuous 
 
 
Hematocrit 
Percentage 
% 
Continuous 
 
 
VGM 
Femto liters 
fL 
Continuous 
 
 
HCM 
picograms 
pg 
Continuous 
 
 
CMHbG 
Grams over 
deciliter 
g/dL 
Continuous 
 
 
Leukocytes 
Thousands per 
liter units 
Mil/uL 
Continuous 
 
 
Platelets 
Thousands per 
liter units 
Mil/uL 
Continuous 
 
 
Myelocytes 
Percentage 
% 
Discreet 
 
 
Metamyelocytes 
Percentage 
% 
Discreet 
 
 
Bands 
Percentage 
% 
Discreet 
 
 
Segmented 
Percentage 
% 
Discreet 
 
 
Lymphocytes 
Percentage 
% 
Discreet 
 
 
Monocytes 
Percentage 
% 
Discreet 
 
 
Eosinophils 
Percentage 
% 
Discreet 
 
 
Basophils 
Percentage 
% 
Discreet 
 
 
Blastos 
Percentage 
% 
Discreet 
 
 
Blood chemistry 
Glucose 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Urea 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Creatinine 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Liver function tests 
 


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Variable 
Unity 
Symbol 
Type 
Method of measurement 
Normal value 
Alanine transferase 
Units on liter 
U/L 
Continuous 
 
 
Aspartate transferase 
Units on liter 
U/L 
Continuous 
 
 
Total bilirubin 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Direct bilirubin 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Indirect Bilirubin 
Milligrams on 
deciliter 
mg/dL 
Continuous 
 
 
Table 5. Scales to be used. 
The following describes the methods and scales that will be used for the measurement of the 
variables, which are in strict alphabetical order: 
6.4.3.1 Visual ability. 
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 separation angle 
(located at the nodal point of the eye) between two objects that allows perceiving them as separate 
objects. 
Snellen's 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 arc minutes. Thus, at 6 meters a letter 6/6 (20/20) 
equals 5 minutes of arc, a letter 6/12 (20/40) equals 10 minutes, and a letter 6/60 (20/200) equals 
50 minutes The Snellen fraction can also be expressed as a decimal (ie 20/20 = 1 and 20/40 = 0.5). 
[38] 
The VA will be evaluated basally, without refractive correction with the Snellen chart. Which will be 
located in a place with adequate lighting, natural or artificial and at a distance of 3m from the subject 
to be evaluated. The visual acuity of each eye will be taken, starting with a right eye (DO) asking the 
subject to keep both eyes open and using an occluder to cover the left eye (OS); the subject will 
read aloud the lines that the evaluator points out, the line of smaller letters that he reaches to see 
will be annotated by the fractional evaluator as the DO of the DO in the clinical record. Proceed to 
the OS with the same method. 
Subsequently the best refractive correction of the subject will be made and the examination will be 
repeated using the obtained refraction. This result will be reported as CV, it will be written in fraction 
in the clinical file and in the CRF, in addition in the CRF it will be written in decimal. By definition, 
the CV can not be inferior to the AV. 
 
6.4.3.2 Goblet cell density (Cytology per impression). 
The density of goblet cells in the conjunctiva can be a reflection of the severity of alteration in the 
ocular surface. [39] It has been determined that the normal density is greater than 500 cel / mm2. 
[40] Impression cytology refers to the application of a cellulose acetate filter to the ocular surface 
to remove the superficial layers of the epithelium; these removed cells can be subjected to 
histological, immunohistological or molecular analysis. [41] 
The cytology per impression of the conjunctiva will be done by the researcher using the device 
provided by the sponsor for this purpose, which may consist of a circular cell of approximately 10 
mm in diameter, with a cellulose acetate filter millicelll. After ocular surface anesthesia, with topical 


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tetracaine, the researcher will ask the subject to expose the temporal surface of the eye to be 
evaluated and gently press the cell on the temporal conjunctiva (2 to 3 mm of the sclerocorneal 
limbus) for 5 seconds and remove the cell with a peeling technique (Illustration 1. Cytology per 
impression). Immediately fix with diethyl ether spray with one or two shots at 15 cm distance. The 
investigator will contact the Courier designated by the sponsor for the delivery of the samples to 
the histopathological analysis. 
The data of the histopathological report to be recorded in the CRF are: density of goblet cells and 
degree of squamous metaplasia according to the Nelson scale. (See Table 6) 
In the visits that are required to perform this procedure, it will be done prior to the use of ocular 
surface stains.  
 
Illustration 1. Cytology per impression. 
 
Table 6. Nelson classification 
Grade 
Detail description of the  
epithelial cells 
Characteristics of goblet cells 
0 
Small and round cells; Large nuclei, 1: 
2 ratio with nuclear cytoplasm 
Abundant goblet cells (> 500 cells / mm2), globose and 
oval with an intense PAS-positive staining of the 
cytoplasm. 
1 
Slightly enlarged cells; smaller nuclei, 
1: 3 ratio with nuclear cytoplasm 
Marked decrease in the number of goblet cells (350 to 
500 cells / mm2) but still maintain their globose and oval 
shape and intense staining 
2 
Enlarged and polygonal cells; small 
nuclei, ratio 1: 4 to 1: 5 with nuclear 
cytoplasm 
Marked decrease in the number of goblet cells (100 to 
350 cells / mm2), less intense PAS - positive with poorly 
defined cell borders 
3 
Even larger and polygonal cells; small 
and pyknotic nuclei, 1: 6 ratio with 
nuclear cytoplasm 
Few goblet cells (<100 cells / mm2) 
Adapted from Nelson & Wright [24] [42]  
 
6.4.3.3 Eye comfort index. 
 
 
It is a questionnaire designed to measure the irritation of the ocular surface with Rasch analysis to 
produce estimates on a linear scale of intervals (ratings: 0-100). Similar to the index for ocular 


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surface diseases, the ocular comfort index (ICO) evaluates symptoms. The ICO contains 8 items (one 
positive and eight negative) that focus on the discomfort associated with alterations of the ocular 
surface. Each of these questions has two parts, which inquire separately the frequency and severity 
of the symptoms. [43] See annex 13.1 Eye comfort index. 
The evaluator will deliver the questionnaire to the subject and allow the subject to answer it calmly 
without any pressure and / or coercion, will only assist him if he has difficulty understanding any of 
the questions. 
6.4.3.4 Eye surface integrity:  
This will be done by means of biomicroscopy using the slit lamp of the research center. A full 
assessment of the previous segment will be made, which will be recorded in the clinical file. The 
lighting techniques used will be at the discretion of the IP. 
The variables that will be registered in this protocol are:  
- Conjunctival hyperemia. 
It is defined as the simplest reaction of the conjunctiva to a stimulus, a red appearance 
secondary to the vasodilation of the conjunctival vessels of variable intensity. He will 
graduate using the Efron scale. [44] See annex 13.2 Efron scale for conjunctival hyperemia 
- Chemosis. 
It is defined as conjunctival edema, the result of an inflammatory reaction. It is qualified as 
present or absent. The evaluator will use a narrow beam of light at 60 ° and will measure if 
the conjunctiva separates from the sclera at ≥ 1/3 of the total palpebral opening or if it 
exceeds the gray line. [45]   
6.4.3.4.1 Stains. 
• Staining with green lysine. 
A drop of topical anesthetic will be instilled in the conjunctival cul-de-sac, then a second 
drop will be applied to the tip of the strip of green lysine and it will be allowed to slip towards 
the bottom of the sac. It is essential to quickly evaluate the staining, in sequence, first in the 
DO and then the OS, so that the observed patterns are equally bright. [19] See Annex 13.3 
Oxford Scale 
• Fluorescein staining. 
A drop of topical anesthetic will be instilled into the conjunctival cul-de-sac, then a second 
drop will be applied to the tip of the fluorescein strip and it will be allowed to slip to the 
bottom of the sac. It is essential to quickly evaluate the staining, in sequence, first in the DO 
and then the OS, so that the observed patterns are equally bright. This valuation will be 
made with the cobalt blue filter. [19] See Annex 13.3 Oxford Scale 
For both stains, the value obtained according to the Oxford scale will be registered in the CRF. 
6.4.3.5 Presence of adverse events.  
The management of the EAs will be done according to what is described in section 9.3 Adverse 
events 
The PI will register in the corresponding section of the CRF the EAs that come to present the subjects 
of the study in addition to referring it in its essential document. 


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6.4.3.6 Intraocular pressure. 
Tonometry is the objective measure of IOP, based primarily on the force required to flatten the 
cornea or the degree of corneal indentation produced by a fixed force. Goldman's tonometry is 
based on the Imbert-Fick principle. [38] The tonometry will be performed, after instillation of a drop 
of topical anesthetic (tetracaine 0.5%), with fluorescein and the use of the cobalt blue filter (after 
evaluation of the corneal surface staining). There will be 3 shots, which will be recorded in the 
clinical file and the average will be registered in the CRF. 
6.4.3.7 Posterior segment. 
The evaluation of the posterior segment will be carried out under medication mydriasis (tropicamide 
0.8% / phenylephrine 5%), in the slit lamp with an aerial loupe (at the choice of the PI). An integral 
assessment of the fundus (including optic disk, posterior pole and periphery) will be performed in 
search of abnormalities that alter the study result. The result of the assessment will be recorded in 
the clinical file. The CRF will record the assessment of the macula and optic nerve as normal, 
abnormal or abnormality that does not affect.  
6.4.3.8 Vital signs. 
The vital signs to be evaluated (FC, FR and TAS) can be measured by an assistant duly indicated in 
the organization of the center and the delegation of responsibilities, the technique to be used for 
the FC and FR will be with the count of repetitions in one minute by Direct auscultation with 
stethoscope. 
The SBP should be measured with 5 minutes of previous rest, in the left arm. The instrument can be 
manual or automatic according to the IP. It is necessary that all measurements are equal in 
circumstances. 3 measurements will be made, with a minimum interval of 5 minutes between them. 
The IP will record the average in the note and the CRF. 
6.4.3.9 Ocular symptomatology. 
The subject will be questioned directly about the presence in general (since the last visit) of the 
following symptoms: burning, foreign body sensation and pruritus. Respond about the severity and 
frequency of symptoms such as: 
Severity: Absent (0), very mild (1), mild (2), moderate (3) and severe (4) 
Frequency: At all times (4), almost at all times (3), 50% of the time (2), almost at no time (1), at any 
time (0). 
The number corresponding to each symptom will be registered in the CRF. 
Symptomatology postinstilación:  
The subject will be requested, that in the subject's daily instrument, after registering the application 
of the product under investigation, mark YES or NO according to the presence of the following 
symptoms: burning, sensation of a foreign body, red eye and pruritus. 
6.4.3.10 Breaking time of the tear film. 
One of the first aspects of the tear film that changes when there is an alteration to 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 to evaluate the stability of the tear film is the evaluation of TRL with 
fluorescein. Once the fluorescein is instilled, with the cobalt blue filter the patient is asked not to 
blink. The precorneal colored fluorescein layer will change to less fluorescent or non-fluorescent 


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regions. The time that elapses from the last blink until the appearance of these regions is the TRL. It 
will be reported in seconds, in the clinical file and in the CRF. 
6.4.3.11 Pregnancy test. 
It refers to the performance of a rapid pregnancy test in all women of childbearing age who wish to 
enter the study. By fertile age we understand women who have not had their menopause, defined 
as 12 months since the last menstrual period in women over 40 years of age; or those who 
underwent bilateral hysterectomy or oophorectomy. Women of childbearing age with 
contraceptive methods including bilateral tubal obstruction should be tested for pregnancy. This 
test will be carried out by the IP or the designated team person according to the instructions of the 
device delivered by the sponsor. When applicable, the completion, result and date must be 
registered in the CRF. If you do not apply, you must write down the reason. 
6.4.3.12 Lab tests. 
The PI will deliver to the subject the order of the studies of BH, QS and PFH, to be carried out in the 
clinical laboratory designated by the sponsor. The clinical laboratory will deliver to the IP the results 
for its assessment and registration. The normal parameters to be considered will be the ranges 
established by the laboratory, Nevertheless the clinical criterion of the PI will prevail in the decision 
of normality or abnormality of the results. 
6.4.4 Measurement time. 
The measurements of the variables of primary and secondary outcome will be made and evaluated 
for each visit, according to the following:  
Basal Visit / Day 0.  
Some of these measurements will be taken at the screening visit to complete the eligibility criteria 
(see Schedule and study diagram), at the discretion of the PI, they may be taken to complete the 
data of the baseline visit. 
1. Visual ability 
2. Density of goblet cells (Cytology per impression) 
3. Intraocular pressure. 
4. Eye comfort index 
5. Evaluation of ocular signs and symptoms 
6. Integrity of ocular surface 
a. Includes stains 
       b. TRL 
7. Subsequent segment evaluation. 
8. Vital signs 
9. Evaluation of results of laboratory tests. 
Visit 1 / Day 3.  
It can be done in a period ± 1 day in relation to day 3 of application. 
1. Visual ability 
2. Intraocular pressure. 
3. Evaluation of ocular signs and symptoms 
4. Integrity of ocular surface 
a. Includes stains 
b. TRL 
5. Vital signs 
6. Evaluation of adverse events. 


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Visit 2 / Day 6.  
It can be done in a period ± 1 day in relation to the 6th day of application. 
1. Visual ability 
2. Intraocular pressure. 
3. Evaluation of ocular signs and symptoms 
4. Integrity of ocular surface 
a. Includes stains 
b. TRL 
5. Vital signs 
6. Evaluation of adverse events. 
Final Visit / Day 11.  
It can be done in a period ± 1 day in relation to the 11th day of the start of application. 
1. Visual ability 
2. Density of goblet cells (Cytology per impression) 
3. Intraocular pressure. 
4. Eye comfort index 
5. Evaluation of ocular signs and symptoms 
6. Integrity of ocular surface 
a. Includes stains 
b. TRL 
7. Subsequent segment evaluation. 
8. Vital signs 
9. Evaluation of adverse events. 
Security call / Day 13.  
It can be done in a period ± 1 day in relation to the 13th day of the start of application. 
1. Ask about the presence of an adverse event. 
2. Evaluation of results of laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5 
6.5 Timeline and study diagram. 
 
Procedures 
Scrutiny 
Basal Visit 
Visit 1 
Visit 2 
Final Visit 
Call  
Security 
  
Day 0 
Day 3 ± 1 
Day 6 ± 1 
Day 11 ± 1 
Day 13 ± 1 
 
 
 
 
 
 
 
CI Signature 
X 
 
 
 
 
 
Clinic history 
X 
 
 
 
 
 
Ophthalmological clinical history 
X 
 
 
 
 
 
Laboratory sample taking 
X 
 
 
 
X 
 
Laboratory tests review 
 
X 
 
 
 
X 
Pregnancy test 
X 
 
 
 
X 
 
Eligibility criteria 
X 
Xa 
 
 
 
 
Assignment 
 
X 
 
 
 
 
Delivery of intervention 
 
X 
X 
X 
 
 
Return of intervention 
 
 
X 
X 
X 
 
Adherence evaluation 
 
 
X 
X 
X 
 
Adverse events 
 
 
X 
X 
X 
X 
Intraocular pressure 
X 
X1 
X 
X 
X 
 
Visual ability 
X 
X1 
X 
X 
X 
 
TRL 
X 
X1 
X 
X 
X 
 
Epithelial defects (TF and TVL) 
X 
X1 
X 
X 
X 
 
Eye signs and symptoms 
X 
X1 
X 
X 
X 
 
posterior segment 
X 
X1 
 
 
X 
 
Vital signs 
X 
X1 
X 
X 
X 
 
Ocular Comfort Index 
 
X 
 
 
X 
 
Goblet cell density (cytology by 
impression) 
 
X 
 
 
X 
 
Daily delivery of the subject 
 
X 
X 
X 
 
 
Return 
/ 
Evaluation 
of 
the 
subject's Journal 
 
 
X 
X 
X 
 
Delivery Quality Questionnaire 
 
X 
 
 
 
 
Return and Evaluation of the 
quality questionnaire 
 
 
 
 
X 
 
Continuity 
evaluation 
of 
the 
subject 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ 
a The eligibility criteria will be completed with the revision of the laboratory exams. 1 These measurements may be 
taken from the result of the screening visit, if it does not exceed the previous 7 days. It is the prerogative of the PI to 
decide whether to repeat the measurements 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 (assent) 
▪ 
General and ophthalmological clinical history: refers to the technical, clinical and legal 
document in which the patient's health conditions, medical acts and other procedures 
performed on the patient are recorded chronologically. It includes the anamnesis and 
comprehensive ophthalmological exploration that allows to discern the patient's eligibility. 
If the patient is taken from the established consultation of the study center, he / she will be 
able to use the existing clinical history, only having to perform an update. 
▪ 
Taking laboratory samples: see 6.4.3.12 Laboratory tests. 
▪ 
Pregnancy test: see 6.4.3.11 Pregnancy test. 
▪ 
Eligibility criteria: refers to the review by the IP, where it states that the subject can be 
included in the study by meeting the inclusion criteria and not meeting the exclusion 
criteria. See 6.2 Eligibility criteria 
▪ 
Intraocular pressure: see 6.4.3.6 Intraocular pressure 
▪ 
Visual ability: see 6.4.3.1 Visual capacity 
▪ 
TRL: see 6.4.3.10 Rupture time of the tear film 
▪ 
Epithelial defects (TF and TVL): see 6.4.3.4.1 Stains 
▪ 
Eye signs and symptoms: see 6.4.3.4 Eye surface integrity: and 6.4.3.9 Ocular 
symptomatology 
▪ 
Subsequent segment; see 6.4.3.7 Subsequent segment 
▪ 
Vital signs: see 6.4.3.8 Vital signs 
6.5.1.2 Basal Visit . 
▪ 
Review of laboratory tests: refers to the review and analysis by the IP of the results of the 
BH, QS and PFH. See 6.4.3.12 Laboratory tests. 
▪ 
Eligibility criteria: with the laboratory results, the subject's profile will be finalized for 
inclusion or not. 
▪ 
Assignment: It refers to determining the intervention that the patient will follow during the 
study. It will be done according to section 7. Methods. Assignment of the intervention. This 
assignment will be made at the baseline visit (day 0) and will go along with the indication to 
start the treatment period the next day (day 1). 
▪ 
Delivery of intervention: Refers to the delivery of the product under investigation to the 
patient of the study, by the research center. It will be done according to sections 6.3.1 
Managed treatments and 6.3.4.1 Delivery and reception. 
▪ 
Evaluation of variables: The data of the evaluation of the variables listed below can be taken 
from the scrutiny visit, as long as it does not exceed 7 days prior to this visit. It is the 
prerogative of the IP to decide whether to use the information from the screening visit or 
to repeat the evaluations in this visit. 
o 
Intraocular pressure 
o 
Visual capacity 
o 
TRL 
o 
Epithelial defects 
o 
Eye signs and symptoms 


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o 
Subsequent segment 
o 
vital signs 
▪ 
Eye comfort index: see 6.4.3.3 Eye comfort index 
▪ 
Density of goblet cells (cytology per impression): see 6.4.3.2 Density of goblet cells (cytology 
per impression) 
▪ 
Delivery of the subject's diary: It refers to the delivery by the IP to the subject, the subject's 
daily instrument. 
▪ 
Delivery of quality questionnaire: It refers to the delivery by the IP to the subject, the quality 
questionnaire instrument. 
6.5.1.3 Visit 1. 
▪ 
Intervention delivery: see 6.5.1.2 Baseline visit 
▪ 
Return of intervention: refers to the return of research products to the center by the 
research subject. 
▪ 
Evaluation of adherence: refers to the assessment made by the IP according to section 
6.3.2.1 Procedure to monitor adherence 
▪ 
Adverse events: see 6.4.3.5 Presence of adverse events 
▪ 
Intraocular pressure: see 6.4.3.6 Intraocular pressure 
▪ 
Visual ability: see 6.4.3.1 Visual capacity 
▪ 
TRL: see 6.4.3.10 Rupture time of the tear film 
▪ 
Epithelial defects (TF and TVL): see 6.4.3.4.1 Stains 
▪ 
Eye signs and symptoms: see 6.4.3.4 Eye surface integrity: and 6.4.3.9 Ocular 
symptomatology 
▪ 
Vital signs: see 6.4.3.8 Vital signs 
▪ 
Submission of the subject's diary: see 6.5.1.2 Baseline visit 
▪ 
Return / daily evaluation of the subject: refers to the delivery of the subject's diary to the IP 
by the subject. The PI will review the diary to assess its correct filler, evaluate postinstilation 
symptoms and record applications. 
▪ 
Continuity assessment of the subject: refers to the determination by the IP and desire of 
the subject to continue with their participation in the study. 
6.5.1.4 Visit 2  
▪ 
Intervention delivery: see 6.5.1.2 Baseline visit 
▪ 
Return of intervention: see 6.5.1.3 Visit 1. 
▪ 
Evaluation of the adherence: it refers to the valuation made by the IP according to the 
section 
▪ 
Adverse events: see 6.4.3.5 Presence of adverse events 
▪ 
Intraocular pressure: see 6.4.3.6 Intraocular pressure 
▪ 
Visual ability: see 6.4.3.1 Visual capacity 
▪ 
 TRL: see 6.4.3.10 Rupture time of the tear film 
▪ 
Epithelial defects (TF and TVL): see 6.4.3.4.1 Stains 
▪ 
Eye signs and symptoms: see 6.4.3.4 Eye surface integrity: and 6.4.3.9 Ocular 
symptomatology 
▪ 
Vital signs: see 6.4.3.8 Vital signs 
▪ 
Submission of the subject's diary: see 6.5.1.2 Baseline visit 
▪ 
Return / daily evaluation of the subject: see 6.5.1.3 Visit 1. 
▪ 
Subject's continuity assessment: see 6.5.1.3 Visit 1. 
6.5.1.5 Final Visit 
▪ 
Laboratory sample taking: ver 6.4.3.12 Laboratory tests 


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▪ 
Pregnancy test: see Pregnancy test 
▪ 
Return of intervention: see 6.5.1.3 Visit 1. 
▪ 
Evaluation of the adherence: it refers to the valuation made by the IP according to the 
section 
▪ 
Adverse events: see 6.4.3.5 Presence of adverse events 
▪ 
Intraocular pressure: see 6.4.3.6 Intraocular pressure 
▪ 
Visual ability: see 6.4.3.1 Visual capacity 
▪ 
TRL: see 6.4.3.10 Rupture time of the tear film 
▪ 
Epithelial defects (TF and TVL): see 6.4.3.4.1 Stains 
▪ 
Eye signs and symptoms: see 6.4.3.4 Eye surface integrity: and 6.4.3.9 Ocular 
symptomatology 
▪ 
Subsequent segment; see 6.4.3.7 Subsequent segment 
▪ 
Vital signs: see 6.4.3.8 Vital signs 
▪ 
Eye comfort index: see 6.4.3.3 Eye comfort index 
▪ 
Density of goblet cells (cytology per impression): see 6.4.3.2 Goblet cell density (Cytology 
per impression) 
▪ 
Return / daily evaluation of the subject: see 6.5.1.3 Visit 1. 
▪ 
Return / evaluation of the quality questionnaire: refers to the delivery of the quality 
questionnaire to the IP by the subject.  
6.5.1.6 Security call. 
▪ 
Adverse events: see 6.4.3.5 Presence of adverse events 
▪ 
Review of laboratory tests: see 6.5.1.2 Baseline visit . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.5.2 Diagram of the study. 
An enrollment time of 30 days is estimated for the total sample. 
In order to increase the safety of the participants with the use of the products under investigation, 
a partial analysis will be carried out following a modification to the Fibonacci method. Said 
methodology will consist of including 33% of the total sample size (3 subjects per group, n = 9), 
which will complete all the visits and procedures described. Once this group of 9 subjects has 
finished their participation in the clinical study, they will proceed to perform a blinded analysis. 
During the period in which this sub-analysis is carried out, the inclusion of new participants will be 
restricted. Inclusion will resume when the sponsor notifies each research center. 
In addition to safety, the therapeutic adherence will be evaluated and problems related to the 
procedures will be solved, should they arise. 
 
Figure 3. Diagram of the study. 
6.6 Sample size. 
A total size of 30 subjects is estimated, divided into 3 intervention groups. (10 subjects per group) 
6.6.1 Calculation of the sample size. 
Although there are no references on the calculation of sample size in phase I studies, it was 
considered pertinent to perform it according to the presentation of adverse events reported by 
Hwang HS, et al, in a case-control study in 150 subjects with ophthalmic solutions with Hyaluronate 
sodium and diquafosol with and without preservative for 3 months. [46]. 
The percentage of adverse events that occurred with the preservative-free HS solution was 8%, 
which is why we consider that at least more than 60% of the exposed subjects will not present this 
rate of adverse events. 
10 days 
Waiting 
for 
laboratory 
results 
Systane Ultra® 
Xyel Ofteno® 
PRO-087 
Day 0 
Basal 
Visita 
Day 3 
Visit 1 
Day 6 
Visit 2 
Day 11 
Final 
Visit 
Day 13 
Called 
security 
-1 to -7 
days 
scrutiny 
Day 1 
Start 
applic
ti
Day 
10 
End 
applic


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The sample size was calculated using the formula for proportions 
𝑛= [(𝑝1)(𝑝2) + (𝑝1)(𝑝2) (𝑍1−𝛼
2
+ 𝑍1−𝛽)
2
]/(𝑝1 −𝑝2)2 
With a statistical confidence of 95% corresponding to the type I error, equal to 1.96, with a power 
of 80%, corresponding to the type II error, equal 0.84. 
According to the previous calculation, the result is 7.6 subjects (8) per group. The total when 
considering 3 intervention groups is 24 subjects, which was increased by 25% due to the probable 
losses. The total sample size required is 30 subjects. Therefore, each group will consist of 10 
subjects, who will provide both eyes for the analysis, so that the total sample to be analyzed will be 
composed of 60 eyes.    
6.7 Recruitment 
It is recommended that during the development of this research protocol, the principal investigator 
requests the approval of the Research Ethics Committee and the Research Committee, as well as 
the authorization to the relevant regulatory entity, to publish or disseminate in the mass media, the 
invitation to participate in the study to those people 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 cabinet exams that will allow the more 
accurate determination of their ocular clinical status by participating in a sponsored clinical research 
protocol. by Sophia Laboratories, SA of C.V. 
 
7. Methods Assignment of the intervention 
7.1 Generation of the allocation sequence 
The random numbers will be generated using the online tool 
: www.randomization.com 
3 strata corresponding to the intervention groups will be used, which will be balanced for a research 
center. The allocation will be 1: 1: 1.  
7.2 Blinding mechanism 
Blinding will be performed by personnel assigned by the Clinical Operations Management of Sophia 
Laboratories, S.A de C.V. This will consist of the elimination of the primary label (commercial) in the 
case of Xyel Ofteno® and Systane Ultra® and the placement of a label identical to the other 
interventions. Because the bottle in which Systane Ultra® is packaged differs in the color and shape 
of the lid used by Xyel Ofteno® and PRO-087, a masking will be carried out on the primary packaging 
which will be identical for the three interventions.   
7.3 Implementation 
The allocation sequence will be generated by personnel assigned by the Clinical Operations 
Management of Sophia Laboratories, S.A. of C.V.The research center will receive a set of envelopes 
which will contain the intervention number individually. The envelopes will be identical on the 


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outside. Each of these envelopes will be shown to the participants for their election by the principal 
investigator or by a designated member of their team.  
7.4 Blinding (Masking) 
The blinding will correspond to the research subject and the principal investigator. In addition, the 
statistical analysis will be carried out in a blinded manner for the partial and final analysis. 
The masking will be done using boxes in the identical primary packaging in the three groups. Blinding 
for the research subject and the researcher will be done by replacing the commercial labels in the 
case of the comparator in the bottles and the use of identical labels that contain the assignment 
number. 
7.4.1 Opening of blinding.  
Blinding may be opened in the following cases: 
1. Presence of a serious adverse event. 
2. Safety alarm due to the use of the drugs under study. 
 
3. In case the sponsor determines it for any security reason or other reason that it considers 
pertinent 
8. Methods Collection, administration and data analysis 
8.1 Methods of data collection 
A clinical monitor will be assigned to each research center, which will be authorized to monitor, 
review, procure and ensure that the quality of the information obtained from the participants is 
reliable and trustworthy. Each monitor will schedule periodic visits to the research centers in order 
to review the source documents and corroborate the information captured in the case report format 
(CRF). All clinical monitors will be trained in relation to the information of the study protocol 
(objective, visits, procedures, range of accepted values, etc.). In the event that the data are not 
identical between the two registers, the clinical monitor will generate a discrepancy, which must be 
resolved by the research center in time that the sponsor deems reasonable to meet the objectives 
of the clinical study. The correction of the discrepancies will be made according to the Good 
Documentation Practices.  
The data registered in the CRF will be reviewed by personnel of Sophia Laboratories, trained in the 
ophthalmological, clinical and pharmacological area, which will be able to generate discrepancies in 
the event that the data do not comply with the stipulations of the research protocol or put the 
participants at risk. 
Once all discrepancies generated by the team of clinical monitors and clinical staff have been 
resolved, the data will be downloaded into an electronic database (Excel Sheet) by personnel 
designated by the sponsor. A new review of the data will be carried out to corroborate the fidelity 
of the same and new discrepancies may be generated in case it was considered. 
The database generated will be safeguarded by the sponsor and will only have personal access 
designated by the same. 
 


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8.1.1 Strategies to complete the follow-up. 
• 
You will be clearly informed of the importance of the study and the benefits that the 
population will obtain from the results of the study. 
• 
Transportation assistance will be provided in order for the participant to attend their visits. 
• 
Calls, messages or a printed calendar will be made in order to remind the participant of their 
appointments and the activities that will be carried out, in addition to the estimated 
duration of the same. 
• 
In case the participant does not attend his appointment, the research center must make a 
call to know the reason and try to arrange a new appointment within the established 
window period or an unscheduled appointment. 
• 
In case it is not possible to make an appointment, it will be asked about the presence of 
adverse events and the reason for leaving the study, such as minimum data. 
8.2 Data management. 
The subject's medical record (including clinical notes, test results, etc.), as well as the subject's diary, 
and the ICO questionnaire are considered source data. 
The IP or the designated person of your team will fill out the Case Report Format (CRF) as well as all 
other documents provided by the sponsor (for example, documents related to the handling of the 
treatment). 
A CRF was designed to record the data that are required in the protocol and that the researcher 
collects in each of the visits. 
In the case of self-assessment questionnaires, it is not permissible for the principal investigator or 
person responsible for filling in to modify what was written by the subject of the study. 
The data capture in the investigator's site will be done by the investigator or the designated person 
of his team after performing the Medical File. The researcher or a designated person of your team 
will be trained in the filling of the CRF 
All corrections to the CRF data should be made by the investigator or the designated person of your 
team in accordance with the instructions provided. 
To ensure the confidentiality and security of the data, user names and access codes will be used to 
restrict access to the system only to authorized personnel. 
The monitor must ensure that all the data has been filled in the CRF. After comparing the data 
against the source documents, the monitor will ask the researcher to make the necessary correction 
/ clarification, so that they are answered and closed as quickly as possible. 
The Scientific Committee of Sophia Laboratories, S.A. of C.V. will give the latest medical-scientific 
review, and will set the standard for freezing the database. 
8.3 Statistical methodology 
8.3.1 Analysis of primary and secondary outcome variables. 
The statistical analysis will be carried out by personnel from Sophia Laboratories, S.A. of C.V The 
statistical program SPSS version 19 (IBM Corporation, Armonk, NY, USA) will be used. 
The designated personnel will be blinded to the intervention groups. The coding will be done using 
consecutive numbers for each intervention group. 


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The data will be collected and sorted in an excel sheet. Later they will be exported to the platform 
of the SPSS program. The variables will be categorized according to their nature. 
The result of the continuous quantitative variables will be presented in measures of central 
tendency: media, standard deviation and ranges. See Table 5. Scales to be used 
The normal distribution of the results will be obtained by the Kolmogorov-Smirnov test. 
The statistical analysis of the continuous quantitative variables to find significant differences (p) will 
be the following:  
• 
Intra-group analysis: Wilcoxon rank test. 
• 
Inter-group analysis: Kruskal-Wallis test.   
The level of difference to consider significance will be an alpha of 0.05 or less. 
The result of nominal and ordinal qualitative variables will be presented in frequencies, proportions 
and percentages. See table 1 (section 6.4.3). 
The statistical analysis to identify significant differences of the qualitative variables will be done by 
creating 2x2 contingency tables and will be done as follows:  
• 
• Intra-group difference: McNemar test. 
• 
• Difference between groups: χ2 test (Chi-square) of Pearson. 
• 
The level of difference to consider significance will be of an alpha of 0.05 or less. 
• 
For the reporting of adverse events all eyes of those participants who were randomly 
assigned to an intervention group after the baseline visit will be considered. The results will 
be expressed in number of cases (eyes). 
• 
The final report of the results will be shown in tables or graphs, as appropriate. 
• 
It will be considered that the investigational drug is safe and tolerable when there are no 
clinical and statistical differences in all the variables of primary outcome, with respect to its 
comparators. 
• 
Those subjects who comply with an adherence greater than 60% will be included in the 
statistical analysis to meet the objective of the study. It was considered that from the 
minimum dose necessary to obtain a pharmacological effect and the presence of adverse 
events (exposure) is sufficient to fulfill the general objective of the design, according to the 
pharmacological characteristics of the product under investigation.  
8.3.2 Additional analyzes 
A partial analysis will be carried out with the objective of evaluating safety and adherence once 3 
subjects per group (33% of the sample size) have completed all the visits and study procedures. Non-
parametric statistics will be used and the same mechanisms described for the total analysis of the 
data will be used.  
8.3.3 Population analysis and management of missing data 
An intention-to-treat analysis will be carried out, which will include the data of the participants who 
have completed at least two visits (Visit 1 and 2), after the baseline visit.  
 


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9. Methods Monitoring 
9.1 Data monitoring 
Monitoring visits by a site monitor of Sophia Laboratories, S.A. of C.V. are intended to confirm that 
studies sponsored by Sophia Laboratories, S.A. of C.V. they are conducted in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
Good Clinical Practices and with the applicable regulatory requirements (verifying a continuous 
compliance with the protocol, amendment or amendments, reviewing accounting records of the 
product under investigation, verifying that the personnel of the site and the facilities remain 
adequate to carry out the study). 
The researcher must ensure that they have sufficient time, space and qualified personnel for the 
monitoring visits. 
In order to carry out the monitoring review, it is mandatory to provide direct access to all source 
data and those related to the study site. The monitor will conduct a review of the CRF and a 
Verification of Source Documents (VDF). By VDF means the verification of the records in the CRF 
through its comparison with the source data that the researcher will make available for this purpose. 
Regarding the CRF, the monitor will mark in each visit the screens completed and approved in case 
of use of electronic platform. 
In accordance with the applicable regulations, Good Clinical Practices, and the procedures of Sophia 
Laboratories, S.A. of C.V. The monitors of Sophia Laboratories, S.A. of C.V. they will contact the site 
before the start of the study to review the protocol, the regulatory and ethical requirements of 
Laboratorios Sophia, S.A. with the staff of the site of C.V. In reviewing the procedures for data 
collection, the conversation will also include the identification, agreement and documentation of 
the individual data for which the records in the CRF serve as source documents. 
Sophia Laboratories, S.A. of C.V. 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 agreement, Good Clinical Practices and all applicable regulatory requirements. 
The investigator and the head of the medical institution (when applicable) agree to allow the 
monitor to have direct access to all relevant documents. 
Study monitoring visits will be conducted at regular intervals, depending on the recruitment rate, 
under the arrangements between the investigator and the sponsor. All information related to these 
visits will be handled as strictly confidential. 
Upon completion or early termination of the study, the monitor will carry out site closure activities 
with the investigator or site staff, as appropriate, in accordance with applicable regulations, Good 
Clinical Practices, and Sophia Laboratories, SA of C.V. procedures. 
 
 
 
 


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After the study is closed, the researcher must keep all study records on the site in a safe place. 
Records should be maintained to allow easy and timely recovery, when necessary (for example, in 
an audit or inspection). Sophia Laboratories, S.A. of C.V. will inform the investigator / institution the 
period of time they will have to retain these records, in order to comply with all applicable regulatory 
requirements. Nevertheless, the investigator / institution must seek the written approval of the 
sponsor before proceeding to the elimination of these records. The minimum retention time will 
satisfy the most stringent standard applicable to that site for the study, in accordance with the 
provisions of the PCBs, any institutional requirements or the applicable laws or regulations, or the 
standards / procedures of Sophia Laboratories, S.A. of C.V. 
The researcher / institution must notify Sophia Laboratories, S.A. of C.V. Of any change in file 
arrangements including, without limitation, the following: file in an off-site facility, ownership 
transfer of records in the event the investigator leaves the site.  
9.2 Preliminary analysis and early termination of the study 
The partial analysis described in section 6.5 and 8.3.2 will allow the sponsor to make a decision 
about the early termination of the study in the event that the safety of the participants is 
compromised. 
The early termination of the study will be considered in the following cases: 
1. Presence of serious adverse events in more than 5% of the participants in each intervention 
group. 
2. The competent authority (COFEPRIS) considers it for security alerts. 
3. The Sponsor determined it for his convenience or eventualities such as: economic support, 
manufacturing errors, etc. 
4. Lack of recruitment as expected.  
In case the decision is the early termination of the clinical study, all the research centers will be 
informed within the first 24 hours by the available communication channels. Likewise, the 
corresponding authority in each country will be informed (if applicable) and the Ethics Committees 
involved. 
Each research center has the obligation to inform the subjects that participate in the clinical study 
in a period no longer than 24 hours, after receiving the information from the sponsor. You must 
inform all the subjects involved in any phase of the study. 
The result of the preliminary evaluation will be in charge of the Clinical Operations Management 
and the Medical Management of Sophia Laboratories, S.A. of C.V., which will have the faculty to 
determine the fate of the present protocol, as they deem convenient. 
9.3 Adverse events 
9.3.1 Investigator's responsibilities 
Perform the verification of adverse events through questioning, relevant physical examination, 
assessment of evolution, as well as adequate medical and pharmacological management, resolution 
or outcome and final discharge following the definitions determined in national and international 
regulations. [47] [48] [49] 


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In case of adverse events or any event that puts the health and well-being of the patients at risk, 
appropriate medical attention will be provided, either at the research site or will be referred to the 
Hospital Center with greater resolving power with which the researcher and / or researcher site 
have medical care agreement. The researcher will notify the clinical monitor of the sponsor, 
according to the times established in the national and international regulations. In the case of 
serious adverse events, notify the sponsor and record the corresponding information in the case 
report form and in turn inform the Research Ethics Committee, the Research Committee.  
The attention of the adverse events will be made according to the diagram of attention of the event 
(see Figure 4. Attention of the adverse event) 
In the final report to be drafted by the Scientific Committee of the Department of Clinical Operations 
of Sophia Laboratories, S.A. of C.V., will include the report of adverse events in compliance with 
current national and international regulations. [48] [47]. 
9.3.1.1 Record of adverse events in the Case Report Form 
The registry of adverse events considers the information concerning the identification data of the 
participating patient as code, age, sex, left eye, right eye. 
Information about the type of adverse event, adverse reaction or suspected adverse reaction to the 
product under investigation or to the study medication, as appropriate. The date on which the 
adverse event occurs is reported, as well as in which the Investigator is aware of it, date of resolution 
or outcome, as applicable. The clinical diagnosis is indicated. Include in concomitant medications 
the therapy used for the pharmacological management of the adverse event, suspected adverse 
reaction, adverse reaction. Record the outcome or resolution of the event: patient recovered 
without sequelae, with sequelae, not recovered. Patient who presented death due to adverse 
reaction / adverse event, patient who presented death and it is judged that the drug could have 
contributed, patient who presented death and this is not related to the investigational product or 
drug, or indicate that it was not knows what the consequence of the event is.  
Consign information about the product or drug under investigation or the drug associated with the 
adverse event, adverse reaction or suspected adverse reaction. As applicable, information 
concerning generic denomination, distinctive denomination or product code in research and / or 
investigational medication should be recorded, as appropriate according to the methodological 
design of the study, this is relevant in the case of blinded studies or those where they use placebo 
as comparators, since there are circumstances that justify opening the cecum to determine if the 
adverse event, the adverse reaction or suspected adverse reaction may be attributable to the active 
agent, the combination of active agents, or the substance (s). s) pharmacologically inert (s), such as 
vehicles or additives, as appropriate to the clinical research phase in which the development of the 
drug is located. It will also be necessary to record the data concerning the batch number, 
manufacturer laboratory, expiration date, dosage, route of administration, start and end dates of 
administration and / or consumption, reason for the prescription; according to whether it is a 
product or investigational medicine (protocol in which the patient currently participates) or is a 
medicine that the subject under investigation consumes for the treatment of basic concomitant 
diseases or used for the management of any sign or transient symptom that does not correspond 
to the Natural History of the pathology that motivated its entry into the research protocol. 
 
 


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Record the withdrawal or maintenance of the medication, investigational product or investigational 
medication, as appropriate. Indicate if the adverse event disappears when the investigational 
product or investigational medication or suspicious medication is removed (if the event is triggered). 
Also indicate if a dose adjustment is made, if the event changes in terms of intensity or seriousness, 
persistence of the reaction. It is important to indicate that in those patients who are exposed again 
to the investigational product, investigational medication or medication, which had previously been 
suspended, if the adverse reaction or adverse event reappears. 
Regarding concomitant pharmacotherapy. Indicate the generic name, the dose, the route of 
administration, start and end dates of its use, as well as the reason for the prescription regardless if 
it is consistent with the information to prescribe or technical data sheet or is used outside the 
regulations or of what the local, national or international regulatory entity has authorized. 
Concerning the relevant clinical antecedents. The analysis of the adverse event, adverse reaction or 
suspicion of adverse reaction considers the information previously reported, notwithstanding the 
clinical context in which said harmful phenomenon occurs in the participants of the clinical research 
protocol, it is of special interest, so that the information about previous ailments, hypersensitivity 
or allergy phenomena, previous surgical procedures, laboratory analysis or cabinet exams that have 
been practiced on the participant, etc., that the researcher deems convenient to mention may do 
so. If you have enough space in the case report format, you can complement the information of 
your clinical note in the clinical file. 
9.3.1.2 Follow up of adverse events 
The IP will provide the attention and guidance of the EA that the participant presents until the end 
of the same, according to what is referred to the following section. 
9.3.1.3 Procedures for a serious adverse event 
The process of attention of the adverse event considers the following stages: 
 
Figure 4. Attention to the adverse event 
 


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A. During the development and conduct of the present clinical investigation, undesirable 
damaging events or adverse reactions, of medical involvement, which do not necessarily have a 
causal relationship with the investigational product or investigational drug, may occur in the 
participant patient. These harmful phenomena can 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 some 
physiological process. Notwithstanding, it can be suspected that the investigational product or 
the investigational drug or the placebo cause some unwanted clinical manifestation. Adverse 
events, adverse reactions or suspected adverse reactions to one or several medications can 
occur during the systematic evaluation of the participants (on the days when the clinical review 
is scheduled, according to the schedule of activities) or suddenly, as such way that,  
B. The investigator must be the first person to whom the patient reports that they have 
developed or presented a harmful clinical phenomenon during their participation in this 
research protocol. 
C. According to their clinical judgment; on the basis of the pertinent physical examination, 
interrogation, etc., as well as the analysis of the information available in the medical literature 
and that referred to in the investigator's manual, information to prescribe or technical data 
sheet of the comparator drug, the principal investigator determines the relevant attention of 
the event / harmful reaction; either 
D. in the research site or in the hospital with the greatest resolving power (1st, 2nd or 3rd level 
of medical attention). In such a way that, in case the patient is sent by the Investigator to a 
hospital, he / she attends by means of a reference system, it can be with an identification card 
that the patient belongs to the present investigation and there is an official number or folio, 
which pertains to the emergency care agreement with the health institution with the greatest 
resolving power, or a medical reference note issued by the principal investigator, so that 
appropriate care is given to the participating patient. It should be noted that the Study Sponsor, 
Sophia Laboratories, S.A. of C.V., will pay the expenses for the medical care of the participating 
patient, only if the adverse event, adverse reaction or suspected adverse reaction to medication 
is associated or found in relation to the investigational product or investigational drug. 
E. Taking the clinical information gathered, either during the care provided in the research site 
or provided by the treating physician (s) in the hospital, the principal investigator records the 
adverse event, suspected adverse reaction or adverse reaction to medication in your clinical 
note of the clinical file, indicating the seriousness, intensity (mild, moderate or severe), 
relationship with the product or investigational medicine, as well as: 
F. The migration of the relevant data to the case report format and to its respective adverse 
event section; noting the pertinent information, already referred to in section 9.3.1.1., this in 
virtue of the fact that in cases of serious adverse events, which must be notified in less than 24 
hours after the moment in which the principal investigator has knowledge of the same, the 
clinical monitor of the study is informed, so that in turn he / she informs the Scientific 
Committee and the Pharmacovigilance Department of the sponsor and later he / she informs 
the Research Ethics Committee. Regarding non-serious adverse events, these will be recorded 
and adequately addressed and the corresponding regulatory entity will be informed about the 
safety profile of the product under investigation or investigational medication in the final report 
of the clinical trial. 


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The record of the outcome of the adverse event, suspicion of adverse reaction or adverse reaction 
to medication depends substantially on the follow-up that the principal investigator makes to the 
participant, since most of the harmful phenomena are expected, consult section of the safety profile 
in number 5.3 and in the researcher's manual, they are ophthalmic in nature, nevertheless there 
may be systemic alterations. Therefore, in the opinion of the researcher, the withdrawal of the 
participant or his / her permanence will be considered, according to the stipulations of section 6.2.2 
Exclusion criteria of the present research protocol. 
9.3.1.4 Causality evaluation 
The assessment of the causality, the methodology used to estimate the probability of attributing to 
a drug, investigational drug or investigational product the adverse reaction, the suspicion of the 
same or the observed adverse event, considers probabilistic categories, according to the evidence 
available and the quality of information, based on national pharmacovigilance regulations. [47] As 
a tool to facilitate the probabilistic categorization of causality, the principal investigator can use the 
algorithm of Karch and Lasagna modified by Naranjo referred by Aramendi I, 2011 in which different 
items are qualified which allow assigning a value to the relationship cause-effect between the 
administration of the drug and the adverse reaction. [50] See Table 7. Algorithm of Karch and 
Lasagna modified by Naranjo  
Algorithm of Karch and Lasagna modified by Naranjo 
No. 
Reagent 
Score 
Yes 
N
o 
1. 
There are previous conclusive reports about the adverse drug reaction, adverse 
event or suspected adverse drug reaction 
+1 
0 
2. 
The adverse event appeared when the suspected drug was administered 
+2 
-1 
3. 
Adverse reaction to medication, adverse event or suspected adverse drug 
reaction improved upon discontinuation or administration of a specific 
antagonist 
+1 
0 
4. 
Adverse reaction to medication / adverse event / suspected adverse drug 
reaction reappeared when administering the drug / investigational product / 
investigational medication 
+2 
-1 
5. 
There are alternative causes that may cause this reaction 
-1 
+2 
6. 
Adverse reaction / adverse event / suspected adverse drug reaction occurred 
after placebo administration 
-1 
+1 
7. 
The drug was determined in blood or other liquids in toxic concentrations 
+1 
0 
8. 
The intensity of the adverse reaction / adverse event / suspected adverse drug 
reaction was higher with higher doses or lower with lower doses 
 
 
+1 
0 
 
 
9. 
The patient has had similar reactions with the drug / product under 
investigation or investigational medication, in the past 
+1 
0 


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Algorithm of Karch and Lasagna modified by Naranjo 
No. 
Reagent 
Score 
Yes 
N
o 
10. 
Adverse reaction / adverse event / suspected adverse reaction to medication 
was confirmed with some objective evidence 
+1 
0 
                                                                                                                               Total score 
summatio
n 
Probabilistic category based on the score obtained 
I 
The causal relationship is checked 
≥,9  
II 
It is likely that ADR is due to the drug or product under investigation 
5 a 8 
III 
It is possible that the RAM is due to the drug or product under investigation 
1 a 4 
IV 
The causal relationship is doubtful 
0 
The reagents considered by the algorithm of Karch and Lasagna modified by Naranjo where each one receives a defined score are 
shown and the final summation allows estimating the probabilistic category of the cause-effect relationship between the 
administration of the drug / product in research / investigational medicine and the adverse reaction, adverse event or suspected 
adverse reaction. Consider that if the information is not available, a score equal to zero is recorded.  
Table 7. Algorithm of Karch and Lasagna modified by Naranjo. 
In such a way that the degree of certainty to establish the investigational product or investigational 
medication (as appropriate) as the causal agent of the harmful phenomenon that befalls the 
participating patient, can be directly indicated by the principal investigator based on his or her 
clinical experience or well through the voluntary application of the tool mentioned previously. 
Nevertheless, it is important that the investigator take into account the following arguments in favor 
of the causal relationship:  
b. Force of association that refers to the number of cases in relation to those exposed. 
c. The consistency of the data, ie the presence of a common characteristic or pattern. 
d. The exposure-effect pattern: which determines the relationship with the site of 
onset, time, dose and reversibility after suppression. 
e. The biological plausibility: which refers to the possible pharmacological or 
physiopathological mechanisms involved in the development or presentation of the 
adverse event. 
f. Experimental findings: for example the appearance of anomalous metabolites or 
high levels of drug or the product of its biotransformation. 
g. Analogy: experience acquired with other related drugs, adverse reactions 
frequently produced by the same family of pharmacological agents. 
h. Nature and characteristics of the data: objectivity, accuracy and validity of the 
relevant documentation. [51]  
9.3.2 Responsibilities of the sponsor. 
The sponsor will be responsible, and will cover the expenses derived from the medical attention to 
adverse events related to the product under investigation. 


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9.4 Audit 
To guarantee compliance with the PCBs and with all applicable regulatory requirements, Sophia 
Laboratories, S.A. of C.V. could carry out a quality assurance audit. Regulatory agencies could also 
carry out a regulatory inspection of this study.  
9.4.1 Pre-study audit 
The research centers included in the study will be subject to a feasibility visit prior to the selection 
of the center, where it will be verified that they meet the minimum requirements indicated by the 
sponsor.  
9.4.2 Audit / Inspection during the conduction 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 performed, the investigator and the institution should agree to allow the auditor / 
inspector direct access to all relevant documents, and will allocate their time and that of their staff 
to the auditor / inspector to discuss the findings and any relevant problems. 
 
10. Ethical considerations 
10.1 Approval of the committees 
 
The present study will be conducted according to the standards of the Declaration of Helsinki, World 
Medical Association 2013. Nuremberg Code; Nuremberg Trial by the International Court of 
Nuremberg, 1947. Belmont Report, National Commission for the Protection of Subjects of 
Biomedical Research and Conduct, 1979. Will be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicines for use of the International 
Conference on Harmonization (The International Council for Harmonization, ICH) Guide to Good 
Clinical Practices. International Ethical Guidelines for Biomedical Research in Human Beings of the 
Council for International Organizations of Medical Sciences (Council for International Organizations 
of Medical Sciences, CIOMS, 2002). International Ethical Guidelines for Epidemiological Studies of 
the Council for International Organizations of Medical Sciences (Council for International 
Organizations 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 
possible modifications for its realization, these Committees should be notified of any significant 
changes to the protocol. In addition to the above, the current regulations issued by the Ministry of 
Health will also be complied with. General Health Law, NOM 012 Official Mexican Standard NOM-
012-SSA3-2012, Which establishes the criteria for the execution of research projects for human 
health. The study is considered as an investigation with a risk greater than the minimum according 
to the Regulation of the General Health Law on Health Research, Title Two, Chapter I, Article 17, 
Category III, published in the Official Gazette on 6 January 1987. 
 
The principal investigators or study coordinators or personnel authorized by the sponsor will be 
evaluated by the Research Ethics Committees, Research Committees, and when applying to the 
Biosafety Committee the essential documentation of the research project: research protocol, letter 


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of informed consent, researcher's manual, subject's diary, as well as those requested, in addition, 
according to local, national or international requirements applicable by regulatory entities.  
The study will not start in the research site if you do not have the confidentiality agreements and 
economic proposal of each of the principal investigators, duly signed and without having previously 
obtained the favorable opinion and / or the approval of the Committees of Ethics in Research, 
Research Committees, and when applicable by the Biosecurity Committee, corresponding. 
The study will not begin without having met the relevant local, national or international regulatory 
requirements and without having the corresponding health authorization. 
10.2 Amendments to the protocol 
The amendment procedure will be relevant when there is a need to make any change to a document 
that is part of the research project or protocol, derived from variations in the methodological 
structure, substitution of the principal investigator or when identifying risks in the research subjects 
. The documents susceptible of amendment will be: protocol, letter of informed consent, 
researcher's manual, documents for the patient, scales of measurement and schedule of activities. 
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 Committee of Inquiry. Biosafety, (entities that issued the 
initial favorable opinion for the conduct of the investigation) will be sent (s) for authorization by the 
relevant regulatory entity.  
Amendments that substantially modify the protocol or confer an additional or different risk to the 
research subjects must be approved by the Committee. It is the investigator's responsibility to take 
action in situations that require immediate action to avoid unnecessary harm to the study 
participants. 
The principal investigator has the responsibility to inform the Research Ethics Committee of any 
amendment to the protocol that could eventually affect the rights, safety or welfare of the research 
participants. Likewise, he must know any situation or new knowledge that shows a greater risk for 
the participants, the termination or premature suspension of the study, the reasons and the results 
obtained up to that moment. You must also inform about the conclusion of the study, when 
completing the research protocol. 
The list of amendments, and in the necessary cases, the relation of the issuance of errata, will be 
referred to in the final report of the investigation. 
10.3 Consent (assent)) 
10.3.1 Obtaining 
 
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. 
The written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guide to Good Clinical Practices and will be in compliance with 
all applicable laws and regulations. 


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The IP will provide the potential participant with all the information regarding the characteristics of 
the study, its potential benefits, risks, objectives and procedures thereof. 
This information will be with a language understandable to the subject, it will be explained to the 
subject that has the right to interrupt their participation in the study at any stage, without affecting 
the relationship with the researcher and / or their future assistance. The informed consent will be 
put to the consideration of the possible participant; this must have enough time to analyze each 
and every one of the aspects mentioned above and if there is any doubt this will be clarified by the 
person in charge of obtaining the informed consent. 
Once the participant agrees to participate in the study, he / she must sign and date the informed 
consent letter in the presence of two witnesses who have or are not related to the subject of study, 
who will participate during the informed consent process and will sign endorse that the process was 
carried out prior to any study procedure, that the information of the study was clearly explained 
and doubts were clarified in case of existing. 
If a subject is illiterate, the acceptance will be with their fingerprint, and in the event that the subject 
is not able to grant an informed written consent, a representative of the "legally authorized" subject 
can provide such consent. The subject in accordance with applicable laws and regulations. 
The IP must also sign and date this consent. 
The informed consent must be signed in duplicate by all involved, and two witnesses, one copy will 
be filed in the file of the subject and the other will be delivered to the participant. The PI must 
document in the patient's medical history, the date on which he signed the informed consent. 
10.3.2 Special considerations 
The auxiliary studies that will be carried out during the conduction of 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 
Any change to "informed consent" constitutes an amendment to this document and must be 
submitted for approval to the Research Ethics Committees, and if applicable before the Competent 
Authorities. 
The amendment will include a copy of the new version in the language or languages of the country. 
Such amendments may be implemented only after obtaining the written approval of the Research 
Ethics Committee and the Regulatory Entity (as applicable), with the exception of an amendment 
that is required to eliminate an immediate danger to the subjects of the study. 
Each subject affected by the amendment must complete, date and sign two originals of the new 
version. The subject will be given a signed original of the amendment and the researcher will keep 
the second original. 
10.4 Confidentiality 
 
All documents and information provided to the researcher by the sponsor are strictly confidential. 
The researcher expressly agrees that the data on their professional and clinical experience, provided 
to the sponsor on paper and stored in electronic format, are only for use related to their activities 
with the sponsor of clinical studies, in accordance with Good Clinical Practices. The researcher 
accepts that he / she and the members of his team will use the information only within the 


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framework of this study, to carry out the protocol. This agreement is mandatory as long as the 
confidential information has not been disclosed to the public by the sponsor. The protocol of the 
clinical study provided to the researcher may be used by him and by his colleagues to obtain the 
informed consent of the subjects for the study. The clinical trial protocol, like any information taken 
from it, should not be disclosed to other parties without the written authorization of the sponsor.  
The researcher will not reveal any information without the prior written consent of Sophia 
Laboratories, S.A. of C.V., except to the representatives of the Competent Authorities, and only by 
request of the same. In the latter case, the researcher undertakes to inform Sophia Laboratories, 
S.A. of C.V. before revealing the information to these authorities. 
The researcher will fill out and maintain a record of the subjects' selection, as well as the 
identification and enrollment list of each of the subjects participating in the study. The researcher 
agrees to give on-site access to the auditor and / or the representatives of the Competent 
Authorities. The information will be treated in compliance with professional secrecy.  
10.5 Declaration of interests 
The PI is committed to making a declaration of financial interests, as well as a conflict of interests 
prior to the start of the study.. 
10.6 Access to information 
The final database of the study will be owned by Sophia Laboratories, S.A. of C.V. and your access 
will be restricted. The IP will not have access to it, unless it has prior written authorization from the 
sponsor. 
10.7 Auxiliary care and after the end of the study 
Once the study is completed and the adverse events are closed according to section 9.3 Adverse 
events, the sponsor will not extend care on the research subject. 
10.8 Biosecurity aspects 
WITHOUT BIOSECURITY IMPLICATIONS 
The present protocol, with the title: "Phase I clinical study, to evaluate the safety and tolerability of 
the preservative-free ophthalmic solution PRO-087 versus Xyel Ofteno® and Systane Ultra®, on the 
ocular surface of ophthalmological and clinically healthy subjects", and number: SOPH087-0616 / I 
DOES NOT HAVE BIOSECURITY IMPLICATIONS, since infectious-contagious biological material will 
NOT be used; pathogenic strains of bacteria or parasites; viruses of any kind; radioactive material of 
any kind; genetically modified animals and / or cells and / or plants; toxic, dangerous or explosive 
substances; any other material that endangers the health or physical integrity of the personnel of 
the research center or the subjects of investigation or affects the environment. In addition, it is 
stated that cell, tissue or organ transplant procedures or cell therapy procedures will not 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 finished, a final report will be drafted with the results obtained, in 
charge of the Scientific Committee of the Department of Clinical Operations of Sophia Laboratories, 


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S.A. of C.V. Said report will be prepared following the recommendations of the E3 Step 4 Guide of 
the ICH. 
10.9.2 Communication of results 
Regardless of the results in the study, Laboratorios Sophia, S.A. de C.V., is committed to 
communicate the final report of the study to the principal investigators and to the corresponding 
regulatory entities of the countries with participating research centers. Maintaining at all times the 
rights on the publication and dissemination of the information contained.  
10.9.3 Publication of the results 
Sophia Laboratories, S.A. C.V., acting as the sponsor of the study, assumes full responsibility for its 
function and retains exclusive ownership rights over the results of the study, which may be used in 
the manner it deems appropriate. 
The PI undertakes not to publish or communicate data collected only in a center or in part of the 
centers before the publication of the full results of the study, unless prior written agreement is given 
by Sophia Laboratories, S.A. of C.V. 
Any publication and / or communication project related to the study and / or the results obtained 
during the study or after the completion of the study will be presented to participating medical 
researchers at least 30 days in the case of a publication and 15 days in the case of a summary, before 
the scheduled date for the communication and / or presentation of a publication. The medical 
researcher or doctors will comment on the project within 15 days in the case of a publication and 7 
days in the case of a summary, from the date on which the project is received. 
Nevertheless, in case the sponsor is in the process of submitting a patent application on the results 
of the study, the sponsor may delay its publication or communication of the results of the study 
until the date of registration. 


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11. Bibliographic references 
Bibliografía 
 
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[29] K. T. Yamada T, «Microbial synthesis of hyaluronan and chitin: New approaches.,» J Biosci 
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[30] G. Snibson, J. Greaves, J. Prydal, C. Wilson y A. Bron, «Precorneal residence times of sodium 
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[47] Secretaría de Salud México, «NORMA Oficial Mexicana NOM-220-SSA1-2012, Instalación y 
operación de la farmacovigilancia.,» Diario Oficial, 2013.  
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12. Signature page 
Medical manager of the study: 
  Dr. Leopoldo Martín Baiza Durán 
Director of the study: 
  Dr. Aldo Arturo Oregon Miranda 
Protocol authors: 
  Dr. Oscar Olvera Montaño 
  Dr. Arieh Roldán Mercado Sesma 
Internal reviewer of the protocol: 
  QFB. Virginia Manuela Villa Felix 
  QFB. Lizeth by Jesús Pérez Lerma 
External reviewer of the protocol: 
    Dr. Mariana Xacil Díaz Salazar 
Principal investigator of the study: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
Sophia Laboratories, S.A. of C.V. 
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PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
Sophia Laboratories, S.A. of C.V. 
Page 63 of 67 
 
13. Annexes 
13.1 Eye comfort index 
 


PRO-087 
 
Clinical study protocol: SOPH087-0616/I  
CONFIDENTIAL                                                               Version: 1.0 
 
Sophia Laboratories, S.A. of C.V. 
Page 64 of 67 
 
13.2 Efron scale for conjunctival hyperemia 
 
13.3 Oxford Scale 
 
 
 
 
Normal 0 
Very slight1 
Mild 2 
Moderate 3 
Severe 4 
Equal or less than panel A 
Equal to or less than panel B, greater 
than A 
Equal to or less than panel C, greater 
than B 
Equal to or less than panel D, greater 
than C 
Equal to or less than panel E, greater 
than D 
Greater than panel E