Conditions: Primary Open Angle Glaucoma Ocular Hypertension
Keywords: timolol dorzolamide brimonidine Glaucoma Ocular hypertension
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 60
Healthy volunteers: no

Brief summary:
Aim: To demonstrate the non-inferiority of the PRO-122 ophthalmic solution manufactured by Laboratorios Sophia S.A. de C.V. versus Krytantek Ofteno® ophthalmic solution like hypotensive therapy in subjects with primary open angle glaucoma or ocular hypertension.

Study design: a multicentric, prospective, crossover (2x2), double blind clinical study. Sample size: one hundred patients with primary open angle glaucoma or ocular hypertension. Patients in the period 1: In the first sequence 30 patients will be assigned to receive the ophthalmic solution: Krytantek Ofteno ® (timolol 0.5%%/brimonidine 0.2%/dorzolamide 2%) 1 drop B.I.D. during 30 days and the second sequence 30 patients will be assigned to receive the ophthalmic solution: PRO-122 1 drop B.I.D. during 30 days in the same period. Washout period: 20 hours. Patients in the period 2: the pharmacological intervention change to the opposite therapy for 30 days

Detailed description:
The American Academy of Ophthalmology Glaucoma Panel: The primary open angle glaucoma (POAG) is a progressive, chronic optic neuropathy in adults in which intraocular pressure (IOP) and other currently unknown factors contribute to damage and in which, in the absence of other identifiable causes, there is a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons. This condition is associated with an anterior chamber angle that is open by gonioscopic appearance.

This is a multicentric, crossover, double blind and prospective clinical study. The investigators will include patients with confirmed diagnosis of primary open-angle glaucoma or ocular hypertension, with target intraocular pressure (TIOP) within a range at which a patient is likely to remain stable or at which worsening of glaucoma will be slow enough that the risk of additional intervention is not justified.

Patients will be randomly divided into 2 groups, one of them treated with a known formulation of timolol 0.5%/brimonidine 0.2%/dorzolamide 2% (Krytantek Ofteno®, Laboratorios Sophia, Mexico) and the other one treated with PRO-122 ophthalmic solution. Patients will receive 1 drop B.I.D. into the lower conjunctival sac of either formulations and were examined at days: 1, 15, 30, 45 and 61 after initiation of treatment. A phone call security at day 75 will be performed.

Primary efficacy outcome: To evaluate the efficacy of PRO-122 versus Krytantek Ofteno® instilled onto the ocular surface in subjects with primary open angle glaucoma (POAG) or ocular hypertension (HTO), to control and maintenance of the target intraocular pressure (TIOP).

Arms:
arm 1: In group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be retested and switched to a PRO-122 solution which will be used for 30 days until the 60th day, The final visit. arm 2: In group B, therapy with Krytantek Ofteno® will be suspended and changes for PRO-122 for 30 days, in which the subject will be retested and later switched to Krytantek Ofteno® solution which will be used for 30 days until the 60th day, The final visit.

Interventions: intervention 1: PRO-122 intervention 2: Krytantek Ofteno®
Intervention descriptions: intervention 1: 1 drop every 12 hours for 30 days of alternating treatment with 30 days intervention 2: 1 drop every 12 hours for 30 days of alternating treatment with 30 days

Protocol document:
Prot_SAP_000.pdf: 
PRO-122 Clinical Trial Protocol SOPH122-0914 / III Version 2 
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A Multicentric, Prospective, Crossover, Double-Blind 
Clinical Study, to Evaluate the Non-inferiority of the 
PRO-122 ophthalmic solution, after treatment with 
Krytantek Ofteno ®, in subjects with primary open-
angle glaucoma (POAG) and / or intraocular 
hypertension (OHT). CONFORT Study K. 
 
 
Drugs under study: Brimonidine 2 mg, Dorzolamide 20 mg, Timolol 
5 mg. 
Therapeutic indication: Antiglaucomatous 
Development phase: Phase 3 
Protocol code: SOPH122-0914 / III 
Sponsor: Laboratorios Sophia, S.A. of C.V. 
Version: No.2 
Date: March 2017 
 
 
 
 
 
 


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2. STUDY SHEET SUMMARY  
Sponsor's name: Laboratorios Sophia, S.A. of C.V. 
Active Ingredient Name: Brimonidine 2 mg, Dorzolamide 20 mg, Timolol 5 mg. 
Study title: A Multicentric, Prospective, Crossover, Double-Blind Clinical Study, to Evaluate the 
non-inferiority of the PRO-122 ophthalmic solution, after treatment with Krytantek Ofteno ®, in 
subjects with Primary Open-angle Glaucoma (POAG) and / or intraocular hypertension (OHT). 
CONFORT Study K. No.: SOPH122-0914 / III 
National multi-center study 
 
 
 
 Study period: 
Duration of the study for the participant: 75 days once the treatment. 
 Development phase of 
Study: Phase 3 
Goals: 
Aim: 
To evaluate the non-inferiority of the PRO-122 ophthalmic solution versus Krytantek Ofteno® 
through its efficacy, tolerability, and safety on intraocular pressure in subjects with POAG and / 
or OHT. 
Primary objective of efficacy: 
To evaluate the efficacy of the PRO-122 ophthalmic solution versus the Krytantek Ofteno® 
ophthalmic solution applied on the ocular surface in subjects diagnosed with POAG and / or OHT 
by control and maintenance of a Target Intraocular Pressure (TIOP). 
Primary objective of tolerability: 
To evaluate the tolerability of the PRO-122 ophthalmic solution versus the Krytantek Ofteno® 
ophthalmic solution in subjects diagnosed with POAG and / or OHT through the evaluation of 
ocular symptoms such as burning, red eye, lacrimation, foreign body sensation; fluorescein stain, 
Visual Function Index (VF-14) questionnaire score and ocular comfort index. 
Primary security objective: 
To evaluate the safety of the PRO-122 ophthalmic solution versus the Krytantek Ofteno® 
ophthalmic solution in subjects diagnosed with POAG and / or OHT by better corrected visual 
acuity, anterior segment biomicroscopy, fundus examination and frequency of adverse events. 
Hypothesis Ha: There is a difference between the efficacy and safety of the PRO-122 ophthalmic 
solution versus the efficacy and safety of the Krytantek Ofteno® ophthalmic solution. 
H0 hypothesis: There is no difference between the efficacy and safety of the PRO-122 ophthalmic 
solution versus the efficacy and safety of the Krytantek Ofteno® ophthalmic solution. 
Methodology: 
A Multicentric, Prospective, Crossover, Double-Blind Clinical Study, with fixed dose. 
 


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Number of participants: 120 subjects. 
Diagnosis and main criteria for inclusion: Older than 18 years old, both genders, with 
primary open angle glaucoma and / or intraocular hypertension, classified as mild, 
moderate, or severe, who achieved their TIOP for 2 months prior to treatment under 
Krytantek Ofteno®, with an informed consent signature obtained during the first visit. 
Medication under study: 
PRO-122 Ophthalmic solution. It will be applied with the following dosage: 
1 drop every 12 hours for 30 days, alternating therapy with 30 more days of Krytantek 
Ofteno® with the same frequency. 
Sponsor's name: Laboratorios Sophia, S.A de C.V. 
Active Ingredient Name: Brimonidine 2 mg, Dorzolamide 20 mg, Timolol 5 mg. 
Comparator: 
1 drop of Krytantek Ofteno ® Ophthalmic Drops every 12 hours for 30 days in the 
sequence corresponding to your assigned group. 
Treatment duration: 
- Inclusion period: 3 months. 
- Treatment period: 30 days. 2 sequences. 
- Follow-up period: 75 days. 
Evaluation criteria: 
Efficacy measurements: 
Main efficacy criterion 
Efficacy will be determined by maintaining the TIOP (like the IOP goal corresponding to 
its degree of damage) during the study. 
Primary tolerability criterion 
Specific signs and symptoms such as burning, hyperemia, lacrimation, foreign body 
sensation, chemosis, anterior segment biomicroscopy, better corrected visual acuity as 
well as measurements with fluorescein staining, VF-14 visual function questionnaire and 
ocular comfort index will be evaluated.  
Primary security criteria: 
Adverse events frequency 
 
 
 
 


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INDEX 
2. STUDY SUMMARY SHEET........................................................... ................................................2  
3. INDEX ............................................... .................................................. .......................................4  
4. GLOSSARY AND DEFINITIONS ............................................. .......................................................6  
5. ADMINISTRATIVE STRUCTURE OF THE STUDY ...........................................................................7  
6. INFORMATION ABOUT BACKGROUND ............................................. ........................................8  
7. STUDY DESIGN ............................................. ...........................................................................14  
7.1. Point or limit points  ..................................................................................................………...14  
7.2. Experimental design .............................................................................................................15 
7.2.1. Study plan  .........................................................................................................................15 
7.3. Measures to minimize deviations ........................................... ......................................….…21 
7.4. Products and system to determine the blindness of the study ............................................22  
7.4.1. Managed products ............................................... ............................................................22  
7.4.2. Treatment management ............................................... ...................................................24  
7.5. Discontinuation of the study ............................................... ...............................................25  
7.5.1. Premature discontinuation of the study ......................................................................... 25  
7.5.2. Center closure......... ............................................... .........................................................25  
7.6. Source data ............................................... .........................................................................26  
8 SELECTION AND REMOVAL OF STUDY SUBJECTS. ..................................................................26  
8.1 Inclusion Criteria .............................................. ..................................................................26 
8.1.1 All subjects includede .......................................... ...........................................................26 
8.1.2 Informed Consent ............................................. ..............................................................26 
8.2 Exclusion criteria .............................................. .................................................................26 
8.2.1 General criteria ............................................. .................................................................26 
8.2.2 Medical and therapeutic criteria ........................................... ........................................27 
8.3 Discontinuation criteria .............................................. ......................................................27 
8.3.1 Withdrawal criteria................................................. .......................................................27 
8.3.2 Procedure .............................................. .......................................................................28 
8.4 Managed treatments  .......................................................................................................29 
8.4.1 Delivery of the treatment  .............................................................................................29 
8.4.2 Previous and concomitant treatments ..........................................................................29 
8.4.3 Authorized treatments before and during the study   .................................................. 29 
8.4.4 Compliance with treatment ......................................................................................... 30 


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9 VALUATION OF EFFICACY ............................................................................................30 
9.1 Measurements of effectiveness ...............................................................................30 
9.2 Methods and times of measurements .....................................................................30 
10 EVALUATION OF SECURITY ........................................................................................34 
10.1 Safety measurements ............................................. ...............................................34 
10.2 Methods and timing of measurements ..................................................................35 
10.2.2 Security visit 1 (Day 15): .....................................................................................36 
10.2.3 Visit 1 crossover (Day 30). ..................................................................................36 
10.2.4 Security visit 2 (Day 45): .....................................................................................36 
10.2.5 Final visit 5 (Day 61) ...........................................................................................37 
10.2.6 Laboratory tests .................................................................................................37 
10.3 Adverse events .....................................................................................................37 
10.3.1 Adverse event records in the Case Report Form ..............................................38 
10.3.1.1 Events to be registered ..................................................................................38 
10.3.2.2 Adverse events follow-up...............................................................................39 
10.3.2.3 Procedure for a serious adverse event ..........................................................39 
10.3.2.4 Causality assessment.... .................................................................................40 
10.3.3 Responsibilities of the sponsor .........................................................................41 
11 STATISTICS ................................................ .............................................................42 
12 DIRECT ACCESS TO THE DATA / DOCUMENTS SOURCE .........................................43 
13 QUALITY CONTROL AND QUALITY ASSURANCE .....................................................44 
13.1 Supervision of the study .....................................................................................44 
13.1.1 Before the study ..............................................................................................44 
13.2 Audit - Inspection-Verification ...........................................................................44 
14 ETHICS .................................................................................................................. 44 
14.1 Research Ethics Committee ...............................................................................45 
14.2 Information for the subject and form of informed consent ..............................45 
14.3 Modification to "informed consent" ..................................................................46 
15 DATA MANAGEMENT AND CONSERVATION OF RECORDS ....................................47 
15.1 Study data .............................................. ............................................................47 
15.2 Data management ..............................................................................................47 
15.3 File ................................................ ......................................................................48 
16. OWNERSHIP OF THE RESULTS - PUBLICATION POLICY .........................................48 


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17. ADMINISTRATIVE CLAUSES ......................................................................................................48 
17.1 Related to the sponsor and the researcher  ......................................................................... 48 
17.1.1 People to report .................................................................................................................48  
17.1.2 Substantial amendment to the protocol ........................................................................... 48  
17.1.3 Final report of the study …........................................................ .........................................49  
17.2 Related to the sponsor  ............................................... .........................................................49 
17.3 Related to the researcher .................................................................................................... 49 
17.3.1 Confidentiality - Use of information ................................................................................. 49 
17.3.2 Organization of the center ................................................................................................50 
17.3.3 Documentation to be delivered to the sponsor ...............................................................50- 
18. APPENDICES  ............................................... ......................................................................... 51  
19. REFERENCES  ............................................... .................................................................... ..- 62  
List of Paintings 
Table 1. Laboratories Sophia S.A. of C.V. .................................................................................. 7  
Table 2 Study Schedule ............................................................................................................17 
Table 3 Description of study medications ............................................ ...................................22  
Table 4 Packaging description ............................................... .................................................23  
Table 5 Main prohibited treatments - Periods of rest to be respected ..................................29  
Table 6. Structures of contacts in the event of an adverse event ..........................................41 
List of figures 
The study plan (Figure 1) .......................................... ............................................................16 
Flow charts of visits ...............................................................................................................18 
List of appendices 
Appendix 1: Declaration of Helsinki of the World Medical Association ................................51 
Appendix 2: Visual function questionnaire VF-14 .................................................................58 
Appendix 3: Eye comfort index questionnaire ......................... .... .......................................59 
Appendix 4: Sample calculation ............................................................................................60 
4. GLOSSARY AND DEFINITIONS 
 AE Adverse Event 
 VA Visual acuity 
 
 
 


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 VC Visual Capacity 
 CRF Case Report Form 
 GCP Good Clinical Practices 
 ICH International Conference on Harmonization 
 IC Informed Consent 
 RM Researcher's Manual 
 ERC Ethics and Research Committee 
 ICL Informed Consent Letter 
 EPIT Estimated Population by Intent to Treat 
 IOP Intraocular Pressure 
 EPPP Estimated Population by Proper Protocol 
 SAE Serious Adverse Event  
 RC Rear Camera 
 SM Study Medication 
 Cr Committee of the researcher 
 OHT Intraocular hypertension 
 POAG Primary Open-angle Glaucoma 
 FMI File Master of the Investigator 
 MSF Master Studio File 
 LRT Lacrimal rupture time 
 TBD Timolol, brimonidine, dorzolamide 
 ABC Area below the curve 
 CMC Camax Maximum concentration 
 
 
 
 
5. ADMINISTRATIVE STRUCTURE OF THE STUDY 
Sponsoring parties 
Table 1. - Laboratorios Sophia S.A. of C.V. 
 


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Laboratorios Sophia, S.A. of C.V., Paseo del Norte Av. No.5255, Guadalajara Technology Park, 
Guadalajara-Nogales Highway Km 13.5 ZC 45010 Zapopan, Jalisco, Mexico. Tel +52 (33) 3000 4200 
Function 
Name / Contact 
Membership 
Medical responsible for the 
study 
 
 
Director of the study 
 
 
Scientific Comittee 
 
 
Scientific Comittee 
 
 
 
Scientific Comittee 
 
 
Coordinator 
of 
regulatory 
procedures 
 
 
Monitoring coordinator 
 
 
International monitor 
 
 
 
Monitor 
 
 
 
Monitor 
 
 
Monitor 
 
 
Monitor 
 
 
Administrative Assistant 
 
 
Dr. Leopoldo Martín Baiza Durán 
leopoldo.baiza@sophia.com.mx 
 
Dr. Aldo Arturo Oregón Miranda 
aldo.oregon@sophia.com.mx 
 
Dr. Oscar Olvera Montaño 
oscar.olvera@sophia.com.mx 
 
Dr. at C. Arieh Roldán Mercado 
Sesma 
arieh.mercado@sophia.com.mx 
 
Dr. at C. Ricardo Alonso Llamas 
ricardo.llamas@sophia.com.mx 
 
LN. Ana Isabel Alcaraz Ledón 
ana.alcaraz@sophia.com.mx 
 
 
QFB Virginia Manuela Villa Felix 
virgina.villa@sophia.com.mx 
 
M. in F. Sandra Carolina Gómez 
Méndez 
sandra.gomez@sophia.com.mx 
 
QFB 
Jessica 
Lizette 
Mejía 
Gutiérrez 
jessica.mejia@sophia.com.mx 
 
LP María Angela González Ávila 
maria.gonzalez@sophia.com.mx 
 
QFB Lizeth by Jesús Pérez Lerma 
lizeth.perez@sophia.com.mx 
 
QFB Priscilla Muriel Lima Mateos 
priscilla.lima@sophia.com.mx 
 
LAET Maira Alejandra Ramírez 
Velazco 
alejandra.ramirez@sophia.com.mx 
Medical and Affairs Director 
Regulatory 
 
Clinical Operations Manager 
 
Ophthalmologist Investigator 
 
 
Clinical Pharmacologist 
 
 
Clinical Pharmacologist 
 
 
Specialist in the beginning of 
clinical studies 
 
Monitor coordinator 
 
 
Senior Monitor 
 
 
 
Senior Monitor 
 
 
Junior Monitor 
 
 
Junior Monitor 
 
 
 
Junior Monitor 
 
 
Clinical Operations Assistant 
 
 
¥ Employees of Laboratorios Sophia, S.A. of 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 
 
6. BACKGROUND 
Glaucoma is an optic neuropathy characterized by progressive coping of the optic nerve  


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whose main risk factor is the increase in intraocular pressure, which causes alterations in 
the visual fields, although in the pre-perimetric stages of glaucoma there is no evidence 
of functional damage. ii Glaucoma is one of the main causes of irreversible blindness in 
the world, it is estimated that until the year 2000, there were approximately 6.7 million 
blind people in the world, secondary to glaucoma, it is estimated that by the year 2020 
this figure will be increase by 11.1 million. 
Epidemiological studies reveal that the race with the highest prevalence of glaucoma is 
black, as well as a consensus that after 40 years there is a greater risk of developing the 
disease. The male sex is affected 3: 1 with respect to the female sex, especially when there 
is an affected first-line relative. iv, v 
Besides age, race, sex and family history, other important risk factores include intraocular 
pressure vi, high myopia vii, central corneal thickness viii, characteristics of the optic 
nerve ix, use of steroids ix, diabetes mellitus, and arterial hypertension, among others. 
Open-angle glaucoma (POAG) and angle-closure glaucoma (ACG) are classified as 
primary and secondary. 
The classification of secondary POAG includes the subjects with pseudoexfoliation, and 
pigmentation because of steroid and facolytics use. In the primary ACG there is a 
population who present with pupillary block and those who do not, this includes: 
inflammatory, neovascular, facomorphic factors and those with ciliary body cysts or 
retinal tumors. 
There are different lines of medications for the treatment of glaucoma which are described 
below: 
Alpha adrenergic 
Brimonidine 
Analogs of prostaglandins 
Bimatoprost 
Latanoprost 
Travaprost 
Unoprostone 
 
Beta-blockers 
Timolol Maleate 
 Carbonic anhydrase inhibitors 
 Systemic: Acetazolamide. 
 Topics: Brinzolamide, Dorzolamide. 
 Myotics: Parasympathomimetics: pilocarpine. 


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There is a consensus regarding the start of treatment: subjects with a diagnosis of 
glaucoma should start medical treatment; monotherapy with first-line drugs is 
recommended for subjects with suspected high-risk glaucoma, subjects with IOP greater 
than 25 mmHg are susceptible to treatment, the first therapeutic step to reach the TIOP is 
monotherapy and finally that the diagnosis of POAG is an indication for surgical 
treatment. Xi 
However, in many cases, two or more concomitant medications are required to achieve 
the TIOP. This leads to poor adherence to treatment, due to the number of doses and a 
higher cost. For this reason, the use of fixed combinations represents a more comfortable 
posology for the subject and with fewer adverse effects. 
Krytantek Ofteno® is a medication useful in glaucoma treatment for cases where more 
than one medication is required to control intraocular pressure. When used, it will have 
an additive effect since the drugs act by different mechanisms. 
JUSTIFICATION 
For these subjects in whom the TIOP cannot be reached according to the therapeutic 
consensus (IOP <14 mmHg +/- 2 mmhg or 30% reduction in baseline IOP), a fixed 
combination therapy is the treatment of choice. 
In this sense, Laboratorios Sophia, S.A. of C.V. offers the only fixed triple combination 
Krytantek Ofteno® (dorzolamide 20 mg, brimonidine 2 mg, timolol 5 mg) which has 
already proven its effectiveness, tolerability, and safety in phase 1, 2 and 3 studies. The 
rapid evolution in medical treatment for glaucoma subjects is a topic that Laboratorios 
Sophia S.A de C.V maintains as a priority. 
For this reason, Laboratorios Sophia S.A de C.V now presents a reformulation free of 
conservative to this same triple combination which aims to demonstrate the same efficacy 
in the control of IOP and better tolerability in the ocular surface of the subjects diagnosed 
with glaucoma through this clinical study. 
All these characteristics are maintained by the same components without containing 
benzalkonium chloride or any other preservative xvii, xviii, xix. 
In a preclinical study in which Krytantek Ofteno® and PRO-122 ophthalmic solution 
versus the same components (TDB) were administered in New Zealand rabbits separately, 
their availability in the aqueous humor was determined by the AUC and Camax, which 
showed similar values without significant differences between availability with 
conservative versus without conservative 20. 
The reasoning by which a formula is proposed with the same effectiveness starts from the 
conclusions enunciated by Dr. Boudin et al. about of the conservator’s effects on the 
ocular surface in which the inflammation factors that lead to histological changes were 
measured. In these studies, first performed on the conjuntiva of healthy patients, then in 
patients diagnosed with primary glaucoma, it was possible to conclude that the following 
differences existed: 
 The goblet cells are depleted by 60% after one month of being exposed to ophthalmic 
solutions with benzalkonium chloride xvii, xviii, xix. 


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 Tear rupture time is altered after 7 days of exposure and peaks at abnormal times after 
3 weeks xviii. 
Likewise, the migration of pro-inflammatory cells from the innate response promotes 
secondary immunological reactions, such as: 
 HLA-DR antigens and pro-kinetic molecules I-cam – 3 are the main molecules found 
in the conjunctival proper substantia and tenon. xix  
 As a result there is a significant increase in CD-20/22/23 as well as CD 4 (Th2) xviii, 
xix.  
These changes in the cellular population of the ocular surface produce the following 
histopathological changes, which are proportional to the time of exposure and the amount 
of BAK to which the tissues have been exposed: 
 Corneal de-epithelization. 
 Loss of epithelial microvilli. 
 Subconjunctival fibrosis. 
 Reduction of the number of goblet cells. 
 Epithelial keratinization. 
 Squamous metaplasia. 
 Increase in the number of desmosomes. 
 Bullous epithelium dystrophy. 
 Subepithelial fibrosis. 
 Increase in subepithelial lymphocytes and plasma cells 
 Thickening of the basement membrane. 
Subsequently, the previous changes were correlated with the results of filtering surgeries 
in subjects in whom it was performed of first intention (without previous treatment) and 
compared with those who underwent filtering surgery after receiving chronic topical 
treatment with a conservative. 23 
In this study a conjunctive sample was taken in which the immunohistochermical markers 
related to apoptosis and metaplasia of ocular surface tissues were analyzed, finding the 
following results. xviii, xix.: 
 


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Conjunctival biopsies and their cellular infiltrates in surgically treated antiglaucomatous 
user patients and nonusers. xix 
 
Non-users 
Monotherapy 
Multi-theraphy 
Normal 
80% 
59% 
12% 
Markkers 
inmunohistochemical 
20% 
27.3% 
42% 
fibrosis 
0% 
12.7% 
46% 
 
 
Percentage of patients in whom cell changes and / or fibrosis were compared according 
to exposure to BAK. xix. 
 
With this, we can estimate that 40% of patients will use more than 2 drugs after 5 years 
of treatment, so that providing the user with eye antihypertensive drugs that remove 
adverse events while retaining the qualities that provide effectiveness to the drug will be 
very useful in the treatment of chronic diseases such as primary open-angle glaucoma. 
 
In our Cross Over study model, the washout period was calculated with 5 times the 
average life time of the medication, which is max. 20 hrs, therefore, is not necessary to 
add a transfer effect period to the period of medication application. 
 
NON-CLINICAL PHARMACOLOGY 
The bioavailability of antiglaucoma drugs in ophthalmic solution depends on their ability 
to pass through the cornea. To achieve its action, it is necessary to reach the site of action 
in optimal concentration. In the case of topical ophthalmic medications, the drug must 
cross hydrophilic and lipophilic barriers to reach the target tissue. The corneal epithelium 
and the endothelium are lipophilic barriers while the stroma is only permeable to 


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hydrophilic compounds. The permeability to different chemical entities is greater if a drug 
presents hydrophobic and hydrophilic regions in the same molecule. This is characteristic 
of weak acids and bases, which can exist in a nonionic form soluble in lipids as in a water-
soluble ionic form. In addition, the continuous renewal of the tear film creates an 
important obstacle to prevent chemical substances of different kinds from penetrating the 
interior of the eye. This reasoning allows us to consider that the active ingredients in 
ophthalmic solutions have high concentrations. Both Dorzolamide, Timolol and 
Brimonidine are hypotensive drugs commonly used in the treatment of ocular 
hypertension and glaucoma. Dorzolamide ([4S, 6S] -2 ethylamino-4-methyl-5,5-dioxo-
5λ, 7- dithiobicyclo [4.3.0] nona-8,10-di en-8-sulfonamide) is an inhibitor of carbonic 
anhydrase that has its effect on the inhibition of bicarbonate synthesis and consequently 
reduces the formation of HA; in the case of Timolol (S) -1- (tert-butylamino) -3 - [(4-
morpholin-4-yl-1,2,5-thiadiazol-3-yl) oxy] propan-2-ol), a beta blocker adrenergic, 
reduces the production of HA by blocking the adrenergic receptors in the ciliary body and 
Brimonidine (5-bromo-N- [4,5-dihydro tartrate]-1H-imidazol-2-yl] quinoxalin-6-amine), 
a selective agonist of alpha adrenergic receptors, decreases the synthesis of HA by 
reducing cyclic AMP (cAMP) and thereof increases the uveoscleral flux. In 
ophthalmology, the dynamics of how a drug reaches its therapeutic target is a 
controversial issue, mainly because of the limited accessibility to measure concentrations 
in different ocular structures in a subject, in addition to its specific mechanism of blood 
supply. The passage of a solute through a membrane has as a limiting speed diffusion in 
the lipid bilayer, which is characterized by the diffusion coefficient. However, an 
experimental way to know the concentration of a solute in an aqueous solution and its 
adjacent compartment, such as a membrane, is to calculate the partition coefficient 
between two immiscible solvents. The Partition Coefficient is the relationship between 
the affinity of the solute in a solvent / water system. A very polar solute will have a very 
small partition value, while a hydrophobic one will have values greater than unity. 
Therefore, the diffusion rate of a solute depends proportionally on the difference in its 
concentration. 
These data are important during the design of ophthalmic application products since they 
help to predict their behavior when applied to the ocular surface. For this reason, 
Laboratorios Sophia, S.A. of CV, conducted a study to analyze the partition coefficient 
of the components of an ophthalmic solution in fixed combination (Brimonidine, Timolol 
and Dorzolamide) and the maximum concentration achieved in the aqueous humor (AH), 
a model of rabbits in an octanol-water system was used for each of them. The final 
concentration for each drug in AH was assessed by diffusion, where it was found that the 
order of solubility was Brimonidine > Timolol > Dorzolamide. The maximum 
concentrations reached in aqueous for Brimonidine, Dorzolamide and Timolol were at 
15, 90 and 60 minutes respectively. With these results, we can conclude that the fixed 
combination of Brimonidina-Dorzolamida-Timolol is compatible and bioavailable for the 
control and management of intraocular pressure and glaucoma. Xii 
On the other hand, a preclinical, unicentric, prospective, longitudinal, comparative, and 
double-blind study of ninety days was conducted in 30 ophthalmologically healthy albino 
New Zealand rabbits to evaluate the safety of Krytantek Ofteno® and its effectiveness in 
the control of intraocular pressure (IOP) versus the separate but concomitant application 
of its three active ingredients -dorzolamide, timolol and brimonidine (DTB). 


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In phase 1 (day 1 to 30) a drop of Krytantek Ofteno® and two drops of polyvinyl alcohol 
were applied to the right eye; a minimum period of 5 minutes was established between 
each application. In the wash period (day 31 to 60) the application of the drug was 
suspended. In phase 2 (day 61 to 90) a drop of DTB was applied to the right eye, each 
drop was applied in the same way as in the first stage. The rabbits were evaluated on days 
0, 4, 11, 18 and 25 in each phase before starting the application of the medicine. The IOP 
was assessed at 08:00 h, 12:00 h and 16:00 h in both eyes. 
According to the results, it could be seen that with Krytantek Ofteno® the IOP decreased 
from basal day 0 to the final day of the study by 40% compared to 20% in those treated 
with DTB. Likewise, Krytantek Ofteno® demonstrated greater security. Xiii 
Clinical data of phase I: 
We conducted a safety study about the tolerance of dorzolamide, brimonidine and timolol 
in a fixed combination applied to the ocular surface of ophthalmologically healthy human 
volunteers, 30 subjects were studied in total, to which the fixed combination was applied 
every 12 hours during a 7 days period, evaluations were made on days 2, 4, 7 and 10 of 
the study. At each visit, the physical examination was performed, and the findings were 
recorded in the following order: 1) visual capacity. 2) revision of the anterior segment 
with slit lamp 3) investigation of specific signs 4) tonometry and 5) indirect 
ophthalmoscopy under drug-induced mydriasis. According the observations during the 
study, there were no changes in the ocular surface of any eye after the application of the 
study article for 10 days, in the same way there were no changes with respect to the ocular 
surface stains in any day of study. Therefore, it was concluded that the fixed combination 
of 2% dorzolamide, 0.5% timolol and 0.2% brimonidine is safe and well tolerated when 
administered topically ophthalmic at the indicated dosage in ophthalmologically healthy 
volunteers. Xiv 
7. STUDY DESIGN 
7.1. Point or limit points 
Main efficacy criterion 
The efficacy of the PRO-122 ophthalmic solution versus the Krytantek Ofteno® 
ophthalmic solution applied on the ocular surface in subjects diagnosed with POAG and 
/ or OHT by maintaining the target IOP will be evaluated. 
Tolerability criteria 
Ocular symptoms such as burning, red eye, lacrimation, foreign body sensation, 
chemosis, better corrected visual acuity, anterior segment biomicroscopy, fundus 
examination will be evaluated; fluorescein staining, VF-14 questionnaire score and ocular 
comfort index will be evaluated. 
 
Security criteria 
Frequency of adverse events. 
 


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7.2. Experimental design 
7.2.1. Study plan 
This is a Phase 3, National, Multicentric, Prospective, Crossover, Double-Blind, fixed-
dose study. 
This study will be carried out with 120 subjects from the ophthalmological consultation 
with diagnosis of primary open angle glaucoma with mild, moderate, or severe damage 
and / or with intraocular hypertension and a previous two-month period use of Krytantek 
Ofteno® and current control of the corresponding TIOP. 
If the subject meets all the inclusion criteria and none of exclusion, they can be included 
in the study. In the same occasion a study group A or B will be assigned randomly, in 
group A the therapy with Krytantek Ofteno® will continue for 30 days, in which the 
subject will be evaluated again, and he will change from therapy to PRO-122 solution 
which will be used for 30 days after the 60th day, date of the final visit. 
In the case of those assigned to group B on day 1, the change to PRO-122 solution will 
be made for 30 continuous days until the date of revision on day 30, day on which the 
treatment with Krytantek Ofteno® will be restored to continue until the day 60 for the 
final evaluation. 
The selected subjects will be observed for 60 days. No subject may use the mentioned 
treatment for more than the established time. 
The valuation days indicated in the activity schedule should be carefully observed. Table 
2. A window variation period of + - 2 days can be accepted in relation to the revision 
visits and +/- 1 day in the safety visits. 
Figure 1- Study plan 
 
 
Table 2. Study Schedule 
* if you have Humphrey visual fields of <6 months of completion these can be considered. 
 
 


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PROCEDURES
Satisfactory eligibility criteria
-corroborate the informed consent signature correctly.
-pregnancy test.
- general and ophthalmological clinic history
-Detail points A, B, C, D, E, F, G, H, I, J, K, L.
-Gosioscopy Shaffer
-Assignment of number.
Questionnaire VF-14 and ICO.
-Make AV capture, refraction (CV).
-Paneal corneal analysis.
Ocular surface staining.
-Tonometry with Goldman.
-Gather white / white campietry 24/2.
126/5000
Delivery of medication
Day 1: application of the medication.
-Evaluation of concomitant medications.
Schedule next visit.
NO
Ineligible subject
Basal visit / day 1


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PROCEDURES
400/5000
Visit 1 CROSS OVER (day 30)
Ophthalmological clinical history.
Detail points A, B, C, D, E, F, G, H, I, J, K, L.
DO NOT dilate pupils.
Application of VF-14 and ocular comfort 
index.
Perform AV socket,
refraction and subjective test.
Central corneal pachymetry.
Ocular surface staining with fluorescein.
Tonometry with Goldman.
Return of medication.
Grant next sequence of medications.
Evaluation of adverse 
events. 
Evaluation of 
concomitant 
medications. 


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Note: A) Burning B) Foreign body sensation C) Lachrymation D) Conjunctival 
hyperemia E) Chemosis F) Crystalline G) Iris H) Retina I) Macula J) Vitreous K) optic 
nerve excavation in decimals L) TRL * ICO = ocular comfort index. 
 
 
 
 
 
 
 
 
 
 
 
 
PROCEDURES
Safety visit
(Day 15 and 45).
-Take AV and CV.
Biomicroscopy. (D, E, F,
G, L).
-Tinction with 
fluorescein
ocular surface
-CHEEP.
- Monitor adverse 
events.
-Monitor medications
concomitants.


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A) Burning B) Foreign body sensation C) Lachrymation D) Conjunctival hyperemia E) 
Chemosis F) Crystalline G) Iris H) Retina I) Macula J) Vitreous K) Optical nerve optic 
nerve excavation in decimals. L) TRL * ICO = ocular comfort index. 
 
 
 
 
 
 
 
Procedures
Visit FINAL / day 61
-Report of Biomicroscopy.
-Detail points: A, B, C, D, E, F, G, H, I, J, K, L.
-Apply questionnaire VF-14 and ocular comfort 
index.
-Test of pregnancy to female subjects.
-Gosioscopy Shaffer.
-Make AV capture, refraction and subjective test.
-Paneal corneal analysis.
- Ocular surface staining with fluorescein.
-Tonometry with Goldman.
-Campimetry 24/2 white / white.
-Final evaluation of the researcher.
Schedule call of surveillance (day 75).
Ask for general signs and symptoms.
A, B, C, D. and complement with possible adverse 
events.
-Evaluation of 
adverse events. 
-Evaluation of 
concomitant 
medications. 


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7.3. Measures to minimize deviations 
On the other hand, adherence to treatment will be evaluated as follows: 
- Once the dropper bottles of each subject are returned by the researcher, each bottle will 
be weighed on an analytical balance and the difference will be obtained with respect to 
the initial weight of the container; any value above 80% will be considered as an adequate 
attachment treatment. 
- The subjects will have a "subject's diary" in which they will answer a questionnaire 
based on analogous visual scales with the main signs and symptoms perceptible to the 
subject and if there is one out of this questionnaire, you can write it down in the space 
designated for its description. 
A meeting of researchers will be organized for the physicians involved in the study before 
starting with the inclusion of subjects, their attendance will be mandatory. 
At the end of the study the subjects will answer a questionnaire of satisfaction of the 
subject in the local language and the researcher will explain the subject. It is not 
authorized for the researcher to report / correct the score of the subject in the self-score 
questionnaires. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4. Products and system to determine the study blind 
7.4.1. Managed products 
Table 3 - Description of study drugs 
Ophthalmic drops of 0.5% timolol maleate, 2% dorzolamide and 0.2% brimonidine. 
Timolol Maleate: 0.5% timolol 
- Chemical Name: (S) -1- (tert-butylamino) -3 - [(4-morpholin-4-yl-1,2,5-thiadiazol-3-
yl) oxy] propan-2-o 
- Molecular weight: 316,421 g / mol 
- Molecular formula: C13H24N4O3S 
- Chemical structure: 
 
 
 
Dorzolamide: 2% dorzolamide 
- Chemical name: (4S-trans) -4- (ethylamino) -5,6-dihydro-6-methyl-4H-thieno [2,3-
b] thiopyr-2-sulfonamide-7,7-dioxide monohydrochloride. 
- Molecular weight: 360.9 
- Molecular formula: C10H16N2O4S3 • HCl. 
- Chemical structure: 
 
 
 
 
 
 
 
 
 
 
 
 


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Brimonidine: 0.2% brimonidine. 
Chemical Name: 5-Bromo- N - (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine 
Molecular weight: 292,135 g / mol 
Molecular formula: C11H10Br1N5 
Chemical structure: 
 
Table 4 - Packaging description 
Primary packaging 
The bottles will be delivered in their primary packaging and they will be identified with 
the protocol code, below the specification of solution or suspension and content in 
milliliters, among others as illustrated below. 
 
Example: 
 
 
 
Secondary package: 
The specifications of the study drugs will be described in the secondary packaging. 
Example: 
 
 
 
 


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7.4.2. Treatment management 
 
The treatments will be provided from the manufacturing site (Laboratorios Sophia, S.A. 
de C.V.) previously weighed. 
Treatment management will be under the responsibility of the researcher and / or 
pharmacist of the health care establishment (when applicable), including: 
- The reception and storage of the study medication (SM). The study medication must be 
stored in a secure area with restricted access. Some special storage conditions are 
requested, such as keeping them at room temperature to no more than 30º Celsius, for 
which the investigating physician will be provided with a humidity and temperature 
recorder as a loan during the study. 
- Data download of the recorder will be done by the clinical monitor in the monitoring 
visits and in turn the previously designated responsible will make a reading of the day 
directly from the recorder's screen. 
- The expiration date will appear on each box and label. 
- The delivery of the treatments will be in accordance with the study plan and following 
the delivery methods that are described in the section. The researcher and / or pharmacist 


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of the healthcare establishment should use the treatment delivered only for the subjects 
participating in the study. 
- The study medication count. 
The researcher and / or pharmacist of the health care establishment and / or a designated 
person of his study team must fill in in real time all the documents that the sponsor 
provides for treatment handling. 
The study monitor will periodically check the management and recounting of the 
treatment. At the end of the study, the researcher and the study monitor will make a final 
inventory of the medicines, and they will write down the corresponding format. 
The study monitor will collect the remaining treatments for storage and subsequent 
destruction, after quantifying the amount in each container. 
All defects or deterioration of treatments or their packaging must be reported to the study 
monitor. The investigator will notify the monitor of all complaints received from a 
subject. 
In case of early return of the treatments to the sponsor (withdrawal of the lot), the sponsor 
will prepare an informative letter addressed to the researcher and / or pharmacist of the 
health care establishment. This letter will be sent by the people locally responsible for the 
study. Upon receiving the letter, the researcher and / or pharmacist will identify the 
subjects who have the treatment in their possession at the time the incident is known, 
using the corresponding format, and will contact them immediately. The monitor will 
organize the return of the study medication to proceed with its destruction. 
 7.5. Discontinuation of the study 
7.5.1. Premature discontinuation of the study 
The sponsor may terminate the study before the scheduled deadline. A written 
confirmation will be sent to the researcher. 
The investigator will date and sign two copies of the written confirmation (one copy to 
return to the sponsor and the other copy to file in the Investigator's Study File). 
The corresponding Committees and the Competent Authorities will be informed in 
accordance with local regulations. 
7.5.2. Closure of the center 
The closure of the research center will be carried out once the last subject visit has been 
included, previously agreed upon between Laboratorios Sophia SA de CV and the 
Investigator. 
A center that does not include subjects in the three months after the initial visit may be 
closed by decision of Laboratorios Sophia S.A. of C.V. 
 
 


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 7.6. Source data 
The following data (s) will be considered as source: 
- The subject's medical record 
- Journal of the subject 
- The self-score questionnaires (VF-14 and ocular comfort index). 
The subject will directly record the data of the self-rating questionnaires in paper form, 
which will be considered source data. 
 8 SELECTION AND REMOVAL OF STUDY SUBJECTS. 
8.1 Selection Criteria 
8.1.1 All subjects included: 
- 18 years of age or older 
- Male or female. 
- Obtained in the external consultation. 
- Diagnosis of primary open angle glaucoma and / or hypertension classified as mild, 
moderate, or severe glaucomatous damage, users of Krytantek Ofteno® for at least two 
months before inclusion and under control of the target IOP. 
- Signed informed consent. 
Physical examination of the subjects 
In the physical examination carried out during the baseline visit, the absence of any 
anomaly that could interfere with the conduct of the study will be reviewed: 
At the baseline visit, white on white 24-2 Humphrey campimetry data should be collected 
with no more than 6 months after having been carried out and considered in reliable 
parameters, in case of not having such characteristics, please realize this study. 
 8.1.2 Informed consent 
Obtained as described in section 14.2 of the protocol. 
8.2 Exclusion criteria 
8.2.1 General criteria 
1. Subjects with topical or systemic medication that interferes decisively in the results of 
the study. (Such as topical immunomodulators, tamponade of lacrimal punctures, 
corticosteroids, ocular hypotensives other than those indicated above, artificial tears with 
conservative). 
2. Subjects (female and male) with active sexual life who are not using a contraceptive 
method. 
 


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3. Subjects of the female sex in a state of pregnancy or who are breastfeeding. 
4. Subjects of the female sex with pregnancy test in positive urine. 
5. Positive substance abuse (illegal drugs). 
6. Subjects who have participated in any clinical research study in the last 40 days. 
7. Subjects legally or mentally incapacitated to give their informed consent for their 
participation in this study. 
8. Subjects who cannot comply with the appointments or with all the requirements of the 
Protocol. 
8.2.2 Medical and therapeutic criteria 
Related to ophthalmological criteria 
1. Subjects with only one eye with vision. 
2. Subjects with visual acuity of 20/200 or worse in either of the two eyes. 
3. Subjects with a narrow angle glaucoma history without treatment, with or without total or partial closure 
of the angle in either of the two eyes. 
4. Subjects with corneal abnormalities that prevent tonometry by applanation. 
5. Subjects with ocular surgery or ocular trauma resolved in the last 6 months prior to inclusion.  
6. Any eye laser surgery in the last 3 months. 
7. Any progressive retinal disease or without control. 
8. Inflammatory diseases of any kind. 
9. Subjects who wear contact lenses. 
Related to various conditions 
1. Subjects with a history of hypersensitivity to any of the ingredients of the research 
product or its analogues. 
2. Subjects who can not comply with the study appointments and / or protocol 
requirements. 
Related to a therapy or previous and / or concomitant treatments 
Previous therapy 
Subjects can not be treated at the time of inclusion with any other type of 
antiglaucomatous than Krytantek Ofteno ®. 
To know the other prohibited treatments and their rest period, please refer to table 5 
"Main prohibited treatments - Rest period to be respected". 
8.3 Discontinuation criteria 
8.3.1 Withdrawal criteria 
The following criteria will result in the mandatory exclusion of the study: 


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The reasons that a subject leaves the study prematurely may be the following: 
- Subject's decision. The subject who wishes to leave the study for any reason can do so 
at any time, but must inform the researcher. In all cases, the investigator should attempt 
to establish contact with the subject as soon as possible for a final evaluation in order to: 
 Document the subject's decision in clinical notes. 
 Obtain the reason (s) for the exit and write them down in the corresponding format. 
 Evaluate the clinical status of the subject. 
 If necessary, take the appropriate therapeutic measures: management of an adverse event. 
In case of failure of all these attempts to contact the subject, the investigator may declare 
"loss of follow-up" of the subject. The investigator will document all the attempts in the 
corresponding medical file. 
- Decision of the investigator. 
 Especially if an adverse event occurs and the investigator believes that this may 
threaten the subject’s health, or if a major disease requires the prescription of a medication 
incompatible with the purpose of the study occurs. 
- Need for another treatment according to the criteria of the medical investigator who will 
have to document it well in his notes. 
- Pregnancy. 
- Any deviation to the protocol that affects the safety of the subject. 
- In all cases, the available data will be saved for the safety analysis (population evaluable 
by intention to treat). 
8.3.2 Procedure 
Whatever the reason for the premature discontinuation of the study treatment, the 
investigator should immediately inform Laboratorios Sophia S.A. of C.V. and the subject 
must return the rest of the study treatments to the center. 
In case of premature withdrawal of treatment, the investigator should record the reason 
(s), the exact date of the premature discontinuation of the treatment in the source 
document and in CRF. If more than one reason is given, the investigator must indicate 
the main reason. 
In case of premature exclusion of the study due to an adverse event (serious or not), the 
investigator should make every effort to gather information related to the outcome of the 
event. If necessary, the information will be collected later. 
This information will be recorded in the CRF part related to non-serious adverse events; 
and the serious adverse events in a format that will be given separately in case the 
researcher can not collect the information in a visit, then it will be collected from the 
doctor who will ensure the follow-up of the subject. 
 


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8.4 Managed treatments 
Subjects with previous treatment with Krytantek Ofteno® every 12 hours for at least 2 
months prior to study and under control of the TIOP for mild, moderate, or severe damage 
will begin to apply PRO-122 or Krytantek Ofteno® without leaving wash period as 
follows: 
1 drop every 12 hours (e.g. 9 am – 9 pm) for 30 days; at the end of the stablished period 
they will change to the opposite formula respectively. Application of the indicated 
treatment will begin at the baseline visit. In the crossover visit, the morning application 
will correspond to the initial sequence of the medication and the second application of the 
day, will correspond to that of the second sequence. 
8.4.1 Treatment delivery 
At the baseline visit, the principal investigator or the previously designated responsible 
person will give the subjects the box with the treatment for the study. 
The researcher will give the subjects the box with the corresponding treatment. 
8.4.2 Previous and concomitant treatments  
Prohibited treatments 
Table 5 shows the list of prohibited treatments before and during the study. 
In case of uncertainty, the researcher will verify the corresponding treatments. 
If a prohibited treatment is absolutely necessary during the study, the subject should be 
removed. 
Table 5. Main prohibited treatments -Periods of rest to respect. 
Medicine 
 
Route 
of 
administration 
Rest period 
Group 
Prototype 
 
 
Artificial tears with 
conservative. 
Anyone 
Ophthalmic 
2 weeks 
Carbonic 
anhydrase 
inhibitor 
Acetazolamide 
Oral or I.V 
1 month 
Prostaglandin 
analogues 
Latanoprost 
Travaprost 
Bimatoprost 
Ophthalmic 
2 months 
Parasympathomimetics Pilocarpine 
Ophthalmic 
2 moths 
 
8.4.3 Authorized treatments before and during the study 
Tretacaine Hydrochloride 
Tropicamide / Phenylephrine Hydrochloride 
Antibiotics of any kind 
 


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8.4.4 Treatment compliance 
Compliance will be assessed through the measurement of the bottle weight before and 
after the start of the study, in the same way the subject will have to fill in the “subject’s 
diary” where it will record the time at which the medication should be applied. 
After the discontinuation of the study treatment, the investigator will propose an 
alternative treatment if necessary, or the appropriate care adapted to the nature of the 
clinical condition of the subject. 
9 VALUATION OF EFFECTIVENESS 
9.1 Efficacy measurements 
Table 2 - Research schedule shows the effectiveness measurements made at each visit or 
period of treatment. 
Primary efficacy parameters are: 
Maintaining control of the TIOP during the time elapsed between the baseline day and 
day 60. 
Secondary efficacy parameters: 
Fluorescein staining, VF-14 questionnaire score and ocular comfort index evaluation, 
signs and symptoms such as such as burning, tearing, foreign body sensation, conjunctival 
hyperemia and / or chemosis. 
Primary security parameters: 
Frequency of adverse events, visual capacity, data of the anterior segment biomicroscopy 
and fundus examination. 
9.2 Measurement methods and times 
Scales to fill out by the researcher: 
A meeting of researchers will be organized for all those involved in carrying out the study 
before starting it, and their participation will be mandatory. The objective of these 
sessions is to train them on the assessment of the efficacy and safety criteria and to ensure 
reliability among the qualifiers. In addition, detailed qualification rules will be provided 
to the qualifiers. 
The same qualified physician should evaluate at the start of each visti the scales 
previously designated in the Delegation of Responsibility format throughout the study. 
Self-qualification questionnaires to be completed by the subject: 
 
 
 
 


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The researcher will explain to the subject the self-score questionnaires; the subjects will 
fill them in the visits of days 1 (basal visit), 30 (crossover) and 61 (final day). Since the 
subject will fill out the self-score questionnaires, these will be provided in local language. 
Only the subject must fill out these questionnaires. 
Visual acuity 
It is a measure of the ability of the visual system to detect and recognize spatial details, it 
is performed in a high contrast test and with a good level of illumination. To measure 
visual acuity (VA) a subject will be presented with different high contrast tests and 
different sizes at a fixed distance, and the value will be noted as far as the subject sees. 
The smallest size that the subject recognizes will be taken as a threshold value and 
expressed in arc minutes. Visual ability is the best visual acuity with optical correction. 
Bailey and Lovie designed and proposed a primer that would standardize the answers for 
each letter size in each of the lines. This was achieved by using a logarithmic progression 
of the size of the optotypes, obtaining equality in the discernment. They proposed that 
each line of optotypes contain five letters and the space between them is exactly the size 
of the letters of the same line and the space between the lines is equal to the size of the 
optotype of the lower line. In such a way that with this booklet, Bailey and Lovie 
innovated the method of assessing visual acuity through the logarithm of the minimum 
resolution angle (logMAR). This type of scale establishes: 1) the visual acuity 20/20 is 
equal to 0.00 in logMAR and 2) the 20/200 represents the unit in log MAR (1,0). 
Therefore, each successive line change represents a change of 0.10 logarithmic units. In 
a line of five letters each letter has a value of 0.02 logarithmic units; in this way, the value 
of the acuity reached within a line can be objectively annotated. This makes the test have 
a high degree of reliability. In the area of research, it is called a "Gold Standard". 
Standardization of the visual examination: 
- At 3 m distance in a room with dim lighting, the research subject will be evaluated as 
follows: 
- This exam will be held at the research center 
- The subject will be asked to always sit in the same place and with the LogMar scale, the 
visual acuity (AV) will be assessed. If he does not have this type of booklet he must carry 
out the conversion (a table is provided below). 
- The research subject will keep both eyes open. 
- The research subject should gently cover one eye with the occluder (always use the same 
occluder to cover the eye, with all research subjects) while reading aloud the smallest line 
of letters you can see. This exam is done in each eye, one at a time, starting with the right 
eye (RE). 
- The doctor must point out the line that the research subject is requested to read. 
- Finally, the same procedure will be performed through the stenopic. 
Equivalence between the different AV scales 
 


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Previous Biomicroscopy 
It refers to the revision of the entire anterior segment: cornea, iris, pupil, anterior chamber, 
crystalline and / or (IOL). 
It will be qualified as follows: 
Normal. 
Abnormal. 
Abnormality that does not affect the result of the study: 
Conjunctival hyperemia / hyperemia: 
 defined as the simplest reaction of the conjunctiva to a stimulus, a red appearance secondary to 
the vasodilation of the conjunctival vessels of variable intensity. It will be classified according to 
the analogous visual scale of hyperemia of The Institute for Eye Research Scale.ix 
 
1.- Very Mild                       2. Mild                         
  3.- Moderate                          4.- Severe 
-Foreign body sensation 
-Burning 
-Lachrymation 
- Chemosis 
 


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These symptoms will be described as present or absent, in case there is a discharge, it will have 
to be described. 
Gonioscopy with Shaffer classification: 
The classification of Shaffer will be carried out with a Goldman gonioscope to establish the open-
angle (grade III and IV) and its characteristics. 
The 3-lens Goldman type lens will be placed on the cornea, after instillation of topical tetracaine 
and 2% hypromellose as a lubricant, the quadrants will be observed and described starting with 
the superior, then temporal, inferior and ending with the nasal side. 
Fluorescein stain 
Fluorescein staining will be performed, standardization of this scan is done as follows: 
1- Subject will be in front of the lamp prior instillation of topical anesthesia that will be provided 
by Laboratorios Sophia S.A. of C.V. 
2.- The subject's lower eyelid will be gently grabbed, first on the right side and then on the left 
side asking the subject to look upwards so that with this maneuver a greater area of the lower 
bulbar conjunctiva is exposed, then the fluorescent filter paper moistened with a drop of anesthetic 
will be placed in the surface of the area previously mentioned, subsequently the subject will be 
asked to blink several times and proceed to examine it without specifying the corneal / 
conjunctival region and will be evaluated with the following classification : 
Absent (without staining) 
Medium (less than 10% of the surface with staining). 
Moderate (from 10 to 50% with surface staining). 
Severe (more than 50% of the surface). 
Central corneal pachymetry 
Under local topical anesthesia with tetracaine, the central corneal thickness will be examined with 
an ultrasonic pachymeter. This value will be used for the adjustment of IOP that will be adjusted 
based on the conversion tables validated for each device that is counted in the research center. 
Note: it is important that in all the visits that require it, the same pachymeter used as in the initial 
visit.  
Applanation tonometry 
The measurement of intraocular pressure will be based on the method of "applanation" which is 
the most commonly used method and is based on the Imbert Fick principle, which establishes that 
the pressure inside a dry and thin-walled ideal sphere is equivalent to the force needed to flatten 
its surface divided by its flattening area. Normally the intraocular pressure ranges from 10 to less 
than 21 mmHg. 
The methodology for taking the pressure will be as follows: 
1.- After having instilled a drop of topical anesthetic on the surface of both eyes of the subject. 
2.- A strip of fluorescein will be placed on the surface of the lower bulbar conjunctiva, first of the 
right eye, and then the whole procedure will be performed on the left eye. 
 


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3.- Through the Goldman tonometer the cornea will be indented with the biprism and the 
intraocular pressure will be determined based on the force and flattened area. In this sense 
the medical ophthalmologist or the person previously designated will make the shot 
without observing the knob, which will be read by another doctor previously designated 
to avoid mistakes in the reading. 
5.- The intraocular pressure will be expressed in mmHg which is the flattening force 
multiplied by 10. 
Subsequent Segment Review 
It refers to the revision of the entire posterior segment, particularly: vitreous, retina, 
macula, and optic nerve. It will be qualified as follows: 
Normal. 
Abnormal. 
Abnormality that does not affect the result of the study (explaining situation in the FRC). 
Optic Nerve Excavation 
It includes the revision of the optic nerve, having to determine mainly the excavation or 
cupping vertically and must be expressed in a decimal way. 
This ophthalmological exploration will be analyzed as an independent parameter of the 
revision of the posterior segment, the rest of the optic nerve structure is also evaluated. 
24-2 Humphrey campimetry: 
Prior to inclusion, the subject must have a 24-2 white / white campimetry as a diagnostic 
method for primary open angle glaucoma, this must be no more than 6 months old after 
being performed, the ophthalmologist will evaluate it only to corroborate the diagnosis. 
In the case report format, the average deviation (DM) and standard deviation of the model 
(DSM) will be recorded. According to the general evaluation by the ophthalmologist, the 
subjects will be classified in mild, moderate, or severe damage corresponding to the 
preferred practice guidelines (PPP). 
10 SECURITFY 
10.1 Safety measurements 
The following safety measurements made in each visit or treatment period must be 
included in the schedule of activities  
The safety measurements are the following: 
- Adverse events. 
- Visual acuity and visual ability. 
- Previous biomicroscopy data. 
- Concomitant medications. 
 


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- Fluorescein staining. 
- Taking IOP with Goldman. 
10.2 Measurement methods and times 
10.2.1 Basal visit (day 1) 
The principal investigator or the head of the research team of the site must obtain the 
letter of informed consent of each of the subjects, before carrying out any procedure of 
the study. 
When the informed consent is obtained, a unique identification number of the subject will 
be assigned, this will be used throughout the study for its identification. 
The female sex subjects who have presented their menarche will undergo a urine 
pregnancy test. 
The following evaluations will be made to ALL enrolled subjects: 
1. Complete general and ophthalmological clinical history. 
2. VF-14 questionnaire and ocular comfort index. 
3. Visual Acuity and Visual Ability 
4. Visual Fields (validity in the last 6 months, if not, realize a new one). 
5. Evaluation of specific signs and symptoms of burning, foreign body sensation, 
lacrimation, conjunctival hyperemia. 
6. Anterior segment biomicroscopy (conjunctival hyperemia, chemosis, crystalline, iris, 
TRL, corneal surface, anterior chamber angle measurement). 
7. Posterior segment biomicroscopy (retina, vitreous, macula, optic nerve) under 
mydriasis. 
8. Vertical excavation of the optic nerve. 
9. Fluorescein staining. 
10. Taking intraocular pressure (IOP) with Goldman tonometer. 
11. Corneal pachymetry. 
12. IOP adjustment with corneal thickness. 
13. Subject number assignment  
14. Evaluation of concomitant medications. 
15. Evaluation of acute adverse events. 
All subjects will begin with the application of the study medication in the corresponding 
dose without leaving a washout period. 
All procedures will be recorded in the subject's clinical record. 


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10.2.2 Safety visit 1: (day 15). 
The subject will attend the review 15 days after the start of treatment, a window period 
of +/- 1 day is allowed. 
In this visit, the following will be evaluated: 
1. Visual acuity and visual capacity. 
2. Anterior segment biomicroscopy. 
3. Taking intraocular pressure (IOP) with Goldman tonometer. 
4. Fluorescein staining of the ocular surface. 
5. Evaluate concomitant medications and adverse events. 
10.2.3. Visit crossover 1 (Day 30) 
A window of ± 2 days is allowed while continuing to apply the study medication as 
stipulated. 
At each follow-up visit, an ophthalmological examination will be performed in order to 
evaluate the following parameters. 
1. Visual acuity and visual capacity. 
2. VF-14 questionnaire and ocular comfort index. 
3. Evaluation of symptoms and specific signs, foreign body sensation, burning, 
lacrimation, conjunctival hyperemia. 
4. Previous biomicroscopy. (conjunctival hyperemia, chemosis, crystalline, iris, TRL, 
corneal surface). 
5. Ultrasonic pachymetry 
6. Fluorescein staining 
7. Taking intraocular pressure (IOP) with Goldman tonometer. 
8. Evaluation of concomitant medications. 
9. Evaluation of adverse events 
10. Delivery of new treatment. 
11. Return of medication granted as first treatment. 
10.2.4 Safety visit 2 (Day 45): 
The subject will go to review 15 days after the start of the new treatment (day 45), a 
window period of +/- 1 day will be allowed for the visit. 
In this visit, the following will be evaluated: 
 
 


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1. Visual acuity and visual capacity. 
2. Anterior segment biomicroscopy. 
3. Taking intraocular pressure (IOP) with Goldman tonometer. 
4. Fluorescein staining of the ocular surface. 
5. Evaluate adverse events and concomitant medications. 
10.2.5 Final visit 5 (Day 61) 
A window period of ± 2 day will be allowed for this visti. The following parameters will 
be evaluated: 
1. Acuity and visual ability. 
2. Visual Fields 24/2 Humphrey, white / white. 
3. VF-14 questionnaire and ocular comfort index day 01, 30 and 60. 
4. Evaluation of symptoms and specific signs foreign body sensation, burning, tearing, hyperemia. 
5. Previous biomicroscopy. (conjunctival hyperemia, chemosis, crystalline, iris, TRL, corneal 
surface, anterior chamber angle measurement. 
6. Ultrasonic corneal pachymetry. 
7. Posterior biomicroscopy (retina, vitreous, macula and optic nerve). 
8. Vertical excavation of the optic nerve. 
9. Fluorescein staining. 
10. Taking intraocular pressure (IOP) with Goldman tonometer. 
11 Urine pregnancy test (if applicable). 
12. Evaluation of concomitant medications. 
13. Evaluation of adverse events. 
14. Return of the second treatment. 
15. Final evaluation by the researcher. 
10.2.6 Laboratory tests 
The urine pregnancy test will be taken in the same facilities of the research center where 
the subject will be given a bottle to collect their urine in private and then deliver the bottle 
with the urine sample to the investigating doctor or responsible person, which will 
introduce a test strip into the sample and wait for the result. 
10.3 Adverse events 
All adverse events should be a matter of follow-up and must be documented in a complete 
and accurate manner to make possible the assessment of the safety of the study drug. 
The same procedure will be applicable if the subject is given the drug under study or the 
comparators. 


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10.3.1 Record of adverse events in the Case Report Form 
10.3.1.1 Events to be registered 
An adverse event is defined as any unfavorable medical occurrence in a subject that is 
participating in a clinical trial, whether or not there is a causal relationship with the study 
drug and / or experimental procedures, and is present or begins with the date the subject 
signs the form of information and consent, regardless of the study period. 
Therefore, the investigator will document as an adverse event: 
 Any unfavorable and unintended sign, including an abnormal finding of an additional 
examination that the investigator considers clinically important, 
 Any intercurrent symptoms or illness, 
 Any worsening symptom or disease during the study or already present when the subject 
entered the study (increase in frequency and / or intensity) 
- Detected during a study visit or in an additional examination, 
- Be present from the previous study visit and notify the subject. 
Adverse Events at the time of application: the subject will document in the diary the 
possible adverse events that arise at the time of the application of the product under 
investigation. The Investigator will periodically review these journals, giving timely 
follow-up to the symptoms. 
Concomitant diseases: are all those diseases that are recorded in the baseline visit of the 
subject. 
Adverse Events of Special Interest: within the research protocol there are certain signs, 
symptoms or diseases characteristic of the disease or treatment that are of special interest 
to the sponsor. 
A serious adverse event, that is, an event that, regardless of the dose of the study drug 
administered: 
 Results in the death of the subject 
 Represents a threat to life 
Note: the term "threat to life" refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically could have caused 
death if it had been more serious. 
 Hospitalization or prolongation of the hospital stay. 
Note: any event that may not be an immediate threat to life or result in death or 
hospitalization, but may endanger the subject or may require intervention to avoid one of 
these outcomes (e.g., edema or allergic bronchospasm requiring intensive treatment at 
home, blood dyscrasia, seizures that do not cause hospitalization, or development of drug 
dependence or drug abuse). 
 


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 How persistent or important disability / disability results. 
Note: an event that seriously alters the ability of the subject to lead a normal life, in other 
words that causes a significant change, deterioration, injury or alteration of the functions 
or body structure of the subject, physical activity and / or quality of life. 
 
 Is a congenital anomaly / birth defect. Exposure to the study drug before conception 
(in man or woman) or during pregnancy that causes an adverse outcome in the child. 
 
Consumption of the study drug by a different person to the subject: 
 Minors: any consumption of the study drug with or without medical consequences must 
be notified immediately to the sponsor. 
 Adults: any accidental consumption of the study drug with clinical symptoms and any 
intentional consumption of the study drug, with or without medical consequences, should 
be notified immediately to the sponsor. 
In these specific cases, the investigator must immediately report by telephone or fax, or 
in non-working hours to the 24-hour telephone line (see Table 6). 
 
10.3.2.2 Follow-up of adverse events 
The researcher must ensure that the subject follow-up is appropriate to the nature of the 
event, and should continune until it is resolved. Any secondary deterioration should be 
reported immediately to the sponsor. 
Any change in terms of diagnosis, intensity, severity, measures taken, causality or result 
related to an adverse event already reported should be written in a full evaluation of the 
event. 
If the adverse event has not been resolved in the final visit of the subject in the study, the 
subject must be followed up correctly, noting any information about the outcome of the 
event in an "Adverse Event" form. 
If it is not the researcher who carries out the subject’s follow-up (hospitalization, follow-
up by a specialist or the general practitioner of the subject) the researcher will do 
everything possible to keep in contact with the person / department in charge of the 
subject’s follow-up, so that you can obtain additional information to report it in an 
"Adverse Event" form. 
 
10.3.2.3 Procedure for a serious adverse event 
In the setting of a serious adverse event that is presented: 
 


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- 
During the study or  
- 
During the 15 days after the final study visit of the subject, regardless of the supposed 
function of the investigation (study drug or required experimental procedures 
according to the protocol of the clinical study) or, 
- 
After these 15 days regardless of whether the start date is after the end of the study 
when the event could be because of the investigation. 
The researcher must: 
Record in the participant's medical record the date on which the event was made known 
(in a follow-up visit or through telephone contact with the participant or with a third party, 
...), immediately after or within 24 hours after being informed about this event, the 
sponsor will be informed by email and / or by telephone through his clinical monitor, to 
fill out the "Serious Adverse Event Report" form. 
If an initially non-serious adverse event worsens and becomes serious, this should be 
reported immediately in the corresponding format. 
Report the initially not serious event on a paper page "Adverse event - Additional 
information". 
- Report the deterioration caused by the seriousness on a paper page "Adverse event - 
Additional information", and 
- Send them by email immediately to the person responsible indicated above, with opia 
to the assigned study monitor. 
If a female subject in the study becomes pregnant, the investigator should: 
- Suspend the study treatment for the subject. 
- Fill out an "adverse event" form of the CRF. 
 
10.3.2.4 Causality assessment 
It is important that the researcher provide his or her opinion regarding the cause-effect 
relationship between the adverse event and the study drug, for the following reasons: 
certain adverse events that occur during clinical investigations may be important enough 
to lead to changes in the drug's development program (for example: changes in dose, 
population of the study or in the information provided to subjects that may lead to the 
preparation of new information and consent forms). This is especially true in case of 
events that are suspected to be related to the study drug (adverse reaction to the drug) and 
which, in its most severe form, could mean a threat to life. 
 
The causality must be assessed at the time of reporting the adverse event. Only cases 
marked by the researcher as "related" or according to the opinion of the sponsor to have 
a causal relationship with the investigational medicinal product under reasonable 
suspicion (relationship of the Adverse Event with the mechanism of action of the drug 
under study...) they will be considered as an Adverse Reaction to the suspect medication. 


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In general, the reasonable causal expression relationship means linking evidence or 
arguments to suggest a causal relationship. 
10.3.3 Responsibilities of the sponsor 
Independently of the normative obligations of the researcher, the sponsor must report the 
pharmacovigilance data to the pertinent authorities and to all participating researchers, in 
accordance with the requirements established in the International Conference on 
Harmonization (ICH), in the guidelines of the Good Clinical Practices and local 
regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 STATISTICS 
Sample size 
Sample calculation: 
To calculate the sample size, we used the average and the general standard deviation of 
the two quantitative variables mentioned (the intraocular pressure and the decrease of the 
intraocular pressure with respect to the basal pressure during and at the end of the 
treatments) and the percentage of cases that presented adverse events. 
The reliability of the study was established at 95% and the power at 80%. 
 
The sampling error was established as follows: in the case of the variable "intraocular 
pressure at the end of treatment" we established a sampling error of ± 1.00 mm Hg, that 
is, if the mean intraocular pressure at the end of the presents differences less than or equal 
to 1.00 mm Hg, we will conclude that the two treatments are equal, we will not be in a 
position to reject the null hypothesis of equal intraocular pressure at the end of treatment; 
but if the difference was higher than 1 mm of Hg in favor of Krytantek Ofteno® compared 
to PRO-122, we could assure with a p <0.05 that PRO 122 is superior to Krytantek 
Ofteno®, given that the former presented lower values than the second and vice versa. 
In the case of the variable "change in intraocular pressure with respect to the baseline 
value prior to treatment", the sampling error proposed is also 1.00 mm Hg. This leads us 
to the following reasoning: if the differences in the decrease in intraocular pressure 
between the treatments in this study were less than ± 1.00 mm Hg, we would conclude 
that there are no differences in this efficacy parameter, if this limit were exceeded, then 
we could speak of superiority of some of these treatments with respect to the rest. 
 
Finally, for the case of the variable "Percentage of subjects who presented adverse 
events", the sampling error was established at ± 15.0%. If the difference between the 
percentage of adverse events between one treatment and another (Krytantek Ofteno® 
versus. PRO-122) was less than 15%, then we will say that the treatments are equal with 
this parameter and if the difference was greater than 15 percent, then we will conclude 
that there are significant differences between treatments for this variable. 
In Appendix 4 (Tables 5, 6 and 7) the calculations are developed for the sample size 
needed to detect the indicated differences and to reach a conclusion about the efficacy of 
these two treatments. 
The study will allow to know if the efficacy (measured in terms of "intraocular pressure" 
and "change in intraocular pressure") is equal or better for PRO-122 when compared to 
Krytantek Ofteno® (null hypothesis) or if PRO-122 is worse than Krytantek Ofteno® 
(alternative hypothesis). 
It will also uncover if the security is the same or better for PRO-122 compared to 
Krytantek Ofteno® (in case the percentage of adverse events of PRO-122 is equal to or 


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less than Krytantek's) or worse (if the percentage of adverse events for PRO-122 results 
in more than 15% above the subjects treated with Krytantek®). 
The resulting sample calculated for the variable "intraocular pressure" was found to be 
91 and 84, for the variable "change in intraocular pressure" and for "percentage of cases 
with adverse events", respectively. 
We propose a sample of 90 cases per group for this study. Table 4 shows the results of 
the sample size calculated for each of the variables with the sampling errors which appear 
in subsection (A) of that table. We did an additional exercise proposing sampling errors 
of 1.5 mm Hg for intraocular pressure variables and 20% for the percentage of adverse 
events. For those sampling error sizes, the appropriate sample is proposed in 60 cases per 
group. 
 
4. Comparison of the sample size required for a 95% reliability and a power of 80% 
considering different levels of sampling error. 
 
For the sampling errors indicated in subsection (A), one sample per group of 90 patients 
would be recommended. 
For the sampling errors indicated in subsection (B), one sample per group of 60 patients 
would be recommended. 
In conclusion we could say that the study sample could be at least 60 subjects per arm, 
which would have sampling errors of 1.5 mm Hg for intraocular pressure variables and 
20% for the percentage of adverse events. We can increase it to 90 cases per group to 
reduce the errors to 1.0 mm Hg and 15% respectively, in all cases we assume a 95% 
reliability and an 80% power. 
12 DIRECT ACCESS TO THE DATA / DOCUMENTS SOURCE 
The researcher will allow the monitors, the people responsible for auditing, the 
representatives of the Ethics Committee, and the Competent Authorities to have direct 
access to the data / source documents. 
 


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13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 Supervision of the study 
13.1.1 Before the study 
The researcher will allow the monitor to visit the site and the facilities where the study 
will be conducted to ensure compliance with the protocol requirements. 
A meeting of researchers will be organized before the study starts. 
The researcher will allow the monitor: 
- Inspect the site, facilities and materials used for the study, 
- Meet with all the members of your team that participate in the study, 
- See all documents related to the study, 
- Have access to the CRFs and that they are filled correctly, 
- Direct access to the source documents to compare the data contained there against the CRF data, 
- Verify that the study is carried out in compliance with the protocols and regulatory requirements. 
If electronic medical records are used, the investigator should: 
- Print all medical records of all participants at the start of the study, 
- Print in real time each of the data entries and each change to the data during the study, 
The researcher will personally put the signature and date on the first page of the printout 
and indicate the number of pages. At each monitor visit, the investigator will provide you 
with all the impressions of the participant’s medical records. 
If the computer system allows tracking of changes made to medical records, the 
investigator will give the monitor an impression of the medical records of the participants 
and the records of the changes made at each visit. The researcher will personally place 
the date and signature on the first page of each printout, and the monitor will do so on all 
pages. The researcher and the monitor will put the number of pages on the first page. 
Study monitoring visits will be conducted at regular intervals, under the arrangements 
between the investigator and the sponsor depending on the recruitment rate. All 
information related to these visits will be handled as strictly confidential. 
13.2 Audit – Inspection - Verification 
The investigator should be informed of the possibility of an audit being conducted during 
or after the end of the study. 
The investigator should be informed that the Competent Authorities may also conduct an 
inspection of the facilities of the sponsor and / or the study center or centers. The sponsor 
will inform the relevant investigators, immediately upon receiving notification of an 


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inspection to the study centers. Likewise, the investigator will inform the sponsor of any 
pending inspection. 
The researcher will allow the representatives of the Competent Authorities and the people 
responsible for the audit to: 
- Inspect the site, the facilities and the material used for the study, 
- Meet with all the members of the team participating in the study, 
- Have direct access to the study data and source documents, 
- See all documents related to the study. 
 If computerized medical records are used, the researcher undertakes to provide all source 
documents and impressions of the medical records of the participants, and the record of 
the changes made during the study if the computer system allows it. 
14 ETHICS 
14.1 Research Ethics Committee 
The Principal Investigator will submit to the Research Ethics Committee the study 
protocol, informed consent, investigator's manual, materials to be delivered to the subject, 
recruitment materials, and the required documents in accordance with local requirements. 
The study will not begin in the center without first having obtained the approval of the 
corresponding Ethics Committees, having complied with the local regulatory 
requirements, and having obtained the signature of the confidentiality agreements and 
economic proposal of each of the principal investigating physicians. 
The study will be conducted in accordance with the ethical principles established in the 
Declaration of Helsinki of 1964, revised in Seoul, 2008 (see appendix 1). 
 
14.2 Information for the subject and form of informed consent 
An informed consent must be obtained before the subject undergoes any procedure 
indicated in the protocol. 
 
The written consent documents will incorporate the elements of informed consent 
described in the Declaration of Helsinki and the ICH Guide to Good Clinical Practices 
and follow all applicable laws and regulations. 
The principal investigator will provide the potential participant with all the information 
regarding the characteristics of the study, its potential benefits, risks, objectives, and 
procedures. This information will be with a language understandable to the subject, the 
right to interrupt their participation in the study at any stage will be explained to the 
subject, this, without affecting the relationship with the researcher and / or their future 
assistance. The informed consent will be put to the consideration of the possible 
participant; and must have enough time to analyze each and every one of the aspects 


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mentioned above and if there is any doubt, this will be clarified by the person in charge 
of obtaining the informed consent. Once the participant agrees to participate in the study, 
he / she must sign and date the letter of informed consent in the presence of two witnesses 
who have or are not related to the subject of study, who will participate during the 
informed consent process and will sign endorse that the process was carried out prior to 
any study procedure, that the study information was clearly explained, and, if present, 
doubts were clarified. 
If a subject is illiterate, the acceptance will be with their fingerprint, and in the event that 
the subject is not able to grant an informed written consent, a representative of the "legally 
authorized" subject can provide such consent in accordance with applicable laws and 
regulations. 
The principal investigator must also sign and date this consent. 
The informed consent must be signed in duplicate by all involved, and two witnesses, one 
copy will be filed in the researcher's folder and the other will be delivered to the 
participant. The Investigator must document the date on which the informed consent was 
signed in the subject's medical history. 
When the informed consent is obtained, a unique identification number of the subject will 
be assigned, this will be used throughout the study for the identification of the participant. 
The letters of informed consent are made in duplicate, a copy is kept by the investigator 
and a second one will be delivered to the subject. 
 
 14.3 Modification to "informed consent" 
Any change to "informed consent" constitutes an amendment to this document and must 
be presented for approval before the Ethics Committees, and if applicable before the 
Competent Authorities. 
The amendment will include a copy of the new version in the language or languages of 
the country. 
Such amendments may be implemented only after having obtained the written approval 
of the Ethics Committee and having complied with the local regulatory requirements, 
except for an amendment that is required to eliminate an immediate danger to the subjects 
of the study. 
Each subject affected by the amendment must fill out, date and sign two originals of the 
new version. The subject will be given a signed original of the amendment and the 
researcher will keep the second original. 
 
 
 
 


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15 DATA MANAGEMENT AND CONSERVATION OF RECORDS 
15.1 Study data 
 
The investigator or the designated person on your team will complete the Case Report 
Format (CRF) as well as all other documents provided by the sponsor (e.g., documents 
related to the handling of the treatment). 
 
CRF 
A CRF was designed to record the data that are required in the protocol and that the 
researcher collects in each of the visits.  
In the case of self-assessment questionnaires, it is not allowed for the principal 
investigator or person responsible for filling in or modify what was written by the subject 
of the study. 
The capturing of the data in the investigator's site will be done by the investigator or the 
designated person of his team after performing the Medical File. The researcher or a 
designated person of your team will be trained in filling the CRF. 
All corrections to the data to the CRF must be made by the investigator or the designated 
person of your team in accordance with the instructions provided. 
To ensure the confidentiality and security of the data, user names and access codes will 
be used to restrict access to the system only to authorized personnel, whether resident 
within the researcher's, the sponsor's or third party's sites. 
The monitor should ensure that all the data in the CRF has been filled. After comparing 
the data against the source documents, the monitor will ask the researcher to make the 
correction using clarifications, so that they are answered and closed as quickly as possible. 
The scientific review team of Laboratorios Sophia S.A. of C.V. will give the latest 
medical-scientific review, and will set the pattern to freeze the database. 
 
15.2 Data management 
The data will be collected in the CRF, once having a copy of the CRF of each of the visits 
of each subject that has completed the study, they will be transcribed to a database, the 
database mask will match the form of report of case and the data of each of the CRFs will 
be captured. A double data capture will be carried out to validate the information, as the 
case report forms are being collected from the center and the data have been validated by 
the clinical monitor. 
 
 


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15.3 File 
The investigator will keep all the information related to the study for at least 10 years 
after the completion of the study. 
 
16. OWNERSHIP OF RESULTS PUBLICATION POLICY 
Laboratorios Sophia S.A de C.V., acting as the sponsor of the study, assumes full 
responsibility for its function and retains exclusive ownership rights to the results of the 
study, which may be used in the manner it deems appropriate. 
Because the study is multicentric, the first publication should be done only with data 
collected from several centers and analyzed under the responsibility of Laboratorios 
Sophia S.A. of C.V. The researcher undertakes not to publish or communicate data 
collected only in a center or in part of the centers before the publication of the full results 
of the study, unless Laboratorios Sophia S.A. of C.V. gives prior written agreement. 
Any project of publication and / or communication related to the study or related to the 
results obtained during the study or after the termination of it, will be presented to the 
participating research doctors (to the sponsor) at least 30 days in the case of a publication 
and 15 days in the case of a summary, before the scheduled date for the communication 
and / or presentation of a publication. From the date on which the project is received, the 
medical researcher or doctors will comment on the project within 15 days in the case of 
a publication and 7 days in the case of a summary. 
However, if the sponsor is in the process of submitting a patent application on the results 
of the study, the sponsor may delay its publication or communication of the results of the 
study until the registration date. 
17. ADMINISTRATIVE CLAUSES 
17.1 Related to the sponsor and the researcher 
17.1.1 People to inform 
In accordance with local regulations, the investigator and / or sponsor will inform the 
Director of the Health Care Facility, the pharmacist involved in the study. The researcher 
will inform in advance, with their consent, the participating general practitioner. 
 
17.1.2 Substantial amendment to the protocol 
If it was necessary to alter the protocol after it was signed, the modification or substantial 
amendment should be discussed with the investigating physicians and staff that will 
participate in the clinical study, as well as with the regulatory entities of each region. It 


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should be kept with the initial protocol. On the cover of the protocol kept by the 
researcher, the number and date of the amendment version must be written. 
All substantive amendments should be sent to the investigators or coordinators or the 
sponsor, and to the Ethics Committees that reviewed the initial protocol, in accordance 
with local regulations. Amendments can be implemented only after obtaining the 
favorable opinion of the Ethics Committee, having complied with the requirements, and 
that the document of the amendment was signed, except when a measure is required to 
eliminate an immediate danger for the subjects in the study. 
In addition, the substantial amendment must be submitted to the Competent Authorities 
in accordance with local regulatory requirements. 
 17.1.3 Final report of the study 
Laboratorios Sophia S A de C.V. will elaborate the study report after completing the 
statistical analysis of the data, a final report will be designed, according to the ICH's 
PCBs. 
17.2 Related to the sponsor 
The sponsor agrees to: 
- Provide the researcher with adequate and sufficient information about the treatment or 
treatments administered during the study, in order to it carry out 
- Obtain any authorization to carry out the study and / or the import license that might be required 
by the local authorities to administer the treatment before starting the study (if it is international). 
17.3 Related to the researcher 
17.3.1 Confidentiality - Use of information 
 
All documents and information provided to the researcher by the sponsor are strictly 
confidential. 
The researcher expressly agrees that the data on their professional and clinical experience, 
provided to the sponsor in paper and stored on the computer, are solely for use related to 
their activities as the sponsor of clinical studies, in accordance with Good Clinical 
Practices. The researcher accepts that he / she and the members of his team will use the 
information only within the framework of this study, to carry out the protocol. This 
agreement is mandatory if the confidential information has not been disclosed to the 
public by the sponsor. The protocol of the clinical study provided to the researcher may 
be used by him and his colleagues to obtain the informed consent of the study subjects. 
The clinical trial protocol, like any information taken from it, should not be disclosed to 
other parties without the sponsor's written authorization. 
The researcher will not disclose any information without the prior written consent of 
Laboratorios Sophia SA. of C.V., except to the representatives of the Competent 
Authorities, and only by request. In the latter case, the researcher undertakes to inform 
Laboratorios Sophia S.A. of C.V. before revealing the information to these authorities. 


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The researcher will fill out and maintain a binnacle of selection of the subjects as well as 
the identification and list of enrollments of each of the subjects. The researcher agrees to 
give on-site access to the auditor and / or the representatives of the Competent Authorities. 
The information will be treated in compliance with professional secrecy. 
The subject's selection log will begin to be filled from the moment the investigator 
determines that a subject could participate in the study (through assessment of the 
subject's medical history during a visit or review of the medical record.) 
17.3.2 Organization of the center 
Any person to whom the researcher delegates a part of the study follow-up (co-
investigator, assistant researcher, nurse) and any other person participating in the study 
of this center (cardiologist, pharmacist, ...) must appear in the format of Delegation of 
Responsibilities (provided by the monitor). 
This document must be submitted at the beginning of the study and updated if one of the 
people participating in the study in the center changes. 
 17.3.3 Documentation to be delivered to the sponsor  
The researcher undertakes, before the start of the study: 
- To provide an updated Curriculum Vitae (maximum 10 pages) in Spanish (or 
corresponding language) dated and signed, and send it or deliver it to the sponsor along 
with your or your collaborators or work team, 
- Copy of Academic Certifications (undergraduate and postgraduate degrees and federal 
professional cedulas) 
- A copy of the operation notice, if applies. (when it is a private practice). 
  
 
 
 
 
 
 
 
 
 
 
 
 


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18. APPENDICES 
 
Appendix 1: Declaration of Helsinki of the World Medical Association 
 
DECLARATION OF HELSINKI OF THE AMM 
Ethical Principles for Medical Research in Human Beings 
Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 
and amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
48th General Assembly Somerset West, South Africa, October 1996 
52nd General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification of Paragraph 29, added by the WMA General Assembly, Washington 2002 
Note of Clarification of Paragraph 30, added by the General Assembly of the AMM, Tokyo 2004 
59th General Assembly, Seoul, Korea, October 2008 
 
A. INTRODUCTION 
1. The World Medical Association (AMM) promulgated the Declaration of Helsinki as a 
statement of ethical principles for medical research in humans, including research with 
identifiable human material and data. 
 The Declaration must be read in its entirety and each of the paragraphs that comprise it 
must not be applied without considering all the other relevant paragraphs. 
2. Although the Declaration is intended primarily for physicians, the AMM encourages 
other participants in medical research involving human subjects to adopt these principles. 
3. The doctor's duty to promote and safeguard the health of the subjects, including those 
who participate in medical research. The knowledge and conscience of the doctor are 
dedicated to the fulfillment of this duty. 
4. The Geneva Declaration of the AMM forces doctors with the words, "the health of my 
subject will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician must act according to what is best for him. the subject when 
providing medical attention. " 
5. Medical progress is based on research, which must ultimately include studies on human 
beings. The populations that are underrepresented in medical research should be given 
access to participate in the research. 
6. In medical research involving human beings, the wellbeing of the research subject must 
take precedence over all other interests. 


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7. The main objective of medical research with human beings is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures, and treatments). Even the most current 
interventions must be evaluated continuously by means of research into their safety, 
effectiveness, efficiency, accessibility, and quality. 
 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
9. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are especially 
vulnerable and require special protection. These populations include those who cannot 
give or withhold their consent on their own and those who may be susceptible to coercion 
or undue influence. 
10. Physicians should consider ethical, legal, and regulatory norms and standards for 
research with humans in their own countries, as well as applicable international norms 
and standards. No ethical, legal, or regulatory requirements, national or international, 
shall reduce or eliminate any of the protection for the research subjects established in this 
Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL INVESTIGATIONS 
11. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right of self-determination, privacy, and confidentiality of 
personal information of research subjects. 
12. Medical research involving human beings must conform to generally accepted 
scientific principles, based on a perfect knowledge of the scientific literature, other 
relevant sources of information, and on correct experimentation in the laboratory, and 
when relevant in animals. The welfare of the animals used for research purposes must be 
respected. 
13. Appropriate precautions should be taken when performing medical research that may 
harm the environment. 
14. The design and implementation of each research study with human beings should be 
clearly described in a research protocol. The protocol must contain a statement of the 
ethical considerations included and must indicate the manner in which this Declaration 
was handled. The protocol must include information related to the obtaining of funds, 
sponsors, institutional affiliations, other possible conflicts of interest, incentives for the 
subjects and provisions on the management and / or compensation to the subjects that are 
damaged   as a consequence of participation in the research study. The protocol should 
describe the arrangements for post-study access of subjects to interventions that are 
identified as beneficial in the study, or access to other appropriate care and benefits. 
 
 


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15. The research protocol must be presented for consideration, comment, guidance, and 
approval to a research ethics committee before the start of the study. This committee 
should be independent of the investigator, the sponsor, and any other undue influence. It 
must take into consideration the laws and regulations of the country or countries in which 
the investigation will be carried out, as well as the applicable international norms and 
standards, however they should not be allowed to reduce or eliminate any of the 
protections for the subjects under investigation. are set forth in this Declaration. The 
committee should have the right to supervise ongoing studies. The investigator should 
provide supervision research to the committee, especially information about serious 
adverse events. No change to the protocol can be made without the consideration and 
approval of the committee. 
16. Medical research involving human beings should be carried out only by individuals 
with the appropriate scientific qualifications and training. Research on healthy subjects 
or volunteers requires the supervision of a competent and appropriately qualified 
physician or health care professional. The responsibility for the protection of research 
subjects always rests with the doctor or the health care professional and never with the 
research subjects, even when they have given their consent. 
17. Medical research that implies a disadvantage or a vulnerable population or community 
will only be justified if the research is in response to health needs and priorities of this 
population or community obtain a benefit from the results of the research. 
18. Every study of medical research with human beings should be preceded by a careful 
assessment of the predictable risks and burdens for the individuals and communities 
participating in the research, compared to the benefits foreseen for them and for other 
affected individuals or communities. for the condition under investigation. 
19. Clinical studies should be recorded in a database with access to the public before 
recruiting the first subject. 
20. Physicians will not be able to participate in a research study with human beings unless 
they have confidence that the risks involved were properly assessed and that they can be 
handled satisfactorily. Physicians should immediately suspend a study when it is 
discovered that the risks outweigh the possible benefits, or when there is conclusive 
evidence of positive and beneficial results. 
21. Medical research involving human subjects may be carried out only if the importance 
of the objective exceeds the risks and burdens inherent to the subjects under investigation. 
 
22. The participation of competent individuals as subjects of medical research must be 
voluntary. Although it may be appropriate to consult with family members or community 
leaders, no competent individual can participate in a research study unless he or she freely 
agrees. 


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23. Every precaution must be taken to protect the privacy of the research subjects, as well 
as their personal information to minimize the impact of the study on their physical, 
mental, and social integrity. 
24. In medical research involving human subjects, each possible subject should be 
adequately informed about the goals, methods, sources of funds, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefit and the possible 
risks of the study, and the discomforts that could imply, as well as any other important 
aspects of the study. The possible subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without reprisal. 
Special attention should be paid to the specific information needs of the possible subjects, 
as well as to the methods used to offer the information. Once having made sure that the 
possible subject understood the information, the doctor or another duly qualified 
individual should try to obtain the informed consent of the subject, freely granted and 
preferably in writing. If it cannot be expressed in writing, the unwritten consent must be 
formally documented and witnessed. 
25. In the case of medical research that uses identifiable human material or data, 
physicians should normally seek consent to collect, analyze, store and / or reuse samples. 
There may be situations in which it is impossible or impractical to obtain consent for such 
an investigation, or that could imply a threat to the validity of the investigation. In such 
situations, the investigation may be carried out only after it has been submitted to the 
research ethics committee for approval. 
26. When trying to obtain the "Information for the subject and form of informed consent" 
for participation in a research study, the doctor should be especially cautious if the 
potential subject has a relationship of dependence with the doctor or could give their 
consent under duress in such situations, informed consent should be sought by a qualified 
individual who is completely independent of this relationship. 
27. In the case of a possible research subject who is incompetent, the doctor will try to 
obtain the informed consent of a legally authorized representative. These individuals 
should not be included in a research study if there is no likelihood of benefit to them, 
unless it is intended to promote the health of the population represented by the potential 
subject and the research cannot be carried out with competent persons, and research 
involves only risks and minimum burdens. 
28. When a potential research subject, who considers himself incompetent, can give his 
consent to participate in the investigation, the doctor must also seek the consent of the 
legally authorized representative. The denial of the possible subject must be respected. 
29. Research involving individuals who are physically or mentally disabled to give their 
consent, for example, unconscious subjects, may be performed only if the physical or 
mental condition that prevents their informed consent from being a necessary 
characteristic of the research population. In such circumstances, the physician must seek 
the informed consent of the legally authorized representative. If such a representative is 
not available and the investigation cannot be delayed, the study will proceed without 
informed consent, as long as the specific reason for including a subject with a condition 
that causes him or her not to give informed consent has been established in the research 


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and study protocol has been approved by a research ethics committee. The consent must 
be obtained to continue in the investigation as soon as possible, the subject or the legally 
authorized representative. 
30. All authors, publishers and printers have ethical obligations regarding the publication 
of research results. The authors have the duty to make publicly available the results of 
their research with human beings, and will be responsible for the integrity and accuracy 
of their reports. They must adhere to the accepted guidelines for the ethical report. 
Negative and inconclusive results should be published, as well as positive results, or made 
publicly available. The publication should include sources of funds, institutional 
affiliations, and conflicts of interest. Reports of an investigation that are not in accordance 
with the principles of this Declaration shall not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL ATTENTION 
31. The physician may combine medical research with medical care only to the extent 
that the research is justified by its potential prevention, diagnostic or therapeutic value 
and the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the subjects that serve as research subjects. 
32. The benefits, risks, burdens, and effectiveness of a new intervention must be tested 
against those of the best intervention currently tested, except in the following 
circumstances: 
 It will be acceptable to use a placebo or not to administer treatment when there is no 
currently proven intervention; or 
 When for methodological and scientific reasons the use of placebo is necessary to 
determine the efficacy or safety of an intervention, and subjects who are given placebo or 
no treatment are not at risk of serious or irreversible damage. Care should be taken to 
avoid abuse of this option. 
33. At the end of the study, the subjects who participated in the study will have the right 
to be informed of the results of the study and to share with them the resulting benefits, 
for example, access to interventions identified as beneficial in the study, or other care or 
adequate benefits. 
34. The doctor must fully inform the subject which aspects of the care are related to the 
investigation. The negation of the subject to participate in a study, or the decision of the 
subject to withdraw from the study should never interfere with the medical subject 
relationship. 
35. In the treatment of a subject, when there are no proven interventions or have been 
ineffective, the doctor, after seeking expert advice and with the informed consent of the 
subject or the legally authorized representative, may use an unproven intervention if in 
his opinion the doctor offers hope to save lives, restore health or relieve suffering. When 
possible, this intervention should be part of the object of the investigation, designed to 


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assess its safety and efficacy. In all cases, the new information must be recorded and, 
when appropriate, made publicly available. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: questionnaire VF14 
 
VF-14 Rating: 
F = results from multiplying the number of boxes in said column by the 
corresponding X value. 
It will be done like this with each column. 
Subsequently, the values of all the columns will be added and divided by the value 
of C. 
The value of C corresponds to the sum of the number of squares answered except 
those that do not apply, the maximum being 14. 
 
 
 
 


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Appendix 3: Eye comfort index questionnaire. 
Version 1.0 / September 2014 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: Sample calculation 
Table 5 
Formula to calculate the sample size considering parameters recorded in periodicals for 
the variable: "Final intraocular pressure in patients with glaucoma or ocular hypertension, 
treated with Krytantek". 
 
       2Sp2 
n = ------------------- (Z1-a / 2 + Z1-b) 2 
       (X1-X2) 2 
 
Sp = Average standard deviation of the test variable in patients treated with Krytantek. 
2.40 
X1 = Average of the reference population (Krytantek) 14.68 
X2 = Average of the experimental population (Other) 15.68 
(X1 - X2) = Difference of expected means, that wants to be contrasted (Sampling error)           
1.00 
a = Level of significance or probability of error type 1 = 0.05 
1-a / 2 = Bilateral percentages for the level of assigned significance. = 0.975 
Z0.975 = Z of the standardized normal distribution that leaves an area of 0.975 to the left. 
It implies 95% reliability. 1.96 
b = Probability of error type 2 = 0.20 
1-b = Unilateral percents for the assigned beta = 0.80 
Z0.80 = Z of the standardized normal distribution that leaves an area of 0.80 to the left. It 
implies a power of proof of 80%. 0.842  
n= 90.4458701 
Minimum necessary sample size that assures us with a probability of 0.80 (Power of 80%) 
that if the difference you want to contrast is true (1 mm Hg or more difference), the study 
confirms it rejecting the null hypothesis and that if this difference is less than 1 mm Hg 
(less than the magnitude of the expected difference - sampling error), then do not reject 
the null hypothesis, and confirm that the difference is not of the magnitude that arises, 
with a probability of: 0.95 which implies a 95% Reliability. 
 
 
 


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Table 6 
Formula to calculate the sample size considering parameters recorded in periodicals for 
the variable: "Decrease in final intraocular pressure in patients with glaucoma or ocular 
hypertension, treated with Krytantek". 
     2Sp2 
n= ------------------- (Z1-a /2 + Z1-b)2 
       (X1-X2)2 
Sp = Average standard deviation of the change in intraocular pressure in patients treated 
with Krytantek 2.30 
X1 = Average of the reference population (Krytantek) 10.20 
X2 = Average of the experimental population (Other) 11.20 
(X1 - X2) = Difference of means expected, that wants to be contrasted 
(Sampling error) 1.00 
a = Level of significance or probability of error type 1 = 0.05 
1-a / 2 = Bilateral percentages for the level of assigned significance. = 0.975 
Z0.975 = Z of the standardized normal distribution that leaves an area of 0.975 to the left. 
It implies 95% reliability. 1.96 
b = Probability of error type 2 = 0.20 
1-b = Unilateral percents for the assigned beta = 0.80 
Z0.80 = Z of the standardized normal distribution that leaves an area of 0.80 to the left. It 
implies a power of proof of 80%. 0.842 
n = 83.0657383 
  Minimum necessary sample size that assures us with a probability of 0.80 (Power of 
80%) that if the difference you want to contrast is true (1 mm Hg more, or less change in 
IOP), the study confirms it by rejecting the null hypothesis and that if this difference is 
less than 1.00 mm Hg (less than the magnitude of the expected difference - sampling 
error), then do not reject the null hypothesis, and confirm that the difference is not of the 
magnitude that arises, with a probability of: 0.95 which implies a 95% Reliability. 
 
 
 
 
 


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Table 7. Fleiss' formula for calculating the sample size for proportions. "Statistical 
Methods for Rates and Proportions" 2a. Ed. Pp. 38-45 Comparison of two proportions. 
 
 
 


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xvii. Pisella, P.J., Pouliquen, P., Baudouin, C., 2002. Prevalence of ocular symptoms and signs 
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