Phase I Clinical Trial to Evaluate Safety by Determining Immunogenicity Following Unilateral Intravitreal Administration of PRO-169 in Patients With Diabetic Macular Edema
Phase: PHASE1
Conditions: Immunogenicity, Anti-drug Antibodies (ADAs)
Sponsor: Laboratorios Sophia S.A de C.V.

  
 
 
 
 
Protocol: 
SOPH169-1224/I 
 
Title: Phase I clinical study to evaluate safety by determining immunogenicity 
after unilateral intravitreal PRO-169 application in patients with diabetic 
macular edema. 
Information about the molecule under study 
Generic name:    Bevacizumab (for ophthalmic use) 25.0 mg/mL  
Distinctive name:    PRO-169  
Note:  Treatment of diabetic macular edema  
 
Protocol Information 
Study Phase:  I  
Version: 4.0 
Release Date: 4-nov.-25 
 
 
This protocol has been carried out in accordance with the principles of the 
Declaration of Helsinki and will be carried out in accordance with Good Clinical 
Practice and in compliance with the ICH guidelines and current local legislation.  
Sponsor: Laboratorios Sophia S.A. de C.V. 

 
 
 

 
C O N F I D E N C I A L 
  
 
Contents    
Signature Page
 
From the sponsor ................................................................................................................................................... 10 
Investigator Agreement
 
List of abbreviations
 
1.1 Synopsis ............................................................................................................................................................ 14 
1.2 Study diagram ................................................................................................................................................... 20 
1.3 Schedule of activities........................................................................................................................................ 21 
1.4 Pharmacokinetics Cohort Schedule ................................................................................................................. 22 
2. Introduction and background
 
2.1 Theoretical framework ..................................................................................................................................... 23 
2.2 Background on the investigational product .................................................................................................... 28 
2.2.1 Preclinical study on the ocular bioavailability of two bevacizumab solutions, PRO-169 vs Avastin®, 
following intravitreal application in albino rabbits in New Zealand.
 
2.2.2 Preclinical study on the safety and toxicity of PRO-169 (bevacizumab) vs Lucentis® (ranibizumab) 
after intravitreal application in albino rabbits in New Zealand.
 
2.2.3 Comparative preclinical study on the efficacy of PRO-169 (bevacizumab) and Avastin® (bevacizumab) 
in laser-induced choroidal neovascularization (CNV) in rhesus monkeys.
 
2.3 Background on the investigation ..................................................................................................................... 32 
2.3.1 Research Question
 
2.4 Risk-benefit assessment ................................................................................................................................... 33 
2.4.1 Known potential risks
 
2.4.2 Known potential benefits
 
2.5 Problem statement .......................................................................................................................................... 34 
2.6 Rationale for the study ..................................................................................................................................... 34 

 
C O N F I D E N C I A L 
  
 
3. Objectives and hypotheses
 
3.1 Objectives ......................................................................................................................................................... 36 
3.1.1 Primary security objective:
 
3.1.2 Secondary security objectives:
 
3.1.3 Objectives for the pharmacokinetics cohort:
 
3.1.4 Exploratory objectives:
 
3.2 Hypothesis ........................................................................................................................................................ 36 
4. Study design
 
4.1 Study Overview ................................................................................................................................................. 37 
4.2 Rationale for the study design ......................................................................................................................... 37 
4.3 Expected duration ............................................................................................................................................ 37 
5. Study population
 
5.1 Selection criteria ............................................................................................................................................... 38 
5.1.1 Inclusion criteria
 
5.1.2 Exclusion Criteria
 
5.2 Criteria for elimination and/or substitution of subjects ................................................................................ 41 
5.2.1 Elimination Criteria
 
5.2.2 Substitution of subjects
 
5.3 Selection failures .............................................................................................................................................. 42 
5.4 Recruitment and retention strategies ............................................................................................................. 42 
5.5 Procedure in case of loss of follow-up ............................................................................................................ 43 
5.6 Identification of the subject ............................................................................................................................. 44 
6. Investigational product and treatment
 
6.1 Investigational product .................................................................................................................................... 45 
6.2 Investigational Product Dosage ....................................................................................................................... 45 

 
C O N F I D E N C I A L 
  
 
6.3 Treatment with the investigational product ................................................................................................... 45 
6.4 Storage and handling of the investigational product in the study center..................................................... 45 
6.5 Concomitant treatments and medications (permitted and prohibited) ....................................................... 47 
6.5.1 Permitted Medications
 
6.5.2 Prohibited Drugs
 
7. Study methods and procedures
 
7.1 Research center ................................................................................................................................................ 49 
7.2 Clinical Study Registration ............................................................................................................................... 49 
7.3 Group assignment and blinding ....................................................................................................................... 50 
7.4 Study variables.................................................................................................................................................. 50 
7.4.1 Safety Primary Outcome Variables
 
7.4.2 Safety Secondary Outcome Variables
 
7.4.3 Pharmacokinetic Secondary Outcome Variables
 
7.4.4 Exploratory variables
 
7.4.5 Definition of variables, methods and scales for their measurement
 
7.4.6 Description of the variables, methods, and scales for their measurement
 
7.5 Description of procedures or assessments during the study ........................................................................ 59 
7.5.1 Signing of informed consent
 
7.5.2 Medical history (general and ophthalmological)
 
7.5.3 Adverse events
 
7.5.4 Evaluation of selection criteria
 
7.5.5 Measuring Vital Signs
 
7.5.6 Laboratory tests
 
7.5.7 Urine Pregnancy Test
 

 
C O N F I D E N C I A L 
  
 
7.5.8 Ophthalmological evaluation
 
7.5.9 Retinal angiography
 
7.5.10 Intravitreal injection
 
7.5.11 Blood sample for pharmacokinetics (applies to PK cohort)
 
7.5.12 Blood Sample for Immunogenicity
 
7.5.13 Application of Medications During Visits
 
7.5.14 Evaluation of concomitant medicinal products
 
7.6 Procedures to be carried out per visit............................................................................................................. 67 
7.6.1 Selection visit (day -8 to 0)
 
7.6.2 Visit 1 (Day 1)
 
7.6.3 Visit 2 (Day 2) – PK cohort only
 
7.6.4 Visit 3 (Day 4) – for PK cohort only
 
7.6.5 Visit 4 (Day 8) – PK cohort only
 
7.6.6 Visit 5 (day 30 ± 5)
 
7.6.7 Visit 6 (day 60 ± 5)
 
7.6.8 Visit 7 (End/Early Termination) (Day 90 ± 5)
 
7.6.9 Unscheduled follow-up visits
 
7.7 Data collection .................................................................................................................................................. 71 
7.7.1 Source documents
 
7.7.2 Electronic forms of data collection
 
7.7.3 Archiving
 
8. Evaluation and management of adverse events
 
8.1 Regulation and regulations on adverse events............................................................................................... 72 

 
C O N F I D E N C I A L 
  
 
8.2 Definition of Adverse Event ............................................................................................................................. 72 
8.3 Use of adverse events as a study safety variable ........................................................................................... 72 
8.4 Definitions relevant to the classification of adverse events .......................................................................... 72 
8.5 Responsibilities of the researcher ................................................................................................................... 73 
8.5.1 Recording of adverse events in the electronic case report form
 
8.5.2 Adverse Event Tracking
 
8.5.3 Procedures for a serious adverse event
 
8.5.4 Causation assessment
 
9. Study Monitoring
 
9.1 Monitoring the Study Site ................................................................................................................................ 84 
9.2 Audit and quality assurance ............................................................................................................................. 85 
10. Sample size calculation and statistical analysis
 
10.1 Sample Size Calculation ................................................................................................................................. 86 
10.1.1 Calculation methodology
 
10.2 Group Assignment and Blinding .................................................................................................................... 88 
10.3 Statistical methodology ................................................................................................................................. 88 
10.4 Study populations .......................................................................................................................................... 89 
10.4.1 Security Population
 
10.4.2 Intention-to-Treat (ITT) Population
 
10.4.3 Population by Protocol (PP)
 
10.4.4 Deviations from the Protocol
 
10.5 Lost Data ......................................................................................................................................................... 89 
10.5.1 Procedure for Handling Missing Data
 
10.5.2 Visitor windows
 
10.5.3 Subgroup Analysis
 

 
C O N F I D E N C I A L 
  
 
10.6 Demographic and baseline characteristics ................................................................................................... 90 
10.6.1 Disposition of Subjects and Losses
 
10.7 Analysis of variables ....................................................................................................................................... 91 
10.7.1 Primary Variable
 
10.7.3 Secondary Variables
 
10.7.4 Pharmacokinetic variables
 
10.7.5 Exploratory variables
 
10.8 Internal Analysis ............................................................................................................................................. 92 
10.8.1 Preliminary Analysis
 
10.9 Clinical Data Management ............................................................................................................................. 92 
11. Ethical considerations
 
11.1 Approval of the committees .......................................................................................................................... 94 
11.2 Amendments to the protocol ........................................................................................................................ 95 
11.3 Early Study Termination ................................................................................................................................. 95 
11.4 Informed Consent .......................................................................................................................................... 96 
11.4.1 Obtaining
 
11.4.2 Special considerations
 
11.4.3 Modifications to Consent
 
11.5 Confidentiality ................................................................................................................................................ 98 
11.6 Conflict of interest.......................................................................................................................................... 99 
11.6.1 Declaration of Interests
 
11.7 Access to Information .................................................................................................................................... 99 
11.8 Ancillary and post-study care ..................................................................................................................... 100 
12. Biosecurity aspects
 
13. Posting Policy
 

 
C O N F I D E N C I A L 
  
 
13.1 Final Report ................................................................................................................................................. 102 
13.2 Communication of results ........................................................................................................................... 102 
13.3 Publication of results................................................................................................................................... 102 
14. Financing and Insurance
 
14.1 Compensation to Study Participants .......................................................................................................... 103 
14.2 Insurance for Study Participants ................................................................................................................ 103 
15. Bibliography
 
16. Annexes
 
16.1 ETDRS Booklet ............................................................................................................................................. 110 
 
 
 

 
C O N F I D E N C I A L 
  
 
Table and Figure Index 
Table 1. Responsible for the study .............................................................................................................................. 9 
Table 2. Schedule of activities .................................................................................................................................... 21 
Table 3. Pharmacokinetics Cohort Timeline .............................................................................................................. 22 
Table 4. Characteristics of the treatment groups ..................................................................................................... 30 
Table 5. Operational definition of variables. ............................................................................................................. 51 
Table 6. Equivalences for best-corrected visual acuity............................................................................................. 56 
Table 7. Adding letters to the ETDRS booklet ........................................................................................................... 57 
Table 8. Visit windows ................................................................................................................................................ 90 
 
Figure 1. Study diagram .............................................................................................................................................. 20 
Figure 2. Overall Study Design ................................................................................................................................... 31 
Figure 3. Adverse Event Care ..................................................................................................................................... 79 
Figure 4. Handling discrepancies. .............................................................................................................................. 93 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  9 of 110 
Responsible for the study
The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia, S.A. de 
C.V., is shown in the following table: 
Table 1. Responsible for the study 
 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  10 of 110 
Signature Page 
From the sponsor  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  11 of 110 
 
Investigator Agreement    
I agree to conduct this clinical study according to the design and guidelines of this protocol, in 
accordance with its provisions. I declare that I will conduct the study in accordance with the standards 
of Good Clinical Practice, and I will report all information or data in accordance with the protocol, 
particularly any adverse events. I will also handle clinical supplies, provided by the sponsor, strictly in 
accordance with this protocol. I understand that the information that identifies me may be used by 
the sponsor. Because the information contained in this protocol and the Investigator's Manual is 
confidential, I understand that it is prohibited from sharing it with any third party, which is not involved 
in the approval, supervision, or conduct of the study. I will ensure that I take the necessary precautions 
to protect the information from loss, inadvertent disclosure, or access by unauthorized third parties.  
 
Name:  
[Insert full name of 
researcher] 
Title:  
Principal Investigator  
Name of the center:  
[Insert Name of Study Site] 
Geographic location (city/state/country)  
[Enter the geographical data of the center]  
  
Signature  
  
Date  
  
  
  
  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  12 of 110 
List of abbreviations 
ADAs 
Anti-drug antibodies 
AUC 
Area under the curve 
BCVA 
Best-Corrected major visual acuity 
GCP 
Good clinical practice 
BSA 
Body Surface Area 
BUN 
Blood urea nitrogen 
CDM 
Clinical data management 
REC 
Research Ethics Committee 
CMPHU 
Committee for Medicinal Products for Human Use  
RC 
Research Committee 
CIOMS 
Committee for the International Organization of Medical Sciences  
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration  
COFEPRIS 
Federal Commission for the Protection against Sanitary Risks 
CONSORT 
Consolidation Standards of Reporting Trials 
SD 
Standard deviation 
IUD 
Intrauterine device 
DRCR 
The Diabetic Retinopathy Clinical Research 
AE 
Adverse Event 
ECL 
Electrochemiluminescence  
eCRF 
Electronic Case Report Form 
EMD 
Diabetic macular edema 
ELISA 
Enzyme-linked Immunosorbent Assay 
RPE 
Retinal Pigment Epithelium 
ETDRS 
Early Treatment Diabetic Retinopathy Study. 
FA 
Fluorescein angiography of the retina (Fluorescein Angiography) 
Fab 
Fragment antigen-binding 
HR 
Heart rate 
ICF 
Informed consent form 
FDA 
Food and Drug Administration. 
RR 
Respiratory rate 
GFRe 
Glomerular Filtration Rate estimate 
CMT 
Central macular thickness 
HbA1c 
Glycosylated hemoglobin 
HMSA 
Homogeneous Mobility Shift Assay 
CI 
Confidence interval 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  13 of 110 
ICH 
International 
Council 
for 
Harmonisation 
of 
Technical 
Requirements 
for 
Pharmaceuticals for Human Use. 
ICMJE 
International Committee of Medical Journal Editors 
BMI 
Body mass index 
PI 
Principal Investigator 
ITT 
Population by intent to treat 
kDa 
Kilodaltons 
KDIGO 
Kidney Disease Improving Global Outcomes. 
LogMAR 
Logarithm of the Least Resolution Angle (Logarithm Logarithm of the Minimum Angle 
of Resolution). 
LOCS III 
Lens Opacities Classification System 
MedDRA 
Medical Dictionary for Regualtory Activities. 
mg 
Milligrams 
mL 
Millilitres 
Nab 
Neutralizing antibodies   
NOM 
Official Mexican Standard 
NVC 
Choroidal neovascularization 
OCT 
Optical Coherence Tomography. 
OCT-A 
Optical Coherence Tomography Angiography   
OD 
Right eye (Latin for its acronym oculus dexter) 
WHO 
World Health Organization 
OS 
Left Eye (by its Latin acronym, oculus sinister) 
IP 
Investigational Product 
IOP 
Intraocular Pressure 
PK 
Pharmacokinetics   
PP 
Population by protocol 
PS 
Security population 
RD 
Diabetic retinopathy 
RIA 
Radioimmunoassay (Radioimmunoassay) 
NCTR 
National Clinical Trials Registry 
SDV 
Source data verification 
SPR 
Surface Plasmon Resonance Spectroscopy  
BP 
Blood pressure 
T1/2 
Half-life 
Tmax 
Time to Maximum Concentration 
UFTLS 
Pharmacovigilance and technovigilance unit of Laboratorios Sophia 
VEGF 
Vascular Endothelial Growth Factor (Vascular Endothelial Growth Factor). 
μg 
Micrograms 
μL 
Microliters 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  14 of 110 
1. Protocol Summary 
1.1 Synopsis 
Title of the study: 
Phase I clinical study to evaluate safety by determining immunogenicity after unilateral 
intravitreal PRO-169 in patients with diabetic macular edema. 
Study Number: 
SOPH169-1224/I 
Sponsor: Laboratorios Sophia, S.A. de C.V. 
Paseo del Norte No.5255, Col. Guadalajara 
Technology 
Park, 
Carretera 
Guadalajara-
Nogales Km13.5 C.P. 45010 Zapopan, Jalisco, 
Mexico 
The company responsible for carrying out the 
monitoring activities is carried out by: Visión 
Integral en Investigación Klini K. Cataratas No. 
3, Col. Jardines del Pedregal, C.P. 01900, 
Alcaldía Álvaro Obregón, Mexico City. 
Date of creation: 
15-Jan-25 
Protocol version: 
4.0 
Release Date:  
Nov 4-25 
Therapeutic indication: 
Treatment of diabetic macular edema. 
Application: 
Diabetic macular edema. 
Estimated duration of the study (from the first 
visit of the first subject to the preparation of 
the final report): 
14 months 
Clinical Development Phase: 
Phase I Clinical Study 
Objectives: 
Primary Objective:  
• 
To evaluate the safety of intravitreal PRO-169 by the presence of serum anti-drug 
antibodies (ADAs) for bevacizumab. 
Secondary security objectives: 
• 
To determine the incidence of adverse events (AEs) related to the investigational product. 
• 
Determine the incidence of serious AEs related to the investigational product. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  15 of 110 
Objectives for the pharmacokinetics (PK) cohort: 
• 
Calculate the total area under the curve (AUC) of the serum concentration of PRO-169. 
• 
To quantify the maximum serum concentration (Cmax) of PRO-169. 
• 
Quantify the time to maximum serum concentration (Tmax) of PRO-169. 
Exploratory objectives: 
• 
To assess the change in best-corrected visual acuity (BCVA) compared to baseline. 
• 
To assess the change in central macular thickness (CMG) compared to baseline. 
Hypothesis: 
This study does not propose any statistical hypothesis testing, so they are not considered formal 
statistical decisions. 
Study Design: 
Phase I clinical study, prospective, interventional, open-label, multicenter.  
Number of subjects (planned): 
Sample size is not based on statistical power calculations. It is chosen based on background and 
feasibility. A total of 60 subjects (60 eyes) is considered suitable to assess the primary objective 
of the study 
In addition to the general safety variables of the study, pharmacokinetics will be evaluated in a 
cohort of 15 subjects. 
Diagnosis and main inclusion criteria: 
- 
Diabetic macular edema. 
Selection criteria: 
Inclusion criteria: 
1. Age ≥ 18 years. 
2. Diagnosis of type 1 or 2 diabetes. 
3. Ability to give signed informed consent. 
4. Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
5. All subjects (male and female) who are biologically capable of having children will be 
required to agree and commit to using a barrier or hormonal method of contraception 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  16 of 110 
(by any route of administration) for the entire duration of the study and for 3 months 
after the last intravitreal injection. 
6. Female subjects, biologically capable of having children, will be required to have a 
negative urine pregnancy test at the screening visit.  
7. Best Corrected Visual Acuity (AVMC) according to the 24- to 78-letter ETDRS primer 
(approximate Snellen equivalent of 20/32 to 20/320) 
8. Diabetic macular edema with central involvement evidenced by spectral domain optical 
coherence tomography (central macular thickness criterion > 300 μm for men and > 290 
μm for women) within 8 days prior to inclusion. All measurements made on a subject 
should be taken with an instrument of the same make and model during the conduct of 
the entire study. 
9. Comply with characteristics that allow an adequate examination of the fundus of the 
eye (transparency of media, adequate pupillary dilation). 
10. Glycosylated hemoglobin < 12% of a result not older than 3 months. 
Exclusion criteria: 
1. Chronic kidney disease in renal failure (glomerular filtration rate [GFRe] <15 
ml/min/1.73m2) requiring dialysis or transplantation; according to the 2020 Clinical 
Practice Guideline for the Management of Diabetes in Chronic Kidney Disease of the 
Organization for Improving Global Outcomes in Kidney Disease (KDIGO).  
2. Active proliferative diabetic retinopathy in the study eye, including rubeosis iridis, 
vitreous hemorrhage, or tractional retinal detachment visible during the screening visit. 
3. Individuals who have required insulin treatment within 4 months prior to the screening 
visit for glycemic control. 
4. Previous participation in clinical studies with investigational, ocular or systemic 
products (at least 30 days must have elapsed between the end of your participation in 
a previous trial and the inclusion of the present study).  
5. Known hypersensitivity or allergy to bevacizumab, or any ingredient in the investigational 
product. 
6. Poorly controlled blood pressure (average of 3 blood pressure readings in a seated 
position with ≥160 mmHg systolic or ≥100 mmHg diastolic) at the screening visit. 
7. Myocardial infarction or other cardiovascular event (cerebral vascular disease, transient 
cerebral ischemia, or hospitalization for heart failure) during the 4 months prior to the 
screening visit, or subjects with active myocardial ischemia. 
8. Systemic treatment with VEGF-related medications within 4 months prior to the 
screening visit. 
9. History of any rheumatological or collagen disease of autoimmune origin related to 
inflammatory processes such as systemic lupus erythematosus, rheumatoid arthritis, 
ankylosing spondylitis, Bechet's disease, dermatomyositis, among others.  
10. History of any disease that causes immunosuppression or immunosuppression, except 
diabetes mellitus.  
11. Concomitant use of immunosuppressive agents, immunotherapy, or monoclonal 
antibodies by any route of administration (other than intravitreal route), within 2 years 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  17 of 110 
prior to the screening visit or during the study period. 
12. Subjects who have received intravitreal anti-VEGF therapy (aflibercept, ranibizumab, 
bevacizumab, faricimab, brolucizumab) in the study eye within 4 months prior to the 
screening visit. 
13. Use of intraocular or periocular corticosteroids in the study eye within 4 months prior 
to the screening visit, or use of intravitreal corticosteroid implants at any time. 
14. Use of anticoagulants or antiplatelet agents by any route of administration within 10 
days prior to the screening visit or during the study period. 
15. Women of childbearing potential who are pregnant, nursing, or plan to become 
pregnant within the study period. 
16. Allergy to fluorescein (topical or intravenous) or to numbing medications used during 
the injection procedure. 
17. Subjects with non-diabetic macular edema. 
18. Lens opacities that are superior in one or more of the following criteria according to the 
LOCS III classification (Lens Opacities Classification System): nuclear component > 
NO3C3 (opalescence/color), cortical component > C2 and posterior subcapsular 
component > P1. 
19. History of eye surgery (cataract removal, any intraocular surgery, aphakia, etc.) or 
panretinal photocoagulation within 3 months prior to the screening visit or planned 
within the study time. 
20. Intraocular pressure greater than 21 mmHg in the selected eye, measured by Goldmann 
tonometry at the screening visit. 
21. Presence of macular ischemia or significant peripheveal capillary loss (increase in the 
foveal avascular zone greater than 350 μm) demonstrated by retinal fluorescein 
angiography (during the screening visit or in a study conducted within 4 months prior to 
the screening visit). 
22. History of YAG capsulotomy in the study eye, within 30 days prior to the screening visit. 
23. Evidence of external eye infections, intraocular inflammation, or significant ocular 
surface disease in either eye, 30 days prior to the screening visit. 
24. History of uveitis in the eye of study. 
25. History of retinal detachment, vitrectomy, any type of filtering surgery, transplant or 
corneal dystrophy in the selected eye. 
26. Advanced glaucoma or optic neuropathy in the selected eye. 
27. Have a single functional eye (finger-counting BCVA or less in the eye with worse vision). 
28. Have previously participated in this same study. 
29. Be or have an immediate family member (e.g., parent/legal guardian or sibling) who is 
part of the research site or sponsor staff. 
30. Subjects who present conditions that make it difficult or impossible to extract the blood 
sample, such as veins that are not visible or palpable, the presence of venous thrombosis 
in the sample collection area, severe edema, or any other criteria of the personnel in 
charge of performing this procedure. 
31. Difficulty interpreting the optotypes of the ETDRS booklet. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  18 of 110 
Additional exclusion criteria  for the pharmacokinetics cohort: 
1. Prior intravitreal treatment with bevacizumab in the contralateral eye, within 3 months 
prior to the screening visit. 
2. Another intravitreal anti-VEGF therapy (ranibizumab, aflibercept, brolucizumab, 
faricimab) in the contralateral eye, within 30 days prior to the inclusion of the study or 
during the conduct of the study. 
NOTE: Only one eye may be selected; if both eyes are eligible for inclusion, one eye will be 
selected at the discretion of the PI. 
Research Product (RP): 
Investigational product, dosage, and route of administration: 
• 
PRO-169. Bevacizumab (for ophthalmic use). 
• 
Dosage: 1 intravitreal injection every 30 days. 
• 
Route of administration: Intravitreal 
• 
Prepared by Laboratorios Sophia, S.A de C.V., Zapopan, Jalisco, Mexico. 
Duration of treatment: 
2 months 
 
Duration of the subject in the study: 
Up to 95 days (counting from visit 1 [day 1]) or 
up to 103 days (counting from screening visit 
[day -8 to 0]). 
Evaluation criteria: 
Safety primary outcome variables 
- 
Proportion of patients with the presence of bevacizumab-positive serum ADAs. 
Safety Secondary Outcome Variables 
- 
Incidence of adverse events related to RP. 
- 
Incidence of serious adverse events related to RP. 
Pharmacokinetic secondary outcome variables 
- 
Total AUC of serum PRO-169 concentration.  
- 
PRO-169 serum Cmax. 
- 
PRO-169 serum Tmax. 
Exploratory variables 
- 
Changes in BCVA from baseline to day 90.  
- 
Changes in the GMC, from baseline to day 90. 
Statistical methodology 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
  
   Page  19 of 110 
The statistical analysis will be carried out by personnel of Laboratorios Sophia, S.A. de C.V. A 
specialized statistical package will be used.  
All analyses will be primarily descriptive. 
 The data will be expressed as means, standard deviation (SD), median, minimum value, 
maximum, 95% confidence interval, geometric mean.  
The categorical variables will be summarized by frequency, and percentages by subjects. They will 
be presented with a decimal place 
The data obtained will be presented in tables and graphs as appropriate. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
 Version 4.0 
 
 
    Nov 4-25 
 
C O N F I D E N C I A L 
 
   Page  20 of 110 
1.2 Study diagram 
 
 
Figure 1. Study diagram 

Laboratorios Sophia, S.A. de C.V.  
 
 
 
            Study No: SOPH1691224/I 
 
 
  
 
 
 
             Version 4.0 
                                                                                                                                                                                                          Nov 4-25 
C O N F I D E N C I A L 
   Page  21 of 110 
1.3 Schedule of activities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 2. Schedule of activities 
 
                  
 
                                                                 Visit of 
                                                                 Selection 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Start of 
treatment 
    Treatment Period 
Final / Early 
Termination 
Protocol Day 
-8 to 0 
1 
2 
4 
8 
30±5 
60±5 
90±5 
Informed consent 
X 
 
 
 
 
 
 
 
Evaluation of selection criteria 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Weight, Height, BMI and Body Mass Surface Area 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, Temperature, RF)ɸ 
X 
X 
 
 
 
X 
X 
X 
% HbA1c* 
X 
 
 
 
 
 
 
 
Glomerular filtration rate (GFRe)a 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Registry 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X 
 
 
 
X 
X 
X 
Best-corrected visual acuity 
X 
 
 
 
 
X 
X 
X 
Biomicroscopy 
X 
 
 
 
 
X 
X 
X 
Indirect ophthalmoscopy 
X 
 
 
 
 
X 
X 
X 
Ocular tonometry 
X 
 
 
 
 
X 
X 
X 
Macular optical coherence tomography 
X 
 
 
 
 
X 
X 
X 
Fluorescein angiography (AF) or optical coherence 
tomography angiography (OCT-A)Ж 
X 
 
 
 
 
 
 
 
Intravitreal injection 
 
X 
 
 
 
X 
X 
Pharmacokinetic blood sample (applies to PK cohort)ᴥ 
X 
X 
X 
X 
X 
X¥ 
X¥ 
X¥ 
Blood Sample Immunogenicity 
X 
 
 
 
 
X¥ 
X¥ 
X¥ 
ɸ Vital signs assessment should be performed prior to blood sample collection. 
*If there is an HbA1c determination dated within 3 months prior to the inclusion of the study, it will not be necessary to perform it at the screening visit. 
a If a serum creatinine result dated within 2 months prior to study inclusion is available, it will not be necessary to perform it at the screening visit and may be used 
to calculate GFRe. 
If you have an AF or OCT-A performed in the 4 months prior to the inclusion of the study, it will not be necessary to perform it at the screening visit. 
ᴥSee pharmacokinetics schedule on the following page. 
¥Blood samples will be collected prior to intravitreal application of PRO-169 (no more than 2 hours prior to the time of application at Visit 1). 

Laboratorios Sophia, S.A. de C.V.  
 
      Study No: SOPH169-1224/I 
 
 
    Version 4.0 
 
 
    Nov 4-25 
C O N F I D E N C I A L 
   Page  22 of 110 
1.4 Pharmacokinetics Cohort Schedule 
 
 
Table 3. Pharmacokinetics Cohort Timeline
Selection 
Visit 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Treatment Period 
Final / Early 
Termination 
Protocol Day 
-8 to 0 
1 
2 
4 
8 
30±5 
60±5 
90±5 
Specific hours to 
perform procedures 
(when applicable) 
 
Research Product Application 
Intravitreal 
injection time 
+ 3 hours 
(± 30 min) 
Intravitreal 
injection 
time  
+ 24 hours  
(± 2 hours) 
Intravitreal 
injection 
time  
+ 72 hours  
(± 2 hours) 
Intravitreal 
injection 
time  
+ 168 hours  
(± 2 hours) 
 
 
 
Pharmacokinetic 
blood sample 
X 
X 
X 
X 
X 
X¥ 
X¥ 
X¥ 
¥Blood samples will be collected prior to intravitreal application of PRO-169 (no later than 2 hours prior to the time of intravitreal application at Visit 1). 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  23 of 110 
2. Introduction and background 
2.1 Theoretical framework 
Diabetic macular edema (DME) is the leading cause of vision loss in diabetic patients of productive 
age. DME consists of the accumulation of fluid and serous macromolecules in the retina, both 
intracellular and extracellular, of the retina. This accumulation interferes with the functions of the 
retina, causing visual deficiencies.    [1]  [2] [3] [4] [1] [5] 
Although DME can manifest in both types of diabetes (type 1 and type 2), its relevance as a public 
health problem is due to the severity of type 2 diabetes as one of the main threats to public health. 
Two studies published in consecutive years in 2017 and 2018, place the estimates of diabetes 
prevalence for 2015 and 2017, at 415 million (uncertainty range: 340 - 536 million) equivalent to 
8.8% (7.2 – 11.4%) of the world population between 20 - 99 years, and 451 million (uncertainty 
range: 367.5 – 585.5 million) equivalent to 8.4% (7.0 - 11.2%) of the world population between 18 - 
99 years,  respectively. Predictions for 2040 and 2045 are 642 million and 693 million adults affected 
by the disease, respectively. [6] [7] 
The ophthalmological complications that occur in patients with diabetes are multiple and include 
keratopathy, cataract, neovascular glaucoma, neuropathy, ischemic optic neuropathy, diabetic 
retinopathy (DR), and secondary macular edema.   DR is the set of alterations in the retina due to 
damage caused by uncontrolled hyperglycemia and affects about 4 million people worldwide.  This 
condition in turn can be subdivided into non-proliferative DR and proliferative DR, depending on the 
presence or absence of secondary ocular neovascularization. While retinal neovascularization leads 
to serious complications resulting in severe vision loss, the leading cause of decreased visual acuity 
in diabetic patients is DME. Historically, the first descriptions of the DR are presented at the end of 
the nineteenth century with descriptions by Jaeger, Mackenzie, and Noyes, among others. 
Mackenzie, on the other hand, is the first author to describe in detail the changes in the retina at 
the histopathological level: "The retina was thickened in all its layers... The thickening of the retina 
appears to be due to the result of chronic edema with connective tissue hypertrophy... microscopic 
cysts are observed... the thickness is two or three times greater than normal tissue." Later, 
Nettleship would publish histopathological observations that clearly demonstrated cystoid 
degeneration of the retina. Even so, the role of DME in the visual acuity of diabetic patients would 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  24 of 110 
not begin to be considered a determinant for vision loss until the studies of Klein et al. published in 
1984, in which a clear relationship was demonstrated between the presence of macular edema and 
the impairment of visual acuity in patients with DR.  mainly in adults diagnosed with diabetes after 
30 years of age.   [8] [9][8] [10] [11] [12] [13] [14] 
DME can develop at any stage of DR, however, its prevalence increases according to the duration of 
diabetes and the severity of DR. In addition, there are other systemic and ocular factors that play an 
important role in its development, such as high blood pressure, hyperlipidemia, previous cataract 
surgery, and elevated levels of glycosylated hemoglobin (HbA1c).  Hyperglycemia conditions the 
abnormal glycosylation of proteins at the level of the retina, which leads to damage to pericytes and 
endothelial cells. Damage to vascular structures alters permeability, resulting in fluid extravasation 
and consequently macular edema. Once edema is established, a vicious cycle of hypoxia and 
inflammation begins. These two elements promote the synthesis of vascular endothelial growth 
factor (VEGF).   [15]     [5]    [16]  [17] [18] [19] [20] [1] [5] vascular endothelial growth factor). VEGF 
values during DME are usually increased by up to 10 times their normal levels. This presence of 
elevated levels of VEGF has two effects within the pathogenesis of DR and the formation of DME: 1) 
it causes capillary damage and increased vascular permeability, which causes disruption of the 
blood-retinal barrier; and 2) promotes the synthesis of new vessels.  [1] [5][21] [22] [23] 
The prevalence of DME globally is estimated to be between 1.4% and 12.8%. However, local 
prevalences vary according to the incidence of diabetes in each region and the degree of disease 
control in the affected population. In Mexico, the estimated prevalence is between 3.1% and 6.6% 
of patients less than 10 years old from the diagnosis of diabetes mellitus.  [24][19] [25] 
The main strategy for the management of DME is prevention. Aggressive glycemic control with 
HbA1c values below 7%, as well as control of elevated blood pressure, have been shown to reduce 
the risk of DR onset and progression, as well as to decrease the incidence of DME.  [26][27] [28] 
Once DME occurs, its treatment is key to preventing severe visual loss. Currently, intravitreal anti-
VEGF drugs are considered the first-line therapy.   Currently available anti-VEGF agents with an 
approved indication for the treatment of DME are ranibizumab, aflibercept, brolucizumab, 
faricimab, and additionally, bevacizumab which is used off-label. Although all these drugs aim to 
inhibit the VEGF pathway, they have differences in their molecular structure, binding affinity, 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  25 of 110 
mechanism of action, and pharmacodynamics, which contribute to their efficacy and duration of 
effect.     [16]     [20]  [22] [23][29] [30] [31] [32] [33][34] 
Although pegaptanib was the first drug authorized for the treatment of DME, its use has fallen into 
disuse because it is only able to bind to the VEGF165 form, so its efficacy is lower than that of other 
anti-VEGF agents. [35] 
Faricimab and brolucizumab are among the newer anti-VEGF drugs. Faricimab is a humanized 
bispecific monoclonal antibody with dual action as it simultaneously inhibits VEGF-A and 
angiopoietin-2. Brolucizumab is a humanized monoclonal antibody with a monocaternary Fv 
fragment that inhibits all VEGF-A isoforms that bind to VEGF, VEGF-1, and VEGF-2 receptors.  [23] 
[34] 
Aflibercept, ranibizumab and bevacizumab are the most widely used medicines worldwide. 
Aflibercept is a fusion protein that acts as a soluble VEGF receptor; binds to VEGF-A, VEGF-B, and 
placental growth factor. Ranibizumab is an antigen-binding fragment (Fab, Fragment antigen-
binding) of a humanized monoclonal antibody, developed specifically for intraocular use; binds to 
and inhibits all active forms of VEGF-A. Bevacizumab is a full-length (149 kDa) humanized 
monoclonal antibody developed for cancer therapy.  At least four studies comparing treatment 
between aflibercept, ranibizumab, and bevacizumab have shown that the efficacy of treatment is 
equivalent in improving visual acuity, but with a lower response of bevacizumab on measurements 
of central macular thickness as assessed by optical coherence tomography (OCT).    [23]  [34][36] 
[37] [38] [39]Optical Coherence Tomography). Except for the study carried out by The Diabetic 
Retinopathy Clinical Research (DRCR) Retina Network (Protocol T), These were carried out with small 
samples or reduced treatment times. 
The T-protocol demonstrated that bevacizumab and ranibizumab were equivalent in their efficacy 
for the treatment of DME, after one year of treatment (improvement of 9.7 + 10.1 letters, and 11.2 
+ 9.4 letters on average, respectively [p = 0.12]), although both were slightly inferior to aflibercept 
(13.3 + 11.1 letters) particularly for the treatment of patients with visual acuity deficiencies below 
69 letters (11.8 + 12.0 for bevacizumab,  14.2 + 10.6 for ranibizumab, and 18.9 + 11.5 for aflibercept). 
Despite these results, there is no ophthalmic presentation of bevacizumab on the market to 
date.[36] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  26 of 110 
The need for an ophthalmic presentation of bevacizumab becomes even more critical when 
treatment costs are taken into consideration. The approximate cost of each aflibercept injection on 
the market is $1,175 USD, while the cost of each ranibizumab injection is $1,050 USD. The high cost 
of these drugs promotes the search for lower-cost alternative therapeutic options, one of the 
reasons why the off-label use of bevacizumab is so prevalent in ophthalmic practice today. [40] 
Additionally, the cost analysis of the T protocol revealed that the use of aflibercept and ranibizumab 
was not cost-efficient with respect to bevacizumab. Similarly, a meta-analysis on the cost-
effectiveness of several treatments for diabetic retinopathy (laser therapy, anti-VEGF, steroids, and 
surgery) also found the use of bevacizumab as the most cost-effective treatment for the treatment 
of DME. [41] [42] 
With the advent of biological therapy, such as intravitreal anti-VEGFs, for the treatment of various 
retinal diseases, along with their high level of efficacy, there have also been reports of related 
immunogenic reactions.  Biologic drugs are produced by a living organism, mostly by genetically 
engineering living bacterial, animal, or plant cells. These drugs have large, complex structures, and 
possess the potential to induce an unwanted immune response.  While not all cases of immune 
response lead to adverse reactions, the development of immunogenicity can impact the 
pharmacokinetics and pharmacodynamics of the biologic drug and; therefore, decrease its 
effectiveness.   [43] [44] [45] [44] [46] 
Immunogenicity refers to a host's immune response to an external agent; in relation to biological 
drugs, this response is manifested through the generation of anti-drug antibodies (ADAs). Anti-drug 
antibodies) by the immune system. It has been postulated that these are generated in response to 
free monoclonal antibodies due to their protein structure.  The development of immunogenicity 
against a biologic drug is influenced both by factors inherent to the patient (age, sex, ethnicity, 
immune status, presence of allergies, history of inflammatory processes, and HLA classification) and 
by product-specific factors (origin, structure and molecular weight, degradation products, post-
translational modifications, impurities, formulation and closure of the container, dose level,  route 
of administration, among others).    Two types of ADAs can be generated: epitope-neutralizing ADAs 
(anti-idiotypic ADAs), and non-neutralizing ADAs (binding-ADAs) directed against the main structure 
of monoclonal antibodies.  Neutralizing ADAs compete with and bind to the antigen-binding site and 
thus reduce the amount of free drug available, resulting in treatment failure or resistance. The 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  27 of 110 
clinical consequences resulting from an immune response range from the absence of measurable 
effects to treatment failure and, rarely, even life-threatening events.  One of the most serious effects 
that is postulated to be induced by these ADAs is hypersensitivity or anaphylactic reactions to 
biotherapeutics, which can cause effects such as sterile endophthalmitis after intravitreal injections.    
[46]     [43] [44][47][48][43][43] [44][43] 
The demonstration of ADAs in the serum of patients who received intravitreal injections of anti-
VEGF has been attributed to the response to molecules entering the systemic circulation through 
the aqueous humor drainage pathways.  [43] 
There are several advanced techniques for assessing ADAs, each with advantages and limitations. 
Among them, antigen-binding tests stand out for using antibodies or immobilized antigens to 
capture ADAs in biological samples. A significant advantage of these tests is their ability to 
incorporate acid dissociation steps, which allows interference caused by ADAs complexes to be 
eliminated with the drug. However, these techniques can be expensive and require rigorous 
protocols to ensure reproducible results. Electrochemiluminescence (ECL) assays offer exceptional 
sensitivity when using luminescent labels such as tris(bipyridine)ruthenium (II). These tags generate 
signals through oxidation-reduction reactions, which makes them highly effective even in the 
presence of high concentrations of the drug in circulation. ECLs are less prone to interference and 
allow for a wide dynamic range. Despite their advantages, ECLs require specialized equipment and 
can have high upfront costs for laboratories that do not have the appropriate technology. The 
radioimmunoassay (RIA), based on the use of radioactive isotopes such as iodine-125, provides 
extremely low detection limits, making it an effective option for samples with minimal levels of 
ADAs. However, handling radioactive materials involves safety risks and requires specialized 
facilities, which has reduced its popularity compared to more modern techniques. Homogeneous 
mobility displacement assays (HMSAs) combine size exclusion chromatography with ligand-binding 
techniques, allowing ADAs of different sizes or classes to be discriminated against. This makes them 
ideal for identifying ADA from different classes of immunoglobulins, such as IgG and IgM. Surface 
plasmon resonance spectroscopy (SPR) uses resonance waves generated at the interface between 
a conductive metal (such as gold or silver) and a dielectric medium, allowing changes in refractive 
index induced by molecular binding events on the sensor surface to be detected. One of the main 
advantages of MMR is its ability to provide detailed kinetic information, including the rates of 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  28 of 110 
association and dissociation of ADAs to drugs. However, these techniques can be complex and 
require advanced technical expertise to implement and analyze. [46] 
The enzyme-linked immunosorbent assay (ELISA) remains the most widely used method for 
detecting and quantifying ADAs due to its ease of use, low cost, and ability to process a high number 
of samples. There is different ELISA methods used for the detection of ADAs such as direct, indirect 
and bridging (or sandwich). Direct and indirect variants are straightforward, but face limitations in 
terms of drug interference and detection of low-affinity ADAs. In contrast, the bridging format, 
which uses two binding points in the ADAs, is highly specific and sensitive, although it can be more 
complex and requires additional optimization to avoid interference under conditions of high drug 
concentration. [46] 
2.2 Background on the investigational product  
2.2.1 Preclinical study on the ocular bioavailability of two bevacizumab solutions, PRO-169 
vs Avastin®, following intravitreal application in albino rabbits in New Zealand. 
A preclinical comparative bioavailability study was conducted that included 96 eyes from 48 healthy 
New Zealand albino rabbits. The research subjects were divided into two groups; Group 1 received 
an intravitreal dose (50 μL) of the PRO-169 test solution (bevacizumab 1.25 mg/0.05 mL) in both 
eyes, while group 2 received the reference product Avastin® (bevacizumab 1.25 mg/0.05 mL). In 
turn, each group was divided into 6 subgroups (4 subjects per subgroup) corresponding to the 
slaughter time points (1 hour, 1, 2, 5, 14, and 30 days) after the application of the drug. [49] 
The primary pharmacokinetic parameters that were quantified and determined were the maximum 
concentration (Cmax), maximum time (Tmax) and half-life (T1/2); and the secondary pharmacokinetic 
parameter was the area under the effect curve (AUC0-t). All parameters were evaluated in three 
tissues: aqueous humor, plasma and vitreous humor after intravitreal administration of a test 
solution (PRO-169) compared to Avastin®. [49] 
1. Aqueous humor: The similarity in bioavailability (Cmax and AUC0-t) and Schuirmann's non-
inferiority test were not met. The Cmax was 67.07 ± 70.5 μg/mL (PRO-169) vs. 80.63 ± 53.63 
μg/mL (Avastin®), reached approximately one hour after injection. The half-lives were 6.59 
± 1.17 days (PRO-169) and 7.65 ± 1.98 days (Avastin®), with total exposures of 7.41% and 
7.64%, respectively. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  29 of 110 
2. Plasma: Similarity in bioavailability was also not achieved. The Cmax was 22.05 ± 24.5 μg/mL 
(PRO-169) and 15.30 ± 6.6 μg/mL (Avastin®), with times of 3.00 ± 1.73 days and 5.67 ± 7.23 
days, respectively. The AUC0-t was higher for PRO-169 (268.67 ± 270.45 days*μg/mL) versus 
Avastin® (145.28 ± 86.57 days*μg/mL). No plasma concentrations were detected beyond 24 
hours (<0.250 μg/mL). 
3. Vitreous humor: The acceptance criteria for most analytical runs were met. The Cmax was 
540.52 ± 108.95 μg/mL after one hour for PRO-169, and 563.16 ± 83.75 μg/mL after one day 
for the Avastin® comparator. The half-lives were similar (4,991 ± 0.89 days vs. 5,182 ± 0.88 
days, respectively), with no significant differences (p=0.711). The drug was not detected 
beyond day 30 (< 3.33 μg/mL). 
The Cmax in vitreous it was 593.75 ± 45.63 for PRO-169 vs 644.79 ± 62.65 μg/mL for Avastin® 
(p=0.136). The Tmax was 0.53 ± 0.82 vs 0.85 ± 0.73 days (p=0.330), respectively. AUC0-t was 3837.72 
± 465.91 vs 4247.31 ± 93.99 days*μg/mL (p= 0.052). [49] 
In conclusion, while there were no significant differences in vitreous humor, in aqueous humor and 
plasma the similarity in bioavailability between PRO-169 and Avastin® was not achieved. 
2.2.2 Preclinical study on the safety and toxicity of PRO-169 (bevacizumab) vs Lucentis® 
(ranibizumab) after intravitreal application in albino rabbits in New Zealand. 
48 eyes of 24 healthy New Zealand albino rabbits were studied randomized into two treatment 
groups (PRO-169 and Lucentis®). In turn, each group was divided into three subgroups (A, B, and C) 
according to the intravitreal application model. Only the right eye of the research subjects was 
injected; subgroup A received a single intravitreal injection. Groups B and C received two and three 
intravitreal injections, respectively, with a lapse of 31 days between each application. 
Ophthalmological check-ups were carried out after injection and one month after the last 
application of the treatments; Each group underwent an electroretinogram, blood sampling, 
euthanasia, enucleation for histopathological analysis of the eyeballs, and necropsy. [50] 
The safety analysis of the study showed no significant differences in the primary variable cellularity 
in the anterior chamber between groups (PRO-169 and Lucentis®). Isolated cases of intraocular 
inflammation were reported in both groups, attributable to the injection procedure and not to the 
drug itself. [50] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  30 of 110 
Laboratory studies indicated that all hematological parameters were within normal ranges and 
without significant differences. In blood chemistry, blood nitrogen (BUN), blood urea nitrogen) was 
higher in the PRO-169 group, with no clinical relevance or relationship to treatment. Alterations in 
liver enzymes in one subject were considered isolated events, possibly related to the use of 
ketamine during anesthetic induction.  One death was also reported in the PRO-169 group, with no 
previous signs of disease or conclusive findings in the necropsy. It is suspected that stress and 
previous anesthesia could have played a role. [50][50] 
Electroretinogram studies performed at 30, 60, and 90 days showed that there were no significant 
differences between treatments in terms of retinal functionality. The parameters analyzed indicated 
that the integrity and sensitivity of the retina were not affected. 
In conclusion, the safety and toxicity profile of PRO-169 was not inferior to that of Lucentis® in albino 
rabbits in New Zealand. [50] 
2.2.3 Comparative preclinical study on the efficacy of PRO-169 (bevacizumab) and Avastin® 
(bevacizumab) in laser-induced choroidal neovascularization (CNV) in rhesus monkeys. 
On behalf of Sophia Laboratories, this preclinical study was conducted by the Sichuan third party 
Primed Shines Bio-tech Co., Ltd., to compare the efficacy of the investigational product PRO-169 
versus the reference product Avastin®, after intravitreal application in a laser-induced CNV model 
in rhesus monkeys (a total of 18 subjects were included in the study). [51] 
CNV was induced by photocoagulation around the macular area of both eyes of each subject. A 
revision was performed by retinal fluorescein angiography (FA) 19 days later (day -2). According to 
the area of fluorescein leakage points, eligible animals were enrolled for treatment and randomly 
divided into three groups as shown below. [51] 
Table 4. Characteristics of the treatment groups 
Group 
Trial Drug 
Number of 
eyes 
enrolled 
Dosage 
(mg/mL) 
Dose 
volume 
(μL) 
Dosage 
Quantity 
(mg) 
Route of 
administration 
Variables 
1 
Vehicle 
7 
0 
 
50 
0 
 
Intravitreal 
injection 
Fundus 
photography 
Fluorescein 
angiography 
OCT 
2 
Avastin 
7 
25 
1.25 
3 
PRO-169 
7 
25 
1.25 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  31 of 110 
The administration of the treatments was carried out 21 days after photocoagulation (day 0) for all 
groups. Group 1 (vehicle) received a single dose; groups 2 (Avastin®) and 3 (PRO-169) received two 
additional doses administered on days 28 and 56 (see Figure 2. Overall Study Design) 
Evaluations by fundus photography, AF, and OCT were performed before photocoagulation (day -
31); before administration of investigational products (day -2); two weeks after administration of 
investigational products (day 14); and four weeks after administration (day 28), see Figure 2. Overall 
Study Design. 
 
Figure 2. Overall Study Design 
FF, fundus photography; AF, Fluorescein Angiography; OCT, Optical Coherence Tomography. 
A total of 14 subjects (belonging to the three treatment groups) were included for the 
immunogenicity assessment. One mL of venous blood was extracted from animals belonging to 
group 1 (vehicle) on days 0, 77 and 114; and additionally, on days 11, 15, 35, 49 to subjects belonging 
to groups 2 (Avastin®) and 3 (PRO-169). [51] 
After photocoagulation, features of CNV, such as increased retinal thickness and fluorescein 
leakage, were observed. Intravitreal administration of PRO-169 (1.25 mg per eye) significantly 
reduced both parameters on days 14 and 28, compared to the vehicle group, suggesting that this 
investigational product may inhibit CNV. [51] 
In the immunogenicity evaluation, four samples tested positive for ADAs antibodies, but the 
confirmatory assays were negative, so it was not necessary to analyze neutralizing antibodies. It was 
concluded that the immunogenicity of PRO-169 was comparable to that of Avastin®. .[51] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  32 of 110 
2.3 Background on the investigation 
2.3.1 Research Question 
Is PRO-169 (bevacizumab) safe as it does not induce an unwanted immune response, after 
intravitreal application, in patients with MDD?  
Bevacizumab is a humanized recombinant monoclonal antibody (the protein sequence corresponds 
to 93% human and 7% murine).  For this type of medicine, the origin of the product is an important 
factor that can influence immunogenicity. It has been shown that murine antibodies elicit robust 
immune responses in humans compared to chimeric, humanized, and human monoclonal 
antibodies; however, it should be noted that the latter can also cause a high rate of immunogenicity 
depending on the dosage regimen and patient population. [52][53] 
The consequences of an immune reaction to a therapeutic protein range from the transient 
appearance of ADAs without clinical significance, to conditions that impact the safety, 
pharmacokinetic properties and efficacy of the drug.   [48][53][54] 
A number of anti-VEGF drugs, including biosimilars, are currently marketed for ophthalmic use; 
however, its high cost has led to the off-label use of other drugs not authorized for this route of 
administration, such as Avastin® (bevacizumab). Immunogenicity profiles have been reported for 
anti-VEGF drugs authorized for intravitreal use; However, in the case of bevacizumab, the available 
information is very limited because this use is off label. The fact that bevacizumab is not available 
for ophthalmic use implies challenges such as differences in manufacturing standards between 
oncology and ophthalmic drugs, possible errors in fractionating the commercially available vial (4 
mL/100 mg) into individual doses, as well as its conservation and storage in insulin syringes.  All 
these factors can also influence an unwanted immune response.      [55] [43][56] [57] [58] 
Having PRO-169 in Mexico, an investigational product with the same active ingredient and in the 
same concentration as Avastin®, but for exclusively ophthalmological use and stored in a prefilled 
syringe, considerably reduces the additional risks previously mentioned. However, it is necessary to 
know its immunogenicity potential. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  33 of 110 
2.4 Risk-benefit assessment 
2.4.1 Known potential risks 
Many of the risks reported with intravitreal anti-VEGF treatments are related to the procedure itself. 
According to the information reported by Lytenava® (bevacizumab gamma 0.05 mL/1.25 mg, 
approved only in the European Union for intravitreal use), the most reported adverse reactions after 
its application were: conjunctival hemorrhage (5.0%), floaters (1.5%), eye pain (1.2%) and increased 
intraocular pressure (1.2%). Some serious but less frequent adverse reactions are transient 
blindness (0.3%), endophthalmitis (0.3%), intraocular inflammation (0.3%). Traumatic cataracts and 
retinal tear/detachment may also occur after intravitreal injection. [59] [60] 
Among the adverse effects related to the drug class (so they can occur with any anti-VEGF, both 
intravitreal and systemic) are thromboembolic events, including stroke and acute myocardial 
infarction. Clinical studies in patients with neovascular age-related macular degeneration who 
received intravitreal bevacizumab gamma have shown a low incidence of arterial thromboembolic 
events. [59] 
2.4.2 Known potential benefits 
Preservation of visual function is the main goal with DME treatment. The importance of this lies in 
the growing incidence and prevalence of diabetes mellitus, as well as its complications, which 
continue to increase both in Mexico and in the world. 
DME causes decreased central vision and therefore significantly affects patients' quality of life. The 
significant financial burden of treating diabetes mellitus and DME has a major impact on patients' 
lives. As a result, there are treatment deficiencies, changes in anti-VEGF medications, and variations 
in treatment intervals in routine practice.  [61][62] 
The evidence currently available supports the recommendation of early and intensive anti-VEGF 
treatment in patients with DME, as it provides greater visual acuity gains and more long-term 
stability; This improves patients' quality of life and opens the possibility of reducing the number of 
annual injections administered. [63] 
In addition to the benefits shown for DME, anti-VEGF therapies have also demonstrated relevant 
benefits in terms of improvement and regression of DR severity, both non-proliferative and 
proliferative. [63] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  34 of 110 
Given the measures taken to minimize the risk to the participants in this study, the potential risks 
identified in association with PRO-169 are justified by the intended benefits that may be conferred 
on patients with diabetic macular edema.  
More detailed information about the known and expected benefits, as well as risks and reasonably 
expected AEs of PRO-169 can be found in the Investigator's Manual. 
2.5 Problem statement 
DR and DME are the main ocular complications of diabetes mellitus and can lead to significant visual 
loss. Although the pathogenesis of these conditions is complex, VEGF overexpression plays a key 
role, which is why intravitreal anti-VEGF drugs are the cornerstone for the management of these 
diseases. [63] 
Different treatment schemes have been proposed; however, in most cases, monthly injections are 
required to achieve anatomical and visual improvement, as well as to maintain the stability of the 
disease. These repeated injections cause a great economic burden for patients and can have an 
impact on adherence to treatment.  [62][64] 
The high cost of anti-VEGF drugs authorized for intravitreal use has led to the off-label use of other 
drugs not authorized for this route of administration, such as Avastin® (bevacizumab) and 
biosimilars. This involves splitting vials designed for oncology into individual doses for intraocular 
use, which entails safety risks, lack of standardization, and limited availability due to regulatory 
restrictions.  
With the development of PRO-169, an investigational product with the same active ingredient and 
in the same concentration as Avastin®, but for exclusively ophthalmological use and stored in a 
prefilled syringe, it would guarantee a product designed and manufactured under standards that 
optimize its safety, efficacy and accessibility for the patients who need it most. 
Because bevacizumab is a biopharmaceutical, clinical evidence that it does not induce 
immunogenicity after intravitreal administration is necessary. 
2.6 Rationale for the study 
Several clinical studies have validated the efficacy of bevacizumab in DME, showing it to be a 
comparable option to other VEGF inhibitors approved for this indication, but at a significantly lower 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  35 of 110 
cost. This accessibility has meant that Avastin® (bevacizumab) or biosimilars manufactured for 
cancer use are widely used off-label in clinical practice. 
This can present dosage, safety, stability, and asepsis risks if not performed under proper conditions; 
in addition to the fact that in our country this practice is not approved.  
Laboratorios Sophia S.A. de C.V., has experience in preclinical studies on the bioavailability, safety 
and efficacy of PRO-169, and a phase III clinical study is currently being carried out in patients with 
DME. However, due to the nature of the drug, it is imperative to have a clinical study in this type of 
population that verifies that no unwanted immune responses are generated after its intravitreal 
application. 
Additionally, it is worth mentioning that the inclusion of a pharmacokinetic (PK) cohort is intended 
to characterize the pharmacokinetic profile of PRO-169 in humans taking into account two 
important aspects: 1) the limited existing information on the systemic and ocular levels of the 
reference drug (Avastin®) after intravitreal administration; and 2) PRO-169 is a biopharmaceutical 
that shares structural characteristics with Avastin®, but corresponds to a compound specifically 
designed for ophthalmic use, an indication that is not approved for Avastin® so far. 
It has been widely documented in the literature that the evaluation of intraocular pharmacokinetics 
(aqueous humor, vitreous humor, etc.) of ophthalmic drugs is not feasible in clinical studies, as it 
requires invasive techniques that expose participants to unnecessary risks. For these reasons, most 
pharmacokinetic data in ophthalmology are based on peripheral blood samples and population 
pharmacokinetic models that allow estimating interindividual exposure and variability from a 
limited number of samples per subject.[1] [2] [3] 
In addition, the international guidelines for biotechnology products (FDA and EMA) mention the 
relevance of the study of immunogenicity and its possible effect on pharmacokinetics, particularly 
in repeated administration treatments.[4] [5] Therefore, the objective of including a PK cohort is to 
have information regarding the pharmacokinetic profile of PRO-169 after intravitreal administration 
in humans, as well as to evaluate the possible relationship between the presence of anti-drug 
antibodies (ADAs) and the influence it may have on drug elimination. 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  36 of 110 
3. Objectives and hypotheses 
3.1 Objectives 
3.1.1 Primary security objective:  
• 
To evaluate the safety of intravitreal PRO-169 by means of the presence of serum anti-drug 
antibodies (ADAs) for bevacizumab. 
3.1.2 Secondary security objectives: 
• 
To determine the incidence of adverse events (AEs) related to the investigational product. 
• 
Determine the incidence of serious AEs related to the investigational product. 
3.1.3 Objectives for the pharmacokinetics cohort: 
• 
Calculate the total AUC of serum PRO-169 concentration. 
• 
To quantify the serum Cmax of PRO-169. 
• 
To quantify the serum Tmax of PRO-169. 
3.1.4 Exploratory objectives: 
• 
To assess the change in BCVA compared to baseline. 
• 
To evaluate the change in GMC compared to baseline. 
3.2 Hypothesis 
This study does not propose any statistical hypothesis testing, so they are not considered formal 
statistical decisions. 
 
 
 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  37 of 110 
4. Study design 
4.1 Study Overview 
Phase I clinical study, prospective, interventional, open-label, multicenter. 
4.2 Rationale for the study design  
The design of the study (clinical trial) is considered the highest standard of data quality when seeking 
to explore the effect of an intervention. The drug development phase (phase I) corresponds to the 
objective of the study, which is to evaluate safety. [65] 
4.3 Expected duration  
The total duration of the study, from the first visit of the first subject to the preparation of the final 
report, is estimated to be 14 months.  
The approximate duration of each subject in the study is up to 95 days (counting from visit 1 [day 
1]) or up to 103 days (counting from the screening visit [day -8 to 0]). 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  38 of 110 
5. Study population  
All subjects will be evaluated to determine if they meet the following inclusion and exclusion criteria. 
Prospective approval of deviations from the protocol's recruitment and enrollment criteria, also 
known as protocol exemptions, is not permitted. 
5.1 Selection criteria 
5.1.1 Inclusion criteria 
To be considered eligible to participate in this study, subjects must meet all the criteria listed below: 
1. Age ≥ 18 years. 
2. Diagnosis of type 1 or 2 diabetes. 
3. Ability to give signed informed consent. 
4. Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
5. All subjects (male and female) who are biologically capable of having children will be 
required to agree and commit to using a barrier or hormonal method of contraception (by 
any route of administration) for the entire duration of the study, and for 3 months after the 
last intravitreal injection. 
6. Female subjects, biologically capable of having children, will be required to have a negative 
urine pregnancy test at the screening visit.  
7. Best Corrected Visual Acuity (AVMC) according to the 24- to 78-letter ETDRS primer 
(approximate Snellen equivalent of 20/32 to 20/320) 
8. Diabetic macular edema with central involvement evidenced by spectral domain optical 
coherence tomography (central macular thickness criterion ≥ 300 μm for men and ≥ 290 
μm for women) within 8 days prior to inclusion. All measurements made on a subject 
should be taken with an instrument of the same make and model during the conduct of 
the entire study. 
9. Comply with characteristics that allow an adequate examination of the fundus of the eye 
(transparency of media, adequate pupillary dilation). 
10. Glycosylated hemoglobin < 12% of a result not older than 3 months. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  39 of 110 
5.1.2 Exclusion Criteria 
A subject will not be eligible for inclusion in this study if they meet any of the following criteria: 
1. Chronic kidney disease in renal failure (glomerular filtration rate [GFRe] <15 
ml/min/1.73m2) requiring dialysis or transplantation; according to the 2020 Clinical 
Practice Guideline for the Management of Diabetes in Chronic Kidney Disease (KDIGO).  
2. Active proliferative diabetic retinopathy in the study eye, including rubeosis iridis, vitreous 
hemorrhage, or tractional retinal detachment visible during the screening visit. 
3. Individuals who have required insulin treatment within 4 months prior to the screening 
visit for glycemic control. 
4. Previous participation in clinical studies with investigational, ocular or systemic products 
(at least 30 days must have elapsed between the end of your participation in a previous 
trial and the inclusion of the present study).  
5. Known hypersensitivity or allergy to bevacizumab, or any ingredient in the investigational 
product. 
6. Poorly controlled blood pressure (average of 3 blood pressure readings in a seated position 
with ≥160 mmHg systolic or ≥100 mmHg diastolic) at the screening visit. 
7. Myocardial infarction or other cardiovascular event (cerebral vascular disease, transient 
cerebral ischemia, or hospitalization for heart failure) during the 4 months prior to the 
screening visit, or subjects with active myocardial ischemia. 
8. Systemic treatment with VEGF-related medications within 4 months prior to the screening 
visit. 
9. History of any rheumatological or collagen disease of autoimmune origin related to 
inflammatory processes such as systemic lupus erythematosus, rheumatoid arthritis, 
ankylosing spondylitis, Bechet's disease, dermatomyositis, among others.  
10. History of any disease that causes immunosuppression or immunosuppression, except 
diabetes mellitus.  
11. Concomitant use of immunosuppressive agents, immunotherapy, or monoclonal 
antibodies by any route of administration (other than intravitreal route), within 2 years 
prior to the screening visit or during the study period. 
12. Subjects who have received intravitreal anti-VEGF therapy (aflibercept, ranibizumab, 
bevacizumab, faricimab, brolucizumab) in the study eye within 4 months prior to the 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  40 of 110 
screening visit. 
13. Use of intraocular or periocular corticosteroids in the study eye within 4 months prior to 
the screening visit, or use of intravitreal corticosteroid implants at any time. 
14. Use of anticoagulants or antiplatelet agents by any route of administration within 10 days 
prior to the screening visit or during the study period. 
15. Women of childbearing potential who are pregnant, nursing, or plan to become pregnant 
within the study period. 
16. Allergy to fluorescein (topical or intravenous) or to numbing medications used during the 
injection procedure. 
17. Subjects with non-diabetic macular edema. 
18. Lens opacities that are superior in one or more of the following criteria according to the 
LOCS III classification (Lens Opacities Classification System): nuclear component > NO3C3 
(opalescence/color), cortical component > C2 and posterior subcapsular component > P1. 
19. History of eye surgery (cataract removal, any intraocular surgery, aphakia, etc.) or 
panretinal photocoagulation within 3 months prior to the screening visit or planned within 
the study time. 
20. Intraocular pressure greater than 21 mmHg in the selected eye, measured by Goldmann 
tonometry at the screening visit. 
21. Presence of macular ischemia or significant peripheveal capillary loss (increase in the 
foveal avascular zone greater than 350 μm) demonstrated by retinal fluorescein 
angiography (during the screening visit or in a study conducted within 4 months prior to 
the screening visit). 
22. History of YAG capsulotomy in the study eye, within 30 days prior to the screening visit. 
23. Evidence of external eye infections, intraocular inflammation, or significant ocular surface 
disease in either eye, 30 days prior to the screening visit. 
24. History of uveitis in the eye of study. 
25. History of detachment of 
26.  retina, vitrectomy, any type of filtering surgery, corneal transplant or dystrophy in the 
selected eye. 
27. Advanced glaucoma or optic neuropathy in the selected eye. 
28. Have a single functional eye (finger-counting BCVA or less in the eye with worse vision). 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  41 of 110 
29. Have previously participated in this same study. 
30. Be or have an immediate family member (e.g., parent/legal guardian or sibling) who is part 
of the research site or sponsor staff. 
31. Subjects who present conditions that make it difficult or impossible to extract the blood 
sample, such as veins that are not visible or palpable, the presence of venous thrombosis in 
the sample collection area, severe edema, or any other criteria of the personnel in charge 
of performing this procedure. 
32. Difficulty interpreting the optotypes of the ETDRS booklet. 
5.1.2.1 Additional exclusion criteria for the pharmacokinetics cohort 
1. Prior intravitreal treatment with bevacizumab in the contralateral eye, within 3 months 
prior to the screening visit. 
2. Another intravitreal anti-VEGF therapy (ranibizumab, aflibercept, brolucizumab, faricimab) 
in the contralateral eye, within 30 days prior to the inclusion of the study or during the 
conduct of the study. 
NOTE: Only one eye may be selected; if both eyes are eligible for inclusion, one eye will be selected 
at the discretion of the PI. 
5.2 Criteria for elimination and/or substitution of subjects 
5.2.1 Elimination Criteria 
- 
Withdrawal of the FCI charter. 
- 
Presentation of a serious adverse event related or not to the investigational product that, 
in the judgment of the PI and/or sponsor, could affect the subject's ability to safely continue 
with study procedures. 
- 
No tolerability or hypersensitivity to any of the compounds used during the tests 
(tetracaine, tropicamide/phenylephrine, or fluorescein). 
- 
No tolerability or hypersensitivity to the investigational product. 
- 
Need to receive any medication, ophthalmic or systemic, that may interfere with the 
performance of the study procedures and/or analysis of blood samples. 
- 
Greater deviation from the protocol. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  42 of 110 
5.2.2 Substitution of subjects 
In order to evaluate the objectives of the study, the sponsor will have the power to substitute 
subjects in the following cases: 
• 
Loss of follow-up. 
• 
Withdrawal of the FCI charter. 
• 
Errors in the collection of blood samples for pharmacokinetics. In this case, the subject will 
be excluded from the pharmacokinetics cohort, but may continue in the evaluations for 
ADAs, if they comply with the other procedures and do not present major deviations from 
the protocol. 
• 
When, in the opinion of the laboratory, the blood sample obtained is unfeasible for 
processing and analysis. 
It is considered that a loss of subjects ≤ 20% does not represent a problem for the validity of the 
results obtained. 
5.3 Selection failures 
A failure of selection is defined as those participants who agree to participate in the study, giving 
their informed consent, but who do not enter the study. It is necessary that the following 
information on selection failures be reported at least in the clinical record:   
1. Demographics.  
2. Details of the selection failure (specify whether it is due to eligibility criteria, which one, or 
some other reason for the failure).  
3. Presence of serious adverse events during screening.  
This is necessary to comply with the CONSORT (Consolidated Standards of Reporting Trials) 
guidelines for the publication of results and to respond to possible questions from regulatory 
authorities.  
5.4 Recruitment and retention strategies  
The duration of the subject's participation in the study is approximately up to 95 days (counting 
from visit 1 [day 1]) or up to 103 days (counting from the screening visit [day -8 to 0]), during which 
time you will be required to attend five visits in total in which clinical evaluations will be carried out 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  43 of 110 
(screening visit,  1, 5, 6, and final); Subjects who are included in the pharmacokinetics cohort will 
require three additional visits for blood sample collection (visits 2, 3, and 4). 
Strategies to improve subject retention include, but are not limited to:  
▪ Inform the subject of the objectives of the study in a clear way. 
▪ Make calls or send text messages to remind you of appointments or activities to do. 
▪ Systematic organization of the study procedures, so that the subject does not last longer 
than necessary on his visit.  
▪ Minimize subject wait times.  
All recruitment strategies implemented by the center will be submitted for approval by the relevant 
committees.  
5.5 Procedure in case of loss of follow-up  
For this protocol, loss of follow-up is defined as those subjects who at some points were active 
subjects of the study, but their final evaluation could not be completed.  
In the event that the subject does not terminate his/her participation due to withdrawal of informed 
consent(s) or major deviation, he/she will be asked to come to the site to perform the 
ophthalmologic evaluations and procedures indicated in the final visit; In the event that you do not 
agree to perform these procedures, the last visit in which your withdrawal was determined will be 
considered your final visit. Subjects who are removed due to the presence of AEs will continue with 
the follow-up that is defined until the closure of their AE. 
In cases where the participating subject does not attend their appointment, the research center 
must make a call to find out the reason and will try to make a new appointment within the 
established window period or an unscheduled appointment to perform the procedures that the 
principal investigator deems necessary (clinical evaluation, AE evaluation, early termination, etc.). 
In these cases, three contact attempts should be made with a separation of 1 day between each 
one, which should be documented in the clinical note. If it is not possible to make an appointment 
within the window period, you will be asked to attend the early termination visit where the same 
procedures as the final visit will be performed. If an appointment for the early termination visit is 
not achieved, the subject will be considered as loss of follow-up and will be asked about the 
presence of adverse events and the reason for leaving the study, as minimum data. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  44 of 110 
In relation to subjects who are part of the pharmacokinetics cohort, who cannot attend the 
additional visits for blood sample collection (visit 2, 3 and 4) or present deviations related to the 
procedures, they may continue in the study as part of the total sample; however, they will be 
excluded from the pharmacokinetics cohort. 
5.6 Identification of the subject 
Study subjects will be identified by a number and the initials of their name.  
The initials of the study subject will be obtained starting with the first letter of the name, followed 
by the first letter of the first surname and the first letter of the second surname, obtaining a 
maximum of three letters, in case the person has two names or compound surname, the first letter 
will always be used. 
Example:  
 
A. Arieh Daniel Carrizalez Market   
 
B. Juan De la Torre Orozco  
 
a. Initials: AMC     
 
 
 
b. Initials: JDO  
In the counting stage, the participant number will be assigned consecutively, using 3 consecutive 
digits.   
Once the subject has been selected, they will be assigned a number with which they will be 
identified throughout the study. This code will be made up of eight numbers in the following order 
from left to right:   
- 
Three digits of the molecule under study according to the name by the sponsor.    
- 
Two digits correspond to the research centre number.   
- 
Three digits of the number following their inclusion are assigned to the research center.  
Example of assigned number:  
 
The subjects' information will be handled confidentially by the sponsor using only the codes 
assigned to them. The research site will be responsible for safeguarding the information 
corresponding to the identity of the subjects. 
169 - 01 - 001   
Key to the  
molecule   
Number of  
Inclusion   
Number of  
Center   

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  45 of 110 
6. Investigational product and treatment 
6.1 Investigational product 
• 
   Product Name under investigation:  PRO-169 . Bevacizumab (for ophthalmic use). 
• 
Route of administration: Intravitreal injection. 
• 
Pharmaceutical form: Solution for injection (25 mg/mL) for ophthalmic use. 
• 
Solution Description: Translucent or slightly yellow particle-free solution. 
• 
Presentation: Prefilled glass syringe for administration of 0.05 mL/dose.  
• 
Packaging description: Type 1 glass syringe, with rubber stopper. 
• 
Prepared by: Laboratorios Sophia S.A. de C.V., Zapopan, Jalisco, Mexico. 
6.2 Investigational Product Dosage 
• 
Dosage: 1 intravitreal injection every 30 days, for two months (3 doses will be applied in 
total). 
Additional information on formulation is provided in the investigator's manual. 
6.3 Treatment with the investigational product 
The investigational product will be administered at the research site during visits 1, 5, and 6. The 
administration of the product will be in charge of the principal investigator or sub-investigator. 
6.4 Storage and handling of the investigational product in the study center  
The transport of the study drug will be carried out with continuous temperature monitoring, which 
must be properly recorded. The delivery will be made by means of a courier service contracted by 
the sponsor, expressly selected for this purpose, to the address of the research center according to 
the study plan.  
The reception will be carried out by the assigned personnel of the research team. You will need to 
check that the primary packaging (box) is in good condition. If you show alterations or defects in its 
integrity that in your judgment could have damaged the content, you must report it to the sponsor. 
If the package does not show significant defects, it will proceed to open it.   

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  46 of 110 
Inside the shipment you must locate the acknowledgment document and the temperature meter 
(data logger). You must check that the temperature recorded complies with what is specified for 
transport and safekeeping. It will verify the content (PI) with what is reported in the document. In 
case the document corresponds to the content, you will sign the receipt and send it to the sponsor. 
Otherwise, it will notify the sponsor.  
Storage and safeguarding are the responsibility of the research center. The medication must be 
stored in a secure area with restricted access and temperature control. 
The storage temperature should be refrigerated between 2 and 8°C, it should be out of reach of 
light and in its packaging until use. 
Access to the investigational product should be restricted. The investigator at each site is 
responsible for the proper storage of the study drug. 
From its receipt at the center and until it has no stock of PI stored, the research center has the 
obligation to review daily (twice a day) the storage conditions of the PI and manually record, in the 
designated format, the temperature marked by the data logger (current, minimum and maximum 
temperature). Such data will be reviewed by the clinical monitor during their monitoring visits 
according to the records stored in the data logger's memory.  
In the event of loss of the product under investigation, this must be documented in the logbook of 
inputs and outputs along with a clear description of the mechanism by which the loss occurred.   
Once treatment/control has been administered, used syringes/vials should be returned to storage 
and recorded in the designated format. 
Upon completion of the protocol, all study material will be retrieved by the sponsor as part of the 
closing visit. The final delivery of material will be made by the principal investigator or the person 
designated by him to deliver material at the end of the study. The refund will be made by the 
research center when the sponsor so indicates. Prior to the return, the research center must carry 
out a count of the assigned medication and the remaining medication, to create an inventory which 
serves for the final completion of the medication return form. 
The sponsor reserves the right to initiate civil and criminal actions against the principal investigator 
for lack of undocumented material after the study.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  47 of 110 
6.5 Concomitant treatments and medications (permitted and prohibited) 
The investigator shall instruct the subject to notify the study site of any new medications they take 
after signing the FCI. All major medications, procedures, and nondrug therapies (e.g., blood 
transfusions) administered after the patient is enrolled in the study must be recorded on the 
appropriate eCRF page. 
Each concomitant drug or procedure must be evaluated individually against all exclusion 
criteria/prohibited drugs. When in doubt, the investigator should contact the sponsor's medical 
monitor before enrolling in a subject or allowing a new drug to be initiated. 
6.5.1 Permitted Medications 
6.5.1.1 Ophthalmology 
The use of ophthalmic drops necessary to perform the corresponding ophthalmological 
examinations (tetracaine 0.5%, tropicamide 0.8% / phenylephrine hydrochloride 5%, and 
fluorescein), antibiotics, corticosteroids or topical medications in the study eye will be allowed. 
If the contralateral eye has DME or other conditions, it may be managed with standard treatment, 
at the discretion of the investigator (e.g., anti-VEGF treatment other than bevacizumab), if it does 
not interfere with the protocol's schedule of visits. This only applies to subjects who are not part of 
the pharmacokinetics cohort (see section 5.1.2.1 Additional exclusion criteria for the 
pharmacokinetics cohort) 
6.5.1.2 Systemic 
Any therapy that is deemed necessary for the subject's well-being, and that does not interfere with 
the evaluation of the investigational product, as well as the use of hormonal contraceptives by any 
route of administration. 
6.5.2 Prohibited Drugs 
6.5.2.1 For the Study Eye 
Patients will not be able to receive any additional standard or experimental treatment to treat DME 
in the selected eye; This includes medications given locally (intravitreal, topical, periocular, or 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  48 of 110 
periorbital). They will only be able to receive the investigational product PRO-169 as specified in the 
protocol.  
6.5.2.2 For the contralateral eye 
Patients participating in the pharmacokinetics cohort may not receive any anti-VEGF treatment in 
the contralateral eye during their participation in the study. 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  49 of 110 
7. Study methods and procedures  
7.1 Research center  
This study will be carried out in several research centers previously evaluated by the sponsor. The 
centers will be institutions or establishments where health research is carried out that complies with 
current regulations.  
The research centers will be responsible for forming a multidisciplinary research team to execute 
clinical study according to the protocol. It is their prerogative to design the organization and select 
the personnel who will perform the functions. However, it is necessary for the sponsor that the PI 
and sub-investigator be ophthalmology specialists, and that at least one of them has a subspecialty 
in retina.  
Any person who is designated, under the responsibility of the PI, as a part of the study monitoring 
(sub-investigator, nurse, etc.) or a specific function of participation in the study (pharmacist, 
administrative assistant, study coordinator, etc.) must appear in the "Delegation of 
Responsibilities". 
The competence and training of any person who has direct participation in the activities of the study 
must be verified prior to the performance of any activity related to the protocol. The above must be 
recorded and the documents that constitute evidence of this competence and/or training must be 
kept in the master file of the study. The competence and training of the staff who have functions in 
the study, both at the central level and in the study center, is the responsibility of the sponsor.  
The sponsor must ensure that all study site personnel participating in the study are adequately 
trained on the study (research protocol, investigator's manual, amendments, standard operating 
procedures, etc.) and on ICH Good Clinical Practice, prior to the start of their participation in the 
study. Training must be recorded in writing, and those records must be filed in the master record of 
the study.  
7.2 Clinical Study Registration  
This clinical study will be registered by the sponsor in public clinical trial registries before its start 
(inclusion of the first subject): National Registry of Clinical Trials (RNEC) of the Federal Commission 
for the Protection against Health Risks (COFEPRIS) and in a WHO primary registry platform. WHO 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
Version 4.0 
 
 
    Nov 4-25 
 
 
C O N F I D E N C I A L 
 
 
   Page  50 of 110 
Primary Registries meet specific criteria for content, quality and validity, accessibility, unique 
identification, technical capacity and administration. WHO Primary Registries meet the 
requirements of the International Committee of Medical Journal Editors (ICMJE).  
7.3 Group assignment and blinding 
As it is an open-label, non-comparative study, randomization of the subjects entering the study is 
not necessary.  
7.4 Study variables  
7.4.1 Safety Primary Outcome Variables 
- 
Proportion of patients with the presence of bevacizumab-positive serum ADAs. 
7.4.2 Safety Secondary Outcome Variables  
- 
Incidence of adverse events related to IP. 
- 
Incidence of serious adverse events related to IP. 
7.4.3 Pharmacokinetic Secondary Outcome Variables  
- 
Total area under the curve (AUC) of serum PRO-169 concentration.  
- 
Serum peak (Cmax) concentration of PRO-169. 
- 
Maximum serum time (Tmax) of PRO-169. 
7.4.4 Exploratory variables  
- 
Changes in BCVA from baseline to day 90.  
- 
Changes in the GMC, from baseline to day 90.

Laboratorios Sophia, S.A. de C.V.  
 
 
 
              Study No: SOPH169-1224/I 
 
 
 
 
 
 
              Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
  
   Page  51 of 110 
7.4.5 Definition of variables, methods and scales for their measurement 
Table 5. Operational definition of variables. 
Variable 
Conceptual Definition 
Operational Definition 
Measurement 
Type 
Reference value 
Statistical test 
Presence of 
serum ADAs 
for 
bevacizumab 
They are antibodies generated by the 
immune system that are directed against 
therapeutic drugs, in particular biological 
products such as monoclonal antibodies, 
enzymes or proteins. 
Baseline result without the presence of 
ADAs (i.e., the one obtained in the blood 
sample for immunogenicity collected at 
the screening visit) and at least one 
sample with the presence of ADAs after 
the start of PRO-169 treatment. 
Baseline result with the presence of ADAs 
and at least one sample with a result ≥ 4 
times in baseline titer values, after the 
start of treatment with PRO-169 
Qualitative 
dichotomou
s 
Continuous 
Quantitative
* 
Present / Absent 
NA 
 
• 
Frequency 
• 
Percentage 
Changes in the 
AVMC 
Visual spatial 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 
Using the ETDRS booklet, the subject's 
best refractive correction (obtained by 
autokeratorrefractometer and subjective 
tests) will be evaluated and the 
examination will be repeated using the 
refraction obtained 
Discrete 
quantitative 
Up to 54 letters 
LogMAR 
• Media 
• Medium 
• Standard deviation 
• Minimum and 
maximum  
• 95% CI 
Changes in 
central 
macular 
thickness 
It corresponds to the thickness 
determined in the area of the fovea 
taking the fovea as the central point of a 
1mm circle 
Change in OCT between  
the initial and final value 
 
Continuous 
quantitative 
Up to 290 μm in 
women and 300 μm in 
men 
• Media 
• Medium 
• Standard deviation 
• Minimum 
and 
maximum  
• 95% CI 
Incidence of 
IP-related 
adverse events 
AEs are considered to be any adverse 
medical event that occurs in a patient or 
clinical research subject to whom a 
pharmaceutical product was 
administered and where the causal 
relationship is at least reasonably 
possible. [66] 
EA that the PI suspects a causal 
relationship with the treatment 
 
 
Nominal 
qualitative 
 
- 
Incidence 
- 
Seriousness 
(severity) 
- 
Causation 
 
• 
Frequency 
• 
Percentage 

Laboratorios Sophia, S.A. de C.V.  
 
 
 
              Study No: SOPH169-1224/I 
 
 
 
 
 
 
              Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
  
   Page  52 of 110 
Variable 
Conceptual Definition 
Operational Definition 
Measurement 
Type 
Reference value 
Statistical test 
Incidence of 
serious 
adverse events 
related to IP 
Serious AEs are considered to be any AEs 
that result in: death, threat to life, 
require hospitalization or prolong 
hospitalization, are causes of permanent 
or significant disability or disability, are 
the cause of alterations or 
malformations in the newborn, or other 
medically important conditions [66] 
All AEs (according to protocol) suspected 
by the PI of a causal relationship to the 
treatment will be reported 
 
Nominal 
qualitative 
- 
Incidence 
- 
Seriousness 
(severity) 
- 
Causation 
• 
Frequency 
• 
Percentage 
Area Under 
Total Curve 
(AUC) 
It reflects the total amount of drug that 
reaches the systemic circulation. It is an 
important measure of bioavailability and 
relates variations in the serum 
concentration of a drug as a function of 
time 
The AUC will be reported (for details on 
reporting or measurement, refer to the 
validation protocol and/or laboratory 
manual provided by the designated 
laboratory) 
 
Continuous 
quantitative 
NA 
• Media 
• Standard deviation 
• Geometric median 
• Range 
• Minimum and 
maximum 
Maximum 
concentration 
(Cmax) 
Maximum serum drug concentration 
C max will be reported (for details on 
reporting or measurement, refer to the 
validation protocol and/or laboratory 
manual provided by the designated 
laboratory) 
Continuous 
quantitative 
NA 
• Media 
• Standard deviation 
• Geometric median 
• Range 
• Minimum 
and 
maximum 
Maximum 
Time (Tmax) 
It is the time expressed in minutes that 
indicates the moment when the drug 
reaches its maximum concentration in 
serum 
The T max will be reported (for details on 
reporting or measurement, refer to the 
validation protocol and/or laboratory 
manual provided by the designated 
laboratory) 
Continuous 
quantitative 
NA 
• Media 
• Standard deviation 
• Geometric median 
• Range 
• Minimum 
and 
maximum 
Abbreviations: ADAs, anti-drug antibodies; NA, not apply; ETDRS, Study on the Early Treatment of Diabetic Retinopathy; OCT, optical coherence tomography; PI, principal investigator; BCVA, best-
corrected visual acuity; AE, adverse event; PI; Investigational product; 95% CI: 95% confidence interval. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  53 of 110 
7.4.6 Description of the variables, methods, and scales for their measurement 
For clinical purposes, ophthalmological assessments will be carried out on the selected eye, and its 
record will be recorded in the clinical file and in the eCRF. Next, the description of the variables is 
made, which are not in order of execution.  
7.4.6.1 Anti-drug antibodies 
Anti-drug antibodies (ADAs) are produced by the immune system in response to biopharmaceuticals 
that are recognized as foreign molecules. In the case of therapeutic antibodies, ADAs bind to the 
idiotope located in the Fv region, some can neutralize them (neutralizing antibodies: Nab), 
decreasing efficacy and increasing the clearance of the biopharmaceutical; resulting in a failure in 
the patient's response leading to worsening of the disease. Likewise, ADAs can induce allergic 
reactions such as anaphylactic shock; so, it is necessary to evaluate their presence and impact. [53] 
Blood samples will be collected according to schedule (see 1.3 Schedule of activities) 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  54 of 110 
1.3 Schedule of activities 
 
For details on the method of processing, quantification, validation and its measurement, refer to 
the validation protocol and/or laboratory manual provided by the designated laboratory, in charge 
of the analysis of samples. 
                  
 
                         
Visit of 
                         
Selection 
Visit 1 
Visit 
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Start of 
treatment 
    Treatment Period 
Final / Early 
Termination 
Protocol Day 
-8 to 0 
1 
2 
4 
8 
30±5 
60±5 
90±5 
Informed consent 
X 
 
 
 
 
 
 
 
Evaluation of selection criteria 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Weight, Height, BMI and Body Mass 
Surface Area 
X 
 
 
 
 
 
 
 
Vital signs (BP, HR, Temperature, RF)ɸ 
X 
X 
 
 
 
X 
X 
X 
% HbA1c* 
X 
 
 
 
 
 
 
 
Glomerular filtration rate (GFRe)a 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Registry 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X 
X 
 
 
 
X 
X 
X 
Best-corrected visual acuity 
X 
 
 
 
 
X 
X 
X 
Biomicroscopy 
X 
 
 
 
 
X 
X 
X 
Indirect ophthalmoscopy 
X 
 
 
 
 
X 
X 
X 
Ocular tonometry 
X 
 
 
 
 
X 
X 
X 
Macular optical coherence tomography 
X 
 
 
 
 
X 
X 
X 
Fluorescein angiography (AF) or optical 
coherence tomography angiography (OCT-
A)Ж 
X 
 
 
 
 
 
 
 
Intravitreal injection 
 
X 
 
 
 
X 
X 
Pharmacokinetic blood sample (applies to 
PK cohort)ᴥ 
X 
X 
X 
X 
X 
X¥ 
X¥ 
X¥ 
Blood Sample Immunogenicity 
X 
 
 
 
 
X¥ 
X¥ 
X¥ 
ɸ Vital signs assessment should be performed prior to blood sample collection. 
*If there is an HbA1c determination dated within 3 months prior to the inclusion of the study, it will not be necessary to 
perform it at the screening visit. 
a If a serum creatinine result dated within 2 months prior to study inclusion is available, it will not be necessary to perform 
it at the screening visit and may be used to calculate GFRe. 
If you have an AF or OCT-A performed in the 4 months prior to the inclusion of the study, it will not be necessary to perform 
it at the screening visit. 
ᴥSee pharmacokinetics schedule on the following page. 
¥Blood samples will be collected prior to intravitreal application of PRO-169 (no more than 2 hours prior to the time of 
application at Visit 1). 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  55 of 110 
7.4.6.2 Area under the total curve of serum concentration  
In pharmacology, the area under the curve of the plasma or serum concentration of a drug as a 
function of the time elapsed since administration, called the "area under the curve" or AUC, allows 
us to know the degree of exposure to a drug and its rate of elimination from the body. By integrating 
over time rather than analyzing individual concentration measurements, a more accurate estimate 
of overall drug exposure is obtained. These measurements have also been found to be significant in 
assessing the net pharmacological response to a given dose of drug. [67] 
Blood samples will be collected according to schedule (see 1.4 Pharmacokinetics Cohort Schedule). 
For details on the method of processing, quantification, validation and its measurement, refer to 
the validation protocol and/or laboratory manual provided by the designated laboratory, in charge 
of the analysis of samples. 
7.4.6.3 Maximum serum concentration  
Plasma or serum concentrations reflect a time curve from the administration of a drug to its 
maximum effect and final elimination. The maximum concentration (Cmax) of a drug in the blood 
serum represents the maximum effect of the drug. The Cmax It is one of the main pharmacokinetic 
measures to evaluate how the body acts in the face of a drug. [68] 
Blood samples will be collected according to schedule (see 1.4 Pharmacokinetics Cohort Schedule). 
For details on the processing method and its validation, as well as the scales for its measurement, 
refer to the validation protocol and/or laboratory manual provided by the designated laboratory, in 
charge of the analysis of samples. 
7.4.6.4 Maximum Concentration Time 
Plasma or serum concentrations reflect a time curve from the administration of a drug to its 
maximum effect and final elimination. The time to reach maximum concentration (Tmax) is of 
pragmatic importance because it varies between individuals and can be manipulated through the 
different routes of administration (e.g., oral, intravenous, and topical) or by modifications of the 
drug delivery mechanism. [69] 
The Tmax it is usually related to the half-life of a drug (T1/2). Drugs with short half-lives tend to peak 
and be eliminated quickly, so more frequent doses are often required to keep a drug within its 
clinically effective therapeutic range. [69] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  56 of 110 
Blood samples will be collected according to schedule (see 1.4 Pharmacokinetics Cohort Schedule). 
For details on the processing method and its validation, as well as the scales for its measurement, 
refer to the validation protocol and/or laboratory manual provided by the designated laboratory in 
charge of the analysis of samples. 
7.4.6.5 Adverse events 
As described in the 8. Evaluation and management of adverse events, an adverse event is defined 
as Any undesirable medical event that may occur in an investigational subject during the clinical 
research stage of a drug or vaccine but does not necessarily have a causal relationship with it.  
Management of adverse events will be performed as described in the 8. Evaluation and 
management of adverse events.  
The Principal Investigator will record in the corresponding section of the eCRF the adverse events 
that the study subjects may present in addition to referring them in the clinical record. 
For an adequate evaluation of adverse events, in addition to directed questioning, it is necessary to 
perform a comprehensive ophthalmological evaluation at each visit, which consists of: 
ophthalmological examination of the eyelids and adnexa; anterior and posterior segment that is 
performed in a routine ophthalmological check-up, whose procedures are not specifically included 
in the study variables. Posterior pole evaluation can be with direct or indirect ophthalmoscopy, with 
or without pharmacological mydriasis, at the discretion of the PI. An assessment of the fundus will 
be carried out in search of abnormalities that alter the result of the study. IOP will be measured in 
this assessment with the Goldmann tonometer and should be measured after the evaluation of 
stains (when applicable). The result of the assessment will be recorded in the clinical file. In the 
eCRF, only findings that are considered by the principal investigator will be reported as an adverse 
event.  
7.4.6.6 Best Corrected Visual Acuity 
Visual acuity (VA) is a test of visual function. Visual spatial acuity is the ability to distinguish separate 
elements of an object and identify them. It is quantified as the minimum angle of separation 
(located at the nodal point of the eye) between two objects that allows them to be perceived as 
separate objects. [70] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  57 of 110 
VA will be evaluated at baseline, without refractive correction, with the patient 4 meters from the 
backlit ETDRS panel. The panel must be calibrated to output 85 cd/m2. Tests will be done on both 
eyes (both the selected eye and the non-selected eye). Each eye should be tested with a chart with 
a different distribution of optotypes to avoid memorization by the patient when it is possible to 
change the character chart, otherwise this evaluation should be started with the eye that is included 
in the study.  
Next, the subject's best refractive correction (obtained by autokeratorrefractometer and subjective 
tests) will be evaluated and the examination will be repeated using the refraction obtained. The 
total number of letters recognized by the patient will be reported as best-corrected visual acuity 
(BCVA), which will be recorded in the clinical record and in the eCRF for both eyes. Forstatistical 
purposes, the value obtained from the AVMC in logarithmic figures (LogMAR) should also be 
recorded, as well as the Snellen equivalent in the clinical record and in the eCRF (see annex 16.1 
ETDRS Booklet). 
The following equivalence table will be used for the recording of the best corrected visual acuity.  
Table 6. Equivalences for best-corrected visual acuity 
LogMAR Value 
Snellen (feet) 
Snellen (meters) 
1.6 
20/800 
20/240 
1.5 
20/640 
6/190 
1.4 
20/500 
6/150 
1.3 
20/400 
6/120 
1.2 
20/320 
6/96 
1.1 
20/250 
6/75 
1.0 
20/200 
6/60 
0.9 
20/160 
6/48 
0.8 
20/125 
6/38 
0.7 
20/100 
6/30 
0.6 
20/80 
6/24 
0.5 
20/63 
6/19 
0.4 
20/50 
6/15 
0.3 
20/40 
6/12 
0.2 
20/32 
6/9.5 
0.1 
20/25 
6/7.5 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  58 of 110 
0.0 
20/20 
6/6 
-0.1 
20/15 
6/4.5 
-0.2 
20/12 
6/3.6 
 
To take the best corrected visual acuity, the patient will be asked to indicate the letters he 
distinguishes until he reaches the line where he cannot identify at least three optotypes, recording 
the number of letters that he could correctly specify.  
It will also be required that in the case of vision cards that do not start from the 20/800 line of sight 
(the point from which the letter count for ETDRS equivalence begins), the following adaptation is 
made by adding the following number of letters to what the examination of a patient yield. 
 
 
Table 7. Adding letters to the ETDRS booklet 
Start of optotypes of the 
primer to be used 
Addition to the number 
of letters obtained 
20/800 
0 
20/640 
5 
20/500 
10 
20/400 
15 
20/320 
20 
20/250 
25 
20/200 
30 
20/160 
35 
 
Below, some examples will be presented to minimize the possibility of errors or ambiguities. 
Example 1. 
Whereas one patient was able to distinguish the optotypes marked in green in this image, he was 
able to distinguish three optotypes from the fourth line and only two from the fifth line. The line 
attributed to him will be the last one in which he was able to read 3 or more optotypes, in this case 
20/100 or 6/30. If we add up the letters that he distinguished, we have 18 letters. However, this 
booklet begins at 20/200, so according to the table in section 7.4.6.6 Visual acuity best corrected 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  59 of 110 
according to the ETDRS guidelines, the figure of 30 must be added to that number, so the amount 
to be reported is 48. The equivalence to be reported in LogMar and Snellen (feet) would be 0.7 and 
30, respectively.  
 
Example 2.  
Considering that one patient was able to distinguish the optotypes marked in green in this image, 
he was able to distinguish up to three optotypes of the fifth line. The line attributed to him will be 
the last one in which he could read 3 or more optotypes, in this case 20/80 or 6/24. If we add up the 
letters that he distinguished, we have 23 letters. However, this booklet begins at 20/200, so 
according to the table in section 7.4.6.6 Visual acuity best corrected according to the ETDRS 
guidelines, the figure of 30 must be added to that number, so the amount to be reported is 53. The 
equivalence to be reported in LogMar and Snellen (feet) would be 0.6 and 24, respectively.  
The BCVA of both eyes (right eye [OD] and left eye [OS]) will be reported, for statistical purposes, in 
Snellen fraction and in logarithmic figures (LogMAR) in the clinical record and in the eCRF. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  60 of 110 
7.4.6.7 Macular optical coherence tomography (OCT) 
It is a diagnostic test for the evaluation of the condition of the retina, including central macular 
thickness (CMG) and central retinal volume (macular area volume known as cube volume in OCT). 
This test uses light to create high-resolution images, allowing layers of the retina to be visualized. 
[71] 
The make and model of the instruments used will be at the discretion of the investigating physician, 
provided that, for each individual patient, the same equipment (brand and model) is used 
throughout the study. The procedure can be performed by the PI, sub-investigator, or specialized 
personnel with the ability to operate the delegated OCT equipment. The results of the GMC of both 
eyes will be reported in the clinical record and in the eCRF. 
7.5 Description of procedures or assessments during the study 
The different procedures that will be done during the study are described below. The list may not 
be in order and may be sorted in the most optimal way according to the needs of the research 
center. 
7.5.1 Signing of informed consent 
Procedure by which it is guaranteed that the subject under investigation has voluntarily expressed 
his approval and authorization to participate in this research, after having understood the 
information that has been given to him or her about the objectives of the research, as well as its 
benefits, discomforts, and possible risks. In this study, this procedure may be repeated since there 
will be a subgroup of patients (15 of the 60 total participants) who will be included for the 
pharmacokinetic evaluation of the investigational product, in which case two independent consents 
must be signed. 
7.5.2 Medical history (general and ophthalmological) 
It must be carried out in accordance with the provisions of NOM-004-SSA3-2012 of the clinical file.  
Considering that the clinical record is the unique set of information and personal data of a subject, 
which is integrated into any type of establishment for medical care, whether public, social or private, 
which consists of written, graphic, imaging, electronic, magnetic, electromagnetic, optical, 
magneto-optical and any other type of documents; in which, health personnel must make the 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  61 of 110 
records, annotations, where appropriate, certificates and certifications corresponding to their 
intervention in the subject's medical care, in accordance with the applicable legal provisions.[72] 
It will consist of: 
Medical history: it must be prepared by medical personnel and other professionals in the health 
area, in accordance with the specific information needs of each of them in particular, it must have, 
in the order indicated, the following sections: 
▪ Interrogation. It must have at least: identification form, if applicable, ethnic group, 
hereditary family history, pathological and non-pathological personal history, current 
condition (inquire about previous conventional, alternative and traditional treatments), 
and interrogation by devices and systems (especially ophthalmological). 
▪ Physical exam. You must have at least: vital signs (temperature, systemic blood 
pressure, heart and respiratory rate), weight, height, BMI and body mass surface area 
(mandatory). 
▪ Previous and current results of laboratory, cabinet and other studies (when applicable). 
▪ Diagnoses or clinical problems (when applicable). 
▪ Prognosis (when applicable). 
▪ Therapeutic indication (when applicable). 
7.5.3 Adverse events 
Described in the 8. Evaluation and management of adverse events. 
7.5.4 Evaluation of selection criteria 
It is the evaluation that the subject meets all the inclusion criteria and none of the exclusion criteria. 
7.5.5 Measuring Vital Signs 
It is the measurement of heart rate, respiratory rate, temperature and systemic blood pressure. 
These measurements can be made with a stethoscope, digital or mercury thermometer, and with a 
manual or digital sphygmomanometer. This information must be contained in the patient's medical 
record. It is necessary that all measures be in equal circumstances. 
7.5.5.1 Heart rate 
Heart rate is the number of times the heart ventricles contract per unit of time, usually per minute. 
Its measurement will be done by direct auscultation in the chest with a stethoscope counting the 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  62 of 110 
beats for one minute. In the case of women, it will be allowed to measure it in the pulse of the wrist; 
however, the method chosen for the subject will be the same to be used in all visits.  [73] 
It is necessary for the subject to be calm and in a state of rest (the subject does not have agitation 
because of unnecessary physical effort). For the measurement of the heart rate, it will be necessary 
for the subject to be calm and in a state of rest. You will be asked to rest for at least 5 minutes upon 
arrival at the clinic, prior to your measurement.  The results will be reported in the clinical record 
and in the eCRF. 
7.5.5.2 Respiratory rate 
Respiratory rate is the number of complete breathing cycles that occur per minute. Its measurement 
will be done by direct auscultation in the chest with a stethoscope counting the beats for one 
minute. To measure the respiratory rate, it will be necessary for the subject to be calm and in a state 
of rest. You will be asked to rest for at least 5 minutes upon arrival at the clinic, prior to your 
measurement. The results will be reported in the clinical record and in the eCRF. 
7.5.5.3 Temperature 
The temperature will be taken through the axillary route, a digital or mercury thermometer may be 
used. The tip of the thermometer should be placed in the center of the armpit, making sure that the 
entire area responsible for recording the temperature is in contact with the skin and should be held 
firmly against the body, with the subject's arm close to the side of the body. The results will be 
reported in the clinical record and in the eCRF. 
7.5.5.4 Systemic blood pressure 
Blood pressure can be measured with a manual or digital sphygmomanometer, making sure that 
the chosen device is calibrated according to the manufacturer's recommendations. Regardless of 
the type of device used, it is essential that a bracelet of the right size for the reading is chosen in 
order to obtain an accurate measurement. 
For the measurement of blood pressure, it will be necessary for the subject to be calm and in a state 
of rest. You will be asked to rest for at least 5 minutes upon arrival at the clinic, prior to your 
measurement. During the measurement, the subject should be seated with the right or left arm 
resting on a flat surface, with the cubital fossa at the level of the heart. The results will be reported 
in the clinical record and in the eCRF. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  63 of 110 
7.5.5.5 Body Mass Index (BMI) 
Waist circumference, weight and height will be taken, and the BMI calculation will be made based 
on the Quetelet formula. The results will be reported in the clinical record and in the eCRF. [74] 
𝐼𝑀𝐶= 𝑝𝑒𝑠𝑜 (𝑘𝑔)
𝑎𝑙𝑡𝑢𝑟𝑎 (𝑚)2 
7.5.5.6 Body mass surface area 
Waist circumference, weight and height will be taken, and the calculation of the body mass surface 
area also known as BSA (Body Surface Area will be made using the Mosteller formula. The results 
will be reported in the clinical record and in the eCRF. [75] 
𝐵𝑆𝐴= √𝑝𝑒𝑠𝑜 (𝑘𝑔) × 𝑎𝑙𝑡𝑢𝑟𝑎 (𝑐𝑚)
3600
 
7.5.6 Laboratory tests  
The designated personnel will perform the extraction of the blood sample, by means of 
venipuncture. The vein will be chosen at the discretion of the personnel in charge and will perform 
asepsis of the skin of the area to be punctured prior to the procedure. Samples will be processed at 
the local laboratory or selected by the site. The following parameters will be evaluated: HbA1c and 
GFRe. 
7.5.6.1 Glycosylated hemoglobin (HbA1c) 
HbA1c is a key indicator in the evaluation of glycemic control in long-term diabetic patients. This 
parameter reflects the average blood glucose concentration over a period of 2-3 months. In the 
context of DME, monitoring of HbA1c is crucial, as elevated levels of this protein are closely linked 
to suboptimal glycemic control, which increases the risk of microvascular complications, such as 
DME. Knowledge of HbA1c levels allows healthcare professionals to adjust diabetic treatment in a 
timely manner, favoring the prevention of DME and preserving the patient's visual function. [16] 
If there is an HbA1c determination 3 months prior to the inclusion of the study, it will not be 
necessary to perform it at the screening visit. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  64 of 110 
7.5.6.2 Glomerular filtration rate (GFRe) 
The glomerular filtration rate is the rate in milliliters per minute at which plasma substances are 
filtered through the glomerulus; In other words, it refers to the removal of a substance from the 
blood. [76] 
If there is a serum creatinine result in the 2 months prior to the inclusion of the study, it will not be 
necessary to perform it at the screening visit, and this can be used to calculate the GFRe. The results 
will be reported in the clinical record and in the eCRF. 
Estimating GFRe requires equations that consider serum creatinine, age, race, and sex.  
One of them is the CKD-EPI equation (Chronic Kidney Disease Epidemiology Collaboration) and is 
considered the most accurate; for this reason, and to standardize the calculation of the GFRe, we 
request that it be used in this clinical study. [76] 
Below are suggestions for websites where you will find calculators to estimate GFRe with the CKD-
EPI formula:  
• 
https://www.merckmanuals.com/medical-calculators/GFR_CKD_EPI-es.htm 
• 
https://www.samiuc.es/calculo-del-filtrado-glomerular-ckd-epi/ 
• 
https://www.senefro.org/modules.php?name=calcfg 
7.5.7 Urine Pregnancy Test 
Pregnancy testing will be performed at screening visits, 1, 5, 6, and 7 for all female research subjects 
of reproductive age (i.e., no natural or induced menopause, menopause defined as 12 consecutive 
months of amenorrhea) with hormonal contraception or intrauterine device (IUD), including 
bilateral tubal obstruction. For patients with bilateral hysterectomy or oophorectomy, it will not be 
necessary. To perform the test, the subject will be allowed to go to the bathroom, have privacy for 
the collection of the urine sample that will later be delivered to the personnel of the corresponding 
site who will perform the test, and after it is performed, the researcher must corroborate the result 
by observing the medical device. The results will be reported in the clinical record and in the 
eCRF.[77] 
7.5.8 Ophthalmological evaluation 
It refers to the evaluation of the eyeball, eyelids, eyelashes, and other structures of your eyes by 
means of inspection, slit lamp (biomicroscopy), as well as palpation (touch). As part of this 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  65 of 110 
evaluation, the BCVA and the anterior segment will be assessed, intraocular pressure will be taken 
and the posterior segment will be evaluated (indirect ophthalmoscopy). This evaluation is intended 
to identify alterations that may interfere with the course of the investigation or to identify AEs. The 
results will be reported in the clinical record and in the eCRF. 
7.5.8.1 Biomicroscopy 
It is the diagnostic procedure that uses the slit lamp, also known as a biomicroscope, to evaluate 
the structures of the anterior segment (cornea, conjunctiva, anterior chamber, iris, pupil including 
pupillary diameter, lens, aqueous humor), using the specific characteristics of the light source such 
as the optical power of the device. This method allows for a detailed evaluation of the anterior 
chamber of the eye. [78] 
7.5.8.2 Ocular tonometry 
Tonometry is the objective measurement of IOP, based primarily on the force required to flatten 
the cornea or the degree of corneal indentation produced by a fixed force. Goldmann tonometry is 
based on the Imbert-Fick principle. [79] 
The tonometry will be performed with a Goldmann tonometer, after instillation of the ophthalmic 
anesthetic, with fluorescein and the use of the cobalt blue filter (after the evaluation of the surface 
staining). 2 samples will be taken, and the average will be calculated, which will be recorded in the 
clinical file. The average IOP of the eye under study (OD or OS) will be recorded in the eCRF. Two 
measurements will be made in the study eye, the average of two shots is recorded, therefore, results 
will be obtained in whole numbers or means (0.5) will not be rounded.  
Ocular tonometry will be performed prior to the application of intravitreal injection, when 
applicable.  
The same measuring instrument used at the screening visit and during all subject visits should be 
used. The appliance must be calculated according to the manufacturer's specifications. The results 
will be reported in the clinical record and in the eCRF. 
7.5.8.3 Indirect ophthalmoscopy  
Indirect ophthalmoscopy, or fundoscopy, is the examination done with a light and a magnifying glass 
to observe the fundus of the eye (optic nerve and retina) through the pupil. Sometimes the pupil 
will need to be dilated so that the fundus of the eye can be fully evaluated. [78] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  66 of 110 
During the baseline and final visits, fundoscopy will be performed, as part of the comprehensive 
ophthalmological check-up, it will be at the discretion of the investigator if it is performed under 
pharmacological mydriasis. The results will be reported in the clinical record and in the eCRF. 
7.5.9 Retinal angiography 
Retinal angiography is a diagnostic procedure that allows the blood circulation of the retina and 
choroid to be assessed. Two techniques are currently available, fluorescein angiography and optical 
coherence tomography angiography; each one requires different devices, supplies and trained 
personnel for its realization. [80] 
The angiographic technique to be used will be up to the PI and/or sub-investigator. 
7.5.9.1 Fluorescein angiography 
Fluorescein angiography (FA) is an essential diagnostic technique for the evaluation of diabetic 
retinopathy and DME. Prior to fasting for 8 hours and pupillary dilation with TP Ofteno® 
(tropicamide 5% / phenylephrine 0.8%), this procedure consists of the intravenous injection of a 
fluorescein solution, usually in one of the upper extremities.  [81] 
Designated personnel shall be responsible for venipuncture. The selection of the vein to be used will 
be determined at the discretion of the professional in charge, who must perform an adequate 
asepsis of the skin in the puncture area before proceeding. 
Images of the retinal vasculature are then captured using a specialized camera. The technique 
makes it possible to identify areas of leakage, capillary non-perfusion, and other abnormalities, 
which is crucial for classifying diabetic retinopathy, excluding patients with macular ischemia or 
significant peripheveal vascular loss, and assessing the severity of DME. In addition, it plays a 
fundamental role in monitoring the response to treatment and appropriate therapeutic planning. 
[81] 
It is not essential that this equipment be of a particular brand or model, as long as a device of the 
same characteristics is used to assess the same patient throughout the study, in case AF is necessary 
in subsequent visits. The procedure can be carried out by the PI, a technician or delegated 
personnel. You may be asked for a period of fasting prior to taking the study, which will be 
determined by the site's delegated staff. The results will be reported in the clinical record and in the 
eCRF. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  67 of 110 
7.5.9.2 Optical Coherence Tomography Angiography 
Optical coherence tomography angiography (OCT-A) is a non-invasive technique that allows 
visualization of the retinal and choroidal circulation in vivo without the need to inject contrast media 
intravenously. Captures multiple repeated cross-sectional images in the same location and analyzes 
changes between scans; In this way, it extracts information about the volumetric movement of 
blood flow, generating high-contrast angiographic images of the capillary plexuses in the different 
layers of the retina and choroid.      [82] [83] [84][85] 
The patient will be placed in front of the OCT-A equipment properly aligned and will be asked to 
stare at the target indicated by the operator of the equipment. It may or may not require pupillary 
dilation with Ofteno® PT (tropicamide 5% / phenylephrine 0.8%) for the performance of this study, 
according to what the PI and/or sub investigator consider. 
The make and model of the instrument used will be at the discretion of the investigating physician, 
provided that, for each individual patient, the same equipment (brand and model) is used 
throughout the study, in case it is necessary to perform OCT-A in subsequent visits. The procedure 
can be performed by the PI, sub-investigator, or specialized personnel with the ability to operate 
the delegated OCT-A equipment. The results will be reported in the clinical record and in the eCRF. 
7.5.10 Intravitreal injection 
An intravitreal injection of the study drug will be administered over a two-month period, with a total 
of three scheduled applications, corresponding to visits 1, 5, and 6. After each injection, a 30-minute 
observation period will be carried out. 
The indication and characteristics of the administration of a prophylactic topical antibiotic regimen 
before and/or after each intravitreal injection will be up to the PI and/or sub-investigator.  
7.5.11 Blood sample for pharmacokinetics (applies to PK cohort) 
The designated personnel will be responsible for the extraction of a blood sample of approximately 
5 mL by venipuncture. The selection of the vein to be used will be determined at the discretion of 
the professional in charge, who must perform an adequate asepsis of the skin in the puncture area 
before proceeding. Subsequently, the samples will be conditioned and sent to the designated 
laboratory for processing and analysis, in accordance with the laboratory manual.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  68 of 110 
All blood samples should be collected prior to intravitreal injection (when applicable) within the 
time stipulated in the pharmacokinetics cohort schedule (see section 1.4 Pharmacokinetics Cohort 
Schedule). 
All specimens will be coded with the patient's number. These samples and any data generated can 
be linked to the patient only by the staff at the research site. The processing of the samples will be 
described in the laboratory manual.  
7.5.12 Blood Sample for Immunogenicity 
The designated personnel will be responsible for the extraction of a blood sample of approximately 
5 mL by venipuncture. The selection of the vein to be used will be determined at the discretion of 
the professional in charge, who must perform an adequate asepsis of the skin in the puncture area 
before proceeding. Subsequently, the samples will be conditioned and sent to the designated 
laboratory for processing and analysis, in accordance with the laboratory manual.  
All blood samples must be collected prior to intravitreal injection (when applicable) within the time 
stipulated in the schedule of activities (see section 1.3 Schedule of activities). 
All specimens will be coded with the patient's number. These samples and any data generated can 
be linked to the patient only by the staff at the research site. The processing of the samples will be 
described in the laboratory manual.  
7.5.13 Application of Medications During Visits 
During the visits to the subjects, different medications or medical devices may be applied to the 
ocular surface for ophthalmological examination.  
Examples:  
- 
Tetracaine 0.5% ophthalmic solution, used to anesthetize the subject's ocular surface and 
facilitate the application of dyes, the measurement of intraocular pressure and prior to the 
application of intravitreal injection. 
- 
Tropicamide 0.8% ophthalmic solution/5% phenylephrine hydrochloride, used to dilate the 
pupil and better assess the posterior segment. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  69 of 110 
7.5.14 Evaluation of concomitant medicinal products 
It is the question about the use of medications, by any route of administration, that they are using 
regularly, that they have used since last month, or since their last visit. 
7.6 Procedures to be carried out per visit 
Listed below are the procedures that will be performed at each visit, which may not show the 
optimal order for the Research Center. The investigator should order it according to their needs, 
and the needs of the study and the sponsor, ensuring that the signing of informed consent and 
assent (when applicable) is the first activity to be performed. 
7.6.1 Selection visit (day -8 to 0) 
• 
Signing of informed consent 
• 
Signature of informed consent from the PHARMACOKINETICS SUBGROUP (when 
applicable) 
• 
Evaluation of selection criteria 
• 
Medical history (general and ophthalmological) 
• 
Measurement of weight, height, BMI, and body mass surface area  
• 
Measurement of vital signs (temperature, blood pressure, heart rate, and breathing 
rate.) 
• 
%HbA1c sampling (when applicable) 
• 
GFRe sampling (when applicable) 
• 
Evaluation of concomitant medications 
• 
Adverse Event Registry 
• 
Urine pregnancy test (where applicable) 
• 
Best Corrected Visual Acuity Measurement (AVMC) 
• 
Biomicroscopy 
• 
Indirect ophthalmoscopy  
• 
Ocular tonometry  
• 
Macular optical coherence tomography  
• 
Fluorescein angiography or optical coherence tomography angiography (when 
applicable) 
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  70 of 110 
• 
Blood sample for immunogenicity  
7.6.2 Visit 1 (Day 1) 
• 
Measurement of vital signs (temperature, blood pressure, heart rate, and breathing 
rate) 
• 
Evaluation of concomitant medications  
• 
Adverse Event Registry  
• 
Urine pregnancy test (where applicable) 
• 
Intravitreal injection of the study drug 
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
7.6.3 Visit 2 (Day 2) – PK cohort only 
• 
Evaluation of concomitant medications  
• 
Adverse Event Registry  
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
7.6.4 Visit 3 (Day 4) – for PK cohort only 
• 
Evaluation of concomitant medications 
• 
Adverse Event Registry  
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
7.6.5 Visit 4 (Day 8) – PK cohort only 
• 
Evaluation of concomitant medications  
• 
Evaluation of adverse events  
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
7.6.6 Visit 5 (day 30 ± 5) 
• 
Measurement of vital signs (temperature, blood pressure, heart rate, and breathing 
rate) 
• 
Evaluation of concomitant medications  
• 
Adverse Event Registry  
• 
Urine pregnancy test (where applicable) 
• 
Best Corrected Visual Acuity Measurement (AVMC) 
• 
Biomicroscopy 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  71 of 110 
• 
Indirect ophthalmoscopy 
• 
Ocular tonometry  
• 
Macular optical coherence tomography  
• 
Intravitreal injection of the study drug 
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
• 
Blood sample for immunogenicity  
7.6.7 Visit 6 (day 60 ± 5) 
• 
Measurement of vital signs (temperature, blood pressure, heart rate, and breathing 
rate.) 
• 
Evaluation of concomitant medications  
• 
Adverse Event Registry  
• 
Urine pregnancy test (where applicable) 
• 
Best Corrected Visual Acuity Measurement (AVMC) 
• 
Biomicroscopy 
• 
Indirect ophthalmoscopy 
• 
Ocular tonometry  
• 
Macular optical coherence tomography  
• 
Intravitreal injection of the study drug 
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
• 
Blood sample for immunogenicity  
7.6.8 Visit 7 (End/Early Termination) (Day 90 ± 5) 
• 
Measurement of vital signs (temperature, blood pressure, heart rate, and breathing 
rate.) 
• 
Evaluation of concomitant medications  
• 
Adverse Event Registry  
• 
Urine pregnancy test (where applicable) 
• 
Best Corrected Visual Acuity Measurement (AVMC) 
• 
Biomicroscopy 
• 
Indirect ophthalmoscopy 
• 
Ocular tonometry  
• 
Macular optical coherence tomography  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  72 of 110 
• 
Blood sample for pharmacokinetics (in patients who will be evaluated for PK) 
• 
Blood sample for immunogenicity  
7.6.9 Unscheduled follow-up visits 
At the request of the subject or the personnel related to the study, unscheduled follow-up visits 
may be carried out for the reporting of adverse events or any situation that warrants it. During these 
visits, all pertinent data on the adverse events reported should be collected and, where appropriate, 
an appropriate management plan should be established. 
7.7 Data collection 
7.7.1 Source documents 
Source documents are all written or printed records derived from automated processes (e.g., 
printouts of laboratory results issued by automated analysis equipment) where the information is 
recorded for the first time and which is part of the permanent records of the subject's history. 
Examples of source documents are medical history, clinical evolution notes, laboratory reports, 
cabinet study reports, nursing notes, follow-up notes, surgery records, etc.  
The PI is obliged to accept the monitoring of the information related to the study, audits, review by 
ethics and research committees, and inspections by the health authority, this obligation implies 
direct access to the source documents.  
7.7.2 Electronic forms of data collection 
All data related to the protocol will be captured through an electronic Case Report Form (eCRF) by 
the investigation team staff. The data related to the protocol should NOT be captured directly in the 
eCRF but should be transcribed from the corresponding source document. This procedure allows 
monitoring to verify the information captured in the eCRFs. It is the responsibility of the researcher 
to ensure that the information is transcribed into the eCRFs in a correct, complete, and timely 
manner. It is understood that all data captured and sent using the eCRF to data analysis is approved 
by the Researcher.  
7.7.3 Archiving 
The data collected in this database is anonymous (it only stores the subject number together with 
other information of interest). The program used for data capture and storage covers the 
traceability requirements necessary for the execution of clinical studies. The data collected will be 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  73 of 110 
stored by the sponsor or the clinical research organization designated for this purpose and its 
storage will have a duration of 10 years. The master file will remain in the participating institutions 
in charge of the PI or his work team and must be safeguarded for at least 10 years from the closure 
of the study.  
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  74 of 110 
8. Evaluation and management of adverse events 
8.1 Regulation and regulations on adverse events 
The registration and reporting of adverse events will be carried out in accordance with the 
guidelines established in NOM-220-SSA1-2016 and the international guidelines ICH E6.      [86] 
[87][88] [89] 
8.2 Definition of Adverse Event 
According to the International Council for Harmonization (ICH), an adverse event (AD) is any 
unfavorable medical appearance in a patient under clinical investigation who is given a 
pharmaceutical product, regardless of causal attribution.[90] 
Therefore, an AE can be any of the following: any unfavorable and unintentional disease, symptom, 
or sign (including an abnormal laboratory finding) that is temporally related to the use of a medical 
product, whether or not it is considered related to such a product; any new illness or exacerbation 
of an existing disease (worsening of the nature, frequency, or severity of a known condition); relapse 
of an intermittent medical condition (e.g., headache) not present at baseline; any deterioration in a 
laboratory value or other clinical test (e.g., electrocardiogram, x-ray) that is related to symptoms or 
that results in a change in study treatment or concomitant treatment or discontinuation of study 
medication. [87] [88] [89] 
As defined in the previous paragraph, an adverse event is defined as any event that occurs during 
treatment with medication. However, the definition can also be applied as any unwanted event that 
occurs during a clinical trial, including behavioral disorders. [89] 
8.3 Use of adverse events as a study safety variable 
Measuring the safety of PRO-169 is paramount to the study, therefore, it is considered important to 
report any unwanted manifestations or diseases that occur during the course of the study, 
regardless of whether or not the manifestation is considered to be related to the investigational 
treatment. [89] 
8.4 Definitions relevant to the classification of adverse events  
Severity (serious/non-serious), also called seriousness (serious/non-serious). Serious or serious is 
defined as any event that: results in death, threatens life, requires hospitalization or prolongs 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  75 of 110 
hospitalization, is a cause of permanent or significant disability or disability, is the cause of 
alterations or malformations in the newborn, other medically important conditions (Medically 
important event or reaction: That clinical manifestation or adverse event that in the opinion of the 
doctor may not be immediately life-threatening,  result in death or hospitalization, but which could 
endanger the subject or require medical intervention to prevent the occurrence of any of the criteria 
listed in the definition of serious adverse reaction).  [86] 
Severity (mild, moderate, or severe). Mild is those that present with minimal symptoms, do not 
require treatment or suspension of the medication; moderate, when they interfere with usual 
activities, without threatening the subject's life, require treatment and may or may not require 
discontinuation of the medication; severe, those that interfere with usual activities and require 
pharmacological treatment and discontinuation of the medication.   [86][87][88] 
Causality. It is the relationship that is 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 no direct evidence is 
available or it is considered unnecessary or dangerous, i.e. the reaction disappears when the 
pharmaceutical product is discontinued; possibly caused by the pharmaceutical, there is additional 
information to suggest that the cause may be due to another pharmaceuticals or disease; unlikely 
to be caused by the pharmaceutical product, there is a clear explanation of 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; non-classifiable, those for which once all possible information has been 
obtained about the adverse event, it remains unclassifiable.  [86][87] [88] [89] 
8.5 Responsibilities of the researcher  
It is the responsibility of the Investigator to verify AEs through questioning, pertinent physical 
examination, assessment of evolution, as well as appropriate medical and pharmacological 
management; as well as to follow up until the resolution or outcome and definitive discharge of the 
AE, following the definitions determined in national and international regulations.  [86] [87] [88] 
In the event of an AE or any event that puts the health and well-being of the subjects at risk, 
pertinent medical care will be provided, either at the research center or will be referred to the 
Hospital Center with the highest resolution power with which the research center has a medical 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  76 of 110 
care agreement. The PI will notify the sponsor's clinical monitor, according to the times established 
in national and international regulations. In the case of serious adverse events, it will notify the 
sponsor and record the corresponding information in the eCRF and in turn, inform the IRB and IC.   
The attention of the AEs will be carried out according to the event attention diagram (see Figure 3. 
Adverse Event Care).  
The sponsor's final report will include the report of adverse events in compliance with current 
national and international regulations. [86] [87] 
If the research subject debuts during their participation in the study with any chronic adverse event, 
such as diabetes or systemic arterial hypertension, they will be referred to the competent health 
professional for chronic treatment. The follow-up and termination of their participation will be in 
accordance with the provisions of NOM-012-SSA3-2012 and NOM-220-SSA1-2016. [72] [86] 
8.5.1 Recording of adverse events in the electronic case report form  
The adverse event registry considers:  
• 
Subject identification information such as subject number, age, gender, and if applicable 
specify the eye.   
• 
Information about the causation of the adverse event, its relationship to the 
investigational products, or to another cause as appropriate.  
• 
Important date information:  
o Date on which the adverse event occurs.  
o Date on which the Principal Investigator becomes aware of it.  
o Date of resolution or outcome, as applicable.   
• 
Information on diagnosis and clinical management. 
• 
Record the outcome or resolution of the event: 
o Recovered/resolved without sequelae 
o Recovered/resolved with sequelae 
o Recovering/Resolving 
o Not Recovered/Unresolved  
o Fatal 
o Unknown  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  77 of 110 
• 
Information about the investigational product or the product associated with the 
Adverse Event must be recorded. The information essential for registration is the 
generic name, distinctive name or code of the investigational product or of the product 
associated with the undesirable clinical manifestation; it will also be necessary to enter 
the data concerning the batch number, manufacturing laboratory, expiration date, 
dose, route of administration, start and end dates of administration and/or 
consumption, reason for prescription; according to whether it is an investigational 
product or drug (protocol in which the subject currently participates) or whether it is a 
drug that the research subject consumes for the treatment of underlying concomitant 
diseases or uses for the management of some transitory sign or symptom that does not 
correspond to the Natural History of the pathology that motivated its entry into the 
research protocol.  
• 
Indicate whether the removal of the suspected product (of causing the event) 
eliminates the adverse event. Also indicate if a dose adjustment is made, if the event 
changes in terms of intensity or seriousness, persistence of the reaction. It is important 
to indicate whether in those subjects who are exposed again to the product, which had 
previously been suspended, the AD reappears.   
• 
Information regarding concomitant pharmacotherapy. Indicate the generic name, dose, 
route of administration, start and end dates of use, as well as the reason for the 
prescription, regardless of whether it is in accordance with the prescribing information 
or technical data sheet or is used outside the regulations or what has been authorized 
by the local, national or international regulatory entity.  
• 
Relevant medical history information. The analysis of the AE considers the information 
previously narrated, despite the clinical context in which this harmful phenomenon 
occurs in the participants of the clinical research protocol, is of special interest, so the 
information about previous conditions, hypersensitivity or allergy phenomena, previous 
surgical procedures, laboratory analyses or cabinet examinations that have been 
performed on the participant,  etc., that the researcher deems it appropriate to mention 
may do so.  
8.5.2 Adverse Event Tracking  
All adverse events should be followed up until the outcome of the event.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  78 of 110 
8.5.2.1 Diagnosis against signs or symptoms 
Whenever possible, an AE should be assessed/reported as a diagnosis and not as a sign or symptom 
(e.g., liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). If a 
diagnosis cannot be made from the signs or symptoms, then each sign or symptom should be 
recorded as an AE. If a diagnosis is made later, all AEs reported as signs or symptoms should be 
nullified and replaced by a single adverse event based on the diagnosis, with an onset date that 
corresponds to the onset date of the first symptom or sign of the eventual diagnosis. 
8.5.2.2 Adverse events secondary to other adverse events 
In general, AEs secondary to other AEs (cascading events or sequelae) should be identified according 
to the primary cause.  
All EAs must register separately if there are concerns regarding the association of events. 
8.5.2.3 Persistent or recurrent adverse events 
A persistent adverse event is one that spread continuously without resolution between different 
points of assessment of the subject. Such events only need to be registered once in the eCRF. The 
initial severity (intensity or degree) of the event will be recorded at the time of the first AD record. If 
a persistent AE becomes acute, the maximum severity should be recorded in the appropriate section 
of the eCRF. If the event becomes a serious event, it must be reported no later than 24 hours after 
the knowledge of the change in the status of the event. The eCRF section should be updated to reflect 
the serious status and will record the date on which the event became serious, thus completing all 
relevant serious EA reporting data. 
A recurrent AE is one that resolves between assessment points and subsequently reappears. Such 
events should only be recorded once in the eCRF if they are of the same nature, intensity, association 
with the product of the investigation and/or cause of the AE, with recurrence and duration being 
recorded within the narrative of the event or in the corresponding sections.  
If AEs are different in nature, association with the product under investigation and/or cause of the 
AE, they must be registered individually in the eCRF. 
8.5.2.4 About the outcomes of adverse events 
The last known outcome of the adverse event should be captured. [90] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  79 of 110 
The possible outcomes of an adverse event are recovered, recovering, not recovered or in progress, 
recovered with sequelae, fatal and unknown. 
In case of irreversible congenital anomalies, the unrecovered or ongoing option should be used. For 
other irreversible medical conditions, resolved outcome with sequelae should be used. [90] 
8.5.2.5 Abnormal vital signs 
Not all abnormal vital signs qualify as AS. For an abnormal vital sign to be reported as an AD, it must 
meet any of the following criteria:  
• 
Be accompanied by clinical symptoms. It results in a change in treatment (dose modification, 
treatment interruption, etc.). 
• 
The report on abnormal values should focus on obtaining a diagnosis and not just a 
description of the abnormality. 
8.5.2.6 Death 
Death should be considered an outcome and not an event. The event or condition that caused or 
contributed to the fatal outcome should be recorded as the EA in the eCRF section. 
8.5.2.7 Pre-existing medical conditions 
A pre-existing medical condition should be recorded as AE only if the frequency, severity, or 
characteristics of the condition worsen during the study. 
8.5.2.8 Hospitalization or prolonged hospitalization 
Any AE that results in hospitalization or prolongation of hospitalization must be documented or 
reported as a serious AE with the following exceptions: 
• Hospitalization for pre-existing conditions if the following are met: 
1. Hospitalization was planned before the study. 
An AE will be considered serious under the criterion of "hospitalization" when there is a stay of more 
than 24 hours in a hospital care area, where the need for hospitalization is also confirmed. 
8.5.2.8 Adverse events exempt from reporting 
Adverse events related to intravitreal injection 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  80 of 110 
Intravitreal injection-related reactions are AEs that occur within 24 hours of administration of a 
medication by this route and are associated with puncture. These events will not be reported as 
AEs. 
If there are doubts regarding the association of AEs and the puncture process, it should be reported 
as AE. 
In the event of an AE that meets severity criteria, it should be reported as an AE, regardless of 
whether it is related to the puncture. 
Adverse events related to ophthalmic procedures 
AEs related to ophthalmic procedures necessary for the exploration and/or application of the 
investigational product will not be handled or reported as AEs, if their use is prior to the application 
of the investigational product, e.g., AEs related to the application of tetracaine, povidone iodine or 
blepharotat placement. 
If there are doubts regarding the association of AEs and the ophthalmic procedure, it should be 
reported as AE. 
In the event of an AE that meets severity criteria, it should be reported as an AE, regardless of 
whether it is related to the ophthalmic procedure, e.g., allergic reactions that meet severity criteria. 
8.5.2.9 Pregnancies, abortions, and birth defects 
Female subjects should contact their physician to report any suspected pregnancy during the study. 
A pregnancy report must be issued, and the sponsor must be informed immediately.  Subject 
monitoring should continue until the outcome of pregnancy and for 6 months after the birth of the 
product. [56] Pregnancy is not by itself an AE. 
Any abortion should be classified as a serious AE. 
Any birth defect or birth defect in a product of female menarche subjects who received the study 
drug should be classified as a serious AE. 
8.5.3 Procedures for a serious adverse event  
The process of attention to the adverse event considers the following stages:  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  81 of 110 
 
Figure 3. Adverse Event Care 
During the development and conduct of this study, undesirable harmful events or adverse 
reactions/incidents, of medical implication, may occur in the research subject, which do not 
necessarily have a causal relationship with the investigational products. These harmful phenomena 
can occur during the use of investigational pharmaceutical products at doses authorized for use in 
humans by a local, national or international regulatory entity. However, it may be suspected that 
the investigational product causes some unwanted clinical manifestation. AEs, Incidents, Adverse 
Incidents, ADRs or SRAMs to one or more pharmaceutical products can occur during the systematic 
evaluation of the participants (on the days when the clinical review is scheduled, according to the 
schedule of activities) or suddenly, in such a way that:  
• 
The investigator must be the first person to be notified that the subject has developed 
or presented any harmful phenomenon of a clinical nature during his or her 
participation in this study.   
Document 
Attention and  
Treatment  
relevant 
Categorization 
Preparation of a medical note 
Registration and reporting in eCRF 
 On-site investigation 
In hospital 1st-3rd level (if 
required) 
  
By outcome: 
Serious/Not Serious 
By severity: 
Mild, moderate, or severe 
Physical examination  
and evaluation of the  
EA 
EA not serious 
EA 
Follow up with the 
EA until its outcome 
END 
 
+ Inform, within 24 hours of 
their knowledge to the sponsor 
+ Follow up on the EA until its 
outcome 
 
Notify to: 
+ Pharmacovigilance Specialist in 
Clinical Research in maximum 24 
hours 
+corresponding Ministry of Health 
END 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  82 of 110 
• 
According to his clinical judgment, Based on the pertinent physical examination, 
interrogation, etc., as well as the analysis of the information available in the medical 
literature and what is referred to in the Investigator's Manual, Information to prescribe 
or Summary of the Comparator Drug Label, the principal investigator determines the 
pertinent care of the harmful event/reaction.  
• 
Such care can be in the research center or in the hospital with the greatest resolution 
power. In such a way that, if the subject is sent by the PI to a hospital, he or she attends 
through a referral system. The reference can be with a card that identifies the subject 
as a study participant and links him or her to the pre-established agreement with the 
institution, or through a medical reference note issued by the Principal Investigator. 
Laboratorios Sophia, S.A. de C.V., will pay the expenses for the medical care of the 
participating subject, when the adverse event is associated with or is related to the 
product under investigation.  
• 
Taking the clinical information collected, either during the care provided at the research 
center or that provided by the treating physician(s) in the hospital, the PI will record the 
AE in its clinical note, stating the seriousness, intensity (mild, moderate or severe) and 
relationship with the investigational product.   
• 
The PI must migrate the relevant data to the eCRF and its respective adverse event 
section. By, in cases of serious adverse events, the clinical monitor of the study must be 
notified within 24 hours after learning of it, so that in turn it informs the Clinical Team 
and the UTFLS, and that the CEI/CI is subsequently notified. Non-serious adverse events 
will be recorded and treated appropriately, and the safety profile of the investigational 
drug or PI will be reported to the appropriate regulatory entity in the final report of the 
clinical trial.  
The recording of the outcome of the AE depends substantially on the follow-up that the Principal 
Investigator performs on the subject, since it is expected that most of the harmful phenomena 
(Consult Subsection 2.4 Risk-benefit assessment and consult the Investigator's Manual) are 
ophthalmic in nature, however, there may be systemic alterations. Therefore, in the opinion of the 
researcher, the withdrawal of the participant or their permanence will be considered.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  83 of 110 
8.5.4 Causation assessment  
Causality assessment is the methodology used to estimate the probability of attributing the 
observed adverse event to a pharmaceutical product. It considers probabilistic categories according 
to the available evidence and the quality of the information, based on the national regulations of 
pharmacovigilance and technovigilance, the World Health Organization and the Uppsala Monitoring 
Center.  [86][91] 
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 
implies a relationship between the time of the intervention and the adverse event (e.g., the adverse 
event occurred shortly after the subject under investigation received the intervention). [89] 
For all adverse events, the Principal Investigator is responsible for examining and evaluating the 
subject to determine the association of the event with the clinical study and the intervention, 
whether related to the experimental treatment, concomitant, surgical procedure, or diagnostic 
procedures performed during the study. [89] 
Accepting that the adverse event is related to the clinical study requires a plausible mechanism of 
action—that is, that there is a logical sequence between the event that occurred and the 
intervention that caused it. In some cases, it is helpful to know the opinion of other doctors directly 
or indirectly involved in the research; as well as whether the subject considers that a relationship 
exists or not. [89] 
The Pharmacovigilance and Technovigilance Unit of Sophia Laboratories (UFTLS) may use the 
categories of causality described by the Uppsala Monitoring Centre, to categorize the likelihood of 
adverse event to the investigational product or concomitant treatments or treatments used during 
visits: [86] [91] 
- 
Definitive (certain): a clinical event, including alterations in laboratory tests, that manifests 
itself with a plausible temporal sequence in relation to the administration of the drug, and 
that cannot be explained by concurrent disease, or by other drugs or substances. The 
response to drug withdrawal (withdrawal) must be clinically plausible. The event must be 
definitive from a pharmacological or phenomenological point of view, using, if necessary, a 
conclusive re-exposure (challenge) procedure. [86] [91] 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  84 of 110 
- 
Probable: A clinical event, including alterations in laboratory tests, that manifests itself with 
a reasonable time sequence in relation to the administration of the drug, that is unlikely to 
be attributed to concurrent disease, or to other drugs or substances, and that a clinically 
reasonable response is presented upon withdrawal. Reexposure (challenge) information is 
not required to assign this definition [86] [91] 
- 
Possible: A clinical event, including alterations in laboratory tests, that manifests itself with 
a reasonable time sequence in relation to the administration of the medicinal product, but 
which can also be explained by concurrent disease, or by other drugs or substances. 
Information regarding the withdrawal of the drug may be missing or unclear. [86] [91] 
- 
Unlikely: A clinical event, including alterations in laboratory tests, that manifests itself with 
an unlikely temporal sequence in relation to the administration of the drug, and that can be 
more plausibly explained by concurrent disease, or by other drugs or substances. [86] [91] 
- 
Conditional/Unclassified: A clinical event, including alterations in laboratory tests, reported 
as an adverse reaction, for which further data are essential for appropriate evaluation, or 
additional data are under review. [86] [91] 
- 
Non-assessable/Unclassifiable: A notification that suggests an adverse reaction but cannot 
be judged because the information is insufficient or contradictory, and that cannot be 
verified or completed in its data. [86] [91] 
Thus, the degree of certainty to establish the investigational product as the causal agent of the 
harmful phenomenon that occurs to the subject of the clinical study, can be indicated directly by 
the Principal Investigator based on his clinical experience or by applying the categories of causality 
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: 
1. Strength of association, which refers to the number of cases in relation to those 
exposed.   
2. The consistency of the data, i.e. the presence of a common characteristic or pattern. 
3. The exposure-effect pattern, which determines the relationship with the site of 
appearance, time, dose and reversibility after deletion.   

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  85 of 110 
4. Biological 
plausibility, 
which 
refers 
to 
the 
possible 
pharmacological 
or 
pathophysiological mechanisms involved in the development or presentation of the 
adverse event.   
5. Experimental findings, e.g., the appearance of abnormal metabolites or high levels of 
the drug or its biotransformation product.  
6. Analogy, which refers to the experience gained with other related drugs, adverse 
reactions frequently produced by the same family of pharmacological agents.   
7. Nature and characteristics of the data, i.e. objectivity, accuracy and validity of the 
relevant documentation. [92] 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  86 of 110 
9. Study Monitoring  
The sponsor will contract with an external provider, who will be responsible for monitoring the 
study. Monitoring activities include, but are not limited to general safety monitoring, general study 
quality monitoring, monitoring by study site, detection monitoring, reporting and tracking of 
adverse events, monitoring for resolution of discrepancies in data capture, etc.  
The details of the monitoring activities are specified in a separate document from this protocol in a 
Monitoring Plan.  
9.1 Monitoring the Study Site  
The research centers participating in the study will be monitored. For each center, at least one start 
visit and one closing visit must be carried out, which does not exclude the carrying out of one or 
more follow-up visits between these two mandatory visits.  
The initial visit must be carried out before the inclusion of the first participant in that center; In it, 
the monitor will verify that the material to be used during the study has been received and that the 
personnel who will participate in the study activities have been trained on the study, as well as verify 
that the regulatory requirements and applicable standard operating procedures are met.  
At the follow-up visit(s), the monitor will conduct a review of the study documents to confirm that 
the applicable research protocol and standard operating procedures are being followed, data 
completion is complete and timely, and that adverse event reports are being conducted 
appropriately. At each visit, the monitor will discuss the findings with the researcher and define the 
actions to be taken.  
The closure visit will take place at the end of the study, once the last site participant has been 
discharged from follow-up. On this visit the monitor will verify that the site has all the necessary 
documents for archiving, that all biological samples have been analyzed, that all IP (used and 
unused) has been returned to the sponsor, and that all unused material has been recovered.  
Details on monitoring are set out in the relevant monitoring plan.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  87 of 110 
9.2 Audit and quality assurance 
To ensure compliance with GCPs and all applicable regulatory requirements, Laboratorios Sophia, 
S.A. de C.V. may conduct quality assurance audits. Regulatory agencies could also conduct a 
regulatory inspection of this study.  
Details about the audit process are set out separately in the Audit Plan.  
They may take place at any time before, during, or after the conclusion of the study. If any audit or 
inspection is conducted, the investigator and the institution shall agree to allow the 
auditor/inspector direct access to all relevant documents and shall allocate their time and that of 
their staff to the auditor/inspector to discuss the findings and any pertinent problems. If the audit 
has not been scheduled by the sponsor, the facility must notify Laboratorios Sophia, S.A. de C.V. 
immediately. 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  88 of 110 
10. Sample size calculation and statistical analysis 
10.1 Sample Size Calculation 
A sample size of 60 subjects, which includes a 20% increase for possible losses, was considered to 
be sufficient to answer the main objective of the study. 
10.1.1 Calculation methodology 
The evaluation of immunogenicity and its potential clinical effect play an important role in the 
evaluation of the safety and efficacy of a biologic. In this sense, the immunogenicity caused by using 
Bevacizumab in healthy volunteers after the application of a single dose has been evaluated. In a 
study with three groups of 38 participants, they found that the three groups developed ADAs in 
different proportions: 12/38, 9/38 and 14/38 respectively  [93]. In another study, also with 
intravenous administration in two treatment groups (42 subjects per group), the formation of ADAs 
was reported in 7/42 and 10/42 participants, respectively  [94]. 
Whereas, in cancer patients, where bevacizumab is administered in combination with 
chemotherapy, an incidence of ADAs of ≤ 5% (approximately 17 subjects) and 16–17% in other 
groups (53/315 and 50/312 patients, respectively) has been documented)[95] [96] 
The available literature on intravitreal bevacizumab-induced immunogenicity in patients with 
diabetic macular edema is very limited. Most of the evidence comes from studies conducted in 
healthy volunteers or in cancer populations, with different routes of administration, different 
clinical conditions, or different anti-GFR drugs. 
The European Medicines Agency through the Committee for Medicinal Products for Human Use 
(CHMP) published an Evaluation Report on the use of bevacizumab for age-related macular 
degeneration. It cites a phase 1 pharmacokinetic study that was conducted in 135 healthy subjects, 
with the aim of comparing a new formulation (CHDR1427_ONS-1045-001) with two reference 
products (U.S.-Avastin and E.U-Avastin), only one subject (1%) was observed to be positive for 
ADAs.[97] 
The immunogenicity of other anti-GFR drugs, such as aflibercept, has been evaluated in patients 
with macular edema. The aim of the studies was to determine the bioequivalence between a 
biosimilar and the reference products. The proportion of subjects who developed ADAs ranged from 
0 to 10.6%         [98] [99][100][101][102][103]. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  89 of 110 
Based on the above, it is expected that a proportion ≤10% of patients could develop ADAs after 
receiving PRO-169 treatment to characterize the immune response to the drug. However, it should 
be taken into account that The response to the drug can be affected by factors that are associated 
with the drug such as: the structure of the drug, the dose and place of administration; and factors 
related to the subject such as age, sex, general medical condition [104] and given that most of the 
studies cited above have been carried out in different populations and pathologies, the present 
study seeks to characterize the immunogenicity and pharmacokinetic profile of PRO-169, to provide 
and generate more evidence for the design of future studies. 
The ICH points out, in terms of sample size, that "The number of subjects should always be large 
enough to provide a reliable answer to the questions posed. This number is usually determined by 
the primary objective of the study. In case the sample size is determined on some other basis, it 
must be clear and justified." The FDA and Muglia & Di Giovanna recommend for phase 1 clinical 
studies, participation of 20 to 100 healthy volunteers or subjects with some condition. For its part, 
the Association of the British Pharmaceutical Industry (ABPI) recommends a participation of 50 to 
200 healthy volunteers or subjects with some condition.   [105] [106][107][108] 
While there is no minimum sample size for phase 1 clinical studies, the FDA mentions that The safety 
profile must be characterized in a reasonable time and considering the duration of exposure to the 
drug and its relationship with adverse events. In these studies, it is important to consider the ethical 
principle of beneficence, which Fisher, J. and Walker, R describe by emphasizing that "researchers 
should seek to minimize the risk of affecting participants and compensate for any remaining 
potential risks so that individuals or society benefit from the research." However, even if these risks 
are mitigated in phase I studies, there will always be a probability that subjects will experience an 
adverse event in the process of generating data on the safety and tolerability of the new drug.[109] 
As for the sample for pharmacokinetic evaluation, there are a limited number of published reports 
on the pharmacokinetic profile of bevacizumab in animals and/or human eyes. However, Avery et 
al. evaluated the systemic pharmacokinetics of three drugs: Bevacizumab (n=15), Ranizumab (n=20), 
and Aflibercept (n=21) in patients with age-related macular degeneration. They observed 
differences in pharmacokinetics between the three treatments. For this study, a sample size was 
not formally calculated, arguing that it was chosen to ensure the completion of the study. 
Moisseeiev et al. studied the pharmacokinetics of an application of bevacizumab in 22 patients (22 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  90 of 110 
eyes) observing that the half-life of the intravitreal injection of bevacizumab obtained in the study 
is comparable to that reported in previous studies. 
In phase 3 clinical studies, where the objective is to evaluate the efficacy of intravitreal Aflibercept 
biosimilars in patients with age-related macular edema, the evaluation of the pharmacokinetic 
profile is included as a secondary measure, the sample size used in these studies per treatment 
group is in a range of 11 to 47 participants (Bressler et al.,  2024; Wolf et al., 2024; Bordón et al., 
2024; Sadda et al., 2023). 
Considering that the objective of a Phase 1 clinical study is to determine safety and provide initial 
pharmacokinetic results, as well as the references cited above, the sample size for the 
pharmacokinetics cohort is not based on a statistical calculation, but rather on a reasonable number 
of participants to provide such data to characterize and generate useful data about the 
investigational drug.  According to the EMA and FDA, at least 12 participants are needed to carry 
out bioequivalence studies. Meanwhile, Lanser et al. observed that the sample sizes of nine studies 
in which pharmacokinetics were evaluated ranged from 10 to 29 patients. 
The sample size proposed in the present study is consistent with the usual practice of exploration 
PK studies in phase 1 and is considered adequate for the objectives of the study. 
10.2 Group Assignment and Blinding 
As it is an open-label, non-comparative study, randomization of the subjects entering the study is 
not necessary.  
10.3 Statistical methodology 
The statistical analysis will be carried out by personnel of Laboratorios Sophia, S.A. de C.V. A 
specialized statistical package SPSS version 19.0 (IBM Corporation, Armonk, NY, USA) or R (The R 
Foundation for Statistical Computing; http://www.R-project.org) for Windows. The coding of the 
subjects will be performed using consecutive numbers. The data will be collected and sorted in an 
Excel spreadsheet (Microsoft® Office). The data will then be exported to the platform of the selected 
statistical package. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  91 of 110 
Continuous variables will be summarized and described using classical measures of central 
tendency: mean, standard deviation (SD), median, minimum value, and maximum, 95% confidence 
interval (95% CI), geometric mean.  
The categorical variables will be summarized by frequency, and percentages by subjects. For this, 
tables of frequencies p x q will be constructed. All percentages will be presented with decimal. 
The operational definition of the variables is described in the Table 5. Operational definition of 
variables. 
10.4 Study populations 
10.4.1 Security Population 
The safety population (HCP) will include all subjects who have been administered at least one dose 
of IP, regardless of whether they have completed the study.  
10.4.2 Intention-to-Treat (ITT) Population 
The ITT population includes all subjects who have received at least one dose of PI, who do not 
present major deviations from the protocol during the conduction of the protocol and who have a 
minimum of 2 blood samples for immunogenicity evaluation. 
10.4.3 Population by Protocol (PP) 
The per-protocol population will include all those subjects who complete the study without major 
deviations from it.  
10.4.4 Deviations from the Protocol 
Deviations from the protocol will be recorded throughout the study. They must be classified as 
minor, major or critical, and will be presented in the Monitoring report.  
10.5 Lost Data 
10.5.1 Procedure for Handling Missing Data 
There is no imputation or plan for the management of missing data.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  92 of 110 
10.5.2 Visitor windows 
Patients who have recurrent out-of-window visits and/or who are life-threatening by omitting to 
perform a critical procedure, or significantly compromising the study data will be considered major 
deviations from the protocol and will be part of the SP and ITT. 
Table 8. Visit windows 
Visit 
Day of the visit 
Window 
Selection visit 
Day 0 
Day -8 
V1 
Day 1 
NA 
V2 
Day 2 
NA 
V3 
Day 4 
NA 
V4 
Day 8 
NA 
V5 
Day 30 
Day 25 to Day 35 
V6 
Day 60 
Day 55 to Day 65 
V7 
Final/Early Termination 
Day 90 
Day 85 to Day 95 
 
10.5.3 Subgroup Analysis 
If the sponsor deems it appropriate, subjects may be stratified for exploratory analysis by age range, 
by sex (females versus males), or some other characteristic. 
10.6 Demographic and baseline characteristics 
A descriptive analysis of the demographic and baseline variables of the security population will be 
carried out. 
10.6.1 Disposition of Subjects and Losses 
The sponsor may decide to replace subjects who present deviations related to the procedures 
(sampling and application of the PI) of the study until the sample size necessary to meet the primary 
objective of the study is completed. 
It is considered that a loss of subjects <20% does not represent a problem for the validity of the 
results obtained. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  93 of 110 
10.7 Analysis of variables  
10.7.1 Primary Variable 
For the descriptive analysis of the primary variable, it will be carried out in the ITT population, only 
one positive result for ADAs per subject will be considered. That is, if a subject tests positive at visit 
1 and subsequently tests positive again at visit 2, it will be considered only once for the calculation 
of the proportion. 
A positive result will be considered in the following cases: 
• 
Baseline result without the presence of ADAs (i.e., the result obtained in the blood sample 
for immunogenicity collected at the screening visit) and at least one sample with the 
presence of ADAs, after the initiation of PRO-169 treatment. 
• 
Baseline result with the presence of ADAs and at least one sample with a value ≥ 4 times 
the baseline result, after the start of treatment with PRO-169 
10.7.3 Secondary Variables 
Analysis of adverse events will be performed in the PS. The results will be expressed as subjects and 
proportions. The causality, intensity, severity, and outcome of the AEs manifested during the 
conduct of the study will be collected through the electronic case report form (eCRF), where the 
clinical team of the research center will carry out the emptying of the information obtained from 
the source documents (medical history, clinical notes). These documents will be reviewed by the 
clinical monitoring team. The AEs reported in the eCRF will be subsequently reviewed by the 
sponsor's Clinical Pharmacovigilance Specialist, to ensure the veracity and concordance of the 
information, based on the stipulations of the PI investigator's manual (PRO-169), as well as its 
agreement with the study protocol. 
The general summary of AEs will be reported in tables or figures using the preferred term (PT) for 
AEs (based on the Medical Dictionary for Regulatory Activities [MedDRA]), according to their 
classification by organs and systems (SOCs). 
The results shall be presented in tables or figures, indicating the number of observations in each 
measurement.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  94 of 110 
10.7.4 Pharmacokinetic variables 
Pharmacokinetic variables will be described by measures of central tendency; mean, standard 
deviation, minimum, maximum, geometric mean, median and range. They shall be presented in 
graphs or tables, as appropriate. 
10.7.5 Exploratory variables 
The analysis of the exploratory variables will be carried out in the PP population. To observe changes 
in BCVA and CMG from baseline at 12 weeks of treatment.  
10.8 Internal Analysis 
10.8.1 Preliminary Analysis 
No preliminary analyses are contemplated for this study. 
10.9 Clinical Data Management 
 Clinical data management (CDM) allows the generation of high-quality, reliable data with statistical 
value. CDM is the process of collecting, cleaning, and managing the information of the subjects of a 
study in accordance with regulatory standards (guidelines 21 CFR Part 11, ICH and GCP). It covers 
eCRF design, eCRF feedback, database design, data entry, source data verification (SDV), queries, 
medical coding, soft lock, and hard lock. 
In accordance with roles and responsibilities, multiple users can be created, whose types of access 
to the eCRF can be limited to capture (IP or authorized site personnel), medical coding, database 
design, or quality control (Quality Check). The  [110] [111]Figure 7 indicates the flow for the 
management of discrepancies that may arise. 
The CDM team will include the following roles (assigned to site staff, sponsor, or third party 
authorized by the sponsor in charge of programming and maintaining the eCRF):  
• 
Data Manager 
• 
Database Designer/Programmer 
• 
Medical Coder 
• 
Clinical Data Coordinator 
• 
Quality Control 
• 
Capturist (data entry associate) 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  95 of 110 
Figure 4. Handling discrepancies. 
(DCF, medical note; CRA, clinical monitor; SEC, self-evident correction) [110] 
The CDM will be carried out by the designated personnel of the biostatistics area. It will be reviewed 
in a subset of the total sample, equivalent to 25% of it (15 subjects). These will be selected randomly 
when 60% of the sample is available, reviewing only the following variables:  
- 
Presence of serum ADAs. 
- 
AVMC. 
- 
GMC. 
- 
Incidence of Adverse Events. 
Only those data entries that have SDV will be reviewed in the CDM. All discrepancies detected will 
be shared via email to the Regional Clinical Studies Leader, Clinical Research Pharmacovigilance 
Specialist and/or the Therapeutic Area Specialist responsible for the study for resolution, according 
to the Sponsor's Current Standard Operating Procedure.  
If discrepancies are detected in more than 50% of the subjects reviewed in the CDM, this percentage 
will be increased by 10%, up to a maximum of 80% of the total sample. 
Data Validation 
Discrepancy? 
DCF 
IP 
CRA 
SDV 
Data 
manager 
SEC 
Resolution 
Database 
NO 
YES 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  96 of 110 
11. Ethical considerations 
11.1 Approval of the committees 
The present study will be conducted in accordance with the standards of the Declaration of Helsinki, 
World Medical Association 2013.  Nuremberg Code; Nuremberg Trial by the International Tribunal 
of Nuremberg, 1947.  Belmont Report, National Commission for the Protection of Biomedical and 
Behavioral Research Subjects, 1979.  It shall be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicinal products for human use by the 
International Council for Harmonization (   [112] [113][114]The International Council for 
Harmonisation, ICH for its acronym in English) Guide to Good Clinical Practices.  International Ethical 
Guidelines for Biomedical Research in Human Subjects of the Council for International Organizations 
of Medical Sciences ([89]Council for International Organizations of Medical Sciences, CIOMS, 2016).  
The Research Ethics Committee (REC) and the Research Committee (IC) will evaluate the protocol 
before conducting the study and will issue their approval or possible modifications for its 
performance, these Committees must be notified of any significant changes to the protocol. In 
addition to the above, the current regulations of the regulatory authority will also be complied with. 
[115] 
The staff will submit to evaluation by the Research Ethics Committees, Research Committees, and 
when applicable to the Biosafety Committee, the essential documentation of the research project: 
research protocol, forms of informed consent, researcher's manual, subject material, as well as 
other documents additionally requested, in accordance with the local, national or international 
requirements applicable by the regulatory entities.  
The study will not begin at the research center if there are not the confidentiality agreements and 
economic proposal of each of the principal investigators, duly signed and without having previously 
obtained the favorable opinion and/or approval of the RECs, CIs, and when applicable, by the 
Biosafety Committee, the corresponding ones. 
The study will not begin without having complied with the relevant local, national or international 
regulatory requirements and without having the corresponding health authorization.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  97 of 110 
The study is a study with a 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 of January 6, 1987. [116] 
11.2 Amendments to the protocol  
The amendment procedure will be pertinent when there is a need to make any change to a 
document that is part of the research project or protocol, derived from variations in the 
methodological structure, substitution of the principal investigator or in the face of the 
identification of risks in the research subjects. The documents subject to amendment will be 
protocol, forms of informed consent, researcher's manual, documents for the subject, 
measurement scales and schedule of activities.  
Any amendment must be approved by the sponsor and/or the principal investigator, the amended 
document(s), once reviewed and approved by the CEI and the IC 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 confer an additional or different risk on the 
research subjects must be approved by the Committees. It is the investigator's responsibility to act 
in situations that require immediate action to avoid unnecessary harm to study participants.  
The principal investigator is responsible for communicating to the IRB any amendments to the 
protocol that could eventually affect the rights, safety, or welfare of research participants. Likewise, 
it must inform of any situation or new knowledge that will show a greater risk for the participants, 
the premature termination or suspension of the study, the reasons and the results obtained so far. 
It must also report on the conclusion of the study upon completion of the research protocol.  
11.3 Early Study Termination  
The study may be suspended or terminated prematurely if there is a sufficiently reasonable cause. 
Written notice, documenting the reason for the suspension or early termination, must be delivered 
by the party executing the suspension. The PI should promptly inform the study participants, the IC, 
and the IRC providing the reasons. 
Situations in which study suspension or early termination will be contemplated include, but are not 
limited to:  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  98 of 110 
• 
The regulatory authority (COFEPRIS) considered it for security alerts.  
• 
The Sponsor determined it for its convenience or eventualities such as financial support, 
manufacturing errors, etc.  
• 
The identification of unexpected risks to the participants, which are significant or 
unacceptable.  
• 
Obtaining new relevant safety information.  
• 
Insufficient adherence to the requirements of the protocol.  
• 
The data obtained is not assessable or is not sufficiently complete.  
• 
The determination that the primary objective has been achieved.  
• 
The determination of futility.  
In the event of suspension, the study may be resumed once the situations that led to the suspension 
have been corrected; if this justification is sufficient for the sponsor, CI, CEI and regulatory 
authorities.  
11.4 Informed Consent 
The FCI contains complete and understandable information on the study and the products under 
investigation, in accordance with the applicable regulations in force and the GCP. 
The FCI will be considered as a source document and will be filed as such. The principal investigator 
of the site is responsible for ensuring that all new versions of the informed consent are submitted 
to the appropriate approvals (the same to which the original informed consent form was submitted) 
and that the most current approved version is the one that is presented to the study subjects after 
authorization from COFEPRIS. 
For this study, there will be two different FCIs. One will be considered the main FCI as it will apply 
to all participants included. The second FCI will be complementary and additional to this main FCI 
and will be applicable only to participants who meet the eligibility criteria and who wish to be part 
of the pharmacokinetics subgroup. This subgroup will be made up of 15 of the total 60 participants.  
11.4.1 Obtaining  
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. Patients must be informed that their participation is voluntary. For this purpose, the 
informed consent form must be signed. 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  99 of 110 
Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guide to GCPs and will be following all applicable laws and 
regulations.  
The PI, or the study staff delegated by him/her, will provide the prospective participant with all the 
information regarding the characteristics of the study, its potential benefits, risks, objectives, and 
procedures.  
This information will be in a language understandable to the subject, it will be explained to the 
subject that he or she has the right to interrupt his or her participation in the study at any stage, 
without this affecting the relationship with the researcher and/or his or her future assistance. 
Informed consent will be put into consideration of the potential participant, which must have 
enough time to analyze each and every one of the aspects mentioned above and, if they have 
doubts, these will be clarified by the person in charge of obtaining consent. The PI will be able to 
explain the study prior to the surgical procedure, obtaining the signature until the baseline visit. 
Once the participant agrees to participate in the study, he/she must sign and date the informed 
consent form in the presence of two witnesses, whether they are related to the study subject, who 
will participate during the informed consent process and sign guarantees that the process was 
carried out prior to any study procedure.  that the information of the study was clearly explained 
and doubts were clarified if any.  
If a subject is illiterate, acceptance will be with his or her fingerprint, and if the subject is unable to 
give adequate written informed consent, a representative of the "legally authorized" subject may 
provide such consent for the subject in compliance with applicable laws and regulations. 
In the same way, the PI, or the study staff delegated by him, must sign and date this consent.  
The FCI must be signed in duplicate by all those involved, one copy will be filed in the researcher's 
folder, and the other will be given to the participant. The PI or delegated personnel must document 
the process of obtaining informed consent by means of a detailed, precise and contemporary 
medical note, specifying the signed version, the date on which the documents were signed and how 
the process was carried out. 
In cases where the participant is going to be part of the pharmacokinetics subgroup, he/she must 
replicate all the above steps and considerations to, in addition to the main FCI, establish his/her 
acceptance of participation by signing the FCI of the PHARMACOKINETICS SUBGROUP.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  100 of 110 
11.4.2 Special considerations  
The procedures that will be performed during the conduct of the study do not pose an additional 
risk that should be considered apart from the listed informed consent procedures.  
11.4.3 Modifications to Consent 
Any changes to these documents constitute an amendment and must be submitted for approval to 
the CEIs and COFEPRIS.  
Such amendments may be implemented only after written approval from the IRB and the Regulatory 
Entity (as applicable), except for an amendment that is required to eliminate an immediate hazard 
to the study subjects.  
A process of re-consent of each subject affected by the amendment must be carried out under the 
same conditions as those described above, to communicate the new information contained in the 
document to them in a timely manner. The subject will be given a signed original of the amendment, 
and the researcher will keep the second original.  
11.5 Confidentiality  
All documents and information provided to the research center by the sponsor are strictly 
confidential. PI expressly agrees that data about your professional and clinical experience, provided 
to the sponsor on paper and stored in electronic form, is solely for use related to your activities with 
the clinical trial sponsor, in accordance with Good Clinical Practice.   
The PI agrees that he and his team members will use the information only within the framework of 
this study, to carry out the protocol. This agreement is binding if the confidential information has 
not been disclosed to the public by the sponsor.   
The clinical study protocol provided to the PI may be used by the PI and his team to obtain informed 
consent(s) from the subjects for the study. The clinical trial protocol, as well as any information 
taken from it, should not be disclosed to other parties without the written permission of the 
sponsor.   
The PI will not disclose any information without the prior written consent of Laboratorios Sophia, 
S.A. de C.V., except to the representatives of the Competent Authorities, and only at their request. 
In the latter case, the investigator undertakes to inform Laboratorios Sophia, S.A. de C.V. before 
disclosing the information to these authorities.   

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  101 of 110 
The PI will fill out and maintain a record of the selection of the subjects, as well as the identification 
and enrollment list of each of the subjects participating in the study. The investigator agrees to give 
on-site access to the auditor and/or representatives of the Competent Authorities. The information 
will be processed in compliance with professional secrecy.  
In the eCRF and all communications related to study subjects, they will identify them only by the 
study subject's identification number, either by the scrutiny number or the assignment number. The 
information collected in this study will be exchanged between the sponsor and the research center 
and must be treated confidentially. The Health Authority, the CEI, the IC, the sponsor, the 
monitors/auditors and third-party auditors will be the only bodies authorized to review the study 
documentation. If publications arise from this research project, in no case will they contain 
information on the identification of the study subjects. If the results of the study are published, no 
personal information on the study subjects will be revealed.  
The protection of personal data will be carried out in accordance with the corresponding regulations 
in force.  
11.6 Conflict of interest  
The independence of the conduct of the study and its results from any current or perceived external 
influences is critical. For this reason, any current conflict of interest of any person who has a role in 
design, conduct, analysis, publication or any aspect of this study will be declared. Furthermore, 
those who have a perceived conflict of interest will be asked to handle it in a manner appropriate 
to their participation in the study.  
11.6.1 Declaration of Interests  
The PI undertakes to make a declaration of financial interests as well as conflict of interest prior to 
the start of the study.  
11.7 Access to Information  
The final database of the study will be the property of Laboratorios Sophia, S.A. de C.V. and its access 
will be restricted. The PI will not have access to it, unless it has prior written authorization from the 
sponsor.  
The information obtained, which is relevant to the safety of the subjects participating in the study, 
must be immediately shared with the research center, so that it can be notified to the study subjects.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  102 of 110 
11.8 Ancillary and post-study care  
Once the study was completed and adverse events were closed according to the 8. Evaluation and 
management of adverse events, the sponsor will not extend care to the research subject. 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  103 of 110 
12. Biosecurity aspects 
This protocol, entitled: "Phase I clinical study to evaluate safety by determining immunogenicity 
after the unilateral application of intravitreal PRO-169 in patients with diabetic macular edema", 
and number: SOPH169-1224/I HAS NO BIOSAFETY IMPLICATIONS, since infectious and contagious 
biological material will NOT be used; pathogenic strains of bacteria or parasites; viruses of any kind; 
radioactive material of any kind; genetically modified animals and/or cells and/or plants; toxic, 
dangerous or explosive substances; any other material that endangers the health or physical 
integrity of the research center’s staff or research subjects or affects the environment. It is also 
declared that this project will not carry out cell, tissue or organ transplant procedures, or cell 
therapy, nor will laboratory, farm or wildlife animals be used. 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  104 of 110 
13. Posting Policy 
13.1 Final Report  
Once the statistical analysis is completed, the final report will be written with the results obtained, 
by the Team of the Regional Management Department of Medical Affairs of Laboratorios Sophia, 
S.A. de C.V. This report will be prepared following the recommendations of the E3 Step 4 Guide of 
the ICH.  
13.2 Communication of results  
Regardless of the results of the study, Laboratorios Sophia, S.A. de C.V., is committed to 
communicating the final report of the study to the principal investigators and COFEPRIS. These 
results will also be shared with the IC and the IEC. It will be the responsibility of the PI to 
communicate it to the research subjects.   
Laboratorios Sophia, S.A. de C.V. will always maintain the rights over the publication and disclosure 
of the information contained.  
13.3 Publication of results  
Laboratorios Sophia, S.A. de C.V., acting as the sponsor of the study, assumes full responsibility for 
its function and retains exclusive ownership rights over the results of the study, which it may use in 
any way it deems appropriate.  
The PI undertakes not to publish or communicate data collected from the study, unless there is the 
prior written agreement of Laboratorios Sophia, S.A. de C.V. Any manuscript derived from the data 
obtained with this protocol must be submitted to review by the sponsor before any attempt to 
submit it for publication in any scientific journal or congress. 
However, if the sponsor is in the process of filing a patent application on the results of the study, 
the sponsor may delay its publication or communication of the results of the study until the date of 
registration or whenever it deems appropriate.  
The assignment of authors for publications derived from this research will be the sole responsibility 
of the sponsor. Researchers invited to participate as authors must express their authorization. All 
researchers who are going to participate as authors can review the article prior to its submission 
and will be free to make comments and suggestions about it within the first 15 calendar days from 
the receipt of the document. 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  105 of 110 
14. Financing and Insurance 
14.1 Compensation to Study Participants  
Participation in this study is completely voluntary and non-profit, so patients will not receive any 
payment directly for participating in the study. However, patients may receive financial support at 
each study visit for travel expenses (transportation and food expenses). 
14.2 Insurance for Study Participants  
In accordance with current local regulations, Laboratorios Sophia S.A. de C.V. has contracted a civil 
liability policy, to comply with the responsibility of providing medical treatment and compensation 
to which a subject would be legally entitled, in the case of damages directly caused by this research. 
In the event of a medical emergency, the research center must have personnel, material, equipment 
and procedures for its immediate management. 
 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  106 of 110 
15. Bibliography 
 
[1]  
K. Miller and J. Fortun, "Diabetic Macular Edema: Current Understanding, Pharmacologic Treatment Options, 
and Developing Therapies.," Asia Pac J Ophthalmol (Phila), vol. 7, p. 28–35, 2018.  
[2]  
A. Yu, M. Masalkhi, R. Brown, B. Chen and J. Chhablani, "Racial and Ethnic Distribution in Diabetic Macular 
Edema Clinical Trials in the United States (2002-2021)," Ophthalmol Retina, vol. 7, no. 12, pp. 1035 - 1041, 2023. 
[3]  
J. Im, Y. Jin, R. Chow and R. Yan, "Prevalence of diabetic macular edema based on optical coherence 
tomography in people with diabetes: A systematic review and meta-analysis," Surv Ophthalmol, vol. 67, no. 4, 
pp. 1244 - 1251, 2022.  
[4]  
Z. Teo, Y. Tham, M. Yu, M. Chee, T. Rim, N. Cheung, M. Bikbov, Y. Wang, Y. Tang and Y. Lu, "Global Prevalence of 
Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis," 
Ophthalmology, vol. 128, no. 11, pp. 1580 - 1591, 2021.  
[5]  
P. Romero-Aroca, M. Baget-Bernaldiz, A. Pareja-Rios, M. Lopez-Galvez, R. Navarro-Gil and R. Verges, "Diabetic 
Macular Edema Pathophysiology: Vasogenic versus Inflammatory.," J Diabetes Res, p. 2156273, 2016.  
[6]  
K. Ogurtsova, J. da-Rocha-Fernandes, Y. Huang and e. al, "IDF Diabetes Atlas: Global estimates for the 
prevalence of diabetes for 2015 and 2040.," Diabetes Research and Clinical Practice, vol. 128, p. 40–50, 2017.  
[7]  
N. Cho, J. Shaw, S. Karuranga and e. al., "IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 
and projections for 2045.," Diabetes Research and Clinical Practice, vol. 138, p. 271–81, 2018.  
[8]  
V. Vieira-Potter, D. Karamichos and D. Lee, "Ocular Complications of Diabetes and Therapeutic Approaches.," 
Biomed Res Int 2016, p. 3801570, 2016.  
[9]  
N. Sayin, N. Kara and G. Pekel, "Ocular complications of diabetes mellitus.," World J Diabetes, vol. 6, p. 92–108, 
2015.  
[10]  E. Jaeger, Beiträge zur Patholgie des Auges, Vienna, 1856.  
[11]  S. Mackenzie, "A case of glycosuric retinitis, with comments. (Microscopical Examination of the Eyes by Mr. 
Nettleship)," V. Graefe's Archiv für Ophthalmalogie, vol. 3, pp. 134 - 157, 1877.  
[12]  H. Noyes, "Retinitis in Glycosuria," Trans Am Ophthalmol Soc, vol. 1, p. 71–5, 1868.  
[13]  E. Nettleship, "On oedema or cystic disease of the retina.," R Lond Hosp Rep, vol. 7, pp. 343 - 351, 1873.  
[14]  R. Klein, B. Klein and S. Moss, "Visual Impairment in Diabetes," Ophthalmology, vol. 91, no. 1, 1984.  
[15]  E. Lundeen, L. Andes, D. Rein, J. Wittenborn, E. Erdem, Q. Gu, J. Saaddine, G. Imperatore and E. Chew, "Trends 
in Prevalence and Treatment of Diabetic Macular Edema and Vision-Threatening Diabetic Retinopathy Among 
Medicare Part B Fee-for-Service Beneficiaries," JAMA Ophthalmol, vol. 140, no. 4, pp. 345 - 353, 2022.  
[16]  T. Wong, C. Cheung, M. Larsen, S. Sharma and R. Simó, "Diabetic retinopathy," Nat Rev Dis Primers, vol. 2, pp. 1 
- 17, 2016.  
[17]  A. Gurreri and A. Pazzaglia, "Diabetic Macular Edema: State of Art and Intraocular Pharmacological 
Approaches," Adv Exp Med Biol, pp. 375 - 389, 2021.  
[18]  D. Browning, M. Stewart and C. Lee, "Diabetic macular edema: Evidence-based management," Indian J 
Ophthalmol, vol. 66, no. 12, pp. 1736 - 1750, 2018.  
[19]  A. García-Ulloa, L. Pérez-Peralta, S. Jaime-Casas, A. Jiménez-Corona, D. Rivera-De la Parra, E. Graue-Hernández 
and S. Hernández-Jiménez, "Risk Factors Associated with Diabetic Retinopathy with and without Macular Edema 
in Recently Diagnosed Patients with Type 2 Diabetes. Group of Study CAIPaDi," Diabetes Metab Syndr Obes, vol. 
17, pp. 231 - 238, 2024.  
[20]  J. Zhang, J. Zhang, C. Zhang, J. Zhang, L. Gu, D. Luo and Q. Qiu, "Diabetic Macular Edema: Current 
Understanding, Molecular Mechanisms and Therapeutic Implications," Cells, vol. 11, no. 21, pp. 1 - 29, 2022.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  107 of 110 
[21]  F. Bandello, P. Battaglia, P. Lanzetta, A. Loewenstein, P. Massin, F. Menchini and D. Veritti, "Diabetic Macular 
Edema," Dev Ophthalmol, vol. 58, pp. 102 - 108, 2017.  
[22]  D. Kuroiwa, F. Malerbi and C. Regatieri, "New Insights in Resistant Diabetic Macular Edema," Ophthalmologica, 
vol. 244, no. 6, pp. 485 - 494, 2021.  
[23]  T. Tatsumi, "Current Treatments for Diabetic Macular Edema," Int J Mol Sci, vol. 24, no. 11, pp. 1 - 25, 2023.  
[24]  V. Lima-Gómez, D. Blanco-Hernández, P. Muñoz-Ibarra and M. Hernández-Rojas, "Severity distribution of 
diabetic macular edema at the time of diagnosis.," Cir Cir, vol. 79, p. 491–7, 2011.  
[25]  E. Graue-Hernández, D. Rivera-De-La-Parra, s. Hernández-Jiménez, C. Aguilar-Salinas, D. Kershnobic-Stalnikowitz 
and A. Jiménez-Corona, "Prevalence and associated risk factors of diabetic retinopathy and macular oedema in 
patients recently diagnosed with type 2 diabetes," BMJ Open Ophthalmol, vol. 5, no. 1, pp. 1 - 11, 2020.  
[26]  "Retinopathy and Nephropathy in Patients with Type 1 Diabetes Four Years after a Trial of Intensive Therapy.," 
New England Journal of Medicine, vol. 342, p. 381–9, 2000.  
[27]  Y. Peng and M. Tsai, "Impact of metabolic control on macular thickness in diabetic macular oedema," Diab Vasc 
Dis Res, vol. 15, no. 2, pp. 165 - 168, 2018.  
[28]  T. Macky and M. Mahgoub, "The effect of glycemic control on visual and anatomic outcomes in response to 
therapy for diabetic macular edema," Eur J Ophthalmol, vol. 23, no. 1, pp. 94 - 100, 2012.  
[29]  W. Amoaku, F. Ghanchi, C. Bailey, S. Banerjee, S. Banerjee, L. Downey, R. Gale and R. Hamilton, "Diabetic 
retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group," Eye 
(Lond), vol. 34, no. Suppl 1, pp. 1 - 51, 2020.  
[30]  Y. Takamura, Y. Yamada, M. Morioka, M. Gozawa, T. Matsumura and M. Inatani, "Turnover of Microaneurysms 
After Intravitreal Injections of Faricimab for Diabetic Macular Edema," Invest Ophthalmol Vis Sci, vol. 64, no. 13, 
pp. 1 - 7, 2023.  
[31]  S. Bakri, J. Wolfe, C. Regillo, H. Flynn, and C. Wykoff, "Evidence-Based Guidelines for Management of Diabetic 
Macular Edema.," Journal of Vitreous Retinal Diseases, vol. 3, p. 145–52, 2019.  
[32]  L. Kodjikian, D. Bellocq, F. Bandello and e. al., "First-line treatment algorithm and guidelines in center-involving 
diabetic macular edema.," Eur J Ophthalmol, no. 1120672119857511, 2019.  
[33]  U. Schmidt-Erfurth, J. Garcia-Arumi, F. Bandello and e. al., "Guidelines for the Management of Diabetic Macular 
Edema by the European Society of Retina Specialists (EURETINA).," Ophthalmologica, vol. 237, p. 185–222., 
2017.  
[34]  A. Cheema and H. Cheema, "Diabetic Macular Edema Management: A Review of Anti-Vascular Endothelial 
Growth Factor (VEGF) Therapies," Cureus, vol. 16, no. 1, pp. 1 - 14, 2024.  
[35]  E. Cunningham, A. Adamis, M. Altaweel and e. al., "A phase II randomized double- masked trial of pegaptanib, 
an anti-vascular endothelial growth factor aptamer, for diabetic macular edema," Ophthalmology, vol. 112, p. 
1747–57, 2005.  
[36]  The Diabetic Retinopathy Clinical Research Network, "Aflibercept, Bevacizumab, or Ranibizumab for Diabetic 
Macular Edema.," N Engl J Med, vol. 372, pp. 1193-203, 2015.  
[37]  A. Nepomuceno, E. Takaki, F. Paes-de-Almeida and e. al., "A prospective randomized trial of intravitreal 
bevacizumab versus ranibizumab for the management of diabetic macular edema.," Am J Ophthalmol, vol. 156, 
pp. 502-510.e2., 2013.  
[38]  B. Ozturk, H. Kerimoglu, B. Bozkurt and S. Okudan, "Comparison of intravitreal bevacizumab and ranibizumab 
treatment for diabetic macular edema.," J Ocul Pharmacol Ther, vol. 27, p. 373–7, 2011.  
[39]  H. Wiley, D. Thompson, C. Bailey and e. al, "A Crossover Design for Comparative Efficacy: A 36-Week 
Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.," Ophthalmology, vol. 123, p. 
841–9, 2016.  
[40]  Registered prices of medicines with a valid patent, "Secretaría de Economía Gobierno de México," 11 01 2014. 
[Online]. Available: 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  108 of 110 
https://economia.gob.mx/files/transparencia/focalizada/precios_max_medicamentos_patente_2014_0111.pdf. 
[Accessed 22 01 2025]. 
[41]  E. Ross, D. Hutton, J. Stein and e. al., "Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for 
Diabetic Macular Edema Treatment: Analysis From the Diabetic Retinopathy Clinical Research Network 
Comparative Effectiveness Trial.," JAMA Ophthalmol, vol. 134, pp. 888-96, 2016.  
[42]  N. Maniadakis and E. Konstantakopoulou, "Cost Effectiveness of Treatments for Diabetic Retinopathy: A 
Systematic Literature Review. Pharmacoeconomics," PharmacoEconomics, vol. 37, p. 995 – 1010, 2019.  
[43]  A. Sharma, N. Kumar and B. D. Kuppermann, "Biotherapeutics and immunogenicity: ophthalmic perspective," 
Eye, vol. 33, p. 1359–1361, 2019.  
[44]  N. Bano, T. McKelvey, N. Spear, T.-Y. Yang, G. Shankar and A. Schantz, "Analysis of regulatory guidance on 
antidrug antibody testing for therapeutic protein products," Bioanalysis, vol. 11, no. 24, p. 2283–2296, 2019.  
[45]  C. Pineda, G. Castañeda-Hernández, I. Jacobs, D. Alvarez and C. Carini, "Assessing the Immunogenicity of 
Biopharmaceuticals," BioDrugs, vol. 30, no. 3, pp. 195 - 206, 2016.  
[46]  K. Suh, I. Kyei and D. S. Hage, "Approaches for the detection and analysis of antidrug antibodies to 
biopharmaceuticals: A review," J Sep Sci, vol. 45, no. 12, pp. 2077-2092, 2022.  
[47]  H. Kim and S. Woo, "Immunogenicity and Potential for Intraocular Inflammation of Intravitreal Anti-VEGF 
Drugs," Curr Ther Res Clin Exp, vol. 14, no. 100, pp. 1 - 3, 2024.  
[48]  EMEA - European Medicines Agency, "CHMP Guideline on immunogenicity assessment of biotechnology-
derived therapeutic proteins," 13 12 2007. [Online]. Available: https://www.tga.gov.au/sites/default/files/2024-
06/guideline-immunogenicity-assessment-biotechnology-derived-therapeutic-proteins-ema.pdf. [Accessed 22 
01 2025]. 
[49]  Sophia Laboratories, "Final Study Report BEVAVSBEVAFCFEB19V2 Preclinical Study of Non-Inferiority of 
Comparative Bioavailability in Vitreous Humor, Aqueous Humor, and Plasma, of the PRO-169 vs. The Avastin® 
solution in healthy albino rabbits New Zealand, later," Internal document, Zapopan, 2019. 
[50]  Sophia Laboratories, "Final Report BEVAVSRANISTMAR19 - Comparative Preclinical Study on the Safety and 
Toxicity of PRO-169 vs ranibiumab (Lucentis) Following Intravitreal Application in Healthy New Zealand Albino 
Rabbits," Internal Document, Zapopan, 2019. 
[51]  Sophia Laboratories, "Study Report "Comparative Study of the Efficacy of Candidate Product and Avastin in 
Laser-Induced Choroidal Neovascularization (CNV) in Rhesus Monkeys," Internal Paper, Chengdu Sichuan. 
[52]  V. Gerriets and A. Kasi, "Bevacizumab - StatPearls," National Library of Medicine, 23 08 2023. [Online]. 
Available: https://www.ncbi.nlm.nih.gov/books/NBK482126/. [Accessed 02 02 2025]. 
[53]  U.S. Department of Health and Human Services Food and Drug Administration, "Immunogenicity Assessment 
for Therapeutic Protein Products Guidance for Industry," 08 2014. [Online]. Available: 
https://www.fda.gov/media/85017/download. [Accessed 04 02 2025]. 
[54]  F. Harding, M. Stickler, J. Razo and R. DuBridge, "The immunogenicity of humanized and fully human antibodies: 
residual immunogenicity resides in the CDR regions," MAbs, vol. 2, no. 3, pp. 256 - 265, 2010.  
[55]  S. Singh, S. Saxena, L. Akduman and C. Meyer, "Off-label use of intravitreal bevacizumab: A global conundrum," 
Indian J Ophthalmol, vol. 72, no. 5, pp. 617 - 619, 2024.  
[56]  A. Lingappan, C. Wykoff, T. Albini, D. Miller, A. Pathengay, J. Davis, and H. Flynn, "Endogenous fungal 
endophthalmitis: causative organisms, management strategies, and visual acuity outcomes," Am J Ophthalmol, 
vol. 153, no. 1, pp. 162 - 166, 2012.  
[57]  F. Wang, S. Yu, K. Liu, F. Chen and Z. Song, "Acute Intraocular Inflammation Caused by Endotoxin after 
Intravitreal Injection of Counterfeit Bevacizumab in Shanghai, China," Ophthalmology, vol. 120, no. 2, pp. 355 - 
361, 2013.  
[58]  S. Gonzalez, P. Rosenfeld, M. Stewart, J. Brown and S. Murphy, "Avastin Doesn't Blind People, People Blind 
People," American Journal of Ophthalmology, vol. 153, no. 2, pp. 196 - 203, 2012.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  109 of 110 
[59]  European Medicines Agency, "Lytenava; EPAR - Product information," 22 01 2025. [Online]. Available: 
https://www.ema.europa.eu/en/documents/product-information/lytenava-epar-product-information_en.pdf. 
[Accessed 06 02 2025]. 
[60]  European Medicines Agency, "Lytenava: EPAR - Risk management plan," 31 05 2024. [Online]. Available: 
https://www.ema.europa.eu/en/documents/rmp/lytenava-epar-risk-management-plan_en.pdf. [Accessed 06 
02 2025]. 
[61]  P. Udaondo, A. Adan, L. Arias-Barquet, F. Ascaso and F. Cabrera-López, "Diabetic Macular Edema Management: 
An Expert Consensus Report," Clin Ophthalmol, vol. 15, pp. 3183 - 3195, 2021.  
[62]  B. Kuo, D. Tabano, V. Garmo, E. Kim and T. Leng, "Long-term Treatment Patterns for Diabetic Macular Edema: 
Up to 6-Year Follow-up in the IRIS® Registry," Ophthalmol Retina, vol. 8, no. 11, pp. 1074 - 1082, 2024.  
[63]  J. Fernández-Vigo, M. Crespo, C. Beckford, I. Flores-Moreno, R. Cobo-Soriano and J. Pareja, "Expert Panel 
Consensus for Addressing Anti-VEGF Treatment Challenges of Diabetic Macular Edema in Spain," Clin 
Ophthalmol, vol. 16, pp. 3097 - 3106, 2022.  
[64]  M. Xu, R. Fan, X. Fan, Y. Shao and X. Li, "Progress and Challenges of Anti-VEGF Agents and Their Sustained-
Release Strategies for Retinal Angiogenesis," Drug Des Devel Ther, vol. 16, pp. 3241 - 3262, 2022.  
[65]  European Medicine Agency, "ICH guideline E8 (R1) on general considerations for clinical studies," 01 12 2022. 
[Online]. Available: https://www.tga.gov.au/sites/default/files/2024-07/International-Scientific-Guideline-ICH-
guideline-E8-R1-general-considerations-clinical-studies-adopted.PDF. [Accessed 05 02 2025]. 
[66]  European Medicines Agency, "ICH Topic E2A Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting," 06 1995. [Online]. Available: https://www.ema.europa.eu/en/documents/scientific-
guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-
human-use-topic-e-2-clinical-safety-data-management-definitions-and-standards-expedited-reporting-step_e. 
[Accessed 12 02 2025]. 
[67]  J. Scheff, R. Almon, D. Dubois, W. Jusko and I. Androulakis, "Assessment of pharmacologic area under the curve 
when baselines are variable," Pharm Res, vol. 28, no. 5, pp. 1081 - 1089, 2011.  
[68]  N. Webb, "Cmax," in Encyclopedia of Clinical Neuropsychology, New York, Springer, 2011, pp. 606 - 607. 
[69]  N. Webb, "Tmax," in Encyclopedia of Clinical Neuropsychology, New York, Springer, 2011, pp. 2521 - 2522. 
[70]  H. Daiber and D. Gnugnoli, "Visual Acuity," StatPearls, 29 05 2023. [Online]. Available: 
https://www.ncbi.nlm.nih.gov/books/NBK563298/. [Accessed 19 12 2023]. 
[71]  J. Fujimoto and E. Swanson, "The Development, Commercialization, and Impact of Optical Coherence 
Tomography.," Invest Ophthalmol Vis Sci, vol. 57, p. OCT1–13, 2016.  
[72]  Ministry of Health, "Official Mexican Standard NOM-004-SSA3-2012 of the Clinical Record," Mexico City, 2012. 
[73]  Pan American Health Organization, "Heart Rate," vvs Virutal Health Library. 
[74]  J. Ruiz-Sandoval, A. Ochoa-Guzmán, L. Sánchez-Orozco, E. Lara-Zaragoza and N. Basaldúa, "The Quetelet index 
revisited in children and adults," Endocrinology and Nutrition, vol. 61, no. 2, pp. 87-92, 2014.  
[75]  K. Fancher, A. Sacco, R. Gwin, L. Gormley and C. Mitchel, "Comparison of two different formulas for body 
surface area in adults at extremes of height and weight.," J Oncol Pharm Pract., vol. 22, no. 5, pp. 690-695, 
2016.  
[76]  K. d. I. g. o. (. D. w. goup., "KDIGO 2020 Clinical practice guideline for diabetes management in chronic kidney 
disease.," Kidney International., vol. 98, no. 45, pp. S1-S115, October 2020.  
[77]  A. P. Torres Jiménez and J. M. Torres Rincón, "Climacteric and menopause," Revisa de la Facultad de Medicina 
UNAM, vol. 61, no. 2, pp. 51-58, 2018.  
[78]  M. Raul, "Cornea and anterior eye assessment with slit lamp biomicroscopy, specular microscopy, confocal 
microscopy, and ultrasound biomicroscopy," Indian Journal of Ophthalmology, vol. 66, no. 2, pp. 195-201, 2018.  
[79]  J. J. Kanski, Clinical Ophthalmology: A Synopsis, Sixth ed., Elsevier, 2009.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  110 of 110 
[80]  C. Enders, F. Baeuerle, G. Lang, J. Dreyhaupt, G. Lang, M. Loidl and J. Werner, "Comparison between Findings in 
Optical Coherence Tomography Angiography and in Fluorescein Angiography in Patients with Diabetic 
Retinopathy," Ophthalmologica, vol. 243, no. 1, pp. 21 - 26, 2020.  
[81]  M. Jay Chhablani and A. S. MD, "Fluorescein Angiography and Optical Coherence Tomography Correlation in 
Various Retinal Diseases," Retina Today, pp. 77-80, 2014.  
[82]  G. Cennamo, M. Romano, G. Nicoletti, N. Velotti and G. de Crecchio, "Optical coherence tomography 
angiography versus fluorescein angiography in the diagnosis of ischaemic diabetic maculopathy," Acta 
Ophthalmol, vol. 95, no. 1, pp. e36 - e42, 2017.  
[83]  H. Shiihara, H. Terasaki and S. Sonoda, "Objective evaluation of size and shape of superficial foveal avascular 
zone in normal subjects by optical coherence tomography angiography," Sci Rep, vol. 8, no. 10143, pp. 1 - 9, 
2018.  
[84]  E. Greig, J. Duker and N. Waheed, "A practical guide to optical coherence tomography angiography 
interpretation," Int J Retin Vitr, vol. 6, no. 55, pp. 1 - 17, 2020.  
[85]  P. Le, K. Kaur and B. Patel, "Optical Coherence Tomography Angiography," StatPearls National Library of 
Medicine, 01 2025. [Online]. Available: https://www.ncbi.nlm.nih.gov/books/NBK563235/. [Accessed 14 04 
2025]. 
[86]  N. O. Mexicana, NOM-220-SSA1-2016, Facilities and Operations of pharmacovigilance., CDMX: Official Gazette 
of the Federation. , 2017.  
[87]  International Conference on Harmanisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use, "Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2A," ICH 
Harmonised Tripartite Guideline, 1994. 
[88]  International Conference on Harmonisation of Technical Requierements for Registration of Pharmaceuticals for 
Human Use, "General Considerations for Clinical Trials," ICH Topic E8, 1998. 
[89]  International Conference of Harmonisation of Pharmaceutical Products, "Guideline for Good Clinical Practice, 
International Conference on Harmonisation (ICH E6 R2)," International Conference of Harmonisation of 
Pharmaceutical Products, 2016. 
[90]  European Medicines Agency, "ICH guideline E2B (R3) on electronic transmission of individual case safety 
reports," 28 07 2013. [Online]. Available: https://www.ema.europa.eu/en/documents/scientific-
guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-
human-use-guideline-e2b-r3-electronic-transmission-individual-case-safety-reports-icsrs-data-elements_en. 
[Accessed 12 02 2025]. 
[91]  The Uppsala Monitoring Centre, "Drug Safety Surveillance," World Health Organization, 2001. 
[92]  R. H. Meyboom, A. C. Egberts, I. R. Edwards, Y. A. Hekster, F. H. de Koning and F. W. Gribnau, "Principles of 
signal detection in pharmacovigilance," Drug Safety, vol. 16, pp. 355-365, 2997.  
[93]  A. Sinn, F. García-Alvarado, V. González, C. Huerga and F. Bullo, "A randomized, double blind, single dose, 
comparative study of the pharmacokinetics, safety and immunogenicity of MB02 (bevacizumab biosimilar) and 
reference bevacizumab in healthy male volunteers," Br J Clin Pharmacol, vol. 88, no. 3, pp. 1063-1073, 2022.  
[94]  W. Dong, M. Chen, S. Niu, B. Wang, L. Xia, J. Wang and T. Shen, "Ther Pharmacokinetic bioequivalence, safety, 
and immunogenicity of GB222, a bevacizumab biosimilar candidate, and bevacizumab in Chinese healthy males: 
a randomized clinical trial," Expert Opin Biol, vol. 22, no. 2, pp. 253-262, 2022.  
[95]  L. Chen, J. Rangel, T. Cil, X. Li, I. Cicin, Y. Shen and Z. Liu, "Efficacy and safety of the proposed bevacizumab 
biosimilar BAT1706 compared with reference bevacizumab in patients with advanced nonsquamous non-small 
cell lung cancer: A randomized, double-blind, phase III study," Cancer Med, vol. 12, no. 22, pp. 20847-20863, 
2023.  
[96]  D. Trukhin, E. Poddubskaya, Z. Andric, T. Makharadze and R. Bellala, "Efficacy, Safety and Immunogenicity of 
MB02 (Bevacizumab Biosimilar) versus Reference Bevacizumab in Advanced Non-Small Cell Lung Cancer: A 
Randomized, Double-Blind, Phase III Study (STELLA)," BioDrugs, vol. 35, no. 4, pp. 429-444, 2021.  

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  111 of 110 
[97]  Committee for Medicinal Products for Human Use (CHMP), "Assessment report: Lytenava International non-
proprietary name: Bevacizumab gamma.," Procedure No. EMEA/H/C/005723/0000., 2024. 
[98]  S. Sadda, M. Bradvica, A. Vajas, M. Sagong and J. Ernest, "Biosimilar SB15 versus reference aflibercept in 
neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial," BMJ 
Open Ophthalmol, vol. 8, no. 1, 2023.  
[99]  S. Bressler, A. Barve, P. Ganapathi, K. Beckmann, R. Apte and D. Marcus, "Aflibercept Biosimilar MYL-1701P vs 
Reference Aflibercept in Diabetic Macular Edema: The INSIGHT Randomized Clinical Trial," JAMA Ophthalmol, 
vol. 142, no. 1, pp. 952-060, 2024.  
[100] S. Wolf, P. Stanga, M. Veselovsky, M. Veith and A. Papp, "Biosimilar Candidate CT-P42 in Diabetic Macular 
Edema: 24-Week Results from a Randomized, Active-Controlled, Phase III Study," Ophthalmol Retina, vol. 8, no. 
12, pp. 1163-1173, 2024.  
[101] R. Karkhaneh, H. Faghihi, H. Riazi-Esfahani, M. Abrishami and F. Bazvand, "Evaluating the Efficacy and Safety of 
Aflibercept Biosimilar (P041) Compared with Originator Product in Patients with Neovascular Age-Related 
Macular Degeneration," Ophthalmol Retina, vol. 8, no. 8, pp. 744-753, 2024.  
[102] B. Li, K. Fan, T. Zhang, Z. Wu, S. Zeng and M. Zhao, "Efficacy and Safety of Biosimilar QL1207 vs. the Reference 
Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial," 
Ophthalmol Ther, vol. 13, no. 1, pp. 353-366, 2024.  
[103] A. Bordon, P. Kaiser, A. Wolf, L. Cen and J. Heyn, "EFFICACY AND SAFETY OF THE PROPOSED BIOSIMILAR 
AFLIBERCEPT, SDZ-AFL, IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52-Week 
Results From the Phase 3 Mylight Study," Retina, vol. 1, no. 44, pp. 1704-1713, 2024.  
[104] M. Hyeong and J. Se, "Immunogenicity and Potential for Intraocular Inflammation of Intravitreal Anti-VEGF 
Drugs," Curr Ther Res Clin Exp., vol. 14, no. 100, 2024.  
[105] I. C. f. H. (ICH), "Guidance for industry E9. Statistical principle for clinical trials.," 1998. 
[106] F. A. D. A. (FDA), "U.S Food and Grug Administration," 2018. [Online]. Available: 
https://www.fda.gov/patients/drug-development-process/step-3-clinical-research. 
[107] D. J. Muglia JJ, "Phase 1 Clinical Trials.," Journal of Cutaneous Medicine and Surgery., vol. 2, no. 4, pp. 236-241, 
1998.  
[108] The Association of the British Pharmaceutical Industry, "Guidelines for Phase I clinical trials," ABPI, 2018. 
[109] W. R. Fisher JA, "Advancing Ethics and Policy for Healthy-Volunteer Research through a Model-Organism 
Framework.," Ethics Hum Res., vol. 41, no. 1, pp. 4-14, 2019.  
[110] B. Krishnankutty, S. Bellary, N. Kumar and L. .. Mooddahadu, "Data management in clinical research: an 
overview.," Indian J Pharmacol, vol. 44, no. 2, pp. 168-72, 2012.  
[111] Z. Lu, "Clinical data management: Current status, challenges, and future directions from industry perspectives," 
Open Access Journal of Clinical Trials, vol. 2, pp. 93 - 105, 2010.  
[112] E. Editorial, "Declaration of Helsinki of the World Medical Association," Arbor, vol. 184, no. 730, pp. 349 - 352, 
2008.  
[113] K. Brandt, "Complete transcript of the Nuremberg Medical Trial: United States (Case 1)," National Archives, 
Washington, DC, 1947. 
[114] Department of Health, Education, and Welfare, & National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research, "The Belmont Report. Ethical principles and guidelines for the protection 
of human subjects of research," The Journal of the American College of Dentists, vol. 81, no. 3, pp. 4 - 13, 2014.  
[115] Council for International Organizations of Medical Sciences (CIOMS), "International Ethical Guidelines for 
Health-related Research Involving Humans, Fourth Edition," Council for International Organizations of Medical 
Sciences (CIOMS), Geneva, 2016. 
[116] Official Gazette of the Federation, "Regulation of the General Health Law on Health Research," DOF, 2014. 
 

Laboratorios Sophia, S.A. de C.V.  
 
Study No: SOPH169-1224/I 
 
 
  Version 4.0 
 
 
Nov 4-25 
 
C O N F I D E N C I A L 
 
 
   Page  112 of 110 
16. Annexes 
16.1 ETDRS Booklet  
 
The above annex is a representation of the ETDRS booklet, it is possible that the booklet designated for the 
study has variations in format and translation.