A Non-inferiority in the Intraocular Pressure Decrease of the Preservative-free Ophthalmic Solution PRO-122 Versus Concomitant Therapy in Subjects With Uncontrolled Primary Open-angle Glaucoma
Phase: PHASE3
Conditions: Primary Open-angle Glaucoma
Sponsor: Laboratorios Sophia S.A de C.V.

 
 
Creation date: march 2016 
A phase III clinical study, to evaluate the non-
inferiority in the intraocular pressure decrease of 
the preservative-free ophthalmic solution PRO-
122, manufactured by Laboratorios Sophia S.A. 
de C.V., versus concomitant therapy in subjects 
with uncontrolled primary open-angle glaucoma 
and/or intraocular hypertension 
Protocol code: SOPH122-0316/III 
Protocol version: 2.0 
Version date: 25/01/2017 
Register: Pending 
Sponsor: Laboratorios Sophia, S.A. de C.V.  

 
 
 

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1. Overview 
Title of the study:  
A phase III clinical study, to evaluate the non-inferiority in the intraocular pressure decrease of the 
preservative-free ophthalmic solution PRO-122, manufactured by Laboratorios Sophia S.A. de 
C.V., versus concomitant therapy in subjects with uncontrolled primary open-angle glaucoma 
and/or intraocular hypertension 
Protocol code: SOPH122-0316/III 
Creation date: 03/30/2016 
Protocol version: 2.0 
Version date: 25/01/2017 
Therapeutic indication: 
Ocular hypotensive 
Study period:  
9 months 
Clinical study phase:  
III 
Objectives: 
To evaluate the non-inferiority in the intraocular pressure decrease of the preservative-free 
ophthalmic solution PRO-122, manufactured by Laboratorios Sophia S.A. de C.V., versus 
concomitant therapy in subjects with uncontrolled POAG and/or IOP. 
Hypothesis: 
The mean (average) value of the IOP final absolute reduction in the experimental group (PRO-
122) is not lower, considering a lower limit of 1 mmHg, compared to the IOP mean absolute 
reduction of the standard group (concomitant therapy). 
Methodology: 
A non-inferiority, phase III, double-blind, randomized, controlled, parallel, clinical trial 
Number of patients: 
51 subjects divided into 3 groups (17 subjects per group) 
Diagnosis and main inclusion criterion: 
Diagnosis: Primary open-angle glaucoma or ocular hypertension 
Main criteria: 
- 
Patients of either sex 
- 
Average intraocular pressure (IOP) ≤ 36 mm/Hg 
- 
Previous management with ocular hypotensive medications ≥ 2 months, without achieving 
control (target IOP) 
- 
Age ≥ 18 years 
- 
Informed consent 
Test product, dosage and route of administration: 
- 
PRO-122. Preservative-free ophthalmic solution of timolol 0.5% / brimonidine 0.2% / 
dorzolamide 2% Manufactured by Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, 
Mexico. + Placebo + Placebo 
- 
Dosage: 1 drop every 12 hours 
- 
Route of administration: ophthalmic 
Treatment duration: 
90 days 
 
 

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Reference product, dosage and route of administration: 
1. Krytantek Ofteno®. Timolol 0.5% / brimonidine 0.2% / dorzolamide 2% ophthalmic solution. 
Manufactured by Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, Mexico. + Placebo 
+ Placebo 
a. Dosage: 1 drop every 12 hours 
b. Route of administration: ophthalmic 
2. Concomitant triple therapy. Imot, timolol 0.5% ophthalmic solution, manufactured by 
Laboratorios Sophia, S.A. de C.V. + Alphagan, brimonidine 0.2% ophthalmic solution, 
manufactured by Allergan, Inc. + Trusopt dorzolamide 2% manufactured by Merck Sharp 
& Dohme Corp. 
a. Dosage: 1 drop every 12 hours 
b. Route of administration: ophthalmic 
Evaluation criteria: 
Efficiency (non-inferiority): 
- 
IOP decrease 
Safety: 
- 
Best corrected visual acuity 
- 
Cup-to-disc ratio  
- 
Visual fields determined by computerized perimetry 
- 
Central corneal thickness determined by pachymetry 
- 
Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining  
- 
Density of goblet cells 
- 
Adverse events 
Tolerability: 
- 
Ocular comfort index 
Statistical methodology: 
The data will be expressed with measures of central tendency: mean and standard deviation for 
quantitative variables. The qualitative variables will be presented in frequencies and percentages. 
Statistical analysis will be done by means of a Kruskal-Wallis test for quantitative variables. The 
difference between qualitative variables will be analyzed using an 2 (Chi2). An alpha ≤ 0.05 would 
be considered as significant. 
 
 
 
 
 
 

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2. Contents 
Contenido 
1. OVERVIEW ........................................................................................................................ 2 
2. CONTENTS ........................................................................................................................ 4 
3. LIST OF ABBREVIATIONS ............................................................................................... 8 
4. ADMINISTRATIVE STRUCTURE OF THE STUDY ......................................................... 9 
5. INTRODUCTION .............................................................................................................. 12 
5.1 THEORETICAL FRAMEWORK.............................................................................................. 12 
5.2 PROBLEM DEFINITION AND RATIONALE ............................................................................. 13 
5.3 BACKGROUND .................................................................................................................. 13 
5.3.1 EFFICACY ................................................................................................................................ 13 
5.3.2 SAFETY .................................................................................................................................... 14 
5.3.3 PRESERVATIVE USE IN OCULAR HYPOTENSIVE MEDICATIONS ............................................. 20 
5.4 JUSTIFICATION ................................................................................................................. 21 
5.5 OBJECTIVES AND HYPOTHESIS ......................................................................................... 21 
5.5.1 GENERAL OBJECTIVE .............................................................................................................. 21 
5.5.2. SPECIFIC OBJECTIVES ........................................................................................................... 21 
5.5.3 HYPOTHESIS ........................................................................................................................... 21 
5.6 STUDY PLAN AND DESIGN ................................................................................................. 22 
5.6.1 DISCUSSION OF THE STUDY DESIGN ...................................................................................... 22 
6. MATERIAL AND METHODS. PARTICIPANTS, INTERVENTIONS AND VARIABLES23 
6.1 STUDY CENTER ................................................................................................................ 23 
6.1.2 CENTER ORGANIZATION ......................................................................................................... 23 
6.1.3 DOCUMENTATION TO BE DELIVERED TO THE SPONSOR ....................................................... 24 
6.1.3 CENTER CLOSURE .................................................................................................................. 24 
6.2 ELEGIBILITY CRITERIA ...................................................................................................... 24 
6.2.1 INCLUSION CRITERIA ............................................................................................................... 24 
6.2.2 EXCLUSION CRITERIA ............................................................................................................. 24 
6.2.3 ELIMINATION CRITERIA ........................................................................................................... 25 
6.2.4 SUBJECT IDENTIFICATION ....................................................................................................... 26 
6.3 INTERVENTION .................................................................................................................. 26 
6.3.1 GIVEN TREATMENTS ............................................................................................................... 26 
6.3.2 STRATEGIES TO IMPROVE THE ADHERENCE AND PROCEDURE FOR MONITORING THE 
ADHERENCE ...................................................................................................................................... 28 
6.3.3 ALLOWED AND PROHIBITED CONCOMITANT TREATMENTS AND INTERVENTIONS BEFORE 
AND AFTER THE STUDY ..................................................................................................................... 29 

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6.3.4 TREATMENT MANAGEMENT .................................................................................................... 30 
6.4 OUTCOME VARIABLES ...................................................................................................... 31 
6.4.1 SAFETY VARIABLES ................................................................................................................. 31 
6.4.2 EFFICACY VARIABLES ............................................................................................................. 32 
6.4.3 METHODS AND GRADINGS TO BE USED IN THE MEASUREMENT OF VARIABLES ................... 32 
6.4.4 MEASUREMENTS BY STAGE .................................................................................................... 35 
6.5 CHRONOGRAM AND STUDY DIAGRAM ................................................................................ 37 
6.5.2 PROCEDURES TO FOLLOW IN EACH VISIT .............................................................................. 38 
6.5.3 STUDY DIAGRAM ..................................................................................................................... 41 
6.6 SAMPLE SIZE .................................................................................................................... 41 
6.6.1 SAMPLE SIZE CALCULATION ................................................................................................... 41 
6.7 RECRUITMENT .................................................................................................................. 42 
7. METHODS. INTERVENTION ASSIGNMENT ................................................................. 42 
7.1 ASSIGNMENT SEQUENCE GENERATION ............................................................................. 42 
7.2 BLINDING MECHANISM ...................................................................................................... 42 
7.3 IMPLEMENTATION ............................................................................................................. 43 
7.4 BLINDING (MASKING) ....................................................................................................... 43 
7.4.1 BLINDING OPENING ................................................................................................................. 43 
8. METHODS. COLLECTION, ADMINISTRATION AND DATA ANALYSIS. ................... 43 
8.1 DATA RECOLLECTION METHODS ....................................................................................... 43 
8.1.1 FOLLOW-UP COMPLETION STRATEGIES ................................................................................. 44 
8.2 DATA ADMINISTRATION ..................................................................................................... 44 
8.3 STATISTICAL METHODOLOGY ............................................................................................ 44 
8.3.1 PRIMARY AND SECONDARY OUTCOME VARIABLES ................................................................ 44 
8.3.2 ADDITIONAL ANALYSIS ............................................................................................................ 45 
8.3.3 POPULATION ANALYSIS AND MISSING DATA MANAGEMENT .................................................. 45 
9. METHODS. MONITORING .............................................................................................. 46 
9.1 MONITOREO DE DATOS ..................................................................................................... 46 
9.2 PRELIMINARY ANALYSIS AND EARLY STUDY TERMINATION ................................................ 47 
9.3 ADVERSE EVENTS ............................................................................................................ 47 
9.3.1 INVESTIGATOR RESPONSIBILITIES .......................................................................................... 47 
9.3.2 RESPONSABILITIES OF THE SPONSOR ................................................................................... 52 
9.4 AUDIT ............................................................................................................................... 52 
9.4.1 STUDY PRE-AUDIT ................................................................................................................... 52 
9.4.2 AUDIT/INSPECTION DURING THE CONDUCT OF THE TRIAL .................................................... 52 
10. ETHICAL CONSIDERATIONS ...................................................................................... 52 
10.1 APPROVAL OF THE COMMITEES ...................................................................................... 52 

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10.2 AMENDMENTS TO PROTOCOL ......................................................................................... 53 
10.3 CONSENT ....................................................................................................................... 54 
10.3.1 OBTAINING ............................................................................................................................ 54 
10.3.2 SPECIAL CONSIDERATIONS .................................................................................................. 54 
10.3.3 MODIFICATION TO THE INFORMED CONSENT ...................................................................... 54 
10.4 CONFIDENTIALITY ........................................................................................................... 55 
10.5 DECLARATION OF INTERESTS ......................................................................................... 55 
10.6 ACCESS TO INFORMATION .............................................................................................. 55 
10.7 AUXILIARY AND POST-STUDY-TERMINATION CARES ........................................................ 55 
10.8 BIOSAFETY ASPECTS...................................................................................................... 55 
10.9 FINAL REPORT AND RESULT PUBLICATION ...................................................................... 56 
10.9.1. FINAL REPORT ..................................................................................................................... 56 
10.9.2 DISCLOSURE OF RESULTS .................................................................................................... 56 
10.9.3 PUBLICATION OF RESULTS ................................................................................................... 56 
11. REFERENCES ............................................................................................................... 57 
12. SIGNATURE PAGE ....................................................................................................... 64 
13. ANNEXES ...................................................................................................................... 65 
13.1 OCULAR COMFORT INDEX ............................................................................................... 66 
13.2 EFRON SCALE FOR CONJUNCTIVAL HYPEREMIA .............................................................. 68 
13.3 OXFORD SCALE .............................................................................................................. 68 
 
 
List of tables and figures 
Table 1. Administrative structure .................................................................................................... 10 
Table 2. Adverse events in the study by Konstas ............................................................................ 16 
Table 3. Adverse events in the study by Realini .............................................................................. 18 
Table 4. Adverse events in the study by Baiza 2009 ....................................................................... 18 
Table 5. Adverse events in the study by Baiza 2012 ....................................................................... 19 
Table 6. Adverse events in the study by García............................................................................... 20 
Table 7. PRO-122 qualitative and quantitative formulation ........................................................... 27 
Table 8. Qualitative/quantitative formulation of Krytantek Ofteno® ............................................ 28 
Table 9. Washout Period .................................................................................................................. 30 
Table 10. Method for the measurement of variables ..................................................................... 32 
Table 11. Study Chronogram ............................................................................................................ 38 
Table 12.  Karch and Lasagna’s algorithm modified by Naranjo ..................................................... 51 
 
Figure 1. Study design ...................................................................................................................... 22 
Figure 2. Minimal organization of the Center ................................................................................. 23 
Figure 3. Impression cytology .......................................................................................................... 34 
Figure 4. Study diagram .................................................................................................................... 41 
Figure 5. Attention to the adverse event ........................................................................................ 49 

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3. List of abbreviations 
 
AA 
 
 
Alpha-adrenergic agonist 
AE / SAE 
 
Adverse event / Serious adverse event 
BAK 
 
 
Benzalkonium chloride 
BB 
 
 
Beta-blocker 
BCVA  
 
Best corrected visual acuity  
BID 
 
 
Twice a day 
CAIs 
Carbonic anhydrase inhibitors 
CCT 
Central corneal thickness 
 
CRF 
 
 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
 
 
Good clinical practice 
IC 
 
 
Informed consent 
ICH 
International Conference on Harmonization 
ICL 
 
 
Informed consent letter 
IOH 
Intraocular hypertension 
IOP 
 
 
Intraocular pressure 
MAO 
 
 
Monoamine oxidase 
MD 
 
 
Mean deviation 
MTMT 
Maximal tolerated medical therapy 
OCI 
Ocular comfort index 
PGA 
 
 
Prostaglandin analogue 
PI 
 
 
Principal investigator of the clinical study 
POAG 
Primary open-angle glaucoma 
QD 
Once a day 
REC 
 
 
Research Ethics Committee 
SDM 
 
 
Standard deviation of the model 
SDV 
Source document verification 
TID 
Three times a day 
 
 

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

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5. Introduction 
5.1 Theoretical framework 
Glaucoma is a progressive optic neuropathy characterized by the loss of retinal ganglion cells and its 
axons, which results in a distinctive optic disc appearance and a concomitant loss of the visual 
function. [1] It is the second cause of blindness worldwide and, it is estimated that by 2020, 79.6 
millions of people will have glaucoma, of which 74% will have primary open-angle glaucoma (POAG). 
[2] The Latin American population, especially those of Mexican origin, are more likely to develop 
POAG compared to white population. [3] [4] 
The mechanism by which the glaucoma damages the optic nerve is probably multifactorial; however, 
high intraocular pressure (IOP) is the main risk factor and the only one that can currently be modified 
to prevent the damage progression by glaucoma, including normotensive glaucoma [5] [6] [7] [8] [9]. 
It has also be shown that IOP reduction decreases the conversion index of ocular hypertension (OH) 
to glaucoma.[7] Chauhan et al. have reported that for each 1 mmHg increase in the IOP, the risk of 
glaucoma progression increases in a 19%. [5] 
Despite the great advances in the filtering surgical treatments, implants and laser procedures that 
improve the trabecular drainage, the pharmacological therapy remains as the initial intervention for 
most of patients with OH and glaucoma; this treatment typically includes the topical application of 
antihypertensive agents. [10] 
At present, pharmacological options for the IOP reduction with topical application include 
prostaglandin analogues (PA), beta-blockers (BB), alpha-adrenergic agonist (AA), carbonic 
anhydrase inhibitors (CAIs) and parasympathomimetic drugs. Commonly, pharmacotherapy starts 
with a single-agent hypotensive application, generally of those referred as first-line drugs 
(prostaglandin analogues or beta-blockers). [11] [8]However, monotherapy can be insufficient in 
many cases, due to its inability to reach the target IOP and/or prevent glaucoma progression. In some 
other cases, a single drug can lose its effectiveness through time, due to Tachyphylaxis. The 5-year 
Ocular Hypertensive Treatment Study reported that about 40% of patients require two drugs to 
achieve an IOP reduction of 20% compared to baseline IOP, while an additional 9% needs more than 
two drugs. [7] [5] Thus, more than one drug is often required to control properly the IOP in the medium 
and long term. This can be achieved by the concurrent use of two or more drugs of different classes, 
either through its concomitant application or in a fixed combination. [12] 
In addition to the efficiency to reduce the IOP, fixed combination offer multiple benefits when 
compared to the concomitant application of its active principles: [13] 1) a lower cost, 2) a simpler 
treatment regimen, 3) better adherence to treatment, and 4) decreasing of washout risk. [14] [15] 
Nevertheless, few studies have compared directly the adherence to fixed combinations versus the 
concomitant use of its active principles, but there is evidence that adherence to glaucoma treatment 
is better when the regimen is simpler.[16] [17]  
The theoretical support of drugs washout is based on the physiological function of the lacrimal 
apparatus. The tear film has an approximate volume of 8 to 10 µl and the lacrimal flow index is of 0.5 
to 2.2 µl/min, which means that, in general, a replacement of the total volume of the tear film can be 
made every 10 minutes in average. Eye drops volume is between 25 and 50 µl, a volume that exceeds 
the capacity of contention that the ocular surface has, so that the excess is quickly drained by 
nasolacrimal duct or spilled at flickering. [18] 
Fixed combinations also offer a risk decrease of corneal damage and ocular surface, related to the 
cumulative exposure of preservatives. For example, chronic exposure to benzalkonium chloride 

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(BAK), used in a large quantity of ophthalmic drugs, has been associated with inflammation, corneal 
and conjunctival damage, tear film disorders and symptomatology of ocular surface disease. [19] [20] 
[21] 
Currently, available fixed combinations include a timolol BB 0.5% combined with a drug from other 
therapeutic families, a PGA, an AA or a topical CAI [22] In Mexico and other South American 
countries, a triple fixed-dose combination therapy also exists, which includes timolol, brimonidine and 
dorzolamide. 
5.2 Problem definition and rationale 
For the OH and POAG treatment, the use of a single drug may result insufficient when trying to 
achieve the target IOP, and must therefore rely on a use of 2 or more ocular hypotensive of different 
families.  
In a simplified scheme for glaucoma treatment, it is proposed to start with monotherapy, based on a 
first-line drug like a PGA or BB, where the PGA is predominantly chosen by the ophthalmologists, 
nowadays. If this first therapy is not sufficient but responsive, a second drug is added, preferably 
another not-previously used first-line drug. In this intermediate therapy, the patient would be already 
receiving 3 to 4 instillations daily by, in theory, engaging its adherence to the treatment and exposing 
the patient to a higher cumulative dose of BAK. So that the attending physician may decide to change 
it to a fixed combination of two drugs. If the target IOP is not achieved, a third drug can be added to 
reach the maximal tolerated medical therapy (MTMT) stipulated by Zimmerman of 3 drugs in 3 daily 
instillations. [23] 
As it has been already established, the use of fixed combinations offers benefits over the concomitant 
application of its components. To our knowledge, there are no reports about the evaluation of a triple 
fixed-dose combination therapy versus the concomitant application of its components. The triple 
fixed-dose combination therapy can increase treatment adherence with MTMT and extend the 
horizon toward the new MTMT plan proposed by Sampaolesi, which includes the triple fixed-dose 
combination therapy + a PGA. [23] 
5.3 Background 
5.3.1 Efficacy 
The effectiveness of fixed combinations has been evaluated to obtain their regulatory approval. To 
get the US Food and Drug Administration (FDA) approval of a fixed combination, this must have a 
greater efficiency than the one of each of its components used as monotherapy. In addition, it must 
be as effective as its components, concomitantly administered. [14] 
5.3.1.1 Timolol-Dorzolamide fixed combination 
Two independent, randomized and double blind studies compared the fixed combination of timolol 
0.5% / dorzolamide 2% versus a monotherapy with it components. Boyle’s study was conducted with 
355 patients prior to drug washout. The study by Cineschmidt was carried out with 253 patients after 
the 3-week run-in of timolol. Posology for the fixed combination and timolol was BID and TID, for 
dorzolamide. The treatment time was of 3 months. Both authors concluded that the fixed combination 
was more effective in controlling IOP that monotherapy with any of the components. [24] [25] 
Other studies have compared the fixed combination versus concomitant application of timolol-
dorzolamide. Hutzelmann conducted a randomized, double blind, 3-month study with 299 patients 
and a run in period of 2 weeks with timolol. The posology was BID for both arms. Based on the 

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averages of months 2 and 3, the fixed and concomitant combinations were equivalent regarding the 
hypotensive effect, with an intergroup difference of IOP average of <0.1 mmHg. [26] 
In contrast, Strohmaier reported in his study (n = 242 patients) that the fixed combination was 
approximately 1 mmHg less effective than the concomitant combination. [27] 
5.3.1.2 Timolol-Brimonidine fixed combination 
In a double-blind, randomized, 12-month study with 1159 patients with glaucoma or OH, the fixed 
combination of timolol 0.5% / brimonidine 0.2% was compared against the monotherapy of its 
components. Throughout the study, the fixed combination was better than monotherapy. [28] 
Goni reported that fixed combination was as effective as the concomitant therapy with an intergroup 
difference of ≤ 0.30 mmHg. The study was conducted with 371 patients for 12 weeks. [14] [29] 
5.3.1.3 Timolol-Brimonidine-Dorzolamide fixed combination 
The triple fixed-dose combination has been evaluated in several studies and has been compared 
versus double fixed-dose combinations. A randomized, double-blind study with 112 patients 
compared the BID application for 180 days of triple fixed-dose combination therapy versus fixed 
timolol 0.5% / dorzolamide 2% combination. The triple combination was superior with a 3.4 mmHg 
difference in the IOP average of month 3. [30] 
Another study compared the triple fixed-dose combination versus the fixed combination of timolol 
0.5% / brimonidine 0.2%. It was a double blind, randomized study in patients with glaucoma and/or 
ocular hypertension, with a BID application for 3 months. The triple combination was better with a 
2.16 mmHg difference in the IOP average of month 3 at the 8:00-hour revision. [31] 
Currently, there is no information about the comparison of the triple fixed-dose combination with the 
concomitant application of its three components. 
5.3.2 Safety 
5.3.2.1 Phase IV clinical studies reports 
In the study of Babic N et al., the safety profile of fixed combinations fixed of travoprost / timolol and 
dorzolamide / timolol was assessed in 60 subjects (divided into 2 intervention groups, n = 30 subjects 
per group) with POAG or OH, who received 1 drop of QD and 1 drop of BID, respectively, for 3 
months. Results: Four subjects were removed from the dorzolamide / timolol group due to a lack of 
complete data. No serious adverse events were recorded during the intervention period with the study 
drugs. Non-serious adverse events reported in the group exposed to travaprost / timolol (n = 30) 
were: hyperemia, blurred vision and pruritus. Hyperemia occurred in 50% of the participants, and  
blurred vision and pruritus occurred in a 6.7%. No subject of study reported eye dry or foreign body 
sensation. No abnormalities were either notified regarding taste perception. 
In the group exposed to dorzolamide/timolol (n = 26), the most frequent adverse event was dry eye 
sensation, which affected 30.8% of the participants and the sensation of foreign body affected 23.1%. 
No subject reported hyperemia. A 3.8% of the patients presented dysgeusia.  
In addition, no patient presented changes in iris pigmentation, changes in eyelashes, cystoid macular 
edema nor systemic disorders, which may affect the cardiovascular or respiratory system. 
Furthermore, nobody suspended the study drug, nor were they affected in their daily activities due to 
an adverse event. Therefore, both drugs were safe and well tolerated by the study patient population. 
[32] 

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In another 2-period, 2-sequence, crossover clinical trial conducted by the research team of Konstas 
A. et al., the safety and tolerability profile of 2 ophthalmic formulations in a fixed combination of 
dorzolamide/timolol and brimonidine/timolol were evaluated. These formulations were given to 
patients with mild to moderate primary open-angle glaucoma or recently diagnosed ocular 
hypertension, who have not previously received any therapy, for 60 days. In this study, 77 patients 
were selected in the screening stage. Seven of these were excluded (4 decided not to participate and 
3 did not complete the inclusion criteria). Seventy subjects started the adherence-assessment period 
by the administration of timolol0.5%, 5 from which were withdrawn (3 due to intraocular hypertension 
< 18 mmHg, and 2 due to an IOP reduction of < 20%). Sixty five subjects in total were randomized 
into 2 groups to receive fixed therapies. Period 1: in the dorzolamide / timolol group, 32 patients 
entered and in the brimonidine / timolol group, 33 patients entered. Five subjects were withdrawn due 
to adverse events: Two subjects did not tolerate the investigational medicinal product of 
dorzolamide/timolol and, for the group that received brimonidine/timolol, 1 patient presented 
hypotension and 2 patients tolerated the investigational medicinal product. In the second period, 30 
subjects completed the evaluation in each intervention group.  
Results: No drug-related serious adverse events were investigated during the entire period of study 
(see Table 2 Adverse events in the study by Konstas). In the group that received 
dorzolamide/timolol, 18.3% of the patients presented bitter taste, 16.7% of patients presented 
fluorescein staining in the ocular surface and 5% referred a conjunctival hyperemia.  
From the group of patients receiving brimonidine/timolol, 16.7% had conjunctival hyperemia.  
In the general analysis, both study drugs were well tolerated by the participating patients. The ocular 
adverse events reported were of a mild intensity and similar in both study groups, except for 
hyperemia which was higher in the group with brimonidine/timolol, and regarding staining and 
changes in taste that were higher in the individuals exposed to dorzolamide / timolol. [33] 
In the analysis of 2 phase III clinical trials developed by Realini T et al., the safety profile of the fixed 
combined formulation of brinzolamide 1% / brimonidine 0.2% versus monotherapies with 
brinzolamide 1% and brimonidine 0.2% was evaluated in subjects with primary open-angle glaucoma 
or ocular hypertension. Such therapies were administered in the affected eye TID for 3 months.  
Results: In the study, 1350 patients were enrolled, who were randomize in 3 study groups: the group 
exposed to brimonidine had 452 patients, the group with brinzolamide had 458 patients and the group 
with a fixed-dose combined therapy had 433 patients. In the brimonidine group, 60 patients were 
withdrawn from the study: 35 due to adverse events, 8 due to voluntary withdrawal, 1 due to lack of 
follow-up, 1 due to an investigation protocol violation and 15 subjects due to an inappropriate control 
of IOP. In the brinzolamide group, 15 subjects were withdrawn from the analysis due to an adverse 
event, 3 due to a voluntary withdrawal, 3 due to an investigation protocol violation and 8 due to an 
inappropriate control of IOP. From the group with a fixed-dose combined therapy, 40 patients were 
withdrawn due to an adverse event, 4 due to a voluntary withdrawal, 1 due to lack of follow-up, 2 due 
to non-compliance to the posology, 3 due to an investigation protocol violation and 2 due to an 
inappropriate control of intraocular pressure. 
 
 

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Adverse event 
Dorzolamide/timolol 
N (%) 
Brimonidine/timolol 
N (%) 
P 
Non-ocular  
Bitter taste 
11 (18.3) 
0 (0) 
0.001 
Systemic 
hypotension 
0 (0) 
4 (6.7) 
0.125 
Dry mouth 
0 (0) 
4 (6.7) 
0.125 
Fatigue 
1 (1.7) 
3 (5.0) 
0.625 
Headache 
0 (0) 
1 (1.7) 
1.000 
Dizziness 
0 (0) 
1 (1.7) 
1.000 
Somnolence 
0 (0) 
1 (1.7) 
1.000 
Ocular 
Stainings 
10 (16.7) 
1 (1.7) 
0.012 
Conjunctival 
hyperemia 
3 (5.0) 
10 (16.7) 
0.039 
Pruritus 
1 (1.7) 
7 (11.7) 
0.070 
Lacrimation 
1 (1.7) 
2 (3.3) 
1.000 
Keratitis punctata 
1 (1.7) 
0 (0) 
1.000 
Foreign 
body 
sensation 
0(0) 
3 (5.0) 
0.250 
Dry eye sensation 
1 (1.7) 
3 (5.0) 
0.625 
Secretion 
0 (0) 
1 (1.7) 
1.000 
Palpebral edema 
1 (1.7) 
0 (0) 
1.000 
Burning 
4 (6.7) 
0 (0) 
0.125 
Adverse events reported with the use of fixed-dose combination therapies in participating patients. Note: 
Several patients experienced multiple adverse events. Abbreviations: p = statistical value 
Table 2. Adverse events in the study by Konstas 
A total of 272 patients experienced at least one adverse event (mostly ocular) associated to the 
investigational product (see table Table 3. Adverse events in the study by Realini): 107 (24.6%) 
subjects in the brimonidine/brinzolamide group, 86 (18.7%) of the brinzolamide group and 79 (17.4%) 
patients in the brimonidine group. Twenty patients presented 29 serious adverse events, 1 of which 
was related to the investigational drug, according to the investigator judgement; it was precordial pain 
of moderate intensity in a subject from the brinzolamide group, which resulted in the withdrawal of 
the patient and the clinical follow-up after the clinical picture remission.  
Patients exposed to brinzolamide had a higher incidence of blurry vision (5.3 to 6.5%), and dysgeusia 
(3.9 to 8.3%) compared with the brimonidine group (0.2% in both studies). Patients receiving 
brimonidine showed higher incidence of ocular hyperemia (2.1 to 3.3%), dry mouth (2.4 to 3.0%), and 
ocular allergy (1.1 to 2.5%) compared to the group exposed to brinzolamide (0.7, 0, and 0% 

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respectively). Seven of the adverse events associated with the investigational product were severe, 
in 3 it was necessary to suspend the investigational product administration, group 
brimonidine/brinzolamide: allergic conjunctivitis, fatigue, blurry vision. Brinzolamide group: 2 cases of 
blurry vision. Brimonidine group: 1 case of eye allergy and atopic dermatitis.  
Overall, 87 patients were removed from the study due to investigational products-related adverse 
events: 43 (9.9%) patients in the combination therapy group, 10 (2.2%) patients in the brinzolamide 
group (2.2%) and 34 (7.5%) subjects of brimonidine group. As can be seen, the incidence of 
investigational product-related adverse events was slightly greater in the group exposed to 
combination therapy that in those patients who received brinzolamide or brimonidine as 
monotherapy.[34] 
Baiza L et al., conducted a study which evaluated the safety profile of timolol 0.5%/dorzolamide 
2%/brimonidine ophthalmic solution versus timolol/dorzolamide ophthalmic solution in patients with 
primary open-angle glaucoma or intraocular hypertension receiving 1 drop BID of investigational 
product and drug comparator for 6 months.  
Results: the study involved 112 patients divided into 2 groups of study, 56 subjects per 
pharmacological intervention. In terms of the safety profile: there were no significant differences in 
visual acuity, hyperemia, stains, visual fields, symptomatology (eye pain, burning, foreign body 
sensation 
and 
photophobia) 
between 
the 
study 
groups. 
Group 
exposed 
to 
dorzolamide/timolol/brimonidine: 2/56 (3.5%) subjects reported at least 1 adverse event. In the group 
receiving timolol/dorzolamide 6/56 subjects showed at least 1 adverse event. None of the events led 
to the withdrawal of any patient. The investigational group concluded that both the investigational 
product and the drug comparator were safe and well tolerated. A better safety profile was seen with 
the triple combination. (¡Error! No se encuentra el origen de la referencia.) [35] 
In another study conducted by the research team of Baiza L, et al it was determined the safety profile 
of the fixed combination therapy in ophthalmic solution, consisting of 0.5%/brimonidine 
0.02%/dorzolamide 2% versus one solution composed of timolol 0.5%/brimonidine 0.2% in patients 
with primary open-angle glaucoma and/or ocular hypertension who were divided into 2 study groups, 
which received 1 drop of the drug comparator or investigational product BID during 3 months. Results: 
112 subjects participated, 56 patients per group. During the development of the study any participant 
presented some serious adverse event. From all participants, only 8 expressed having presented at 
least 1 non-serious adverse event.  6 subjects were removed from the study due to the development 
of adverse events. 2 people with ocular burning, one with light intensity and another one with 
moderate intensity, severe itching in one subject, foreign body sensation of slight intensity in one 
participant, red eye of severe intensity in another patient, severe dizziness in another patient, mild 
headache in other participant and bradycardia of mild intensity in one more. 
 
 
 
 
 
 

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Adverse event 
Brimonidine/brinzolamide 
N = 435 
n (%) 
Brinzolamide: 
N = 460 
n (%) 
Brimonidine: 
N = 455 
n (%) 
Ocular  
 
 
 
Blurry vision. 
23 (5.3%) 
30 (6.5%) 
1 (0.2%) 
Eye irritation  
18 (4.1%) 
6 (1.3%) 
10 (2.2%) 
Eye allergy 
11 (2.5%) 
0 (0%) 
5 (1.1%) 
Ocular 
hyperemia 
9 (2.1%) 
3 (0.7%) 
15 (3.3%) 
Eye pain 
9 (2.1%) 
8 (1.7%) 
5 (1.1%) 
Allergic 
conjunctivitis 
8 (1.8%) 
2 (0.4%) 
7 (1.5%) 
Eye pruritus 
7 (1.6%) 
5 (1.1%) 
3 (0.7%) 
Conjunctival 
hyperemia 
7 (1.6%) 
5 (1.1%) 
5 (1.1%) 
Dry eye 
6 (1.4%) 
4 (0.9%) 
7 (1.5%) 
Conjunctivitis 
6 (1.4%) 
1 (0.2%) 
8 (1.8%) 
Foreign 
body 
sensation 
5 (1.1%) 
3 (0.7%) 
2 (0.4%) 
Non-ocular  
 
 
 
Dysgeusia 
17 (3.9%) 
38 (8.3%) 
1 (0.2%) 
Dry mouth 
13 (3.0%) 
0 (0%) 
11 (2.4%) 
Fatigue 
3 (0.7%) 
0 (0%) 
6 (1.3%) 
Table 3. Adverse events in the study by Realini 
 
Adverse event 
Brimonidine/timolol/dorzolamide 
group 
N = 56 
Group 
dorzolamide/timolol 
N = 56 
Eye pain 
1 
- 
Eye pain and burning 
1 
- 
Eye pain and headache 
- 
1 
Keratitis and eye pain 
- 
2 
Keratitis and chemosis 
- 
1 
Keratitis and burning 
- 
1 
Burning 
- 
1 
Subjects who reported at least 1 adverse event during their participation in the study.  
Table 4. Adverse events in the study by Baiza 2009 
 

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Adverse event 
Brimonidine/timolol/dorzolamide 
group 
N = 56 
Group 
timolol/brimonidine 
N = 56 
Eye burning 
1 
1 
Itching 
1 
- 
Foreign body sensation 
1 
- 
Red eye 
- 
1 
Dizziness 
- 
1 
Headache 
- 
1 
Bradycardia 
- 
1 
Subjects who reported at least 1 adverse event during their participation in the study.  
Table 5. Adverse events in the study by Baiza 2012 
The research team concluded that the safety profile of brimonidine, timolol and dorzolamide 
ophthalmic solution was better, under that there were only 3 events compared to the 5 reported in 
patients who received the dual therapy. However, both therapies were considered safe. [36] (¡Error! N
o se encuentra el origen de la referencia.) 
Garcia A, et al., reported the safety profile by developing a cross-over clinical trial, 2 periods, 2 
sequences involving patients with primary open-angle glaucoma or ocular hypertension who 
previously received ophthalmic solution in fixed combination of bimatoprost 0.03%/timolol 0.5% or 
ophthalmic solution in fixed combination of brimonidine 0.2%/timolol 0.5%/dorzolamide 2% at a 
dosage of 1 drop 2 times a day for 3 months; in each period, for subjects exposed to triple therapy 
and a dose of 1 drop once a day for 3 months; in each period, for patients with double combined 
therapy.  
Results: Few adverse events were reported by participants throughout the study. The most common 
event was hyperemia and was the only event associated with the investigational drug [37]. 
As it could be observed in the ¡Error! No se encuentra el origen de la referencia. Adverse events 
in the study by García, it is shown that the event took place in the whole population evaluated during 
the course of the study, however, or refers to the type of intervention that the participant was receiving 
when the event that led to the withdrawal of the patient happened. 
Adverse reactions associated with the timolol maleate 0.5% at eye level can be: transient burning, 
decreased corneal sensitivity, allergic blepharoconjunctivitis, superficial punctate keratitis, 
conjunctival hyperemia, keratoconjunctivitis sicca, ptosis, diplopia, blurry vision and refractive 
changes (due to, in some cases, the suspension of treatment with miotics). At the level of the central 
nervous system: headache, dizziness, lethargy, confusion, hallucinations, fatigue and depression.  
Cardiovascular: Systemic arterial hypotension, bradycardia, arrhythmia, atrioventricular heart block, 
cardiac arrest, congestive heart failure, syncope, stroke, tachycardia and cerebral ischemia; the latter 
have been most common in older people or people with previous cardiovascular alterations. Adverse 
reactions to respiratory level: bronchial spasm, (especially in subjects with a history of 
broncoespasticos disorders), respiratory failure and shortness of breath. Other reactions: worsening 
of the myasthenia gravis, alopecia, nail pigmentary changes, nausea, localized and widespread rash 

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skin, urticaria, asthenia, sexual dysfunction, including impotence, decrease of the libido and reduced 
ejaculation; hyperkalaemia, masking of symptoms of hypoglycemia in patients with diabetes insulin, 
diarrhoea and paraesthesia. [38] 
Adverse reactions reported frequently with the use of brimonidine tartrate 0.2% are: dry mouth 
sensation, drowsiness, fatigue, cardiopulmonary disorders. At eye level: hyperemia, burning, 
blepharoconjunctivitis and allergic conjunctivitis, acute eye conjunctivitis, transient miosis in people 
sensitive to the formula.[39] 
Adverse event 
Brimonidine/timolol/dorzolamide 
group 
N = 78 
Group 
timolol/bimatoprost 
N = 78 
Vitreous hemorrhage 
1 
Pruritus 
1 
Severe hyperemia* 
1 
2 
Sensation of foreign body 
and conjunctival edema * 
- 
1 
Serious eyelid edema 
1 
Visual field reduction* 
1 
- 
Allergy 
1 
Significantly 
reduced 
visual acuity 
1 
Blurry vision. 
1 
Not specified* 
1 
- 
Events reported in patients during the 6 month study. Overall 12 patients showed at least 1 adverse event, 6 of them had 
to withdraw from the research protocol because of the severity and seriousness of the event. *Subjects withdrawn from the 
study. 
Table 6. Adverse events in the study by García 
Dorzolamide hydrochloride 2% is generally well tolerated. Adverse effects reported with greater 
frequency have been transient burning eye, taste distortion, corneal erosion, conjunctival injection, 
blurry vision, tearing and eye itching. [40] 
5.3.3 Preservative use in ocular hypotensive medications 
Preservatives are used in order to inhibit microbial growth and to suppress the biodegradation of 
drugs. [41] Throughout history a variety of preservatives have been used. Chronic use of drugs has 
been linked to irritation and alterations of the ocular surface; it has been established that preservatives 
have the same adverse events, which are attached to the active principle that preserve. [42] 
Preservatives are divided into detergents and oxidative, and a more recent version of oxidatives 
named ionic buffered. [41] Historically, BAK is the most widely used preservative, it is a class of 
detergents, and its concentration in ocular hypotensive drugs ranges from 0.004-0.02%. The reasons 
of their popularity are its broad action spectrum and the familiarity with the industry.  
While its effectiveness is well recognized, there are numerous studies documenting the harmful 
effects of BAK. BAK, at 0.05-0.1% concentration, induces necrosis, and at 0.01%, apoptosis. Its 
effects are cumulative and are more severe at higher concentrations and more frequent exhibitions. 
[41] [43] It has been proposed that BAK is responsible for changes in the conjunctival surface 
identified by impression cytology, as the decrease in the density of calyceal cells.[44] [45] 

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5.4 Justification 
During the treatment of a patient with glaucoma, it is possible that, at some point, 2 or more drugs 
are required to achieve the IOP desired control. Fixed combinations offer many advantages, including 
a simplified regime that can lead to a better attachment, a convenience for patient as a result of using 
fewer bottles and instillations, a less exposure to preservatives that could potentially damage the 
ocular surface, eliminating the washing effect and finally a cost-savings in the cost of therapy.  
In Mexico, since 2007, and recently in other Latin American countries, such as Bolivia, Colombia, 
Costa Rica, Ecuador, El Salvador, Guatemala, Honduras, Panama, Peru, Dominican Republic and 
Uruguay, is commercially available Krytantek Ofteno®, developed by Laboratorios Sophia, S.A. de 
C.V., which is the fixed combination of timolol 0.5%/brimonidine 0.2%/dorzolamide 2% ophthalmic 
solution. During these years, Krytantek Ofteno® has shown its effectiveness in clinical practice of 
ophthalmologists who use it, and has been known for its safety profile by pharmacovigilance systems.  
PRO-122 is a preservative-free Krytantek Ofteno® reformulation, and there are currently no reports 
of the effectiveness of this fixed triple combination compared to its components applied concomitantly. 
A clinical study of non-inferiority is the more appropriate tool to assess this information. 
5.5 Objectives and hypothesis 
5.5.1 General objective 
To evaluate the non-inferiority in the ocular pressure decrease of the preservative-free ophtalmic 
solution PRO-122, manufactured by Laboratorios Sophia, S.A. de C.V., versus concomitant therapy 
in subjects with uncontrolled POAG and/or IOP. 
5.5.2. Specific objectives 
- 
To compare the effectiveness of reducing the IOP in the ophthalmic solution PRO-122 versus 
reducing the IOP in Krytantek Ofteno® and concomitant therapy. 
- 
Compare the safety of the ophthalmic solution PRO-122 versus Krytantek Ofteno® and the 
concomitant therapy.  
- 
Compare the safety of the ophthalmic solution PRO-122 versus Krytantek Ofteno® and the 
concomitant therapy by the adverse events.  
- 
Compare the safety of the ophthalmic solution PRO-122 versus Krytantek Ofteno® and the 
concomitant therapy by the ocular surface integrity. 
- 
Analyze the tolerability of the ophthalmic solution PRO-122 versus Krytantek Ofteno® and the 
concomitant therapy. 
5.5.3 Hypothesis 
H0: The mean (average) value of the IOP final absolute reduction in the experimental group (PRO-
122) is lower, considering a lower limit of 1 mmHg, compared to the IOP mean absolute reduction of 
the standard group (concomitant therapy). 
Ha: The mean (average) value of the IOP final absolute reduction in the experimental group (PRO-
122) is not lower, considering a lower limit of 1 mmHg, compared to the IOP mean absolute reduction 
of the standard group (concomitant therapy).  
Note: Absolute reduction means the total decrease in mmHg of the PIO expressed in positive 
numbers. It is calculated as the subtraction of the IOP value on the final visit to the baseline visit 
(basal IOP - final IOP)  

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5.6 Study plan and design 
A non-inferiority, double-blind, randomized, controlled, parallel, phase-III clinical trial. Patients 
participating have primary open-angle glaucoma and/or ocular hypertension without control with dual-
fixed combined therapy or concomitant dual therapy, who will be randomly assigned to 3 groups of 
hypotensive pharmacological intervention. A group will receive the test formulation PRO-122 + 
approved placebo (2 multidose dropper bottle), another group will be exposed to Krytantek Ofteno® 
+ approved placebo (2 multi-dose dropper bottle) and finally a group will receive concomitantly 3 
multidose dropper bottle, which contain individually the active agents: brimonidine 0.02%, 
dorzolamide 2% and timolol 0.5%.  
 
 
Figure 1. Study design 
 
5.6.1 Discussion of the study design 
In clinical investigation, it is common to propose tests in order to assess the efficacy of an 
investigational product against a drug reference or active control, in order to show that the new 
investigational product is not inferior from the clinical or statistical perspective to a medication 
commercially available. Studies with objectives such as the former are referred to as trials of unilateral 
equivalence or non-inferiority. The most important criterion of this kind of research designs is the a 
priori definition of a quantity or value (of the variable of primary outcome) that marks a clinical or 
statistically acceptable difference between the treatments being compared. Like this, the hypothesis 
testing planning, results in the selection of a proper non-inferiority limit, which can be obtained from 
the reference drug product superiority studies results versus placebo.  
The clinical trial is the ideal model to evaluate the effectiveness of two interventions, allows to obtain 
evidence of greater quality between the different types of research. The features of randomization 
and double-blind allow to avoid bias (selection, assessment, etc.) which cannot be avoided with other 
models. The controlled and parallel-group characteristic allows to distinguish the effects of the 
interventions alone. 
Random allocation (patients with POAG or 
OHT without control with dual therapy)
PRO-122 + placebo approved
Efficiency
Safety 
Tolerability
Krytantek Ofteno® + placebo 
approved
Efficiency
Safety 
Tolerability
Concomitant triple therapy (timolol 
0.5% + dorzolamide 2% + brimonidine 
0.02%)
Efficiency
Safety 
Tolerability

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In the present research is determined the limit of non-inferiority as the value obtained of the difference 
of the intraocular pressure (mean baseline number minus mean final number of absolute reduction, 
expressed in positive numbers) - 1, i.e. delta of intraocular pressure -1 will be the limit of unilateral 
equivalence or of non-inferiority to establish the compliance of patients exposed to the investigational 
product PRO-122. When exceeding that limit it does not comply with the assumption of not be lower 
with regard to hypotensive drugs administered concomitantly. To understand the previously said, it is 
important to consider the following: it is known, from others prospective studies, that by each 
millimeter of mercury increasing in the intraocular pressure in a patient with POAG, the risk of disease 
progression increased in a 5%, this is why the main goal of treatment is reduction. [46] 
The proposed clinical trial aims to evaluate the profile of efficacy, safety and tolerability of a fixed 
combined formulation, without benzalkonium chloride, formed by  brimonidine 0.2%/dorzolamide 
2%/timolol 0.5% and to compare it against the profile of safety, tolerability and efficacy of the 
concomitant administration of active agents in individual pharmaceutical forms. The addition of a 
group of patients who were exposed to the reference drug product Krytantek Ofteno®, which is 
dispensed equally as a fixed combination therapy consisting of the same active agents and with the 
use of benzalkonium chloride in the formulation was judged as suitable.   
 
6. Material and methods. Participants, interventions and variables 
6.1 Study center 
This study will take place in ophthalmology practices properly equipped and registered for their proper 
functioning. According to the needs of the sponsor these may be either private or public, be attached 
to a hospital or practice or be independent. 
This is a multicenter study intended to be performed in Argentina, Mexico and Colombia. 
6.1.2 Center organization 
Each study center will have a principal investigator (PI). The PI is the specialist in ophthalmology, 
leader of the clinical study.  
The PI is responsible of conforming a multidisciplinary research team to run the clinical study 
according to the protocol, under scientific guidance. IP prerogative is the organization design from its 
core and the selection of the staff who shall perform such functions. However, the minimum 
organization of research team requested by the sponsor requires the subinvestigator, studies 
coordinator and pharmacist. 
 
 
 
 
 
 
 
Figure 2. Minimal organization of the Center 
Principal 
investigator
Subinvestigador
Pharmacist
Studies 
coordinator

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Every person appointed by the PI, under their responsibility, a part of the follow-up of the study 
(coinvestigador, subinvestigador, nurse, etc.) or a study participation specific function 
(pharmaceutical, administrative auxiliary, study coordinator, etc.) must appear in the form "Delegation 
of Responsibilities". 
The "delegation of responsibilities" and "Flow chart of the Center" will be delivered to the sponsor 
before the start of the study and updated if members or their responsibilities change. 
6.1.3 Documentation to be delivered to the sponsor 
PI must deliver it to the sponsor before starting the study: 
- Updated curriculum vitae in Spanish, dated and signed (maximum 10 pages), of PI and staff of the 
organization chart.  
- Copy of academic certificates of PI (degree diplomas in ophthalmology; professional ID or equivalent 
corresponding to the country) 
- Copies of academic certificates of maximum grade achieved, of each member of the research team 
that support their capacity to play their corresponding roles. 
- Copy of notice of performance or equivalent issued by the corresponding regulatory entity (if 
applicable) 
- Certificate of current good clinical practices. In case the certificate of the issuing institution does not 
specify the validity date, the date of issue of the certificate shall not exceed one year 
6.1.3 Center closure 
The closing of the center will be done once the last visit of the last subject included previously agreed 
between the sponsor and the PI has been performed. The closing process will be performed 
according to the in-house standard operation procedures of the sponsor. 
The premature closure of a study center is the prerogative of the sponsor, and it should be informed 
to the PI the reasons for the closure. 
6.2 Elegibility criteria 
6.2.1 Inclusion criteria 
 
Signed informed consent 
 
Age ≥ 18 years 
 
Both sexes 
 
Women of childbearing age with birth control method  
 
Diagnosis of POAG (according to the Guidelines of the Preferred Practice Pattern of the 
American Academy of Ophthalmology) or OHT  
 
IOP not controlled with dual therapy according to the investigator judgement. 
 
IOP on the selection visit at 9 am, after the washing period, from 21 - 36 mmHg in at least 
one eye. 
6.2.2 Exclusion criteria 
6.2.2.1 General criteria 
- 
Pregnant, breastfeeding or planning to get pregnant women. 

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- 
Women of childbearing age and who do not intake a hormonal contraceptive method, IUD or 
bilateral tubal obstruction. 
- 
Participation in another clinical research study ≤ 30 days before the screening visit. 
- 
People who cannot comply with their attendance at appointments or with all the Protocol 
requirements 
6.2.2.2 Medical and therapeutic criteria 
- 
Anterior chamber angle grade <2 of Shaffer rating. 
- 
Excavation of optic nerve > 0.80 horizontal or vertical (ratio cup-disc) 
- 
Serious loss of central visual field in any eye (sensitivity ≤10 dB in ≥ 2 of 4 points of the visual 
field test close to the fixation point)  
- 
People not able to safely suspend ocular hypotensives drug products for the washout period 
according to the IP judgement. 
- 
Chronic, recurrent, or active ocular inflammatory diseases (e.g. uveitis, scleritis, keratitis, 
herpetic) in any eye. 
- 
Eye trauma ≤ 6 months prior to the study 
- 
Eye infection / inflammation ≤ 3 months prior to the study 
- 
Clinically significant or progressive retinal disease (e.g. degenerations, diabetic retinopathy, 
retinal detachment) 
- 
CV 20/200 or worse in any of the eyes. 
- 
Subject with only one eye 
- 
Eye diseases that contraindicate the use of BB, AA or IAC 
- 
Intraocular surgery ≤ 6 months prior to the study 
- 
Laser intraocular surgery ≤ 3 months prior to the study 
- 
Any abnormality preventing reliable applanation tonometry  
- 
Unstable or uncontrolled cardiovascular disease 
- 
Chronic pulmonary disease (e.g. bronchial asthma) 
- 
Any condition or illness that do not fit the subject for the study according to the PI judgment. 
- 
Use of high doses of salicylate (1 g daily) ≤ 4 weeks before the eligibility visit 
- 
In treatment with psychotropic medications that increase the adrenergic response 
- 
Known hypersensitivity to BB medications (e.g. timolol), AA (e.g. brimonidine) and IAC (e.g. 
dorzolamide), sulfonamide derivatives, or any of the components of the study drugs 
- 
Concomitant use of MAO inhibitors 
- 
Systemic or topical use of corticosteroids 
6.2.3 Elimination criteria 
- 
Subject decision. The subject can decide unilaterally to withdraw the study in any moment, 
and should inform it to the PI. 
- 
Pregnancy (considered an SAE) 
- 
Presence of a SAE 
- 
Decrease of IOP in less than 20%, compared to the baseline, for consider it an AE by lack of 
efficiency 
- 
Decision of the investigator: 
o 
By an AE that, according to the IP judgement, threatens the subject health and 
requires the prescription of a drug product not authorized in the Protocol 
- 
Any deviation to the Protocol that affects the subject safety 
- 
Adherence lower than 40% in some of the visits  
- 
Subject that does not attend to two consecutive visits 

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6.2.4 Subject identification 
 Patients of the study will be identified by a number and their name initials. 
The subject’s initials will be the first letter of the name, followed of the first letter of the first last name 
and the first letter of the second last name, obtaining a maximum of three letters;  in case the person 
has two names or a compound last name it will always be used the first letter of the first name or 
compound last name. 
Example: 
1. Adolfo Daniel Mercado Carrizalez 
a. Initials: AMC 
2. Juan De la Torre Orozco 
a. Initials: JDO 
3. Luis Carlos Pérez-Gómez Ramírez 
a. Initials LPR 
In the screening stage you will assign a participant number consecutively, using 3 consecutive digits. 
Once the subject has been selected, it will be assigned with a number with which will be identified 
during all the study. This code shall consist of eight numbers in the following order from left to right:  
• 
three numbers of the study molecule according to the denomination by the sponsor.   
• 
two digits corresponding to the number of investigational center  
• 
three digits of the consecutive number of the inclusion assigned in the investigational center. 
Example:  
 
 
 
6.3 Intervention 
6.3.1 Given treatments 
Treatments will be administered twice a day, at 9:00 am (09:00 hours) and at 9:00 pm (21:00 hours). 
In all treatment groups 3 bottles will be given to each subject, these will be tagged with a random 
assignment number and the management sequence letters: A, B and C (see 7.2 Blinding 
mechanism), the subject must start with the application of bottle A, wait 5 minutes before applying 
the contents of bottle B, after this second application wait another 5 minutes for the application of 
bottle C. 
6.3.1.1 Study treatment 
- 
PRO-122  
o 
Drug substances: Timolol 5 mg/mL, brimonidine 2 mg/mL and dorzolamide 20 
mg/mL. See ¡Error! No se encuentra el origen de la referencia. [48] 
o 
Pharmaceutical form: Conservative-free ophthalmic solution 
o 
Dosage form: 5 mL multidose dropper bottle 
o 
Made by: Laboratorios Sophia, S.A. de C.V. 
o 
Posology: 1 drop every 12 hours for 90 days 
o 
Description of the solution: clear, visibly particle free solution, with a pH range of 5.4 
to 5.9 and a slightly yellow color 
Molecule key number 
Inclusion number 
Center number 

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o 
Description of the container: low density polyethylene white bottle with 5mL capacity. 
Assembled high density polyethylene container-closure system with a silicone and 
low density polyethylene valves system, which allows to preserve the sterile solution 
without any additives. 
- 
Placebo  
o 
Two pieces of approved placebo. Administered in 2 multidose dropper bottles. 
o 
Posology: 1 drop of each dropper bottle every 12 hours for 90 days 
 
Type of agent 
Amount mg/mL 
Function 
Dorzolamide hydrochloride 
22.25* 
Drug substance 
Timolol maleate 
 
6.80+ 
Drug substance 
Brimonidine tartrate 
2.00 
Drug substance 
Hydroxypropyl 
methylcellulose 
Not shown 
Additive 
Mannitol 
Not shown 
Additive 
Citric acid monohydrate 
Not shown 
Additive 
Sodium citrate dihydrate 
Not shown 
Additive 
Water for injection q.s. 
1.00 
Vehicle 
Investigational product PRO-122 qualitative and quantitative formulation. Concentration of those drug substances, as well 
as the substances functioning as additives, is shown. 
(*) Equivalent to dorzolamide 20.00 mg/mL (+) equivalent to timolol 5.00 mg/mL 
Table 7. PRO-122 qualitative and quantitative formulation 
6.3.1.2 Reference treatment 
6.3.1.2.1 Krytantek Ofteno Group 
- 
Krytantek Ofteno®. 
o 
Drug substances: Timolol 5 mg/mL, brimonidine 2 mg/mL and dorzolamide 20 
mg/mL. See Table 8: Qualitative/quantitative formulation of Krytantek Ofteno® 
[49] 
o 
Pharmaceutical form: Ophthalmic solution  
o 
Made by: Laboratorios Sophia, S.A. de C.V. 
o 
Posology: 1 drop every 12 hours for 90 days 
o 
Description of the solution: clear, visibly particle free, slightly yellow solution 
o 
Package description: 5 m multidose dropper bottle. 
- 
Placebo  
o 
Two pieces of approved placebo. Administered in 2 multidose dropper bottles. 
o 
Posology: 1 drop of each dropper bottle every 12 hours for 90 days 
6.3.1.2.2 Concomitant triple therapy group  
o 
Imot Ofteho® 
▪ 
Drug substance: Timolol 5 mg/mL 
▪ 
Pharmaceutical form: Ophthalmic solution 
▪ 
Made by: Laboratorios Sophia, S.A. de C.V. 

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o 
Alphagan® 
▪ 
Drug substance: Brimonidine 2 mg/mL 
▪ 
Pharmaceutical form: Ophthalmic solution 
▪ 
Made by: Allergan, Inc. 
o 
Trusopt® 
▪ 
Drug substance: Dorzolamide 20 mg/mL 
▪ 
Pharmaceutical form: Ophthalmic solution 
▪ 
Made by: Merck Sharp & Dohme Corp. 
o 
Posology: 1 drop every 12 hours for 90 days 
Agent type 
Quantity in mg/mL 
Function 
Dorzolamide hydrochloride 
22.25* 
Active ingredient 
Timolol maleate 
6.80+ 
 
Brimonidine tartrate 
2.00 
 
Polyethylene glycol Monostearate 
Not available 
Additive 
Manitol 
Not available 
Additive 
Sodium Chloride 
Not available 
Additive 
Sodium Tetraborate Decahydrate 
Not available 
Additive 
Benzalkonium chloride 
Not available 
Additive 
Water for injection c.b.p 
1.00 
Vehicle 
Qualitative/quantitative formulation of test drug Krytantek Ofteno® (Reg. No. 074M2077 SSA IV). Concentrations of active 
ingredients and additive substances. 
(*) Equivalent to 20.00 mg/mL of Dorzolamide (+) Equivalent to 5.00 mg/mL of Timolol 
Table 8. Qualitative/quantitative formulation of Krytantek Ofteno® 
6.3.2 Strategies to improve the adherence and procedure for monitoring the adherence 
Strategies: 
• 
During visit 2, visit 3 and the final visit, the test subject must return the assigned bottle in 
order to verify the treatment adherence by checking the weight of the bottle returned to the 
site. 
• 
In each visit the PI must remind the test subject of the importance of following the assigned 
treatment and must ask whether he/she had any difficulties in following the instructions and, 
if necessary, must retrain the subject to apply the test drug. 
• 
The PI or a designee must send emails to subjects in order to remind them of the treatment 
adherence and the importance of it. The content of such emails must be previously approved 
by the Institutional Review Board. 
• 
Use of a printed reminder. 
• 
Use of the subject diary. 
Procedure for monitoring the adherence: 

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• 
Procedure for the investigation center: before supplying the test subject with the drug, the 
pharmacist must weigh the bottles to be supplied. The weighing must be performed once 
again after the subject had returned the drug. Considerations to take into account: 
o 
Pharmacist must use the scale provided by the sponsor. 
o 
He/she must put the bottle in the center of the scale and check the weights. 
o 
He/she must remove the bottle from the scale and put it back again in order to verify 
that the measurement taken is the same as the previous one. If different, he/she 
must weight it again and record the average of three measurements. 
o 
He/she must record the result in a log provided especially for this purpose. 
Adherence must be assessed based on the weight of an empty bottle, the weight of a single drop, 
the weight of the filled bottle, the total amount of drops to be applied during the intervention period 
and the total weight of all applied drops. This simplified formula must be used: 
𝐴𝑑= (𝑃𝑖−𝑃𝑓)100
𝑃𝑇
 
Where: 
Ad = adherence 
𝑃𝑖 = weight of the bottle initially supplied to the subject 
𝑃𝑓 = weight of the bottle returned by the subject. 
𝑃𝑇 = weight of the dose indicated for the intervention. 
𝑃𝑇= (𝑃𝑔)𝐺 
Where: 
𝑃𝑔= weight of the intervention drop, determined by the R&D department. 
G = number of drops indicated for the intervention. 
Adherence is assessed at every visit with the return of bottles by test subjects. Results will allow the 
PI to determine if the subject continues being part of the study, as per the exclusion criteria. 
Adherence must be assessed by reviewing the subject diary. This formula must be used: 
𝐴𝑑= (𝐴𝑟)100/𝐴𝑖 
Where: 
Ad = Adherence 
Ar = Recorded applications 
Ai = Applications indicated for the intervention 
 
Final (global) adherence must be determined based on the adherence average of each visit. 
If a subject fails to return 2 to 4 bottles at least, his/her data must not be taken into account for the 
calculation of the final adherence. 
6.3.3 Allowed and prohibited concomitant treatments and interventions before and after the study 
Subjects duly enrolled to the study and complying with all eligibility criteria area will be able to continue 
their systemic treatments for baseline diseases. If during the study, they need to add a new allowed 
drug, they will be able to do so. All used concomitant drugs must be duly recorded in the clinical file 
notes and in the corresponding section. 
Allowed drugs: 

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 
Ophthalmics: 
All ophthalmic allowed drugs during the study must be applied at least 10 minutes after the last 
application of the study/reference treatments. This procedure has the aim of avoiding treatment 
interactions in the tear film, based on tear flow rate and physiological tear volume. [18] 
o 
Tetracaine 0.5% 
o 
Tropicamide 0.8%/ phenylephrine 5% 
o 
Any antibiotic 
o 
Ocular lubricants 
 
- 
Other drugs not ophthalmically applied: 
 
o 
The use of drugs whose effect could have an effect on some of the efficacy, safety and 
tolerability parameters of this investigation protocol must be notified to the clinical monitor or 
the sponsor scientific committee in order to determine the convenience of the subject 
admission, stay or withdrawal. 
Prohibited drugs: 
 
Any other ophthalmic drug that is not part of the list of allowed drugs. 
 
Systemic carbonic anhydrase inhibitors (e.g., acetazolamide) 
6.3.3.1 Washout period 
Washout periods for ocular hypotensive drugs must be: ≥5 days for topical miotic agents and 
topical/oral carbonic anhydrase inhibitors; ≥14 days for AA and ≥28 days for prostaglandin analogues 
and BB (See Table 9, Washout period), based on the periods used from previous studies. [50] For 
combined administrations, the longest washout period for individual components must be used. At 
the discretion of the PI, patients will be moved to a drug requiring a shorter washout period. 
Drug Group 
Example 
Washout period 
(days) 
Miotics (topical agents) 
Pilocarpine 
≥5 
Carbonic anhydrase 
inhibitors 
(oral and topical agents) 
Acetazolamide/ Brinzolamide, 
Dorzolamide 
≥5 
α-Agonist 
Brimonidine, Apraclonidine 
≥14 
Prostaglandin analogues 
Travoprost, Latanoprost 
≥28 
β-blockers 
Timolol, Betaxolol 
≥28 
Table 9. Washout Period 
6.3.4 Treatment management 
Treatments will be provided by Laboratorios Sophia, S.A. de C.V. to each investigation center. Drugs 
must be previously labeled, reconciled and weighed. The PI or some designated member of his/her 
team is responsible for the treatment management. 

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6.3.4.1 Supply and reception 
The sponsor has the responsibility for supplying the study drugs in each investigation center as per 
the internal procedures. Drugs must be supplied in closed boxes through delivery service or directly 
by the sponsor personnel to the address of the investigation center as per the study plan. 
Reception will be exclusively performed by the investigation center team, including the PI. The 
primary packaging (box) has to be in good state. Any alteration or imperfection which, at his/her 
discretion, might compromise the integrity of its contents must be reported to the sponsor. If the 
package does not show significant imperfections, he/she must proceed to open it. 
Inside he/she will find the goods received note and a temperature/humidity data logger. He/she will 
also check that the recorded temperature and humidity meet the specifications for transport and 
storage conditions (see 6.3.4.2, “Storage”). Then, he/she must check the contents (treatment drugs) 
against the contents stated in the document. Provided the contents match the information stated in 
the document, he/she must sign the goods received note and must mail it to the sponsor. Otherwise, 
he/she will notify the sponsor of the given discrepancies. 
At the study center, personnel assigned by the PI must supply subjects with their corresponding 
treatments by giving them quantities enough to cover the treatment period. Treatment drug supply 
must be performed by stages: at baseline and in visit 2 and visit 3. 
6.3.4.2 Storage 
Drug must be stored in a safe area with restricted access. Storage temperature must be at room 
temperature, no greater than 30 °Celsius. 
The investigation center is responsible for recording, in the form supplied by the sponsor, the 
temperature and humidity reported by the data logger. The record must include current temperature 
and humidity, and minimum and maximum recorded values for both of them. This must be done on a 
daily basis (on business days) and as long as the protocol remains effective. 
The clinical monitor must compare the data against the data reported by the data logger. 
6.3.4.3 Returns 
Test subjects must return the drugs to the personnel assigned by the PI in the treatment centers at 
visit 2, visit 3 and the final visit. 
Returns will be performed by the investigation center personnel whenever the sponsor indicates so. 
Before returning the drugs to the investigation center, the remaining amount of drug must be counted 
and checked against the initial amount in order to produce an inventory that serves in the filling of the 
drug return form. 
6.4 Outcome variables 
6.4.1 Safety variables 
6.4.1.1 Primary outcome variables 
Best corrected visual acuity 
Cup-to-disc ratio 
Visual fields determined by computerized perimetry 
Ocular surface integrity 
-Conjunctival hyperemia 
- Chemosis 

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- Fluorescein staining 
Central corneal thickness 
Adverse events 
Goblet cell density 
6.4.1.2 Tolerability variables 
Ocular comfort index 
6.4.2 Efficacy variables 
6.4.2.1 Primary outcome variables 
IOP lowering 
6.4.2.2 Secondary outcome variables 
Not applicable 
6.4.3 Methods and gradings to be used in the measurement of variables 
Variable 
Unit 
Symbol 
Type 
Measurement method 
Best corrected 
best corrected 
visual acuity 
Decimals 
--- 
Continuous 
Snellen chart 
Visual fields 
Decibels 
dB 
Continuous 
Computerized 
perimetry 
Goblet cell 
density 
Cells per square 
millimeter 
cel/mm2 
Continuous 
Impression cytology 
Central corneal 
thickness 
Micra 
µm 
Continuous 
Ultrasound pachymetry 
Conjunctival 
hyperemia 
Normal/ very mild/ mild/ 
moderate/ severe 
--- 
Ordinal 
Direct observation 
(biomicroscopy) 
Ocular comfort 
index 
Points 
--- 
Discrete 
Questionnaire 
Presence of 
adverse events 
Number of cases 
n 
Discrete 
Count of cases 
Intraocular 
pressure 
Millimeters of mercury 
mmHg 
Continuous 
Goldman applanation 
tonometry 
Chemosis 
Presence/ absence 
--- 
Nominal 
Direct observation 
(biomicroscopy) 
Cup-to-disc ratio 
Decimals 
--- 
Continuous 
Direct observation 
(biomicroscopy) 
Surface staining 
Points 
--- 
Discrete 
Direct observation 
(biomicroscopy) 
Table 10. Method for the measurement of variables 

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The following are methods and gradings used in the measurement of variables: 
6.4.3.1 Visual fields 
Visual field refers to the perception by the visual cortex of objects and light sources in a given moment 
through visual fixation. Perception in the cortex implies that the object or light source was visually 
processed through retinal stimuli. The visual field comprise a three-dimensional cone (Traquair's 
Island of vision) having its apex at the nodal point of the eye and its base at infinity. [51] The peripheral 
nature of the visual field covers approximately 60 °in the top section, 60 ° in the nasal section, 80 ° in 
the low section and 90 ° in the temporal section. The blind point is located in the temporal section 
between 10° and 20°. 
Perimetry represents a psychophysical test that aims to determine the peripheral limits of the visual 
field of any given subject. 
Humphrey’s perimetry is an automated test whose software includes programming for standardized 
strategies with predefined intervals (e.g. 30-2, 24-2, 10-2). The full threshold strategy represents the 
reference standard for glaucoma testing. Nevertheless, the Swedish Interactive Thresholding 
Algorithm (SITA) can replace such strategy as it is faster and more likeable and sensitive. [52] 
Visual fields must be obtained with an automated perimeter (Humphrey’s perimeter) by performing 
white on white tests using the 24-2 SITA-standard. All perimetry results included in the study will be 
deemed as reliable if they show at least 20% of fixation loss, false positives, and false negatives. [53] 
Mean deviation, a global measure of visual field loss, and the standard deviation of model, a measure 
of focal loss or field variability, must be recorded in the CRF. 
6.4.3.2 Best corrected visual acuity 
Visual acuity represents a visual function test. Spatial visual acuity is the capacity to distinguish 
separate elements from an object and identify them as a whole. It is quantified as the minimum angle 
of separation (located in the nodal point of the eye) between two objects that allows the perception 
as separate objects. 
The Snellen notation is described as the distance used in the test, divided by the distance at which 
letters subtend an angle of 5 minutes of arc. Therefore, with a distance of 6 meters a 6/6 letter (20/20) 
equals 5 minutes of arc, a 6/12 letter (20/40) equals 10 minutes and a 6/60 letter (20/200) equals 50 
minutes. Snellen fractions can also be expressed as decimal numbers (i.e. 20/20 = 1 and 20/40 = 
0.5). [52] 
Visual acuity represents a basal assessment for patients without previous refractive corrections and 
it involves a Snellen chart located in a place with sufficient amount of natural/artificial light and at a 
distance of 3 meters from the subject to be examined. Visual acuity is assessed in both eyes, 
beginning with the right eye. The subject is asked to keep both eyes open and, having the left eye 
covered with an occluder, the subject must be asked to read out loud the lines that the evaluator 
points. The line having the smallest letters which the subject still is able to read must be recorded by 
the evaluator in the clinical file as visual acuity fractions. The left eye must be evaluated in the same 
way. 
Afterwards, the best refractive corrections must be performed and the test must be performed once 
again using the obtained refraction. Results must be recorded in the clinical file and in the CRF as 
fractions of best corrected visual acuity (the CRF must include decimal numbers.) By definition, the 
best corrected visual acuity cannot be inferior to the visual acuity. 

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6.4.3.3 Goblet cell density 
The density of goblet cells in the conjunctiva can reflect the seriousness of ocular surface alterations 
[54]. Normal density has been determined as superior to 500 cells/mm2. [55] Impression cytology 
refers to the application of a cellulose acetate on the ocular surface in order to remove epithelium 
surface layers; cells, once removed, can be subject to histological, immunohistological and molecular 
analyses. [56] 
Impression cytology in the conjunctiva must be performed by the investigator using cellulose acetate 
filter millicell and the device supplied by the sponsor especially designed for this purpose. Such device 
has a circular cell of approximately 10 mm of diameter. Once the ocular surface be anesthetized with 
topical tetracaine, the subject must be asked to expose the temporal ocular surface to be evaluated 
by the investigator and the latter will gently press the cell against the temporal conjunctiva (2 to 3 mm 
from the corneal-scleral limbus) for 5 seconds and remove the cell by peeling (Figure 1. Impression 
cytology). Immediately after, the investigator must adhere it with diethyl ether in spray by releasing 
one or more discharges 15 cm away. The investigator must contact the courier designated by the 
sponsor in order to send the samples for histopathological analyses. 
Ocular surface staining, when required, must be performed after this procedure. 
 
 
 
 
 
 
 
Figure 3. Impression cytology 
6.4.3.4 Ocular comfort index 
The ocular comfort index is measured by a questionnaire designed for the measurement of the ocular 
surface irritation by Rasch analysis in order to produce estimates in a lineal interval scale (0-100 
scale). Like ocular surface disease index, ocular comfort index (OCI) evaluates symptoms. OCI 
comprises eight items (one positive and seven negative) that focus on the discomfort associated with 
ocular surface diseases. Each of these questions have two parts, which separately establish the 
frequency and severity of symptoms. [57] See annex 13.1 Ocular comfort index. 
The evaluator must supply the subject with the questionnaire and ask him/her to fill it with calm and 
without any kind of pressure and/or coercion. The evaluator must be of assistance only if he/she has 
any difficulty in understanding the questions. 
6.4.3.5 Ocular surface integrity 
This test is performed in the investigation center by slit lamp microscopy. A complete examination of 
the anterior segment must be performed and results must be recorded in the clinical file. Lighting 
techniques must be determined by the PI. 
The variables to be recorded in the CRF are the following: 
- 
Conjunctival hyperemia. It is defined as the simplest conjunctiva reaction against any given 
stimulus. A red appearance derived from variable-intensity vasodilatation of conjunctiva 

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vessels. Grading must be performed following the Efron scale [58]. See annex 13.2, Efron 
scale for conjunctival hyperemia. 
- 
Chemosis. It is defined as a conjunctival edema as a result of inflammatory reaction. It is 
qualified as either present or absent. The evaluator must use a narrow beam of light directed 
from an angle of 60° and must check whether the separation of the conjunctiva from the 
sclera is >1/3 of the total height of the palpebral fissure or whether the conjunctiva prolapses 
the grey line of eyelid. [59] 
- 
Fluorescein staining. A drop of topical anesthetic is instilled in the conjunctival cul de sac. 
Afterwards, a second drop must be instilled in the edge of the fluorescein strip, allowing it to 
slip to the cul de sac. It is important to perform the staining in a quick and sequential manner 
—first the right eye and then the left eye— so that the observed patterns be equally bright. 
This test must be performed with cobalt blue filter. Grading must be as per the Oxford scale. 
[60] See annex. 
6.4.3.6 Corneal pachymetry 
Although the central corneal thickness (CCT) and IOP have an independent effect on the risk of 
developing glaucoma, such factors do interact between themselves. With the introduction of 
Goldmann’s applanation tonometry, the CCT has since been the potential confounding factor in the 
measurement of IOP. The CCT must be measured by ultrasound pachymetry. Three measurements 
must be recorded in the clinical file and the average of them must be noted down in the CRF. Baseline 
and final pachymetry must be performed by the same evaluator using the same pachymeter. IOP 
must be readjusted using the Ehlers formula: [61] 
𝐼𝑂𝑃−
[5.0 ∗( 𝐺𝐶𝐶
1000 −0.520)]
0.070
 
6.4.3.7 Adverse event presence 
Adverse events must be handled as per section 9.3, Adverse events. 
The PI must record in the corresponding section of the CRF all AEs of study subjects. 
6.4.3.8 Intraocular pressure 
Tonometry is the objective measurement of the IOP —based must of all on the force necessary to 
applane the cornea— or the level of corneal indentation produced by a fixed force. Goldman’s 
tonometry is based on the Imbert-Fick law. [52] 
Once the eye is instilled with a topical anesthetic, fluorescein tonometry must be performed using a 
blue cobalt filter (after corneal surface staining test). Two readings are to be taken and recorded in 
the clinical file. The average  must also be recorded in the CRF. Tonometry must performed between 
9:00 a.m. and 11:00 a.m. (± 30 minutes), which is the time after which a minimum effect (12 hours 
post-instillation) and a maximum effect (+2 hours post-instillation) of IOP lowering is reached, 
respectively. Throughout the treatment, the investigator must make sure that the test subject applies 
the treatment after the IOP check at 09:00 a.m. 
6.4.3.9 Cup-to-disc ratio 
Cup-to-disc ratio is measured by slit lamp indirect ophthalmoscopy. Lens is to be chosen at the 
discretion of the PI. Mydriasis has to be induced by pharmacological means (tropicamide 0.8% / 
Phenylephrine 5%) in order to perform an accurate examination of the optic disc. 
6.4.4 Measurements by stage 
6.4.4.1 Measurements taken during screening 

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- Intraocular pressure 
- Best corrected visual acuity 
- Cup-to-disc ratio 
- Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 
6.4.4.2 Measurements taken at baseline 
- Intraocular pressure 
- Best corrected visual acuity 
- Cup-to-disc ratio 
- Visual fields determined by computerized perimetry 
- Central corneal thickness determined by pachymetry: 
- Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 
- Goblet cell density 
- Ocular comfort index 
6.4.4.3 Measurements taken during visit 1 
- Intraocular pressure 
- Best corrected visual acuity 
- Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 
- Adverse events 
6.4.4.4 Measurements taken during visit 2 
- Intraocular pressure 
- Best corrected visual acuity 
- Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 
- Adverse events 
6.4.4.5 Measurements taken during visit 3 
- Intraocular pressure 
- Best corrected visual acuity 
- Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 
- Adverse events 
6.4.4.6 Measurements taken during final visit 
- Intraocular pressure 
- Best corrected visual acuity 
- Cup-to-disc ratio 
- Visual fields determined by computerized perimetry 
- Central corneal thickness, determined by pachymetry 
Ocular surface integrity, including: 
o 
Conjunctival hyperemia 
o 
Chemosis 
o 
Fluorescein staining 

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- Goblet cell density 
- Ocular comfort index 
- Adverse events 
6.4.4.7 Measurements taken for safety call 
- Adverse events 
6.5 Chronogram and study diagram 
Screening test represents a visit that takes place 5 to 28 days before the baseline visit. Such period 
of time is related to the washout period, which in turns depends on the previously administered 
hypotensive drug(s). 
The Baseline visit must be performed strictly after the washout period with a window of 2 days. 
Visit 1 is to be performed 14 days after starting the treatment, with a window of ±2 days. 
Visit 2, visit 3 and final visit must be performed after 28, 56 and 93 days, respectively, with a window 
of ±3 days. 
Safety call must be performed at day 106, with a window of ±3 days. 
Procedure 
Visits 
S 
B 
1 
2 
3 
Final 
SC 
Days 
-5 a   
-28 
0 
14 ± 
2 
28 ± 
3 
56 ± 
3 
91 ± 
3 
106   
± 3 
Eligibility criteria 
X 
X 
 
 
 
 
 
Signed informed consent 
X 
 
 
 
 
 
 
Pregnant test (if applicable) 
X 
 
 
X 
X 
X 
 
General/ ophthalmic clinical history 
X 
 
 
 
 
 
 
Instruction of starting the washout period  
X 
 
 
 
 
 
 
Subject code assignment 
 
X 
 
 
 
 
 
Treatment group assignment 
 
X 
 
 
 
 
 
Drug supply 
 
X 
 
X 
X 
 
 
Drug return 
 
 
 
X 
X 
X 
 
Adherence assessment 
 
 
X 
X 
X 
X 
 
Tonometry 
X 
X 
X 
X 
X 
X 
 
Best corrected visual acuity 
X 
X 
X 
X 
X 
X 
 
Cup-to-disc ratio 
X 
X 
 
 
 
X 
 
Computerized perimetry 
 
X 
 
 
 
X 
 
Pachymetry 
 
X 
 
 
 
X 
 
Surface integrity evaluation 
X 
X 
X 
X 
X 
X 
 

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Procedure 
Visits 
S 
B 
1 
2 
3 
Final 
SC 
Days 
-5 a   
-28 
0 
14 ± 
2 
28 ± 
3 
56 ± 
3 
91 ± 
3 
106   
± 3 
Impression cytology 
 
X 
 
 
 
X 
 
Ocular comfort index 
 
X 
 
 
 
X 
 
Adverse event assessment 
 
 
X 
X 
X 
X 
X 
Concomitant drugs assessment 
X 
X 
X 
X 
X 
X 
X 
Assessment for subject stay 
 
 
X 
X 
X 
 
 
Diary handed over to subjects 
 
X 
X 
X 
X 
 
 
Subject diary review 
 
 
X 
X 
X 
X 
 
Safety call 
 
 
 
 
 
 
X 
S = screening, B = baseline, SC = safety call 
Table 11. Study Chronogram 
6.5.2 Procedures to follow in each visit 
The following are the procedures to be followed in each visit, as well as a brief description of each 
one of them. 
6.5.2.1 Screening visit 
▪ 
Eligibility criteria: the PI must include subjects in the study if they meet all inclusion criteria 
and do not meet any exclusion criteria. See 6.2 Eligibility criteria. 
▪ 
Signed informed consent: subjects must sign a written informed consent. See 10.3 Consent. 
▪ 
Pregnancy test: it refers to a quick pregnancy test performed in all women with an age of 
pregnancy potential who would like to be enrolled in the study. Fertile age is understood as 
an age at which women have not presented menopause, defined as 12 months since the last 
menstruation in women with more than 40 years old or women who have undergone 
hysterectomy or bilateral oophorectomy. Fertile age women using birth control methods, 
including bilateral tubal obstruction, are subject to pregnancy tests too. Pregnancy tests must 
be performed by the PI or a team designee by following the instructions of the device supplied 
by the sponsor. 
▪ 
General/ ophthalmic clinical history: it refers to any technical, clinical and legal document in 
which the patient health conditions, medical actions and any other procedures performed in 
the patient are chronologically recorded. It includes anamnesis and full ophthalmological 
examinations that help to determine the patient eligibility. If any patient comes from the visit 
established by the study center, his/her existing clinical history can be used for the purposes 
of the study, provided the corresponding updates be made. 
▪ 
Instruction of starting the washout period: it means the suspension of hypotensive drug 
administration, as per Table 9 Washout period. 
▪ 
Tonometry: see 6.4.3.8 Intraocular pressure. 
▪ 
Best corrected visual acuity: see 6.4.3.2 Best corrected visual acuity 
▪ 
Cup-to disc ratio: see 6.4.3.9 Cup-to-disc ratio 

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▪ 
Surface integrity evaluation: see 6.4.3.5 Ocular surface integrity. 
▪ 
Concomitant drugs assessment: the PI must query about the drugs the patient used before, 
during and after the study. All active substances, doses and periods of time must be recorded 
in the corresponding section of the CRF by the PI. 
6.5.2.2 Baseline visit 
▪ 
Eligibility criteria: see 6.5.2.1 Screening visit 
▪ 
Subject code assignment: it means the assignment of numbers that will identify the patient 
throughout the whole study. The assignment must be performed as per section 6.2.4, Subject 
identification. 
▪ 
Treatment group assignment: it means the determination of the treatment the patient will 
receive throughout the study. It must be performed as per Section 7, Methods. Intervention 
assignment. This assignment is to be performed at the baseline visit (day 0) and must take 
place simultaneously with the instruction to start the treatment period the next day (day 1). 
▪ 
Drug supply: the investigation center must supply study patients with the test drug. It must 
be performed as per sections 6.3.1. Administered treatments and 6.3.4.1. Supply and 
reception. After each drug supply, a training/retraining on the study drug application must be 
performed. 
▪ 
Best corrected visual acuity: see 6.4.3.2 Best corrected visual acuity 
▪ 
Tonometry: see 6.4.3.8 Intraocular pressure. 
▪ 
Cup-to-disc ratio: see 6.4.3.9 Cup-to-disc ratio. 
▪ 
Computerized perimetry: see 6.4.3.1 Visual fields. If the test subject has undergone previous 
perimetry and met the established requirements, the results of such perimetry might be used 
for the purposes of the trial provided the period between the date of the previous taste and 
the inclusion date is no greater than 6 months. 
▪ 
Pachymetry: see 6.4.3.6 Corneal pachymetry. 
▪ 
Surface integrity evaluation: see 6.4.3.5 Ocular surface integrity. 
▪ 
Impression cytology: see 6.4.3.3 Goblet cell density. 
▪ 
Ocular comfort index: see 6.4.3.4 Ocular comfort index. 
▪ 
Subject diary submission: the PI must hand over the instrument “subject diary” to the subject. 
▪ 
Concomitant drugs assessment: see 6.3.3 Allowed and prohibited concomitant treatments 
and interventions before and after the study. 
6.5.2.3 Visit 1 
▪ 
Tonometry: see 6.4.3.8  Pressure. 
▪ 
Best corrected visual acuity: see 6.4.3.2 Best corrected visual 
▪ 
Surface integrity assessment: see 6.4.3.5  
▪ 
Subject diary submission: see 6.5.2.2  visit. 
▪ 
Subject diary review: the activity from the PI in which the diary tool is collected from the 
subject and its correct completion is evaluated. 
▪ 
Adherence assessment: see 6.3.2  
▪ 
Adverse events assessment: see 6.4.3.7  
▪ 
Concomitant drugs assessment: see 6.3.3  
▪ 
Continuity assessment: the determination from the PI and the subject’s desire to continue 
with is participation in the study. 
 

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6.5.2.4 Visit 2 and 3 
▪ 
Pregnancy test: see 6.5.2.1  visit. 
▪ 
Drug return: the delivery of the drug from the research subject to the center of the study. See 
6.3.4.1  Returns. 
▪ 
Drug delivery: the delivery of the drug from the patient in the study, from the research center. 
This will be performed according to section 6.3.4.1  and reception. 
▪ 
Adherence evaluation: see 6.3.2  
▪ 
Tonometry: see 6.4.3.8  
▪ 
Best corrected visual acuity: see 6.4.3.2 Best corrected visual capacity. 
▪ 
Surface integrity assessment: see 6.4.3.5  
▪ 
Subject diary review: see 6.5.2.3 Visit 1. 
▪ 
Subject diary submission: see 6.5.2.2  visit. 
▪ 
Adverse events evaluation: see 6.4.3.7  events presence. 
▪ 
Concomitant drugs assessment: see 6.3.3  and forbidden concomitant treatments and 
interventions before and after the study. 
▪ 
Continuity assessment: see 6.5.2.3 Visit 1. 
6.5.2.5 Final visit 
▪ 
Pregnancy test: see 6.5.2.1  visit. 
▪ 
Drug return: the delivery of the drug from the research subject to the center of the study. See 
6.3.4.1  Returns. 
▪ 
Adherence assessment: see 6.3.2  
▪ 
Tonometry: see 6.4.3.8  pressure. 
▪ 
Best corrected visual acuity: see 6.4.3.2 Best corrected visual capacity. 
▪ 
Cup/disc ratio: see 6.4.3.9  ratio. 
▪ 
Computerized perimetry: see 6.4.3.1  fields. In final computerized perimetry, a window period 
of ± 5 days will be allowed. 
▪ 
Pachymetry: see 6.4.3.6 pachymetry.  
▪ 
Surface integrity assessment: see 6.4.3.5  
▪ 
Impression cytology: see 6.4.3.3  cells density. 
▪ 
Ocular comfort index: see 6.4.3.4 comfort index. 
▪ 
Subject diary review: see 6.5.2.3 Visit 1. 
▪ 
Adverse events assessment: see 6.4.3.7  events presence. 
▪ 
Concomitant drugs assessment: see 6.3.3  and forbidden concomitant treatments and 
interventions before and after the study. 
6.5.2.6 Safety call: 
▪ 
Adverse events assessment: see 6.4.3.7  events presence. 
▪ 
Concomitant drugs assessment: see 6.3.3  and forbidden concomitant treatments and 
interventions before and after the study. The antihypertensive agent with which the subject 
study continued the trial will be recorded. 

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6.5.3 Study diagram 
 
Figure 4. Study diagram 
6.6 Sample size 
The simple size calculated for this study is 51 subjects. 
Each group will consist of 17 subjects and there will be three intervention groups. 
6.6.1 Sample size calculation 
Sample size was calculated using the formula for continuous quantitative variable in clinical trials, [9] 
the data were also entered into the online calculator, software developed by David Schoenfeld, Ph.D. 
with support by the MGH Mallinckrodt General Clinical Research Center. [63] 
𝑛= 2[(𝑍𝛼−𝑍1−𝛽)(𝛿)
𝑑
]2 
With a 95% statistical confidence, corresponding to type I error, equal to 1.96, with an 80% potency, 
corresponding to type II error, equal to 0.84. A standard deviation was considered from the intraocular 
pressure value measured on day 90, after the use of a 2.0 mmHg triple fixed combination (timolol + 
brimonidine + dorzolamide). The calculated expected difference in comparison with the intraocular 
pressure of the double 2.2 mmHg fixed combination group (timolol, brimonidine), reported in a clinical 
trial for the assessment of efficacy and safety with 212 Mexican subjects with primary open-angle 
glaucoma or intraocular hypertension. [31] 
According to the previous calculation, the result is 13 subjects (12.5) per group. The total amount 
when considering 3 intervention groups is 39 subjects, which was incremented by a 20% (8 subjects) 
by the possible losses. The total size of a required sample is 47 subjects. This is the reason why each 
group will consist of 17 subjects. 
Per group n = 17 subjects, one ye will be studied in the efficacy analysis. 
Total n = 51 subjects, one eye will be studied in the efficacy analysis. 
Considering an analogue method developed by Gandolfi S, et al. [64] in which the reduction of the 
intraocular pressure modification with the fixed antihypertensive therapy comprised by brinzolamide 
1%/brimonidine 0.2% is compared against the concomitant brinzolamide 1% + brimonidine 0.2% 
The sample size was calculated using the formula for continuous quantitative variables in clinical 
trials. 
Baseline 
(Day 0) 
Visit 1 
Visit 2 
Visit 3 
Final 
visit 
(Day 91 ±3) 
Safety call 
Washout period 
(5 to 28 days) 
Screening 
Treatment period in study groups: 
- 
PRO-122 
- 
Krytantek Ofteno® 
- 
Triple concomitant therapy 
(90 days) 
Security 
profile 
(15 days) 
Start of 
application 
(Day 1) 
(Day 90) 
End of 
application 

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𝑛= 2[(𝑍𝛼−𝑍1−𝛽)(𝛿)
𝑑
]2 
With a 95% statistical confidence corresponding to type I error, equal to 1.96, with an 80% potency, 
corresponding to type II error, equal to 0.84. A standard deviation was considered from the baseline 
difference value – final of the intraocular pressure measured at 3 months at 9:00 hours in 373 patients 
with primary open-angle glaucoma or intraocular hypertension, after the use of the 0.16 mmHg dual 
concomitant therapy (brimonidine + dorzolamide). [64] The difference in the IOP expected in 
comparison with the patients who received antihypertensive therapy in a double fixed combination 
(brinzolamide/brimonidine) would be at least 0.2 mmHg. 
According to the previous calculation, the result is 12.0 per group. The total amount when considering 
3 groups is 36 subjects, which was incremented by a 20% (6 subjects) by the possible losses. The 
total size of the required sample is 42 subjects. This is the reason why each group will consist of 14 
subjects. 
Per group n = 14 subjects, one eye will be studied in the efficacy analysis.  
Total n = 42 subjects, one eye will be studied in the analysis. 
Since the sample size calculation, using the values stated by Baiza L, et al., it was decided that a 
total of 51 patients with primary open-angle glaucoma or ocular hypertension was evaluated on this 
research protocol. 
6.7 Recruitment 
It is recommended that, during the development of this research protocol, the principal investigator 
requests the approval of the Research Ethics Committee and the Research Committee, as well as 
the authorization of the corresponding regulatory entity, to publish or disseminate in mass media, an 
invitation to participate in the trial for people with an incorrect antihypertensive control. 
It is possible to comment with other healthcare professionals, especially with those evaluating patients 
with chronic and degenerative diseases about the opportunity for them to receive gratuitous 
treatments, appropriate ophthalmologic assessment at no charge, as well as clinical studies which 
will allow to determine their ocular clinical status in a more precise way by participating in a clinical 
research protocol sponsored by Laboratorios Sophia, S.A. de C.V. 
7. Methods. Intervention assignment 
7.1 Assignment sequence generation 
The random numbers will be generated by the online tool: www.randomization.com  
3 strata corresponding to the intervention groups will be used, said strata will be balanced for a 
research center. Assignment will be 1:1:1. 
7.2 Blinding mechanism 
Blinding will be performed by the personnel assigned by the Laboratorios Sophia S.A. de C.V. Clinical 
Operations Management. The blinding will consist in the elimination of the primary label (commercial) 
for Krytantek Ofteno® and the triple concomitant therapy and the placement of a label identical to 
those of the other interventions. Since the bottles in which Krytantek Ofteno® and the concomitant 
therapies are different in color and cap shape to the ones used for the placebo and the PRO-122, a 
masking will be performed in the primary packaging, which shall be identical for all three interventions. 

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7.3 Implementation 
The assignment sequence will be generated by the Laboratorios Sophia S.A. de C.V. Clinical 
Operations Management. The research center will receive a set of envelopes which will have an 
individual intervention number. The envelopes will be identical on the outside. Each one of said 
envelopes will be shown to the participants for the principal investigator or a designated member of 
the investigator’s team to choose. 
7.4 Blinding (Masking) 
Blinding will be for the research subject and the principal investigator. Also, the statistical analysis will 
be performed in a blind manner in case a partial and final analysis is performed. 
Masking will be performed using identical boxes in primary packaging in all three groups. Blinding for 
the research subject and the investigator will consist in the replacement of the commercial labels for 
the comparator in the bottles and the use of identical labels containing an assignment number. 
7.4.1 Blinding opening 
Blinding might be opened in the following cases: 
1. Presence of a serious adverse event. 
2. Security alarm by the use of study drugs.  
3. In case the sponsor considers so by any safety reason or any other relevant motive. 
 
8. Methods. Collection, administration and data analysis. 
8.1 Data recollection methods 
A clinical monitor will be assigned to each research center, said monitor will be authorized to watch, 
review, procure and ensure the quality of the information obtained from the participants is trustworthy 
and reliable. Each monitor will schedule periodic visits to the research centers in order to review the 
source documents and verify all the information captured in the CRF. All clinical monitors will be 
trained regarding the study protocol information (objective, visits, procedures, accepted values range, 
etc.) In case the data are not identical between both records, the clinical monitor will generate a 
discrepancy, which will be resolved by the research center in the time the sponsor deems reasonable 
to fulfill the objectives of the clinical trial. The correction of discrepancies will be performed according 
to Good Documentation Practices. 
The data recorded in the CRF will be reviewed by Laboratorios Sophia personnel, trained in the 
ophthalmologic, clinical and pharmaceutical areas; the personnel will have the ability to generate 
discrepancies in case the data do not adhere to the stipulations in the research protocol or put the 
participants in risk. 
Once all discrepancies generated by the clinical monitors team and the clinical personnel are 
resolved, data will be downloaded in an electronical database (Excel worksheet) by personnel 
designated by the sponsor. A new review of the data will be made to verify the reliability of said data 
and new discrepancies can be generated in case it is considered to do so. 
The generated database will be safeguarded by the sponsor and only the designated personnel will 
have access to it. 

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8.1.1 Follow-up completion strategies 
• 
Participants will be given clear information on the importance of the study and the benefits 
the population will get from its results. 
• 
Participants will be given aid for transport in order for them to attend their visits.  
• 
Calls or messages will be made or a printed calendar will be given in order to remind the 
participants about their appointments and the activities to be performed and their estimated 
duration time. 
• 
In case the participant subject does not attend the appointment, the research center shall 
make a phone call to know the reason and will try to arrange a new appointment in the 
established window period or an non-scheduled appointment 
• 
In case the arrangement of an appointment is not possible, the participant will be questioned 
about the presence of adverse events and the motive of the study withdrawal as minimum 
data. 
8.2 Data administration 
The subject medical record (including clinical notes, test results, etc.) as well as the subject’s diary 
and the OCI questionnaire are considered as source data. 
The PI or the designated person of its team will fill the Case Report Form (CRF) as well as all the 
other documents provided by the sponsor (for example, the documents related with the treatment 
management). 
An electronical CRF was designed to record the data required in the protocol and that the investigator 
gathers in each one of the visits. 
For the self-assessment questionnaires it is not allowed that the principal investigator or the person 
in charge of filling modifies the parts written by the trial subject. 
The data recollection in the investigator’s site will be performed by the investigator him/herself or a 
designated person of its team after elaborating the Medical Record. The investigator or a designated 
person of its team will be trained regarding the filling of the CRF. 
All the corrections of the CRF data shall be made by the investigator or the designated person of its 
team according to the provided instructions. 
To ensure the confidentiality and safety of the data, user names and access codes will be used to 
restrict access to the system only to authorized personnel. 
The monitor shall ensure all the fields of the CRF are filled. After comparing the data against the 
source documents, the monitor will request the investigator to make a correction /clarification to be 
responded and closed as soon as possible. 
The Laboratorios Sophia S.A. de C.V. Scientific Committee will provide a last medical-scientific review 
and set the tone to lock the database. 
8.3 Statistical methodology 
8.3.1 Primary and secondary outcome variables 
The statistical analysis will be performed by the Laboratorios Sophia. The version 19 SPSS statistical 
program will be used. 

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The designated personnel will be blinded to the intervention groups. Codification will be performed 
using consecutive numbers for each intervention group. 
Data will be recollected and arranged in an Excel program worksheet. After this, data will be exported 
to the SPSS program platform. Variables will be categorized according to their nature. 
The result of the continuous quantitative variables will be presented as measures of central tendency: 
mean, standard deviation and ranges. See ¡Error! No se encuentra el origen de la referencia. m
easurement method. The total sample size will consider an eye as a case for the assessment of 
efficacy. In patients whose both eyes are eligible for the study, the right eye will be studied for the 
analysis. 
The normal results distribution will be obtained by the Kolmogorov-Smirnov and Shapiro-Wilks tests, 
as applicable. 
The statistical analysis of the continuous quantitative variables to find significant differences (p) 
will be as follows: 
• 
Intra-group analysis: Wilcoxon range test. 
• 
Inter-group analysis: Mann-Whitney U test. 
For the analysis, IOP measurements before the application of the intervention and two hours 
after will be considered. The difference level to consider significance will be 0.05 alpha or less. 
Nominal and ordinal qualitative variables result will be presented as frequencies, ratios and 
percentages. See ¡Error! No se encuentra el origen de la referencia. 
Statistical analysis to identify significant differences of the qualitative variables will be performed 
creating 2 x 2 contingency tables and it will be performed as follows: 
• 
Intra-group difference: McNemar test. 
• 
Inter-group difference: Pearson’s χ2 (chi square) test or Fisher’s exact test in expected 
values less than 5. 
The difference level to consider significance will be 0.05 alpha or less. 
For the report of adverse events, all eyes of participants randomly assigned to an intervention 
group will be considered. Results will be expressed in a number of cases and both eyes will be 
considered. 
The final report of results will be displayed in tables or graphics, as appropriate. 
8.3.2 Additional analysis 
An internal analysis will be performed to know the changes occurring between each visit. Also, 
a comparison between the IOP previous to the application of any of the interventions and the 
change 2 hours later; however, these results will not be considered as part of the efficacy 
analysis. 
8.3.3 Population analysis and missing data management 
The efficacy analysis will considered those cases in which the measurements of the baseline 
and final visits are completed. Those subjects without some of these measurements shall not be 
integrated to the final database to assess efficacy. In case the efficacy variables measurement 

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cannot be performed in the right eye, due to medical reasons or other, the left eye data will be 
used. 
The safety assessment will include in the analysis all those subjects (considering one eye or 
both) who have been exposed at least once to any of the interventions regardless of the visit in 
which they were eliminated from the study. 
 
9. Methods. Monitoring 
9.1 Monitoreo de datos 
The monitoring visits from a site monitor from Laboratorios Sophia, S.A. de C.V. have the purpose of 
confirming the studies sponsored by Laboratorios Sophia, S.A. de C.V. are performed according to 
the ethical principles from the Declaration of Helsinki which are consistent with the Good Clinical 
Practices and with the applicable regulatory requirements (verifying the continuous protocol 
compliance, amendment (s), reviewing the accounting logs of the research product, verifying the site 
personnel and the facilities remain appropriate to perform the study).The investigator shall assure to 
have enough time, space and qualified personnel for the monitoring visits. 
In order to perform the monitoring review, it is obligatory to provide a direct Access to all source data 
and data regarding the study site. The monitor will perform a review of the CRF and a Source 
Document Verification (SDV). An SDV is the verification of the CRF records via a comparison with 
the source data provided by the investigator for this purpose. 
Regarding the CRF, the monitor will mark the complete and approved screens in every visit. 
According to applicable regulations, the Good Clinical Practices and the Laboratorios Sophia, S.A. 
de C.V. procedures; Laboratorios Sophia, S.A. de C.V. monitors will contact the site before the start 
of the trial to review, along with the site personnel, the protocol, the regulatory, ethical and 
Laboratorios Sophia, S.A. de C.V. requirements. When reviewing the data collection procedures, the 
discussion will also include the identification, agreement and documentation of individual data for 
which the individual CRF records function as source document. 
Laboratorios Sophia, S.A. de C.V. will monitor the study to verify, among other things, the following: 
• 
The data are authentic, correct and complete. 
• 
The safety and rights of the subjects are being protected. 
• 
The study is being performed according to the currently approved protocol, any other study 
agreement, Good Clinical Practices and all applicable regulatory requirements. 
The investigator and Head of the medical institution (whenever applicable) agree to allow the monitor 
to have direct access to all relevant documents. 
The study monitoring visits will be performed at regular intervals, depending on the recruitment rate, 
according to the arrangements made by the investigator and the sponsor. All information related to 
these visits will be handled as strictly confidential. 
When completing or prematurely discontinue the study, the monitor will perform the activities for the 
site closure along with the investigator or the site personnel, as appropriate, according to the 
applicable regulations, Good Clinical Practices and Laboratorios Sophia, S.A. de C.V. procedures. 

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After the study is closed, the investigator shall keep all the records from the study in the site in a safe 
place. All records shall be kept to allow for their easy and appropriate retrieval, whenever necessary 
(for example, in an audit or an inspection). Laboratorios Sophia, S.A. de C.V. will inform the 
investigator/institution about the time period in which these records shall be kept in order to comply 
with all applicable regulatory requirements; however, the investigator/institution shall seek the written 
approval of the sponsor before proceeding to the elimination of these records. The minimum retention 
time will satisfy the strictest applicable standard to that site for the study, according to the GCP 
dispositions, any institutional requirement or the applicable laws and regulations or the Laboratorios 
Sophia, S.A. de C.V. standards/procedures. 
The investigator/institution shall notify Laboratorios Sophia, S.A. de C.V. about any change in the file 
arrangement including, but not limited to, the following: file in an off-site facility, property transfer of 
the records in case the investigator leaves the site. 
9.2 Preliminary analysis and early study termination 
The partial analysis will allow the sponsor to take a decision on the early termination of the study in 
case the safety of the participants is compromised. 
The early termination study will be considered in the following cases: 
1. Presence of serious adverse events in more than 5% of the participants in each intervention 
group. 
2. The competent authority (e.g. COFEPRIS) considers termination due to safety alerts. 
3. The sponsor determines termination due to self-interest or events such as: financial support, 
manufacturing errors, etc. 
4. Recruitment lower than expected. 
In case the decision is early clinical trial termination, this will be informed within the first 24 hours to 
all research centers, via the available communication paths. Also, this will be informed to the 
corresponding authority in each country (if applicable) and to the involved Ethics Committees. 
Each research center has an obligation to inform the subjects participating in the clinical trial in a 
period no longer than 24 hours, after receiving the information from the sponsor. All involved subjects 
in any phase of the study shall be informed. 
The Laboratorios Sophia, S.A. de C.V. Clinical Operation Management and Medical Direction will be 
in charge of the preliminary assessment and will have the ability to determine the fate of this protocol, 
as they deem appropriate. 
9.3 Adverse events 
9.3.1 Investigator responsibilities 
To perform the adverse events verification via interrogation, relevant physical examination, and 
assessment of progress as well as the appropriate medical and pharmaceutical management, 
resolution or outcome and definitive discharge following the definitions determined in the national and 
international regulations. [65] [66] [67] 
In case of adverse events or any occurrence which compromises the health and wellbeing of the 
patients, relevant medical services will be provided in the research site or the patient will be referred 
to the hospital center with the best health care capabilities with which the research site or investigator 
has a medical attention agreement. The investigator shall notify the sponsor’s clinical monitor, 
according to the periods established in the national and international regulations. In case of serious 

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adverse events, the sponsor shall be notified and the corresponding information shall be recorded in 
the case report form and the Research Ethics Committee and the Research Committee shall be 
informed also. 
The treatment of adverse events shall be performed according to the event attention diagram (See 
Figure 5. Attention to the adverse event). 
In the final report elaborated by the Laboratorios Sophia, S.A. de C.V. Clinical Operations Department 
Scientific Committee, the adverse events report shall be included in compliance of the current national 
and international regulations. [65] [66] 
9.3.1.1 Adverse events record in the Case Report Form  
The record of adverse events considers the information regarding the identification data of the 
participating patient such as code, age, sex, left eye, right eye. 
Information about the type of adverse event, adverse reaction or investigational drug or product 
adverse reaction suspicion, as appropriate. The date on which the adverse event is occurred as well 
as the date in which the investigator is notified about it, outcome or resolution date, as applicable. 
Clinical diagnosis is indicated. If there is a lack of therapeutic response to the investigational drug or 
product, this shall be notified as an adverse reaction. In concomitant drugs, the used therapy for the 
pharmacological management of the adverse event, adverse reaction suspicion or adverse reaction 
shall be included. Record the outcome or resolution of the event: patient recovered without side 
effects, patient did not recover. Patient died due to the adverse reaction/event, patient died and it is 
considered that the drug might have contributed to this, patient died and death is not related to the 
investigational drug/product or also state that the event consequence is unknown. 
Record information on the investigational drug or product or the drug associated with the adverse 
event, adverse reaction or adverse reaction suspicion. As applicable, the information regarding the 
generic name, nonproprietary name or code of the investigational drug or product, according to the 
methodological design of the study; this is relevant in the case of blinded studies or studies in which 
placebos are used as comparators, since there are circumstances that justify the opening of the 
blinding procedure to determine if the adverse event, adverse reaction or adverse reaction suspicion 
might be attributable to the active agents or to the pharmacologically inert substance (s), as might be 
the case of vehicles or additives, according to the clinical investigation phase in which the drug 
development is in. 
 It will also be necessary to capture the data relating to the a) lot number, b) manufacturer laboratory, 
c) expiration date, d) dose, e) route of administration, f) dates of start and g) term of the Administration 
and/or consumption, because of the prescription. According to whether it's an investigational product 
or medicinal product (a protocol currently involving the patient), or either it is a medication consumed 
by the subject in research as a base for the treatment of comorbid diseases or that it is used for the 
handling of any sign or transient symptoms that does not correspond to the Natural history of 
pathology that motivated his entry into the research protocol.   
Record the removal or maintenance of the drug, investigational product or medicinal product, as 
appropriate. Indicate if at the moment of the withdrawal of the investigational product or medicinal 
product or the suspicious (of the event) drug product, the adverse event disappears. Also indicate if 
a dose adjustment is made, if the event changes in terms of intensity or severity and persistence of 
the reaction. It is important to indicate if the adverse reaction or event reappears in those patients 
that are exposed again to the drug or investigational product or drug product, which previously had 
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Regarding the concomitant pharmacotherapy. Indicate the generic name, dose, route of 
administration, dates of start and term of its employment, as well as the reason of its prescription 
regardless if it is according to the prescribing information or data sheet, or if it is employed out of the 
norm or of what has been authorized by the local, national or international regulatory entity. 
Concerning the relevant medical history. The analysis of the adverse event, adverse reaction or 
suspected adverse reaction considers the information previously narrated, however the clinical 
context in which the said damaging phenomenon in the participants of the Clinical research Protocol 
is of special interest. Consequently, if the investigator considers convenient to mention the information 
about the participant’s previous condition, hypersensitivity or allergy phenomena, previous surgical 
procedures, laboratory or cabinet tests which the participant has undergone, etc., he/she has to do 
so. In case of having enough space in the case report format, the information can be completed in 
his/her clinical note, on the medical record. 
9.3.1.2 Monitoring of adverse events 
The PI will provide care and conduct the AE that the participant shows until the outcome of it, 
according to what it is refer into the following paragraph. 
9.3.1.3 Procedures for a serious adverse event 
The process of care of the adverse event considers the following stages: 
 
Figure 5. Attention to the adverse event 
 
A. During the development and conduction of this clinical research the patient can present 
undesirable adverse events or adverse reactions, of medical involvement, which do not 
necessarily have a causal relationship with the investigational product or drug product. These 
damaging phenomena can occur through the usage of the investigational drugs, in an 
unintended way, with licensed doses for human use granted by a local, national or 
international regulatory entity, whether for the prophylaxis, diagnosis, treatment or 
modification of any physiological process. However it may be suspected that the 
investigational drug or product or the placebo cause some unwanted clinical manifestation. 
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can occur during the systematic evaluation of the participants (in the days when the clinical 
review, according to the schedule of activities, is scheduled) or suddenly , in such a way that,  
B. The investigator must be the first person to who the patient notifies that he/she has developed 
or presented any damaging phenomenon of clinical nature during his/her participation in the 
present Protocol of research.  
C. According to his/her clinical trial, based on the relevant physical exam, interrogation, etc.; as 
well as to the analysis of the information available in the medical literature and of the referred 
in investigator manual; the prescribing information or data sheet  of the comparator drug, the 
principal investigator determines the relevant attention of the damaging event/ reaction; 
either:  
D. in the site of research or in the hospital of greater resolution capacity (1st, 2nd or 3rd level of 
medical care). In such a way that, if the investigator sends the patient to the hospital, he/she 
participates as a reference system. It can be through an ID card which indicates that the 
patient belongs to this research and there is a number of trade or folio, which belongs to the 
Convention of urgent care with the health institution of greater resolution capacity or by 
means of a medical reference note issued by the principal investigator so that the proper 
attention is provided to the participant patient.  It should be noted that the sponsor of the 
study, Laboratorios Sophia, S.A. de C.V., will pay the expenses for the participant patient 
medical care, only if the adverse event, adverse reaction or suspected adverse reaction to a 
drug is related or associated with the investigational drug product or product.  
E. Taking the clinical information collected, whether during the attention on the research site or 
provided by the treating physician(s) at the hospital, the principal investigator records the 
adverse event, suspected adverse reaction or adverse reaction to medicine in his/her clinical 
note of the clinical file recording its seriousness, intensity (mild, moderate or severe), its 
relation to the investigational drug or product , as well as 
F. The migration of the relevant data to the case report format and to its respective adverse 
event section. Indicate the relevant information, already referred to in section 9.3.1.1., by 
virtue of that in the cases of serious adverse events, which should be reported in less than 
24 hours after the time in which the principal investigator have knowledge thereof, the clinical 
study monitor is aware, in order to inform to the Scientific Committee and the sponsor’s 
Pharmacovigilance department and subsequently to inform to the Research Ethics 
Committee. Regarding to the non-serious adverse events, these will be registered and 
properly cared, and in the final report of the clinical trial the regulatory entity must be informed 
about the safety profile of the investigational product or drug product. 
Registration of the outcome of the adverse event, suspected adverse reaction or adverse reaction 
depends substantially on the monitoring that the principal investigator made to the participant, as it is 
expected that most damaging phenomena, see section of the safety profile in paragraph 5.3 and in 
the investigator manual, are of ophthalmic nature, there may however be systemic alterations. 
Therefore, according to the investigator, the patient withdrawal or permanence will be considered in 
accordance with the provisions taken in section 6.2.3 Elimination Criteria of this Research Protocol. 
9.3.1.4 Causality assessment 
The causality assessment of the methodology used to estimate the probability of attributing the 
adverse reaction, the suspicious of the same or the observed adverse event to a drug, investigational 
product or drug product, considers probabilistic categories according to the  available evidence and 
to the information quality, based on the national pharmacovigilance standards.[65] As a tool to 
facilitate the causality probabilistic categorization, the principal investigator can use the Karch and 
Lasagna’s algorithm modified by Naranjo referred by Aramendi I, 2011 in which different items are 

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graded which allow to assign a value to the cause and effect relationship between the drug 
administration and the adverse reaction.[68] See table ¡Error! No se encuentra el origen de la 
referencia. 
Karch and Lasagna’s algorithm modified by Naranjo 
No. 
Reagent 
Score 
Yes 
No 
1. 
There are previous conclusive reports on adverse reactions to medication, adverse event 
or suspected adverse reaction to medication. 
+1 
0 
2. 
The adverse event occurred when it the suspicious medication was administered 
+2 
-1 
3. 
The adverse reaction to medication, adverse event or  suspected adverse reaction to a 
medication improved upon suspension or with the administration of a specific antagonist 
+1 
0 
4. 
The adverse reaction to medication/ adverse event/ suspected adverse reaction to 
medication appeared again with the administration of the drug/ investigational 
product/drug product 
+2 
-1 
5. 
There are alternative causes which can cause this reaction 
-1 
+2 
6. 
The adverse reaction/ event adverse / suspected adverse reaction to medication occurred 
after the placebo administration 
-1 
+1 
7. 
It was determined the concentration of the drug into the bloodstream or other liquids in 
toxic concentrations 
+1 
0 
8. 
The intensity of the adverse reaction/ adverse event / suspected  adverse reaction to 
medication was greater at higher doses or less with lower doses 
+1 
0 
9. 
In the past, the patient has had similar reactions to the investigational product/drug 
product. 
+1 
0 
10. 
The adverse reactions/ adverse event/ suspected adverse reaction to medication was 
confirmed by any objective evidence 
+1 
0 
                                                                                                                               Total score 
sum 
Probabilistic category based on the score obtained 
I 
The causal relationship is verified  
≥,9  
II 
It is possible that the RAM is due to the medication or the investigational product 
5 to 8 
III 
It is possible that the RAM is due to the medication or the investigational product 
1 to 4 
IV 
The causal relationship is questionable 
0 
Shows the reagents considered by the Karch and Lasagna’s algorithm modified by Naranjo where everyone receives a defined score and 
the final sum allows to estimate the probabilistic category of the cause-effect relationship  between the administration of the investigational 
product/ drug product, and the adverse reaction, adverse event or suspected adverse reaction. Consider that if the information is not 
available, a score equal to zero should be registered.  
Table 12.  Karch and Lasagna’s algorithm modified by Naranjo 
So that the degree of certainty to establish as an agent of the damaging phenomenon occurring to 
the participant patient to the investigational product or investigational drug product (as appropriate), 
can be directly indicated by the principal investigator on the basis of his/her clinical experience or by 
the voluntary application of the aforementioned tool. However, it is important that the investigator 

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takes into account the following arguments in favor of the causal relationship: the strength of 
association refered to the number of cases related to the exposed. The consistency of the data, i.e. 
the presence of a feature or common pattern. The exposition-effect pattern: that determines the 
relationship with the site of manifestation, time, dose and reversibility after discontinuation. Biological 
plausibility: referring to the possible pharmacological or pathophysiologic mechanisms involved in the 
development or presentation of the adverse event. Experimental findings: for example the 
appearance of abnormal metabolites or high levels of the biotransformation of the drug product or 
product. Analogy: the acquired experience with other related drugs, adverse reactions often produced 
by the same family of pharmacological agents. Nature and characteristics of the data: objectivity, 
accuracy and validity of the relevant documentation.[69] 
9.3.2 Responsabilities of the sponsor 
The sponsor will be responsible for, and will cover the medical care costs of the adverse events 
related to the investigational product. 
9.4 Audit 
To ensure compliance with all applicable regulatory requirements and the GCP, Laboratorios Sophia 
S.A. de C.V. could carry out a quality assurance audit. The regulatory agencies could also carry out 
a regulatory inspection to this study.  
9.4.1 Study pre-audit 
The study centers included in the study will be subject to a feasibility visit prior to the selection of the 
Center, which will verify that the facility complies with the minimum requirements indicated by the 
sponsor.  
9.4.2 Audit/inspection during the conduct of the trial 
May take place at any time: prior, during or after the conclusion of the study. If any audit or inspection 
is performed, the investigator and the institution must agree to allow the auditor/inspector to have 
direct access to all relevant documents, and will assign their time and that of its staff to the 
auditor/inspector in order to discuss the findings and any outstanding issue. 
 
10. Ethical considerations 
10.1 Approval of the commitees 
This study will be performed according to the Declaration of Helsinki guidelines, World Medical 
Association 2013. Nuremberg Code; Nuremberg trial by the International Tribunal at Nuremberg, 
1946 Belmont Report, National Commission for Protection of Human Subjects of Biomedical and 
Behavioral Research, 1979.  It will be led in accordance with the scientific and technical requirements 
needed for the registration of human medicinal products of the Good Clinical Practice guide of the 
International Council for Harmonization. International Ethical Guidelines for the Biomedical Research 
in Humans of the Council for International Organizations of Medical Sciences, CIOMS, 2002. 
International Ethical Guidelines for epidemiological studies of the Council for International 
Organizations of Medical Sciences, CIOMS, 2008.  
The Research Ethics Committee and the Research Committee will evaluate the Protocol before 
carrying out the study and they will issue its approval or possible modifications for its realization, these 
committees must be notified of any significant change to the Protocol. Besides the above, the current 

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regulations issued by the Ministry of Health or their counterpart in the correspondent countries, shall 
be complied. The Mexican General Health Law (Ley General de Salud), NOM 012 Official Mexican 
Standard NOM-012-SSA3-2012, that establishes the criteria for the execution of research projects 
for health in humans. The Argentinian National Administration of Food, Drugs and Medical 
Technology (ANMAT) 6677/2010 disposition. The study is considered as a research with greater risk 
than the minimum according to the regulations of the Mexican General Health Law in the Research 
for health, Title II, Chapter I, Article 17, Category III, published in the Official Gazette on January 6, 
1987. 
The principal investigators or the studies coordinators or the authorized personnel by the sponsor will 
submit for evaluation, by the Research Ethics Committees, the Research Committees and when apply 
by the Biosafety Committee, the investigational project essential documentation: Research protocol, 
the Informed consent letter, the investigator manual, the subject journal, as well as the ones 
additionally requested, according to the local , national or international requirements applicable by 
the regulatory entities.  
The study will not start at the research site if the confidentiality agreements and the economic 
proposal of each of the principal investigators doesn’t exist, duly signed and without the previous 
favorable opinion and/or the approval of the Research Ethics Committees, Research, Research 
Committees and, when apply, by the appropriate Biosafety Committee.  
The study will not start if the relevant local, national or international regulatory requirements are not 
fulfilled and if the appropriate Sanitary Authorization is not available. 
10.2 Amendments to protocol 
The amendment process will be relevant where there is a need to make any changes to a document 
that is part of the project or research protocol, resulting from changes to the methodology framework, 
replacing the principal investigator or the risks identification in the research subjects. The documents 
likely to be amended will be: Protocol, the informed consent letter, the investigator manual, 
documents for the patient, measuring scale, and the activities schedule. 
Any amendment must be approved by the sponsor and/or the principal investigator. The document(s) 
amended, once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, where applicable, by the Biosafety Committee, (entities that issued the initial favorable 
opinion for the research conduction) will be sent for its authorization by the relevant regulatory entity.  
The amendments which substantially altered the Protocol or conferred it an additional or different risk 
to the research subjects must be approved by the Committee. Is responsibility of the investigator to 
take measures in situations that require an immediate action in order to avoid unnecessary damage 
to the study participants. 
The principal investigator is responsible to inform the Research Ethics Committee about any 
amendment to the Protocol that could eventually affect the rights, safety and well-being of research 
participants. Likewise, the investigator must make known any situation or new knowledge that shows 
an increased risk for the participants, term or premature termination of the study, the reasons and the 
results obtained so far. Additionally, the investigator must inform about the conclusion of the study, 
at the moment of the completion of the research protocol.  
The list of amendments, and where necessary the issuance of the list of errata, will be referred in the 
final report of the investigation. 

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10.3 Consent 
10.3.1 Obtaining 
The Informed consent must be obtained before the performance of any procedure indicated in the 
Protocol in the subject. 
The written informed consent documents will incorporate the elements of it described in the 
Declaration of Helsinki guidelines and the ICH guidelines for the Good Clinical Practices and these 
must be consistent with all the applicable Laws and Regulations. 
The PI will provide to the potential participants all the information related to the characteristics of the 
study, as well as the potential benefits, risks, objectives and procedures of the study.  
This information shall be in an understandable language for the subject, it will be explain to the subject 
who has the right to end his/her participation in the study at any stage, without affecting the 
relationship with the investigator and/or its future assistance. The Informed consent will be submitted 
for consideration of the potential participant; he/she must have enough time to analyze each and 
every one of the aforementioned aspects and in case he/she has a doubt, this will be clarified by the 
person in charge of obtaining the informed consent. Once the participant accepts to participate in the 
study, he/she must sign and date the letter of informed consent in the presence of two witnesses who 
are related or unrelated to the subject of study, they will participate in the informed consent process 
and sign endorsing that the process was carried out prior to any study procedures, that the study 
information was clearly explained and that all the doubts were clarified, if any. 
In case of a subject is illiterate, the acceptance will be done with his/her fingerprint, and if the subject 
is not able to give and appropriate informed  written consent, a representative of the subject “legally 
authorized" can provide such consent instead of the subject in accordance with the applicable laws 
and regulations. 
The PI must also sign and date this consent. 
The informed consent must be signed in duplicate by all involved, and two witnesses, a copy will be 
filed in the folder of the investigator and the other will be delivered to the participant. The IP shall 
document in the clinical history of the subject, the date on which he/she signed the informed consent. 
10.3.2 Special considerations  
Auxiliary studies to be carried out during the conduct of the trial (pachymetry, perimetry and 
impression cytology) do not have an invasive nature and pose no additional risk that must be 
considered part of the listed procedures of the informed consent.  
10.3.3 Modification to the informed consent 
Any change to the "informed consent" is an amendment to this document and shall be submitted 
before the Research Ethics Committees, and if applicable, before the competent authorities for its 
approval. 
The amendment shall include a copy of the new version in the language or languages of the country. 
Such amendments may be implemented only after obtaining the written approval of the Research 
Ethics Committe and the Regulatory agency (as applicable), except a required amendment to remove 
an immediate hazard to the subjects of the study. 

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Each subject affected by the amendment should fill it, date it and sign two original documents of the 
new version. A signed original document of the amendment shall be given to the subject and the 
second original of this document shall be kept by the investigator. 
 
10.4 Confidentiality 
All the documents and information provided to the investigator by the sponsor are strictly confidential. 
The investigator expressly agrees that the data about his/her professional and clinical experience, 
provided to the sponsor on paper and stored in electronic or digital form, are solely for the related 
usage to his/her activities with the clinical studies sponsor, in accordance with Good Clinical 
Practices. The investigator accepts that he/she as well as the members of his/her team will use the 
information only within the framework of this study in order to carry out the Protocol. This Convention 
is mandatory as long as the confidential information has not been disclosed to the public by the 
sponsor. The Protocol of the clinical study, provided to the investigator, may be used by his/herself 
and by his/her colleagues to obtain the informed consent of the subjects of the study. The Protocol 
of the clinical study, as any information taken of the same must not be reveal to other parts without 
the written authorization of the sponsor.  
The investigator 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 for their 
request. In the last instance, the investigator is obliged to inform Laboratorios Sophia, S.A. de C.V. 
before disclosing the information to these authorities. The investigator will fill and keep a record of 
the subjects selection as well as the identification and enrollment list of each of the participant 
subjects in the study. The investigator agrees to give access on the site to the auditor or the 
representatives of the competent authorities. The information will be treated pursuant to professional 
secrecy. 
10.5 Declaration of interests 
 The PI is committed to make a declaration of financial interests and conflict of interests prior to the 
start of the study. 
10.6 Access to information 
The final study database will be property of Laboratorios Sophia, S.A. de C.V. and its access will be 
restricted. The PI won’t have access to this, except with the prior written permission of the Sponsor. 
10.7 Auxiliary and post-study-termination cares 
The care of the AE will be carried out according to the section 9.2 Adverse Events. 
10.8 Biosafety aspects 
WITHOUT IMPLICATIONS FOR BIOSAFETY 
This protocol titled: “Phase III clinical study, to evaluate the no inferiority in the ocular pressure 
decrease of the preservative-free ophthalmic solution PRO-122, manufactured by Laboratorios 
Sophia S.A. de C.V., versus concomitant therapy in subjects with no-controlled primary open-angle 
glaucoma and/or intraocular hypertension” and number: SOPH122-0316/III do not have implications 
of BIOSAFETY, since no infectious or contagious biological material; pathogenic strains of bacteria 
or parasites; virus of any kind; Radioactive material of any kind; animals and/ or cells and/ or 
genetically modified plants; toxic, hazardous or explosive substances; any other material that may 

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endanger the health or physical integrity of the staff of the research center or research subjects or 
affect the environment will be used. In addition, it is stated that in this project transplant procedures 
of cells, tissues or organs, or cell therapy won’t be carried out, neither laboratory animals, livestock 
nor wildlife will be used. 
10.9 Final report and result publication  
10.9.1. Final report 
Once the statistical analysis is completed, a final report shall be drawn up with the obtained results, 
carried out by the Scientific Committee of the Department of Clinical Operations of Laboratorios 
Sophia, S.A. de C.V. Such report shall be drawn up following the recommendations of the ICH E3 
guideline, Step 4. 
10.9.2 Disclosure of results 
Sponsor’s plan to communicate the results of the study to the investigators, participants, and 
regulatory entities. 
Regardless of the study outcomes, Laboratorios Sophia, S.A. de C.V., is committed to communicate 
the study final report to the principal investigators and the corresponding regulatory entities of the 
countries with participating research centers. Always maintaining the rights over the publication and 
disclosure of the information.  
10.9.3 Publication of results 
Laboratories Sophia, S.A. of C.V., serving as the study sponsor, assumes full responsibility for its 
function and retains the proprietary rights on the results of the study, which can be used in the manner 
it deems appropriate. 
Since it is a multicenter study, the first publication must be made only with data collected from various 
centers and analyzed under the responsibility of Laboratorios Sophia, S.A. de C.V. The PI is 
committed to not publish or communicate the data collected just in one center or only in a part of the 
centers before the publication of the full results of the study, unless he/she has the prior written 
consent of Laboratorios Sophia, S.A. de C.V. 
Any project of publication and/or communication related to the study and/or the results obtained 
during the study or after the completion of the study must be presented to the participating medical 
investigators at least 30 days in the case of a publication and 15 days in the case of a summary, 
before the scheduled date for communication and/or presentation of a publication. The medical 
investigator(S) will make their comments on the project within 15 days in the case of a publication 
and within 7 days in case of a summary, from the date the project is received. 
However, if the sponsor is in the process of submitting a patent application on the study results, the 
sponsor may delay the publication or communication of the results of the study to date of registration. 
 
 
 
 

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11. References 
 
[1]  R. Weinreb y P. Khaw, «Primary open-angle glaucoma,» Lancet, vol. 363, pp. 1711-1720, 2004. 
[2]  H. Quigley y A. Broman, «The number of people with glaucoma worldwide in 2010 and 2020,» 
Br J Ophthalmology, vol. 90, pp. 262-267, 2006.  
[3]  B. Chauhan, F. Mikelberg, A. Balaszi y C. G. S. Group, «Canadian Glaucoma Study Group: 2. Risk 
factors for the progression of open-angle glaucoma,» Arch Ophthalmol, vol. 126, pp. 1030-
1036, 2008.  
[4]  Collaborative Normal-Tension Glaucoma Study Group, «Comparison of glaucomatous 
progression between untreated patients with normal-tension glaucoma and patients with 
therapeutically reduced intraocular pressures,» Am J Ophthalmol, vol. 126, pp. 487-497, 1998. 
[5]  M. Kass, D. Heuer y E. Higginbotham, «The Ocular Hypertension Treatment Study: a 
randomized trial determines that topical ocular hypotensive medication delays or prevents 
the onset of primary open-angle glaucoma,» Arch Ophthalmol, vol. 120, pp. 701-713, 2002.  
[6]  D. Musch, B. Gillespie y L. Nisiol, «CIGTS Study Group. Intraocular pressure control and long-
term visual field loss in the Collaborative Initial Glaucoma Treatment Study,» Ophthalmology, 
vol. 118, pp. 1766-1773, 2011.  
[7]  A. Heijl, M. Leske y B. Bengtsson, «Early Manifest Glaucoma Trial Group. Reduction of 
intraocular pressure and glaucoma progression,» Arch Ophthalmol, vol. 120, pp. 1268-1279, 
2002.  
[8]  European Glaucoma Society, Terminology and guidelines for glaucoma, Savona, Italia: 
SvetPrint, 2014.  
[9]  L. Jeyaseelan y P. Rao, «Methods of determining sample sizes in clinical trials,» Indian 
Pediatrics, vol. 26, pp. 115-121, 1989.  
[10] E. Kim y R. Varma, «Glaucoma in Latinos/Hispanics,» Curr Opin Ophthalmol, vol. 21, nº 2, pp. 
100-105, 2010.  
[11] R. Varma, D. Wang, C. Wu, B. Francis, B. Nguyen, V. Chopra, F. Memarzadeh, M. Torres y S. 
Azen, «Los Angeles Latino Eye Study Group: Four.year incidence of open-angle glaucoma and 
ocular hypertension,» Am J Ophthalmol, vol. 154, nº 2, pp. 315-325, 2012.  
[12] R. Germano, R. J. Susanna, C. De Moraes, B. Susanna, C. Susanna y M. Chibana, «Effect of 
switching from latanoprost to bimatoprost in primary open-angle glaucoma patients who 
experienced intraocular elevation during treatment,» J Glaucoma, vol. 25, pp. e359-e366, 
2016.  
[13] P. Bhagat, K. Sodimalla, C. Paul, S. Pandav, G. Raman, R. Ramakrishnan, A. Joshi y A. Raut, 
«Efficacy and safety of benzalkonium chloride-free fixed dose combination ot latanoprost and 
timolol in patients with open-angle glaucoma or ocular hypertension,» Clin Ophthalmol, vol. 
8, pp. 1241-1253, 2014.  

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[14] S. Sharma, S. Trikha, S. Perera y T. Aung, «Clinical effectiveness of brinzolamide 1%- 
brimonidine 0.2% fixed combination for primary open-angle glaucoma and ocula 
hypertension,» Clin Ophthalmol, vol. 9, pp. 2201-2207, 2015.  
[15] G. Hollo, F. Topouzis y R. Fechtner, «Fixed-combination intraocular pressure-lowering therapy 
for glaucoma and ocular hypertension: advantages in clinical practice,» Expert Opin 
Pharmacother, vol. 15, pp. 1737-1747, 2014.  
[16] C. Olthoff, J. Shcouten, B. van de Borne y C. Webers, «Noncompliance with ocular 
hyupotensive treatment in patients with glaucoma or ocular hypertensive treatment in 
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vol. 112, nº 6, pp. 953-931, 2005.  
[17] I. Goldshtein, V. Shalev, N. Zigman, G. Chodick y H. Levkovitch-Verbin, «The MAcabbi 
Glaucoma Study: treatment patterns and persistence with glaucoma therapy in a large israeli 
health maintenance organization,» J Glaucoma, vol. 25, nº 4, pp. e386-e391, 2016.  
[18] E. Higginbotham, «Considerations in glaucoma therapy: fixed combinations versus their 
component medications,» Clin Ophthalmol, vol. 4, pp. 1-9, 2010.  
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12. Signature page 
Sponsor’s responsible medical officer: 
 
Dr. Leopoldo Martín Baiza Durán 
Study Director: 
 
Dr. Aldo Arturo Oregon Miranda 
Protocol authors: 
Dr. Oscar Olvera Montaño 
Dr. Adolfo Daniel Rodríguez Carrizalez 
Dr. Arieh Roldán Mercado Sesma 
Protocol internal reviewer 
 
QFB. Virginia Manuela Villa Félix 
Protocol external reviewer: 
 
Dr. Juan Roberto Sampaolesi 
English version: 
 
Quality Pro Translations S.A. de C.V 
 
Saul 17, Guadalupe Tepeyac, 07840 Ciudad de México 
 
 
 
 
 
 
 

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13. Annexes 
13.1 Ocular comfort index 
 
Page 1 of 2 
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13.2 Efron scale for conjunctival hyperemia 
 
13.3 Oxford scale  
 
 
 
 
 
Normal 0 
Very mild 1 
Mild 2 
Moderate 3 
Severe 4