Non Inferiority Phase IV Clinical Study, to Compare the Efficacy of the Ophthalmic Solution Humylub Ofteno® PF Against Hyabak® and Lagricel Ofteno® PF When Applied on the Ocular Surface of Patients With Mild to Moderate Dry Eye.
Phase: PHASE4
Conditions: Dry Eye
Sponsor: Laboratorios Sophia S.A de C.V.

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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This protocol has been developed in accordance with 
the principles of the Declaration of Helsinki and will be 
conducted in accordance with Good Clinical Practice 
and in compliance with ICH guidelines and applicable 
local legislation. 
Sponsor: Laboratorios Sophia, S.A. de C.V. 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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Intentionally blank page  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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Content  
 
 
1. Summary ............................................................................................................................... 1 
1.2 Synopsis........................................................................................................................... 1 
2. Introduction and Background ................................................................................................. 8 
2.1 Theoretical framework ...................................................................................................... 8 
2.2 Background on active ingredients ............................................................................................ 10 
2.2.1 Background on Sodium Hyaluronate .................................................................................. 10 
2.2.1.1 Pharmacology of Sodium Hyaluronate ......................................................................... 10 
2.2.1.1.1  
Pharmacokinetics in the eyeball ............................................................................ 11 
2.2.1.1.2  
Systemic pharmacokinetics ................................................................................... 12 
2.2.1.1.2.1 Preclinical studies ................................................................................................ 12 
2.2.1.1.2.2 Clinical studies ..................................................................................................... 12 
2.2.1.2 Efficacy of Sodium Hyaluronate ...................................................................................... 12 
2.2.1.3 Safety of Sodium Hyaluronate ................................................................................. 13 
2.2.1.3.1  
Preclinical studies ................................................................................................ 13 
2.2.1.3.2  
Clinical Trials ....................................................................................................... 14 
2.2.2  
Background on chondroitin sulfate ............................................................................. 14 
2.2.2.1 Pharmacology of chondroitin sulfate........................................................................... 14 
2.2.2.1.1  
Pharmacokinetics in the eyeball ............................................................................ 15 
2.2.2.1.2  
Systemic pharmacokinetics ................................................................................... 15 
2.2.2.2 Efficacy of chondroitin sulfate .................................................................................... 15 
2.2.2.3 Safety of Chondroitin Sulfate .................................................................................. 16 
2.3 Summary of pharmaceutical development of Humylub Ofteno® PF ................................... 16 
2.4 Background on the investigation .......................................................................................... 17 
2.4.1  
From the research question ................................................................................... 17 
2.4.2  
From the investigational product development phase ............................................. 17 
2.5 Risk-benefit assessment ..................................................................................................... 17 
2.5.1 Known potential risks .................................................................................................... 17 
2.5.2  
Known potential benefits ................................................................................... 18 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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2.6 Problem statement .............................................................................................................. 18 
2.7 Justification......................................................................................................................... 18 
3. Objectives and hypotheses ....................................................................................................... 20 
3.1 Primary objective ............................................................................................................. 20 
3.2 Secondary objectives ....................................................................................................... 20 
3.3 Hypothesis .......................................................................................................................... 21 
4. Study design ........................................................................................................................... 22 
4.1 Design Overview .............................................................................................................. 22 
4.2 Rationale for the study design .......................................................................................... 22 
4.3 Expected duration ............................................................................................................ 22 
5. Study population ..................................................................................................................... 23 
5.1 Eligibility Criteria .............................................................................................................. 23 
5.1.1  
Inclusion criteria ................................................................................................ 23 
5.1.2  
Exclusion Criteria............................................................................................... 23 
5.2 Patient Removal and Replacement Criteria ....................................................................... 24 
5.3 Lifestyle Considerations ................................................................................................... 24 
5.4 Counting failures ............................................................................................................. 25 
5.5 Recruitment and Retention Strategies .............................................................................. 25 
5.6 Procedure in case of loss of follow-up ............................................................................... 26 
5.7 Patient Identification ........................................................................................................ 26 
6. Investigational Product ............................................................................................................. 27 
6.1 Managed Products ........................................................................................................... 27 
6.1.1  
Investigational Product .......................................................................................... 27 
6.1.2  
Reference product ................................................................................................. 27 
6.1.2.1 Justification of the reference product ...................................................................... 28 
6.1.3  
Dosage of investigational product .......................................................................... 28 
6.1.3.1 Dose justification ................................................................................................... 28 
6.2 Storage and handling of research products at the study site .............................................. 28 
6.3 Concomitant treatments and medications not approved during the study .......................... 29 
6.4 Procedure for monitoring and measuring adherence ......................................................... 29 
6.5 Strategies to improve adherence ...................................................................................... 31 
7. Study methods and procedures ................................................................................................ 32 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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7.1 From the research centre ................................................................................................. 32 
7.2 Clinical Study Registration ............................................................................................... 32 
7.3 Randomization ................................................................................................................ 32 
7.4 Outcome variables .......................................................................................................... 33 
7.4.1  
Primary outcome variables ................................................................................. 33 
7.4.2  
Secondary outcome variables of efficacy ............................................................ 33 
7.4.3  
Safety variables ................................................................................................. 33 
7.4.4.1 Adverse events ....................................................................................................... 37 
7.4.4.2 OSDI Score ............................................................................................................ 37 
7.4.4.3 Better Corrected Visual Acuity ................................................................................ 38 
7.4.4.4 TRLNI ..................................................................................................................... 38 
7.4.4.5 Corneal and conjunctival fluorescein staining ......................................................... 39 
7.4.4.6 Conjunctival staining with lysmine green ................................................................. 39 
7.4.4.7 Conjunctival hyperemia .......................................................................................... 40 
7.4.4.8 Chemosis .............................................................................................................. 40 
7.5 Study visit and activities program ..................................................................................... 40 
7.5.1  
Description of activities per visit ......................................................................... 40 
7.5.1.1 Counting Visit ......................................................................................................... 40 
7.5.1.2 Basal Visit .............................................................................................................. 41 
7.5.1.3 Visit 1 ..................................................................................................................... 42 
7.5.1.4 Final Visit ............................................................................................................... 42 
7.5.2  
Unscheduled follow-up visits ............................................................................. 43 
7.6 Data collection ................................................................................................................ 43 
7.6.1  
Source documents ............................................................................................ 43 
7.6.2  
Electronic forms of data collection ..................................................................... 43 
7.6.3  
File .................................................................................................................... 44 
7.6.4  
Unscheduled follow-up visits ............................................................................. 44 
8. Evaluation and management of adverse events ...................................................................... 45 
8.1 Regulation and regulations on adverse events ................................................................... 45 
8.2 Definition of Adverse Event ............................................................................................... 45 
8.3 Definitions relevant to the classification of adverse events ................................................ 45 
8.4 Responsibilities of the researcher ..................................................................................... 46 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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8.4.1  
Record of adverse events in the electronic case report form ................................ 46 
8.4.2  
Adverse Event Tracking ................................................................................................ 48 
8.4.3  
Procedures for a serious adverse event .......................................................................... 48 
8.4.4  
Causation assessment .......................................................................................... 49 
8.5 Unanticipated Issues ....................................................................................................... 50 
8.5.1  
PNA Report ........................................................................................................... 51 
9. Study Monitoring ................................................................................................................... 52 
9.1 Monitoring of study centers .............................................................................................. 52 
9.2 Audit and quality control .................................................................................................. 52 
9.2.1  
Pre-study audit .................................................................................................. 53 
9.2.2  
Auditing during the conduct of the study ............................................................. 53 
10. Statistical analysis .................................................................................................................. 54 
10.1 Data analysis ................................................................................................................. 54 
10.1.1 Statistical Analysis .................................................................................................. 54 
10.1.2 Data Interpretation .................................................................................................. 54 
10.1.3 Procedure for handling missing data......................................................................... 56 
10.1.4 Deviations from the statistical analysis plan ............................................................. 56 
10.1.5 Patients included in the analysis .............................................................................. 56 
10.2 Sample Size Calculation ................................................................................................ 56 
10.2.1 N Calculated ........................................................................................................... 56 
10.2.2 Justification for sample calculation .......................................................................... 56 
11. Ethical considerations ............................................................................................................ 58 
11.1 Approval of the committees ........................................................................................... 58 
11.2 Amendments to the protocol .......................................................................................... 58 
11.3 Early Study Termination .................................................................................................. 59 
11.4 Informed Consent .......................................................................................................... 60 
11.4.1 Obtaining ................................................................................................................ 60 
11.4.2 Special considerations ............................................................................................ 61 
11.4.3 Modifications to informed consent ........................................................................... 61 
11.5 Confidentiality ............................................................................................................... 61 
11.6 Conflict of interest ......................................................................................................... 62 
11.6.1 Declaration of Interests ........................................................................................... 62 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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11.7 Access to Information .................................................................................................... 62 
11.8 Ancillary and post-study care ......................................................................................... 62 
12. Biosecurity aspects ................................................................................................................ 63 
13. Posting Policy ........................................................................................................................ 64 
13.1 Final Report ................................................................................................................... 64 
13.2 Communication of results .............................................................................................. 64 
13.3 Publication of results ..................................................................................................... 64 
14.Financing and Insurance ...................................................................................................... 65 
14.1 Compensation to Study Participants ............................................................................... 65 
14.2 Insurance for Study Participants ..................................................................................... 65 
15. References .......................................................................................................................... 66 
16. Annexes .............................................................................................................................. 74 
 
Figure Index  
Figure 2 Diagram of study ______________________________________________________________ 6 
Figure 3 Chemical structure of HS __________________________________________________________ 10  
Figure 4 Chemical structure of CS __________________________________________________________ 14  
Figure 5 Operational definition of variables ___________________________________________________ 34  
Figure 6 Adverse Event Care ________________________________________________________ 48  
Table of Contents  
Table 1 Study managers ............................................................................................................  VI 
Table 2 Patient schedule .................................................................................................................... 7  
Table 3 Triangulation of concepts ................................................................................................................. 55 
 
 
 
 
 
 
 
 
 
 
 
 

Laboratorios Sophia, S.A. de C.V.                                                                                  Study No: SOPH087-0120/IV   
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Responsible for the study  
 
The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia, S.A. 
de C.V., is shown in Table and figure 1.   
  
 
 
 
 

Laboratorios Sophia S.A. de C. 
 
Study SOPH087-0120/IV 
Ver 2.0 
Signature Pages  
 
From the sponsor  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Laboratorios Sophia S.A. de C. 
 
Study SOPH087-0120/IV 
Ver 2.0 
Investigator Agreement  
I agree to conduct this clinical study according to the design and guidelines of this protocol, in 
accordance with the provisions of this protocol and in accordance with the accepted standards of 
Good Clinical Practice (GCP).   
I agree to report all information or data in accordance with what is indicated in the protocol, 
particularly any AEs. 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 
it is prohibited from sharing it with any third party, which is not involved in the approval, supervision, 
or conduct of the study. I will ensure that I take the necessary precautions to protect the information 
from loss, inadvertent disclosure, or access by unauthorized third parties.  
  
  
Name:  
  
Title:  
  
Name of the center:  
  
Geographic location (city/state/country)  
  
 
Signature  
  
Date  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 

Laboratorios Sophia S.A. de C. 
 
Study SOPH087-0120/IV 
Ver 2.0 
List of abbreviations 
 
AH  
Hyaluronic acid  
ANOVA  
Analysis of variance test  
BPC  
Good Clinical Practices  
CIS  
Research Ethics Committee  
COFEPRIS  
Federal Commission for the Protection against Sanitary Risks  
IUD  
Intrauterine device  
EA  
Adverse Event  
FRCE  
Electronic Case Report Form   
FCI  
Informed consent form  
HS  
Sodium Hyaluronate  
ICH 
International Council for Harmonisation 
IP  
Principal Investigator  
ITT  
Intent to Treat  
MAVC  
Better corrected visual acuity  
OD  
Right eye  
WHO  
World Health Organization  
YOU  
Left eye  
SIDA  
Ocular surface disease index  
PEGs  
Polyethylene glycol oligomers  
PNA  
Unanticipated problems  
PIO  
Intraocular pressure  
PI  
Research Products  
QID  
Four times a day  
RNEC  
National Clinical Trials Registry  
SCE  
Foreign body sensation  
SOS  
Dry eye syndrome  
TFOS DEWS II  
Tear Film and Ocular Surface Society Dry Eye Workshop II  
TRL  
Tear rupture time  
TRLNI  
Non-invasive tear rupture time  

Laboratorios Sophia S.A. de C. 
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Study SOPH087-0120/IV 
Ver 2.0 
1. Summary  
 
1.2 Synopsis  
Title of the study: 
Phase IV non-inferiority clinical trial to compare the efficacy of Humylub Ofteno® PF ophthalmic 
solution against Hyabak® and Lagricel Ofteno® PF on the ocular surface of patients with mild to 
moderate dry eye syndrome 
Study number: 
SOPH087-0120/IV  
Data created: 
15-ene-20 
Protocol version: 
2.0 
Date of version:  
27-abr-20 
Therapeutic indication: 
Ocular lubricant 
Use: 
Dry eye 
Estimated duration of the study (from the first 
visit of the first patient to the preparation of 
the final report):  
12 months 
Clinical development phase: IV 
Objectives: 
Objective principal:  
• Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel Ofteno® 
PF in the efficacy of treating patients with dry eye, using the OSDI (ocular surface disease index) test 
score 
Secondary objectives:   
• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the efficacy of treating patients with dry eye, through non-invasive measurement of 
tear breakup time (TBUT).  
• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the efficacy of treating patients with dry eye, through changes in corneal and 
conjunctival staining with fluorescein.  
• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the efficacy of treating patients with dry eye, based on changes in corneal and 
conjunctival staining with lysamine green.  

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Study SOPH087-0120/IV 
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• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the efficacy of treating patients with dry eye, based on changes in conjunctival 
hyperemia.  
• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the safety of treating patients with dry eye, based on the incidence of chemosis.  
• 
Demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the safety of treatment of patients with dry eye, based on the incidence of adverse 
events (AEs). 
Hypotesis: 
H0= The Humylub Ofteno® PF ophthalmic solution is not inferior in efficacy to its comparators after 30 days 
of treatment, showing a 35% decrease in the final OSDI test score from baseline in at least 30% of exposed 
patients.  
𝐻0: 𝑃𝐴−𝑃𝐵≤𝛿 
H1= The Humylub Ofteno® PF ophthalmic solution is inferior in efficacy to its comparators after 30 days of 
treatment, as it does not show a 35% decrease in the final OSDI test score from baseline in at least 30% of 
exposed patients.  
𝐻1: 𝑃𝐴−𝑃𝐵>𝛿 
Study design: 
Phase IV non-inferiority, controlled, open-label, comparative, multicenter clinical trial. 
Number of subjects (planned and analyzed): 
 
Number of patients planned: 60 evaluable patients per arm. 
Total sample = 180 evaluable patients. 
Diagnosis and main inclusion criteria: 
- 
Patients diagnosed with mild to moderate dry eye. 
Selection criteria: 
Inclusion criteria:  
- 
Can voluntarily give their signed informed consent.  
- 
Be able and willing to comply with scheduled visits, treatment plan, and other study procedures.  
- 
Be of legal age.  
- 
Women of childbearing potential must ensure the continuation (initiated ≥ 30 days prior to signing 
the informed consent form [ICF]) of the use of a hormonal contraceptive method or intrauterine 
device (IUD) during the study period.  
- 
Present a diagnosis of mild to moderate dry eye, defined by an OSDI rating ≥ 13 and one of the 
following:  
o 
Corneal staining with more than 5 sites.  

Laboratorios Sophia S.A. de C. 
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Study SOPH087-0120/IV 
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o 
Conjunctival staining with more than 9 sites.  
o 
Tear film breaking time < 10 seconds.  
Exclusion criteria:  
- 
Women who are pregnant, breastfeeding, or planning to become pregnant within the study period.  
- 
Have participated in another clinical research study ≤ 30 days prior to the screening visit.  
- 
Have previously participated in this study.  
- 
Have a CVAM of 20/200 or worse in one of the eyes.  
- 
Present an ophthalmological diagnosis of:  
o 
Allergic, viral, or bacterial conjunctivitis.  
o 
Blefaritis anterior.  
o 
Parasitic infestations in any ocular structure or its appendages.  
o 
Unresolved eye trauma.  
o 
Healing diseases of the ocular surface.  
o 
Corneal or conjunctival ulcers.  
o 
Filamentous keratitis.  
o 
Neurotrophic keratitis.  
o 
Bullous keratopathy.  
o 
Neoplastic diseases on the ocular surface or adnexa.  
o 
Diseases with fibrovascular proliferations on the conjunctival and/or corneal surface.  
o 
Retinal and/or posterior segment diseases that require treatment or threaten visual 
prognosis.  
o 
Glaucoma.  
o 
Disorders of the eyelids that cause palpebral malpositions, limit the proper closing or 
opening of the eyelids, or are the cause of epiphora.  
- 
Have a management of your dry eye that requires the implementation of all the treatments in stage 
2 of the recommendations on the treatment and staged management for dry eye disease of the 
TFOS DEWS II (Tear Film and Ocular Surface Societies II Dry Eye Workshop, Tear Film and Ocular 
Surface Society Dry Eye Workshop II).  
- 
Have a history of drug addiction or drug dependence current or within the last two years prior to 
signing the FCI.  
- 
Have a history of eye surgical procedure within the last 3 months prior to signing the FCI.  
- 
Be a soft or hard contact lens wearer. You will be able to enter in case of suspending its use during 
the study, you must comply with 15 days without using the contact lens prior to your inclusion.  

Laboratorios Sophia S.A. de C. 
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Study SOPH087-0120/IV 
Ver 2.0 
- 
Have another medical condition, acute or chronic, that in the investigator's judgment 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 results of the study.  
- 
Have known hypersensitivity to the components of investigational products  
Research Product (PI): 
Investigational product, dosage and route of administration:  
- 
Humylub Ofteno® PF. Sodium Hyaluronate 0.1% / Chondroitin Sulfate 0.18% Ophthalmic Solution. 
Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, Mexico.  
- 
Dosage: 1 drop 4 times a day (QID), with a minimum interval of 3 hours between applications.  
- 
Route of administration: Ophthalmic  
Reference products, dosage and route of administration:  
Hyabak®. Sodium Hyaluronate 0.15% Ophthalmic Solution. Laboratoires Théa, Clermont-Ferrand, France.  
- 
Dosage: 1 QID drop, with a minimum interval of 3 hours between applications.  
- 
Route of administration: Ophthalmic.  
Lagricel Ofteno® PF. Sodium Hyaluronate 0.4% Ophthalmic Solution. Laboratorios Sophia, S.A. de C.V., 
Zapopan, Jalisco, Mexico.  
- 
Dosage: 1 QID drop, with a minimum interval of 3 hours between applications.  
- 
Route of administration: Ophthalmic.  
Duration of treatment: 
30 days 
Duration of the subject in the study: 
Up to 41 days 
Evaluation criteria: 
Primary outcome variables 
- 
OSDI score (ET: visits 1 and final).  
Secondary outcome variables: 
- 
Changes in the measurement of the TRLNI (ET: visits 1 and final).  
- 
Changes of corneal and conjunctival stains with lysmine green (ET: visits 1 and final).  
- 
Corneal and conjunctival staining changes with fluorescein (ET: visits 1 and final).  
- 
Conjunctival hyperemia changes (ET: visits 1 and final).  
Safety variables: 
- 
Incidence of unexpected AEs related to the research product. (ET: visits 1, final and evaluation)  
- 
Changes in the MAVC (ET: visits 1 and final).  
- 
Incidence of chemosis (ET: visits 1 and final).  

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Study SOPH087-0120/IV 
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Statistical methodology 
The Kolmogorov-Smirnov and Shapiro Wilk tests will be performed, as appropriate, to know if the 
distribution presents normality in the results obtained in each study group. The data will be expressed with 
measures of central tendency: mean and standard deviation for the quantitative variables. Qualitative 
variables will be presented in frequencies and percentages. The statistical analysis will be performed by 
means of the analysis of variance test (ANOVA) for the quantitative variables for the difference between the 
groups. The difference between the qualitative variables will be analyzed by means of the X2 (Chi-square) or 
Fisher's exact test. A non-inferiority margin (δ) of 10% will be used for the OSDI score based on the primary 
endpoint of the study, a α ≤ 0.05 will be considered significant.  
 
 

Laboratorios Sophia S.A. de C. 
 
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Study SOPH087-0120/IV 
Ver 2.0 
 
 
1.2 Study diagram  
 
Arm 1 
Humylub Ofteno® 
PF 
Arm 3 
Lagricel Ofteno® PF 
n=60 
Randomization 
Start of treatment D 1 to 3 
V1 
D17 a 19 (± 1) 
FV 
D31 a 33 (± 1) 
SV = screening visit 
BV = baseline visit 
V1 = visit 1 
FV = final visit 
SC = safety call 
Arm 2 
Hyabak® 
n=60 
Clinical evaluations 
SC 
D38 a 40 (±1) 
Clinical evaluations 
Compliance with all selection criteria 
n= 180. 
Clinical evaluations 
Signature of informed consent. 
SV  
D 0 
BV  
D 0 a 2 
Figure 2. Study diagram 

Laboratorios Sophia S.A. de C. 
 
7 
Study SOPH087-0120/IV 
Ver 2.0 
1.3 Patient Timeline  
The screening visit will correspond to an appointment that will be considered on day 0 for each 
patient.  The baseline visit should be carried out 0 to 2 days after the scrutiny visit and can therefore 
be carried out on the same day as the latter.   
Visit 1 will be carried out in relation to the start of treatment on day 17, with a window period of ±1 
day.   
The final visit will take place on day 31 of the study, in relation to the start of treatment, with a window 
period of ±1 day.   
The safety call will be made 38 days after the start of treatment, with a window period of ±1 day.   
  
                                                                                                                                                    V1                        FV                     SC  
                                                            SV              BV   
 
Procedures                                                                                                                       D 17 to 1        D 31 to 33      D 38 to 40  
                                                                               D 0           D 0 to 2        D 1 to 3           (±1)                    (±1)                    (±1) 
FCI Signature  
X  
  
  
  
  
  
Medical history  
X  
  
  
  
  
  
Concomitant Drug Evaluation  
X  
  
  
X  
X  
  
Urine pregnancy test  
X  
  
  
  
X  
  
Vitals signs 
X  
  
  
X  
X  
  
BCVA 
X  
  
  
X  
X  
  
Ocular Surface Integrity (Stains 
and Evaluation of Hyperemia 
and Conjunctival Chemosis)  
X  
  
  
X  
X  
  
Comprehensive 
ophthalmological evaluation  
X  
  
  
X  
X  
  
OSDI 
X  
  
  
X  
X  
  
Eligibility Criteria  
X  
X  
  
  
  
  
AE´s Assessment  
X  
X  
  
X  
X  
X  
TBT  
  
X  
  
X  
X  
  
Investigational Product (PI) 
Randomization  
  
X  
  
  
  
  
Delivery of the PI   
  
X  
  
  
  
  
Delivery of patient material and 
filling instructions  
  
X  
  
  
  
  
Start of intervention  
  
  
X  
  
  
  
Adherence assessment  
  
  
  
X  
X  
  
Patient Journal Return / 
Evaluation  
  
  
  
  
X  
  
Return of PI  
  
  
  
  
X  
  
 
  
Table 2. Patient schedule 

Laboratorios Sophia S.A. de C. 
 
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Study SOPH087-0120/IV 
Ver 2.0 
2. Introduction and Background  
 
2.1 Theoretical framework  
The stability of the tear film is the main characteristic of a healthy ocular surface, as it allows it to fulfill 
its main functions such as forming an adequate refractive surface and providing protection and 
moisture to the cornea. The loss of homeostasis of this layer of 2 – 5.5 μm causes dry eye syndrome 
(SOS). [1]  
The tear film is composed of two layers, one lipid and one mucoaqueous. The lipid layer, thanks to its 
wax content and cholesterol esters, is generally attributed with preventing evaporation and tear 
rupture; however, this function is now considered to be fulfilled thanks to the interactions of all the 
compounds of the tear film, including lipids, mucins and salts. [1]   
SOS is a multifactorial disease that affects millions of people around the world, with a prevalence 
ranging from 5 to 50%. It is a symptomatic condition characterized by a vicious circle of tear film 
instability and hyperosmolarity that causes inflammation of the ocular surface and neurosensory 
alterations. Being one of the main causes of ophthalmological consultation, it significantly impacts the 
lives of patients who suffer from it, as it is associated with: pain, limitation in the execution of activities 
of daily living, reduction of vitality and even depression. [2]  
Economically, it also represents one of the most relevant diseases within ophthalmological diseases, 
with an estimated annual expenditure of 3.8 billion dollars related to SOS in the United States of 
America alone. [2]  
Some of the risk factors associated with SOS are advanced age, female sex, use of contact lenses, 
systemic diseases such as Sjögren's Syndrome and Diabetes Mellitus, Asian race, use of screens, 
nutritional factors, refractive surgery, bone marrow transplant, meibomian gland dysfunction, and 
environmental factors. [2, 3]  
According to its etiology and pathophysiology, SOS can be divided into two categories, which are not 
mutually exclusive, the aqueefficient type and the evaporative type. Epidemiology suggests a 
preponderance of the latter. [3, 4]  
Regardless of the etiology and severity of SOS, the TFOS DEWS II recommends symptomatic evaluation 
of affected patients through a symptom questionnaire such as OSDI. See Annex 1 16.1 OSDI. This tool 
is reliable and has proven to be reliable both in detecting SOS and in classifying the degree of severity 
of the condition. [5, 6]  
 In addition, a complete ophthalmologic evaluation should be performed that includes the 
examination techniques necessary to evaluate the signs related to SOS. For the confirmation of this 
pathology, any of the following are considered evidence of alteration of tear homeostasis: reduction 
of TRLNI, hyperosmolarity or uptake of stains on the corneal, conjunctival or palpebral margin surface. 
[3]   

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The assessment of conventional tear rupture time (LRT) is performed invasively, by instilling 
fluorescein on the ocular surface. However, this method generates a destabilizing action of the tear 
film due to the increase in volume represented by the application of the stain, in addition to the 
production of reflex tears secondary to contact with said substance and exposure to intense light 
during the review in the slit lamp. [7] Because noninvasive methods of measuring TRL avoid this 
disruption of ocular surface balance, they are considered superior for the determination of this 
parameter. Currently, the use of equipment with computational algorithms that evaluate TRL has 
made it possible to ensure its objective and automated detection. [7] Among the options available 
today for the determination of TRLNI (non-invasive tear rupture time) is the Oculus Keratogaph 5M. 
It measures TRL by detecting localized tear film breaks using infrared waves. 22 rings are projected 
onto the corneal surface, with more than 1,000 measurement points per ring, while a real-time video 
record is taken. The evaluation yields two readings, the time it takes to observe the first tear film 
rupture, and the average time to show tear tear rupture in all monitored regions. [8]  
In a study of 126 patients diagnosed with mild to moderate dry eye syndrome, Lee et al reported an 
average of 8.39 sec of 8.39 sec of LRT assessed by Keratograph 5M. [8] On the other hand, Bandlitz et 
al described an average of 12.9± 6.8 sec of TRL in apparently healthy patients. [9] Although variable 
results have been reported when comparing TRL values measured by conventional method with 
TRLNI, the TFOS DEWS II has established a TRLNI of 10 sec as the cut-off criterion for the diagnosis of 
SOS. This test is considered to have a sensitivity of 82 to 84% and a specificity of 76 to 94% for the 
diagnosis of this pathology. [10, 6, 11]  
Once diagnosed, there are many therapeutic options for the treatment of SOS, with the main goal of 
its management being the restoration of homeostasis of the ocular surface and tear film. In general, 
the treatment of patients suffering from SOS begins with the indication of lubricants, which are 
accessible, low-risk and effective for the symptomatic treatment of the condition. [12]   
Thanks to the rheological characteristics of eye lubricants, these products make it possible to relieve 
SOS-related discomfort. The properties of these ocular lubricants, including viscosity, lubricity, pH and 
osmolarity, have been described in other works. [13, 14, 12]  
There are currently multiple formulations of tear substitutes, which can include the following 
components: an aqueous base, viscous agents, excipients, electrolytes, lipid supplements, buffers, 
and preservatives. However, the latter have important AEs. Some of the known alterations generated 
by conservators are cellular apoptosis of the corneal and conjunctival epithelium, damage to the 
corneal nerves, delayed corneal healing, interference with the stability of the tear film and loss of 
goblet cells. [12, 15]   
Because the harmful effects of preservatives in ophthalmic formulations are widely documented, 
particularly in patients with chronic treatments, more and more attention has been directed to the 
development of dispensing devices that avoid the need to use such preservatives. [12] One of these 
is the Novelia® System, which allows patients to be offered a topical ophthalmic product presentation 
that reliably avoids contamination of the contents of the trophy without the need to use a preservative 
as part of the formulation.   

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2.2 Background on active ingredients   
    2.2.1 Background on Sodium Hyaluronate   
2.2.1.1 Pharmacology of Sodium Hyaluronate  
Sodium hyaluronate (HS), the sodium salt of hyaluronic acid (HA), is a naturally occurring 
glycosaminoglycan that has important biological functions in bacteria and higher animals, including 
humans. It is widely distributed in the cellular matrix of connective, epithelial, and neural tissue. It is 
present in cartilage, synovial fluid, in the skin and in the umbilical cord. In the eye it can be found in 
the vitreous humor and in the aqueous humor. [16, 12, 13]  
It is synthesized on the inner side of the plasma membrane as a linear polymer, in contrast to other 
glycosaminoglycans which are synthesized by Golgi enzymes. The enzymes for the synthesis of HS are 
hyaluronate synthetases, which are part of the plasma membrane; and glycosyltransferases, which in 
coordination polymerize and translocate HS out of the cell into the extracellular matrix. [17] [18]  
 
 
 
 
 
 
HS has several functions such as cell adhesion, migration, and proliferation. An important function is 
the ability to paralyze safe molecules in specific parts of the body by means of receptors (aggrecan, 
versican, neurocan, brevican, CD44 and RHAMM). [19] HS has been reported to be involved in several 
events during morphogenesis and differentiation. [17] [18]  
It has the property of retaining water, and it has been determined that each HS molecule retains 1000 
times its weight in water. This ability is compromised by factors such as sudden changes in 
temperature and pH. When the eye is open or the ocular surface is exposed, HS is more viscous, and 
coats the entire corneal surface, increasing tear film rupture time. If the eye is closed, HS spreads 
through the eye and eyelids, so it needs to be given again. [19]    
Due to the properties HS has several physiological functions, one of the main ones is to act as a 
viscoelastic agent, being useful in the treatment of severe dry eye as it has viscous properties similar 
to mucin. It provides hydration and retention for long periods, and with its use good lubrication of the 
ocular surface is obtained. [19, 13]  
Its beneficial effects on corneal healing have also been described. [13]  
A hyaluronate receptor, CD44, has been shown to be expressed in corneal and conjunctival cells, and 
its activation promotes interaction with cytoskeletal proteins, suggesting a role for hyaluronate in cell 
adhesion and motility. It has also been proposed that hyaluronate may have a role in controlling 
  
  
Figure 3. Chemical structure of HS 

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localized inflammation present in patients with SOS. It has been reported that CD44 expression is 
increased in patients with mild and moderate stages of the disease, and that, after a period of two 
months of application of HS, decreases the expression of this molecule. [13]  
 2.2.1.1.1 Pharmacokinetics in the eyeball  
There is preclinical evidence on the pharmacokinetics of HS and HA after dermal, subdermal, 
intravenous, intraperitoneal, and intraocular administration. [20] However, no information is available 
on the pharmacokinetic profile of this molecule following topical ophthalmic application.   
The corneal and conjunctival epithelium allows the passage of molecules through their cells by 
diffusion through the transcellular route and between their spaces through the paracellular route, for 
hydrophobic and hydrophilic substances, respectively. Molecular size is a limiting factor for the 
absorption of any substance through these structures. [21]  
Hamalainen et al. (1997) characterized paracellular permeability in the cornea, conjunctiva, and sclera 
of albino rabbits New Zealand using polyethylene glycol oligomers (PEGs) such as HS and chondroitin 
sulfate. This study reported that both corneal and conjunctival permeability decreased proportionally 
with increasing molecular weight of the PEGs used. In addition, the concentration of PEGs in the 
subjects' anterior chamber did not present significant variations due to their small permeation 
fraction. The corneal permeability coefficient was 0.22 x 106 cm/sec for PEGs with a molecular weight 
of 942 g/mol.  
The conjunctiva, both palpebral and bulbar, was 15 to 25 times more permeable than the cornea. This 
difference can be attributed to the fact that the conjunctival epithelium has wider paracellular pores 
(4.9 nm ± 2.5 and 3.0 nm ± 1.6, for palpebral and bulbar conjunctiva, respectively) compared to those 
of the cornea (2.0 nm ± 0.2).   
Even considering the greater permeability of the conjunctiva compared to the cornea, the results of 
the tests on rabbit conjunctivae show that the neutral hydrophilic molecules that present 
penetration are those with molecular weights less than 1000 g/mol. [22]  
Considering the above information, it can be concluded that HS and chondroitin sulfate (CS) 
molecules, which are classified as high molecular weight ( 800 Kg/mol), will not present intraocular 
penetration.   
Evaluating its intraocular use, HA rotation was tested by injection into the anterior chamber of the 
eyes of New Zealand white rabbits. The concentration of the solution used was determined to be 10 
mg/mL by radioassay. Two rabbits had 0.2 mL of aqueous humor extracted to be replaced by HA, and 
two more had 0.55 mL extracted and replaced. In addition, one rabbit was injected intramuscularly 
and another rabbit subcutaneously with 0.1 mL of the solution. Baseline blood samples were taken 
and 1, 2, 4, 8, and 24 hours, as well as daily for four days, and then every other day for 9 to 13 days 
after injections. Radiolabeling was detectable in the blood 2 to 3 hours after intraocular injection. It 
peaked at 2 days and then declined exponentially. The HA half-life at 0.2 mL injections was 14 hours 
and 8 hours for those with 0.55 mL injections. The hyaluronic acid injected subcutaneously had a half-
life of 50 hours, and the intramuscular material of 30 hours.  

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In another experiment conducted on cynomolgus monkeys, HA was injected into the anterior 
chamber at a concentration of 10 mg/mL. After extracting 100 μL of aqueous humor, 50 μL of HA was 
injected into the eyes of 5 monkeys. The procedure was repeated using 75 μL in 3 monkeys and in 4 
additional monkeys 50 μL plus pilocarpine addiction was injected, 10 μL at 4% instilled in the eye at 
hours 1, 8 and 24, after injection. The authors reported that radiolabeling was detected in blood 2 to 
3 hours later, reaching the maximum in 2 to 3 days in animals that were not administered pilocarpine 
and after 1 day in the rest. This concentration decreased exponentially. The half-life for the 8 monkeys 
was 21 hours without the addition of pilocarpine, and 9.5 hours with the latter. [20]  
 2.2.1.1.2 Systemic pharmacokinetics  
2.2.1.1.2.1 Preclinical studies  
Balogh et al. (2008) determined the absorption, distribution, and excretion of high-molecular-weight 
hyaluronate radiolabeled with technetium following oral dosing to Wistar rats and Beagle dogs. All 
tissues examined showed incorporation of radioactivity from 15 min to 48 hours. A concentration of 
radioactivity in joints, vertebrae, and salivary glands was observed through a whole-body scan 4 hours 
after administration. An excretion of 86.7% - 95.6% of radioactivity in feces was reported. [23]  
Another study examined the transfer of radioactivity to fetuses of pregnant rats that were injected 
intravenously with sodium hyaluronate. The fetuses' radioactivity increased up to 24 hours after 
injection and remained for up to 48 hours, before decreasing again after 72 hours. Radioactivity was 
distributed through the body of rats 1 to 4 hours after administration and decreased in whole-body 
tissues progressively. [20]  
2.2.1.1.2.2 Clinical studies  
After oral ingestion, absorption of a high molecular weight polysaccharide is difficult. It has been 
reported that HA with a molecular weight greater than 100 kg/mol is rarely absorbed by the intestinal 
epithelium. When ingested, enteric bacteria break down HA to its low molecular weight form, free 
polysaccharides that can travel to other systems such as joints. Approximately 90% of orally 
administered HA is metabolized and excreted through expiration and urine. [24]  
In humans, after intravenous administration, HA has a plasma half-life of 2.5 to 5.5 minutes. From the 
circulation, it is mostly catabolized by the liver where it is degraded into acetate and lactate. The half-
life of HA in cartilage has been reported to be 1 to 3 weeks. [25]  
2.2.1.2 Efficacy of Sodium Hyaluronate  
HA is a polymer with distinctive viscoelastic and hygroscopic properties that has demonstrated its 
therapeutic effect in patients with SOS. As an active ingredient, HA has shown an increase in the 
quality of life and satisfaction level (44.5% – 70.2%) of patients with SOS after 7 days of treatment. 
[26]  
Saeed et al. studied the efficacy, safety, and tolerability of HA in 240 patients treated with a 0.4% HA 
ophthalmic solution. After 8 weeks of treatment, ocular signs and symptoms decreased compared to 
baseline, reporting a 5.3% difference in foreign body sensation (SCS) and pruritus. Similarly, Pito-Fraga 

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et al. reported a significant increase in patient satisfaction with mild SOS after being part of a one-
month crossover study with 0.2% HA compared to 0.9% saline (26.8% vs 13.3%). [26]  
Aragona et al. also described the efficacy of HS in patients with SOS who, after 3 months of treatment, 
showed improvement in the results of impression cytology. They concluded that long-term treatment 
with artificial tears containing HS reduces ocular surface damage in patients with SOS. [27]  
Combinations of lubricants such as 0.1% HA with 0.5% carboxymethylcellulose have also been 
studied, finding this formulation effective in reducing SOS symptoms in patients recovering from 
cataract surgery, as evidenced by the OSDI questionnaire. [26]  
HS, like other viscous materials, has been shown to have greater effects than other conventional 
aqueous artificial tears on decreased fluorescein uptake in patients with SOS.  
These additional effects have been attributed to both the prolonged retention time and the 
physiological activity of HS. In a study published by Shimmura et al. comparing a 0.3% HS preservative-
free solution with a non-viscous saline solution, it was observed that the HS formulation was more 
effective in reducing fluorescein staining in patients with SOS. [13]  
2.2.1.3 Safety of Sodium Hyaluronate   
 2.2.1.3.1 Preclinical studies  
Several studies of the safety of HA have been conducted. No toxicity has been observed in single-
dose, repeated-dose, reproductive or developmental toxicity, mutagenicity, and antigenicity studies. 
[24]  
In a study performed on a human conjunctival cell line by cytofluorometry with cold light 
microtitration to evaluate cellular tolerance to HS and look for a protective action in vitro. Various 
cellular functions such as cell viability, cell proliferation, and the production of reactive oxygen species 
were evaluated. 0.18% HA was used. The tests were carried out after 15 minutes of treatment and 
after 24 hours of recovery of the cells in the culture medium. Ocular viability was assessed by a neutral 
red fluorimetry test. Chromatin condensation was assessed by measuring total cellular DNA as a 
reference in the assessment of apoptosis. Each test was performed at least three times. No decrease 
in cell viability was observed with HA, nor any change in membrane integrity after 24 hours. [28]  
For the evaluation of single-dose toxicity, >1200 mg/kg HA has been administered orally to mice. In 
addition, the toxicity of acute and chronic HA administered by different routes such as inhalation in 
Beagle dogs, implantation in the paravertebral muscles of rabbits, peritoneal administration in albino 
rabbits New Zealand and pleural administration in white rats has been evaluated. All the studies 
mentioned supported the safety of HA. [29]  
It was reported that after vitreous humour supplanting in rhesus monkeys and owl monkeys, when 
assessing inflammation by leukocyte count in the aqueous humour, no significant differences were 
observed. Only two eyes of the owl monkeys and two rhesus monkeys showed slight vitreous turbidity, 
a reaction that disappeared between 72 and 96 hours for all subjects. These same authors repeated 
the procedure up to 6 times in owl monkeys, concluding that repeated HS implantation did not cause 

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increased turbidity and flare, as well as any other immune response. Even after a follow-up period of 
up to 9 years, in subjects who received 2 to 4 HS injections, it was concluded that all eyes were 
completely normal, with no alterations in the anterior segment, lens, vitreous, retina or choroid. [29]  
With respect to dermal irritation, it was shown that HA does not cause alterations after a single dose 
in Japanese rabbits and Hartley guinea pigs. The ototoxicity of HA was also evaluated in pigmented 
Sprague-Dawley rats, concluding that the administration of this compound in the middle ear does not 
cause alterations to the auditory system. [29]  
The reproductive and developmental toxicity of HS has been studied in preclinical studies in vivo. In a 
multigenerational study in Sprague-Dawley rats and in another conducted in Japanese white rabbits, 
HA solutions were administered subcutaneously at three different concentrations. Weights and feed 
intake, as well as the pathology of intraperitoneal organs and skeletal system after the sacrifice of the 
selected mothers and calves, were analyzed, without finding significant differences. There were also 
no differences between the intervened subjects and the control subjects when assessing gestation 
time, number of offspring, sex ratio, live embryos and fetuses, and viable fetuses. [29]   
 2.2.1.3.2 Clinical Trials  
Aragona et al. (2002) reported that no AEs were present during a clinical study of efficacy and safety, 
after three months of treatment, in addition to good tolerability to the formulation. [27]  
The immunogenicity of HS has been tested in humans, by allergy skin tests, without finding adverse 
reactions related to the compound. In addition, its safety has been reported when used in the 
treatment of vesicoureteral reflux and as an aid in tissue augmentation. [29]  
2.2.2  
Background on chondroitin sulfate   
2.2.2.1 Pharmacology of chondroitin sulfate   
Chondroitin sulfate is a proteoglycan, a class of high molecular weight glycoprotein that is highly 
glycosylated. It is an endogenous natural substance that is part of the physiological components of 
connective tissues, being one of the constituent elements of cartilage. It is part of the group of 
glycosaminoglycans, like sodium hyaluronate, it is a mucopolysaccharide found in the extracellular 
matrix of connective tissues, including the vitreous, cornea and aqueous humor. [25]  
  
 
Figure 4. Chemical structure of CS 

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 2.2.2.1.1 Pharmacokinetics in the eyeball  
As for HS, there is currently no pharmacokinetic information following topical application of CS. 
However, due to its characteristics, particularly its high molecular weight, absorption by this route is 
not expected. To read more about this property and its interaction with the ocular surface epithelium, 
see section 2.2.1.1.1 Pharmacokinetics in the eyeball.   
 2.2.2.1.2 Systemic pharmacokinetics  
CS, due to its high molecular weight, is partially absorbed in the intestine after being degraded to its 
polymeric form. The products of intestinal degradation are simple sugars, amino sugars and inorganic 
sulfate. Cueto-Galán et al. describe that the bioavailability of CS ranges from 15% to 24% of the orally 
administered dose. Of the absorbed fraction of CS, 10% is in the form of CS and 90% in the form of 
depolymerized derivatives of lower molecular weight, suggesting a first-pass effect. After oral 
administration of CS, the maximum concentration of CS in the blood is reached in about four hours.   
In the case of intravenous administration, the plasma half-life of CS has been described as between 
3-15 minutes, suggesting that the systemic effects of orally administered CS could be mediated by the 
intestinal immune system, including the gastrointestinal lymphoid system. The half-life of total CS is 
15 hours, reaching a stationary period in 3-4 days. [25]  
2.2.2.2 Efficacy of chondroitin sulfate  
In 2013, Llamas-Moreno et al. published a clinical study sponsored by Laboratorios Sophia, S.A. de 
C.V. in which the efficacy and safety of a preservative-free ophthalmic solution containing 
chondroitin sulfate in combination with xanthan gum was evaluated, comparing it with a 
combination of polyethylene glycol/propylene glycol/hydroxypropyl guar.  After two months of 
treatment in patients with mild to moderate SOS, it was reported that in both groups the TRL was 
similar, however, the OSDI test score showed a greater decrease in the chondroitin sulfate 
0.09%/xanthan gum 0.1% group. [30]  
The efficacy of this same combination was also studied in a phase III study published by Pérez-
Balbuena, et al (2016). This was another comparative study in which it was compared with a solution 
of polyethylene glycol 400 0.4 % / propylene glycol 0.3 %. The variables studied in the 148 included 
patients with mild to moderate SOS were the TRL, OSDI test score, and Schirmer test. The results 
showed that both groups had similar clinical efficacy after two months of treatment. [31]   
Limberg et al. (1987) published a clinical study in which 20 patients with keratoconjunctivitis sicca 
were treated with a viscoelastic formulation of chondroitin sulfate alone, another in combination 
with sodium hyaluronate, a third of sodium hyaluronate alone, and finally a polyvinyl alcohol 
solution. It was observed that treated patients showed marked improvement in terms of reduced 
pruritus, burning, and ECS severity. A reduction in corneal uptake and formation of mucosal 
filaments was also observed. It was reported that those patients who presented initial low results 
in the Schirmer test preferred the solution containing CS. [32]  

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2.2.2.3 Safety of Chondroitin Sulfate  
In both studies previously mentioned in section 2.2.2.2 Efficacy of chondroitin sulfate published by 
Llamas-Moreno et al. (2013) and Pérez-Balbuena et al. (2016), the safety of the preservative-free 
ophthalmic solution composed of chondroitin sulfate 0.09%/xanthan gum.0.1% was analyzed by 
the incidence of ocular and systemic AEs during a period of 2 months of treatment. During this 
period, no AEs related to the intervention were presented in any of these studies, concluding that 
this formulation is safe. [30, 31]  
2.3 Summary of pharmaceutical development of Humylub Ofteno® PF  
Humylub Ofteno® PF has been developed at Laboratorios Sophia, S.A. de C.V. and has the 
physicochemical characterization and the protocol of accelerated and long-term stability.   
In 2014, a preclinical safety and toxicity study was carried out in which Humylub Ofteno® PF was 
evaluated. This preservative-free formulation was compared with Humylub Ofteno®, after QID was 
applied for one month to the surface of both eyes of albino New Zealand rabbits. The primary 
variables evaluated were conjunctival hyperemia, corneal surface status, and histopathology toxicity 
data. Secondary endpoints included conjunctival secretion and other anterior segment alterations. 
During the execution of the study, only one subject with moderate hyperemia was presented, 
however, this finding was not statistically significant. In the same way, only one case of fluorescein 
staining was presented in the control group, without this being statistically relevant.  The rest of the 
variables, including revision of the posterior pole, intraocular pressure, and staining with lysmine 
green, did not show alterations. Due to the results obtained, it was concluded that Humylub Ofteno® 
PF was safe, as was its comparator. [33]  
Subsequently, a Phase I clinical study was conducted in which the safety and tolerability of Humylub 
Ofteno® PF was demonstrated compared to Xyel Ofteno® and Systane Ultra® products, on the ocular 
surface of ophthalmologically and clinically healthy subjects. As variables to evaluate tolerability, 
burning, ECS, pruritus, and ocular comfort index were analyzed. For the safety study, goblet cell 
density, presence of AEs, intraocular pressure, visual capacity, laboratory tests, epithelial defects in 
the cornea and conjunctiva, conjunctival hyperemia, and chemosis were considered. No statistically 
significant differences were observed between the density of initial goblet cells between the three 
treatments, nor in the final treatments. A total of 28 AEs were reported in 46.7% of the subjects in 
the total sample (14/30), of which 100% were classified as mild. For lysmine green staining, a 
statistically significant difference was observed at visit 2, while for fluorescein staining, statistically 
significant differences were observed at visits 1, 2, and final at the expense of a higher number of 
grade 0 cases in the comparator group. For conjunctival hyperemia, statistically significant 
differences were only observed at visit 1 where the group treated with  
Systane Ultra® showed a higher frequency of normal values compared to Humylub Ofteno® PF and 
Xyel Ofteno®. No statistically significant differences were observed between the density of initial 
goblet cells between the three treatments, nor in the final treatments. In the variables evaluated, 
both safety and tolerability, Humylub Ofteno® PF showed a safety profile like that of the 
comparators, so it was concluded that it is a safe and tolerable formulation. [34]  

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Finally, in 2019, a multicenter phase IV study was carried out, in which the efficacy and safety of 
Humylub Ofteno® PF was evaluated compared to Systane® Ultra and Systane® Ultra free of 
preservatives. In this study, with a duration of 90 days, 326 patients were included. In efficacy 
variables, such as TRL, Schirmer's test, OSDI, and goblet cell density, all three treatment groups were 
effective, showing statistically significant improvement between their baseline and final visits. 
However, no group was consistently and statistically significantly superior to the other. For the 
variables defined as primary safety outcomes, such as presence of AEs, TRL, visual acuity and ability, 
intraocular pressure (IOP), and surface stains, no statistically significant differences were observed 
between groups in any of the measurement times. Finally, for the variables marked as tolerability 
(burning, SCE, tearing, and conjunctival hyperemia) there were no differences between groups; 
however, there was improvement in relation to the baseline visit. Based on the results presented 
above, it was concluded that Humylub Ofteno® PF is a safe and effective lubricant in the treatment 
of mild to moderate dry eye. [35]  
2.4 Background on the investigation  
 
2.4.1  From the research question  
SOS is a multifactorial pathology whose treatment can include multiple topical medications, oral 
medications, and even surgical procedures. However, ocular lubricants represent the most widely 
used therapeutic tool by patients with any degree of disease severity. Despite this, there are few 
comparative studies that allow us to determine the superiority of any lubricant over the rest. [12] 
However, the properties of each active ingredient provide them with specific characteristics that are 
exploited to reduce symptoms and signs associated with SOS. There are many commercially 
available lubricant formulations, so this study aims to test the non-inferiority in efficacy and safety 
of Humylub Ofteno® PF compared to two other known products, Hyabak® and Lagricel Ofteno® PF.   
 
2.4.2  From the investigational product development phase  
Humylub Ofteno® PF is a product that is available for purchase without a prescription in Mexico 
and Latin America. It has a research and development profile that includes a preclinical in vivo 
safety and toxicity study, as well as a phase I clinical study and a previous phase IV study in which it 
was compared with Humylub Ofteno® with preservative. See point 2.3 Summary of the 
pharmaceutical development of Humylub Ofteno® PF.  
2.5 Risk-benefit assessment  
 
2.5.1 Known potential risks  
Due to the characteristics of the active ingredients of Humylub Ofteno® PF, particularly its high 
molecular weight and the fact that it is composed of endogenous substances widely distributed in 
healthy organisms, the occurrence of serious adverse effects related to the investigational product 
is not expected. The safety profile of both assets, both individually and in combination, has been 
described in other studies. See points 2.2.1.3 Safety of sodium hyaluronate, 2.2.2.3 Safety of 
chondroitin sulfate, and 2.3 Summary of pharmaceutical development of Humylub Ofteno® PF.  

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As with the rest of the topical ophthalmic application formulations, the possibility of mild and 
transient burning, SCE and blurred vision is anticipated, with a post-instillation duration of no more 
than one minute. The procedures involved in the execution of this study, and the medications used 
for them, are also safe and have been described as part of the complete ophthalmological 
examination.   
 
2.5.2  Known potential benefits  
The use of ocular lubricants has been shown to decrease SOS-related signs and symptoms such as 
burning, SCE, corneal fluorescein uptake, etc. See points 2.2.1.2 Efficacy of sodium hyaluronate and 
2.2.2.2 Efficacy of chondroitin sulfate. Patients participating in this study will be exposed to the 
potential benefit of presenting a significant clinical improvement in the clinical picture related to 
SOS, with the consequent improvement in their quality of life.  
2.6 Problem statement  
SOS is a disease that affects millions of people around the world. These patients present a disruption 
of the homeostasis of their tear film and may suffer multiple signs and symptoms associated with the 
inadequate protection of their ocular surface due to an insufficient tear in quantity or quality. 
Although there are multiple therapeutic options available, it is a pathology that continues to be 
studied due to its great social and economic impact. In addition to seeking therapeutic measures that 
eliminate the specific etiology of this syndrome, a priority of treatment is to eliminate the symptoms 
that cause a significant decrease in quality of life. This can be achieved thanks to the use of eye 
lubricants, whose rheological properties largely determine their effectiveness and safety. It is 
necessary to continue evaluating the available lubricants to assess their clinical effect and confirm 
their efficacy and safety in the population exposed to them.   
2.7 Justification  
The great impact that the diagnosis of SOS represents, both socially, economically and scientifically, 
has been established, without a doubt; but above all for the quality of life of patients who suffer from 
it. Epidemiological evidence describes that in some regions the incidence of this disease can reach up 
to more than 50% of the population. There are currently multiple therapeutic options for the 
management of SOS, among which ocular lubricants occupy a main place due to their effectiveness 
in reducing the symptoms associated with the condition and as an aid in the restoration of tear film 
homeostasis. In the search for the best formulation to manage this type of patient, the rheological 
properties of substances such as glycosaminoglycans, a family to which both active ingredients of 
Humylub Ofteno® PF belong, have been used. By combining HS and CS, it is possible to offer patients 
with SOS symptomatic relief, as well as improvement in signs and alterations related to the vicious 
circle that characterizes SOS.   
Humylub Ofteno® PF is a product that is already marketed, and whose safety profile has already been 
previously studied; however, it was decided to carry out this study to compare its efficacy with two 
formulations containing sodium hyaluronate at different concentrations. The intention of this study is 
to confirm that patients with mild to moderate dry eye find an equal or greater decrease in their 

Laboratorios Sophia S.A. de C. 
 
19 
Study SOPH087-0120/IV 
Ver 2.0 
symptoms with the use of Humylub Ofteno® PF, compared to reference products, and to continue in 
this way to expand the information available on this ophthalmic solution and strengthen its efficacy 
and safety profile.  
  
  

20 
3. Objectives and hypotheses  
3.1 Primary objective  
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and Lagricel 
Ofteno® PF in the efficacy of the treatment of patients with dry eye, by means of the OSDI 
(Ocular Surface Disease Index) test score.  
3.2 Secondary objectives  
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the efficacy of the treatment of patients with dry eye, by means of 
the measurement of the LRLR.   
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the efficacy of the treatment of patients with dry eye, by means of 
changes in corneal and conjunctival stains with fluorescein.  
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the efficacy of the treatment of patients with dry eye, by changing 
corneal and conjunctival stains with lysmine green.  
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the efficacy of the treatment of patients with dry eye, through 
changes in conjunctival hyperemia.  
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the safety of the treatment of patients with dry eye, through the 
incidence of chemosis.   
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the safety of the treatment of patients with dry eye, through the 
incidence of AEs.  
- 
To demonstrate the non-inferiority of Humylub Ofteno® PF compared to Hyabak® and 
Lagricel Ofteno® PF in the safety of the treatment of patients with dry eye, by means of 
changes in CVAM.  
 
 
 
 
 

21 
3.3 Hypothesis  
H0= The Humylub Ofteno® PF ophthalmic solution is not inferior in its efficacy compared to its 
comparators, after 30 days of treatment, presenting a 35% decrease in the final score of the OSDI 
test compared to its initial value in at least 30% of exposed patients.   
H0:P A − PB ≤ δ  
H1= The Humylub Ofteno® PF ophthalmic solution is inferior in its efficacy compared to its 
comparators, after 30 days of treatment, as it does not present a 35% decrease in the final score 
of the OSDI test compared to its initial value in at least 30% of exposed patients.   
 
H1: PA − PB > δ   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

22 
4. Study design  
4.1 Design Overview  
Phase IV non-inferiority, controlled, open-label, comparative, multicenter clinical study.   
4.2 Rationale for the study design  
Humylub Ofteno® PF is a product that is currently available for consumption not only in Mexico, but 
in several Latin American countries such as: Bolivia, Chile, Colombia, Costa Rica, Costa Rica, Colombia, 
Costa Rica, Colombia Dominican Republic, Ecuador, Guatemala, Haiti, Honduras, Nicaragua, Panama 
and El Salvador.   
 
Both the efficacy and safety of its compounds, HS and CS, have been proven for use as a treatment 
for SOS, reducing both the signs and symptoms associated with this pathology. There are several 
ophthalmic solutions on the market that contain these compounds, including the comparators chosen 
for this study, Hyabak® and Lagricel® PF. The latter are composed of sodium hyaluronate, at different 
concentrations, and are also used for the treatment of SOS. One of the main purposes of SOS 
treatment is to reduce the symptoms described by patients such as burning, SCE, blurred vision, etc. 
The objective evaluation of these is carried out through internationally approved and accepted 
questionnaires, which are described in reference documents such as the TFOS DEWS II. One of these 
tools is the OSDI, the results of which will be considered in this study as the primary outcome variable. 
Like most efficacy studies for lubricating eye solutions, assessing improvement in patient-reported 
symptoms compared to reference products is the primary objective of this study. [36]  
Due to the differences in the presentation of Humylub Ofteno® PF with one of its comparators, 
Hyabak®, and thanks to the characteristics of its bottles, this will be an open-label study.   
Finally, considering the evaluation of the secondary variable of TRL efficacy by means of a non-invasive 
method, and since the equipment required to carry out this assessment is not so widely disseminated 
in ophthalmological offices and clinics in general, multiple research centers will be in charge of 
executing this study.     
4.3 Expected duration  
The total duration of the study, from the first visit of the first patient to the preparation of the final 
report, is estimated to be 12 months.  
The planned recruitment period is 7 months. Considering that the proposed sample is 180 patients, 
the total average recruitment rate during the study should be no less than 0.86 patients per day. 
Competitive recruitment will be carried out among authorized research centers.   
The approximate duration of each patient in the study is up to 41 days.  
  
  
 

23 
5. Study population  
5.1 Eligibility Criteria  
 
5.1.1  Inclusion criteria  
- 
Can voluntarily give their signed informed consent.  
- 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures.  
- 
Be of legal age.  
- 
Women of childbearing potential must ensure continued use (initiated ≥ 30 days prior to 
signing the CRF) of hormonal contraceptive method or IUD during the study period.  
- 
Present a diagnosis of mild to moderate dry eye, defined by an OSDI rating ≥ 13 and one 
of the following:  
o Corneal staining with more than 5 sites. o Conjunctival 
staining with more than 9 sites. o Tear film breakdown time 
< 10 seconds.  
 
5.1.2  Exclusion Criteria  
- 
Women who are pregnant, breastfeeding, or planning to become pregnant within the 
study period.  
- 
Have participated in another clinical research study ≤ 30 days prior to the screening visit.  
- 
Have previously participated in this study.  
- 
Have a CVAM of 20/200 or worse in one of the eyes.  
- 
Present an ophthalmological diagnosis of:  
o Allergic, viral, or bacterial conjunctivitis.  
o Anterior blepharitis. o Parasitic infestations in any ocular structure or its appendages.  
o Unresolved eye trauma. o Healing diseases of the ocular surface. o Corneal or 
conjunctival ulcers.  
o Filamentous keratitis. o Neurotrophic keratitis. o Bullous keratopathy. o Neoplastic 
diseases on the ocular surface or adnexa.  
o Diseases with fibrovascular proliferations on the conjunctival and/or corneal surface.  

24 
o Retinal and/or posterior segment diseases that require treatment or threaten visual 
prognosis.  
o Glaucoma.  
o Disorders of the eyelids that cause palpebral malpositions, limit the proper closing or 
opening of the eyelids, or are the cause of epiphora.  
- 
Have a management of your dry eye that requires the implementation of all stage 2 
treatments of the TFO DEWS II treatment and stage management recommendations for 
dry eye disease.   
- 
Have a history of drug addiction or drug dependence current or within the last two years 
prior to signing the FCI.  
- 
Have a history of eye surgical procedure within the last 3 months prior to signing the FCI.  
- 
Be a soft or hard contact lens wearer. You will be able to enter in case of suspending its 
use during the study, you must comply with 15 days without using the contact lens prior 
to your inclusion.  
- 
Have another medical condition, acute or chronic, that in the investigator's judgment 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 results of the 
study.  
- 
Have known hypersensitivity to the components of the investigational products.  
5.2 Patient Removal and Replacement Criteria  
- 
Withdrawal of the letter from the FCI.  
- 
Presentation of serious AEs related or not to the investigational product, which at the 
discretion of the PI and/or sponsor could affect the patient's ability to continue with study 
procedures safely.  
- 
Non-tolerability or hypersensitivity to any of the compounds used during the tests 
(fluorescein, lysmine green, tetracaine).  
- 
Non-tolerability or hypersensitivity to any of the investigational drugs.  
5.3 Lifestyle Considerations  
For the study, participants may need to modify some lifestyle activities to comply with the following:  
- 
Abstain from tobacco use.  
- 
Refrain from using electronic vaporizers.  

25 
- 
Avoid submerging yourself in water without eye protection (goggles).  
- 
Avoid direct exposure to fans (including air conditioning vents) during activities that 
involve vision. 24 hours before your check-up visits.  
- 
Maintain your sleep-wake cycle with which you enter the study.  
5.4 Counting failures  
A screening failure is defined as those participants who agree to participate in the study, giving their 
consent, but who are not assigned to a treatment group, i.e., do not enter the study. It is necessary 
to report at least the following information on counting failures:   
- 
Demographics.  
- 
Details of the failure to count (specify whether it is due to eligibility criteria, which one, 
or some other reason for the failure).  
- 
Presence of serious AEs during the count.  
This is necessary to comply with the CONSORT (Consolidated Standards of Reporting Trials) guidelines 
for the publication of results or to respond to possible questions from regulatory authorities.  
Patients who do not meet the eligibility criteria to participate in the study due to a specific modifiable 
factor may re-participate in the scrutiny. Patients in this case must use the same initial count number.  
5.5 Recruitment and Retention Strategies  
This is a phase IV study, which is planned to be conducted at several research centers. The selected 
centers will be responsible for the recruitment of patients.  
The minimum expected recruitment rate is 0.93 patients per business day. Because this study will be 
carried out in patients with mild to moderate SOS, a very common condition in the usual 
ophthalmological consultation, the participation of at least three research centers will be required.   
The duration of the patient's participation in the study is approximately 41 days, during which time 
they will only have to attend three visits after the screening, however, the screening and baseline 
appointments can be made on the same day, so no retention problems are anticipated. However, 
patients will be entitled to travel support for transportation and to comply with their visits. Other 
strategies to improve patient retention include, but are not limited to:  
• 
Clearly inform the importance of the study and the benefits that the population will obtain 
from its results.   
• 
Make calls or send text messages to remind you of appointments or activities to do.   
• 
Provide a printed calendar and an identification card to remember appointments and 
activities that will be carried out, in addition to the estimated duration of the same.  
• 
Offer flexible hours of operation.  
• 
Systematic organization of the study procedures, so that the patient does not last longer than 
necessary in his visit.  
• 
Minimize patient wait times.  
All materials to be delivered to the patient or recruitment strategies implemented by the Centers will 
be submitted for approval by the corresponding committees.  

26 
5.6 Procedure in case of loss of follow-up  
For this protocol, loss of follow-up is defined as those patients who were randomized, who at some 
points were active patients in the study, but their final evaluation could not be completed.  
If the participating patient does not attend their appointment, the research center must make a call 
to find out the reason and will attempt to make a new appointment within the established window 
period or an unscheduled appointment. In case it is not possible to make an appointment, the 
presence of AEs and the reason for leaving the study will be asked, as minimum data.  
A follow-up loss of <20% is considered not to be a problem for the validity of the results obtained 
based on the sample size calculations. See point 10.2 Calculation of the sample size.  
5.7 Patient Identification  
Study patients will be identified by a number and their initials.  
The initials of the study patient 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:  
 
To. Arieh Daniel Carrizalez Market  
B. Juan De la Torre Orozco  
 
to. Initials: AMC  
b. Initials: JDO  
At the counting visit, the participant number will be assigned consecutively, using 3 consecutive 
digits. Once the patient has been selected, they will be assigned a number with which they will be 
identified throughout the study. This code will be made up of eight numbers in the following order 
from left to right:   
• 
three digits of the molecule under study according to the name by the sponsor.    
• 
Two digits corresponding to the research centre number.   
• 
three digits of the number following their inclusion assigned in the research centre.  
Example:   
 
  
 
  
  
  
  
087 - 01 - 001   
Key to the  
molecule   
Number of  
inclusion   
Number of  
center   

27 
6. Investigational Product  
 
6.1 Managed Products  
 
6.1.1  Investigational Product  
−  
Generic name: Sodium hyaluronate / Chondroitin sulfate.  
−  
Distinctive name: Humylub Ofteno® PF.  
−  
Active ingredients: Sodium hyaluronate 0.1% / Chondroitin sulfate 0.18%.  
−  
Pharmaceutical form: Ophthalmic solution.  
−  
Presentation: multi-dose dropper bottle, 10 mL.  
−  
Prepared by: Laboratorios Sophia, S.A. de C.V.  
−  
Solution description: Transparent solution, free of visible particles.  
−  
Packaging description: White bottle made of low-density polyethylene with system  
Novelia  filled to 10 mL.  
 
6.1.2  Reference product  
−  
Generic name: 0.15% sodium hyaluronate.   
−  
Distinctive name: Hyabak®.  
−  
Active ingredients: Sodium hyaluronate 0.15%.  
−  
Pharmaceutical form: Ophthalmic solution.  
−  
Presentation: multi-dose dropper bottle, 10 mL.  
−  
Prepared by: Laboratoires Théa, Clermont-Ferrand, France.  
−  
Solution description: Transparent solution, free of visible particles.  
−  
Packaging description: Abak® multidose bottle of 10ml. 
−  
Generic name: Sodium hyaluronate   
−  
Distinctive name: Lagricel Ofteno® PF.  
−  
Active ingredients: Sodium hyaluronate 0.4%   
−  
Pharmaceutical form: Ophthalmic solution.  
−  
Presentation: multi-dose dropper bottle, 10 mL.  
−  
Prepared by: Laboratorios Sophia, S.A. de C.V.  
- 
Solution description: Transparent solution, free of visible particles.  

28 
- 
Packaging description: White bottle made of low-density polyethylene with Novelia system  filled 
to 10 mL.  
6.1.2.1 Justification of the reference product  
Hyabak® is a preservative-free lubricant manufactured by Théa Laboratories, which is indicated for 
the treatment of SOS. [37] It is composed of 0.15% HS and is packaged in a multi-dose bottle. It is 
currently a direct commercial competitor of Humylub Ofteno® PF and Lagricel Ofteno® PF.   
As it is composed of HS, it shares with the products of Laboratorios Sophia, S.A. de C.V. already 
mentioned, some of the benefits that it can offer to patients diagnosed with SOS. However, it lacks 
the association with CS as in the case of Humylub Ofteno® PF, and the properties attributed to a higher 
concentration of HS, as in Lagricel Ofteno® PF.   
On the other hand, Lagricel Ofteno® PF is an ocular lubricant also manufactured by Laboratorios 
Sophia, S.A. de C.V. It has a broad safety profile from its development phase to the pharmacovigilance 
to which it has been subjected since its international commercialization, both in its single-dose 
presentation and in its multi-dose version, both free of preservatives.   
6.1.3  Dosage of investigational product   
One QID drop, with a minimum interval of 3 hours between applications, for 30 days.  
6.1.3.1 Dose justification  
The dosage of treatment for SOS based on ocular lubricants will depend on the severity of the clinical 
picture. In the case of this study, as these are patients diagnosed with mild to moderate SOS, a dose 
of 4 lubricating drops per day will be used in accordance with the dosage stipulated in the prescribing 
information of Humylub Ofteno® PF and Lagricel Ofteno® PF. In both cases, it is indicated to apply 
every 4 – 6 hours. On the other hand, the Hyabak® insert refers to a dosage of 1 drop in each eye as 
often as necessary. [37]  
The requirement to wait at least three hours between each application is added to distribute the 
dosage throughout the day, ensuring the protection of the ocular surface during waking hours.   
6.2 Storage and handling of research products at the study site  
The delivery will be made by means of a courier service contracted by the sponsor, expressly selected 
for this purpose, to the address of the research center according to the study plan.  
The reception will be carried out by the assigned personnel of the research team. You will need to 
check that the primary packaging (box) is in good condition. If you show alterations or defects in its 
integrity that in your judgment could have damaged the content, you must report it to the sponsor. If 
the package does not show significant defects, it will proceed to open it.   
Inside you must locate the acknowledgment document and the temperature logger. You must check 
that the temperature recorded complies with what is specified for transport and safekeeping. It will 
verify the content (PI) with what is reported in the document. In case the document corresponds to 
the content, you will sign the receipt and send it to the sponsor. Otherwise, it will notify the sponsor.  

29 
Storage and safeguarding is the responsibility of the research center. The medication must be stored 
in a secure area with restricted access.   
The storage temperature should be less than 25°C.  This limit is stipulated as described in the Hyabak® 
comparator product information, since Humylub Ofteno® PF and  
Lagricel Ofteno® PF require to be kept at a temperature below 30°C. [37]  
The research center is obliged to record, in the designated format, the temperature recorded in the 
data logger, every day while the protocol is in force and has PIs. These data will be reviewed by the 
clinical monitor according to the record in the data logger.  
In the event of loss of material, it must be documented in the logbook of inputs and outputs along 
with a clear description of the mechanism by which the loss occurred.   
Upon completion of the protocol, all study material will be retrieved by the sponsor as part of the 
closing audit. The final delivery of material will be made by the principal investigator (PI) or the person 
designated by him to deliver material at the end of the study.   
The sponsor reserves the right to initiate civil and criminal action against the PI in the event of a lack 
of undocumented material at the conclusion of the study.  
6.3 Concomitant treatments and medications not approved during the study  
The use of concomitant medications by any route of administration will not be allowed during the 
intervention period. Except those specified for study procedures and the use of hormonal 
contraceptives in women of childbearing potential. The objective of this restriction is to avoid drug 
interactions that could alter the results of the variables evaluated.  
Allowed medications:  
 
-  Ophthalmic:  
o Tetracaine 0.5%  
o Tropicamide 0.8% /Phenylephrine 5%  
6.4 Procedure for monitoring and measuring adherence  
For more than four decades, there has been a lot of research on the appropriate way to measure and 
quantify medication adherence, but none has reached a consensus to stand as the gold standard, 
both in cross-sectional and longitudinal studies.  
[38] [39] [40] [41] [42] [43] [44] [45]  
There are different procedures to measure adherence to pharmacological interventions. The most 
common procedure includes self-reports, which include patient interviews, questionnaires and self-
monitoring diaries. Its strengths are speed, flexibility, low cost and ease of implementation; They have 
a high degree of specificity for non-adherence, however, the sensitivity and reliability for adherence 
is low. [45] [46]  

30 
The biochemical measurement of the drug, or its metabolite, is one of the methods that best confirms 
the use of the drug. However, in addition to raising costs and being impractical, it is of little use in the 
context of ophthalmic applications, since concentrations at the peripheral level could be 
undetectable, particularly in this study since ocular lubricants whose absorption is not expected will 
be evaluated. [45]  
Medication counting is another way to measure adherence. Classically referred to as "pill counting," 
in ophthalmology it translates to the weight of the bottle. This is a simple, inexpensive, and non-
invasive method. The main disadvantages of this method are: 1. The application of the medication 
cannot be confirmed (it may have been intentionally pulled or instilled outside the eye) and  
2. It depends on the patient bringing back the medication. [45] [46]  
A multi-procedure approach to measuring adherence is recommended. Because there is no 
measurement of ideal adherence, it is appropriate to use more than one method when trying to 
achieve results that resemble reality. Selecting two or more methods allows their strengths and 
weaknesses to be compensated, to more accurately capture adherence levels. [44] There is no 
standardized parameter to define adequate adherence, it must be defined and delineated by the 
objectives of the research. [45]  
Considering all the antecedents presented above, for this study adherence will be measured by the 
weight of the bottle and the record of applications of the patient's diary. A patient will be considered 
to comply with the required adherence if they have a positive record of applications in the patient's 
diary of at least 80%; as well as at least 65% of the decrease in the expected weight of the bottle used.   
The evaluation of adhesion by means of the weight of the bottle will be carried out as follows, 
considering the following information: the weight of the drop, the initial weight of the container, the 
final weight of the container and the calculation of the total applications. The following simplified 
formula shall be used:  
Ad =   (Pi − Pf) 100 
          PT 
 
Where:  
Ad = adherence  
Pi = Initial weight 
Pf = final weight 
PT = Total treatment weight 
PT = (Pg)G 
Where:  
Pg = weight of one drop of the intervention, determined by the research and development 
department  

31 
G = number of applications indicated for the intervention  
The adherence calculation according to the patient's diary will be evaluated as follows:  
Ad = (Ar)100/Ai 
Where:   
Ad = Adherence 
Ar = Registered Applications  
Ai = Applications indicated for the intervention  
The research center will designate a person in charge of monitoring adherence through the diary, 
during the visits. The measurement of grip by weight will be the responsibility of the sponsor.  
In cases where the container is not returned, or it has not preserved its physical integrity, adherence 
will only be measured through the patient's diary.  
6.5 Strategies to improve adherence  
- 
The PI will make the patient aware of the importance, to achieve the objectives of the study, 
of the correct application of the PI.  
- 
Direct questioning by the PI about the application of the PI.  
- 
Delivery of a printed calendar specifying the date of the visit and its activities.   
- 
Training in the completion and review of the Patient Diary.  
- 
If deemed necessary, text messages may be sent as reminders. The content of these messages 
must be previously approved by the Ethics and Research Committee (CEI).  
 
 
 
 
 
 
 
 
 
 

32 
7. Study methods and procedures  
 
7.1 From the research centre  
This study will be carried out in the research centers previously evaluated by the sponsor. These 
centres will be institutions or establishments where health research is carried out that complies with 
current regulations.  
The research centers will be responsible for forming a multidisciplinary research team to execute the 
clinical study according to the protocol. It is their prerogative to design the organization and select 
the personnel who will perform the functions. However, it is the sponsor's need for the Principal 
Investigator (PI) to be a specialist in ophthalmology.  
Any person who is designated, under their responsibility, a part of the study monitoring (co-
investigator, sub-investigator, nurse, etc.) or a specific function of participation in the study 
(pharmacist, administrative assistant, study coordinator, etc.) must appear in the "Delegation of 
Responsibilities".   
The competence and training of any person who has direct participation in the activities of the study 
must be verified prior to the performance of any activity related to the protocol. The above must be 
recorded and the documents that constitute evidence of this competence and/or training must be 
kept in the master file of the study. The competence and training of the personnel who have functions 
in the study, both at the central level and in the study centers, is the responsibility of the sponsor.  
The sponsor must ensure that all study site personnel participating in the study are adequately trained 
on the study (research protocol, investigator's manual, amendments, standard operating procedures, 
etc.) and on the ICH (International Council for Harmonisation) GCPs), before the start of their 
participation in it. Training must be recorded in writing and those records must be filed in the master 
record of the study.  
7.2 Clinical Study Registration  
This clinical study will be registered by the sponsor in public clinical trial registries before its start 
(inclusion of the first patient): National Registry of Clinical Trials (RNEC) of the Federal Commission for 
the Protection against Health Risks (COFEPRIS) and in a platform of primary registries of the World 
Health Organization (WHO). WHO primary registries meet specific criteria for 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).  
7.3 Randomization   
Randomization of subjects will be carried out using a computer-based assignment system. After 
signing the FCI, the patient will receive a patient number with which all their information will be 
encrypted pseudonymity during collection and completely anonymized during analysis.  

33 
The containers will be identified by means of labels, which, in accordance with current and applicable 
regulations, must contain at least:  
1. 
Sponsor's name, address, and phone number.  
2. 
Dosage form and route of administration.  
3. 
Batch number.  
4. 
Legend "For clinical studies only"  
5. 
Expiration date.  
7.4 Outcome variables  
 
7.4.1  Primary outcome variables  
- 
OSDI score (TE: visits 1 and final).  
 
7.4.2  Secondary outcome variables of efficacy  
- 
Changes in the measurement of the TRLNI. (TE: visits 1 and final).  
- 
Changes of corneal and conjunctival stains with lysmine green (ET: visits 1 and final).  
- 
Corneal and conjunctival staining changes with fluorescein (ET: visits 1 and final).  
- 
Conjunctival hyperemia changes (ET: visits 1 and final).  
 
7.4.3  Safety variables  
- 
Incidence of unexpected AEs related to the research product. (TE: Visits 1, Final and Safety 
Call)   
- 
Changes in the MAVC (TE: visits 1 and final).  
- 
Incidence of chemosis (ET: visits 1 and final).  

 
34 
 
7.4.4  
Definition of variables, methods and scales to be used for the measurement  
 
 
Variable  
Conceptual Definition  
Operational Definition  
Measurement 
Type  
Normal value  
Statistical test  
OSDI Score 
OSDI is a questionnaire designed to 
establish a severity and 
Classification of dry eye according 
to its symptoms. 
The evaluator will apply the 
questionnaire to the subject and 
allow the subject to answer it 
calmly without any pressure 
and/or coercion. See annex 
16.1 OSDI. 
Continuous 
quantitative 
Score: 
OSDI= 
(∑score)25 n 
answers  answered 
• ANOVA of repeated 
measures. 
• One-way ANOVA* 
TRLNI 
Measurement of tear rupture 
time using non- 
is based on the observation 
of the film's mirror 
reflection 
in a grating design or in the 
placid discs of the 
corneal topographers and 
their analysis using specialized 
software. 
The TRLNI will be 
measured by means of 
the Oculus 
Keratograph 5M. 
Discrete 
quantitative 
>10s 
• ANOVA of repeated 
measures. 
• One-way ANOVA* 
Corneal and 
conjunctival 
staining with 
lysmine green 
Detection of epithelial defects 
in the conjunctiva and 
cornea. 
Direct observation with slit 
lamp, graduation on Oxford 
scale. See annex 16.2 Oxford 
scale. 
Ordinal 
Qualitative 
Degrees: 
The stain is presented in a 
series of panels (A-E). The 
points 
Stains range from 0-5 for 
each panel and from 0-15 
for the exposed toral area 
of the conjunctiva and 
cornea. 
• X2 (Chi-square) of 
Pearson or Fisher's 
Exacta 
• McNemar Test* 
 
 

 
35 
 
Corneal and 
conjunctival 
staining with 
fluorescein 
Detection of epithelial defects 
in the conjunctiva and 
cornea. 
Direct observation with slit 
lamp, graduation on Oxford 
scale. See annex 16.2 Scale of  
Oxford. 
Ordinal 
Qualitative 
Degrees: 
The stain is presented in a 
series of panels (A-E). The 
points 
Stains range from 0-5 for 
each panel and from 0-15 
for the exposed toral area 
of the conjunctiva and 
cornea. 
• X2 (Chi-square) of 
Pearson or Fisher's 
Exacta 
• McNemar Test* 
Conjunctival 
Hyperemia 
Changes 
It is defined as the simplest 
reaction of the conjunctiva 
to a 
stimulus, a red appearance is seen 
secondary to vasodilation of 
the conjunctival vessels of 
variable intensity. 
Direct observation. 
Classification by Efron scale. 
See annex 16.3 Efron's scale. 
Ordinal 
qualitative 
Degrees: 
0= Normal, 
1= Very mild, 
2= mild, 
3= Moderate and 
4= Severe 
• X2 (Chi-square) of 
Pearson or Fisher's 
Exacta 
• McNemar Test* 
Incidence of 
chemosis 
It is defined as conjunctival edema 
resulting from an inflammatory 
reaction. It is classified as present 
or absent. 
The evaluator will use a narrow 
beam of light at 60° and measure 
whether the conjunctiva 
separates by ≥1/3 of the total 
palpebral aperture or whether it 
exceeds the gray line 
Ordinal 
qualitative 
Present/absent 
 
• 
One-way 
ANOVA 
• 
Pearson's X2 
(Chi-square) or 
Fisher's Exact test 
Incidence of 
AEs 
Any adverse medical event 
that occurs in a patient or 
clinical research subject who 
has been administered a 
pharmaceutical product and 
that does not 
The AEs manifested during the 
conduct of the study will be 
collected using the FRCE. 
 
Continuous 
quantitative 
Categorical 
qualitative 
Frequency 
Subjects presenting EA/total 
number of subjects exposed. 
Intensity 
• 
Mild 
• 
Moderate 
• 
Severe 
Causality 
One-way ANOVA 
Pearson's X2 (Chi-
square) or Fisher's 
Exact test 

 
36 
 
• 
Probable 
• 
Possible 
Unlikely 
Changes BCVA 
Spatial VA is the ability to 
distinguish separate elements of an 
object and identify them. 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 chart 
Discrete 
quantitative 
 
 
Fraction 
0.6 to 2.0 
 
 
ANOVA for repeated 
measures. 
• One-way ANOVA* 
 
  

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7.4.4.1 Adverse events  
An AE is any unfavorable medical appearance in a patient who is administered a PI, regardless of 
causal attribution.  
Management of AEs will be performed as described in the Adverse Events section. See point 8 
Evaluation and management of adverse events.  
The PI will record in the corresponding section of the electronic case report form (FRCE) the AEs 
that the patients in the study may present, in addition to referring them in the clinical file.  
For an adequate evaluation of AEs, in addition to directed questioning, it is necessary to perform 
the Comprehensive Ophthalmological Evaluation at each visit, which consists of: the 
ophthalmological examination of the eyelids and adnexa; anterior and posterior segment that is 
performed in a routine ophthalmological examination, whose procedures are not specifically 
included in the study variables. Posterior pole evaluation can be with direct or indirect 
ophthalmoscopy, with or without pharmacological mydriasis, at the discretion of the PI. An 
assessment of the fundus will be carried out in search of abnormalities that alter the result of the 
study. IOP will be measured in this evaluation, with the PI choice instrument, it should be 
measured after the evaluation of stains. The result of the assessment will be recorded in the 
clinical file. In the electronic case report form (FRCE), only the findings that are considered so by 
the PI will be reported as AEs.  
7.4.4.2 OSDI Score  
OSDI is the most widely used symptomatic assessment tool in SOS clinical studies. It is referred to 
in the TFOS DEWS II as it is a diagnostic means already established among ophthalmologists.   
It is a self-adpilating questionnaire of 12 questions, which is divided into three sections: frequency 
of symptoms, alteration of activities of daily living, worsening due to environmental factors in the 
last week. Each answer is assigned a numerical value which is then multiplied by 25 and then 
divided by the number of questions answered. The result can range from 0 to 100, classifying the 
severity of symptoms as specified below:   
- 
< 12 = normal  
- 
13 – 22 = mild  
- 
23 – 32 = moderate  
- 
≥ 33 = severe   
The OSDI score will be recorded in the FRCE.  
Management as AE: A ≥ 40% increase in the baseline OSDI score value should be reported and 
managed as an AE due to lack of efficacy.  

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7.4.4.3 Better Corrected 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. 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's notation is described as the distance at which the test is performed, divided by the 
distance at which the letter is vertically equivalent to 5 arc minutes. Thus, at 6 meters a letter 6/6 
(20/20) is equivalent to 5 minutes of arc, a letter 6/12 (20/40) is equivalent to 10 minutes, and a 
letter 6/60  
(20/200) equals 50 minutes. The Snellen fraction can also be expressed as a decimal (i.e., 20/20 = 
1 and 20/40 = 0.5). [47]   
VA will be evaluated at baseline, without refractive correction with the Snellen chart. It will be in 
a place with adequate lighting, natural or artificial, and at 3m from the patient to be evaluated. 
The visual acuity of each eye will be taken, starting with the right eye (OD) asking the patient to 
keep both eyes open and using an occlude to cover the left eye (OS); the patient will read aloud 
the lines that the evaluator points out, the line of smaller letters that he can see will be noted by 
the evaluator in fraction as the VA of OD in the clinical record. The OS is proceeded with the same 
method.  
Subsequently, the patient's objective and subjective refractive correction will be performed. The 
result of the subjective refraction will be reported as CVMA, it will be noted in fraction in the 
clinical record and in the FRCE, in addition to the FRCE it will be noted in decimal. CVAM cannot 
be inferior to VA.  
Management as EA: A decrease of more than 2 lines on the Snellen card must be reported and 
handled as EA.  
7.4.4.4 TRLNI  
For this study, it is required that the TRLNI be taken using the Oculus Keratograph 5M. This 
topographer has a high-resolution camera that allows the evaluation of the height of the tear 
meniscus, TRLNI and observation of meibomian glands.   
The rings of Placido are reflected on the surface of the cornea, and when a distortion of the 
reflected sights occurs, it is recorded as a break in the tear film. The software then analyzes this 
information, and the results are expressed through a color-coded map. The red/orange segments 
correspond to a shorter rupture time, which will be evidenced in a map showing the total area of 
the cornea affected by tear film ruptures. The initial breakout time and average time will be 
displayed in the result presentation.   

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You will enable the "NIKBUT" button, then select infrared light. The patient will be asked to blink 
naturally, and when the device is aligned and the message "Blink twice” appears, it will prompt 
them to blink twice. After the second blink, the measurement will automatically start. The patient 
should keep their eyes open without blinking, as the measurement is automatically interrupted if 
the patient blinks, moves a lot, or the tear film breaks significantly.   
As previously mentioned, a TRLNI of less than 10 sec. Viewpoint  
The value of the first break-up time will be recorded in the FRCE under TRLNI. This study may be 
carried out within a window of 0 to 2 days between the screening visit and the baseline visit, prior 
to the latter; as well as ± 2 days with respect to visits 1 and final. It must be carried out at least 2 
hours after having applied any stain or drug allowed by this protocol for ophthalmic check-ups.   
7.4.4.5 Corneal and conjunctival fluorescein staining  
A drop of topical anesthetic will be instilled in the bottom of the conjunctival sac, then a second 
drop will be applied to the tip of the fluorescein strip, allowing it to sit on the strip for 5 seconds 
to elute the dye, shaking off the excess at the end. A small contact of the strip is made with the 
conjunctiva at the fundus of the temporal sac, while the patient looks upwards, without damaging 
the conjunctiva. It will be graded according to the Oxford scale. [48]    
The PI will record in the file and the FRCE the grade granted for fluorescein staining of DO and OS, 
respectively.   
Management as AE: corneal stains that are equal to or greater than grade III will be considered as 
AEs.  
7.4.4.6 Conjunctival staining with lysmine green  
After the revision with fluorescein, a drop of saline solution will be applied to the tip of the green 
lysam strip, allowing it to sit on the strip for 5 seconds to elute the dye. A drop of the strip is 
instilled at the bottom of the temporal sac, while the patient looks upwards, without damaging 
the conjunctiva. The patient may be asked to blink repeatedly to prevent accumulations in the 
conjunctival folds. The examination should be done between 1 and 4 minutes after instillation 
through a neutral density filter or with the red-free filter. It will be graded according to the Oxford 
scale. [48]    
The PI will record in the file and the FRCE the grade granted for fluorescein staining of DO and OS, 
respectively.   
Management as AE: corneal stains that are equal to or greater than grade III will be considered as 
AEs.  

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7.4.4.7 Conjunctival hyperemia  
Conjunctival hyperemia is defined as the simplest reaction of the conjunctiva to a stimulus, with a 
red appearance secondary to vasodilation of the conjunctival vessels of variable intensity. It will 
be graduated using the Efron scale. [49] See annex 16.3 Efron's scale.  
Management as AS: conjunctival hyperemias classified as grade 3 or higher will be considered as 
AD.  
7.4.4.8 Chemosis  
It is defined as conjunctival edema, the result of an inflammatory reaction. It is qualified as present 
or absent. The evaluator will use a narrow beam of light at 60° and will measure whether the 
conjunctiva separates from the sclera by ≥ 1/3 of the total eyelid opening or if it exceeds the gray 
line. [50] Management as an EA: its presence will be considered as an EA.  
7.5 Study visit and activities program  
 
7.5.1  Description of activities per visit  
The procedures are listed in the order in which they are suggested to be performed, trying to 
maintain the coherence of the evaluations and as far as possible, from the least invasive to the 
most invasive.  
7.5.1.1 Counting Visit  
• 
Signature of the CRF: refers to the signing of the written informed consent document. 
Without obtaining informed consent, it is not possible to perform any of the study 
procedures.  
• 
Clinical history: refers to the technical, clinical and legal document in which the patient's 
health conditions, medical acts and other procedures performed on the patient are 
chronologically recorded. It includes anthropometric measurements, anamnesis, 
comprehensive ophthalmological examination that allows discerning the patient's 
eligibility, that is, evaluation of both eyes of ocular adnexa, slit lamp examination of the 
ocular surface and anterior segment and fundoscopy. If the patient is taken from the 
established population base of the study center, the existing medical history may be used, 
and only one update must be made.  
• 
Evaluation of concomitant medications refers to the questioning by the PI of the patient, 
inquiring about the use of medications.  

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• 
Urine pregnancy test: This refers to performing a rapid pregnancy test on all women of 
childbearing potential who wish to enter the study. By fertile age we mean women who 
have had their menarche and have not presented their menopause. Menopause is defined 
as 12 months from the last menstruation in women over 40 years of age, or who have had 
a hysterectomy or bilateral oophorectomy. Women of childbearing potential with 
contraceptive methods including bilateral tubal obstruction should be tested for 
pregnancy. This test will be performed by the IP or designated team person in accordance 
with the instructions on the device provided by the sponsor.  
• 
Vital signs: refers to the measurement of heart rate, respiratory rate, systemic blood 
pressure and temperature. This information must be contained in the patient's medical 
history and the evolution notes of the patient's clinical file.   
• 
OSDI: see section 7.4.4.2 OSDI score.  
• 
CVAM: see section 7.4.4.3 Better corrected visual acuity.  
• 
Ocular surface stains: see points 7.4.4.5 Corneal and conjunctival staining with fluorescein 
and 7.4.4.6 Conjunctival staining with lysmine green.   
• 
Comprehensive ophthalmological evaluation: see point 7.4.4.1 Adverse events.   
• 
Eligibility criteria: refers to the review by the PI, where it is found that the patient can be 
included in the study by meeting the inclusion criteria and not meeting the exclusion 
criteria.   
• 
Evaluation of AEs: see section 7.4.4.1 Adverse events.  
It will be at the discretion of the principal investigator whether the clinical evaluations that 
will be considered the baseline values of each variable will be those evaluated during the 
screening visit, or if he or she considers it necessary to repeat any test during the baseline 
visit. In the latter case, these results should be considered as baseline values.   
7.5.1.2 Basal Visit  
• 
Eligibility criteria: refers to the review by the PI, where it is found that the patient can be 
included in the study by meeting the inclusion criteria and not meeting the exclusion 
criteria.   
• 
Evaluation of AEs: see section 7.4.4.1 Adverse events.  
• 
TRLNI: see point 7.4.4.4 TRLNI.   

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• 
IP randomization: refers to determining the intervention that the patient will follow during 
the study. This assignment will be made at baseline visit (day 0). See point 7.3 
Randomization   
• 
Delivery of the PI and initiation of intervention refers to the delivery of the PI to the study 
patient, by the research center.   
• 
Delivery of patient material and filling instructions refers to the delivery by the PI to the 
patient of the patient's diary, ID card and calendar improving adherence. The staff 
assigned by the research center will carry out prior training to the patient, on the 
completion of the diary.  
7.5.1.3 Visit 1  
• 
Evaluation of concomitant medications: see point 7.5.1.1 Screening Visit.  
• 
Vital signs: refers to the measurement of heart rate, respiratory rate, systemic blood 
pressure and temperature. This information must be contained in the patient's 
medical history and the evolution notes of the patient's clinical file.   
• 
OSDI: see section 7.4.4.2 OSDI score.  
• 
CVAM: see section 7.4.4.3 Better corrected visual acuity.  
• 
TRLNI: see point 7.4.4.4 TRLNI.  
• 
Ocular surface stains: see points 7.4.4.5 Corneal and conjunctival staining with 
fluorescein and 7.4.4.6 Conjunctival staining with lysmine green.  
• 
Comprehensive ophthalmological evaluation: see point 7.4.4.1 Adverse events.  
• 
Evaluation of AEs: see section 7.4.4.1 Adverse events.  
• 
Evaluation of adherence: see point 7.5.1.1 Scrutiny visit.  
7.5.1.4 Final Visit  
• 
Evaluation of concomitant medications: see point 7.5.1.1 Screening Visit.  
• 
Urine pregnancy test: see point 7.5.1.1 Screening Visit.  
• 
Vital signs: see point 7.5.1.1 Scrutiny visit.  
• 
Evaluation of AEs: see section 7.4.4.1 Adverse events.  
• 
OSDI: see section 7.4.4.2 OSDI score.  
• 
CVAM: see section 7.4.4.3 Better corrected visual acuity.  

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• 
TRLNI: see point 7.4.4.4 TRLNI.  
• 
Ocular surface stains: see points 7.4.4.5 Corneal and conjunctival staining with 
fluorescein and 7.4.4.6 Conjunctival staining with lysmine green.  
• 
Comprehensive ophthalmological evaluation: see point 7.4.4.1 Adverse events.  
• 
Evaluation of the Patient's Diary: see point 7.5.1.1 Screening Visit.  
• 
Evaluation of adherence: see point 7.5.1.1 Scrutiny visit.  
• 
Return of PI and patient diary: refers to the return by the patient, the PI and the 
patient's diary to the research site.  
7.5.2  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 for AE reporting. During these visits, all pertinent data on the AEs reported 
should be collected and, where appropriate, an appropriate management plan should be 
established.  
7.6 Data collection  
 
7.6.1  Source documents  
Source documents are all written or printed records derived from automated processes (e.g., 
printouts of laboratory results issued by automated analysis equipment) where the information is 
recorded for the first time and that is part of the permanent records of the patient's history. 
Examples of source documents are the medical history, clinical evolution notes, laboratory reports, 
cabinet study reports, nursing notes, follow-up notes, surgery records, etc.  
The PI is obliged to accept the monitoring of the information related to the study, audits, review 
by ethics and research committees, and inspections by the health authority, this obligation implies 
direct access to the source documents.  
 
7.6.2  Electronic forms of data collection  
All data related to the protocol will be captured through an eCRF by the research team staff. The 
data related to the protocol should NOT be captured directly in the eCRF but should be transcribed 
from the corresponding source document. This procedure allows monitoring to verify the 
information captured in the eCRF. It is the responsibility of the researcher to ensure that the 
information is transcribed to the eCRF in a correct, complete, and timely manner. It is understood 
that all FRCEs captured and submitted for data analysis are approved by the Investigator.  

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7.6.3  File  
The data collected in this database is anonymous (it only stores the patient number together with 
other information of interest). The program used for data capture and storage covers the 
traceability requirements necessary for the execution of clinical studies. The data collected will be 
stored by the sponsor or the clinical research organization designated for this purpose and its 
storage will have a duration of 10 years. The patient number assignment records will remain in the 
participating institutions in charge of the PI or his work team and must be kept for at least 5 years.  
 
7.6.4  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 for AE reporting. During these visits, all pertinent data on the AEs reported 
should be collected and, where appropriate, an appropriate management plan should be 
established. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8. Evaluation and management of adverse events  
 
8.1 Regulation and regulations on adverse events  
The registration and reporting of AEs will be carried out in accordance with the guidelines 
established in NOM220-SSA1-2016, which is in accordance with the international guidelines ICH 
E6.  
8.2 Definition of Adverse Event  
According to the ICH, an AE is any unfavorable medical appearance in a patient under clinical 
investigation who is administered a pharmaceutical product, regardless of causal attribution.   
Therefore, an EA can be any of the following: any undesirable medical event that is temporally 
related to the use of a medical product, whether or not it is considered related to such a product; 
any new illness 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 symptoms or that results in a change in study 
treatment or concomitant treatment or discontinuation of study medication.  
8.3 Definitions relevant to the classification of adverse events  
Severity (serious/non-serious), also called seriousness (serious/not serious). Serious or serious is 
defined as any event that: results in death, threatens life, requires hospitalization or prolongs 
hospitalization, is a cause of permanent or significant disability or disability, is the cause of 
alterations or malformations in the newborn, other medically important conditions.   
Severity (mild, moderate, or severe). Mild is those that present with minimal symptoms, do not 
require treatment or suspension of the medication; moderate, when they interfere with usual 
activities, without threatening the patient's life, require treatment and may or may not require 
discontinuation of the medication; severe, those that interfere with usual activities and require 
pharmacological treatment and discontinuation of the medication.   
Causality. It is the relationship that is assigned between the drug and the AE: certainly caused by 
the drug, there is clear evidence of causality, i.e. the AE reappears with the administration of the 
drug; probably caused by the drug, there is a high suspicion of causality but there is no direct 
evidence or it is considered unnecessary or dangerous, i.e. the reaction disappears when the drug 
is stopped; possibly caused by the drug, there is additional information to suggest that the cause 
may be due to another drug or disease; unlikely to be caused by the drug, there is a clear 
explanation of 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 about the EA has been obtained, it remains unclassifiable.   

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8.4 Responsibilities of the researcher  
It is the responsibility of the Investigator to verify AEs through questioning, review of the 
information recorded in the patient's diary, pertinent physical examination, assessment of 
evolution, as well as appropriate medical and pharmacological management; as well as to follow 
up until the resolution or outcome and definitive discharge of the AE, following the definitions 
determined in national and international regulations. [51] [52] [53]  
In the event of AEs or any event that puts the health and well-being of patients at risk, relevant 
medical care will be provided, either at the research center or referred to the Hospital Center with 
the greatest resolution power with which the research center has a medical care agreement. The 
PI will notify the sponsor's clinical monitor, according to the times established in national and 
international regulations. In the case of serious AEs, it will notify the sponsor and register the 
corresponding information in the FRCE and in turn, inform the IEC and IC.   
The attention of the AEs will be carried out according to the event attention diagram. See Figure 
6 Adverse Event Care.  
The final report to be written by the Clinical Team of the Medical Management Department of 
Laboratorios Sophia, S.A. de C.V., will include the report of the AEs in compliance with current 
national and international regulations. [52] [51]  
If the research patient debuts during their participation in the study with a chronic AE, such as 
diabetes or systemic arterial hypertension, they will be referred to the competent health 
professional for chronic treatment. The follow-up and termination of your participation will be in 
accordance with the stipulations of the ICH.  
 
8.4.1  Record of adverse events in the electronic case report form  
EA registration considers:  
 
−  The patient's identifying information such as: code, age, gender, left eye, right eye.   
−  Information about the type of AE to the PI or the drug under study, as appropriate.  
−  Important date information:  
o Date the EA occurs  
o Date on which the PI becomes aware of it 
o Date of resolution or outcome, as applicable.   
−  Information on diagnosis and clinical management. If a lack of therapeutic response 
to the PI and/or investigational drug is detected, it must be reported as a serious AE 
within the period stipulated by current regulations. Include in concomitant 
medications the therapy used for the pharmacological management of AEs. 

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Record the outcome or resolution of the event:  
o Recovered patient without sequelae 
o Recovered patient with sequelae 
o Patient not recovered  
o Patient who died due to AE  
o Patient who died and it is judged that the drug may have contributed 
o Patient who had death and it is not related to the product or drug under 
investigation,  
o Or indicate that you do not know what the consequence of the event is. 
−  Information about the investigational product or drug or the drug associated with the EA, 
AMR, or SRAM. As applicable, the information concerning the generic name, distinctive name 
or code of the IP and/or investigational drug must be recorded, as appropriate according to 
the methodological design of the study, this is relevant in the case of blinded studies or in 
those where placebo is used as comparators, since there are circumstances that justify the 
opening of the blinded to determine if the AE may be attributable to the active agent.  the 
combination of active agents, or the pharmacologically inert substance(s), such as vehicles or 
additives, as appropriate to the phase of clinical research in which the development of the 
drug is located. It will also be necessary to include the data concerning the batch number, 
manufacturing laboratory, expiration date, dose, route of administration, start and end dates 
of administration and/or consumption, reason for prescription; according to whether it is an 
investigational product or drug (protocol in which the patient currently participates) or is a 
drug that the investigational patient consumes for the treatment of underlying concomitant 
diseases or uses for the management of some transitory sign or symptom that does not 
correspond to the Natural History of the pathology that motivated his or her entry into the 
research protocol.   
−  Indicate the withdrawal or maintenance of the investigational drug, PI, or drug, as 
appropriate. Indicate whether withdrawing the PI or investigational drug or suspected drug 
(of causing the event) makes the EA disappear. Also indicate if a dose adjustment is made, if 
the event changes in terms of intensity or seriousness, persistence of the reaction. It is 
important to indicate whether in those patients who are exposed again to the PI, 
investigational drug or drug, which had previously been discontinued, the AD reappears.   
−  Information regarding concomitant pharmacotherapy. Indicate the generic name, dose, route 
of administration, start and end dates of use, as well as the reason for the prescription, 
regardless of whether it is in accordance with the prescribing information or technical data 
sheet or is used outside the regulations or what has been authorized by the local, national or 
international regulatory entity.  

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−  Relevant medical history information. The analysis of the EA considers the information 
previously narrated, despite the clinical context in which this harmful phenomenon 
occurs in the participants of the clinical research protocol, is of special interest, so the 
information about previous conditions, hypersensitivity or allergy phenomena, 
previous surgical procedures, laboratory analyses or cabinet examinations that have 
been performed on the participant,  etc., that the researcher deems it appropriate to 
mention may do so. 
8.4.2  Adverse Event Tracking  
The PI will provide the attention and management of the EA presented by the participant until 
the outcome of the same, according to what is referred to in the following section.  
8.4.3  Procedures for a serious adverse event  
The AE care process considers the following stages:  
During the development and conduct of this study, undesirable harmful events or adverse 
reactions of medical implication may occur in the investigational patient, which do not necessarily 
have a causal relationship with the PI or investigational drug. These harmful phenomena can occur 
during the use of investigational drugs at doses authorized for use in humans by a local, national 
Figure 6. Adverse event reporting 
  
  
Inform   
Care and treatment  
relevant   
Categorization 
  
Preparation of a medical note 
  
Registration and notification in 
eCRF
  
On-site investigation   
In hospital 1er 3er 
  
level  
  
) 
if required 
( 
  
   
By  denouemen
  
Serious/Not   
By severity:   
Mild, moderate, or severe 
  
Physical examination 
evaluation of the EA 
  
EA not serious   
AE serious   
Track the  
EA to his  
denoueme
  
End   
+  Report, within 24 hours  
of their knowledge to the  
sponsor 
  
+  Track the EA up to  
Its outcome   
+  Reporting to the 
  
Notify to:   
+  Pharmacologist  
Clinical Safety   
+  Unit of  
Pharmacovigilance 
  
End   

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or international regulatory entity. However, it may be suspected that the PI or the investigational 
drug causes some unwanted clinical manifestation. AEs, ADRs or SRAMs to one or more 
medications can occur during the systematic evaluation of the participants (on the days when the 
clinical review is scheduled, according to the schedule of activities) or suddenly, in such a way that:  
1. The investigator must be the first person to whom the patient notifies that he or she has 
developed or presented any harmful phenomenon of a clinical nature during his or her 
participation in this study.   
2. According to his clinical judgment, Based on the pertinent physical examination, 
interrogation, etc., as well as the analysis of the information available in the medical 
literature and what is referred to in the Investigator's Manual, Information to prescribe or 
Summary of the Comparator Drug Label, the principal investigator determines the 
pertinent care of the harmful event/reaction.  
3. Such care can be in the research center or in the hospital with the greatest resolution 
power. In such a way that, in the event that the patient is sent by the PI to a hospital, he 
or she attends through a referral system. The referral can be with a card that identifies the 
patient as a study participant and links him or her to the pre-established agreement with 
the institution, or through a medical reference note issued by the PI. Laboratorios Sophia, 
S.A. de C.V., will pay the expenses for the medical care of the participating patient, when 
the EA is associated with or is in relation to the PI or investigational drug.  
4. Taking the clinical information collected, either during the care provided at the research 
center or that provided by the treating physician(s) in the hospital, the PI will record the 
AE in its 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 FRCE and its respective EA section. By, in 
cases of severe AEs, which must be notified in less than 24 hours after the PI becomes 
aware of it, the clinical monitor of the study is informed, so that in turn it informs the 
Clinical Team and the Pharmacovigilance and Technovigilance Unit of Laboratorios Sophia 
(UTFLS), so that it can later inform the CEI. With respect to non-serious AEs, they will be 
registered and treated appropriately, 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  
The recording of the outcome of the AE depends substantially on the follow-up that the PI 
performs on the patient, since it is expected that most of the harmful phenomena (see section of 
the safety profile in the investigator's manual) are ophthalmic in nature, however, there may be 
systemic alterations. Therefore, in the opinion of the researcher, the withdrawal of the participant 
or their permanence will be considered.  
8.4.4  Causation assessment  
Causality assessment is the methodology used to estimate the probability of attributing the 
observed AE to a drug, investigational drug or IP. It considers probabilistic categories according to 
the available evidence and the quality of the information, based on national pharmacovigilance 
regulations. [51]   

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The UFTLS can use the algorithm of Karch and Lasagna modified by Naranjo referred to by 
Aramendi I, as a tool to facilitate the probabilistic categorization of causality. In this algorithm, 
different items are scored, which allow assigning a value to the cause-effect relationship between 
the administration of the drug and the adverse reaction. [54] See Appendix 16.4 Karch and 
Lasagna algorithm modified by Naranjo.  
In such a way, the degree of certainty to establish the PI or investigational drug (as appropriate) as 
the causal agent of the harmful phenomenon that occurs to the patient of the clinical study. It can 
also be indicated directly by the PI based on their clinical experience or through the voluntary 
application of the tool mentioned above. However, it is important for the researcher and the UFTLS 
to consider the following arguments in favor of causation:   
 
a. Strength of association, which refers to the number of cases in relation to those exposed.   
b. The consistency of the data, i.e. the presence of a common characteristic or pattern.   
c. The exposure-effect pattern, which determines the relationship with the site of 
appearance, time, dose and reversibility after deletion.   
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, e.g., the appearance of abnormal metabolites or high levels of the 
drug or its biotransformation product.   
f. Analogy, which refers to the experience gained 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. [55]  
8.5 Unanticipated Issues  
Unanticipated problems (APNs) consider those situations that pose risks to participating patients, 
in general, any incident, experience or outcome that meets all the following criteria:  
• 
Unexpected in terms of its nature, severity, or frequency in relation to 1) study-related 
documents such as the investigator's manual, study protocol, and informed consent form; and 
2) the characteristics of the population being studied.  

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• 
Related or possibly related to your participation in the study (possibly related means that there 
is a reasonable possibility that the incident, or results, was caused by study procedures).  
• 
Indicative that the research places participants at a higher risk of harm (including physical, 
psychological, economic, or social) than previously recognized.  
8.5.1  PNA Report  
The PI will be responsible for reporting NAPs to the sponsor, IC, CEI. The report must contain the 
following information:  
• 
Identification of the study: protocol title and number, name of the PI and, if applicable, of the 
centre.  
• 
Detailed description of the event, incident, experience, or outcome.  
• 
Explanation, justification of the reasons why the incident represents a NAP.  
• 
Description of changes to the protocol or corrective actions taken or proposed in response to 
the NAP.  
NAPs that are SEA must be reported to the IEC and the sponsor within the first 24 hours of the PI 
becoming aware of it.   
Any other NAPs will be reported to the CEI and the sponsor within the first 5 business days after 
the PI became aware of it.  
  
  
 

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9. Study Monitoring  
 
The study sponsor is responsible for monitoring the study. Monitoring activities include, but are 
not limited to general safety monitoring, general study quality monitoring, monitoring by study 
site, detection monitoring, reporting and tracking of AEs, monitoring for resolution of 
discrepancies in data capture, 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.  
9.1 Monitoring of study centers  
The research centers participating in the study will be monitored. For each center, at least one 
start visits and one closing visit must be carried out, which does not exclude the carrying out of 
one or more follow-up visits between these two mandatory visits.  
The initial visit must be carried out before the inclusion of the first participant in that center; In it, 
the monitor will verify that the material to be used during the study has been received and that 
the personnel who will participate in the study activities have been trained on the study, as well 
as verify that the regulatory requirements and applicable standard operating procedures are met.  
At the follow-up visit(s), the monitor will conduct a review of the study documents to confirm that: 
the research protocol has been followed, the applicable standard operating procedures have been 
followed, the data has been completed and timely, and that the AE reports have been carried out 
appropriately. During this visit, the monitor will discuss the findings with the researcher and define 
the actions that should be taken.  
The closure visit will take place at the end of the study, once the last site participant has been 
discharged from follow-up. On this visit the monitor will verify that the site has all the necessary 
documents for archiving, that all biological samples have been sent for analysis, that all the drug 
under study (used and unused) has been recovered and sent to the sponsor, and that all unused 
material has been recovered.  
Details on monitoring are set out in the relevant plan  
9.2 Audit and quality control  
To ensure compliance with GCPs and all applicable regulatory requirements, Laboratorios Sophia, 
S.A. de C.V. may conduct quality assurance audits. Regulatory agencies could also conduct a 
regulatory inspection of this study.  

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Details about the audit process are set out separately in an Audit Plan.  
9.2.1  Pre-study audit  
Study sites included in the study will be patient for a pre-site site feasibility visit, where they will 
be verified to meet the minimum requirements indicated by the sponsor.  
9.2.2  Auditing during the conduct of the study  
They may take place at any time before, during, or after the conclusion of the study. If any audit 
or inspection is conducted, the investigator and the institution shall agree to allow the 
auditor/inspector direct access to all relevant documents and shall allocate their time and that of 
their staff to the auditor/inspector to discuss the findings and any pertinent problems. If the audit 
has not been scheduled by the sponsor, the facility must notify Laboratorios Sophia, S.A. de C.V. 
immediately.  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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10. Statistical analysis  
 
10.1 Data analysis  
10.1.1 Statistical Analysis  
The statistical analysis will be carried out by personnel of Laboratorios Sophia, S.A. de C.V. The SPSS 
statistical package version 19.0 for Windows (IBM Corporation, Armonk, NY, USA) will be used. The 
coding will be done using consecutive numbers. The data will be collected and sorted in an Excel 
spreadsheet (Microsoft® Office). The data will then be exported to the SPSS package platform. The 
variables will be categorized according to their nature. See point 7.4.4 Definition of variables, 
methods and scales to be used for their measurement.  
10.1.2 Data Interpretation  
 The Kolmogorov-Smirnov and Shapiro Wilk tests will be performed, as applicable, to determine if 
the distribution of the data is normal in the results obtained in each study group [56].  
The results of the continuous quantitative variables will be presented in measures of central 
tendency: mean, standard deviation, standard error and/or ranges.   
- 
Intra-group analysis: For equal variances, Tukey's POST-HOC test will be used, otherwise 
the Dunnett statistic will be used. One-way analysis of variance (one-way ANOVA) will be 
used when applicable.   
- 
Intergroup analysis: Differences between groups will be analyzed using the Repeated 
Measures Analysis of Variance (ANOVA) test or the Student's t-statistic when applicable.   
A non-inferiority margin (δ) of 10% will be used for the primary efficacy endpoint, based on the 
primary endpoint of the study. 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.   
The statistical analysis to identify significant differences in the qualitative variables will be carried 
out by creating 2x2 contingency tables and will be carried out as follows:   
- 
Intra-group difference: McNemar test. This is applied to 2×2 contingency tables with a 
dichotomous feature, with pairs of paired subjects, to determine if the marginal 
frequencies of row and column are equal (marginal homogeneity) [7].   

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- 
Difference between groups: Pearson's X2 (Chi-square) test or Fisher's exact test at 
expected values less than 5.   
The level of difference to consider significance will be an alpha (α) of 0.05 or less.   
For the reporting of adverse events, all subjects who were randomly assigned to an intervention 
group after baseline (intention-to-treat population, ITT) will be considered.   
The final report of the results will be shown in tables or graphs, as appropriate.  
  
Variable Type  
Variable  
A1  
B1  B2  C1  D1  D2  D3  D4  
E1  E2  
Background  
 
 
 
 
 
 
 
 
A1  
Demographic  
DT  
  
  
  
  
  
  
  
  
  
Basal  
 
 
 
 
 
 
 
 
B1  
Medical History/Selection Criteria  
DT  
  
  
  
  
  
  
  
  
  
B2  
Comprehensive ophthalmological 
evaluation  
DT  
  
  
  
TB  
T  
T  
T  
TB  
TB  
Efficiency  
C1  
OSDI  
DB  
  
  
B  
  
  
  
  
TB  
  
Secondary efficacy outcome  
D1  
TRLNI  
  
  
  
DB  
B  
  
  
  
TB  
  
D2  
Corneal and conjunctival stains (TVL 
and TF)  
  
DT  DT  
  
  
TB  
  
  
TB  
  
D3  
Conjunctival Hyperemia  
  
DT  DT  
  
  
TB  
  
  
TB  
  
D4  
Chemosis  
  
DT  DT  
  
  
TB  
  
  
TB  
  
Safety  
 
 
 
 
 
 
 
 
 
 
E1  
Incidence of AD  
  
  
  
TB  TB  TB  TB  TB  TM  
  
E2  
MAVC  
  
DB  
  
  
  
  
  
  
TM  
B  
D, Descriptive Statistics; T, 2x2 contingency table; B, Bivariate Analysis; M, Multivariate Analysis.  
 
 
Table 3. Triangulation of concepts 

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10.1.3 Procedure for handling missing data  
The safety assessment will include in the analysis all those patients (both eyes) who have been 
exposed at least once to the intervention, regardless of the visit at which they were eliminated 
from the study (ITT).  
10.1.4 Deviations from the statistical analysis plan  
According to the calculation of the sample size to meet the objective of the study, 50 evaluable 
patients are required per arm. If this number is not met due to a loss of patients greater than 20% 
contemplated in this protocol (loss of follow-up or withdrawal of ICF), the sponsor may replace 
these patients.  
The results obtained from the replaced patients will continue to be used for safety analysis and 
will be part of the ITT.  
10.1.5 Patients included in the analysis  
Those patients who meet an adherence ≥65% of the expected weight of the PI and ≥80% of 
expected applications in the patient's diary, will be included in the statistical analysis to meet the 
objective of the study. If it is not possible to assess the weight of the IP, only the patient's diary will 
be considered.   
10.2 Sample Size Calculation  
10.2.1 N Calculated  
Number of planned patients: 60 evaluable patients (both eyes) per arm  
Total N = 180 patients  
10.2.2 Justification for sample calculation  
Sample size calculation was performed based on the results of the phase IV, multicenter, 
prospective, double-blind, randomized efficacy and safety clinical study of Humylub Ofteno® PF 
ophthalmic solution, versus Systane® Ultra and Systane® Ultra preservative free performed in 
subjects diagnosed with mild to moderate dry eye. The reduction in the mean score of the OSDI 
test was considered as the main efficacy variable, with a dosage of 1 drop QID. In this study, after 
one month of treatment, subjects assigned to Humylub Ofteno® PF had a decrease of -49.3% vs -
41.3% for Systane Ultra and -48.3% for Systane Ultra PF, with respect to their initial mean values 
with no statistical differences between treatments (p>0.05) [57].  
For the present protocol, it is expected that, after 3 days of treatment, 30% of subjects treated 
with Humylub Ofteno® PF will have a 35% decrease in OSDI score compared to their initial mean 
value.   
 

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The sample size was calculated using the equation for two proportions [58], considering a power 
of 80% (β), a significance level of 0.05 (α) and a margin of non-inferiority (δ) of 10% and based on 
the following working hypotheses:   
H0: PA − PB ≤ δ 
H1: PA − PB > δ 
  Where, δ is the margin of non-inferiority and, the ratio between the sample size of the two groups 
is:   
𝑘= 𝜂𝐴
𝜂𝐵 
Equations   
The calculation to estimate sample size and power was performed using an online tool and 
following the equations: [59]  
 
 
 
 
k=nA/nB 
Φ is the standard normal distribution function 
Φ -1 is the standard normal quantile function 
α is a Type I error, 
β is the Type II error, which means that 1-β is the power, and 
δ is the test margin. 
According to the previous calculation, the result was 50 subjects, this calculation was increased by 
20% considering possible losses (10 subjects). The total suggested sample size is 180 subjects  
(60 cases per arm), which will provide both eyes for the study.    
 
 
 
 

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11. Ethical considerations  
 
11.1 Approval of the committees  
This study will be conducted in accordance with the standards of the Declaration of Helsinki, World 
Medical Association 2013. Nuremberg Code; Nuremberg Trial by the International Tribunal of 
Nuremberg, 1947. Belmont Report, National Commission for the Protection of Biomedical and 
Behavioral Research Subjects, 1979. It will be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicines for human use of the ICH, GCP 
Guide. Council for International Organizations of Medical Sciences (CIOMS, 2016) International 
Ethical Guidelines for Biomedical Research in Human Subjects. The Research Ethics Committee 
and the Research Committee will evaluate the protocol before conducting the study and will issue 
their approval or possible modifications for its performance, these Committees must be notified 
of any significant changes to the protocol. In addition to the above, the current regulations of the 
regulatory authority will also be complied with.  
Personnel authorized by the sponsor will submit to evaluation by the Research Ethics Committees, 
Research Committees, and when applicable to the Biosafety Committee the essential 
documentation of the research project: research protocol, letter of informed consent, 
investigator's manual, patient diary and patient material, as well as other additionally requested 
documents,  in accordance with the local, national or international requirements applicable by the 
regulatory entities.   
The study will not begin at the research center if there are no confidentiality agreements and 
economic proposal from each of the principal investigators, duly signed and without having 
previously obtained the favorable opinion and/or approval of the Research Ethics Committees, 
Research Committees, and when applicable by the Biosafety Committee.  Corresponding.   
The study will not begin without having complied with the relevant local, national or international 
regulatory requirements and without having the corresponding health authorization.  
The study is a study with greater than the minimum risk, according to  
Regulations of the General Health Law on Health Research, Title Two, Chapter I, Article 17, Section 
III, published in the Official Gazette of January 6, 1987.  
11.2 Amendments to the protocol  
The amendment procedure will be relevant when there is a need to make any change to a 
document that is part of the research project or protocol, derived from variations in the 
methodological structure, substitution of the principal investigator or in the face of the 
identification of risks in the patients who will participate in the research. The documents that can 

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be amended will be protocol, letter of informed consent, investigator's manual, documents for the 
patient, measurement scales and schedule of activities.  
Any amendment must be approved by the sponsor and/or the principal investigator, the amended 
document(s), once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, where applicable, by the Biosafety Committee, (entities that issued the initial 
favorable opinion for the conduct of the research) will be sent for authorization by the relevant 
regulatory entity.   
Amendments that substantially modify the protocol, confer an additional or different risk on 
patients, must be approved by the Committees. It is the investigator's responsibility to act in 
situations that require immediate action to avoid unnecessary harm to study participants.  
The principal investigator is responsible for communicating to the Research Ethics Committee any 
amendments to the protocol that may eventually affect the rights, safety, or welfare of research 
participants. Likewise, it must inform of any situation or new knowledge that will show a greater 
risk for the participants, the premature termination or suspension of the study, the reasons and 
the results obtained so far. It must also report on the conclusion of the study, upon completion of 
the research protocol.  
11.3 Early Study Termination  
The study may be suspended or terminated prematurely if there is a sufficiently reasonable cause. 
Written notice, documenting the reason for the suspension or early termination, shall be delivered 
by the party enforcing the suspension. The PI should promptly inform the study participants, the 
IC, and the IRC providing the reasons.   
Situations in which study suspension or early termination will be contemplated include, but are 
not limited to:  
1. 
Presence of serious AEs in more than 10% of participants in a study group.  
2. 
The regulatory authority (COFEPRIS) considered it for security alerts.  
3. 
The Sponsor determined it for your convenience or eventualities such as:  
economic support, manufacturing errors, etc.  
4. 
Lower recruitment than stipulated.  
5. 
Identification of unexpected risks to participants, which are significant or 
unacceptable.  
6. 
Obtaining new relevant safety information.  
7. 
Insufficient adherence to the requirements of the protocol.  
8. 
The data obtained are not assessable or are not sufficiently complete.  
9. 
Determination that the primary objective has been achieved.  

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10. 
Determination of futility.  
In the event of suspension, the study may be resumed once the situations that led to the 
suspension have been corrected; if this justification is sufficient for the sponsor, CI, CEI and 
regulatory authorities.  
11.4 Informed Consent  
The FCI contains complete and understandable information about the study and the product 
under investigation, in accordance with the applicable regulations in force and the GCP.   
The FCI will be considered as 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 are submitted 
to appropriate approvals (the same as the original informed consent letter was submitted to) and 
that the most current approved version is presented to patients.  
11.4.1 Obtaining   
Informed consent must be obtained before the patient undergoes any procedure indicated in the 
protocol. For this purpose, the letter of informed consent must be signed.  
Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guide to GCPs and will be following all applicable laws and 
regulations.  
The PI will provide the prospective participant with all the information regarding the characteristics 
of the study, its potential benefits, risks, objectives and procedures.  
This information will be in a language understandable to the patient, it will be explained to the 
patient that he or she has the right to interrupt his or her participation in the study at any stage, 
without affecting the relationship with the investigator and/or his or her future care. Informed 
consent will be put to the consideration of the potential participant; He must have enough time 
to analyze every one of the aspects mentioned above and in case he has any doubts, it will be 
clarified by the person in charge of obtaining the informed consent.   
Once the participant agrees to participate in the study, he/she must sign and date the letter of 
informed consent in the presence of two witnesses who may or may not be related to the study 
patient, who will participate during the informed consent process and sign guaranteeing that the 
process was carried out prior to any study procedure.  that the information of the study was clearly 
explained, and doubts were clarified if any.  
The PI will also need to sign and date this consent.  
The FCI must be signed in duplicate by all those involved, 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 delegated 
personnel must document the process of obtaining the Informed Consent by means of a detailed 

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medical note, specifying the signed version, the date on which the document was signed and how 
the process was carried out.  
11.4.2 Special considerations  
The procedures that will be performed during the conduct of the study do not pose an additional 
risk that should be considered apart from the procedures listed for informed consent.  
11.4.3 Modifications to informed consent  
Any changes to the FCI constitute 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 the written approval of the Research 
Ethics Committee and the Regulatory Entity (as applicable), except for an amendment that is 
required to eliminate an immediate danger to patients.  
A process of re-consent of each patient affected by the amendment must be carried out under the 
same conditions as those described above, to communicate the new information contained in the 
document to the patient in a timely manner. The patient will be given a signed original of the 
amendment, and the investigator will keep the second original.  
11.5 Confidentiality  
All documents and information provided to the research center by the sponsor are strictly 
confidential. PI expressly agrees that data about your professional and clinical experience, 
provided to the sponsor on paper and stored in electronic form, is solely for use related to your 
activities with the clinical trial sponsor, in accordance with the GCP.   
The investigator 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 if the confidential 
information has not been disclosed to the public by the sponsor.   
The clinical study protocol provided to the investigator may be used by the investigator and his 
team to obtain informed consent from patients for the study. The clinical trial protocol, as well as 
any information taken from it, should not be disclosed to other parties without the written 
permission of the sponsor.   
The researcher will not disclose any information without the prior written consent of Laboratorios 
Sophia, S.A. de C.V., except to the representatives of the Competent Authorities, and only at their 
request. In the latter case, the investigator undertakes to inform Laboratorios Sophia, S.A. de C.V. 
before disclosing the information to these authorities.   
The investigator will fill out and maintain a patient selection record, as well as the identification 
and enrollment list of each of the patients participating in the study. The investigator agrees to 
give on-site access to the auditor and/or representatives of the Competent Authorities. The 
information will be processed in compliance with professional secrecy.  

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All FRCE and communications related to study patients will identify them only by the study patient 
identification number. The information collected in this study will be exchanged between the 
sponsor and the research center and must be treated confidentially. The Health Authority, the CEI, 
the IC, the sponsor, the monitors/auditors and third-party auditors will be the only bodies 
authorized to review the study documentation. If publications arise from this research project, in 
no case will they contain information on the identification of the patients in the study. If the results 
of the study are published, no personal information of patients will be revealed.  
The protection of personal data will be carried out in accordance with the corresponding 
regulations in force.  
11.6 Conflict of interest  
The independence of the conduct of the study and its results from any current or perceived 
external influences is critical. For this reason, any current conflict of interest of any person who 
has a role in the design, conduct, analysis, publication or any aspect of this study will be declared. 
Furthermore, those who have a perceived conflict of interest will be asked to handle it in a manner 
appropriate to their participation in the study.  
11.6.1 Declaration of Interests  
The PI undertakes to make a declaration of financial interests as well as conflict of interest prior to 
the start of the study.  
11.7 Access to Information  
The final database of the study will be the property of Laboratorios Sophia, S.A. de C.V. and its 
access will be restricted. The PI will not have access to it, unless it has prior written authorization 
from the sponsor.  
The information obtained, which is relevant to the safety of the patients participating in the study, 
must be immediately shared with the research center, so that in turn it can be notified to the 
patients of the study.  
11.8 Ancillary and post-study care  
Once the study is completed and the AEs are closed according to section: 8, the sponsor will not 
extend care to the research patient.  
  
  
 

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12. Biosecurity aspects  
 
NO BIOSECURITY IMPLICATIONS  
The present protocol, entitled: "Phase IV non-inferiority clinical study, to compare the efficacy of 
the ophthalmic solution Humylub Ofteno® PF against Hyabak® and Lagricel Ofteno® PF, on the 
ocular surface of patients with mild to moderate dry eye syndrome.", and number: SOPH087-
0120/IV HAS NO BIOSAFETY IMPLICATIONS, since infectious and contagious biological material will 
NOT be used; pathogenic strains of bacteria or parasites; viruses of any kind; radioactive material 
of any kind; genetically modified animals and/or cells and/or plants; toxic, dangerous or explosive 
substances; any other material that puts the health or physical integrity of the research centre 
staff or patients at risk or affects the environment. It is also declared that this project will not carry 
out cell, tissue or organ transplant procedures, or cell therapy, nor will laboratory, farm or wildlife 
animals be used.  
  
  
 

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13. Posting Policy  
 
13.1 Final Report  
Once the statistical analysis is completed, the final report will be written with the results obtained, 
by the Clinical Team of the Medical Management Department of Laboratorios Sophia, S.A. de C.V.  
This report will be prepared following the recommendations of the E3 Step 4 Guide of the ICH.  
13.2 Communication of results  
Regardless of the results of the study, Laboratorios Sophia, S.A. de C.V., is committed to 
communicating the final report of the study to the principal investigators and COFEPRIS. These 
results will also be shared with the research committee and the IRC. It will be the responsibility of 
the PI to communicate to patients.   
Laboratorios Sophia, S.A. de C.V. will always maintain the rights over the publication and disclosure 
of the information contained.  
13.3 Publication of results  
Laboratorios Sophia, S.A. de C.V., acting as the sponsor of the study, assumes full responsibility for 
its function and retains exclusive ownership rights over the results of the study, which it may use 
in any way it deems appropriate.  
The PI undertakes not to publish or communicate data collected from the study, unless there is 
the prior written agreement of Laboratorios Sophia, S.A. de C.V. Any manuscript derived from the 
data obtained with this protocol must be reviewed by the sponsor before any attempt to submit 
it for publication in any scientific journal or congress  
However, if the sponsor is in the process of filing a patent application on the results of the study, 
the sponsor may delay its publication or communication of the results of the study until the date 
of registration or whenever it deems appropriate.  
The assignment of authorship of publications, which is the responsibility of the sponsor, will be 
the prerogative of the latter. However, the express authorization of the people who are invited to 
participate as authors must be obtained. Authors have the right to review the manuscript prior to 
its publication, as well as to issue comments and suggestions in this regard, such comments must 
be delivered within the first 15 calendar days from the date on which the project is received.  
  
  
 

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14.Financing and Insurance  
 
14.1 Compensation to Study Participants  
Patients who participate in the study will not receive financial compensation for their participation 
in the study. However, randomized patients will receive financial support for travel expenses at 
each scheduled visit they attend punctually. Such support, as well as the amount. It will be 
specified in the informed consent letter.  
14.2 Insurance for Study Participants  
Patients participating in the study will sign the informed consent letter, which specifies that 
Laboratorios Sophia, S.A. de C.V. agrees to pay for immediate treatment resulting from injuries or 
illnesses caused by the investigational products until their resolution, according to medical criteria.  
All study participants will be entitled to the coverage of a liability policy, contracted by Laboratorios 
Sophia, S.A de C.V. The information of the policy contracted will be found in the informed consent 
letter. In the event of a medical emergency, the research center must have personnel, material, 
equipment and procedures for its immediate management.  
  
  

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16. Annexes  
 
 
16.1  
OSDI  
OSDI (Ocular Surface Disease Index) 
 
 The OSDI test is a simple test created to establish a severity/classification of dry eye according to its symptoms. Answer the following 
questions by checking the box that best represents your answer: 
  
Subtotal of the answered cells                      
                       
 
 
 
 
 
 
 
Subtotal of the answered cells 
 
 
 
 
 
Over the past week, 
Have you experienced any of 
the following alterations? 
Frequency 
In all  
moment 
Almost 
everywhere 
moment 
50% of the 
time 
Almost 
nowhere  
moment 
In no  
moment 
1. Light sensitivity 
4 
3 
2 
1 
0 
2. Gritty feeling in the eyes 
4 
3 
2 
1 
0 
3. Eye pain 
4 
3 
2 
1 
0 
4. Blurred vision 
4 
3 
2 
1 
0 
5. Poor vision 
4 
3 
2 
1 
0 
Over the past week, 
Have you felt discomfort in 
your eyes with any of the 
following situations? 
Frequency 
In all  
moment 
Almost 
everywhere  
moment 
Almost in  
50% of the  
no  
Time Moment 
In no  
moment 
NA 
10. Wind 
4 
3 
2 
1 
0 
NA 
11. Places with low humidity  
(dry) 
4 
3 
2 
1 
0 
NA 
12. Air-conditioned areas 
4 
3 
2 
1 
0 
NA 
(B) 
SOPH087-0120/IV 
/ 
/ 
Subject's initials: 
Subject No.: 087- ______-_____ 
Directions: 
No. of Study: 
Date:  
Identification card 

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 Sum of A+B+C = 
 
  Subtotal of the answered cells  
 
Number of items answered, do not include responses as NA 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
16.2  
Oxford Scale  
  
Over the past week, 
Have you had eye problems 
that have limited you from 
performing these actions? 
Frequency 
In all  
moment 
Almost 
everywhere 
moment 
50% of the 
time 
Almost 
nowhere  
moment 
In no  
moment 
NA 
6. Read 
4 
3 
2 
1 
0 
NA 
7. Driving at night 
4 
3 
2 
1 
0 
NA 
8. Working with a computer or 
an ATM 
4 
3 
2 
1 
0 
NA 
9. Watch TV 
4 
3 
2 
1 
0 
NA 
(D) 
(C) 
(E) 

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16.3  
Efron's Scale  
  
 
  
  
  
  
  
  
  
  
  
  
  
16.4  
Karch and Lasagna's algorithm modified by Naranjo  
No. 
Question 
Score 
 
Yes 
No 
Equal to or less than panel A   
Equal to or less than panel B,  
greater than the A 
  
Equal to or less than panel C, 
 greater than B 
  
Equal to or less than panel D, 
 greater than C 
  
Equal to or less than panel E,  
greater than D 
  
Larger than panel E   
Normal   0  
Very mild 1   
Mild 2   
Moderate 3   
Severe 4   

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1 
There are conclusive previous reports of adverse drug 
reactions, adverse events, or suspected adverse drug 
reactions. 
+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 
reappeared 
when 
the 
drug/investigational product/investigational drug was 
administered 
+2 
-1 
5 
There are alternative causes that may trigger this 
reaction. 
-1 
+2 
6 
The 
adverse 
reaction/adverse 
event/suspected 
adverse drug reaction occurred after administration 
of placebo. 
-1 
+1 
7 
The drug was detected in the 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 lower 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 by some 
objective evidence 
+1 
0 
 
Total score   
Probabilistic category based on the score obtained 
I 
The causal relationship is verified. 
≥ 9 
II 
The RAM is likely due to the investigational drug or 
product. 
5 to 8 
III 
It is possible that the RAM is due to the investigational 
drug or product. 
1 to 4 
IV 
The causal relationship is questionable. 
0 
Each reagent receives a defined score, and the final sum allows for an estimate of 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