Phase IV Clinical Study to Evaluate the Efficacy of Lagricel® Ofteno PF Compared to Thealoz® Duo for Corneal Re-epithelialization After Photorefractive Keratectomy (PRK)
Phase: PHASE4
Conditions: Photorefractive Keratectomy, Corneal De-epithelialization
Sponsor: Laboratorios Sophia S.A de C.V.

 
 
 
 
 
Generic name Sodium hyaluronate 0.4% 
Distinctive name Lagricel® Ofteno PF 
Indication: Eye lubricant
 
Sponsor: Laboratorios Sophia, S.A. de C.V. 
Phase of the study: IV 
Clinical Trial Code: NCT04704518 
Version date: January 26th 2022

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Content ................................................................................................................................................ 1 
Study leaders ....................................................................................................................................... 6 
Signature pages ................................................................................................................................... 8 
From the sponsor ............................................................................. ¡Error! Marcador no definido. 
Researcher Agreement.................................................................................................................... 8 
List of abbreviations .......................................................................................................................... 10 
1. 
Summary ................................................................................................................................... 12 
1.1 
Synopsis ............................................................................................................................. 12 
1.2 
Study diagram ................................................................................................................... 16 
1.3 
Study schedule .................................................................................................................. 17 
2. 
Introduction and Background ................................................................................................... 18 
2.1 
Theoretical framework ...................................................................................................... 18 
2.2 
Background on the product under study .......................................................................... 22 
2.2.1 
Pharmacology of the investigational product ........................................................... 22 
2.2.2 
Product efficacy under investigation ........................................................................ 22 
2.2.3 
Safety of the investigational product ........................................................................ 23 
2.2.4 
Summary of the pharmaceutical development of the investigational product ........ 24 
2.3 
Background on the research ............................................................................................. 24 
2.3.1 
From the research question ...................................................................................... 24 
2.4 
Risk benefit assessment .................................................................................................... 24 
2.4.1 
Known potential risks ................................................................................................ 24 
2.4.2 
Known potential benefits .......................................................................................... 25 

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2.5 
Problem statement ........................................................................................................... 25 
2.5.1 
Justification ............................................................................................................... 25 
3. 
Objectives and hypotheses ....................................................................................................... 26 
3.1 
Main objective ................................................................................................................... 26 
3.2 
Specific objectives ............................................................................................................. 26 
3.3 
Hypothesis ......................................................................................................................... 27 
4. 
Study design .............................................................................................................................. 28 
4.1 
Design Overview ................................................................................................................ 28 
4.2 
Justification of the study design ........................................................................................ 28 
4.3 
Expected duration ............................................................................................................. 28 
5. 
Study population ....................................................................................................................... 29 
5.1 
Eligibility criteria ................................................................................................................ 29 
5.1.1 
Inclusion criteria ........................................................................................................ 29 
5.2 
Criteria for exclusion and substitution of subjects ........................................................... 29 
5.2.1 
Exclusion criteria ....................................................................................................... 29 
5.2.2 
Subject substitution .................................................................................................. 31 
5.3 
Lifestyle considerations ..................................................................................................... 31 
5.4 
Scrutiny failures ................................................................................................................. 31 
5.5 
Recruitment and retention strategies ............................................................................... 32 
5.6 
Procedure in case of loss of follow-up .............................................................................. 32 
5.7 
Subject identification ........................................................................................................ 33 
6. 
Investigational product ............................................................................................................. 34 
6.1 
Managed products ............................................................................................................ 34 
6.1.1 
Investigational product ............................................................................................. 34 
6.1.2 
Reference product ..................................................................................................... 34 
6.1.3 
Dose of the investigational product .......................................................................... 35 

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6.2 
Storage and handling of the investigational product at the study center ........................ 35 
6.3 
Concomitant treatments and medications not authorized during the study ................... 36 
6.4 
Procedure for monitoring and measuring adherence ...................................................... 37 
6.5 
Strategies to improve adherence ...................................................................................... 38 
7. 
Methods and procedures of the study ...................................................................................... 40 
7.1 
From the research center .................................................................................................. 40 
7.2 
Clinical study registration .................................................................................................. 41 
7.3 
Randomization .................................................................................................................. 41 
7.4 
Outcome variables ............................................................................................................ 42 
7.4.1 
Primary efficacy outcome variable ............................................................................ 42 
7.4.2 
Primary safety outcome variable .............................................................................. 42 
7.4.3 
efficacy outcome variables ........................................................................................ 42 
7.4.4 
Definition of variables, methods and scales to be used for measurement .............. 42 
7.4.5 
Program of visits and activities of the study ............................................................. 45 
7.4.6 
Data collection ........................................................................................................... 49 
8. 
Evaluation and management of adverse events ....................................................................... 50 
8.1 
Regulation and standards on adverse events ................................................................... 50 
8.1.1 
Definition of adverse event ....................................................................................... 50 
8.1.2 
Definitions relevant to the classification of adverse events ..................................... 51 
8.1.3 
Researcher Responsibilities ....................................................................................... 51 
8.1.4 
Recording of adverse events in the electronic case report form .............................. 52 
8.1.5 
Monitoring of adverse events ................................................................................... 54 
8.1.6 
Procedures for a serious adverse event .................................................................... 54 
8.1.7 
Assessment of causality ............................................................................................ 57 
9. 
Study monitoring ....................................................................................................................... 60 
9.1 
Monitoring of study centers .............................................................................................. 60 

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9.2 
Audit and quality assurance .............................................................................................. 61 
10. 
Statistical analysis.................................................................................................................. 62 
10.1 
Data analysis ...................................................................................................................... 62 
10.1.1 
Statistical analysis ...................................................................................................... 62 
10.1.2 
Data interpretation ................................................................................................... 62 
10.1.3 
Procedure for handling missing data ........................................................................ 63 
10.1.4 
Deviations from the statistical analysis plan ............................................................. 63 
10.1.5 
Subjects included in the analysis ............................................................................... 64 
10.2 
Sample size calculation ..................................................................................................... 64 
10.2.1 
Number of subjects calculated .................................................................................. 64 
10.2.2 
Justification of the sample calculation ...................................................................... 64 
11. 
Ethical considerations ........................................................................................................... 66 
11.1 
Approval of the committees ............................................................................................. 66 
11.2 
Amendments to the protocol ............................................................................................ 67 
11.3 
Early termination of study ................................................................................................. 67 
11.4 
Informed consent .............................................................................................................. 68 
11.4.1 Obtaining ........................................................................................................................... 68 
11.5 
Special considerations ....................................................................................................... 69 
11.6 
Modifications to informed consent................................................................................... 70 
11.7 
Confidentiality ................................................................................................................... 70 
11.8 
Conflict of interest ............................................................................................................. 71 
11.9 
Declaration of interests ..................................................................................................... 71 
11.10 Access to information ....................................................................................................... 71 
11.11 Ancillary and post-study care ............................................................................................ 72 
12. 
Biosecurity aspects ................................................................................................................ 73 
12.1 
No Biosecurity Implications ............................................................................................... 73 

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13. 
Publication Policy .................................................................................................................. 74 
13.1 
Final report ........................................................................................................................ 74 
13.2 
Publication of the results .................................................................................................. 74 
14. 
Financing and insurance ........................................................................................................ 75 
14.1 
Compensation to study participants ................................................................................. 75 
14.2 
Study insurance ................................................................................................................. 75 
15. 
References ............................................................................................................................. 76 
 
Index of tables, figures and charts 
Table 1. Study leaders  ....................................................................................................................... 6 
Table 2. Study schedule.  .................................................................................................................. 17 
Table 3. Operational definition of variables  ................................................................................... 42 
Table 4. Karch and Lasagna algorithm modified by Naranjo  ........................................................ 58 
 
Figure 1. Administrative structure  .................................................................................................... 7 
Figure 2. Study diagram.  ................................................................................................................. 16 
Figure 3. Adverse event care  ........................................................................................................... 55 
  
 
 

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The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia, S.A. 
de C.V., is shown in Table 1. Study leaders. 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Study leaders 
 
 
 
 
 
 
 

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Figure 1. Administrative structure 
 
 
Clinical Study 
Director 
Medical Director of 
the study 
Regional Strategic 
Alliance Leader 
Regional Leader of 
Clinical Operations 
Clinical Trial Start-
Up and Regulatory 
Specialist 
Therapeutic Area 
Specialist/Head of 
Medical Affairs 
Operations 
Biostatistics 
Manager 
Regional Logistics 
Leader 
Clinical Logistics 
Associate 
Pharmacovigilance 
Specialist in Clinical 
Clinical team 
Regional Clinical 
Studies Leader 
Clinical monitor 

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Laboratorios Sophia S.A. de C.V.  
 
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I agree to conduct this clinical study in accordance with the design and guidelines of this protocol, 
adhering to the provisions of this protocol and in adherence to accepted standards of Good Clinical 
Practice. 
I agree to report all information or data in accordance with the protocol, particularly any adverse 
events. I also agree to handle clinical supplies provided by the sponsor strictly in accordance with 
this protocol. 
I understand that the information that identifies me may be used by the sponsor. Because the 
information contained in this protocol and the Investigator's Manual is confidential, I understand 
that sharing it with any third party not involved in the approval, supervision, or conduct of the study 
is prohibited. I will ensure that I take the necessary precautions to protect the information from 
loss, inadvertent disclosure, or access by unauthorized third parties. 
 
 
 
 

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AE 
Adverse event 
CI 
Confidence interval 
COFEPRIS 
Federal Commission for the Protection against Sanitary Risks 
CONSORT 
Consolidated Standards of Reporting Trials 
D 
Day 
eCRF 
Electronic Case Report Form 
FDA 
United States Food and Drug Administration Administration 
IC 
Investigation Committee 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
ICO 
Eye comfort index 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
ITT 
Intention-to-treat population 
IUD 
Intrauterine device 
n 
Number 
NIBUT 
Non-invasive tear film break-up time 
NRCT 
National Registry of Clinical Trials 
OD 
Right eye 
OSD 
Ocular surface disease 
OU 
Both eyes 
PEE 
Punctate epithelial erosion 
PI 
Principal Investigator 
PP 
Per-protocol population 
PRK 
Photorefractive keratectomy 
PRN 
Pro re nata 
QID 
Four times a day (quater in die) 
RA 
Rheumatoid arthritis 
SC 
Safety call 

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SH 
Sodium hyaluronate 
SICCA 
Sjögren’s International Collaborative Clinical Alliance 
SLE 
Systemic lupus erythematosus 
TBUT 
Tear film break-up time 
TEAE 
Evaluation time 
TID 
Three times a day (ter in die ) 
UP 
Unanticipated problems 
VA 
Visual acuity 
BV 
Baseline visit 
V1, V2, V3 
Follow-up visits 
FV 
Final visit 
WHO 
World Health Organization 
 
 
 
 
 
 

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Title of the study: 
Phase IV clinical study to evaluate the efficacy of Lagricel® Ofteno PF compared to Thealoz® Duo 
in corneal reepithelialization following PRK (Photorefractive Keratectomy) 
Study number: 
 SOPH037-0120/IV  
Creation date: 
02-Jan-20 
Protocol version: 
Clinical Trial Code: NCT04704518 
Version date: 
January 26, 2022 
Therapeutic indication: 
Eye lubricant 
Use: 
Corneal reepithelialization 
Estimated duration of the study (from the first visit 
of the first patient to the preparation of the final report) : 
11 months 
Clinical development phase: IV 
Goals: 
Main objective: 
- 
To evaluate the efficacy of Lagricel® Ofteno PF compared to Thealoz ® Duo in corneal 
reepithelialization of post-PRK surgery patients. 
 
Specific objectives 
- 
To evaluate the safety of Lagricel® Ofteno PF compared to Thealoz® Duo by 
the incidence of unexpected adverse events (AEs) related to the 
investigational product in post-PRK surgery patients . 
- 
To determine the efficacy of the Lagricel® Ofteno PF formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients by 
means of corneal fluorescein staining by direct observation and photographic 
record . 
- 
To determine the efficacy of the Lagricel® Ofteno PF formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients using 
the ICO test . 
- 
To determine the efficacy of the Lagricel® Ofteno PF formulation compared to 

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Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients by 
assessing pain perception. 
- 
To determine the safety of Lagricel® Ofteno PF formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients 
through changes in visual acuity . 
 
Hypothesis : 
H0: Lagricel® Ofteno PF does not contribute to complete corneal reepithelialization at the 3rd 
day of post-PRK treatment and is not equivalent to Thealoz® Duo . 
H0: |µ𝐴 - µ𝐵| ≥ 𝛿 
 
H1: Lagricel® Ofteno PF contributes to a reepithelialization corneal complete to the 3rd day 
of post-surgical treatment of PRK being equivalent a Thealoz® Duo . 
H1: |µ𝐴 - µ𝐵| < 𝛿 
 
Study design: 
A Phase IV, multicenter, comparative, controlled, randomized, open-label, parallel-group study. 
Number of subjects (planned and analyzed): 
 
Number of planned subjects: 96 evaluable patients 
• 
Both eyes (OU): safety assessment 
• 
Right eye (RO): efficacy assessment 
48 evaluable patients per group (2 Groups) 
Diagnosis and main inclusion criteria: 
- 
Patients in the 1-day post-PRK surgery period. 
 
Selection criteria: 
Inclusion criteria: 
- 
Be between 18 and 45 years old. 
- 
Period of 1st day post-surgical of PRK (HE will evaluate for effectiveness eye right). 
- 
Having performed the epithelium removal technique with 20% alcohol (ethanol) for a 
time within the range of 30-40 seconds. 
- 
Having used a de-epithelialization area (transition area) in the range of 8-9 mm. 
- 
Surface of ablation corneal surgical of 5.5 to 6.0 mm. 
- 
Corneal expenditure less than or equal to 60 microns. 
- 
Refraction pre-surgical of -1.0 to -4.5 D of myopia either astigmatism myopic (the 

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addition of both values in this case, equivalent spherical no elderly to -4.5). 
- 
Have the ability of grant of shape voluntary his consent informed signed. 
- 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
- 
Be willing to modify the activities of your style of life. See 5.3 Lifestyle considerations 
- 
Women of childbearing age must ensure continuation (started ≥ 30 days prior to 
signing) of the Shape of Consent Informed [ICF]) of use of a method contraceptive 
hormonal either device intrauterine (IUD) during he period of the study. 
 
Exclusion criteria: 
- 
Transurgical complications and during the post-surgical period prior to inclusion in the 
study. 
- 
Use of mitomycin during PRK. 
- 
PRK retreatments or history of other types of refractive surgery. 
- 
For women: be pregnant, breastfeeding, or planning to become pregnant during the 
study period. 
- 
Having participated in another clinical research study ≤ 30 days prior to the screening 
visit. 
- 
Having previously participated in this study. 
- 
Present an additional diagnosis of: 
o Allergic, viral or bacterial conjunctivitis. 
o Dry eye. 
o Anterior blepharitis. 
o Parasitic eye infections (e.g., Demodex). 
o History of ocular herpes. 
o History of ocular inflammatory processes (such as uveitis). 
o History of corneal or conjunctival ulcers. 
o Glaucoma. 
- 
Have a history of drug addiction or dependence, currently or within the last two years 
prior to signing the ICF. 
- 
Have a history of ocular surgical procedures within the last 3 months prior to signing the 
ICF. 
- 
Having another medical condition, acute or chronic (such as Diabetes Mellitus type I / II, 
autoimmune diseases or HIV) that, in the opinion of the investigator, could increase the 
risk associated with participation in the study or the administration of the investigational 
product, or that could interfere with the interpretation of the study results. 
- 
Use medications (such as retinoic acid ) that, in the opinion of the investigator, may 
increase the risk associated with participation in the study or administration of the 
investigational product, or that may interfere with the interpretation of the study results. 
- 
Have a known hypersensitivity to the components of the investigational products. 
- 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is an employee of the research site or the sponsor and who is directly 
involved in this study. 
 
 

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Research Product: 
Lagricel® Ofteno, multidose presentation. Sodium hyaluronate 0.4% ophthalmic solution. 
- 
Manufacturer: Laboratorios Sophia, S.A. de C.V. 
- 
Posology: Group 1, 1 drop QID, OU. 
- 
Route of administration: Ophthalmic topical. 
Thealoz® Duo, Trehalose 3% / Sodium hyaluronate 0.15% ophthalmic solution. 
- 
Manufacturer: Laboratorios THEA. 
- 
Posology: Group 2, 1 drop QID, OU. 
- 
Route of administration: Ophthalmic topical. 
 
Duration of treatment: 
14 days 
Subject's duration in the study: 
Up to 18 days 
Evaluation criteria: 
Primary efficacy outcome variable: 
- 
Corneal re-epithelialization time (TEAE: Day 1, 2, 3, and 7). 
 
Secondary efficacy outcome variables: 
- 
Percentage of postoperative corneal re-epithelialization (TEAE: Day 1, 2, 3, and 7). 
- 
Test score (TEAE: Day 1, 7, and 15). 
- 
Pain perception assessment (TEAE: Day 1, 2, 3, 7, and 15). 
 
Primary safety outcome variable: 
- 
Incidence of AE (TEAE: Day 2, 3, 7, and 15). 
- 
Changes in VA (TEAE: Day 2, 3, 7, and 15). 
 
Statistical methodology 
The Shapiro–Wilk test will be performed to assess whether the distribution of the results in 
each study group follows a normal distribution. Quantitative variables will be summarized using 
measures of central tendency, including mean and standard deviation. Qualitative variables will 
be presented as frequencies and percentages. 
For comparisons between groups, quantitative variables will be analyzed using the Student’s t-
test. If the assumption of normality is not met, the Mann–Whitney U test will be used. 
Differences between qualitative variables will be analyzed using the Chi-square (χ²) test or 
Fisher’s exact test, as appropriate. 
A two-sided significance level (α) of ≤ 0.05 will be considered statistically significant. 
 

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Figure 2. Diagram of the study. 
14 days of 
treatment 
Day 1 
Start 
application 
Informed consent obtained. All selection 
criteria met. Baseline values obtained  
n= 96 
Group 1 
Lagricel® Ofteno 
PF 
n=48 
Group 2 
Thealoz® Duo 
n=48 
 
Random assignment 
BV 
D1 
FV 
D15 
(+1) 
SC 
D17 
(+1) 
VB = Baseline visit, V1 = Follow-up visit 1, V2 = Follow-up visit 2, V3 = Follow-up visit 3, VF = Final visit, SC = Safety call, D = Day.  
(Allowed window period) 
V1 
D2 
 
Day 14 
Complete 
application  
  
Clinical 
evaluations  
Clinical evaluations  
V2 
D3 
  
V3 
D7  
(±1) 
  
Clinical evaluations  
Clinical evaluations  
Clinical evaluations  

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PROCEDURES 
BV 
D1 
V1 
D2 
V2 
D3 
 
V3 
D7 
±1 
FV 
D15 
±1 
SC 
D17 
±1 
ICF SIGNATURE 
X 
 
 
 
 
 
MEDICAL RECORD 
X 
 
 
 
 
 
CONCOMITANT DRUG 
EVALUATION 
X 
X 
X 
X 
X 
 
URINE PREGNANCY TEST 
X 
 
 
 
X 
 
VITAL SIGNS 
X 
X 
X 
X 
X 
 
VA 
X 
X 
X 
X 
X 
 
EVALUATION OF CORNEAL 
REEPITHELIALIZATION (BY 
PHOTOGRAPHIC RECORD, 
USING FLUORESCEIN) 
X 
X 
X 
X 
 
 
COMPREHENSIVE 
OPHTHALMOLOGICAL 
EVALUATION 
X 
X 
X 
X 
X 
 
PAIN PERCEPTION 
ASSESSMENT 
X 
X 
X 
X 
X 
 
ELIGIBILITY CRITERIA 
X 
 
 
 
 
 
AE ASSESSMENT 
X 
X 
X 
X 
X 
X 
IP ASSIGNMENT 
X 
 
 
 
 
 
ICO TEST 
X 
 
 
X 
X 
 
DELIVERY OF THE IP 
X 
 
 
 
 
 
START OF INTERVENTION 
X 
 
 
 
 
 
DELIVERY/TRAINING OF 
SUBJECT'S DIARY 
X 
 
 
 
 
 
ADHERENCE ASSESSMENT 
 
X 
X 
X 
X 
 
RETURN/EVALUATION OF 
THE SUBJECT'S DIARY 
 
 
 
 
X 
 
RETURN OF PI 
 
 
 
 
X 
 
BV, BASELINE VISIT; V1, FOLLOW-UP VISIT 1; V2, FOLLOW-UP VISIT 2; V3, FOLLOW-UP VISIT 3; FV, FINAL VISIT; SC, 
SAFETY CALL; ICF, INFORMED CONSENT FORM; VA, VISUAL ACUITY; AE, ADVERSE EVENTS; IP, INVESTIGATIONAL 
PRODUCT; ICO, OCULAR COMFORT INDEX. 
 
Table 2. Study schedule. 
 
 

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Refractive surgical procedures aim to improve visual acuity, without the aid of over-the-eye lenses 
or contact lenses, by correcting spherocylindrical errors through reshaping the central cornea. In 
myopic patients, the curvature is reduced, while hyperopic patients require an increase in the 
central curvature. [1] 
The modern era of refractive surgery began in 1983 with the introduction of the excimer laser to 
modify the structure of the cornea. [2] 
Keratectomy Photorefractive (PRK) was first introduced over 30 years ago [3], this procedure was 
developed to alter the eye's refractive power in a predictable and permanent manner. [4] 
PRK is one of the most popular and effective refractive procedures for correcting  
refractive errors. It involves reshaping the corneal surface following laser ablation of the stroma, 
after carefully removing the epithelium.  [5] After the procedure, reepithelialization occurs through 
fibroblast migration and collagen synthesis. [6] 
PRK was initially established as a surgical procedure for the refractive correction of myopia; 
however, its popularity declined in favor of laser-assisted in situ keratomileusis (LASIK). However, 
PRK is still a technique used in conditions where LASIK is not possible. [7] 
PRK is a safe and effective technique for correcting low and moderate myopia.  [8]In high myopia, 
its use is controversial because other factors, such as UV rays, are involved in the development of 
adverse effects, such as corneal haze, associated with the surgical procedure. [6] 
PRK has also been shown to be an effective and safe surgical procedure in the correction of 
compound myopic astigmatism  [9]and hyperopia. [10] [6] 
Corneal expenditure or depth of corneal ablation in PRK can be calculated using the Munnerlyn 
formula (t=S 2 D/3), where t is the amount of corneal tissue resected in microns, S is the diameter of 
the optical zone of ablation in millimeters, and D is the refraction in diopters. For example, if the 
optical zone of ablation were 6 mm and the diopters to be corrected were -4, the corneal 
expenditure or depth of corneal ablation would be 48 microns. [3] 

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PRK is an option for patients with myopia up to -12 diopters, astigmatism up to -6 diopters, and 
hyperopia up to +5 diopters. [6]Results are better and more predictable at lower levels of each; a 
high refractive error correlates with a higher likelihood of corneal regression and haze. [6] 
Some of the most well-known adverse effects of PRK are corneal haze (cloudiness), corneal 
reepithelialization abnormalities, and pain. [11] The development of adjuvant [12]mitomycin C 
(MMC) therapy in PRK as prophylaxis for corneal haze has demonstrated benefits in the refractive 
correction of high myopia. [13] [14] 
In the early days of PRK, surgical optic zone diameters ranged from 4 to 6 mm, with computer 
algorithms used to control wound depth. Theoretically, corrections of up to -7 diopters removed 
less than 10% of the axial corneal thickness. [4] 
Currently, optical zone diameters of 6.5 mm and 7.0 mm in PRK have proven to be very successful 
in correcting refractive errors. [15]  
One disadvantage of PRK is the postoperative ocular pain associated with corneal de-
epithelialization , which leads to the exposure of corneal nerve fibers and the release of 
inflammatory factors. [16] The pain associated with the PRK procedure improves with corneal re-
epithelialization. 
In PRK, photoablation reaches the subbasal nerve plexus and anterior corneal stroma, leaving 
injured nerve fibers at the base and edges of the corneal ablation.  [17] Cytokines and nerve growth 
factor (NGF) released after corneal ablation can also sensitize corneal nerves, lowering the 
excitation threshold. [18] [19] 
Various modifications to the conventional PRK technique have been introduced in an attempt to 
reduce pain and accelerate epithelial recovery; these attempts have focused primarily on the 
corneal de-epithelialization method . [20]  
Rodrigues et al. reported complete epithelialization in all their patients by day 5 post-PRK; however, 
they noted that a limitation of their study was that they did not perform daily monitoring of the 
epithelial healing process. [21] 
PRK is not indicated in patients with cataracts, glaucoma, and uncontrolled ocular surface diseases 
such as blepharitis, dry eye syndrome, and allergies. [6] Keratoconus and other corneal 

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abnormalities, such as corneal ectasias, thinning, edema, interstitial or neurotrophic keratitis, and 
extensive vascularization, are considered absolute contraindications. [6] 
Patients with active connective tissue diseases such as systemic lupus erythematosus (SLE) and 
rheumatoid arthritis (RA) are considered less than ideal candidates for PRK because of the increased 
risk of corneal haze . [6]  
patient's manifest refraction as well as  [6]cycloplegic refraction should be obtained . Pupil size 
should be measured, as large pupils can contribute to glare and halos postoperatively. Slit-lamp 
examination is necessary to rule out significant corneal abnormalities such as neovascularization, 
keratoconus, or the presence of a cataract. Corneal pachymetry allows for the determination of 
corneal thickness and will detect keratoconus or other types of corneal ectasia. The eyelids and tear 
film require examination for signs of blepharitis or dry eye. [6] 
Preoperative medications are usually administered 20 minutes before refractive surgery. To reduce 
postoperative pain, nonsteroidal anti-inflammatory drops such as ketorolac tromethamine 0.5% or 
diclofenac 0.1% can be applied. Topical anesthetic drops such as tetrazine hydrochloride 0.5% or 
proparacaine 0.5% are placed in the eye a few minutes before surgery. Topical fluoroquinolones 
such as ciprofloxacin 0.3%, moxifloxacin 0.5%, and gatifloxacin 0.3% are administered to reduce the 
possibility of infection. Sedation may be considered. [22] 
Postoperative treatment for PRK includes topical ophthalmic medications such as nonsteroidal anti-
inflammatory drugs, antibiotics, steroids, and lubricants, as well as a soft bandage contact lens. 
Patients should be informed that their vision will likely be blurred while the corneal surface re-
epithelializes. [6] 
Corneal reepithelialization is complete in most patients by the 3rd postoperative day. [6] 
Long-term visual outcomes for patients undergoing PRK are generally very good. [6] Alio et al. 
reported in a study of patients with a 15-year follow-up that 55% of eyes were within +/- 1 diopter 
and 85% within +/- 2 diopters. [23] 
When comparing LASIK and PRK, systematic reviews have shown no differences in long-term 
efficacy, accuracy, or adverse effects in patients with low to moderate myopia [24] [25], however, 
LASIK has a shorter recovery time and less postoperative pain. 

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The characteristics of the tear film and the hydrodynamics of the tear system cause ophthalmic 
formulations to have a short retention period on the ocular surface, so frequent application is 
necessary to achieve the appropriate concentration of the substance used. [26] 
Pharmacokinetic studies conducted in 12 patients with dry eye showed that 0.2% sodium 
hyaluronate (SH) solution had a mean residence time on the ocular surface of 11.1 minutes, while 
for 0.3% SH solution it was 23.5 minutes, these solutions were eliminated from the ocular surface 
in approximately 45 minutes through the tear system. [27] 
Benzalkonium chloride is the most widely used preservative in multi-dose ophthalmic products. [28] 
It is a bactericidal and antifungal agent that helps minimize the growth of microorganisms in multi-
dose containers. [28] However, there is scientific evidence supported by in vitro, in vivo, and clinical 
models of the disruptive behavior of benzalkonium chloride on tear stability. It also causes cellular 
damage to the corneal and conjunctival epithelium, induces inflammatory changes, and leads to a 
decrease in the function of the corneal epithelial barrier. [29] [30] 
With the development of new technologies, such as the Novelia® bottle used in Lagricel® Ofteno 
multidose , a new generation of preservative-free products in multidose presentations has been 
created at an affordable price. The Novelia® bottle 's Preservative-Free system has proven capable 
of protecting the contents from contamination, adding safety to the drug's use by avoiding the 
addition of preservatives. [31] [32]  
In 2019, Laboratorios Sophia SA de CV conducted a Phase I clinical trial to evaluate the safety and 
tolerability of Lagricel® Ofteno multi-dose ophthalmic solution compared to Lagricel® Ofteno single-
dose. A total of 34 healthy subjects were evaluated in two parallel groups, demonstrating that both 
products are safe and tolerable. [33] 
This study will be conducted in a population diagnosed on the 1st day post-surgical with PRK, and 
will evaluate the efficacy of Lagricel ® Ofteno multidose (Sodium Hyaluronate 0.4%) compared to 
Thealoz ® Duo in corneal reepithelialization after PRK. 

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Sodium hyaluronate (SH) is a glycosaminoglycan with viscoelastic rheology. It is composed of 
repeating units of N-acetyl-D-glucosamine and sodium-D- glucuronate .  [34] SH has a high water-
retention capacity, which is one of its reasons for being present in a large number of artificial tear 
formulations, as it improves ocular hydration, reduces surface friction, and has excellent 
biocompatibility. [35] [36]  
Hyaluronic acid-derived SH shares many of its beneficial properties with hyaluronic acid. In addition 
to retaining water, which makes it a good humectant and lubricant, SH is hypoosmolar. This latter 
characteristic allows it to decrease the osmolarity of tears and mucinoid filaments . [37] 
 
The efficacy of 0.15% SH in the treatment of patients with dry eye syndrome has been determined, 
using 1 drop every 4 hours in each eye for 30 days. It was shown that this pharmacological agent 
decreases inflammatory markers expressed by cells of the corneal surface (macrophages and T 
lymphocytes) and restores the tear film, which results in a decrease in corneal inflammation.  [38]It 
can be postulated that by decreasing inflammation of the ocular surface with SH, there would be a 
greater density of goblet cells in the conjunctiva and less apoptosis in corneal cells. [35] 
In another clinical trial, the efficacy of 0.18% SH in the treatment of dry eye was evaluated and 
shown to be more effective than 1% carboxymethylcellulose . Using fluorescein staining as a marker 
of corneal status, it was determined that SH restores the corneal surface more quickly and reduces 
dry eye symptoms. [39]   
Hyo L et al., evaluated the efficacy of a hypotonic formulation of 0.18% SH in the treatment of dry 
eye. The study included 30 patients with mild dry eye syndrome, divided into: Group 1: Consisting 
of 15 patients who received isotonic preservative-free 0.1% SH (300 mOsm / l) 1 drop 4 times a day 
for 90 days, Group 2: Consisting of 15 patients who received hypotonic preservative-free 0.18% SH 
(150 mOsm / l) 1 drop 4 times a day for 90 days. The study included 30 patients with moderate dry 
eye syndrome, divided into: Group 3: 15 patients exposed to isotonic 0.1% SH (1 drop 4 times a day) 
+ fluorometholone 0.1% (2 times a day) + cyclosporine 0.05% (2 times a day). Group 4: 15 patients 

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exposed to hypotonic 0.18% SH (1 drop 4 times daily) + fluorometholone 0.1% (twice daily) + 
cyclosporine 0.05% (twice daily). The results demonstrated that the use of 0.1% and 0.18% SH were 
equally effective in treating mild to moderate dry eye syndrome after 90 days of intervention, 
considering the stability of the tear film and improvement of the corneal surface. [40]  
In a phase II clinical study, the efficacy and safety of Lagricel® Ofteno was evaluated compared to 
0.2% polyacrylic acid gel (Viscotears®) after LASIK surgery. This was a prospective, randomized, 
controlled study that included 30 patients who received the study drug three times a day (TID) for 
28 days. Outcome variables included: red eye, foreign body sensation, dryness sensation, pain, 
photophobia, BCVA (best corrected visual acuity), conjunctival hyperemia, corneal surface integrity, 
corneal opacity, rose bengal staining, and periocular and fundus findings. The efficacy of Lagricel® 
Ofteno was demonstrated in this study. [41] 
 
The safety of Lagricel® Ofteno has been evaluated in several clinical studies. A Phase II clinical study 
evaluated its safety and efficacy compared to 0.2% polyacrylic acid gel (Viscotears®) after LASIK 
surgery. This study demonstrated the safety of Lagricel® Ofteno. [41] 
In another randomized, controlled, crossover clinical study in 20 patients, the efficacy in reducing 
signs and symptoms (e.g., red eye, foreign body sensation, and dryness) associated with dry eye 
disease was tested. [42] 
A phase IV clinical study was recently completed evaluating the effect of bromfenac 0.09% 
ophthalmic solution on conjunctival hyperemia in patients with pterygium, administered twice daily, 
compared with placebo. Both groups concomitantly used Lagricel® Ofteno TID. The results 
demonstrated the efficacy of both arms in reducing hyperemia and symptoms associated with 
pterygium, with statistical significance when compared to baseline. In turn, the bromfenac group 
was statistically superior to the placebo group. No AEs related to Lagricel® Ofteno were reported. 
[43]  

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Lagricel® Ofteno multidose has been developed by Laboratorios Sophia, SA de CV. It has undergone 
physicochemical characterization and a protocol for accelerated and long-term stability. The 
formulation is identical to that of Lagricel® Ofteno single-dose in a multidose presentation. 
 
 
There is no prior documented information on the efficacy of Lagricel® Ofteno multidose in corneal 
reepithelialization following PRK. However, the efficacy and tolerability of Lagricel® Ofteno single-
dose has been previously evaluated in two single-center clinical studies .  [41, 43, 42, 43] The efficacy 
and tolerability of Lagricel® Ofteno multidose have been evaluated in a phase I study. 
In the three clinical studies of Lagricel® Ofteno single-dose and Lagricel® Ofteno multidose, the 
outcome variables evaluated were TRPL, comfort, blurred vision, ocular surface staining, and the 
incidence of AEs. Both formulations were well tolerated, and the final results were statistically 
significant when compared with baseline. 
 
 
Ocular lubricants are safe formulations. SH has a known safety profile. The diagnostic tests 
considered in the study design are also considered safe. 
The only anticipated side effects with ophthalmic applications are burning, a foreign body sensation, 
and blurred vision. These are mild and transient, lasting no more than one minute post-instillation.  
[33, 41, 42, 43] 

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As these subjects were diagnosed with post-PRK surgery, they are expected to show improvement 
by reducing the time to complete corneal reepithelialization after surgery and, secondary to this, 
also improving ocular comfort during this study. 
 
Although corneal de-epithelialization is part of the standard PRK procedure, shortening the 
epithelial regeneration time is an important part of the post-surgical recovery process, which is why 
the initial treatment common denominator is the use of ocular lubricants. There are a wide variety 
of topical lubricants; however, there is no evidence that one is better than another. 
Although ocular lubricants have not been shown to be sufficient to completely resolve the alteration 
of the ocular surface secondary to corneal de-epithelialization observed in post-PRK surgery 
patients, they have been shown to be effective in providing protection to the ocular surface and 
reducing symptoms and clinical findings. 
Lagricel® Ofteno multidose, obtains its viscoelastic, hypo-osmolar and water retention properties 
from SH, to function as an effective lubricant that protects the ocular surface, reconstitutes the tear 
film and contributes to corneal reepithelialization without the association of a preservative. 
 
Patients undergoing post-PRK surgery will need to use ocular lubricants to reduce the symptoms 
associated with corneal de-epithelialization. Ocular lubricants are the first line of treatment for 
ocular symptoms related to corneal de-epithelialization secondary to PRK. [44] Preservative-free 
lubricants have gained importance by reducing the deleterious effect of the accumulated dose of 
preservatives. One of the disadvantages of preservative-free ophthalmic products is their single-
dose presentation, which increases treatment costs for various reasons, including product loss. 
 With the development of new technologies, a new generation of preservative-free products in 
multi-dose presentations has been created. Lagricel® Ofteno multidose is a preservative-free 
lubricant in multidose presentation for which documentation of its efficacy in corneal 
reepithelialization after PRK compared to Thealoz ® Duo is required . 

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• 
To evaluate the efficacy of Lagricel® Ofteno PF compared to Thealoz ® Duo in corneal 
reepithelialization of post-PRK surgery patients. 
 
• 
To evaluate the safety of Lagricel® Ofteno PF compared to Thealoz® Duo by the incidence 
of unexpected adverse events (AEs) in post-PRK surgery patients . 
• 
To determine the efficacy of the multidose Lagricel® Ofteno formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients by means of 
photographic recording using fluorescein. 
• 
To determine the efficacy of the multidose Lagricel® Ofteno formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients using the ICO test . 
• 
To determine the efficacy of the multidose Lagricel® Ofteno formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients by assessing pain 
perception. 
• 
To determine the safety of the multidose Lagricel® Ofteno formulation compared to 
Thealoz® Duo in corneal reepithelialization of post-PRK surgery patients through changes in 
visual acuity. 
 
 

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H0: Lagricel® Ofteno PF does not contribute to complete corneal reepithelialization at the 3rd day 
of post-PRK treatment and is not equivalent to Thealoz ® Duo . 
H0: |µ 𝐴 − µ 𝐵| ≥ 𝛿 
 
H1: Lagricel® Ofteno PF contributes to complete corneal reepithelialization on the 3rd day of post-
PRK treatment and is equivalent to Thealoz ® Duo . 
H1: |µ 𝐴 − µ 𝐵| < 𝛿 
 

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Phase IV, multicenter, comparative, controlled, parallel-group, open-label, randomized clinical trial. 
 
The study design (clinical trial) is considered the highest standard of data quality when exploring the 
effect of an intervention. The drug development phase (Phase IV) corresponds to the study 
objective, which is to evaluate the post-marketing efficacy and safety of products. The presence of 
parallel groups allows for comparisons between the intervention groups on outcome variables. Due 
to the nature of the design, blinding was considered for this study. 
 
The total duration of the study, from the first patient visit to the final report, is estimated to be 11 
months. 
The approximate duration of each subject in the study is up to 18 days. 
 
 

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− 
Be between 18 and 45 years old. 
− 
1-day post-PRK surgery period (right eye will be evaluated for study). 
− 
Having performed the epithelium removal technique with 20% alcohol (ethanol) for a time 
within the range of 30-40 seconds. 
− 
Having used a de-epithelialization area (transition area) in the range of 8-9 mm. 
− 
Surgical corneal ablation surface from 5.5 mm to 6.0 mm. 
− 
Corneal expenditure less than or equal to 60 microns. 
− 
Pre-surgical refraction of -1.0 to -4.5 D of myopia or myopic astigmatism (the sum of both 
values in this case, spherical equivalent no greater than -4.5). 
− 
Have the ability to voluntarily grant signed informed consent. 
− 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
− 
Be willing to modify your lifestyle activities. See 5.3 Lifestyle considerations 
− 
Women of childbearing potential must ensure continued use (started ≥ 30 days prior to 
signing the Informed Consent Form [ICF]) of a hormonal contraceptive method or 
intrauterine device (IUD) during the study period. 
 
 
− 
Transurgical complications and during the post-surgical period prior to inclusion in the 
study. 
− 
Use of mitomycin during PRK. 
− 
PRK retreatments or history of other types of refractive surgery. 

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− 
For women: be pregnant, breastfeeding, or planning to become pregnant during the study 
period. 
− 
Having participated in another clinical research study ≤ 30 days prior to the screening visit. 
− 
Having previously participated in this study. 
− 
Present an additional diagnosis of: 
− 
Allergic, viral or bacterial conjunctivitis. 
− 
Dry eye. 
− 
Anterior blepharitis. 
− 
Parasitic eye infections (e.g., Demodex). 
− 
History of ocular herpes. 
− 
History of ocular inflammatory processes (such as uveitis). 
− 
History of corneal or conjunctival ulcers. 
− 
Glaucoma. 
− 
Have a history of drug addiction or dependence, currently or within the last two years prior 
to signing the ICF. 
− 
Have a history of ocular surgical procedures within the last 3 months prior to signing the 
ICF. 
− 
Having another medical condition, acute or chronic (such as Diabetes Mellitus type I / II, 
autoimmune diseases or HIV) that, in the opinion of the investigator, could increase the risk 
associated with participation in the study or the administration of the investigational 
product, or that could interfere with the interpretation of the study results. 
− 
Use medications (such as retinoic acid) that, in the opinion of the investigator, may increase 
the risk associated with participation in the study or administration of the investigational 
product, or that may interfere with the interpretation of the study results. 
− 
Have a known hypersensitivity to the components of the investigational products. 
− 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is an employee of the research site or the sponsor and who is directly involved 
in this study. 
 

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The sponsor may decide to replace subjects who withdraw their ICF or those who are lost to follow-
up, if it is necessary to balance the study groups so that they are evaluable. 
 
For the study, participants may need to modify some lifestyle activities to accomplish the 
following: 
- 
Refrain from smoking. 
- 
Refrain from using electronic vaporizers. 
- 
Avoid immersing yourself in water without eye protection ( goggles ). 
- 
Avoid direct exposure to fans (including air conditioning vents) during activities that involve 
your vision, 24 hours before your checkup visits. 
- 
Maintain your sleep-wake cycle with the one you entered the study. 
 
A screening failure is defined as a participant who agrees to participate in the study, giving their 
consent, but who is not assigned to a treatment group; that is, they do not enter the study. The 
following information regarding screening failures must be reported, at a minimum: 
- 
Demographic data. 
- 
Details of the counting failure (specify whether due to eligibility criteria, which one, or some 
other reason for the failure). 
- 
Presence of serious adverse events during the scrutiny. 
This is necessary to comply with the CONSORT ( Consolidated Standards for the Publication of 
Clinical Trials ) guidelines for publishing results or to respond to potential questions from regulatory 
authorities. 
Subjects who do not meet the eligibility criteria for participation in the study due to a specific 
modifiable factor may be re-screened. Subjects in this situation must use the same initial screening 
number. 

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This is a Phase IV study, planned to be conducted in at least four centers. The selected centers will 
be responsible for subject recruitment. 
The minimum expected recruitment rate is 1 subject every 3 days. 
The duration of the subject's participation in the study is approximately 18 days, during which they 
will only be required to attend four visits after the initial visit. Subjects will be eligible for travel and 
visit allowances. Other strategies to improve subject retention include: 
• 
Clearly communicate the importance of the study and the benefits that the population will 
obtain from its results . 
• 
Make calls or send text messages to remind yourself of appointments or activities to do. 
• 
Provide a printed calendar and an identification card to remind you of appointments and 
activities to be carried out, as well as their estimated duration . 
• 
Offer flexible business hours. 
• 
Systematic organization of the study procedures, so that the subject does not stay longer 
than necessary during his visit. 
• 
Minimize subject wait times. 
All materials to be delivered to the subject or recruitment strategies implemented by the Centers 
will be submitted for approval by the corresponding committees. 
 
For this protocol, loss to follow-up is defined as those subjects who were randomized, who at some 
point were active subjects in the study, but their final evaluation could not be completed. 
If the participating subject does not attend their appointment, the research site will call to 
determine the reason and attempt to schedule a new appointment within the established window 
or an unscheduled appointment. If an appointment cannot be scheduled, the subject will be asked 
about the presence of adverse events and the reason for discontinuing the study, as minimum 
information. 
A loss to follow-up <20% is not considered to represent a problem for the validity of the results 
obtained. [45, 46]  

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Study subjects will be identified by a number and the initials of their name. 
The initials of the subject of study will be obtained starting with the first letter of the name, followed 
by the first letter of the first surname and the first letter of the second surname, obtaining a 
maximum of three letters. In case the person has two names or a compound surname, the first letter 
will always be used. 
Example: 
A. A rieh Daniel M ercado C arrizalez  
 
B. J uan D e la Torre O rozco 
a. Initials: AMC   
 
 
 
b. Initials: JDO 
During the screening phase (during the initial visit), you will be assigned a consecutive participant 
number, using three consecutive digits. Once the subject has been selected, they will be assigned a 
number that will be used to identify them throughout the study. This code will consist of eight 
numbers in the following order from left to right: 
• 
Three digits of the molecule under study according to the sponsor's designation. 
• 
two digits corresponding to the research center number. 
• 
three digits of the consecutive number assigned to its inclusion in the research center. 
Example: 
 
 
037-01-001 
Molecule code 
Inclusion number 
Site number 

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− 
Generic name: Sodium hyaluronate. 
− 
Distinctive name: Lagricel® Ofteno multidose. 
− 
Active ingredients: Sodium hyaluronate 0.4%. 
− 
Excipients: sodium chloride, monobasic sodium phosphate monohydrate, anhydrous 
dibasic sodium phosphate, water for the manufacture of injectables. 
− 
Pharmaceutical form: ophthalmic solution. 
− 
Presentation: multi-dose dropper bottle. 
− 
Prepared by: Laboratorios Sophia S.A. de C.V. 
− 
Solution description: Clear solution, free of visible particles. 
− 
Packaging description: White bottle with a capacity of 10 mL, made of low-density 
polyethylene. 
 
− 
Generic name:Trehalosa 3% / Hialuronato de sodio 0.15%. 
− 
Distinctive name: Thealoz ® Duo . 
− 
Active ingredients:Trehalosa 3% / Hialuronato de sodio 0.15%. 
− 
Excipients: sodium chloride, trometamol , hydrochloric acid, water for the manufacture of 
injectables. 
− 
Pharmaceutical form: Ophthalmic eye drop solution. 
− 
Presentation: multi-dose dropper bottle. 
− 
Prepared by:Laboratorios THEA. 
− 
Solution description: Clear solution, free of visible particles. 
− 
Packaging description: white bottle with 10 mL capacity. 
 

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The same dosage will be used for Lagricel® Ofteno multidose presentation and Thealoz ® Duo : 
- 
One drop 4 times a day, OU, for 14 days (minimum time between applications of 3 hours). 
6.1.3.1 Justification of the dose 
Ophthalmic lubricants are generally prescribed as needed ( pro re nata [PRN]).  [47]However, in the 
Asbell study et al. compared the efficacy of four times daily (QID) dosing versus PRN dosing. Their 
results showed that, although there was no difference in clinical signs, the QID group had greater 
symptom improvement.  [48]For this reason, they propose the four-times-daily dosing regimen. 
 
Delivery will be made via a courier service contracted by the sponsor, specifically selected for this 
purpose, to the address of the research center in accordance with the study plan. 
Reception will be carried out by the assigned research team staff. The primary packaging (box) must 
be inspected for its condition. If it shows alterations or defects in its integrity that, in your opinion, 
could have damaged the contents, you must report this to the sponsor. If the package shows no 
significant defects, it will be opened. 
Inside, you should find the receipt acknowledgment document and the temperature data logger . 
You must check that the recorded temperature meets the specifications for its transport and 
storage. The contents (PI) will be verified with what is reported on the document. If the document 
matches the contents, the receipt will be signed and sent to the sponsor. If not, the sponsor will be 
notified. 
Storage and safeguarding are the responsibility of the research center. The medication must be kept 
in a secure area with restricted access. 
Storage temperature should be no more than 30°C. 
The research center is required to record, in the designated format, the temperature recorded in 
the data logger , every day while the protocol is in force and has PI. Said data will be reviewed by 
the clinical monitor according to the record in the data logger . 

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In the event of material loss, this must be documented in the input and output log along with a clear 
description of the mechanism by which the loss occurred. 
Upon completion of the protocol, all study materials will be retrieved by the sponsor as part of the 
closure audit. The final return of materials will be made by the principal investigator or the person 
designated by the principal investigator to return materials at the end of the study. 
The sponsor reserves the right to initiate civil and criminal action against the principal investigator 
in the event of undocumented material missing at the end of the study. 
 
The use of concomitant medications by any route of administration will not be permitted during the 
intervention period, except for those specified for the study procedures. The purpose of this 
restriction is to avoid drug interactions that could alter the results of the evaluated variables . 
Permitted medications: 
• 
Ophthalmics: 
Tetracaine 
0.5% 
(Ponti), 
Tropicamide 
0.8% 
/ 
Phenylephrine 5% (TP) (for study procedures), PI, Ciprofloxacin 0.3% 
(Sophixin), Fluorometholone 0.1% ( Flumetol NF). 
• 
No ophthalmic: Contraceptives hormonal, painkillers: Stadium ( 
Dexketoprofen , oral 25 mg/6hrs: initial intake after surgery, after PRN 
[For Necessary Reason]) and Supradol (Ketorolac, sublingual 30 mg 
every 6 hours: take initial later to surgery, after PRN). TO criterion of the 
researcher HE They may use systemic medications whose effects do not 
modify the parameters of efficacy or safety of this protocol, but they 
must be notified to the committee scientist of the sponsor for determine 
the situation of the participant according to corresponds. 
Medications prohibited: 
 
• 
Any medicine ophthalmic that No HE find in the list of medications 
allowed. Medications systemic: immunomodulators and tetracyclines. 

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For more than four decades, numerous studies have been conducted on the appropriate way to 
measure and quantify medication adherence; however, none have reached a consensus that could 
serve as the gold standard, whether in cross-sectional or longitudinal studies. [49, 50, 51, 52, 53, 54, 
55, 56] 
There are different procedures for measuring adherence to pharmacological interventions. The 
most common procedure involves self-reports , which include patient interviews, questionnaires, 
and self-monitoring diaries. Their strengths are speed, flexibility, low cost, and ease of 
implementation; they have a high degree of specificity for nonadherence, but their sensitivity and 
reliability for adherence are low. [56, 57] 
Biochemical measurement of the drug, or its metabolite, is one of the methods that best confirms 
drug use. However, in addition to being costly and impractical, it is of little use in ophthalmic 
applications, as peripheral concentrations may be undetectable; and samples from other tissues 
require more invasive methods that would be inadvisable. [56] 
Medication counting is another way to measure adherence. Classically referred to as "pill counting," 
in ophthalmology it is translated as the weight of the bottle. This is a simple, inexpensive, and 
noninvasive method. The main disadvantages of this method are: 1. It cannot confirm the 
application of the medication (it could have been intentionally dropped or instilled outside the eye), 
and 2. It depends on the subject bringing the medication back.  [56, 57]However, in this study, the 
initial and final weight of the bottle will also be taken into account to measure adherence. 
A multi-method approach to adherence measurement is recommended. Because there is no ideal 
adherence measure, it is appropriate to use more than one method when aiming to achieve results 
that resemble reality. Selecting two or more methods allows for balancing their strengths and 
weaknesses, thus more accurately capturing adherence levels. [55] 
Adhesion assessment will be based on the bottle's weight and will be performed as follows: drop 
weight, initial container weight, final container weight, and a calculation of the total number of 
applications. The following simplified formula will be used: 
𝐴𝑑= (𝑃𝑖−𝑃𝑓)100
𝑃𝑇
 

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Where: 
Ad = adhesion 
𝑃𝑖= weight of the container delivered to the subject at the beginning 
𝑃𝑓= weight of the container returned by the subject 
𝑃𝑇 = weight of the dosage indicated for the intervention 
𝑃𝑇= (𝑃𝑔)𝐺 
Where: 
𝑃𝑔= weight of a drop of the intervention, determined by the research and development department 
G = number of applications indicated for the intervention 
Packaging that does not maintain its physical integrity will not be considered for the calculation of 
adhesion. 
In cases where the container is not returned, or has not maintained its physical integrity, adherence 
will be measured using the subject's diary, as follows: 
𝐴𝑑= (𝐴𝑟)100/𝐴𝑖 
Ad = Adhesion 
A r = Registered applications 
A i = Indicated applications for investigational products 
There is no standardized parameter for defining adequate adherence; it must be defined and 
outlined by the objectives of the particular research. [56]  
For this study, a minimum adherence of 70% will be considered necessary to meet the research 
objectives, both through the subject diary and by bottle weight. Therefore, subjects with less than 
70% adherence will not be considered for the efficacy analysis; they will only be included in the 
safety analysis. 
 
1. The Principal Investigator (PI) will educate the subject on the importance of correctly 
applying the research product (PI) to achieve the study objectives. 
2. Direct questioning by the IP regarding the application of the PI. 

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3. Delivery of a printed calendar specifying the date of the visit and its activities. 
4. Training in completing and reviewing the “Subject Diary.” 
5. If deemed necessary, text messages may be sent as reminders. The content of these 
messages must be approved in advance by the Research Ethics Committee (REC). 
 
 

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This study will be conducted at research centers previously evaluated by the sponsor. These centers 
will be institutions or establishments where health research is conducted in compliance with current 
regulations. 
The number of centers to be included will be determined based on the capacity of the centers 
evaluated during the feasibility studies. The suggested number is four or more. 
The research center will be responsible for forming a multidisciplinary research team to execute the 
clinical study according to the protocol. It is its prerogative to design the organization and select the 
personnel who will perform these functions. However, the sponsor requires that the PI be a 
physician specialized in ophthalmology. 
Any person assigned responsibility for part of the study monitoring (coinvestigator, sub-investigator, 
nurse, etc.) or a specific role in the study (pharmacist, administrative assistant, study coordinator, 
etc.) must be listed in the "Delegation of Responsibilities." 
The competency and training of all individuals directly involved in study activities must be verified 
prior to the conduct of any protocol-related activities. This must be recorded, and documents 
constituting evidence of this competency and/or training must be retained in the study master file. 
The competency and training of personnel involved in the study, both at the central level and at the 
study sites, is the responsibility of the sponsor. 
The sponsor must ensure that all study center personnel participating in the study are adequately 
trained in the study (research protocol, investigator's manual, amendments, standard operating 
procedures, etc.) and in the International Council for Harmonization (ICH) Good Clinical Practices 
prior to the start of their participation in the study. Training must be documented in writing and 
filed in the study's master file. 

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This clinical study will be registered by the sponsor in public clinical trial registries prior to its 
initiation (inclusion of the first patient): the National Registry of Clinical Trials (RNEC) of the Federal 
Commission for the Protection against Sanitary Risks (COFEPRIS) and on a primary registry platform 
of the World Health Organization (WHO). WHO primary registries meet specific criteria regarding 
content, quality and validity, accessibility, unique identification, technical capacity, and 
administration. WHO primary registries meet the requirements of the International Committee of 
Medical Journal Editors (ICMJE). 
 
Subject randomization will be performed using a computerized allocation system. After signing the 
ICF, the patient will receive a patient number, which will be used to coded all information pseudo -
anonymously during data collection and completely anonymously during analysis. 
The generation will be carried out by a third party authorized by Laboratorios Sophia, SA de CV, 
through its electronic system. The information corresponding to this third party will be found in the 
file. 
Although this is an open-label study, secondary packaging will be blinded. 
The PI will be identified by means of labels in compliance with current and applicable regulations, 
which must contain at least: 
- 
Name, address and telephone number of the sponsor. 
- 
Pharmaceutical form and route of administration. 
- 
Batch number. 
- 
Legend “Exclusively for clinical studies” 
- 
Expiration date. 
 

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- 
Corneal reepithelialization time (TEAE: day 1, 2, 3 and 7). 
 
- 
Incidence of AE (TEAE: day 2, 3, 7 and 15). 
- 
Changes in VA (TEAE: day 2, 3, 7 and 15). 
 
- 
Percentage of postoperative corneal reepithelialization (TEAE: day 1, 2, 3 and 7). 
- 
ICO test score (TEAE: day 7 and 15). 
- 
Pain perception assessment (TEAE: day 2, 3, 7 and 15). 
 
Variable 
Type 
Unit 
Measurement 
Method 
Normal 
Value 
Evaluation 
Time 
Statistical Test 
Primary efficacy outcome 
Corneal 
reepithelialization time 
Discrete 
Days 
Direct observation 
and photographic 
record 
3 days 
BV, V1, V2, 
V3 
Student’s t-test / 
Mann–Whitney U* 
Secondary efficacy outcomes 
Percentage of daily 
post-surgical 
reepithelialization 
Continuous 
Percentage (%) 
Direct observation 
100% 
BV, V1, V2, 
V3 
Student’s t-test 
/ Mann–
Whitney U* 
ICO Score 
Discrete 
Numeric ( score) 
Questionnaire 
0 
BV, V3 FV 
Student’s t-test / 
Mann–Whitney U* 
Pain perception 
Ordinal 
Severity and 
frequency 
scales 
Questionnaire 
Absent / 
None 
BV, V1, V2, 
V3, FV 
χ 2 (Chi-square) or 
Fisher's exact test; 
McNemar test * 
Primary safety outcome 
AE (number) 
Discrete 
Number of 
cases (n) 
Counting 
0 
BV, V1-3, FV 
Student's t test 
AE (ocurrance) 
Nominal 
categorical 
Present / absent 
(-) 
Observation 
Absent 
BV, V1-3 and 
FV 
χ 2 (Chi-square) 
Pearson or Fisher 
exact. 
VA 
Discreet 
Fraction (-) 
Snellen chart 
1 
BV, V1-3 and 
FV 
Student’s t-test / 
Mann–Whitney U* 
Abbreviations: ICO = Eye Comfort Index; AE = Adverse Event; VA = Visual Acuity. 
*Applied when the assumption of normality is not met. 
Table 3. Operational definition of variables 

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The variables, method, and scales used to measure them are described in detail below. They are 
listed in order according to Table 3. 
7.4.4.1 Corneal reepithelialization  
Corneal reepithelialization will be assessed by photographic record using fluorescein. The bandage 
lens will be removed, then a drop of topical anesthetic will be instilled in the conjunctival fornix. A 
second drop will then be applied to the tip of the fluorescein strip, allowing it to sit on the strip for 
5 seconds to elute the dye, finally shaking off the excess. A small contact of the strip with the 
conjunctiva is made in the temporal fornix while the patient looks upward, without damaging the 
conjunctiva. A photographic record will be taken to evaluate the progress of the reepithelialization 
process. The magnification or magnification used in the slit lamp for the photographs will be 6x and 
16x. A minimum of 3 frontal photographs will be taken, visualizing the entire corneal surface by 
magnification, 6 photographs in total per patient per visit. The photographic evidence will be stored 
in a virtual storage network and the images will be recorded in accordance with the stipulations of 
the current operating manual. After taking photographs, a new contact lens will be placed. 
The IP will record in the file and the eCRF the daily percentage of progress of the corneal 
reepithelialization process (considering the corneal de -epithelialization zone a total of 100%) on the 
post-surgical days indicated in the protocol. 
Management as AE: Corneal stains that do not show 100% progress in the corneal reepithelialization 
process within the first 3 days postoperatively will be considered AE due to lack of efficacy. 
7.4.4.2 ICO Score 
The OCI is a questionnaire designed to measure ocular surface irritation using Rasch analysis to 
produce estimates on a linear interval scale (scores: 0–100). Similar to the index for ocular surface 
diseases, the Ocular Comfort Index (OCI) assesses symptoms. The OCI contains items that focus on 
discomfort associated with ocular surface disorders. Each of these questions has two parts, which 
separately inquire about the frequency and severity of symptoms. [58]  
The evaluator will give the questionnaire to the subject and allow them to answer it calmly without 
any pressure or coercion. They will only assist them if they have difficulty understanding any of the 
questions. 

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Management as an AE: The ICO assesses symptoms, which may or may not be related to an AE. The 
ICO score alone should not be considered an AE. 
7.4.4.3 Pain perception assessment 
The subject will be questioned directly about the presence of pain. They will respond to the severity 
and frequency of symptoms, such as: 
Severity: Absent (0), very mild (1), mild (2), moderate (3) and severe (4) 
Frequency: All the time (4), almost all the time (3), 50% of the time (2), almost never (1), never (0). 
The number corresponding to each symptom will be recorded in the eCRF . 
7.4.4.4 Adverse events 
As defined in section 8.1.1, an EA It is any unfavorable medical occurrence in a subject to whom a 
PI is administered, regardless of the causal attribution. 
The management of AEs will be carried out as described in the Adverse Events section. 
any AEs that the study subjects present in the corresponding section of the eCRF and will also report 
them in the clinical record. 
For an adequate assessment of AEs, in addition to the targeted questioning, a Comprehensive 
Ophthalmologic Evaluation must be performed at each visit. This evaluation consists of an 
ophthalmologic examination of the eyelids and adnexa, anterior segments, and posterior segments, 
which are performed during a routine ophthalmologic examination and are not specifically included 
in the study variables. The posterior pole evaluation may be performed with direct or indirect 
ophthalmoscopy , with or without pharmacological mydriasis, at the discretion of the PI. The fundus 
will be assessed for abnormalities that could alter the study results. IOP will be measured during this 
evaluation, using the PI's instrument of choice. It should be measured after the stain evaluation. The 
results of the evaluation will be recorded in the clinical record. Only those findings that the PI 
considers to be AEs will be reported in the eCRF . 
The expected adverse effects associated with the use of PIs are: blurred vision, burning, eye 
irritation, foreign body sensation, and sticky eyelashes. They are expected to be transient, lasting 
no more than 30 seconds after PI instillation , and to be mild in intensity. 

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7.4.4.5 Visual acuity 
Visual acuity (VA) is a test of visual function. Spatial VA is the ability to distinguish separate elements 
of an object and identify them as a whole. It is quantified as the minimum angle of separation 
(located at the nodal point of the eye) between two objects that allows them to be perceived as 
separate objects. 
Snellen notation is described as the distance at which the test is performed divided by the distance 
at which the letter vertically equals 5 minutes of arc. 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 (i.e., 20/20 = 1 and 20/40 = 0.5). 
[59]  
VA will be assessed using the Snellen chart. This chart will be placed in a location with adequate 
natural or artificial lighting and at a distance of 3 m from the subject being assessed. Visual acuity 
will be measured in each eye, starting with the right eye (RE), asking the subject to keep both eyes 
open and using an occluder to cover the left eye (LE); the subject will read aloud the lines indicated 
by the evaluator. The line with the smallest letters visible will be recorded by the evaluator as a 
fraction of the RE VA in the clinical record. The LE is then assessed using the same method. 
Management as an AE: A decrease of more than 2 lines on the Snellen chart, taking into account the 
baseline visit, should be reported and managed as an AE. 
 
7.4.5.1 Description of activities per visit 
The procedures are listed in the order in which they are suggested to be performed, trying to 
maintain the consistency of the evaluations and, as far as possible, from the least invasive to the 
most invasive. 
7.4.5.2 Baseline Visit 
• 
Signature of the ICF: refers to the signing of the written informed consent document. 
Without informed consent, none of the study procedures can be performed. 
• 
Medical history: It must be carried out in accordance with the provisions of NOM-004-SSA3-
2012 of the clinical record. [60]Considering that the clinical record is the unique set of 
information and personal data of a patient, which is integrated within all types of 

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establishments for medical care, whether public, social or private, which consists of written, 
graphic, imaging, electronic, magnetic, electromagnetic, optical, magneto-optical and any 
other type of documents, in which health personnel must make records, annotations, where 
appropriate, certificates and certifications corresponding to their intervention in the 
medical care of the patient, in accordance with the applicable legal provisions. 
And it will consist of: 
- 
Medical history: It must be prepared by medical staff and other health professionals, 
according to the specific information needs of each of them in particular, and must 
have, in the order indicated, the following sections: 
- 
Interview. - It should include, at a minimum, the following: identification form, if 
applicable, ethnic group, family history, medical and non-medical history, current 
condition (inquire about previous conventional, alternative, and traditional 
treatments), and a history of equipment and systems (especially ophthalmologic). 
- 
Physical examination. - At a minimum, the following should be included: vital signs 
(temperature, blood pressure, heart rate, and respiratory rate), weight, and height 
(when applicable). 
- 
Previous and current results of laboratory, office and other studies (when applicable). 
- 
Diagnoses or clinical problems (when applicable). 
- 
Forecast (when applicable). 
- 
Therapeutic indication (when applicable). 
• 
Evaluation of concomitant medications: refers to the IP questioning the subject, inquiring 
about the use of medications. 
• 
Urine pregnancy test: This refers to the performance of a rapid pregnancy test in all women 
of childbearing age who wish to enter the study. By childbearing age, we mean women who 
have experienced menarche but have not yet experienced menopause. Menopause is 
defined as 12 months since the last menstrual period in women over 40 years of age, or 
those who have undergone a hysterectomy or bilateral oophorectomy. Women of 
childbearing age using contraceptive methods, including bilateral tubal obstruction , must 
undergo a pregnancy test. This test will be performed by the PI or a designated team 
member according to the instructions on the device provided by the sponsor. 

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• 
Vital signs: This refers to heart rate, respiratory rate, systemic blood pressure, and 
temperature. This information should be recorded in the patient's medical history and 
progress notes (values outside the range will be reported as AEs at the discretion of the PI). 
• 
VA: See 7.4.4.5 
• 
ICO: See 7.4.4.2 
• 
Corneal reepithelialization : See 7.4.4.1 
• 
Pain perception: See 7.4.4.3 
▪ 
Ophthalmological evaluation: Refers to the evaluation of the subject's ophthalmic 
structures, eyelids and adnexa, ocular surface, anterior segment, and posterior segment; 
not considered within the outcome variables. This evaluation is intended to identify 
alterations that may interfere with the course of the investigation or identify adverse 
events. This examination will be recorded in the clinical record; only those considered 
adverse events will be reported in the CRF. 
• 
Eligibility criteria: Refers to the PI's review, which verifies that the subject can be included 
in the study if they meet the inclusion criteria and do not meet the exclusion criteria. See 
5.1. 
• 
PI Allocation: This refers to determining the intervention the patient will undergo during the 
study. This assignment will be carried out in accordance with Section 7.3. This assignment 
will be made at the initial visit (Day 1). 
• 
Delivery of the PI and start of intervention: Refers to the delivery of the PI to the study 
patient by the research center. 
• 
EA Assessment: See 7.4.4.47.4.4.4 
• 
Delivery of patient materials and instructions for completion: Refers to the IP providing the 
subject with the subject's diary, identification card, and adherence-enhancing calendar. The 
assigned staff will provide the subject with pre-training on how to complete the diary. 
7.4.5.3  Follow-up visits 1 to 3 
• 
Evaluation of concomitant medications: See 7.4.5.2 
• 
Vital signs: See 7.4.5.2 
• 
VA: See 7.4.5.2 
• 
ICO: Ver 7.4.5.2(only on visit 3) 
• 
Corneal reepithelialization: See 7.4.5.2 

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• 
Pain perception: See 7.4.5.2 
▪ 
Ophthalmological evaluation: See 7.4.5.2 
• 
EA Assessment: See 7.4.5.2 
 
7.4.5.4 Final visit 
• 
Evaluation of concomitant medications: See 7.4.5.2 
• 
Urine pregnancy test: See 7.4.5.2 
• 
Vital signs: See 7.4.5.2 
• 
VA: See 7.4.5.2 
• 
ICO: See 7.4.5.2 
• 
Corneal reepithelialization: See 7.4.5.2 
• 
Pain perception: See 7.4.5.2 
▪ 
Ophthalmological evaluation: See 7.4.5.2 
• 
EA Assessment: See 7.4.5.2 
• 
Adherence assessment: See 6.4 
▪ 
Subject Diary Assessment: This refers to the review of the Subject Diary instrument by the 
PI or designated facility staff; it will be reviewed for correct completion, as well as the 
patient's comments. The PI may question these comments for AEs. At the PI's discretion, 
the comments may or may not be reported as AEs. 
▪ 
Adherence assessment: See 6.4 
▪ 
Return of PI and Subject Diary: Refers to the return by the subject of the PI and subject diary 
to the research center. 
7.4.5.5  Unscheduled follow-up visits 
At the request of the patient or any other individual involved in the study, unscheduled follow-up 
visits may be conducted to report adverse events. During these visits, all relevant data on reported 
adverse events must be collected, and an appropriate management plan must be established, if 
applicable. 

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7.4.6.1  Source documents 
Source documents are all written or printed records derived from automated processes (for 
example, printouts of laboratory results issued by automated analysis equipment) where 
information is first recorded and which become part of the patient's permanent record. Examples 
of source documents include medical records, clinical progress notes, laboratory reports, office 
study reports, nursing notes, follow-up notes, surgical records, etc. 
The PI is obligated to accept monitoring of study-related information, audits, review by ethics and 
research committees, and inspections by the health authority. This obligation implies direct access 
to source documents. 
7.4.6.2 Electronic forms of data collection 
All protocol-related data will be captured via an electronic case report form ( eCRF ) by research 
team staff. Protocol-related data should NOT be captured directly into the eCRF , but rather 
transcribed from the corresponding source document. This procedure allows for monitoring to 
verify the information captured in the eCRF . It is the researcher's responsibility to ensure that the 
information is transcribed into the eCRF correctly, completely, and in a timely manner. It is 
understood that all eCRF forms captured and submitted for data analysis are approved by the 
Researcher. 
7.4.6.3  Archive 
The data collected in this database is anonymous (only the patient number is stored, along with 
other relevant information). The software used for data capture and storage meets the traceability 
requirements necessary for conducting clinical studies. The collected data will be stored by the 
sponsor or designated clinical research organization for a period of 10 years. The master file will 
remain at the participating institutions under the care of the PI or their team and must be 
safeguarded for at least 5 years. 

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The registration and reporting of adverse events will be carried out in accordance with the 
guidelines established in NOM-240-SSA1-2012 Installation and operation of technovigilance and 
which are in accordance with the international ICH E6 guidelines. [61] 
 
According to the ICH, an AE is any adverse medical occurrence in a patient undergoing clinical 
research who is administered a pharmaceutical product, regardless of causal attribution. 
Therefore, an AE may be any of the following: any unfavorable, unintended disease, symptom, or 
sign (including an abnormal laboratory finding) that is temporally related to the use of a medical 
product, whether or not considered to be related to that product; any new disease or exacerbation 
of an existing disease (worsening of the nature, frequency, or severity of a known condition); relapse 
of an intermittent medical condition (e.g., headache) not present at baseline; any deterioration in a 
laboratory value or other clinical test (e.g., electrocardiogram [ECG], x-ray) that is related to the 
symptoms or that results in a change in study or concomitant treatment or discontinuation of study 
drug. 
Similarly, according to NOM-240-SSA1-2012, an incident is described as: any event related to the 
use of a medical device, and an adverse incident is described as: any proven event related to the 
use of a medical device that has conclusive evidence of the causal relationship between the incident 
and the medical device, and that could be caused by a malfunction or alteration of the 
characteristics of the medical device and that could cause death or serious deterioration of the 
user's health. An adverse incident will not be considered an incident derived from abnormal use or 
a use different from that recommended by the holder of the sanitary registration of the medical 
device or its legal representative in Mexico. [61] 

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Severity (serious/non-serious), also called seriousness (serious/non-serious). A serious event is 
defined as any event that: results in death, is life-threatening, requires hospitalization or prolongs 
hospitalization, causes permanent or significant disability or incapacity, causes alterations or 
malformations in the newborn, or other medically important conditions (Medically important event 
or reaction: A clinical manifestation or adverse event that, in the judgment of the physician, may 
not be immediately life-threatening, result in death, or cause hospitalization, but that could 
endanger the patient or require medical intervention to avoid the occurrence of any of the criteria 
listed in the definition of a serious adverse reaction). [61]  
Severity (mild, moderate, or severe). Mild conditions present with minimal symptoms and do not 
require treatment or discontinuation of medication; moderate conditions interfere with normal 
activities without threatening the patient's life, require treatment, and may or may not require 
discontinuation of medication; severe conditions interfere with normal activities and require 
pharmacological treatment and discontinuation of medication. 
Causality. This is the relationship assigned between the drug and the adverse event: certainly caused 
by the drug, there is clear evidence of causality, i.e. the adverse event reappears with the 
administration of the drug; probably caused by the drug, there is a high suspicion of causality but 
no direct evidence is available or it is considered unnecessary or dangerous, i.e. the reaction 
disappears when the drug is discontinued; possibly caused by the drug, there is additional 
information suggesting that the cause may be due to another drug or disease; unlikely to be caused 
by the drug, there is a clear explanation for the origin due to the underlying disease or the use of 
another drug; conditional, there is a lack of data to issue a clear causality; unclassifiable, those for 
which, once all possible information on the adverse event has been obtained, it remains 
unclassifiable. 
 
The investigator is responsible for verifying the AE by conducting a questioning, reviewing the 
information recorded in the subject's diary, conducting a relevant physical examination, assessing 
progress, and providing appropriate medical and pharmacological management. The investigator is 

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also responsible for monitoring the AE until it is resolved or resolved, and the patient is discharged, 
following the definitions established in national and international regulations.[61] [62] [63] 
In the event of an AE or any event that puts the health and well-being of the subjects at risk, 
appropriate medical care will be provided, either at the research center or by referring the subject 
to the highest-resolution hospital with which the research center has a medical care agreement. 
The PI will notify the sponsor's clinical monitor, in accordance with the timeframes established in 
national and international regulations. In the case of serious adverse events, the PI will notify the 
sponsor and record the corresponding information in the eCRF . In turn, the PI will inform the 
Research Ethics Committee (REC) and the Research Committee (RC). 
The attention of the AE will be carried out according to the event attention diagram (see Figure 3. 
Adverse event care). 
The final report prepared by the Clinical Team of Laboratorios Sophia, SA de CV's Medical 
Management Department will include adverse event reports in compliance with current national 
and international regulations. [62] [61] 
If the research subject develops a chronic adverse event during their participation in the study, such 
as diabetes or high blood pressure, they will be referred to a healthcare professional for chronic 
treatment. Follow-up and termination of participation will be in accordance with the provisions of 
NOM-012-SSA3-2012.[64] 
 
The EA registry considers: 
− 
Subject identification information such as: subject number, age, sex, and if applicable, 
specify the eye. 
− 
Information about the causality of the AE, its relationship to the PI, or to another study-
related drug, as appropriate. 
− 
Information on important dates: 
o Date on which the EA occurs. 
o Date on which the IP becomes aware of the same. 
o Date of resolution or outcome, as applicable. 
− 
Information on diagnosis and clinical management. 

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− 
If a lack of therapeutic response to PIs is detected, include in concomitant medications the 
therapy used for the pharmacological management of the adverse event. 
− 
Establish the outcome or resolution of the event: 
o Recovered/Solved 
o Recovered/resolved with sequelae 
o Recovering/resolving 
o Not recovered/unresolved 
o Fatal 
o A stranger 
− 
Information about the investigational product or medicinal product or the medicinal 
product associated with the AE, ADR or SRAM. As applicable, information concerning the 
generic name, distinctive name or code of the PI and/or investigational medicinal product 
must be recorded, as appropriate according to the methodological design of the study. This 
is relevant in the case of blinded studies or those where placebo is used as comparators, 
since there are circumstances that justify opening the blind to determine whether the 
adverse event can be attributable to the active agent, the combination of active agents, or 
to the pharmacologically inert substance(s), such as the vehicle or additives, as appropriate 
to the phase of clinical research in which the development of the medicinal product is 
located. It will also be necessary to record data concerning the batch number, 
manufacturing laboratory, expiration date, dose, route of administration, start and end 
dates of administration and/or consumption, reason for the prescription; depending on 
whether it is an investigational product or medication (a protocol in which the patient is 
currently participating) or a medication that the subject under investigation consumes for 
the treatment of underlying concomitant diseases or uses to manage some temporary sign 
or symptom that does not correspond to the natural history of the pathology that motivated 
their entry into the research protocol. 
− 
Indicate the withdrawal or continuation of the medication, as appropriate. Indicate whether 
the adverse event disappears upon withdrawal of the PI, investigational medication, or 
suspected medication (of causing the event). Also indicate whether a dose adjustment is 
made, if the event changes in intensity or severity, and if the reaction persists. It is important 
to indicate whether the AE reappears in subjects who are re-exposed to the medication 
after having been previously discontinued. 

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− 
Information regarding concomitant pharmacotherapy. Indicate the generic name, dose, 
route of administration, start and end dates, and the reason for the prescription, regardless 
of whether it is in accordance with the prescribing information or the data sheet or if it is 
used outside of the regulations or as authorized by the local, national, or international 
regulatory body. 
− 
Information on relevant clinical history. The analysis of the AE considers the information 
previously described. However, the clinical context in which the adverse event occurs in the 
participants in the clinical research protocol is of particular interest. Therefore, information 
about previous conditions, hypersensitivity or allergy symptoms, previous surgical 
procedures, laboratory tests or imaging examinations the participant has undergone, etc., 
that the researcher deems appropriate may be mentioned. 
 
The IP will provide care and follow-up of the EA presented by the participant until its outcome , in 
accordance with the provisions of the following section. 
 
The EA care process considers the following stages ( Figure 3): 

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Figure 3. Adverse event care 
 
 
Adverse Event 
Inform 
Appropriate 
care and 
treatment 
Categorization 
Preparation of medical notes 
Registration and notification to FERC 
At the research site. At a 1st-3rd 
level hospital (if required)  
By outcome: 
Serious/Not Serious 
By severity: 
Mild, moderate, or severe  
Physical 
examination and 
evaluation of 
the EA 
EA not serious 
Serious EA 
Follow up the EA 
until its outcome 
END 
+ Inform the sponsor within 
24 hours of becoming aware 
of it 
+ Follow up on the AE until 
its resolution 
Notify: Who? 
+ Pharmacovigilance 
and Technovigilance 
Unit (CRA) 
END 

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During the development and conduct of this study, undesirable adverse events or adverse reactions 
of medical significance may occur in the research subject, which are not necessarily causally related 
to the investigational medicinal products. These adverse events may occur during the use of 
investigational medicinal products at doses authorized for human use by a local, national, or 
international regulatory body. However, it may be suspected that the investigational medicinal 
product or the investigational medicinal product may cause some undesirable clinical manifestation. 
AEs, ADRs, or SARs associated with one or more medicinal products may occur during the systematic 
evaluation of participants (on the days when clinical reviews are scheduled, according to the activity 
schedule) or suddenly, such that: 
1. The researcher should be the first person to whom the patient notifies that he or she 
has developed or experienced any harmful clinical phenomenon during his or her 
participation in this study. 
2. Based on their clinical judgment, the principal investigator will determine the 
appropriate treatment for the adverse event/reaction based on the relevant physical 
examination, history, etc., as well as the analysis of information available in the medical 
literature and the information contained in the investigator's manual, Prescribing 
Information, or the comparator drug's data sheet. 
3. This care may be provided at the research center or at the hospital with the highest 
capacity for treatment. Thus, if the patient is referred by the PI to a hospital, they will 
receive care through a referral system. The referral may be through a card identifying 
the subject as a study participant and linking them to the pre-established agreement 
with the institution, or through a referral medical note issued by the PI. Laboratorios 
Sophia, SA de CV, will pay the costs for medical care for participating patients when the 
adverse event is associated with or related to the PI or investigational drug. 
4. Taking into account the clinical information collected, either during the care provided 
at the research center or provided by the treating physician(s) at the hospital, the IP will 
record the AE in his/her clinical note, stating the seriousness, intensity (mild, moderate, 
or severe), and relationship with the product or drug under investigation. 
5. The PI must migrate the relevant data to the eCRF and its respective adverse event 
section. In the case of serious adverse events, they must be reported to the clinical 
monitor of the study within 24 hours of becoming aware of them , so that they can then 
inform the Clinical Team and the UTFLS. Regarding non-serious adverse events, these 

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will be recorded and appropriately addressed, and the corresponding regulatory entity 
will be informed about the safety profile of the PI or investigational drug in the final 
report of the clinical trial. 
Recording the outcome of an AE depends substantially on the PI's follow-up of the subject, as most 
adverse events (see the investigator's manual) are expected to be ophthalmic in nature; however, 
systemic changes may occur. Therefore, at the investigator's discretion, the participant's withdrawal 
or continuation will be considered. 
 
Causality assessment is the methodology used to estimate the probability of attributing an observed 
adverse event to a medication. It considers probabilistic categories according to the available 
evidence and the quality of the information, based on national pharmacovigilance regulations, the 
World Health Organization, and the Uppsala Monitoring Center. [61]  
The Pharmacovigilance and Technovigilance Unit of Sophia Laboratories (UFTLS) can use the 
causality assessment provided by the World Health Organization and the Uppsala Monitoring Center 
as a tool to facilitate the probabilistic categorization of causality. Similarly, the Karch and Lasagna 
algorithm modified by Naranjo, referred to by Aramendi I, can be used as an aid to perform the 
causality categorization. In this algorithm, different items are scored, which allow a value to be 
assigned to the cause-effect relationship between the administration of the drug and the adverse 
reaction.  [64] 
 
 

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No . 
Reagent 
Score 
Yes 
No 
1. 
There are conclusive previous reports on adverse drug reaction, adverse event or suspected adverse drug 
reaction 
+1 
0 
2. 
The adverse event occurred when the suspected drug was administered 
+2 
-1 
3. 
The adverse drug reaction, adverse event, or suspected adverse drug reaction improved upon 
discontinuation or administration of a specific antagonist 
+1 
0 
4. 
The adverse drug reaction/adverse event/suspected adverse drug reaction recurred upon administration 
of the investigational drug/investigational product/investigational drug 
+2 
-1 
5. 
There are alternative causes that can provoke this reaction. 
-1 
+2 
6. 
The adverse reaction/adverse event/suspected adverse drug reaction occurred after placebo 
administration 
-1 
+1 
7. 
The drug was determined in blood or other fluids in toxic concentrations 
+1 
0 
8. 
The intensity of the adverse reaction/adverse event/suspected adverse drug reaction was greater with 
higher doses or less with lower doses 
+1 
0 
9. 
The patient has had similar reactions to the investigational drug/product or investigational drug in the 
past 
+1 
0 
10. 
The adverse reaction/adverse event/suspected adverse drug reaction was confirmed with some objective 
evidence 
+1 
0 
Total score 
Total 
Probabilistic category based on the score obtained 
l 
The causal relationship is verified 
≥ ,9 
II 
The ADR is likely due to the investigational drug or product 
5 to 8 
III 
The ADR may be due to the investigational drug or product 
1 to 4 
IV 
The causal relationship is doubtful 
0 
Each reagent receives a defined score and the final sum allows estimating the probabilistic category of the cause-effect 
relationship between the administration of the investigational product and the adverse reaction, adverse event or suspected 
adverse reaction. 
Table 4. Karch and Lasagna algorithm modified by Naranjo. 
 
 

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There are no guidelines or algorithms available to determine the causality of an adverse event in 
the case of the use of a medical device. This means that the relationship is established by the 
investigator's opinion and the reasoning behind how the adverse event occurred. However, the 
Pharmacovigilance and Technovigilance Unit of Sophia Laboratories (UFTLS) may use the causality 
categories described by the Uppsala Monitoring Centre to categorize the probability of an adverse 
event related to concomitant or experimental treatment. Medical devices, for convenience, may be 
evaluated as medicines within the categories mentioned in the section "Definitions relevant to the 
classification of adverse events, Causality." 
Thus, the degree of certainty required to establish the PI as the causal agent of the harmful 
phenomenon occurring to the subject of the clinical study is essential. This can also be indicated 
directly by the PI based on their clinical experience or through the voluntary application of the 
aforementioned tool. However, it is important that the researcher and the UFTLS consider the 
following arguments in favor of a causal relationship: 
a) Strength of association, which refers to the number of cases in relation to those exposed. 
b) The consistency of the data, that is, the presence of a common characteristic or pattern. 
c) The exposure-effect pattern, which determines the relationship with the site of onset, time, 
dose and reversibility after suppression. 
d) Biological plausibility, which refers to the possible pharmacological or pathophysiological 
mechanisms involved in the development or presentation of the adverse event. 
e) Experimental findings, for example, the appearance of anomalous metabolites or high levels 
of drug or its biotransformation product. 
f) Analogy, which refers to the experience acquired with other related drugs, adverse reactions 
frequently produced by the same family of pharmacological agents. 
g) Nature and characteristics of the data, i.e. objectivity, accuracy and validity of the relevant 
documentation. [65]  
 
 

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The study sponsor is responsible for monitoring the study. Monitoring activities include, but are not 
limited to: general safety monitoring, general study quality monitoring, study site monitoring, 
adverse event detection monitoring, reporting and follow-up, monitoring to resolve data entry 
discrepancies, etc. 
Responsibility for monitoring activities and ultimate responsibility for monitoring rests with the 
sponsor. 
The details of the monitoring activities are specified in a separate document from this protocol in a 
Monitoring Plan. 
 
The research centers participating in the study will be monitored. At least one initial visit and one 
closing visit must be conducted for each center, although one or more follow-up visits may be 
required between these two mandatory visits. 
The initial visit must be conducted before the first participant is enrolled at that center. During this 
visit, the monitor will verify that the materials to be used during the study have been received and 
that the personnel involved in study activities have been trained in the study. The monitor will also 
verify compliance with applicable regulatory requirements and standard operating procedures. 
At the follow-up visit, the monitor will review the study documents to confirm that the research 
protocol and applicable standard operating procedures are being followed, that data entry is 
complete and timely, and that adverse event reporting is being conducted appropriately. At each 
visit, the monitor will discuss the findings with the investigator and determine the appropriate 
actions to be taken. 
The closing visit will take place at the end of the study, once the last participant at the site has been 
discharged from follow-up. During this visit, the monitor will verify that the site has all the necessary 
documentation for archiving, that all biological samples have been sent for analysis, that all study 

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drug (used and unused) has been recovered and sent to the sponsor, and that all unused materials 
have been retrieved. 
Details of monitoring are set out in the relevant plan. 
 
To ensure compliance with GCPs and all applicable regulatory requirements, Laboratorios Sophia, 
SA de CV may conduct quality assurance audits. Regulatory agencies may also conduct a regulatory 
inspection of this study. 
Details of the audit process are set out separately in an Audit Plan. 
They may take place at any time before, during, or after the conclusion of the study. If an audit or 
inspection is conducted, the investigator and the institution must agree to allow the 
auditor/inspector direct access to all relevant documents and must allocate their time and staff time 
to the auditor/inspector to discuss the findings and any pertinent issues. If the audit has not been 
scheduled by the sponsor, the center must notify Laboratorios Sophia, SA de CV immediately. 
 
 

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Statistical analysis will be performed by staff of Laboratorios Sophia, SA de CV. The statistical 
package SPSS version 19.0 for Windows (IBM Corporation, Armonk, NY, USA) will be used. 
The personnel assigned to statistical data management will be blinded to the intervention groups. 
Coding will be performed using consecutive numbers for each intervention group. 
The data will be collected and organized in an Excel spreadsheet (Microsoft® Office). The data will 
then be exported to the SPSS platform. Variables will be categorized according to their nature (see 
Table 3. Operational definition of variables). 
 
Wilk test will be performed to determine whether the distribution is normal in the results obtained 
in each study group  [66]. In case of p <0.05, the Mann-Whitney U statistic will be used for the 
analysis of quantitative variables or the Wilcoxon rank test when applicable. 
The results of continuous quantitative variables will be presented in measures of central tendency: 
mean, standard deviation and/or ranges. 
• 
Intra-group analysis : Differences within groups will be analyzed using Student's t-statistic . 
[67]  
• 
Between-group analysis : Differences between groups will be determined using Student's t-
test for independent groups. 
The level of difference to consider significance will be an alpha (α) of 0.05 or less. 
The result of the nominal and ordinal qualitative variables will be presented in frequencies, 
proportions and/or percentages. 

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Statistical analysis to identify significant differences in qualitative variables will be performed by 
creating pxqy contingency tables and will be carried out as follows: 
 
• 
Intra-group difference: McNemar's test. This test is applied to p × q contingency tables with 
a dichotomous trait, with matched subject pairs, to determine whether the row and column 
marginal frequencies are equal (marginal homogeneity).[68] 
• 
Difference between groups: Pearson's Chi-square test (X2 ) or Fisher's exact test for expected 
values less than 5. 
The level of difference to consider significance will be an alpha (α) of 0.05 or less. Both eyes will be 
considered for the safety report. Only the right eye will be considered for the efficacy report. 
For the reporting of adverse events, all participants who were randomly assigned to an intervention 
group after the baseline visit (intention-to-treat population; ITT) will be considered. 
The final results report will be displayed in tables or graphs, as appropriate. 
 
• 
Efficacy: Subjects who meet a minimum adherence of 70% will be included in the statistical 
analysis to meet the study objective. This is based on the weight of the patient and does not 
present major deviations from the protocol (PP; per-protocol population). In cases where 
the container is not returned or has not maintained its physical integrity, adherence will be 
measured using the subject diary tool. 
• 
Safety: The safety assessment will include in the analysis all subjects (AO) who have been 
exposed at least once to the intervention, regardless of the visit at which they were 
eliminated from the study (ITT population). 
 
For the following protocol, a sample size of 96 subjects (48 per group) is suggested. According 
to the sample size calculation to meet the primary objective of the study, 84 evaluable subjects 
are required (42 subjects per treatment arm). If this number is not met due to a loss of subjects 
exceeding the 15% threshold contemplated in this protocol (loss to follow-up or withdrawal 
from ICF), the sponsor may substitute these subjects to balance the treatment groups. 

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Results obtained from the replaced subjects will continue to be used for safety analysis and will 
be part of the ITT population. 
 
Those subjects who meet a minimum adherence of 70% by weight and 70% by diary will be 
included in the statistical analysis to meet the primary objective of the study (PP population). 
 
 
n = 96 evaluable subjects 
48 subjects per arm. 
 
The sample size calculation was based on the clinical study by Lee et al. (2001), where they 
compared the efficacy, safety, and stability of LASEK vs. conventional PRK in mild to moderate 
myopia. The study included 27 patients (54 eyes) with a refraction of -3.00 to -6.50 diopters who 
received traditional PRK in one eye and LASEK in the contralateral eye. Patients were monitored 
daily until reepithelialization was complete, applying 1 drop of antibiotic (ofloxacin/ 
chloramphelicol ) QID and an artificial tear ( dexatran /hypromellose) every 2 hours until 
reepithelialization was complete. Reepithelialization was complete on the fourth day for PRK 
and on the fifth for LASEK. The mean for PRK was 3.18 ± 0.50 days (range: 2 ~ 4 days) and for 
LASEK 3.64 ± 0.63 days (range: 3 ~ 5 days), without being statistically different (p=0.100). 
For the present protocol, subjects treated with multidose Lagricel® PF are expected to show 
complete reepithelialization by day 3 of treatment. 
The sample size was calculated using the equivalence equation between two means [67]. To 
prove that Lagricel® PF multidose is equivalent to its comparator, considering a power of 80% 
(β), a significance level of 0.05 (α), and a test margin (δ) of 0.5, based on the following working 
hypotheses: 
𝐻0:|µ𝐴−µ𝐵| ≥𝛿 

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𝐻1:|µ𝐴−µ𝐵| < 𝛿 
 
Where, δ is the non-inferiority margin and, the ratio between the sample size of the two groups 
is: 
𝑘= 𝑛𝐴
𝑛𝐵
 
The calculation to estimate the sample size and power was performed using an online tool and 
following the equations  [68]: 
 
𝑛𝐴= 𝑘𝑛𝐵 𝑦 𝑛𝐵= (1 + 1
𝑘)(𝜎
𝑧1−𝛼+ 𝑧1−𝛽
|𝜇𝐴−𝜇𝐵−𝛿|)
2
 
 
1 −𝛽= 2[𝜃(𝑧−𝑧1−𝛼) + 𝜃(−𝑧−𝑧1−𝛼)] −1, 𝑧=
|𝜇𝐴−𝜇𝐵| −𝛿
√1
𝑛𝐴+ 1
𝑛𝐵
𝜎
 
Where: 
k= nA /n B is the relationship between groups 
σ is the standard deviation, 
Φ is the function of the standard normal distribution 
Φ-1 is the normal standard quantile function 
α is the Type I error 
β is the Type II error, which means that, 1-β is the power 
δ is the test margin 
According to the previous calculation, the result was 42 eyes (cases); this calculation was 
increased by 15% to account for possible losses (6 cases). The total suggested sample size is 96 
subjects (48 cases per arm), who will provide their OD for the study. 

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This study will be conducted in accordance with the standards of the Declaration of Helsinki, World 
Medical Association 2013. Nuremberg Code; Nuremberg Judgment by the International Tribunal of 
Nuremberg, 1947. Belmont Report, National Commission for the Protection of Subjects of 
Biomedical Research and Conduct, 1979. It will be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicines for human use of the 
International Council on Harmonization (ICH). International Ethical Guidelines for Biomedical 
Research Involving Human Subjects of the Council for International Organizations of Medical 
Sciences ( CIOMS , 2002 ). International Ethical Guidelines for epidemiological studies of the 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 any possible modifications for its implementation. These Committees must be 
notified of any significant changes to the protocol. In addition to the above, the current regulations 
of the regulatory authority must also be complied with. 
Site personnel will submit essential documentation of the research project for review by the 
Research Ethics Committees, Research Committees, and, when applicable, to the Biosafety 
Committee: research protocol, informed consent form, researcher's manual, patient materials, as 
well as any other additionally requested documents, in accordance with local, national, or 
international requirements applicable by regulatory entities. 
The study will not be initiated at the research centers without the confidentiality agreements and 
financial proposals from each of the principal investigators, duly signed, and without having 
previously obtained the favorable opinion and/or approval of the Research Ethics Committees (CEI), 
Research Committees (CI), and, when applicable, the Biosafety Committee. 
The study will not begin without meeting the relevant local, national, or international regulatory 
requirements and obtaining the appropriate health authorization. 

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The study is considered to be research with greater than minimum risk, in accordance with the 
Regulations of the General Health Law on Health Research, Title Two, Chapter I, Article 17, Section 
III, published in the Official Gazette on January 6, 1987 / Last reform published DOF 04/02/2014. 
 
The amendment process will be relevant when there is a need to make any changes to a document 
that is part of the research project or protocol, due to changes in the methodological structure, 
replacement of the principal investigator, or the identification of risks to the research subjects. 
Documents that may be amended include: the protocol, informed consent letter, researcher's 
manual, patient documents, measurement scales, and activity schedule. 
Any amendment must be approved by the sponsor and/or the principal investigator. The amended 
document(s), once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, when applicable, by the Biosafety Committee (entities that issued the initial 
favorable opinion for the conduct of the research), will be sent for authorization by COFEPRIS. 
Amendments that substantially modify the protocol or impose additional or different risks to 
research subjects must be approved by the aforementioned Committees. It is the investigator's 
responsibility to take measures in situations requiring immediate action to prevent unnecessary 
harm to study participants. 
The principal investigator is responsible for communicating to the Research Ethics Committee any 
amendments to the protocol that could affect the rights, safety, or well-being of the research 
participants. They must also report any situation or new knowledge that indicates an increased risk 
to the participants, the premature termination or suspension of the study, the reasons for this, and 
the results obtained to that point. They must also report the conclusion of the study upon 
completion of the research protocol. 
 
The study may be temporarily suspended or terminated prematurely if there is sufficiently 
reasonable cause. Written notification, documenting the reason for the suspension or early 
termination, must be provided by the party executing the suspension. The PI must promptly inform 
the study participants, the IC, and the IRB, providing the reasons. 

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Situations in which suspension or early termination of the study will be considered include, but are 
not limited to: 
1. 
The presence of serious adverse events in more than 10% of participants in a study 
group. 
2. 
The regulatory authority (COFEPRIS) considers it to be a security alert. 
3. 
The Sponsor will determine this for its convenience or due to eventualities such as: 
financial support, manufacturing errors, etc. 
4. 
The determination of unexpected risks to participants that are significant or 
unacceptable. 
5. 
Obtaining new relevant safety information. 
6. 
Insufficient adherence to protocol requirements. 
7. 
The data obtained are not evaluable or are not sufficiently complete. 
8. 
The determination that the primary objective has been achieved. 
9. 
The determination of futility. 
In the event of suspension, the study may be resumed once the situations that led to the suspension 
have been resolved, provided this justification is sufficient for the sponsor, IC, IEC, and regulatory 
authorities. 
 
The ICF contains complete and understandable information about the study and the investigational 
product, in accordance with current applicable regulations and Good Clinical Practices. 
The ICF will be considered a source document and will be filed as such. The site's principal 
investigator is responsible for ensuring that all new versions of the informed consent form undergo 
the appropriate approvals (the same ones that the original informed consent form underwent) and 
that the most current approved version is presented to the study subjects . 
 
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. For this purpose, the informed consent form must be signed. 

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Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice and will be in compliance 
with all applicable laws and regulations. 
The IP will provide the potential participant with all information regarding the characteristics of the 
study, its potential benefits, risks, objectives and procedures . 
This information will be provided in a language understandable to the subject. The subject will be 
explained that they have the right to discontinue their participation in the study at any stage, 
without affecting their relationship with the researcher and/or their future participation. Informed 
consent will be presented to the potential participant; they must have sufficient time to review each 
and every aspect mentioned above. Any questions they may have will be clarified by the person 
responsible for obtaining informed consent. 
Once the participant agrees to participate in the study, he or she must sign and date the informed 
consent letter in the presence of two witnesses, whether or not related to the study subject. These 
witnesses will participate in the informed consent process and sign, confirming that the process was 
carried out prior to any study procedure, that the study information was clearly explained, and that 
any questions were clarified. 
If the research subject does not know how to sign, he will print his fingerprint and another person 
he designates will sign his name. 
The IP must also sign and date this consent. 
The ICF must be signed in duplicate by all involved parties and two witnesses. One copy will be filed 
in the researcher's folder and the other will be given to the participant. The PI or designated staff 
member must document the process of obtaining Informed Consent through a detailed medical 
note, specifying the signed version, the date the document was signed, and how the process was 
carried out. 
 
The procedures that will be performed during the conduct of the study do not pose any additional 
risk that should be considered apart from the procedures listed in the informed consent. 

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Any change to the ICF constitutes an amendment to this document and must be submitted for 
approval to the Research Ethics Committees and, if applicable, to the Competent Authorities. 
Such amendments may be implemented only after obtaining written approval from the Research 
Ethics Committee and the Regulatory Body (as applicable), except for an amendment that is 
required to eliminate an immediate danger to the study subjects. 
re-consent process must be conducted for each subject affected by the amendment under the same 
conditions as those described above, in order to promptly communicate the new information 
contained in the document. The subject will be given a signed original of the amendment, and the 
researcher will retain the second original. 
 
All documents and information provided to the research center by the sponsor are strictly 
confidential. The PI expressly agrees that the data regarding his or her professional and clinical 
experience, provided to the sponsor in paper form and stored electronically, are solely for use in 
connection with his or her activities with the clinical study sponsor, in accordance with Good Clinical 
Practice. 
The researcher agrees that he and his team members will use the information only within the 
framework of this study, to carry out the protocol. This agreement is binding as long as the 
confidential information has not been publicly disclosed by the sponsor. 
The clinical study protocol provided to the investigator may be used by the investigator and his or 
her team to obtain informed consent from the subjects for the study. The clinical study protocol, as 
well as any information derived from it, must not be disclosed to other parties without the sponsor's 
written authorization. 
The researcher will not disclose any information without the prior written consent of Laboratorios 
Sophia, SA de CV, except to representatives of the Competent Authorities, and only at their request 
. In the latter case, the researcher is obligated to inform Laboratorios Sophia, SA de CV before 
disclosing the information to these authorities. 

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The researcher will complete and maintain a subject selection record, as well as the identification 
and enrollment list of each subject participating in the study. The researcher agrees to grant on-site 
access to the auditor and/or representatives of the Competent Authorities. The information will be 
processed in compliance with the Federal Law on the Protection of Personal Data Held by Private 
Parties. 
All eCRFs and communications related to study subjects will identify them only by their study subject 
identification number. The information collected in this study will be exchanged between the 
sponsor and the research site and must be treated confidentially. The Health Authority, the IRB, the 
IC, the sponsor, the monitors/auditors, and third-party auditors will be the only bodies authorized 
to review study documentation. If publications arise from this research project, under no 
circumstances will they contain information about the identification of study subjects. If the study 
results are published, no personal information about the study subjects will be disclosed. 
The protection of personal data will be in accordance with the corresponding current regulations. 
 
The independence of the study's conduct and results from any actual or perceived external 
influences is critical. Therefore, any current conflict of interest of any person playing a role in the 
design, conduct, analysis, publication, or any other aspect of this study will be declared. 
Furthermore, those with a perceived conflict of interest will be asked to manage it in a manner 
appropriate to their participation in the study. 
 
The PI agrees to declare his or her financial interests and conflicts of interest prior to the start of the 
study. 
 
The final study database will be the property of Laboratorios Sophia, SA de CV, and access to it will 
be restricted. The PI will not have access to it except with prior written authorization from the 
sponsor. 

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Any information obtained that is relevant to the safety of the subjects participating in the study 
must be immediately shared with the research center, so that the study subjects can be notified. 
 
Once the study is completed and adverse events are closed according to section 8, the sponsor will 
not extend care to the research subject. 
 
 

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This protocol, with title: “ Phase IV clinical study to evaluate the efficacy of Lagricel® Ofteno PF 
compared to Thealoz® Duo in corneal reepithelialization following PRK (Photorefractive 
Keratectomy)”, and number: SOPH037-0120/IVDOES NOT HAVE BIOSECURITY IMPLICATIONS, 
since infectious-contagious biological material will NOT be used; pathogenic strains of bacteria 
or parasites; viruses of any type; radioactive material of any type; genetically modified animals 
and/or cells and/or plants; toxic, hazardous or explosive substances; any other material that 
puts the health or physical integrity of the research center staff or research subjects at risk or 
affects the environment. Likewise, it is declared that no cell, tissue or organ transplant 
procedures, or cell therapy will be carried out in this project, nor will laboratory, farm or wildlife 
animals be used. 
 

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Once the statistical analysis is complete, the final report will be prepared with the results obtained 
by the Medical Management of Laboratorios Sophia, SA de CV. This report will be prepared following 
the recommendations of the ICH E3 Guide . Communication of results 
Regardless of the results of the study, Laboratorios Sophia, SA de CV, is committed to 
communicating the final study report to the principal investigators and COFEPRIS. These results will 
also be shared with the research committee and the IEC. The PI will be responsible for 
communicating the results to the research subjects. 
Laboratorios Sophia, SA de CV will retain at all times the rights to the publication and dissemination 
of the information contained herein. 
 
Laboratorios Sophia, SA de CV, acting as the sponsor of the study, assumes full responsibility for its 
role and retains exclusive ownership rights to the study results, which it may use as it sees fit. 
The PI agrees not to publish or communicate data collected from the study, unless prior written 
agreement is obtained from Laboratorios Sophia, SA de CV. Any manuscript derived from the data 
obtained with this protocol must be submitted for review by the sponsor before any attempt to 
submit it for publication in any journal or scientific conference. 
However, if the sponsor is in the process of filing a patent application on the results of the study, 
the sponsor may delay publication or communication of the results of the study until the date of 
registration or when it deems appropriate. 
Authorship assignments for publications are the sponsor's responsibility. However, express 
authorization from those invited to participate as authors is required. Authors have the right to 
review the manuscript prior to publication, as well as to provide comments and suggestions. Such 
comments must be submitted within the first 15 calendar days of receipt of the project. 
 
 

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

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