Clinical Study to Evaluate the Safety of the Viscoelastic Substance PRO-149 When Used as a Device During Phacoemulsification and Intraocular Lens Implantation in Patients With Age-related Cataract, Compared to Healon® EndoCoat.
Phase: NA
Conditions: Age-related Cataract, Phacoemulsification
Sponsor: Laboratorios Sophia S.A de C.V.

Sophia Laboratories, SA de CV  
 
Study No: SOPH149-0220/I 
Version 1.0 
February 25, 2020 
Page1 de 67 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol: 
 SOPH149-0220/I 
 
Proposed title for the study: Clinical study to evaluate the safety of the viscoelastic 
solution PRO-149 when used as an ophthalmic viscosurgical device during 
phacoemulsification surgery and intraocular lens placement in subjects 
diagnosed with senile cataracts, compared to Healon® EndoCoat 
Information on the molecule under study  
Generic name: Sodium hyaluronate 3% 
Indication: Surgical medical device for use in patients undergoing 
anterior segment ophthalmic surgery. 
Protocol information  
Development phase: Pilot 
Version: 2.0 
Version date: 02-oct-20 
This protocol has been developed in accordance with the principles 
of the Declaration of Helsinki and will be carried out in accordance 
with Good Clinical Practices and in compliance with ICH guidelines 
and current local legislation 
Sponsor: Laboratorios Sophia, S.A de C.V  

  
 
 
 
Page intentionally left blank

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 1 of 66 
CONFIDENTIAL 
Changelog 
Changes from version 1.0 dated February 25, 2020, to version 2.0 dated October 2, 2020: 
1. Cover. – Updated date and version number. 
2. Change History. – The Change History sheet has been added. 
3. Headers. – Updated version number and date. 
4. Contents and index of tables and figures. – Updated. 
5. Study Manager and Sponsor Signature Pages. – The name of the Operations Manager has been 
changed. 
6. Summary of protocol SOPH149-0220/I. – The statistical methodology has been modified, and the 
protocol version number and date have been updated. 
7. Illustration 1.- The name of illustration 1 is changed to figure 3. 
8. Investigational Product Safety (Section 2.2.2). - A list of incidents or adverse reactions reported 
with sodium hyaluronate viscoelastic agents has been added. 
9. Randomization and blinding (section 7.3). – It is added that the groups have the same probability 
of being assigned to one treatment or another and that randomization is performed by a third 
party using a list of random numbers. 
10. Definition of variables, methods, and scales to be used for measurement (section 7.4.4). – The 
Student’s t-test can also be used on variables that were previously evaluated with Mann-
Whitney’s U test. 
11. Adverse events (section 7.4.4.3). – The fifth paragraph, which mentions expected adverse events, 
has been amended because it described adverse events expected for a topically applied product, 
not a viscoelastic device. The new text describes adverse events (including incidents and adverse 
events) reported with the use of viscoelastic medical devices. 
12. Evaluation and management of adverse events and incidents (section 8). – In all texts derived 
from section 8, the word "drug" could be replaced with "product," "investigational product," 
"medical device," "device," "pharmaceutical product," or continued with the name "drug," 
depending on the best option. Also, in some sections of the texts where the abbreviations for 
"Principal Investigator," "adverse event," "adverse reactions," "suspected adverse drug 
reactions," or "investigational product" were used, the decision was made to remove the 
abbreviations to improve the wording. 
13. Regulation and standards for adverse events and incidents (section 8.1). – The following text has 
been amended: The recording and reporting of adverse events and incidents will be carried out 
in accordance with the guidelines established in NOM-240-SSA1-2012, NOM-220-SSA1-2016, and 
the international ICH E6 guidelines.  
14. Definition of adverse event, incident, adverse incident, and adverse effect (section 8.2). – The 
definition of incident, adverse incident, and adverse effect has been added (the previous version 
only included the definition of adverse event). 
15. Use of adverse events as a study safety variable (section 8.3). - This section is created to explain 
the importance of assessing adverse events in the study. 
16. Adverse event registration in the electronic case report form (section 8.5.1) – If a lack of 
therapeutic response to the investigational products is detected, it must be reported as a serious 
adverse event within the timeframe stipulated by current regulations, has been eliminated. The 
therapy used for the pharmacological management of the adverse event must be included among 
concomitant medications. The removal of the previous paragraph is because the investigational 
product is a medical device with no direct pharmacological effect and is for temporary use, which 
makes it impossible to evaluate a therapeutic response. The evaluation of the therapy used for 
the pharmacological management of the adverse event is included in the previous line. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 2 of 66 
CONFIDENTIAL 
Also, in this section, the texts are modified to improve their writing. 
17. Procedures for a serious adverse event (section 8.5.3). – In Figure 4, the Clinical Safety 
Pharmacologist is removed, and the Study Director and Protocol Author are added. 
18. Causality assessment (section 8.5.4). – The Karch-Lasagne algorithm modified by Naranjo is 
eliminated, and the causality categories described by the Uppsala Monitoring Centre are 
introduced to categorize the probability of adverse events related to concomitant and 
experimental treatment. 
The following 3 paragraphs are added: 
An adverse event may or may not be related to the clinical study. A causal relationship 
means that the intervention caused (or is reasonably likely to have caused) the adverse 
event. This usually involves a relationship between the timing of the intervention and the 
adverse event (for example, the adverse event occurred shortly after the research subject 
received the intervention). 
For all adverse events, the Principal Investigator is responsible for examining and 
evaluating the patient to determine the association of the event with the clinical study 
and intervention, whether related to experimental treatment, concomitant treatment, 
surgical procedure, or diagnostic procedures performed during the study. 
Accepting that the adverse event is related to the clinical study requires a plausible 
mechanism of action, that is, a logical sequence between the event and the intervention 
that caused it. In some cases, it is helpful to know the opinions of other physicians directly 
or indirectly involved in the study, as well as whether the patient believes there is a 
relationship. 
19. Data interpretation (section 10.1.2). – It is added that: 
If the normality of the data is observed (p > 0.05; for KS and SW), the statistical analysis of the 
continuous quantitative variables to find significant differences (p) will be as follows: 
• Intra-group analysis: will be determined using the Student’s t-test for repeated 
measures. 
• Between-group analysis: differences between groups will be analyzed using Student's 
t-test for independent groups. 
For p < 0.05 in KS and SW, the statistical analysis of continuous quantitative variables to find 
significant differences (p) will be as follows: 
• Intra-group analysis: will be determined using the Wilcoxon rank test. 
• Between-group analysis: differences between groups will be analyzed using the Mann-
Whitney U statistic. 
The level of difference to consider significance will be an alpha (α) of 0.05 or less. 
20. References. – References 38 from version 1 have been removed, and 5 new references have 
been added. 
21. Throughout the document, full stops are added to some lines where they were omitted in the 
paragraphs, and the section titles are standardized. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 3 of 66 
CONFIDENTIAL 
Content 
Changelog  ..................................................................................................................................................... 1 
Contents  ....................................................................................................................................................... 3 
Index of charts, tables and figures  ............................................................................................................... 6 
Those responsible for study  ......................................................................................................................... 7 
Signature Page  ............................................................................................................................................. 8 
From sponsor  ........................................................................................................................................... 8 
Researcher Agreement  ............................................................................................................................ 9 
List of abbreviations  ................................................................................................................................... 10 
1.  Summary of protocol SOPH149-0220/I  ............................................................................................. 11 
1.1 Synopsis  ............................................................................................................................................ 11 
1.2 Study diagram  .................................................................................................................................. 15 
1.3 Study schedule  ................................................................................................................................. 16 
2.  Introduction and Background  ............................................................................................................ 17 
2.1 Theoretical framework  ..................................................................................................................... 17 
2.1.1 Ophthalmic viscosurgical devices  ............................................................................................. 17 
2.1.2 Waterfalls  .................................................................................................................................. 19 
2.2 Background on the product under study  ......................................................................................... 20 
2.2.1 Product efficacy under investigation  ........................................................................................ 21 
2.2.2 Investigational Product Safety  .................................................................................................. 21 
2.2.3 Summary of the pharmaceutical development of the investigational product  ....................... 21 
23 Background on the research  ............................................................................................................. 22 
2.3.1 From research question  ............................................................................................................ 22 
2.4 Risk benefit assessment  ................................................................................................................... 22 
2.4.1 Known potential risks  ............................................................................................................... 22 
2.4.2 Known potential benefits .......................................................................................................... 22 
2.5 Problem statement  .......................................................................................................................... 22 
2.6 Justification  ...................................................................................................................................... 23 
3.  Objectives and hypotheses  ................................................................................................................ 24 
3.1 Primary objectives  ........................................................................................................................... 24 
3.2 Specific objectives  ............................................................................................................................ 24 
3.3 Secondary objectives  ....................................................................................................................... 24 
3.4 Exploratory objectives  ..................................................................................................................... 24 
3.5 Hypothesis  ....................................................................................................................................... 24 
4.  Study design  ....................................................................................................................................... 25 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 4 of 66 
CONFIDENTIAL 
4.1 Design Overview  .............................................................................................................................. 25 
4.2 Justification of the study design  ...................................................................................................... 25 
4.3 Expected duration  ............................................................................................................................ 25 
5.  Study population  ................................................................................................................................ 26 
5.1 Eligibility Criteria  .............................................................................................................................. 26 
5.1.1 Inclusion criteria ........................................................................................................................ 26 
5.1.2 Exclusion criteria  ....................................................................................................................... 26 
5.2 Criteria for elimination and/or substitution of subjects  .................................................................. 26 
5.2.1 Elimination criteria  .................................................................................................................... 27 
5.2.2 Subject substitution  .................................................................................................................. 27 
5.3 Scrutiny failures  ............................................................................................................................... 27 
5.4 Recruitment and retention strategies  ............................................................................................. 27 
5.5 Procedure in case of early discontinuation  ..................................................................................... 28 
5.6 Identification of subject  ................................................................................................................... 28 
6.  Investigational Product  ...................................................................................................................... 30 
6.1 Managed products  ........................................................................................................................... 30 
6.1.1 Investigational Product  ............................................................................................................. 30 
6.1.2 Reference product  .................................................................................................................... 30 
6.1.3 Dosage of investigational products  .......................................................................................... 30 
6.1.4 Concomitant treatment  ............................................................................................................ 30 
6.2 Storage and handling of investigational products at the study center  ........................................... 31 
6.3 Concomitant treatments and medications (permitted and prohibited)  ......................................... 31 
6.4 Procedure for monitoring and measuring adherence  ..................................................................... 32 
6.5 Strategies to improve adherence  .................................................................................................... 33 
7.  Methods and procedures of the study  .............................................................................................. 34 
7.1 Research Center  ............................................................................................................................... 34 
7.2 Clinical Study Registration  ............................................................................................................... 34 
7.3 Randomization and blinding  ............................................................................................................ 34 
7.4 Outcome variables  ........................................................................................................................... 35 
7.4.1 Primary outcome variables  ....................................................................................................... 35 
7.4.2 Secondary outcome variables  ................................................................................................... 35 
7.4.3 Exploratory outcome variable  .................................................................................................. 35 
7.4.4 Definition of variables, methods and scales to be used for their measurement  ..................... 35 
7.5 Program of visits and activities of study  .......................................................................................... 39 
7.5.1 Description of activities per visit  ............................................................................................... 39 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 5 of 66 
CONFIDENTIAL 
7.5.2 Unscheduled follow-up visits  .................................................................................................... 42 
7.6 Data collection  ................................................................................................................................. 42 
7.6.1 Source documents  .................................................................................................................... 42 
7.6.2 Electronic forms of data collection  ........................................................................................... 42 
7.6.3 File  ............................................................................................................................................. 42 
8.  Evaluation and management of adverse events and incidents  ......................................................... 43 
8.1 Regulation and standards on adverse events and incidents  ........................................................... 43 
8.2 Definition of adverse event, incident, adverse incident and adverse effect  ................................... 43 
8.3 Use of adverse events as a safety variable of the study  .................................................................. 43 
8.4 Definitions relevant to the classification of adverse events  ............................................................ 44 
8.5 Researcher Responsibilities  ............................................................................................................. 44 
8.5.1 Recording of adverse events in the electronic case report form  ............................................. 44 
8.5.2 Adverse event monitoring  ........................................................................................................ 46 
8.5.3 Procedures for a serious adverse event  ................................................................................... 46 
8.5.4 Causality Assessment  ................................................................................................................ 47 
8.6 Unanticipated Problems  .................................................................................................................. 49 
8.6.1 PNAs Report  .............................................................................................................................. 49 
9.  Study monitoring ................................................................................................................................ 50 
9.1 Monitoring of study centers  ............................................................................................................ 50 
9.2 Audit and quality control  ................................................................................................................. 50 
9.2.1 Pre-study audit  .......................................................................................................................... 50 
9.2.2 Audit during the conduct of study  ............................................................................................ 50 
10.  
Statistical analysis  .......................................................................................................................... 51 
10.1 Data Analysis  .................................................................................................................................. 51 
10.1.1 Statistical analysis  ................................................................................................................... 51 
10.1.2 Data interpretation  ................................................................................................................. 51 
10.1.3 Procedure for handling missing data  ...................................................................................... 52 
10.1.4 Deviations from the statistical analysis plan  ........................................................................... 52 
10.1.5 Subjects included in the analysis  ............................................................................................ 52 
10.2 Sample size calculation  .................................................................................................................. 52 
10.2.1 Number of subjects calculated  ............................................................................................... 52 
10.2.2 Justification of the sample calculation  .................................................................................... 52 
11.  
Ethical considerations  .................................................................................................................... 54 
11.1 Approval of committees  ................................................................................................................. 54 
11.2 Amendments to Protocol  ............................................................................................................... 54 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 6 of 66 
CONFIDENTIAL 
11.3 Early termination of the study  ....................................................................................................... 55 
11.4 Informed consent ........................................................................................................................... 55 
11.4.1 Obtaining ................................................................................................................................. 55 
11.4.2 Special Considerations  ............................................................................................................ 56 
11.4.3 Modifications to informed consent  ........................................................................................ 56 
11.5 Confidentiality  ................................................................................................................................ 56 
11.6 Conflict of interest  ......................................................................................................................... 57 
11.6.1 Declaration of interests  .......................................................................................................... 57 
11.7 Access to information  .................................................................................................................... 57 
11.8 Ancillary and post-study care  ......................................................................................................... 58 
12.  
Biosecurity aspects  ......................................................................................................................... 59 
13.  
Publication Policy  ........................................................................................................................... 60 
13.1 Final Report  .................................................................................................................................... 60 
13.2 Communication of results  .............................................................................................................. 60 
13.3 Publication of results  ..................................................................................................................... 60 
14.  
Financing and insurance ................................................................................................................. 61 
14.1 Compensation to study participants  .............................................................................................. 61 
14.2 Insurance for study participants  .................................................................................................... 61 
15.  
Annexes  .......................................................................................................................................... 62 
15.1 Performance evaluation of OVD  .................................................................................................... 62 
References  ................................................................................................................................................. 63 
 
Index of tables, charts and figures 
Table 1. Study managers......................................................................................................7 
Table 2. Desirable properties of OVDs during phacoemulsification……................................ 19 
Table 3. Operational definition of variables.................................................................................... 36 
Table 4. Scale for anterior chamber cellularity................................................................................ 39 
Table 5. Flare scale...................................................................................................................... 39 
 
Figure 1. Administrative structure...................................................................................................... 7 
Figure 2. Types of fluid behavior................................................................................................ 19 
Figure 3. Lens Opacities Classification System III (LOCS III) ……………………………………………………………. 20 
Figure 4. Adverse event care....................................................................................................... 48 
  
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 7 of 66 
CONFIDENTIAL 
Study leaders 
The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia, S.A. de C.V., 
is shown in Table 1. Study managers. 
Table 1. Study leaders  
Function 
Name/Contact 
Membership ¥  
Medical director of 
the study 
 
Medical Director 
Clinical director of the 
study 
Medical Manager 
Operations Manager 
Regional Clinical Research 
Manager 
Author of the Protocol 
Medical Editor 
Head of Biostatistics 
Biostatistics Manager 
¥ Employees of Laboratorios Sophia, S.A. de C.V., Av. Paseo del Norte No. 5255, Col. Guadalajara Technology Park, Guadalajara-Nogales 
Highway Km 13.5 CP 45010 Zapopan, Jalisco, Mexico Tel +52(33) 3000 4200  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Administrative structure 
Project 
leader 
Clinical 
research 
associate 
Medical director of 
the study 
Startup 
specialist 
Logistics 
coordinator 
Logistics 
assistant 
Operations 
Manager 
Clinical director of 
the study 
Clinical 
development 
team 
Medical writer 
Head of 
Biostatistics 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 8 of 66 
CONFIDENTIAL 
Signature page 
From the sponsor  
Name:  
 
Qualification:  
Medical director of the study  
 
Signature 
  
Date 
  
Name:  
  
Qualification:  
Clinical director of the study  
 
Signature 
  
Date 
  
Name:  
  
Qualification:  
Operations Manager  
 
Signature 
  
Date 
  
Name:  
  
Qualification:  
Author of the Protocol  
 
Signature 
  
Date 
 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 9 of 66 
CONFIDENTIAL 
Researcher Agreement  
  
I agree to conduct this clinical study according to the design and guidelines of this protocol, adhering 
to its provisions. I declare that I will conduct the study in accordance with the standards of Good 
Clinical Practice and will report all information and data as indicated in the protocol, particularly any 
adverse events. I will also manage clinical supplies provided by the sponsor strictly in accordance with 
this protocol. I understand that the information that identifies me may be used by the sponsor. 
Because the information contained in this protocol and the Investigator's Manual is confidential, I 
understand that sharing it with any third party not involved in the approval, supervision, or conduct 
of the study is prohibited. I will ensure that necessary precautions are taken to protect the 
information from loss, inadvertent disclosure, or access by unauthorized third parties. 
 
Name:  
[Write the full name of the 
researcher] 
Qualification:  
Principal Investigator 
Name of the center: 
[Write name of study center] 
Geographic location (city/state/country) 
[Write the geographic data of the center] 
 
Signature 
  
Date 
  
  
  
  
 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 10 of 66 
CONFIDENTIAL 
List of abbreviations 
VA 
Visual Acuity 
BCVA 
Best Corrected Visual Acuity 
CBC 
Complete blood count 
AC 
Anterior chamber 
CCC 
Continuous circular capsulorhexis 
CEC 
Corneal endothelial cells 
COFEPRIS 
Federal Commission for the Protection against Sanitary Risks (COFEPRIS due 
to its abbreviation in Spanish, Comisión Federal para la Protección contra 
Riesgos Sanitarios). 
OVD 
Ophthalmic viscosurgical device 
OVDs 
Ophthalmic viscosurgical devices 
AE 
Adverse event 
AEs 
Adverse events 
eCRF  
electronic Case Report Form 
ECG 
Electrocardiogram 
ICF 
Informed consent form 
HPMC 
Hydroxypropyl methylcellulose 
SH 
Sodium hyaluronate 
I/A 
Irrigation/aspiration 
INR 
International Normalized Ratio 
PI 
Principal Investigator 
IWRS 
Integrated web response system  
IOL 
Intraocular lens 
IP 
Investigational product 
IOP 
Intraocular pressure 
UAP 
Unanticipated problems 
BC 
Blood chemistry 
RNEC 
National Registry of Clinical Trials (RNEC due to its abbreviation in Spanish, 
Registro Nacional de Estudios Clínicos). 
CS 
Chondroitin sulfate 
BSS 
Balanced salt solution 
PT/PTT 
Prothrombin time/partial thromboplastin time 
KS 
Kolmogorov-Smirnov 
SW 
Shapiro-Wilk 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 11 of 66 
CONFIDENTIAL 
1. Summary of protocol SOPH149-0220/I 
1.1 Synopsis 
Title of the study: 
Clinical study to evaluate the safety of the viscoelastic solution PRO-149 when used as an 
ophthalmic viscosurgical device during phacoemulsification surgery and intraocular lens 
placement in subjects diagnosed with senile cataracts, compared to Healon® EndoCoat  
Protocol code: 
SOPH149-0220/I 
Creation date: 
February 25, 2020 
Protocol version: 
2.0 
Version date: 
October 2, 2020 
 
Therapeutic indication: 
Ophthalmic 
viscosurgical 
device 
(OVD) 
indicated in the ophthalmic surgery of the 
anterior segment. 
Use: 
Intraocular surgery of the anterior segment, 
including: 
• 
Cataract surgery with intraocular lens 
implantation. 
• 
Cataract surgery without intraocular 
lens implantation. 
• 
Secondary 
intraocular 
lens 
implantation. 
Estimated duration of the study (from the first 
visit of the first patient to the preparation of 
the final report): 
7 months 
Development phase: 
Pilot 
Aim: 
To evaluate the safety of PRO-149, manufactured by Laboratorios Sophia, S.A. de C.V., when used 
as an OVD during phacoemulsification surgery and intraocular lens (IOL) placement in patients 
diagnosed with senile cataracts, compared to Healon® EndoCoat. 
Hypothesis: 
H1: PRO-149 viscoelastic solution is equivalent in safety to Healon® EndoCoat for use as an OVD in 
phacoemulsification surgery and IOL placement in patients with senile cataracts. 
H0: PRO-149 viscoelastic solution is not equivalent in safety to Healon® EndoCoat for use as an 
OVD in phacoemulsification surgery and IOL placement in patients with senile cataract. 
 
Study design: 
Pilot, controlled, parallel-group, open-label, randomized clinical trial. 
Number of subjects: 
n = 36 evaluable subjects. 
Main inclusion criteria: 
Senile cataract. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 12 of 66 
CONFIDENTIAL 
18 evaluable subjects per group (one eye per 
subject) (2 groups). 
Selection criteria: 
Inclusion criteria: 
▪ 
Age equal to or greater than 49 years. 
▪ 
Diagnosis of age-related cataract (senile cataract) requiring cataract phacoemulsification 
surgery and placement of a monofocal intraocular lens. 
Grade I to IV cataracts based on nuclear opacity (opalescence and/or color) of the lens 
opacity classification system (LOCS III). 
▪ 
Ability to voluntarily grant informed consent. 
▪ 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
▪ 
Desire and willingness to undergo phacoemulsification surgery and placement of a 
monofocal IOL. 
▪ 
Have an anterior chamber depth ≥ 2.8 mm as measured by IOL Master. 
▪ 
Preoperative cardiology evaluation that qualifies the patient for the surgical procedure, 
with supporting laboratory studies: complete blood count (CBC), three-element blood 
chemistry (BC), coagulation times (PT/PTT, INR), and electrocardiogram (ECG). If a prior 
evaluation is available, it must not be performed more than 45 days prior to signing the 
informed consent form (ICF). 
Exclusion criteria: 
▪ 
History of any systemic disease or condition that makes you ineligible for the surgical 
procedure under sedation and topical anesthesia. 
▪ 
Diabetes mellitus with A1C ≥ 6.5% (48 mmol/mol) or fasting glucose (no caloric intake for 
≥ 8 hours) of ≥ 126 mg/ dL (7.0 mmol/L) 
▪ 
Uncontrolled systemic hypertension. Defined as blood pressure greater than 140/90 
mmHg with the use of three antihypertensives (one of which is a diuretic) at the 
maximum dose. 
▪ 
Have a history of eye diseases that could limit the best corrected visual acuity, or be 
reactivated and/or exacerbated by the surgical procedure or by the use of topical steroids 
(e.g. retinal detachment, macular degeneration, pathological myopia, proliferative 
diabetic retinopathy, diabetic macular edema, optic neuritis, uveitis or other types of 
ocular inflammation, glaucoma, ocular hypertension, corneal dystrophy or ectatic 
disorder, history of an ocular infection by herpes or varicella zoster). 
▪ 
Active eye infection. 
▪ 
Pseudo exfoliation syndrome in the eye to be operated on or other type of zonular 
involvement. 
▪ 
Pharmacological mydriasis less than 6 mm. 
▪ 
Any congenital ocular anomaly in the eye to be operated on. 
▪ 
Any ocular abnormality that prevents obtaining a reliable Goldmann tonometry in the 
eye to be operated on. 
▪ 
An intraocular pressure (IOP) >21 mmHg in the eye to be operated on, or a history of 
intraocular pressure >21 mmHg with the use of topical steroids. 
▪ 
A corneal endothelial cell (CEC) density < 1500 cells/mm 2 in the eye to be operated on. 
▪ 
History of previous corneal or intraocular surgery. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 13 of 66 
CONFIDENTIAL 
▪ 
Having multiple procedures planned during cataract surgery (i.e., trabeculectomy, 
relaxing keratotomies, etc.). 
▪ 
History of ocular trauma in the eye to be operated on (includes surgical procedures). 
▪ 
Having a one single evaluable eye. 
▪ 
Having participated in another clinical research study ≤ 30 days prior to signing the ICF. 
▪ 
Having previously participated in this study. 
▪ 
A history of drug addiction or drug dependence, currently or within the last two years 
prior to signing the ICF. 
▪ 
A history of ocular surgical procedures within the last 3 months prior to signing the ICF. 
▪ 
Any type of surgical intervention scheduled during the study period. 
▪ 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is a member of the research site or sponsor staff. 
Investigational products: 
Investigational product, dosage and route of administration: 
▪ 
PRO-149. Sodium hyaluronate 3%. Viscoelastic solution in a pre-filled syringe. 
Laboratorios Sophia, S.A. de C.V. 
▪ 
Posology: Enough to create the desired intraocular space and perform the required 
intraocular maneuvers. 
▪ 
Route of administration: Intraocular, in the anterior chamber. 
Comparator product, dose and route of administration: 
▪ 
Healon® EndoCoat. Sodium hyaluronate 3%. Viscoelastic solution in a pre-filled syringe. 
Johnson & Johnson Vision Surgical. 
▪ 
Posology: Enough to create the desired intraocular space and perform the required 
intraocular maneuvers. 
▪ 
Route of administration: Intraocular, in the anterior chamber. 
Duration of treatment: 
Transurgical. 
Approximate duration of the subject in the 
study: 
45 days. 
Evaluation criteria: 
Primary outcome variables: 
• 
Changes in CEC density. 
• 
IOP. 
 
Secondary outcome variables: 
• 
Incidence of adverse events (AEs). 
• 
Changes in corneal thickness. 
• 
Cellularity in AC. 
• 
Flare in AC. 
• 
Best corrected visual acuity (BCVA). 
 
Exploratory outcome variables: 
• 
Investigator's report of the transurgical evaluation. 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 14 of 66 
CONFIDENTIAL 
Statistical methodology: 
Data will be expressed with measures of central tendency: mean and standard deviation for 
quantitative variables, while qualitative variables will be presented as frequencies and 
percentages. The Kolmogorov-Smirnov (KS) and Shapiro-Wilk (SW) tests will be performed to 
determine whether the distribution is normal for the results obtained in each study group (p > 
0.05). If normality is observed in the data, the Student's t-test for independent groups will be 
used to evaluate differences between groups on quantitative variables, while intragroup 
differences will be analyzed using the Student's t-test for repeated measures. If p < 0.05 for both 
KS and SW, the statistical analysis will be performed using the Mann-Whitney U test for 
differences between groups on quantitative variables, while intragroup differences will be 
analyzed using the Wilcoxon rank test. Differences between qualitative variables will be analyzed 
using the X2 (chi-square) test or Fisher's exact test. An α ≤ 0.05 will be considered significant. 
 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 15 of 66 
CONFIDENTIAL 
1.2 Study diagram 
 
 
 
 
N (x) ICF, participant screening, request for pre-
surgical cardiac evaluation 
CBC, BC, PT/PTT, ECG 
Pre-surgical cardiac evaluation 
n = 36, eligibility confirmation, surgical programming 
Pre-anesthetic evaluation 
Allocation 
Arm 1     
n = 18 
Arm 2     
n = 18 
Phacoemulsification and IOL implantation 
Safety evaluation 
Safety evaluation 
Final evaluation 
ScrV 
D -15 (±2) 
SchV 
D -8 (±3) 
SurV 
D 0 
1SV 
D 1  
(SurV +1) 
2SV 
D 8  
(±2) 
FV 
D 29  
(±2) 
ScrV: Scrutiny visit; SchV: Scheduling visit; SurV: Surgery visit; 1SV: 1st safety visit; 2SV: 2nd safety visit; FV: Final visit. 
ScrV: includes specular microscopy, IOL calculation and corneal pachymetry.      
FV: includes specular microscopy and corneal pachymetry. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 16 of 66 
CONFIDENTIAL 
1.3 Study schedule 
PROCEDURES 
Scrutiny 
Visit 
D -15±2 
Scheduling  
Visit 
D -8±3 
Surgery 
Visit 
D 0 
1st Safety 
Visit 
D 1 
2nd Safety 
Visit 
D 8±2 
Final 
Visit 
D 29 ±2 
ICF Signature 
X 
 
 
 
 
 
Medical record 
X 
 
 
 
 
 
Somatometry 
X 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
Evaluation of Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
BCVA 
X 
 
 
X 
X 
X 
Comprehensive 
ophthalmologic evaluation 
(cellularity, flare, posterior 
segment) 
X 
 
 
X 
X 
X 
Ocular tonometry 
X 
 
 
X 
X 
X 
Gonioscopy 
X 
 
 
 
 
 
Assessment of 
pharmacological mydriasis 
X 
 
 
 
 
 
Specular microscopy 
X 
 
 
 
 
X 
Corneal pachymetry 
X 
 
 
 
 
X 
Eligibility criteria 
X 
X 
 
 
 
 
IOL Calculation 
X 
 
 
 
 
 
Review of anterior chamber 
depth by IOL Master 
X 
 
 
 
 
 
Request for pre-surgical 
cardiology assessment 
X 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
Pre-surgical cardiology 
assessment review 
 
X 
 
 
 
 
Surgical scheduling 
 
X 
 
 
 
 
Delivery of subject material 
 
X 
 
 
 
 
Investigational product (IP) 
Assignment 
 
 
X 
 
 
 
Phacoemulsification surgery 
and IOL placement 
 
 
X 
 
 
 
Transurgical evaluation 
 
 
X 
 
 
 
Continuity assessment 
 
X 
X 
X 
X 
 
Suture removal (if 
applicable) 
 
 
 
 
X 
 
Return of concomitant 
treatment 
 
 
 
 
 
X 
SchV: Scheduling visit; SurV: surgery visit; 1SV: 1st safety visit; 2SV: 2nd safety visit; FV: final visit. 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 17 of 66 
CONFIDENTIAL 
2. Introduction and Background 
2.1 Theoretical framework 
2.1.1 Ophthalmic viscosurgical devices 
Ophthalmic viscosurgical devices (OVDs), also known simply as viscoelastics, have been present in 
ophthalmic surgery since the early 1960s, although they were initially attempted as vitreous substitutes. 
[1] However, it was not until the late 1970s that Balazs, Miller and Stegmann reported the successful use 
of OVDs in cataract surgery and intraocular lens (IOL) implantation, even introducing the term 
viscosurgery. [2] 
Since their introduction in cataract surgery, OVDs have had a tremendous influence on the evolution of 
extracapsular cataract extraction techniques to phacoemulsification. [3] This is because the protection of 
the corneal endothelium, as well as the creation and maintenance of space, were recognized as the main 
advantages of viscosurgery. When an OVD is used in phacoemulsification surgery, corneal endothelial cell 
(CEC) loss is reduced by up to 70%, compared to when no OVD is used. [1] 
Currently commercially available OVDs contain one or more of the following polymers in different 
concentrations: sodium hyaluronate (SH), chondroitin sulfate (CS), or hydroxypropyl methylcellulose 
(HPMC). These products, composed mainly of water, have practically the same density (1.0 kg/m3). The 
protective, retaining, cohesive, and lubricating properties of OVDs reside in their polymeric structure, 
molecular weight, electrical charge, purity, and interchain molecular interactions. [4] 
The physical properties commonly recognized as differentiating between OVDs are viscosity, elasticity, 
stiffness, pseudoplasticity, and cohesion; these properties clinically translate into tissue protection, space 
maintenance, and ease of injection and removal. 
[1] 
2.1.1.1 Rheological properties of OVDs 
Viscosity (dynamic) 
Viscosity is a parameter of fluids. The viscosity of pure substances varies significantly with temperature 
and, to a lesser extent, with pressure. The ease with which a liquid flows is a guideline for its viscosity. [5] 
Viscosity is defined as the property of fluids that resists the relative motion of their molecules. For certain 
fluids, viscosity is constant and depends only on temperature and pressure. This group is called Newtonian 
fluids. Fluids that do not follow this proportional relationship are called non-Newtonian fluids; see Figure 
2.  
Dynamic viscosity is the property of fluids characterized by their resistance to flow due to the friction 
between their molecules. In the International System of Fluids, it is measured in Pascals per second; 
previously, the most commonly used unit was the centipoise (cps), equivalent to 1 mPas. 
Plasticity 
Plasticity refers to the property of a material that allows it to continuously deform, without breaking, 
when sufficient force is applied, maintaining this new shape after the force has been removed. The greater 
the plasticity of a material, the more the force required to deform decreases as the strain rate increases. 
Pseudoplasticity  
The property of becoming less viscous with increasing shear rate, when the viscosity is limited to zero 
shear, is called pseudoplasticity. In this sense, an OVD with a high viscosity at zero shear would be ideal 
for maintaining formed spaces; however, pseudoplasticity would allow its viscosity to decrease when 
injected through a cannula (at high shear rates), making its application easier. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 18 of 66 
CONFIDENTIAL 
Elasticity 
Elasticity is defined as the tendency of a substance to return to its original shape after being deformed. 
By definition, viscoelastics possess this characteristic, but to varying degrees. It is desirable for OVDs to 
be elastic to absorb shocks caused by manipulation; however, they should not exceed their viscosity, as 
this would hamper fine surgical procedures. 
Stiffness 
Stiffness is also known as complex viscosity and refers to the perceived resistance to moving an object 
through a viscoelastic substance. Mathematically, stiffness is equal to the square root of the sum of the 
squares of the dynamic viscosity and the elasticity. 
The stiffness of an OVD depends on the shear rate and vibration frequency and will be close to the 
viscosity or elasticity value, whichever is greater under the operating conditions of measurement. 
Therefore, both viscosity and elasticity will appear to predominate as the tactile quality "response" when 
the surgeon manipulates the OVD at a given shear rate; this translates to the surgeon's tactile perception 
of the OVD's behavior as viscous or elastic in a given situation. 
Cohesion and dispersion 
OVDs are generally divided into cohesive or dispersive behavior. In reality, this behavior is a continuum, 
but for study purposes, it is easier to separate them into these categories. Cohesion is the tendency of 
the molecules that make up a material to adhere to one another rather than disperse. A low concentration 
of high-molecular-mass polymers entangled in a network in solution will exhibit cohesive behavior, while 
a high concentration of low-molecular-mass polymers will exhibit dispersive behavior. 
2.1.1.2 Rheological properties of OVDs of importance in phacoemulsification. 
As surgical techniques evolve in complexity and meticulousness, the demands on OVD performance 
increase. Newer techniques require greater delicacy and precise manipulation to be successful. However, 
each step of phacoemulsification has different requirements; see Table 2.  
  
 
Y-axis = Log Viscosity (mPas) 
Figure 2. Types of fluid behavior 
 
  
X-axis = Log Cut-off Rate (sec-1) 
0 
1 
2 
3 
4 
5 
6 
7 
-3 
-2 
-1 
0 
1 
2 
3 
Plastic 
Newtonian 
Pseudoplastic 
Dilatant 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 19 of 66 
CONFIDENTIAL 
 
STEP                                               CUT RATE                           IMPORTANT PROPERTIES 
AC formation 
1000 
High pseudoplasticity 
Capsulorhexis 
0 
High viscosity, elasticity 
Core emulsification 
Varies with the position of the 
AC 
High retention 
Cortical I/A 
Varies with the position of the 
AC 
High retention 
Formation of capsular bag 
1000 
High pseudoplasticity 
Keep bag open 
0 
High viscosity, elasticity 
IOL insertion 
2-5 
High pseudoplasticity 
Removal 
Varies with the position of the 
AC 
High cohesion, displacement 
Table 2. Desirable properties of OVDs during phacoemulsification [1]  
2.1.2 Cataracts  
A cataract is an opacity of the lens; it affects visual function in different ways depending on its 
characteristics. Cataracts are multifactorial in origin; according to their pathophysiology, they can be 
classified as senile, congenital, drug-induced, traumatic, metabolic, and uveitis-associated cataracts. [6] 
However, most are age-related, so they are more common in the elderly. [7] Cataracts are the leading 
cause of blindness worldwide, responsible for 51% of global blindness, which in 2010 represented about 
20 million people. As life expectancy increases, the number of people with cataracts is expected to 
increase in direct proportion. Cataracts are also an important cause of decreased visual acuity (VA) and 
low vision in both developed and developing countries. [8] In Mexico, there are three internationally 
recognized studies on cataract blindness, which report that cataracts are responsible for 48 to 64% of 
blindness in the study population. [9, 10, 11] 
Cataract classification based on the degree of opacity or progression has not been sufficient for 
epidemiological or therapeutic studies of cataracts. The Lens Opacities Classification System III (LOCS III) 
Classification System III) is a standardized system used to stage and compare the type and severity of 
cataracts. [12] It was derived from LOCS II [13], and consists of three sets of standardized photographs 
(See Figure 3). The classification evaluates four features, nuclear opalescence (NO), nuclear color (NC), 
cortical opacity (C), and posterior subcapsular opacity (P). The use of this classification has allowed better 
recording of cataract progression, decreased interobserver subjective influence, and allowed the creation 
of perisurgical plans according to the needs of each patient. [14] 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 20 of 66 
CONFIDENTIAL 
 
Figure 3. Lens Opacity Classification System III (LOCS III) 
There is no universally defined and accepted minimum visual acuity (VA) or minimum cataract grade 
classification for cataract surgery; however, with the advent of new surgical techniques, more advanced 
phacoemulsification machines, the introduction of femtosecond laser-assisted cataract surgery (FLACS), 
and the evolution of intraocular lenses (IOLs), cataract surgery has become consistently safer and more 
predictable in terms of good visual rehabilitation, often not requiring corrective lenses. This has led to VA 
levels of 20/30 or better being considered for cataract surgery in industrialized countries. [15] [16]VI 
In 2014, an estimated 2 million cataract surgeries were performed in the United States of America (USA). 
[17] By 2015, an estimated 3.6 million surgeries were performed in the USA and more than 20 million 
worldwide. [18] In Mexico, the cataract surgery rate is estimated to be 1,530 surgeries per million 
inhabitants. [19] 
As previously mentioned, OVDs are currently an essential part of cataract surgery, both for space 
formation and for protecting structures, primarily the ECCs. 
2.2 Background information on the investigational product 
SH is a glycosaminoglycan with viscoelastic rheology. It is composed of repeating units of N-acetyl-D-
glucosamine and sodium-D-glucuronate. [20] It has a high molecular weight (2.5–4 million daltons) and 
low protein content. Its half-life is 1 day in aqueous humor and 3 days in vitreous humor. [3] SH is naturally 
found in various tissues of the body, mainly found in high concentrations in vitreous humor, synovial fluid, 
and umbilical cord. 
SH is used in various concentrations in many of the currently available OVDs and can be extracted and 
purified from different sources, such as rooster combs or by bacterial cell-assisted fermentation. 
Depending on the extraction source, the molecular weight may vary, but the structure remains the same. 
The SH used in PRO-149, like that in Healon® EndoCoat, is a highly purified extract obtained by bacterial 
fermentation, well tolerated by the eye, non-antigenic, and non-pyrogenic. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 21 of 66 
CONFIDENTIAL 
2.2.1 Efficacy of the investigational product  
The efficacy of various SH-containing OVDs has been established in several clinical studies. A multicenter, 
double-blind, randomized clinical study was conducted with the Healon® EndoCoat OVD, which contains 
the same concentration of SH as PRO-149, in 400 patients undergoing phacoemulsification and IOL 
implantation. 
Two hundred patients were assigned to the Healon® EndoCoat group and 200 to the control group, 
corresponding to Viscoat®. Efficacy was measured by CEC protection. Healon® EndoCoat demonstrated 
non-inferiority when compared to Viscoat® in the CEC count from pre-surgery to 3 months post-surgery 
(p < 0.0001, 1-tailed t-test, δ = 5%). The mean percentage changes observed were -4.7% for Healon® 
EndoCoat and -7.0% for Viscoat® with a percentage point difference of 2.3 (90% confidence interval: [ 
0.23, 4.33]). [21] 
2.2.2 Safety of the investigational product  
In the same clinical study described above, safety was evaluated by the cumulative rate of intraocular 
pressure (IOP) peaks ≥30 mmHg and the presence of adverse events (AEs). 
The results demonstrated that the percentage of subjects with IOP spikes in the Healon® EndoCoat group 
was not higher than that in the Viscoat® group (cumulative percentage of subjects with IOP ≥ 30mmHg 
during the study (p = 0.0003, δ = 0.13, 90% confidence interval [-1.74, 7.72]). 
Surgical complications reported were 3% (6/200) in the Healon® EndoCoat group and 8% (16/200) in the 
Viscoat® group. 
Regarding AEs, 39 subjects reported an AE during the study. None of these were considered unexpected. 
Ninety-two percent of the AEs were IOP ≥30 mmHg; the incidence of this AE was 10.5% in the Healon® 
EndoCoat group and 7.5% in the Viscoat® group. The three AEs that did not correspond to an increase in 
IOP included: one subject in the Healon® EndoCoat group who developed cystoid macular edema 
(requiring treatment) and two subjects in the Viscoat® group : one subject who required IOL exchange for 
haptic damage and one who underwent removal of an ocular surface foreign body. None of the above 
AEs were considered related to OVD use. [21] 
List of incidents or adverse reactions reported with a 3% sodium hyaluronate viscoelastic or with the use 
of intraocular sodium hyaluronate: [21] [22] 
• 
Eye inflammation (iritis, hypopyon, endophthalmitis) 
• 
Increased intraocular pressure 
• 
Corneal edema 
• 
Secondary glaucoma 
• 
Corneal decompensation 
All of the described incidents or adverse reactions may potentially occur with the use of PRO-149 or 
Healon® EndoCoat. [21] [22] 
2.2.3 Summary of the pharmaceutical development of the investigational product  
The development of PRO-149 included physicochemical and rheological characterization tests, as well as 
stability tests. In addition, preclinical studies were conducted in New Zealand albino rabbits using two 
models: an aqueous exchange model and an aqueous humor replacement model with subsequent AC 
washout. [23] 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 22 of 66 
CONFIDENTIAL 
Twenty eyes of 20 research subjects (rabbits) were studied and divided into two groups of 10, group 1 
underwent aqueous humor exchange (anterior chamber exchange, via paracentesis, 0.05 mL of aqueous 
humor for 0.05 mL of OVD) and group 2 underwent AC lavage (exchange of the total volume of aqueous 
humor in AC for the OVD, which was lavaged and replaced with balanced saline solution by manual I/A). 
In turn, both groups were subdivided into A and B, with 5 subjects per group, for the PRO-149 and Healon® 
EndoCoat groups. 
The primary safety variables were IOP, corneal opacity, AC cellularity and flare, presence of fibrin, iris 
congestion, conjunctival hyperemia, discharge, conjunctival edema, and incidence of AEs. Toxicity 
variables included abnormalities in histopathological examinations of the tissues studied. 
In both models, no statistically significant differences were observed in the safety variables between both 
DVOs. [23] 
2.3 Background on the research  
2.3.1 From the research question  
There is no prior data on PRO-149 in clinical trials. However, the efficacy and tolerability of SH-containing 
OVDs have been previously tested. 
2.4 Risk benefit assessment  
2.4.1 Known potential risks  
OVDs are safe formulations whose use during phacoemulsification surgery and IOL placement has been 
recognized as beneficial in increasing the safety of the procedure. Since SH is a polysaccharide naturally 
present in many body tissues, it is very well tolerated by the human eye. However, transient postoperative 
inflammation and increased IOP have been reported in clinical studies with these OVDs. 
Cataract surgery, currently performed by phacoemulsification, is the most frequently performed surgery 
worldwide by ophthalmic surgeons [18]. Like any medical procedure, it is not exempt from complications; 
however, the risk-benefit balance is favorable to the procedure. 
2.4.2 Known potential benefits  
The benefits are described in three orders. First, for the study subjects, it restores vision lost directly due 
to lens opacity. Second, for phacoemulsification surgery, the use of an OVD protects structures such as 
the CECs and facilitates surgical maneuvers. Third, for the investigational product, it documents the safety 
profile of PRO-149. 
2.5 Problem statement  
A few decades ago, cataract surgery was performed with the aid of an air bubble to maintain the AC 
formation. This technique provided poor protection to the structures and was minimally effective in 
maintaining the AC formation. With the advent of OVDs, this changed, allowing cataract surgery to evolve 
toward a safer process. 
However, there is no ideal OVD; each case or even each surgical step may require specific OVD 
characteristics. For this reason, various OVDs have been developed, ranging across the spectrum from 
dispersivity to cohesiveness. 
PRO-149 has rheological characteristics that could make it a safe and efficient dispersive OVD. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 23 of 66 
CONFIDENTIAL 
2.6 Justification  
Unlike pharmaceutical compounds, in which the active ingredient maintains its pharmacokinetic and 
pharmacodynamic properties between formulations, provided the concentrations and compatibility with 
excipients are respected, OVDs cannot be properly designated as generics. 
The chain length, pH, osmolarity, presence of other solutes, polymer conformation, and electrical charge 
can vary between these apparently identical formulations, which would directly affect their rheological 
properties and, consequently, their clinical behavior. 
This study is necessary to test the safety of PRO-149 by comparing it with the safety found in a product 
already on the market (Healon® EndoCoat) and to understand its behavior during phacoemulsification 
surgery. 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 24 of 66 
CONFIDENTIAL 
3. Objectives and hypotheses 
3.1 Primary objectives  
To evaluate the safety of PRO-149, manufactured by Laboratorios Sophia, S.A. de C.V., when used as an 
OVD during phacoemulsification surgery and intraocular lens (IOL) placement in patients diagnosed with 
senile cataracts, compared to Healon® EndoCoat. 
3.2 Specific objectives   
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, through changes in pre and postoperative CEC density. 
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, through changes in IOP. 
3.3 Secondary objectives  
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, with the incidence of AEs. 
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, through changes in central corneal thickness. 
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, with the presence of cellularity in postoperative AC. 
• 
To compare the safety of OVD PRO-149 versus Healon® EndoCoat in cataract phacoemulsification 
surgery and intraocular lens implantation, with the presence of postoperative AC flare. 
• 
To compare the best-corrected visual acuity obtained after cataract phacoemulsification surgery 
and intraocular lens implantation between PRO-149 and Healon® EndoCoat. 
3.4 Exploratory objectives  
•  To compare the intraoperative performance of PRO-149 versus Healon® EndoCoat in cataract 
phacoemulsification surgery and intraocular lens implantation, as assessed by the surgeon. 
3.5 Hypothesis  
H1: PRO-149 viscoelastic solution is equivalent in safety to Healon® EndoCoat for use as an OVD in 
phacoemulsification surgery and IOL placement in patients with senile cataracts. 
H0: PRO-149 viscoelastic solution is not equivalent in safety to Healon® EndoCoat for use as an OVD in 
phacoemulsification surgery and IOL placement in patients with senile cataract. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 25 of 66 
CONFIDENTIAL 
4. Study design  
4.1 Design Overview  
Pilot, controlled, parallel-group, open-label, randomized clinical trial. 
4.2 Justification of the study design  
The study design (clinical trial) is considered the highest standard of data quality when exploring the effect 
of an intervention. The development, or pilot, phase for a device corresponds to the study objective, 
which is to evaluate safety, so the intervention time is short and the required sample size is smaller than 
that of a pivotal clinical trial. The presence of parallel groups allows for comparisons between the 
intervention groups on outcome variables. Primary blinding was not considered for this study due to the 
characteristics of both investigational products; however, the statistical analysis will be blinded. 
4.3 Expected duration  
The total duration of the study, from the first patient’s first visit to the preparation of the final report, is 
estimated to be 7 months. 
The planned recruitment period is 4 months. Considering the proposed sample size of 36 subjects, the 
average total recruitment rate during the study should be no less than 1 subject enrolled every 4 days. 
The approximate duration of each subject in the study is 45 days. 
  

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 26 of 66 
CONFIDENTIAL 
5. Study population 
5.1 Eligibility criteria  
5.1.1 Inclusion criteria  
▪ 
Age equal to or greater than 49 years. 
▪ 
Diagnosis of age-related cataract (senile cataract) requiring cataract phacoemulsification surgery 
and placement of a monofocal intraocular lens. 
Grade I to IV cataracts based on nuclear opacity (opalescence and/or color) of the lens opacity 
classification system (LOCS III). 
▪ 
Ability to voluntarily grant informed consent. 
▪ 
Be able and willing to comply with scheduled visits, treatment plan, and other study procedures. 
▪ 
Desire and willingness to undergo phacoemulsification surgery and placement of a monofocal IOL. 
▪ 
Have an anterior chamber depth ≥ 2.8 mm as measured by IOL Master. 
▪ 
Preoperative cardiology evaluation that qualifies the patient for the surgical procedure, with 
supporting laboratory studies: complete blood count (CBC), three-element blood chemistry (BC), 
coagulation times (PT/PTT, INR), and electrocardiogram (ECG). If a prior evaluation is available, it 
must not be performed more than 45 days prior to signing the informed consent form (ICF). 
5.1.2 Exclusion criteria  
▪ 
History of any systemic disease or condition that makes you ineligible for the surgical procedure 
under sedation and topical anesthesia. 
▪ 
Diabetes mellitus with A1C ≥ 6.5% (48 mmol/mol) or fasting glucose (no caloric intake for ≥ 8 
hours) of ≥ 126 mg/ dL (7.0 mmol/L) 
▪ 
Uncontrolled systemic hypertension. Defined as blood pressure greater than 140/90 mmHg with 
the use of three antihypertensives (one of which is a diuretic) at the maximum dose. 
▪ 
Have a history of eye diseases that could limit the best corrected visual acuity, or be reactivated 
and/or exacerbated by the surgical procedure or by the use of topical steroids (e.g. retinal 
detachment, macular degeneration, pathological myopia, proliferative diabetic retinopathy, 
diabetic macular edema, optic neuritis, uveitis or other types of ocular inflammation, glaucoma, 
ocular hypertension, corneal dystrophy or ectatic disorder, history of an ocular infection by herpes 
or varicella zoster). 
▪ 
Active eye infection. 
▪ 
Pseudo exfoliation syndrome in the eye to be operated on or other type of zonular involvement. 
▪ 
Pharmacological mydriasis less than 6 mm. 
▪ 
Any congenital ocular anomaly in the eye to be operated on. 
▪ 
Any ocular abnormality that prevents obtaining a reliable Goldmann tonometry in the eye to be 
operated on. 
▪ 
An intraocular pressure (IOP) >21 mmHg in the eye to be operated on, or a history of intraocular 
pressure >21 mmHg with the use of topical steroids. 
▪ 
A corneal endothelial cell (CEC) density < 1500 cells/mm 2 in the eye to be operated on. 
▪ 
History of previous corneal or intraocular surgery. 
▪ 
Having multiple procedures planned during cataract surgery (i.e., trabeculectomy, relaxing 
keratotomies, etc.). 
▪ 
History of ocular trauma in the eye to be operated on (includes surgical procedures). 
▪ 
Having a one single evaluable eye. 
▪ 
Having participated in another clinical research study ≤ 30 days prior to signing the ICF. 
▪ 
Having previously participated in this study. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 27 of 66 
CONFIDENTIAL 
▪ 
A history of drug addiction or drug dependence, currently or within the last two years prior to 
signing the ICF. 
▪ 
A history of ocular surgical procedures within the last 3 months prior to signing the ICF. 
▪ 
Any type of surgical intervention scheduled during the study period. 
▪ 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) 
who is a member of the research site or sponsor staff.5.2 Criteria for elimination and/or 
substitution of subjects 
5.2.1 Elimination criteria  
▪ 
Withdrawal of informed consent. 
▪ 
Major deviation from the protocol that could impact the integrity of the results. 
▪ 
Presentation of an adverse event, whether or not related to the investigational product, which, 
in the opinion of the PI and/or the sponsor, could affect the subject's ability to safely continue 
the study procedures. 
▪ 
Non-tolerability or hypersensitivity to any of the compounds used during the tests (fluorescein, 
lissamine green, tetracaine). 
▪ 
Non-tolerability or hypersensitivity to any of the investigational drugs. 
5.2.2 Subject substitution  
The sponsor, with prior authorization from the research ethics committees, may decide to replace 
subjects who withdraw their ICF or those who are lost to follow-up, if it is necessary to balance the study 
groups so that they are evaluable. 
5.3 Scrutiny failures  
A screening failure is defined as a participant who agrees to participate in the study, giving their consent, 
but who is not assigned to a treatment group; that is, they do not enter the study. The following 
information regarding screening failures must be reported, at a minimum: 
- 
Demographic data. 
- 
Details of the counting failure (specify whether due to eligibility criteria, which one, or some other 
reason for the failure). 
- 
Presence of serious adverse events during the scrutiny. 
The above is necessary to comply with the CONSORT guidelines (Consolidated Standards of Reporting 
Trials) for the publication of results or to respond to potential questions from regulatory authorities. 
Subjects who do not meet the eligibility criteria for participation in the study due to a specific modifiable 
factor may be re-screened. Subjects in this situation must use the same initial screening number. 
5.4 Recruitment and retention strategies  
This is a pilot study and the minimum expected recruitment rate is 1 subject every 4 days. 
The duration of the subject's participation in the study is approximately 45 days, during which they will 
be required to attend six visits in total, which correspond to standard screening and surgery scheduling 
visits, as well as cataract surgery follow-up visits. Strategies to improve subject retention include, but are 
not limited to: 
• 
Clearly communicate the importance of the study and the benefits the population will gain from 
its results. 
• 
Make calls or send text messages to remind yourself of appointments or activities to do. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 28 of 66 
CONFIDENTIAL 
• 
Provide a printed calendar and ID card to remind you of upcoming appointments and activities, 
as well as their estimated duration. 
• 
Offer flexible business hours. 
• 
Systematic organization of the study procedures, so that the subject does not stay longer than 
necessary during his visit. 
• 
Minimize subject wait times. 
All materials to be delivered to the subject or recruitment strategies implemented by the Centers will be 
submitted for approval by the corresponding committees. 
5.5 Procedure in case of early discontinuation  
For this protocol, early discontinuation is defined as those subjects who were randomized, and who at 
some point were active subjects in the study, but their final evaluation could not be completed. 
If the subject does not complete their participation due to withdrawal of consent or a major deviation, 
the last visit at which their withdrawal was determined will be considered their final visit. Subjects 
withdrawn due to the presence of AEs will continue the follow-up as determined until their AE is resolved. 
In cases where the participating subject does not attend their appointment, the research site will call to 
determine the reason and will attempt to schedule a new appointment within the established window or 
an unscheduled appointment. If an appointment cannot be scheduled, the subject will be considered lost 
to follow-up, and the presence of adverse events and the reason for discontinuing the study will be asked 
as minimum data. 
5.6 Subject identification  
Study subjects will be identified by a number and the initials of their name. 
The initials of the subject of study will be obtained starting with the first letter of the name, followed by 
the first letter of the first surname and the first letter of the second surname, obtaining a maximum of 
three letters. In case the person has two names or a compound surname, the first letter will always be 
used. 
Example: 
              Name: Ariel Daniel Mercado Carrizalez.                            Name: Juan De la Torre Orozco. 
Initials: AMC. 
                                                          Initials: JDO. 
During the counting stage, you will be assigned a participant number consecutively, using 3 consecutive 
digits. 
Once the subject has been selected, they will be assigned a randomization number, which will be used to 
identify them throughout the study. This code will consist of eight numbers in the following order from 
left to right: 
• 
three digits of the molecule under study according to the name given by the sponsor. 
• 
two digits corresponding to the research center number. 
• 
three digits of the consecutive number assigned to its inclusion in the research center. 
Example of randomization number: 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 29 of 66 
CONFIDENTIAL 
 
 
 
 
 
149 - 01 - 001   
Molecule Key 
  
inclusion number 
  
Center number 
  

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 30 of 66 
CONFIDENTIAL 
6. Investigational product 
6.1 Managed Products  
6.1.1 Investigational product  
▪ 
Generic name: Sodium Hyaluronate. 
▪ 
Distinctive name: PRO-149. 
▪ 
Active ingredients: Sodium Hyaluronate 3%. 
 
 
▪ 
Pharmaceutical form: Viscoelastic solution. 
▪ 
Presentation: prefilled syringe, 1 cc.  
▪ 
Prepared by: Laboratorios Sophia, S.A. de C.V. 
▪ 
Solution description: Clear solution, free of visible particles. 
6.1.2 Reference product  
▪ 
Generic name: Sodium Hyaluronate. 
▪ 
Distinctive name: Healon® EndoCoat. 
▪ 
Active ingredients: Sodium Hyaluronate 3%. 
▪ 
Excipients: sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium 
acetate, sodium citrate, dibasic sodium phosphate, monobasic sodium phosphate, water for the 
manufacture of injectables. 
▪ 
Pharmaceutical form: Viscoelastic solution. 
▪ 
Presentation: 0.85 cc prefilled syringe.  
▪ 
Prepared by: Johnson & Johnson Vision Surgical, Santa Ana, CA, USA. 
▪ 
Solution description: Clear solution, free of visible particles. 
6.1.2.1 Justification of the reference product 
Healon® EndoCoat is a commercially available OVD with a previously described safety and efficacy profile. 
6.1.3 Dosage of investigational products   
As much as is necessary for the formation of spaces and the performance of surgical maneuvers. 
6.1.3.1 Justification of the dose 
There is no standardized dose for OVDs; each case is customized according to the anatomical 
characteristics and surgical needs. 
6.1.4 Concomitant treatment  
Both groups will be treated with: 
▪ 
Generic name: Ciprofloxacin 0.3%/Dexamethasone 0.1% 
▪ 
Distinctive name: Sophixin DX 
▪ 
Active ingredients: Ciprofloxacin 0.3%, Dexamethasone 0.1%.  
▪ 
Pharmaceutical form: Ophthalmic solution. 
▪ 
Presentation: 5 mL dropper bottle. 
▪ 
Prepared by: Laboratorios Sophia, S.A. de C.V. 
▪ 
Solution description: Clear solution, free of visible particles. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 31 of 66 
CONFIDENTIAL 
▪ 
Dosage: 1 drop every 4 hours for 10 days in the operated eye. 
6.2 Storage and handling of investigational products at the study center  
Delivery will be made via a courier service contracted by the sponsor, specifically selected for this purpose, 
to the address of the research center in accordance with the study plan. 
Reception will be carried out by the assigned research team staff. They must verify the condition of the 
primary packaging (box). If it shows alterations or defects in its integrity that, in their judgment, could 
have damaged the contents, they must report this to the sponsor. If the package shows no significant 
defects, they will proceed to open it. 
Inside the shipment, you must locate the receipt and temperature data logger. You must verify that the 
recorded temperature meets the specifications for its transport and storage. You will verify the contents 
(PI) with what is reported on the document. If the document matches the contents, you will sign the 
receipt and send it to the sponsor. If not, you will notify the sponsor. 
Storage and safeguarding are the responsibility of the research center. The medication must be kept in a 
secure area with restricted access. 
Storage temperature should be 2° to 30°C. 
Upon receipt at the center and until the IP is out of stock, the research center is required to review the 
IP’s storage conditions daily and manually record, in the designated format, the temperature recorded by 
the data logger (current, minimum, and maximum temperatures). These data will be reviewed by the 
clinical monitor during monitoring visits according to the records stored in the data logger's memory.  
In the event of material loss, this must be documented in the input and output log along with a clear 
description of the mechanism by which the loss occurred. 
Upon completion of the protocol, all study materials will be retrieved by the sponsor as part of the final 
visit. The final return of materials will be made by the principal investigator or the person designated by 
the principal investigator to return materials at the end of the study. 
The sponsor reserves the right to initiate civil and criminal action against the principal investigator in the 
event of undocumented material missing at the end of the study. 
6.3 Concomitant treatments and medications (permitted and prohibited)  
Any medication used, in addition to appearing in the clinical note, must be recorded in the concomitant 
medications section of the electronic Case Report Form (eCRF). 
Permitted medications:  
- 
Ophthalmic: 
All permitted ophthalmic medications administered during the study must be after the last application 
of the study or reference treatments, waiting a minimum of 10 minutes. This is to avoid treatment 
interactions with the tear film, based on the physiological tear flow rate and volume. [24] 
o Tetracaine 0.5% 
o Tropicamide 0.8% / Phenylephrine 5% 
o Any antibiotic 
o β -blocker* 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 32 of 66 
CONFIDENTIAL 
o  α -agonist* 
o Any topical steroid 
o Any topical nonsteroidal anti-inflammatory drug 
*Topical antihypertensives are permitted after the 1st safety visit; they cannot be used 
prophylactically. 
- 
Administered by a route other than ophthalmic: 
o The use of medications for the treatment of chronic diseases that do not appear as an 
exclusion criterion (e.g., medications for the treatment of systemic arterial hypertension) 
will be permitted. 
o Medications with ocular hypotensive action, such as acetazolamide or mannitol, are 
prohibited as prophylactic agents; their use may be permitted after 1st safety visit. 
o Any medication whose effect may be susceptible to modifying any of the efficacy, safety 
or tolerability parameters of this research protocol must be notified to the clinical 
monitor or the sponsor's clinical team to determine the appropriateness of the 
participant's admission, continuation or elimination as appropriate. 
Prohibited medications: 
- 
Any medication with ophthalmic application that is not on the list of permitted medications 
- 
Systemic immunomodulators 
- 
Anticoagulants 
- 
Medications with non-ophthalmic applications and with hypotensive action at the ocular level 
6.4 Procedure for monitoring and measuring adherence  
For over four decades, numerous investigations have been conducted on the appropriate way to measure 
and quantify medication adherence, however, none has reached a consensus to establish itself as the gold 
standard, both in cross-sectional and longitudinal studies. [25, 26, 27, 28, 29, 30, 31, 32] 
Due to the characteristics of the study, which evaluates the use of a device during a surgical procedure, 
the IP’s adherence is directly dependent on the principal investigator's (PI) application during surgery. 
This rules out adherence errors such as applications outside the eye or forgetting to apply them (the 
surgical procedure cannot be performed without the use of OVDs). There is no predetermined dosage, so 
the quantity (volume of the syringe applied) to be used will be customized for each surgical event at the 
PI's discretion. Adherence will be measured by the clinical monitor during monitoring visits by counting 
the syringes used. 
However, adherence to concomitant treatment (Ciprofloxacin 0.3%/Dexamethasone 0.1% ophthalmic 
solution) will be measured, as adherence is critical for managing postoperative inflammation; such 
inflammation could be a confounding factor in the evaluation of study variables. 
There are different procedures for measuring adherence to pharmacological interventions. The most 
common procedure involves self-reports, which include patient interviews, questionnaires, and self-
monitoring diaries. Their strengths are speed, flexibility, low cost, and ease of implementation; they have 
a high degree of specificity for non-adherence; however, their sensitivity and reliability for adherence are 
low. [32, 33] 
Biochemical measurement of the drug, or its metabolite, is one of the methods that best confirms drug 
use. However, in addition to being costly and impractical, it is of little use in ophthalmic applications, as 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 33 of 66 
CONFIDENTIAL 
peripheral concentrations may be undetectable; and samples from other tissues require more invasive 
methods that would not be advisable. [32] 
Medication counting is another way to measure adherence. Classically referred to as "pill counting," in 
ophthalmology it is translated as the weight of the bottle. This is a simple, inexpensive, and noninvasive 
method. The main disadvantages of this method are: 1. It cannot confirm the application of the 
medication (it could have been intentionally dropped or instilled outside the eye), and 2. It depends on 
the subject bringing the medication back. [32, 33] 
Adhesion assessment will be based on the bottle's weight and will be performed taking into account the 
following information: drop weight, initial container weight, final container weight, and the total number 
of applications. The following simplified formula will be used: 
(𝑃𝑖 − 𝑃𝑓)100 
𝐴𝑑 = 
  
𝑃𝑇 
Where: 
Ad = adhesion 
𝑃 𝑖 = weight of the container delivered to the subject at the beginning 
𝑃 𝑓 = weight of the container returned by the subject 
𝑃 𝑇 = weight of the dosage indicated for the investigational products 
𝑃 𝑇 = (𝑃 𝑔)𝐺  
  
Where: 
𝑃 𝑔 = weight of one drop of the medicine, determined by the research and development department 
G = number of applications indicated for the investigational products 
Containers that are not physically intact will not be considered for adherence calculations. Subjects who 
do not return the concomitant treatment container at the final visit will be considered non-adherent. 
There is no standardized parameter to define adequate adherence; this must be defined and outlined by 
the objectives of the particular research. [32] 
For this study, a minimum adherence of 60% will be considered necessary to meet the research objectives. 
Therefore, subjects with less than 60% adherence will be included in the intention-to-treat population. 
6.5 Strategies to improve adherence  
1. The PI will educate the subject on the importance of correctly administering concomitant 
treatment to achieve the study objectives. 
2. Direct questioning by the PI regarding the application of concomitant treatment. 
3. Delivery of a printed calendar specifying the date of the visit and its activities. 
If deemed necessary, text messages may be sent as reminders. The content of these messages must be 
approved in advance by the IEC. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 34 of 66 
CONFIDENTIAL 
7. Methods and procedures of the study 
7.1 Research center  
This study will be conducted at one or more research centers previously evaluated by the sponsor. The 
center will be an institution or facility that conducts health research and complies with current 
regulations. 
The research center will be responsible for forming a multidisciplinary research team to execute the 
clinical study according to the protocol. It is its prerogative to design the organization and select the 
personnel who will perform these functions. However, the sponsor requires that the PI and sub-
investigator be physicians specializing in ophthalmology. 
Any person assigned, under the PI's responsibility, to a part of the study monitoring (sub-investigator, 
nurse, etc.) or a specific role in the study (pharmacist, administrative assistant, study coordinator, etc.) 
must be listed in the "Delegation of Responsibilities." 
The competency and training of all individuals directly involved in study activities must be verified prior 
to the conduct of any protocol-related activities. This must be recorded, and documents constituting 
evidence of this competency and/or training must be retained in the study master file. The competency 
and training of personnel involved in the study, both at the central level and at the study sites, is the 
responsibility of the sponsor. 
The sponsor must ensure that all study site personnel participating in the study are adequately trained in 
the study (research protocol, investigator's manual, amendments, standard operating procedures, etc.) 
and in ICH Good Clinical Practices prior to the start of their participation in the study. Training must be 
documented in writing and filed in the study master file. 
7.2 Clinical study registration  
This clinical study will be registered by the sponsor in public clinical trial registries prior to its initiation 
(inclusion of the first subject): the National Registry of Clinical Trials (RNEC) of the Federal Commission 
for the Protection against Sanitary Risks (COFEPRIS) and on a WHO primary registry platform. WHO 
primary registries meet specific criteria regarding content, quality and validity, accessibility, unique 
identification, technical capacity, and administration. WHO primary registries meet the requirements of 
the International Committee of Medical Journal Editors (ICMJE). 
7.3 Randomization and blinding  
Treatment allocation/randomization will be performed centrally using an integrated web-based response 
system (IWRS). There are two treatment groups. Participants will be randomly assigned 1:1 to treatment 
with PRO-149 or Healon® EndoCoat, with equal probability of being assigned to either treatment. 
After signing the ICF, the subject will receive a patient number under which all information will be coded 
pseudo-anonymously during collection and completely anonymized during analysis. 
The generation will be carried out by a third party, authorized by Laboratorios Sophia, S.A. de C.V., 
through its electronic system, using a list of random numbers (SAS Institute Inc, Cary, NC, USA). 
Information corresponding to this third party will be found on file. 
This is an open-label study, meaning there is no blinding, except for the statistical analysis. The 
investigational products will be identified by labels that comply with current and applicable regulations. 
These labels must contain, at a minimum, the following: 
- 
Name, address and telephone number of the sponsor. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 35 of 66 
CONFIDENTIAL 
- 
Pharmaceutical form and route of administration. 
- 
Number of doses. 
- 
Batch number. 
- 
Legend “Exclusively for clinical studies” 
- 
Expiration date. 
7.4 Outcome variables  
7.4.1 Primary outcome variables  
-  Changes in CEC density. 
-     IOP.  
7.4.2 Secondary outcome variables  
- 
Incidence of adverse events. 
- 
Changes in corneal thickness. 
- 
Cellularity in AC. 
- 
Flare in AC. 
- 
Best corrected visual acuity 
7.4.3 Exploratory outcome variable  
 
-  
Transurgical evaluation investigator's report. 
7.4.4 Definition of variables, methods and scales to be used for measurement  
 
Variable 
Guy 
Unit 
(symbol) 
Measurement 
method 
Normal 
value 
Evaluation 
time 
Statistical 
test 
Of outcome primary 
Endothelial cell 
count (cornea) 
Continuous 
quantitative 
Cells / mm2 
Microscopy 
speculate 
1500-
3500 
VE and VF 
Student t -
test 
Mann-
Whitney U 
 
Wilcoxon 
ranks * 
Intraocular 
Pressure 
Continuous 
quantitative 
mmHg 
Goldmann 
tonometry 
10-21 
VE, V1, V2 
and VF 
Student t 
test 
Mann-
Whitney U 
 
Wilcoxon 
ranks * 
Of outcome secondary 
Events adverse 
Discreet 
Number of 
cases (n) 
Counting 
0 
VE, VP, VC, 
V1, V2 and 
VF 
Student t 
test 
Mann-
Whitney 
U* 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 36 of 66 
CONFIDENTIAL 
Events adverse 
(Bis) 
Nominal 
categorical 
Present / 
Absent 
Observation 
Absent 
VE, VP, VC, 
V1, V2 and 
VF 
χ 2 or 
Fisher's 
exact test 
 
McNemar 
test ** 
Changes 
in 
corneal 
thickness 
Continuous 
quantitative 
μm 
Corneal 
pachymetry 
545 ± 40 
VE and VF 
Student t 
test 
Mann-
Whitney U 
 
Wilcoxon 
ranks * 
Cellularity 
of 
the 
anterior 
chamber 
Qualitative 
ordinal 
Degrees 
Biomicroscopy 
0= None 
VE, V1, V2 
and VF 
χ 2 or 
Fisher's 
exact test 
 
McNemar 
test ** 
Flare 
in 
the 
anterior 
chamber 
Qualitative 
ordinal 
Degrees 
Biomicroscopy 
0= No 
flare 
VE, V1, V2 
and VF 
χ 2 or 
Fisher's 
exact test 
 
McNemar 
test ** 
AVMC 
Discreet 
Fraction (-) 
Snellen chart 
0.6-2.0 
VE, V1, V2 
and VF 
Student t 
test 
Mann-
Whitney U 
 
Wilcoxon 
ranks * 
Of outcome exploratory 
Transurgical 
evaluation 
Qualitative 
ordinal 
Bad (0) / 
Very good 
(5) 
Observation 
… 
VC 
χ 2 or 
Fisher's 
exact test 
 
McNemar 
test ** 
BCVA, best-corrected visual acuity; ScrV, scrutiny visit; SurV, surgery visit; SchV, scheduling visit; V1-2, 1st / 
2nd safety visits; VF, final visit; χ2, Chi-square; *For KS/SW, p < 0.05; **When applied 
Table 3. Operational definition of variables 
The variables, method, and scales used to measure them are described in detail below. They are listed in 
order according to Table 3.  
7.4.4.1 Corneal endothelial cell density 
Specular microscopy allows a clear view of live endothelial cells without altering their function or 
morphology. In turn, a surface area count can be performed to determine if there is an alteration in the 
shape or size of the endothelial cells, parameters that must be taken into account to determine the 
functional capacity of the corneal endothelium. CEC density decreases over time, due to diseases and 
intraocular surgical procedures. Analysis of CEC density will be performed using a specular microscope 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 37 of 66 
CONFIDENTIAL 
(the make and model of the equipment must be specified). The density in cells/mm2 will be recorded in 
the eCRF. The area and strategy used in the scrutiny visit must be the same as the final visit. 
Management as AE: This value, by itself, will not be considered an AE regardless of the changes; the AE 
will correspond in each case to a clinical corneal decompensation when so judged by the PI. 
7.4.4.2 Intraocular pressure 
Tonometry is the objective measure of IOP, based primarily on the force required to flatten the cornea, 
or the degree of corneal depression produced by a fixed force. Goldman tonometry is based on the 
Imbert-Fick principle. [34] 
Tonometry will be performed after instillation of topical anesthetic with fluorescein and the use of a 
cobalt blue filter (after assessing surface staining). Two readings will be taken, and the average will be 
recorded in the clinical record. The average will be recorded in the eCRF. 
Management as AE: IOP peaks ≥30mmHg should be reported as AE. 
7.4.4.3 Adverse events 
As described in section 8.2, an adverse event is defined as Any adverse medical occurrence in a subject 
to whom an investigational product is administered, regardless of causal attribution. 
The management of adverse events will be carried out in accordance with the provisions of Section 8. 
Evaluation and management of adverse events and incidents. 
Any adverse events that study subjects experience will be reported by the PI in the corresponding section 
of the eCRF and also in the clinical record. 
For an adequate assessment of adverse events, in addition to the targeted questioning, a Comprehensive 
Ophthalmologic Evaluation must be performed at each visit. This evaluation consists of: ophthalmologic 
examination of the eyelids and adnexa; anterior and posterior segments, which are performed during a 
routine ophthalmologic examination, procedures not specifically included in the study variables. The 
posterior pole evaluation may be performed with direct or indirect ophthalmoscopy, with or without 
pharmacological mydriasis, at the discretion of the PI. The fundus will be assessed for abnormalities that 
could alter the study results. IOP will be measured during this evaluation, using the PI's chosen 
instrument, and should be measured after the stain evaluation. The results of the evaluation will be 
recorded in the clinical record. Only those findings that the Principal Investigator considers to be adverse 
events will be reported in the eCRF. 
Adverse events (including incidents, adverse events) that may occur with the use of PRO-149 or Healon® 
EndoCoat medical devices are: ocular inflammation (iritis, hypopyon, endophthalmitis), increased 
intraocular pressure, corneal edema, secondary glaucoma, corneal decompensation, cystoid macular 
edema, blurred vision, burning, ocular pain, ocular irritation, breakage of intraocular lens haptics, foreign 
body on ocular surface. 
7.4.4.4 Changes in corneal thickness 
Pachymetry, the measurement of central corneal thickness, will be performed simultaneously with the 
CEC density measurement using a specular microscope (the brand and model of the equipment used must 
be specified). It will be recorded in the eCRF. 
Management as AE: This value, by itself, will not be considered an AE regardless of the changes; the AE 
will correspond, in each case, to clinical corneal decompensation when so judged by the PI. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 38 of 66 
CONFIDENTIAL 
7.4.4.5 Cellularity and flare in the anterior chamber 
In the presence of intraocular inflammation, increased permeability of the non-pigmented layer of the 
ciliary epithelium, the posterior iris epithelium, and the iris vascular endothelium results in the 
accumulation of cells and proteins (visible to the examiner as flare) in the anterior chamber. Using a 
0.2mm X 0.2mm light beam directed obliquely into the anterior chamber with a forward tilt of the light 
source (slit lamp tower), the degree of flare and cellularity will be determined according to the Uveitis 
Nomenclature Standardization Working Group. [35] The degree of agreement will be reported in the eCRF 
according to the given grade (See Table 4 and Table 5). 
  
Table 4. Scale for anterior chamber cellularity 
Degree 
Number of cells 
0 
None 
½ + 
1-5 
1 + 
6-15 
2 + 
16-25 
3 + 
26-60 
4 + 
More than 60 
Visible in a 0.2mm x 0.2mm field 
  
Table 5. Flare scale 
Degree Number of cells 
0 
There is no flare 
1 + 
Mild 
2 + 
Moderate (iris and lens clearly visible) 
3 + 
Marked (iris and lens slightly blurred) 
4 + 
More than 60 (fibrin) 
  
Management as AE: Reported values ≥3 for cellularity or flare should be reported as AE. 
7.4.4.6 Best Corrected Visual Acuity 
Visual acuity (VA) is a test of visual function. Spatial visual acuity is the ability to distinguish separate 
elements of an object and identify them as a whole. It is quantified as the minimum angle of separation 
(located at the nodal point of the eye) between two objects that allows them to be perceived as separate 
objects. 
Snellen notation is described as the distance at which the test is performed divided by the distance at 
which the letter is vertically equivalent to 5 minutes of arc. Thus, at 6 meters a letter 6/6 (20/20) is 
equivalent to 5 minutes of arc, a letter 6/12 (20/40) is equivalent to 10 minutes, and a letter 6/60 (20/200) 
is equivalent to 50 minutes. The Snellen fraction can also be expressed as a decimal (i.e., 20/20 = 1 and 
20/40 = 0.5).[34] 
VA will be assessed at baseline, without refractive correction, using the Snellen chart. This chart will be 
placed in a location with adequate natural or artificial lighting and at a distance of 3 m from the subject 
being assessed. Visual acuity will be measured in the study eye, asking the subject to keep both eyes open 
and using an occluder to cover the contralateral eye. The subject will read aloud the lines indicated by the 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 39 of 66 
CONFIDENTIAL 
evaluator. The line with the smallest letters visible will be recorded by the evaluator as a fraction of the 
OD VA in the clinical record. 
The subject's best refractive correction will then be performed, and the examination will be repeated 
using the obtained refraction. This result will be reported as best-corrected visual acuity, recorded as a 
fraction and decimal in both the clinical record and the eCRF. 
Management as AE: This value, by itself, will not be considered an AE regardless of the changes; the AE 
will correspond, in each case, to clinical corneal decompensation when so judged by the PI. 
7.4.4.7 Transurgical evaluation 
During the surgical procedure, the surgeon will assess the clinical behavior of the PI. Immediately after 
completing the procedure, he or she will answer the questionnaire “Evaluation of OVD performance”, 
appendix 15.1. The ability of the OVD to maintain the AC formed during continuous circular capsulorhexis 
(CCC) and IOL implantation, retention during phacoemulsification, ease of use (including blister removal, 
syringe assembly, ease of injection), ergonomics, facilitation of CCC performance, transparency during 
surgery, and ease of removal will be evaluated. They will be graded on a 5-point scale: 0 = very poor; 1 = 
poor; 2 = acceptable; 3 = good; 4 = very good. The results will be recorded in the eCRF. 
Management as AE: Not applicable. The results of this questionnaire should not be considered AE. 
7.5 Program of visits and activities of the study  
7.5.1 Description of activities per visit  
The procedures are listed in the order in which they are suggested, attempting to maintain consistency 
in the assessments and, as far as possible, from the least invasive to the most invasive. 
7.5.1.1 Scrutiny Visit 
Signature of the ICF: refers to the signing of the written informed consent document. Without informed 
consent, none of the study procedures can be performed. 
Medical record: refers to the technical, clinical, and legal document that chronologically records the 
subject's health conditions, medical procedures, and other procedures performed on the subject. It 
includes anthropometric measurements, anamnesis, a comprehensive ophthalmological examination 
that allows determining the patient's eligibility, i.e., evaluation of both eyes and ocular adnexa, slit-lamp 
examination of the ocular surface and anterior segment, and fundoscopy. If the subject is taken from the 
study center's established population base, the existing medical record may be used; only one update is 
required. 
Somatometry: refers to the measurement of the research subject's weight and height, expressed in kg 
and cm, respectively. It will be performed with calibrated instruments of the center's choice. 
Concomitant Medication Assessment: Refers to the PI questioning the subject about medication use. 
Vital signs: refers to taking heart rate, respiratory rate, systemic blood pressure and temperature. 
AVMC: See 7.4.4.6 
Ophthalmological evaluation: See 7.4.4.3 
Ocular tonometry: See 7.4.4.2* 
Gonioscopy: Refers to the evaluation of the AC angle. After applying a drop of 0.5% tetracaine ophthalmic 
solution, the 60° lateral mirror of the goniolens is used to evaluate the iridocorneal angle, which is graded 
according to the Shaffer classification. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 40 of 66 
CONFIDENTIAL 
Assessment of pharmacological mydriasis: After checking the AC angle, apply one drop of 5% 
Phenylephrine/0.8% Tropicamide every 5 minutes, on three occasions. Five minutes after the last 
application, the pupillary diameter will be measured using a slit lamp. This measurement will be recorded 
in the eCRF. 
Specular microscopy: See 7.4.4.1 
Corneal pachymetry: See 7.4.4.4 
Eligibility criteria: Refers to the PI's review, which verifies that the subject can be included in the study if 
they meet all the inclusion criteria and do not meet the exclusion criteria. See 5.1 
IOL calculation and anterior chamber measurement: Once the relevant eligibility criteria have been met, 
the IOL calculation will be performed. This involves biometric measurements (keratometry, anterior 
chamber depth, and axial length) and their integration into the PI selection formula to determine the 
power, expressed in diopters, of the IOL to be implanted. This will be performed using the Zeiss IOL Master 
device (the model must be specified). 
Preoperative cardiology evaluation request: This refers to the delivery to the research subject of the 
requests for laboratory tests (blood pressure, serum calcium and PT/TPT, INR), ECG, and subsequent 
preoperative cardiology evaluation. The subject must arrive at the scheduled time and date for the tests 
and evaluation. 
AE Assessment: See 7.4.4.3 
7.5.1.2 Scheduling Visit 
Vital signs: See 7.5.1.1 
Evaluation of concomitant medications: See 7.5.1.1 
Preoperative cardiology assessment review: Refers to the review, by the PI or designated staff member, 
of the preoperative cardiology evaluation. This assessment must be performed by a physician specializing 
in cardiology or internal medicine, who must confirm that the patient is suitable for the indicated surgical 
procedure. 
Eligibility criteria: Subject selection criteria are completed by reviewing the pre-surgical cardiology 
assessment. 
Surgical scheduling: This refers to the scheduling of a date for the surgical procedure and the request for 
pre-anesthesia evaluation. An anesthesiologist must perform this evaluation. 
Subject Material Delivery: Once your participation has been confirmed, your subject's calendar and ID 
card will be delivered. 
AE Assessment: See 7.4.4.3 
7.5.1.3 Surgery Visit 
Vital signs: See 7.5.1.1 
Evaluation of concomitant medications: See 7.5.1.1 
PI Assignment: Refers to the randomization and assignment of the OVD to be used during surgery using 
the IWRS system. 
Phacoemulsification surgery: refers to the surgical procedure, which will be performed with topical 
anesthesia, 0.5% tetracaine ophthalmic solution, and sedation. A drop of 5% povidone-iodine solution will 
be used as prophylaxis in the conjunctival fornix. After asepsis and antisepsis, sterile drapes with complete 
eyelash coverage and a blepharostat will be placed, the following steps will be performed: 
 1mm limbal incision, with a 15º knife. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 41 of 66 
CONFIDENTIAL 
Capsular staining with 0.6% trypan blue, at the surgeon's discretion, air bubbles may or may not be used 
and washing with BSS. 
Application of the OVD to form the anterior chamber, quantity at the surgeon's discretion. 
2.2mm limbal incision with double-bevel knife, with self-sealing wound architecture. 
Continuous circular capsulorhexis, assisted by the surgeon's preferred instrument. 
Hydrodissection and hydrodelineation with BSS. 
Phacoemulsification with the surgeon's preferred technique for the case. 
Cortical aspiration with coaxial I/A. 
Capsular bag formation with OVD. 
Insertion of enVista® IOL (Bausch & Lomb) 
Removal of the OVD with coaxial I/A piece. 
If necessary, close the 2.2mm wound with 10-0 Nylon. 
The procedures and order mentioned here are for informational purposes only; the 
surgeon's judgment should prevail over the order, modification, or waiver of any 
procedure. The OVD may be used at another time during surgery at the surgeon's 
discretion. 
AE Assessment: See 7.4.4.3 
Transurgical evaluation: See 7.4.4.7 
Continuity assessment: refers to the PI's assessment to ensure that there are no reasons for the subject 
to withdraw from the study. 
7.5.1.4 1st Safety Visit 
Vital signs: See 7.5.1.1 
Evaluation of concomitant medications: See 7.5.1.1 
AVMC: See 7.4.4.6 
Ophthalmological evaluation: See 7.4.4.3 
Ocular tonometry: See 7.4.4.2 
AE Assessment: See 7.4.4.3 
Delivery of concomitant treatment: refers to the delivery, by the research center to the subject, of the 
concomitant treatment (Sophixin DX® Ofteno) and the indication of the dosage to follow. 
Continuity assessment: See 7.5.1.3 
7.5.1.5 2nd Safety Visit 
Vital signs: See 7.5.1.1 
Evaluation of concomitant medications: See 7.5.1.1 
AVMC: See 7.4.4.6 
Ophthalmological evaluation: See 7.4.4.3 
Ocular tonometry: See 7.4.4.2 
AE Assessment: See 7.4.4.3 
If a stitch has been placed in the main port, remove it. 
Continuity assessment: See 7.5.1.3 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 42 of 66 
CONFIDENTIAL 
7.5.1.6 Final Visit 
Vital signs: See 7.5.1.1 
Evaluation of concomitant medications: See 7.5.1.1 
AVMC: See 7.4.4.6 
Ophthalmological evaluation: See 7.4.4.3 
Ocular tonometry: See 7.4.4.2 
Specular microscopy: See 7.4.4.1 
Corneal pachymetry: See 7.4.4.4 
AE Assessment: See 7.4.4.3 
Return of concomitant treatment: refers to the return of the Sophixin DX® Ofteno bottle by the subject to 
the research center. 
7.5.2 Unscheduled follow-up visits  
At the request of the subject or study personnel, unscheduled follow-up visits may be conducted to report 
adverse events or any other situation that warrants it. During these visits, all relevant data on reported 
adverse events must be collected, and an appropriate management plan must be established, if 
applicable. 
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 analytical equipment) where information is first recorded and 
which become part of the subject's permanent medical record. Examples of source documents include 
medical records, clinical progress notes, laboratory reports, office study reports, nursing notes, follow-up 
notes, surgical records, etc. 
The PI is obligated to accept monitoring of study-related information, audits, review by ethics and 
research committees, and inspections by the health authority. This obligation implies direct access to 
source documents. 
7.6.2 Electronic forms of data collection  
All protocol-related data will be captured via an electronic case report form (eCRF) by research team staff. 
Protocol-related data should NOT be captured directly into the eCRF, but rather transcribed from the 
corresponding source document. This procedure allows for monitoring to verify the information captured 
in the eCRF. It is the researcher's responsibility to ensure that the information is transcribed into the eCRF 
correctly, completely, and in a timely manner. It is understood that all data captured and submitted via 
the eCRF for data analysis have been approved by the researcher. 
7.6.3 Archive  
The data collected in this database are anonymous (only the subject number is stored along with other 
relevant information). The software used for data capture and storage meets the traceability 
requirements necessary for conducting clinical studies. The collected data will be stored by the sponsor 
or designated clinical research organization for a period of 10 years. Records of subject number 
assignment will remain at the participating institutions under the care of the PI or their team and must 
be maintained for at least 5 years. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 43 of 66 
CONFIDENTIAL 
8. Evaluation and management of adverse events and incidents 
8.1 Regulation and standards on adverse events and incidents 
The registration and reporting of adverse events and incidents will be carried out in accordance with the 
guidelines established in NOM-240-SSA1-2012, NOM-220-SSA1-2016 and the international ICH E6 
guidelines. [36, 37, 38, 39, 40] 
8.2 Definition of adverse event, incident, adverse incident and adverse effect  
According to the International Conference on Harmonization (ICH), an adverse event (AE) is any 
unfavorable medical occurrence in a clinical research subject administered a pharmaceutical product, 
regardless of causal attribution. [38, 39, 40] 
Therefore, an AE may be any of the following: any unfavorable, unintended disease, symptom, or sign 
(including an abnormal laboratory finding) that is temporally related to the use of a medical product, 
whether or not considered to be related to that product; any new disease or exacerbation of an existing 
disease (worsening of the nature, frequency, or severity of a known condition); relapse of an intermittent 
medical condition (e.g., headache) not present at baseline; any deterioration in a laboratory value or 
other clinical test (e.g., electrocardiogram [ECG], X-ray) that is related to the symptoms or that results in 
a change in study or concomitant treatment or discontinuation of study drug. [38, 39, 40] 
As defined in the previous paragraph, an adverse event is defined as any event that occurs during 
treatment with a drug or device. However, the definition can also apply to any undesirable event that 
occurs during a clinical trial, including behavioral disturbances. [40] 
According to NOM-240-SSA1-2012, an incident is any event related to the use of a medical device; while 
an adverse incident is any proven event related to the use of a medical device that has conclusive evidence 
of the causal relationship between the incident and the medical device, and that could be caused by a 
malfunction or alteration of the characteristics of the medical device and that could cause death or serious 
deterioration of the health of the user. An adverse incident will not be considered an incident derived 
from abnormal use or a use different from that recommended by the holder of the sanitary registration 
of the medical device or its legal representative in Mexico. [37] 
According to NOM-012-SSA3-2012, an adverse effect is the set of uncalculated and unexpected signs and 
symptoms that occur in a research subject, as a consequence of the application of experimental 
maneuvers planned in a protocol or research project for health in human beings and that potentially 
represent a risk to their health. [41] 
8.3 Use of adverse events as a study safety variable 
Measuring the safety of PRO-149 use is paramount to the study, therefore, it is considered important to 
report any undesirable manifestation or illness that occurs during the course of the study, regardless of 
whether the manifestation is considered related to the investigational treatment or not. [40] 
Reporting all adverse events occurring during the investigation will allow us to subsequently determine 
their causality to the investigational treatment (medical devices) and determine whether they are 
incidents or adverse events; or determine their causality to concomitant medical treatment or other 
procedures. [36, 37, 38, 39, 40, 41] 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 44 of 66 
CONFIDENTIAL 
8.4 Definitions relevant to the classification of adverse events  
Severity (serious/non-serious), also called seriousness (serious/non-serious). A serious event is defined as 
any event that: results in death, threatens life, requires hospitalization or prolongs hospitalization, causes 
permanent or significant disability or incapacity, causes abnormalities or malformations in the newborn, 
or other medically significant conditions. 
Severity (mild, moderate, or severe). Mild symptoms are those that present with minimal symptoms and 
do not require treatment or discontinuation of the medication; moderate symptoms interfere with 
normal activities without threatening the subject's life, require treatment, and may or may not require 
discontinuation of the medication; severe symptoms interfere with normal activities and require 
pharmacological treatment and discontinuation of the medication. [36, 38, 39] 
Causality. It is the relationship assigned between the pharmaceutical product and the adverse event: 
certainly caused by the pharmaceutical product, there is clear evidence of causality, i.e. the adverse event 
reappears with the administration of the pharmaceutical product; probably caused by the pharmaceutical 
product, there is a high suspicion of causality but direct evidence is lacking or it is considered unnecessary 
or dangerous, i.e. the reaction disappears upon discontinuation of the pharmaceutical product; possibly 
caused by the pharmaceutical product, there is additional information suggesting that the cause may be 
due to another pharmaceutical product or disease; unlikely to be caused by the pharmaceutical product, 
there is a clear explanation for the origin due to the underlying disease or the use of another 
pharmaceutical product; conditional, there is a lack of data to issue a clear causality; unclassifiable, those 
for which once all possible information on the adverse event has been obtained, it remains unclassifiable. 
[36, 38, 39, 40] 
8.5 Researcher Responsibilities  
It is the investigator's responsibility to verify AEs and incidents through questioning, a relevant physical 
examination, assessment of progress, and appropriate medical and pharmacological management; as well 
as to follow up until the AE or incident is resolved or resolved and finally discharged, following the 
definitions established in national and international regulations. [36, 38, 39] 
In the event of an AE or any event that puts the health and well-being of the subjects at risk, appropriate 
medical care will be provided, either at the research center or by referring the subject to the highest-
resolution hospital with which the research center has a medical care agreement. The PI will notify the 
sponsor's clinical monitor, in accordance with the timeframes established in national and international 
regulations. In the case of serious adverse events, the PI will notify the sponsor and record the 
corresponding information in the eCRF, and in turn, will inform the IEC and the IC. 
The attention of the AE will be carried out according to the event attention diagram (see Figure 4. Adverse 
event attention). 
The final report that will be drafted by the Clinical Team of the Clinical Operations Department of 
Laboratorios Sophia, S.A. de C.V., will include the report of adverse events in compliance with current 
national and international regulations. [36] [38] 
If the research subject develops a chronic adverse event during their participation in the study, such as 
diabetes or arterial hypertension, they will be referred to a healthcare professional for chronic treatment. 
Follow-up and termination of participation will be in accordance with ICH guidelines. 
8.5.1 Recording of adverse events in the electronic case report form  
The adverse event registry considers: 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 45 of 66 
CONFIDENTIAL 
 Subject identification information such as: subject number, age, sex, and if applicable, specify the 
eye. 
 Information about the causality of the adverse event, its relationship to the investigational 
products, or to another study-related drug, as appropriate. 
 Information on important dates: 
o Date on which the adverse event occurs. 
o Date on which the Principal Investigator is informed of the same. 
o Date of resolution or outcome, as applicable. 
 Information on diagnosis and clinical management. 
 Establish the outcome or resolution of the event: 
o Recovered/resolved without sequelae 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Subject who died due to the adverse event 
o Subject who presented death and it is judged that the investigational product may have 
contributed 
o Subject who died and this was not related to the product under investigation, 
o A stranger 
 Information about the investigational product or the product associated with the adverse event, 
incident, adverse event, ADR, or SRAM must be recorded. The essential information to be 
recorded is the generic name, distinctive name, or code of the investigational product or the 
product associated with the undesirable clinical manifestation. It will also be necessary to record 
data concerning the lot number, manufacturing laboratory, expiration date, dose, route of 
administration, start and end dates of administration and/or consumption, and reason for the 
prescription, depending on whether it is an investigational product or medication (a protocol in 
which the subject is currently participating) or a medication that the research subject is taking for 
the treatment of underlying concomitant diseases or for the management of any transient signs 
or symptoms that do not correspond to the natural history of the pathology that motivated their 
entry into the research protocol. 
 Indicate whether the adverse event disappears upon withdrawal of the suspected product (which 
caused the event). Also indicate whether a dose adjustment is made, whether the event changes 
in intensity or severity, and whether the reaction persists. It is important to indicate whether the 
AE reappears in subjects who are re-exposed to the product after having been previously 
discontinued. 
 Information regarding concomitant pharmacotherapy. Indicate the generic name, dose, route of 
administration, start and end dates, and the reason for the prescription, regardless of whether it 
is in accordance with the prescribing information or the data sheet or if it is used outside of the 
regulations or as authorized by the local, national, or international regulatory body. 
 Information on relevant clinical history. The analysis of the AE considers the information 
previously described. However, the clinical context in which the adverse event occurs in the 
participants in the clinical research protocol is of particular interest. Therefore, information about 
previous conditions, hypersensitivity or allergy symptoms, previous surgical procedures, 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 46 of 66 
CONFIDENTIAL 
laboratory tests or imaging examinations the participant has undergone, etc., that the researcher 
deems appropriate may be mentioned. 
8.5.2 Monitoring of adverse events  
The Principal Investigator will provide care and follow-up of the adverse event presented by the 
participant until its outcome, in accordance with the provisions of the following section. 
8.5.3 Procedures for a serious adverse event  
The adverse event handling process considers the following stages: 
Figure 4. Adverse event care 
During the development and conduct of this study, undesirable harmful events or adverse 
reactions/incidents with medical implications may occur in the research subject, which are not necessarily 
causally related to the investigational products. These harmful phenomena may occur during the use of 
investigational pharmaceutical products at doses authorized for human use by a local, national, or 
international regulatory body. However, it may be suspected that the investigational product may cause 
some unwanted clinical manifestation. AEs, Incidents, Adverse Incidents, ADRs, or SRAMs related to one 
or more pharmaceutical products may occur during the systematic evaluation of participants (on the days 
on which the clinical review is scheduled, according to the schedule of activities) or suddenly, in such a 
way that: 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 47 of 66 
CONFIDENTIAL 
1. The investigator should be the first person to whom the subject notifies that he or she has 
developed or experienced any clinically harmful phenomena during his or her participation in 
this study. 
2. Based on their clinical judgment, the principal investigator will determine the appropriate 
treatment for the adverse event/reaction based on the relevant physical examination, 
history, etc., as well as the analysis of information available in the medical literature and the 
information contained in the investigator's manual, Prescribing Information, or the 
comparator drug's data sheet. 
3. This care may be provided at the research center or at the hospital with the highest capacity 
for treatment. Thus, if the subject is referred by the PI to a hospital, they will be provided 
care through a referral system. The referral may be through a card identifying the subject as 
a study participant and linking them to the pre-established agreement with the institution, or 
through a referral medical note issued by the Principal Investigator. Laboratorios Sophia, S.A. 
de C.V., will pay the costs for the participating subject's medical care when the adverse event 
is associated with or related to the investigational product. 
4. Taking into account the clinical information collected, either during the care provided at the 
research center or provided by the treating physician(s) at the hospital, the PI will record the 
AE in his/her clinical note, stating the seriousness, intensity (mild, moderate, or severe), and 
relationship to the investigational product. 
5. The PI must migrate the relevant data to the eCRF and its respective adverse event section. 
Serious adverse events must be reported to the study's clinical monitor within 24 hours of 
becoming aware of them, so that they can then inform the Clinical Team and the UTFLS, and 
subsequently notify the IEC/CI. Non-serious adverse events will be recorded and 
appropriately addressed, and the corresponding regulatory body will be informed about the 
safety profile of the PI or investigational drug in the final clinical trial report. 
Recording the outcome of the AE depends substantially on the Principal Investigator's follow-up of the 
subject, as most adverse events (see the safety profile section in section 2.2.2 and the investigator's 
manual) are expected to be ophthalmic in nature; however, systemic alterations may occur. Therefore, 
at the investigator's discretion, the participant's withdrawal or continuation will be considered. 
8.5.4 Assessment of causality  
Causality assessment is the methodology used to estimate the probability of attributing an observed 
adverse event to a pharmaceutical product. It considers probabilistic categories according to the available 
evidence and the quality of the information, based on national pharmacovigilance and technovigilance 
regulations. [36] [42] 
An adverse event may or may not be related to the clinical trial. A causal relationship means that the 
intervention caused (or is reasonably likely to have caused) the adverse event. This usually involves a 
relationship between the timing of the intervention and the adverse event (e.g., the adverse event 
occurred shortly after the research subject received the intervention). [40] 
For all adverse events, the Principal Investigator is responsible for examining and evaluating the patient 
to determine the association of the event with the clinical study and intervention, whether related to 
experimental treatment, concomitant treatment, surgical procedure, or diagnostic procedures performed 
during the study. [40] 
Accepting that the adverse event is related to the clinical study requires a plausible mechanism of action—
that is, a logical sequence between the event and the intervention that caused it. In some cases, it is 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 48 of 66 
CONFIDENTIAL 
helpful to know the opinions of other physicians directly or indirectly involved in the study, as well as 
whether the patient believes there is a relationship. [40] 
There are no guidelines or algorithms available to help determine the causality of an adverse event in the 
case of the use of a medical device. This means that the relationship is established by the opinion of the 
researcher and the reasoning on how the adverse event occurred. However, the Pharmacovigilance and 
Technovigilance Unit of Sophia Laboratories (UFTLS) may use the causality categories described by the 
Uppsala Monitoring Centre, to categorize the probability of the adverse event to concomitant or 
experimental treatment (medical devices for convenience may be evaluated as drugs within the 
categories): [36] [42] 
• 
Definite (certain): A clinical event, including laboratory test abnormalities, which occurs in a 
plausible time sequence related to drug administration and that cannot be explained by 
concurrent disease or by other drugs or substances. The response to drug withdrawal must be 
clinically plausible. The event must be definitive from a pharmacological or phenomenological 
point of view, using, if necessary, a conclusive rechallenge procedure. [36] [42] 
• 
Probable: A clinical event, including laboratory test abnormalities, which occurs in a reasonable 
time sequence related to drug administration, is unlikely to be attributed to the concurrent 
disease or to other drugs or substances, and to which withdrawal of the drug produces a clinically 
reasonable response. Rechallenge information is not required for this definition. [36] [42] 
• 
Possible: A clinical event, including laboratory test abnormalities, which occurs in a reasonable 
time sequence related to drug administration, but that may also be explained by concurrent 
disease, or by other drugs or substances. Information regarding drug withdrawal may be missing 
or unclear. [36] [42] 
• 
Unlikely: A clinical event, including laboratory test abnormalities, which occurs in a time sequence 
that is unlikely to occur in relation to the administration of the drug and that can be more 
plausibly explained by concurrent disease, or by other drugs or substances. [36] [42] 
• 
Conditional/Unclassified: A clinical event, including laboratory test abnormalities, reported as an 
adverse reaction, for which further data are essential for proper evaluation, or additional data 
are under review. [36] [42] 
• 
Not evaluable/Unclassifiable: A report that suggests an adverse reaction, but which cannot be 
judged due to insufficient or contradictory information, and which cannot be verified or 
completed in its data. [36] [42] 
Thus, the degree of certainty to establish the investigational product as the causal agent of the harmful 
phenomenon that occurs in the subject of the clinical study can be indicated directly by the Principal 
Investigator based on his or her clinical experience or through the application of the causality categories 
described by the Uppsala Monitoring Centre. It is important that the researcher and the UFTLS consider 
the following arguments in favor of the causal relationship: 
a) Strength of association, which refers to the number of cases in relation to those exposed. 
b) The consistency of the data, that is, the presence of a common characteristic or pattern. 
c) The exposure-effect pattern, which determines the relationship with the site of onset, time, dose 
and reversibility after suppression. 
d) Biological plausibility, which refers to the possible pharmacological or pathophysiological 
mechanisms involved in the development or presentation of the adverse event. 
e) Experimental findings, for example, the appearance of anomalous metabolites or high levels of 
drug or its biotransformation product. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 49 of 66 
CONFIDENTIAL 
f) Analogy, which refers to the experience acquired with other related drugs, adverse reactions 
frequently produced by the same family of pharmacological agents. 
g) Nature and characteristics of the data, i.e., objectivity, accuracy and validity of the relevant 
documentation. [43] 
8.6 Unanticipated problems  
Unanticipated problems (ANP) are considered situations that pose risks to the participating subjects, 
generally any incident, experience or result that meets all of 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 study population. 
• 
Related or possibly related to your participation in the study (possibly related means that there is a 
reasonable possibility that the incident or results were caused by study procedures). 
• 
Indication that the research places participants at greater risk of harm (including physical, 
psychological, economic, or social) than previously recognized. 
8.6.1 UAPs Report  
The PI will be responsible for reporting UAPs to the sponsor, the IC, and the IEC. The report should contain 
the following information: 
• 
Study identification: protocol title and number, name of the PI and, where applicable, the center. 
• 
Detailed description of the event, incident, experience or outcome. 
• 
Explanation, justification of the reasons why the incident represents a UAP. 
• 
Description of changes to the protocol or corrective actions taken or proposed in response to the 
UAP. 
UAPs that are EAS must be reported to the IEC/ CI and the sponsor within the first 24 hours of the PI 
becoming aware of it. 
Any other UAP will be reported to the IEC/CI and the sponsor within the first 5 business days after the PI 
becomes aware of it. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 50 of 66 
CONFIDENTIAL 
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, study site monitoring, adverse 
event detection monitoring, reporting and follow-up, monitoring to resolve data entry discrepancies, etc. 
Responsibility for monitoring activities and ultimate responsibility for monitoring rests with the sponsor. 
The details of the monitoring activities are specified in a separate document from this protocol in a 
Monitoring Plan. 
9.1 Monitoring of study centers  
The research centers participating in the study will be monitored. At least one initial visit and one closing 
visit must be conducted for each center, although one or more follow-up visits may be required between 
these two mandatory visits. 
The initial visit must be conducted before the first participant is enrolled at that center. During this visit, 
the monitor will verify that the materials to be used during the study have been received and that the 
personnel involved in study activities have been trained in the study. The monitor will also verify 
compliance with applicable regulatory requirements and standard operating procedures. 
At the follow-up visit(s), the monitor will review the study documents to confirm that the research 
protocol and applicable standard operating procedures are being followed, that data entry is complete 
and timely, and that adverse event reporting is being conducted appropriately. At each visit, the monitor 
will discuss the findings with the investigator and determine the appropriate actions to be taken. 
The closing visit will take place at the end of the study, once the last participant at the site has been 
discharged from follow-up. During this visit, the monitor will verify that the site has all necessary 
documentation for archiving, that all biological samples have been analyzed, that all PI (used and unused) 
has been returned to the sponsor, and that all unused materials have been recovered. 
Details of 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 may also conduct a regulatory inspection 
of this study. 
Details of the audit process are set out separately in an Audit Plan. 
9.2.1 Pre-study audit  
The study centers included in the study will be subject to a feasibility visit prior to center selection, where 
they will be verified to meet the minimum requirements indicated by the sponsor. 
9.2.2 Audit during the conduct of the study  
They may take place at any time before, during, or after the conclusion of the study. If an audit or 
inspection is conducted, the investigator and the institution must agree to allow the auditor/inspector 
direct access to all relevant documents and must allocate their time and staff time to the 
auditor/inspector to discuss the findings and any pertinent issues. If the audit has not been scheduled by 
the sponsor, the center must notify Laboratorios Sophia, S.A. de C.V. immediately. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 51 of 66 
CONFIDENTIAL 
10. 
Statistical analysis 
10.1 Data analysis 
10.1.1 Statistical analysis 
Statistical analysis will be performed by staff of Laboratorios Sophia, S.A. de C.V. The statistical software 
SPSS version 19.0 for Windows (IBM Corporation, Armonk, NY, USA) will be used. 
Although the study design is open-label, to avoid potential interpretation bias, the staff assigned to the 
statistical data management will be blinded to the intervention groups. Coding will be performed using 
consecutive numbers for each intervention group. 
The data will be collected and organized in an Excel spreadsheet (Microsoft® Office). The data will then 
be exported to the SPSS software platform. Variables will be categorized according to their nature; see 
Table 3. 
10.1.2 Data interpretation 
The results of continuous quantitative variables will be presented in measures of central tendency: mean, 
standard deviation and ranges. 
KS and SW tests will be performed, as applicable, to determine whether the distribution presents 
normality in the results obtained in each study group. [44]  
If normality of the data is observed (p > 0.05; for KS and SW), the statistical analysis of the continuous 
quantitative variables to find significant differences (p) will be as follows: 
• Intra-group analysis: will be determined using the Student’s t-test for repeated measures. 
• Between-group analysis: differences between groups will be analyzed using Student's t-test for 
independent groups. 
For p < 0.05 in KS and SW, the statistical analysis of continuous quantitative variables to find significant 
differences (p) will be as follows: 
• Intra-group analysis: will be determined using the Wilcoxon rank test. [45] 
• Between-group analysis: differences between groups will be analyzed using the Mann-Whitney U 
statistic. 
The level of difference to consider significance will be an α of 0.05 or less [46]. 
The results of the nominal and ordinal qualitative variables will be presented in frequencies, proportions 
and percentages. 
Statistical analysis to identify significant differences in qualitative variables will be performed by creating 
2x2 contingency tables and will be carried out as follows: 
• 
Intra-group differences: will be determined by the McNemar test [47], which is applied to 2×2 
contingency tables with a dichotomous trait and pairs of matched subjects to determine whether 
the marginal frequencies of row and column are equal (marginal homogeneity). 
• 
Difference between groups: Differences between groups will be analyzed using Pearson's X2 test 
or Fisher's exact test when expected values are less than 5. 
The level of difference to consider significance will be an α of 0.05 or less. 
For the reporting of adverse events, participants who were randomly assigned to an intervention group 
after application of the investigational product will be considered. 
The final results report will be displayed in tables or graphs, as appropriate. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 52 of 66 
CONFIDENTIAL 
The investigational product will be considered safe when there are no clinical and statistical differences 
in all primary outcome variables, with respect to its comparator (Healon EndoCoat®). 
10.1.3 Procedure for handling missing data 
The safety assessment will include in the analysis all subjects who have been exposed to any of the 
interventions, regardless of the visit at which they were eliminated from the study (ITT; intention-to-treat 
population). 
10.1.4 Deviations from the statistical analysis plan 
According to the sample size calculation to meet the study objective, 28 evaluable subjects (14 cases per 
arm) are required. If this number is not met due to a loss of subjects exceeding the 20% threshold 
established in this protocol (loss to follow-up or withdrawal from ICF), the sponsor may substitute these 
subjects to balance the treatment groups. 
The results obtained from the replaced subjects will continue to be used for safety analysis and will be 
part of the ITT. 
10.1.5 Subjects included in the analysis 
Those subjects who complete all their visits will be included in the statistical analysis to meet the study 
objective (PP; per-protocol population). 
The variables, method and scales for their measurement are described in detail below. 
10.2 Sample size calculation 
10.2.1 Number of subjects calculated 
36 evaluable subjects were estimated (18 subjects per arm, one eye per subject). 
10.2.2 Justification of the sample calculation 
Although there are no references on sample size calculation for pilot studies, it was considered 
appropriate to perform the calculation based on the clinical study by Storr-Paulsen et al [48], who 
compared the influence of three OVDs of 1%, 2% and 3% SH on corneal endothelial cell count during 
cataract surgery up to three months postoperatively. All three OVDs showed a decrease in postoperative 
cell count, for SH-1% it was 18.46%, for SH-2% it was 18.03% and for SH-3% it was 6.97%. [48] 
The percentage decrease in dispersive OVD at 3% SH was considered. The sample size was calculated using 
the equation for an equivalence ratio [49], which is useful when we want to test whether a ratio p, is 
different from a standard reference value, p0. In this case, we want to test that PRO-149 is equivalent to 
its comparator (Healon® EndoCoat). Here the test falls on PRO-149; that is, equivalence is represented by 
the alternative hypothesis (H1), rather than the null hypothesis (H0). 
Working hypothesis for calculating the sample size: 
𝐻0: |𝑃−𝑃0| ≥𝛿 
𝐻1:|𝑃−𝑃0| < 𝛿 
 
Considering an α = 0.05 corresponding to the type I error (95% confidence level), a power (β) = 0.20 
corresponding to the type II error (80% power) and a test margin (δ) of 5%. The calculation to estimate 
the 
sample 
size 
was 
performed 
using 
an 
online 
tool 
(Sample 
size 
calculators, 
http://powerandsamplesize.com), following the following equations: 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 53 of 66 
CONFIDENTIAL 
𝑛= 𝑝(1 −𝑝) (
𝑍1−𝛼+ 𝑍1−𝛽/2
|𝑝−𝑝0| −𝛿)
2
 
 
1 −𝛽= 2[Φ(𝑧−𝑧1−𝛼) + Φ(−𝑧−𝑧1−𝛼)] −1, 𝑧= |𝑝−𝑝0| −𝛿
√𝑝(1 −𝑝)
 𝑛
 
Where: 
n: sample size, 
p0: comparison value, 
Φ: function of the standard normal distribution 
Φ-1: normal standard quantile function 
α: Type I error 
β: Type II error (1-β is the power) 
δ: test margin. 
According to the previous calculation, the result was 14 cases (eyes) per arm; this calculation was 
increased by 20% to account for potential losses. The total sample size required is 18 cases (eyes) per 
treatment arm, a total of 36 cases. This calculation is consistent with the sample size used in similar clinical 
studies where OVDs were employed. [50, 51, 52]

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 54 of 66 
CONFIDENTIAL 
11. 
Ethical considerations 
11.1 Approval of committees  
This study will be conducted in accordance with the standards of the Declaration of Helsinki, World 
Medical Association 2013. Nuremberg Code; Nuremberg Judgment by the International Tribunal at 
Nuremberg, 1947. Belmont Report, National Commission for the Protection of Subjects of Biomedical and 
Conduct Research, 1979. It will be conducted in accordance with the scientific and technical requirements 
necessary for the registration of medicines for human use of the International Conference on 
Harmonization (The International Council for Harmonisation (ICH) Guideline for Good Clinical Practice. 
International Ethical Guidelines for Biomedical Research Involving Human Subjects of the Council for 
International Organizations of Medical Sciences of Medical Sciences, CIOMS, 2002). International Ethical 
Guidelines for Epidemiological Studies of the Council for International Organizations of Medical Sciences 
of Medical Sciences, CIOMS, 2008). The Research Ethics Committee and the Research Committee will 
evaluate the protocol before conducting the study and will issue their approval or any possible 
modifications for its implementation. These Committees must be notified of any significant changes to 
the protocol. In addition to the above, the current regulations of the regulatory authority must also be 
complied with. 
The sponsor's authorized personnel will submit the essential documentation of the research project for 
evaluation by the Research Ethics Committees, Research Committees, and when applicable, to the 
Biosafety Committee: research protocol, informed consent form, researcher's manual, subject material, 
as well as other additionally requested documents, in accordance with the local, national or international 
requirements applicable by regulatory entities. 
The study will not be initiated at the research center without the confidentiality agreements and financial 
proposals from each of the principal investigators, duly signed, and without having previously obtained 
the favorable opinion and/or approval of the corresponding Research Ethics Committees, Research 
Committees, and, where applicable, the Biosafety Committee. 
The study will not begin without meeting the relevant local, national, or international regulatory 
requirements and obtaining the appropriate health authorization. 
The study is considered to be research with greater than minimum risk, in accordance with the 
Regulations of the General Health Law on Health Research, Title Two, Chapter I, Article 17, Section III, 
published in the Official Gazette on January 6, 1987. 
11.2 Amendments to the protocol  
The amendment process will be relevant when there is a need to make any changes to a document that 
is part of the research project or protocol, due to changes in the methodological structure, replacement 
of the principal investigator, or the identification of risks to the research subjects. Documents that may 
be amended include: the protocol, informed consent letter, researcher's manual, subject documents, 
measurement scales, and activity schedule. 
Any amendment must be approved by the sponsor and/or the principal investigator. The amended 
document(s), once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, when applicable, by the Biosafety Committee (entities that issued the initial favorable 
opinion for the conduct of the research), will be sent for authorization by COFEPRIS. 
Amendments that substantially modify the protocol or impose additional or different risks to research 
subjects must be approved by the aforementioned Committees. It is the investigator's responsibility to 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 55 of 66 
CONFIDENTIAL 
take measures in situations requiring immediate action to prevent unnecessary harm to study 
participants. 
The principal investigator is responsible for communicating to the Research Ethics Committee any 
amendments to the protocol that could affect the rights, safety, or well-being of the research participants. 
They must also report any situation or new knowledge that indicates an increased risk to the participants, 
the premature termination or suspension of the study, the reasons for this, and the results obtained to 
that point. They must also report the conclusion of the study upon completion of the research protocol. 
11.3 Early termination of the study  
The study may be temporarily suspended or terminated prematurely if there is sufficiently reasonable 
cause. Written notification documenting the reason for the suspension or early termination must be 
provided by the party executing the suspension. The PI must promptly inform the study participants, the 
IC, and the IRB, providing the reasons. 
Situations in which suspension or early termination of the study will be considered include, but are not 
limited to: 
1. 
The presence of serious adverse events in more than 10% of participants in a study group. 
2. 
The regulatory authority (COFEPRIS) considered it due to security alerts. 
3. 
The Sponsor determines this for its convenience or eventualities such as: financial support, 
manufacturing errors, etc. 
4. 
The determination of unexpected risks to participants that are significant or unacceptable. 
5. 
Obtaining new relevant safety information. 
6. 
Insufficient adherence to protocol requirements. 
7. 
The data obtained are not evaluable or are not sufficiently complete. 
8. 
The determination that the primary objective has been achieved. 
9. 
The determination of futility. 
In the event of suspension, the study may be resumed once the situations that led to the suspension have 
been resolved, provided this justification is sufficient for the sponsor, IC, IEC, and regulatory authorities. 
11.4 Informed consent  
The ICF contains complete and understandable information about the study and the investigational 
product, in accordance with current applicable regulations and Good Clinical Practices. 
The ICF will be considered a source document and will be filed as such. The site's principal investigator is 
responsible for ensuring that all new versions of the informed consent form undergo the appropriate 
approvals (the same ones that the original informed consent form underwent) and that the most current 
approved version is presented to the study subjects. 
11.4.1 Obtaining  
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. For this purpose, the informed consent form must be signed. 
Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice and will be in compliance with all 
applicable laws and regulations. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 56 of 66 
CONFIDENTIAL 
The PI, or the study staff delegated by him or her, will provide the potential participant with all 
information regarding the characteristics of the study, its potential benefits, risks, objectives, and 
procedures. 
This information will be provided in a language understandable to the subject. The subject will be 
explained that they have the right to discontinue their participation in the study at any stage, without 
affecting their relationship with the researcher and/or their future participation. Informed consent will 
be presented to the potential participant; they must have sufficient time to review each and every aspect 
mentioned above. Any questions they may have will be clarified by the person responsible for obtaining 
informed consent. 
Once the participant agrees to participate in the study, he or she must sign and date the informed consent 
letter in the presence of two witnesses, whether or not related to the study subject. These witnesses will 
participate in the informed consent process and sign, confirming that the process was carried out prior to 
any study procedure, that the study information was clearly explained, and that any questions were 
clarified. 
In the event that a subject is illiterate, acceptance will be specified with his or her fingerprint, and in the 
event that the subject is not capable of providing adequate written informed consent, a “legally 
authorized” representative of the subject may provide such consent for the subject in accordance with 
applicable laws and regulations. 
Likewise, the PI, or the study staff delegated by him, must sign and date this consent. 
The ICF must be signed in duplicate by all involved; one copy will be filed in the researcher's folder and 
the other will be given to the participant. The PI or designated staff member must document the process 
of obtaining Informed Consent through a detailed, accurate, and contemporaneous medical note, 
specifying the signed version, the date 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 any additional risk 
that should be considered apart from the procedures listed in the informed consent. 
11.4.3 Modifications to informed consent  
Any change to the ICF constitutes an amendment to this document and must be submitted for approval 
to the Research Ethics Committees and COFEPRIS. 
Such amendments may be implemented only after obtaining written approval from the Research Ethics 
Committee and the Regulatory Body (as applicable), except for an amendment that is required to 
eliminate an immediate danger to the study subjects. 
A re-consent process must be conducted for each subject affected by the amendment under the same 
conditions as those described above, in order to promptly communicate the new information contained 
in the document. The subject will be given an original signed amendment, and the researcher will retain 
the second original amendment. 
11.5 Confidentiality  
All documents and information provided to the research center by the sponsor are strictly confidential. 
The PI expressly agrees that the data regarding his or her professional and clinical experience, provided 
to the sponsor in paper form and stored electronically, are solely for use in connection with his or her 
activities with the clinical study sponsor, in accordance with Good Clinical Practice. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 57 of 66 
CONFIDENTIAL 
The PI agrees that he and his team members will use the information only within the scope of this study, 
to carry out the protocol. This agreement is binding as long as the confidential information has not been 
publicly disclosed by the sponsor. 
The clinical study protocol provided to the PI may be used by the PI and his or her team to obtain informed 
consent from the subjects for the study. The clinical study protocol, as well as any information derived 
from it, must not be disclosed to other parties without the sponsor's written authorization. 
The PI will not disclose any information without the prior written consent of Laboratorios Sophia, S.A. de 
C.V., except to representatives of the Competent Authorities, and only at their request. In the latter case, 
the researcher is obligated to inform Laboratorios Sophia, S.A. de C.V. before disclosing the information 
to these authorities. 
The PI will complete and maintain a subject selection log, as well as the identification and enrollment list 
of each subject participating in the study. The researcher agrees to grant on-site access to the auditor 
and/or representatives of the Competent Authorities. The information will be treated in compliance with 
professional secrecy. 
In the eCRF and all communications related to study subjects, they will be identified only by their study 
subject identification number, either the screening number or the randomization number. The 
information collected in this study will be exchanged between the sponsor and the research site and must 
be treated confidentially. The Health Authority, the IRB, the IC, the sponsor, the monitors/auditors, and 
third-party auditors will be the only bodies authorized to review the study documentation. If publications 
arise from this research project, under no circumstances will they contain information about the 
identification of the study subjects. If the study results are published, no personal information about the 
study subjects will be disclosed. 
The protection of personal data will be in accordance with the corresponding current regulations. 
11.6 Conflict of interest  
The independence of the study's conduct and results from any actual or perceived external influences is 
critical. Therefore, any current conflict of interest of any person playing a role in the design, conduct, 
analysis, publication, or any other aspect of this study will be declared. Furthermore, those with a 
perceived conflict of interest will be asked to manage it in a manner appropriate to their participation in 
the study. 
11.6.1 Declaration of interests  
The PI agrees to declare his or her financial interests and conflicts of interest prior to the start of the 
study. 
11.7 Access to information  
The final study database will be the property of Laboratorios Sophia, S.A. de C.V., and access to it will be 
restricted. The PI will not have access to it except with prior written authorization from the sponsor. 
Any information obtained that is relevant to the safety of the subjects participating in the study must be 
immediately shared with the research center, so that the study subjects can be notified. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 58 of 66 
CONFIDENTIAL 
11.8 Auxiliary and post-study care  
Once the study is completed and adverse events are closed in accordance with section 8, the sponsor will 
not extend care to the research subject. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 59 of 66 
CONFIDENTIAL 
12. 
Biosecurity aspects 
NO BIOSECURITY IMPLICATIONS 
This protocol, titled: “Clinical study to evaluate the safety of the PRO-149 viscoelastic solution when used 
as an ophthalmic viscosurgical device during phacoemulsification surgery and intraocular lens placement 
in subjects diagnosed with senile cataracts, compared to Healon® EndoCoat.”, and number: SOPH149-
0220 / I HAS NO BIOSECURITY IMPLICATIONS, since infectious biological material will NOT be used; 
pathogenic strains of bacteria or parasites; viruses of any type; radioactive material of any type; 
genetically modified animals and / or cells and / or plants; toxic, hazardous or explosive substances; any 
other material that puts the health or physical integrity of the research center personnel or the research 
subjects at risk or affects the environment. It is also declared that this project will not involve cell, tissue, 
or organ transplantation procedures, or cell therapy, nor will it involve the use of laboratory, farm, or 
wildlife animals. 
 
 
 
 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 60 of 66 
CONFIDENTIAL 
13. 
Publication Policy 
13.1 Final report  
Once the statistical analysis is completed, the final report will be written with the results obtained, by the 
Medical Management Department Team of Laboratorios Sophia, S.A. de C.V. This report will be prepared 
following the recommendations of the ICH E3 Step 4 Guide. 
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 study report to the principal investigators and COFEPRIS. These results will also be shared with 
the research committee and the IEC. The PI will be responsible for communicating the results to the 
research subjects. 
Laboratorios Sophia, S.A. de C.V. will retain at all times the rights to the publication and dissemination of 
the information contained herein. 
13.3 Publication of results  
Laboratorios Sophia, S.A. de C.V., acting as the sponsor of the study, assumes full responsibility for its role 
and retains exclusive ownership rights to the study results, which it may use as it sees fit. 
The PI agrees not to publish or communicate data collected from the study, unless prior written 
agreement is obtained from Laboratorios Sophia, 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 journal or scientific conference. 
However, if the sponsor is in the process of filing a patent application on the results of the study, the 
sponsor may delay publication or communication of the results of the study until the date of registration 
or when it deems appropriate. 
Authorship assignments for publications are the sponsor's responsibility. However, express authorization 
from those invited to participate as authors is required. Authors have the right to review the manuscript 
prior to publication, as well as to provide comments and suggestions. Such comments must be submitted 
within the first 15 calendar days of receipt of the project. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 61 of 66 
CONFIDENTIAL 
14. 
Financing and insurance 
14.1 Compensation to study participants  
Subjects participating in the study will not receive financial compensation for their participation. 
14.2 Insurance for study participants  
Subjects participating in the study will sign the informed consent form, 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 resolved, in accordance with medical judgment. 
All study participants will be covered by a liability insurance policy contracted by Laboratorios Sophia, S.A. 
de C.V. Information on the policy will be made available to the research centers. In the event of a medical 
emergency, the research center must have the personnel, materials, equipment, and procedures in place 
for immediate management. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 62 of 66 
CONFIDENTIAL 
15. 
Annexes 
15.1 OVD performance evaluation  
OVD performance evaluation 
Identification card 
Study No. SOPH149-0220-I 
Subject's initials:
 
 
Date:  
// 
Subject No.: 149-______-_______ 
Directions: 
This questionnaire must be answered by the surgeon immediately after completing the surgical procedure. 
For each question, circle your answer. 
Where: 
0=very bad; 1=bad; 2=acceptable; 3=good; 4=very good 
 
1 How do you consider the ability of the OVD to form and maintain the AC during CCC and IOL implantation? 
              0                                      1                                      2                                      3                                      4 
2 
How do you rate the ability of the OVD to be retained during phacoemulsification? 
0                                      1                                      2                                      3                                      4 
 3  
How do you consider the overall ease of use of the OVD? 
              0                                      1                                      2                                      3                                      4 
4 
How do you rate the ergonomics of the OVD? 
0                                      1                                      2                                      3                                      4 
 5  How do you consider the transparency of the OVD during surgery? 
             0                                      1                                      2                                      3                                      4 
6 
How do you consider the ease of withdrawing the OVD from the AC? 
0                                      1                                      2                                      3                                      4 
 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 63 of 66 
CONFIDENTIAL 
References 
[1] S. Arshinoff, “Ophthalmic Viscosurgical Devices,” Kohnen T., Koch DD (eds) Cataract and Refractive 
Surgery. Essentials in Ophthalmology., Berlin, Heidelberg, Springer, 2005, pp. 3762. 
[2] BE, “Sodium hyaluronate and viscosurgery,” from Healon (sodium hyaluronate): a guide to its use in 
ophthalmic surgery, New York, Wiley, 1983, pp. 5–28. 
[3] American Academy of Ophthalmology, “Lens and Cataracts,” from Basic and Clinical Science Course, 
San Francisco, AAO, 2016, pp. 98–99. 
[4] H. Bissen-Miyajima, « Ophthalmic viscosurgical devices, » Curr Opinion Oftalmol, no. 50-54, p. 19, 
2008. 
[5] T. (. Mang, « Rheology», from Encyclopedia of Lubricants and Lubrication., Berlin, Heidelberg, 
Springer, 2014. 
[6] American Academy of Ophthalmology, Lens and Cataracts. Basic and Clinical Sciences Course, AAO, 
2015. 
[7] National Eye Institute, "NEI", NIH, [Online]. Available : 
https://nei.nih.gov/eyedata/cataract. [Last accessed: July 4, 2016]. 
[8] G. Brian and H. Taylor, "Cataract Blindness: Challenges for the 21st Century," Bull World Health 
Organ, vol. 79, no. 3, pp. 249-256, 2001. 
[9] H. Limburg, F. Barria -von -Bischhoffshausen, P. Gomez et al., «Review of recent surveys on blindness 
and visual impairment in Latin America», Br J Ophthalmol, vol. 92, pp. 315-319, 2008. 
[10] S. Polack, D. Yorston, A. Lopez-Ramos et al., «Review of recent surveys on blindness and visual 
impairment in Latin America», Br J Ophthalmol, vol. 92, pp. 315-319, 2008. 
[11] A. Jiménez-Corona, M. Jiménez-Corona, S. Ponce-de-León, M. Chávez-Rodríguez et al., «Social 
determinants and their impact on visual impairment in southern Mexico ». Ophthalmic Epidemiol, 
vol. 0, pp. 1–17, 2014. 
[12] L. Chylack, J. Wolfe, D. Singer, M. Leske et al., «Lens Opacity Classification System III. Longitudinal 
Study of the Cataract Study Group». Arch Ophthalmol, vol. 111, no. 6, pp. 831-836, 1993. 
[13] L. Chylack, M. Leske, D. McCarthy, P. Khu, T. Kashiwagi and R. Sperduto, “Lens Opacity Classification 
System II (LOCS II)” Arch Ophthalmol, vol. 107, no. 7, pp. 991-997, July 1989. 
[14] G. Bencic, M. Zoric -Geber, D. Saric, M. Corak, and Z. Mandic, “ Clinical significance of the lens opacity 
classification system III (LOCS III) in phacoemulsification.” Coll Anthropol, vol. 29, no. S1, pp. 91-94, 
2005. 
[15] C. McCarty, J. Keeffe, and H. Taylor, “The Need for Cataract Surgery: Projections Based on Lens 
Opacity, Visual Acuity, and Personal Concern,” Br J of Ophthalmol, vol. 83, pp. 62-65, 1999. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 64 of 66 
CONFIDENTIAL 
[16] B. Klein, R. Klein, and S. Moss, “Incidental cataract surgery. The Beaver Dam ophthalmologic study.” 
Oftalmol, vol. 104, pp. 753-780, 1997. 
[17] S. Dang, “ Cataract Surgery Infographic,” AAO, 2014. 
[18] R. Lindstrom, "Journal of Ophthalmology," March 9, 2015. [Online]. Available at : 
https://www.reviewofophthalmology.com/article/thoughts-on-cataract-surgery-2015. 
[Last 
accessed: 22 07 2016]. 
[19] P. Gómez-Bastar, V. Lansingh, J.C.-S.B. Penniecook-Sawyers, et al., “Cataracts remain the leading 
cause of blindness in emerging economies, including Mexico,” Rev Mex de Oftalmol, vol. 88, no. 4, 
2014. 
[20] M. Johnson, P. Murphy, and M. Boulton, “Effectiveness of sodium hyaluronate eyedrops in the 
treatment of dry eye,” Graefe's Arch Clin Exp Ophthalmol, vol. 244, pp. 109-112, 2006. 
[21] FDA, “PMA P110007: FDA Summary of Safety and Effectiveness Data,” FDA, [Online ]. 
Available : https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110007b.pdf. [Last accessed: 
February 14, 2019]. 
[22] Abbott Medical Optics Inc. Healon® EndoCoat. Santa Ana, CA: Abbot Medical Optics Inc, 2012. 
[Online] Available at: https://www.accessdata.fda.gov/cdrh_docs/pdf11/P110007c.pdf [Last 
accessed: September 23, 2020] 
[23] Sophia Laboratories SA de CV, «Comparative preclinical study on the safety and acute toxicity of 
sterile viscoelastic solutions PRO-149 and Healon Endocoat ®, applied to the anterior chamber of 
healthy New Zealand albino rabbits,» Zapopan, 2018. 
[24] R. Fiscella, “ Ophthalmic Drug Formulations,” Clinical Ocular Pharmacology, St Louis, MO, 
Butterworth Heinemann Elsevier, 2008, pp. 17–37. 
[25] L. Gordis, «General concepts for the use of markers in clinical trials», Control Clin Trials, vol. 5, pp. 
481-487, 1984. 
[26] M. Mattson and L. Friedman, "Issues in Assessing Medication Adherence in National Heart, Lung, and 
Blood Institute Clinical Trials," Control Clin Trials, vol. 5, pp. 488-496, 1984. 
[27] S. Norell, "Methods for assessing compliance with drug treatment", Acta Med Scand, vol. S 683, pp. 
34-50, 1984. 
[28] P. Rudd, R. Byyny, V. Zachary et al., “Pill Count Compliance Measures in a Clinical Trial: 
variability and suitability,» Am J Hypertens, vol. 1, pp. 309-312, 1988. 
[29] K. Farmer, "Methods for measuring and monitoring adherence to medication regimens in clinical 
trials and clinical practice," Clin Ther, vol. 21, pp. 1074-1090, 1999. 
[30] H. Liu, C. Golin, L. Miller, et al., “A comparative study of multiple measures of adherence to HIV 
protease inhibitors,” Ann Intern Med, vol. 134, pp. 968-977, 2001. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 65 of 66 
CONFIDENTIAL 
[31] W. Lam and P. Fresco, “Medication adherence measures: an overview,” BioMed Research 
International, vol. 2015, 2015. 
[32] M. Vitolins, C. Rand, S. Rapp, P. Ribisl, and M. Sevick, “Measuring adherence to behavioral and 
medical interventions,” Controll Clin Trial, vol. 21, pp. 188S-194S, 2000. 
[33] J. Lee, K. Grace, T. Foster, M. Crawley and e. al, «How should we measure medication adherence in 
clinical trials and practice? », Ther and Clin Risk Manag, vol. 3, no. 4, pp. 685690, 2007. 
[34] J. Kanski, Clinical Ophthalmology, Barcelona: Elsevier, 2009. 
[35] C. Foster and A. Vitale, Diagnosis and treatment of uveitis, Philadelphia, PA: WB Saunders Company, 
2002. 
[36] Mexican Ministry of Health, «Official Mexican Standard NOM-220-SSA1-2016, Installation and 
operation of pharmacovigilance.,» Official Gazette, 2017. 
[37] Mexican Ministry of Health, «Official Mexican Standard NOM-240-SSA1-2012, Installation and 
operation of technovigilance.», Official Gazette, 2012. 
[38] International Conference on Harmonization of Technical Requirements for Registration of 
Human Pharmaceuticals, “Clinical Safety Data Management: Definitions and Standards for 
Accelerated E2 A Reporting,” ICH Harmonized Tripartite Guideline, Vol. 4, 1994. 
[39] International Conference on Harmonization of Technical Requirements for the Registration of 
Pharmaceutical Products for Human Use, "General Considerations for Clinical Trials", ICH Topic E8, 
1998. 
[40] Good Clinical Practice. Participant Safety & Adverse Events. Gcp.nidatraining.org [Online] Available 
at: 
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiqu6258v_r
AhVOPK0KHVEED5MQFjABegQIDBAD&url=https%3A%2F%2Fgcp.nidatraining.org%2Fmodules%2F4
%2Fpdf&usg=AOvVaw3aaaE_mb1rxgPhfWcTkJ1M [Accessed: September 24, 2020] 
[41] Mexican Ministry of Health, "Official Mexican Standard NOM-012-SSA3-2012, which establishes the 
criteria for the execution of research projects for human health" Official Gazette, 2013. 
[42]   The Uppsala Monitoring Centre. Medicines Safety Surveillance. World Health Organization, 2001. 
[Online] 
Available 
at: 
http://www.essalud.gob.pe/ietsi/pdfs/informacion_tecnica/OMS_guia_farmacovigilancia.pdf [Last 
accessed: October 1, 2020] 
[43] R. Meyboom, A. Egberts, I. Edwards, Y. Hekster, F. Koning and Gribnau, "Principles of signal detection 
in pharmacovigilance.," Drug Safety, vol. 16, pp. 355-365, 1997. 
[44] A. Haffajee, S. Socransky, and J. Lindhe, “Comparison of statistical methods for analyzing data from 
periodontal clinical trials.” J Clin Periodontal, vol. 10, pp. 247-56, 1983. 
[45] R. Woolson, “Wilcoxon signed- rank,” from Wiley Encyclopedia of Clinical Trials, Wiley, 2008, pp. 1-3. 

Laboratorios Sophia, S.A. de C.V.  
  
                               Study No: SOPH149-0220/I 
Version 2.0 
 
   October 2, 2020 
 
    Page 66 of 66 
CONFIDENTIAL 
[46] J. Schumi and J. Wittes, “Through the looking glass: Understanding noninferiority.” Essays, vol. 62, 
pp. 921-28, 2011. 
[47] B. Klingenberg and A. Agresti, «Multivariate extension of the McNemar model proof," Biometrics, 
vol. 62, pp. 921-28, 2006. 
[48] A. Storr -Paulsen, J. Norregaard, G. Farik, and J. Tarnhoj, “The influence of viscoelastic substances on 
the corneal endothelial cell population during cataract surgery: a prospective study of cohesive and 
dispersive viscoelastics.” Acta Oftalmol Scand, vol. 85, no. 2, pp. 183-7, 2007. 
[49] S. Chow, J. Shao, and H. Wang, Sample Size Calculation in Clinical Research, Boca Raton, FL: Chapman 
& Hall/CRC, 2008. 
[50] M. Garzon and M. Morales-Gómez, «Comparative study with two types of viscoelastics in 
phacoemulsification.», Rev Mex Oftalmol, vol. 77, no. 6, pp. 219-22, 2003. 
[51] S. Kugu, G. Erdogan, M. Sahin-Sevim, and Y. Ozerturk, “Clinical comparison of the safety and efficacy 
of phacoemulsification with and without an ophthalmic viscoelastic device.” Semin Ophthalmol, vol. 
30, no. 2, pp. 96-100, 2015. 
[52] A. Gibelalde, J. Mendicute, A. Bidaguren and C. Irigoyen, “Prospective randomized trial comparing 
Dicovisc versus Healon in phacoemulsification.” Arch Soc Esp Ophthalmol, vol. 82, no. 8, pp. 489-94, 
2007.