Clinical trial NCT02801617
Conditions: Primary Open Angle Glaucoma Ocular Hypertension
Keywords: Latanoprost Glaucoma Ocular hypertension Crossover study
Sponsor: Laboratorios Sophia S.A de C.V.
Start date: 2015-09-01; Completion date: 2017-07-19
Enrollment: 116 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Aim: To demonstrate the non-inferiority of the PRO-067 ophthalmic solution manufactured by Laboratorios Sophia S.A. de C.V. versus GAAP 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 60 patients will be assigned to receive the ophthalmic solution: GAAP Ofteno ® (latanoprost 0.005%) 1 drop per day (QD) during 30 days and the second sequence 60 patients will be assigned to receive the ophthalmic solution: PRO-067 1 drop QD during 30 days in the same period. Washout period: 21 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 Latanoprost 0.005% (GAAP Ofteno®, Laboratorios Sophia, Mexico) and the other one treated with PRO-067 ophthalmic solution. Patients will receive 1 drop per day (QD) into the lower conjunctival sac of either formulations and were examined at days: 1, 15, 30, 45 ad 60 after initiation of treatment. A phone call security at day 75 will be performed.

Primary efficacy outcome: To evaluate the efficacy of PRO-067 versus GAAP 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: study subjects will be allocated to receive PRO-067 QD for 30 days, after which they will be crossed over to the other medication (GAAP Ofteno®) for another 30 days. The Intraocular pressure-reducing effect of the medications will be assessed by the reduction in IOP after each medication compared to baseline.

Washout period: 21 hours arm 2: study subjects will be allocated to receive GAAP Ofteno® QD for 30 days, after which they will be crossed over to the other medication (PRO-067) for another 30 days. The Intraocular pressure-reducing effect of the medications will be assessed by the reduction in IOP after each medication compared to baseline.

Washout period: 21 hours
Interventions: intervention 1: PRO-067 intervention 2: GAAP Ofteno®
Intervention descriptions: intervention 1: 1 drop QD during 30 days is a sterile ophthalmic solution formulated by Laboratorios Sophia S.A. de C.V. intervention 2: 1 drop QD during 30 days Active comparator, reference medication.

Protocol documents:
Prot_SAP_000.pdf: 
PRO-067                 Protocol of the clinical study SOPH067-0914 / III                 Version 3 
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A Multicentric, Prospective, Crossover, Double-Blind Clinical 
Study, to Evaluate the Non-inferiority of the PRO-067 ophthalmic 
solution, Manufactured by Laboratorios Sophia, S.A. de C.V., 
Previous Treatment with GAAP Ofteno ®, In Subjects With 
Primary Open-angle Glaucoma (POAG) or Ocular Hypertension 
(OHT): "COMPLIANCE" Study. 
 
 
 
 
 Drug under study: Latanoprost 0.005% 
 Indication: Antiglaucomatous 
 Development phase: Phase 3 
 Protocol code: SOPH067-0914 / III 
 Sponsor: Laboratorios Sophia, S.A. of C.V. 
 Version: 3 
 Date: February 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PRO-067                 Protocol of the clinical study SOPH067-0914 / III                 Version 3 
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2. STUDY SHEET SUMMARY 
Sponsor's name: Laboratorios Sophia, S.A. of C.V. 
Active Ingredient Name: Latanoprost 0.005% 
Study title: A Multicentric, Prospective, Crossover, Double-Blind Clinical Study, to Evaluate the Non-
inferiority of the PRO-067 ophthalmic solution, Manufactured by Laboratorios Sophia, S.A. de C.V., 
Previous Treatment with GAAP Ofteno ®, In Subjects with Primary Open-angle Glaucoma (POAG) or Ocular 
Hypertension (OHT): ("COMPLIANCE" Study) Protocol No.: SOPH067-0914 / III 
Study period:                                                                                 Study development phase 
Duration of the study for the participant: 75 days.                Phase: 3 
Goals: 
Aim: To demonstrate the non-inferiority of the PRO 067 ophthalmic solution manufactured by 
Laboratorios Sophia, S.A. de C.V., versus GAAP Ofteno ® ophthalmic solution like hypotensive therapy in 
subjects with a diagnosis of POAG or OHP. 
Primary Outcome Measures: To evaluate the efficacy of the PRO-067 ophthalmic solution elaborated by 
Laboratorios Sophia, S.A. of C.V. versus the GAAP Ofteno® ophthalmic solution applied on the ocular 
surface in subjects with a diagnosis of POAG or OHT by control and maintenance of a Target Intraocular 
Pressure (TIOP). 
Secondary Outcome Measures: To assess the tolerability of the PRO-067 ophthalmic solution elaborated 
Laboratorios Sophia, S.A. of C.V. versus the GAAP Ofteno® ophthalmic solution in subjects with a diagnosis 
of POAG or OHT through the evaluation of ocular symptoms such as burning, hyperemia, lacrimation, 
foreign body sensation; fluorescein staining, the Visual Function Index (VF-14) questionnaire score and 
ocular comfort index. 
Primary security objective: To evaluate the safety of the PRO-067 ophthalmic solution elaborated by 
Laboratorios Sophia, S.A. of C.V. versus GAAP Ofteno® ophthalmic solution in subjects with a diagnosis of 
POAG or OHT through visual capacity, anterior segment biomicroscopy, fundus examination and 
frequency of adverse events.  
Work hypothesis / Ho: The proportion of subjects with open-angle primary glaucoma and / or intraocular 
hypertension exposed to GAAP Ofteno ® who maintained the TIOP values during the study is greater than 
or equal to the proportion of subjects with primary open-angle glaucoma and / or intraocular 
hypertension exposed to PRO-067 who maintained the TIOP values plus 2mmHg during the study. 
Ha: The proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension 
exposed to GAAP Ofteno® who maintained the TIOP values during the study is lower than the proportion 
of subjects with primary open-angle glaucoma and / or intraocular hypertension exposed to PRO-067 who 
maintained the TIOP values plus 2mmHg during the study. 
 
 
 
 
 
 
 


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Methodology 
A national, multicenter, prospective, crossover, longitudinal, double-blind study, with fixed dose. Number 
of participants: 120 subjects. 
Diagnosis and main inclusion criteria: Female or male, age ≥18 years, with primary open-angle glaucoma 
with or without pseudoexfoliation or pigmentary dispersion previously treated with GAAP Ofteno® at 
least for two months before inclusion and under TIOP corresponding to their condition in at least 2 
previous visits without concomitant eye surface diseases and an informed consent signature. 
Study medication: 
The PRO-067 Ophthalmic drops. They will be applied with the following posology: 
1 drop every 24 hours for 30 days, alternating therapy with 30 more days of GAAP Ofteno® with the same 
frequency. 
 
Comparator: GAAP Ofteno® 
 
Treatment duration: 
- Inclusion period: 3 months 
- Period of treatment: 60 days 
- Follow-up period: 75 days. 
Evaluation criteria: 
Efficacy measurements: 
Main efficacy criteria: 
Efficacy will be determined by maintaining the TIOP throughout the study. 
Secondary efficacy criteria: 
Specific signs and symptoms such as burning, hyperemia, lacrimation, foreign body sensation, 
measurements with fluorescein staining, the VF-14 questionnaire score and ocular comfort index will be 
evaluated. 
Primary security criteria 
Visual capacity, anterior segment biomicroscopy, fundus examination and frequency of adverse events. 
 
 
 
 
 
 
 
 


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INDEX 
 
1.-COVERAGE ................................................ ....................................................................1 
2.- STUDY SUMMARY SHEET.....................................................................................………..2 
4. GLOSSARY AND DEFINITIONS ............................................. ...........................................8 
5. ADMINISTRATIVE STRUCTURE OF THE STUDY ...............................................................9 
5.1. Sponsoring parties ......................................................................................................9 
6. BACKGROUND ............................................... ..............................................................10 
7. STUDY DESIGN ............................................. .............................................................…21 
7.1. Point or limit points .............................................. .................................................. 21 
7.2 Study plan .............................................. .................................................................. 22 
7.2.1 Study schedule ............................................ ......................................................... 24 
7.3 Measures to minimize deviations .......................................... .........................……….29 
7.4 Products administered ............................................... ..............................................29 
7.4.1 Treatment management ............................................ ...........................................31 
7.5 Discontinuation of the study .............................................. ......................................32 
7.5.1 Premature discontinuation of the study .................................................................32 
7.5.2 Center closure......... ...............................................................................................32 
7.6 Source data ............................................... ...............................................................32 
8 SELECTION AND REMOVAL OF STUDY SUBJECTS. ...................................................32 
8.5 Selection criteria .............................................. .......................................................32 
8.5.1 Informed Consent ............................................. ...............................................….33 
8.6 Exclusion criteria .............................................. .......................................................33 
8.6.1 General criteria ............................................. .......................................................33 
8.6.2 Medical and therapeutic criteria .........................................................................33 
8.7 Non-inclusion criteria..............................................................................................34 
8.8 Participant discontinuation criteria ................................................. ..................... 34 
8.8.1 Withdrawal criteria .... ........................................... .............................................34 
8.8.2 Procedure .............................................. .............................................................35 
 
9 SUBJECTS OF STUDY TREATMENT...............................................................35 
9.1 Managed treatments .............................................................................................. 35 
9.2 Treatment delivery...................................................................................................35 


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9.3 Previous and concomitant treatments ....................................................................35 
9.5 Drug compliance............... .............................................. ........................................36 
10 EFFICACY EVALUATIONS...........................................................................36 
10.1 Effectiveness measurements .................................................................................36 
10.2 Methods and timing of measurements .................................................................37 
11 SECURITY EVALUATIONS..........................................................................40 
11.1 Security measurements .........................................................................................40 
11.2 Specific procedures by type of visit. ...................................................................….40 
Clinical examination ................................................ ..................................................... 40 
11.2.1 Laboratory tests ............................................ .....................................................43 
11.3 Adverse events ............................................... ..................................................... 43 
11.3.1 Investigator's Responsibilities ............................................ ................................43 
11.3.2 Record of adverse events in the Case Report Form .................................…………43 
-Registration of events ....................................... ..........................................................43 
11.3.2.1 Registration methods... ........................................... .......................................44 
11.3.2.2 Adverse events follow-up................................................ ................................44 
11.3.2.3 Serious adverse event procedure.................................................................... 45 
11.3.2.4  Causality assessment.............................................. ........................................46 
11.3.3 Sponsor responsabilities......... ............................................ ...............................46 
11.4 Biosecurity aspects .............................................. .................................................46 
12 STATISTICS ................................................ .............................................46 
13 DIRECT ACCESS TO THE DATA / DOCUMENTS SOURCE ............................48 
14 QUALITY CONTROL AND QUALITY ASSURANCE .......................................48 
14.1 Study supervision...................................................................................................48 
14.1.1 Before the study ............................................ ................................................... 48 
14.2 Electronic medical record ......................................................................................49 
14.3 Audit - Inspection .............................................. .................................................. .49  
15 ETHICS ....................................................................................................50 
15.1 Ethics Committee .............................................. .................................................. .50 
15.2 Realization of the study .............................................. ...........................................50 
15.3 Information for the subject and form of informed consent ...................................50 
15.4 Modification to "informed consent" ........................................... .......................... 51 
16 DATA MANAGEMENT AND CONSERVATION OF RECORDS .................................. 51 


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16.1 Study data .............................................. ...............................................................51 
16.2 Data management .............................................. ................................................. 52 
16.3 File ................................................ .................................................. .................... 52 
17 OWNERSHIP OF THE RESULTS - PUBLICATION POLICY .........................................52 
18 ADMINISTRATIVE CLAUSES .................................................................................53 
18.1 Related to the sponsor and the researcher .......................................................... 53 
18.1.1 People to report .................................................................................................53 
18.1.2 Substantial amendment to the protocol ........................................................... 53 
18.1.3 Final study report................................................................................................53 
18.2 Related to the sponsor ............................................. .......................................…..53 
18.3 Related to the researcher .....................................................................................53 
18.3.1 Confidentiality - Information use........................................................................53 
18.3.2 Center organization........................................................................................... 54 
18.3.3 Documentation to be delivered to the sponsor ................................................54 
19 APPENDICES ......................................................................................................55 
REFERENCES .......................................................................................................... 64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Tables 
Table 1. Laboratories Sophia S.A. of C.V. ..................................................................... 9 
Table 2 Study Schedule ............................................. ..................................................24 
Table 3 Description of the study drugs ........................................................................29 
Table 4 Packaging description .................................................................................... 30 
Table 5 Main prohibited treatments .......................................................................... 36 
Table 6 Contact structures in case of a serious or not serious Adverse Event ............45 
List of figures 
Figure 1 - Study Plan ............................................ .......................................................23 
Figure 2: Descriptive flow charts by type of visit ........................................................ 25 
List of appendices 
Appendix 1: Declaration of Helsinki of the World Medical Association ........................559 
Appendix 2: Visual function questionnaire VF-14 .......................................................... 61 
Appendix 3: Eye Comfort Questionnaire Version 1 ........................................................62 
Appendix 4: Sample size calculation ...............................................................................63 
References ................................................. ................................................................... 64 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. GLOSSARY AND DEFINITIONS 
 AE Adverse Event 
 VA Visual acuity 
 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 
 mmHg Mercury milimiters 
 
 
 
 
 
 
 
 
 
 
 


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5. ADMINISTRATIVE STRUCTURE OF THE STUDY 
5.1. Sponsoring parties 
Table 1. - Laboratorios Sophia, S.A. of C.V. 
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 / email 
Phone number 
Manager of clinical operations. 
Biochemist Pharmacist M.B.A. 
Marco A. Cid López 
marco.cid@sophia.com.mx 
+33 3001 4200 Ext. 1074  
 
Medical 
Ophthalmologist 
Researcher 
Dr. Aldo Arturo Oregon Miranda 
aldoregon@gmail.com 
+33 3001 4200 Ext. 1125  
 
Senior Monitor 
Biochemist Pharmacist Jessica 
Mejía Gutiérrez  
jessica.mejia@sophia.com.mx  
+33 3001 4200  
Ext. 1192  
Junior Monitor 
Biochemist Pharmacist M.en.F 
Sandra C. Gómez M.  
sandra.gomez@sophia.com.mx  
+33 3001 4200  
Ext.1191  
Junior Monitor 
LN. Ana Isabel Alcaraz Ledón  
ana.alcaraz@sophia.com.mx  
+33 3001 4200  
Ext. 1193  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. BACKGROUND 
 
Most drugs for the management of intraocular pressure were introduced before having reports in the 
literature about their ocular effects. In contrast, hundreds of publications on the ocular effects of 
prostaglandins can be found.i 
Prostaglandins are normally present in ocular tissues, and are known to modulate a broad spectrum of 
biological processes and responses, either alone or in combination with other autacoids. Although 
prostaglandins can reduce intraocular pressure (IOP) sufficiently, they have considerable adverse effects 
on human eyes, in some cases including the rupture of the blood-aqueous barrier and an initial 
hypertensive phase. The esterification of the carboxylic acid of PGF2α reduces the amount of drug needed 
to decrease intraocular pressure, thereby minimizing its side effects.ii 
Glaucoma is a progressive optic neuropathy, characterized by structural alterations, which result in 
functional anomalies. These alterations are manifested by: specific changes in the optic disc, defects in 
the nerve fiber layer, visual field alterations and other signs usually related to the difficulty of outflow of 
aqueous humor and a constant or intermittent abnormal intraocular pressure.iii 
Ocular hypertension is currently considered the main risk factor in the pathophysiology of damage to the 
head of the optic nerve; the ischemia of the optic nerve, at the level of the lamina cribosa, is also 
important. Three variables determine the average level of intraocular pressure: (1) production of aqueous 
humor by the non-pigmented epithelium of the ciliary body; (2) outflow of aqueous humor; (3) pressure 
of the episcleral veins. In this way, medical treatment should be aimed at modifying these variables. 
 
 
 Agents that modify the rate of formation of aqueous humor: 
1. Beta-adrenergic antagonists. 
2. Alpha adrenergic agonists. 
3. Carbonic anhydrase inhibitors. 
 Agents that alter the outflow of aqueous humor: 
1. Cholinergic agents. 
2. Alpha adrenergic agonists (non-conventional route). 
3. Prostaglandin analogues. 
 Agents that modify the episcleral venous pressure.iii 
 
Sophia Laboratories, S.A. of C.V. has developed a formula of Latanoprost at 0.005% which remains stable 
at different temperatures and at different periods of time, thus showing advantages over Xalatan®, which 
is unstable under certain environmental conditions. iv 
Glaucoma is a silent disease, being the second cause of legal blindness worldwide and the first cause of 
irreversible blindness in the adult population.v. 


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Among the ocular hypotensive drugs currently used for the treatment of primary open-angle glaucoma 
(POAG) and ocular hypertension, prostaglandin analogs are considered to be the most potent. Although 
the mechanism of action of these drugs is yet not fully understood, it is believed that these act by 
increasing the drainage of the aqueous humor by both conventional and non-conventional routes. In a 
study carried out by Dr. Masanobu and Col. in the Department of Ophthalmology at the University of 
Hiroshima, in Japan, a total of 124 Japanese subjects diagnosed with primary open-angle glaucoma were 
included, showing that the intraocular pressure was decreased with Latanoprost, maintaining its reducing 
effect for 1 year, the duration of the study. In addition, in this same study Latanoprost demonstrated good 
tolerance. Vi 
Jean Philippe Nordmann et al. developed a clinical study comparing the effect of Latanoprost in 
monotherapy versus the effect of the combination of timolol maleate plus pilocarpine in subjects with 
glaucoma or ocular hypertension, with a poor response and lack of control of IOP with the use of β-
adrenergic antagonists. We included 237 subjects who were assigned the randomized study article, those 
who were administered Latanoprost at 0.005% once a day and those whom the combination was 
administered twice a day, evaluating its intraocular pressure reducing effect, reaching the conclusion that 
a single application of Latanoprost a day is as effective as two daily applications of the combination of 
timolol maleate with pilocarpine to reduce intraocular pressure in those subject’s refractory to treatment 
with β-adrenergic alone.vii 
 
JUSTIFICATION 
 
Recently, an increase in the prevalence of ocular surface disease in glaucoma subjects has been reported 
in approximately 48.4% compared to 15% in the 1990s. It is believed that this increase in dry eye 
symptoms is due in part to the chronic use of medications and to the preservatives they contain, with 
benzalkonium chloride as the most widely used in ophthalmic preparations. 
Due to its efficacy, prostaglandin analogs have been positioned as first-line drugs for the treatment of 
primary open-angle glaucoma, its application once a day has also favored compliance by subjects. 
It has been reported that Latanoprost is the best tolerated analog of prostaglandin in the market, although 
there is controversy in the different references with respect to other prostaglandins. Regarding this, 
Laboratorios Sophia S.A. of C.V. developed a new formulation in the search to provide subjects with 
greater comfort, compliance, and effectiveness. 
Starting from the conclusions enunciated by Dr. Boudinxii and collaborators in studies of the effects of the 
conservators on the ocular surface in which the inflammation factors that lead to histological changes 
were measured, it is logical to propose a formula with the same effectiveness. In these studies, first 
performed on the conjunctiva of healthy patients, then in patients diagnosed with primary glaucoma it 
was concluded that the following differences existed: 
 The goblet cells are depleted by 60% after one month of being exposed to ophthalmic solutions with 
benzalkonium chloride, xii, xiii. 
 The tear rupture time is altered after 7 days of exposure and reaches abnormal times after 3 weeks.xi. 
Also, the migration of pro-inflammatory cells from the innate response promotes secondary 
immunological reactions, 
 
 
 


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 such as: 
 HLA-DR antigens and pro-kinetic molecules I-cam – 3 are the main molecules found in the conjunctival 
proper substantia and tenon. xiii. 
 As a result, there is a significant increase of CD 20/22/23 as well as CD 4 (Th2) xii, xiii. 
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.xii. 
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. Xii, xiii. 
 
Conjunctival biopsies and their cellular infiltrates in surgically treated antiglaucomatous user patients and 
nonusers.xiii. 
 
 
 


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No users 
Monotherapy 
Multi-therapy 
Nomal 
80% 
59% 
12% 
Immunohistochemical 
markers 
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. xiii. 
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. 
 
Hypothesis 
Ha: πs <πe + ᵟ 
Ha: The proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension 
exposed to GAAP Ofteno® who maintain the TIOP values during the study is lower than the proportion of 
subjects with primary open-angle glaucoma and / or intraocular hypertension exposed to PRO-067 who 
maintain TIOP values plus 2mmHg during the study. 
H0: πs ≥ πe + ᵟ 
Ho: The proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension 
exposed to GAAP Ofteno ® who maintain the TIOP values during the study is greater than or equal to the 
proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension exposed to 
PRO-067 who maintain the TIOP values plus 2mmHg during the study. 
Where: 
H0: Null hypothesis 
Ha: Alternative hypothesis 
πs: Proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension exposed 
to GAAP Ofteno ® who maintained the TIOP values during the study 
πe: Proportion of subjects with primary open-angle glaucoma and / or intraocular hypertension exposed 
to PRO-067 who maintained the TIOP values during the study 
ᵟ Noninferiority limit determined at +2 mmHg. That is, the study subjects should not exceed the values of 
their TIOP by more than 2mmHg with respect to the baseline value during their participation in the 
present study. VIII 
 
 


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Therefore, the evaluation of efficacy in the present clinical trial focuses on the maintenance of the TIOP, 
which was previously achieved with the antiglaucomatous  stablished treatment, VIII, IX when receiving 
for 75 days the formulation PRO-067 or GAAP ofteno® (as active control). XI 
NON-CLINICAL PHARMACOLOGY 
Laboratorios Sophia S.A. of C.V. studied the bioavailability of Latanoprost® from 3 products containing its 
prodrug Latanoprost, which were GAAP Ofteno, PRO 067 ophthalmic solution elaborated by Laboratorios 
Sophia S.A. of C.V and Xalatan®. The study times were 30, 60, 120, 180 minutes, using two rabbits in both 
eyes with an n = 4. Table 4 (curve from 10 to 40 ng / mL) and table 6 (curve from 40 to 300 ng / mL) show 
the calibration curves used for the quantification of Latanoprost Acid in aqueous humor, it should be 
noted that two curves were used since a single curve of 10 to 300 ng does not present a good linearity 
contrary to what was presented when using two of them. 
Figures 1 and 2 show the individual bioavailability of Latanoprost® from PRO-067 ophthalmic solution 
developed by Laboratorios Sophia S.A. of C.V and GAAP Ofteno® respectively, where a vertical line marks 
the minimum, average value and the maximum value obtained, plotting in the tempo using only the 
average. 
Tables 8, 10 show the 4 values obtained for each study time, in the last column, the average of them is 
shown in bold. Viii 
 
 
Table showing the standard recoverability loaded in aqueous humor. 


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CLINICAL DATA FROM PHASE I 
An unicentric, prospective and open study was carried out to evaluate the safety and the tolerance of the 
PRO-067 ophthalmic solution elaborated by Laboratorios Sophia S.A. of C.V applied on the ocular surface 
of ophthalmologically healthy human volunteers. 
We studied 30 subjects in total (60 eyes) who met the eligibility criteria of the study, and  received a drop 
of Latanoprost ophthalmic solution developed by Laboratorios Sophia S.A. of C.V in each eye. The Principal 
Investigator only made the clinical assessment. The study article was applied once a day, at night (22:00 
hrs.), during a period of 15 days. 
 
 
 
 
 
 


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On day 0 of the study, the researcher confirmed that each subject met the essential requirements for 
participation in the protocol, in the same way he asked each subject to sign the informed consent. As part 
of the direct questioning of the subject, demographic information, reason for consultation, background, 
evolution, and current status were obtained and recorded, as well as investigation of specific symptoms. 
Evaluations were conducted on days 2, 4, 7, 10 and 15 of the study. At each visit, a physical examination 
was performed, and the findings were recorded in the following order: 1) Visual capacity 2) Review of the 
anterior segment with slit lamp 3) Investigation of specific signs 4) Tonometry and 5) Indirect 
ophthalmoscopy under pharmacologic mydriasis. 
Each subject was assigned and delivered his study article, and they were instructed to apply it once a day, 
at 22:00 hrs., for 15 days. The results were the following: 
 
 
Graph 1. Behavior of the IOP, in which a reduction of 1 mmHg is observed in the study group. 


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Graph 2. Conjunctival Hyperemia. The graph shows an insignificant degree of hyperemia during the entire 
study period. 
Regarding intraocular pressure, the results show an average reduction of 1 mmHg below the baseline 
(graph 1). 
Continuing with the safety data, conjunctival hyperemia (graph 2) did not show a significant increase 
during the 15 days of treatment. 
As to the tolerance data, the degree of burning (graph 3) increased in day 2 of treatment, but gradually 
decreased in subsequent visits. Finally, in terms of ciliary injection (graph 4), and hyperemia (graph 5) 
both parameters showed no appreciable changes during the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Graph 3. Referred burning sensation by the participants during the study period. Although an increase 
was observed between day 4 and day 7 of treatment, in reality the intensity of the burning was not 
significant. 
Graph 4. Ciliary injection during the treatment period. No significant changes are appreciated. 
 
 
 
 


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Graph 5. Hyperemia during the treatment period. No significant changes are appreciated. 
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 regarding ocular surface stains in any day of study. 
Therefore, it was concluded that Latanoprost elaborated by Laboratorios Sophia S.A. C.V is safe and well 
tolerated when administered topically ophthalmic at the indicated dosage in ophthalmologically healthy 
volunteers. 
7. STUDY DESIGN 
7.1. Point or limit points 
Main efficacy criterion 
The effectiveness of the GAAP Ofteno® ophthalmic solution versus PRO-067 ophthalmic solution 
elaborated by Laboratorios Sophia S.A. will be evaluated. of C.V applied on the ocular surface in subjects 
with a diagnosis of POAG and / or OHT by controlling the target IOP. 
Tolerability criteria 
Ocular symptoms such as burning, hyperemia, lacrimation, foreign body sensation, fluorescein stain, VF-
14 questionnaire score and ocular comfort index will be evaluated. 
Security criteria 
Visual capacity, anterior segment biomicroscopy, fundus examination and frequency of adverse events. 
 


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7.2 Study plan 
A national, multicenter, prospective, crossover, longitudinal, doble-blind study, with fixed dose. This study 
will be conducted with 120 subjects from the ophthalmologic consultation who were using GAAP Ofteno® 
for at least two months prior to the study and are under control of the TIOP for glaucoma with mild or 
moderate damage. 
Subjects that meet all the inclusion criteria and none of exclusion can be included in the study. At the 
same time, a study group with a predetermined sequence will be assigned randomly, respecting the 
double-blind system, in the sequence "A" the therapy with GAAP Ofteno® will continue for 30 days, in 
which will evaluate the subject again and then change the therapy to the PRO-067 ophthalmic solution 
elaborated by Laboratorios Sophia SA of C.V which will be used for 30 days until the 60th day, date of the 
final visit. 
Those assigned to sequence B on day 1, the change to PRO-067 ophthalmic solution prepared by 
Laboratorios Sophia S.A. of C.V will be for 30 continuous days until the date of revision on day 30, day in 
which the treatment with GAAP Ofteno® will be restored to continue until the 60th day, for the final 
evaluation. 
The selected subjects will be observed for 75 days, 60 days under treatment and 15 days later a telephone 
interview will be conducted to monitor adverse events. 
All subjects in both groups should go on the 15th and 45th day of the study to a safety evaluation to 
monitor that there are no adverse events resulting from the change of medication. 
No subject may use the mentioned treatment for more than the established time. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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* security visit 
Surveillance call. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.2.1 Study Schedule 
Table 2 - Study Schedule 
 
* if you have Humphrey visual fields of <6 months of completion these can be considered. 
 
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. 
 
 
 
 


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Fig. 2 
 
A) 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 = index of eye comfort. 
 
 
 
 
 
 
procedures
Basal visit / day 1.
Satisfactory eligibility criteria
-Corroborate the informed consent 
signature correctly.
-Pregnancy test.
-History, general and 
ophthalmological clinic.
-Detail points A, B, C, D, E, F, G, H, I, 
J, K, L.
Shaffer -gonioscopy
-Assignment of number.
Questionnaire VF-14 and ICO
-Make AV capture, refraction (CV).
-Paneal corneal analysis.
-Ocular surface tint.
-Tonometry with Goldman.
-Gather white / white campimetry 
24/2.
Delivery of medication
Delivery of medication
-Evaluation of concomitant buildings.
Schedule next visit.
NO
Subject not eligible.


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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
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 subjective AV, 
refraction and 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).
Ocular surface fluorescein-
staining
-CHEEP.
- Monitor adverse events.
- Monitor concomitant 
medications.


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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.
-Ghosioscopy 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.
-Devolution of medication.


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7.3 Measures to minimize deviations 
On the other hand, adherence to treatment will be evaluated as follows: 
- With the accounting of the medicine returned. 
- The subjects will have a "diary of the subject" where they will have to write down the time of application 
of the drop and any incident or setback at the time of the application of the drop, e.g. forgetting the 
application of the drop, application of extra drops, etc.  
The adherence to treatment must be greater than 80%. 
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. 
7.4 Managed products 
Table 3 gives a description of the study's products. 
Table 3 - Description of study drugs 
Ophthalmic drops PRO-067 
Latanoprost 0.005% free of preservative 
- Chemical Name: (13,14-dihydro-17-phenyl-18,19,20 trinor-prostaglandin F2α- isopropyl ester) 
- Molecular weight: 432.593 g / mol 
- Molecular formula: C26H40O5 
- Chemical structure: 
 
 
 
 
 
 


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Table 4 - Packaging description 
Primary packaging: 
PRO-067 Ophthalmic solution developed by Laboratorios Sophia S.A. of C.V. will have a primary label with 
the protocol code to which it belongs, but not the name of the content, to respect the double blind. 
Example: (subject to changes). 
 
 
Secondary package 
PRO-067 Ophthalmic solution developed by Laboratorios Sophia S.A. of C.V. will be delivered in its box 
and also, the primary packaging will be there without labeling. The specifications of the study will be 
described in the box and envelope as shown in the example. 
Example: 
 
 
 
 
 
 
 
 


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7.4.1 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 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. 
 
 
 
 
 
 
 


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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 
A center that does not include subjects in the first month after the initial visit may be closed by decision 
of Laboratorios Sophia S.A. of C.V. 
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. 
8.5 Selection criteria 
All selected subjects: 
- Age from ≥ 18 years to ≤ 90 years. 
- Male or female. 
- Obtained in the external consultation. 
- Diagnosis of primary open-angle glaucoma and / or chronic intraocular hypertension, classified as mild 
to moderate or severe, previously treated with GAAP Ofteno® at least two months before inclusion and 
while under control of their TIOP. 
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. 
 
 
 


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8.5.1 Informed consent 
Obtained as described in section 15.3 of the protocol. 
8.6 Exclusion criteria 
8.6.1 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. 
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. 
8.6.2 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 another etiology of glaucoma different from primary open-angle. 
4. Subjects with intraocular hypertension secondary to a different etiology at open-angle or linked to 
another ocular condition. 
5. Subjects with corneal abnormalities that prevent tonometry by applanation. 
6. Subjects with ocular surgery or ocular trauma resolved in the last 6 months prior to inclusion. 
7. Uncontrolled or progressive retinal diseases that threaten vision. 
8. Chronic ocular surface diseases not controlled or recently diagnosed (last 3 months). 
 
Related to various conditions 
1. Subjects with a history of hypersensitivity to any of the ingredients of the research product or its 
analogues. 
Related to a therapy of previous and / or concomitant treatments 
Previous therapy 
 Subjects cannot be treated at the time of inclusion with any other type of antiglaucomatous drug other 
than GAAP Ofteno ®. 
 


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To know the other prohibited treatments and their rest period, please refer to section 10.3 (Table 5) "Main 
prohibited treatments - Rest period to be respected". 
8.7 Criteria for non-inclusion 
- Any exclusion criteria that may appear after the screening visit. 
- Any clinically important abnormalities detected during the clinical examination, laboratory tests that 
could interfere with the conduct of the study or with efficacy, tolerability, and safety evaluations. 
- Any complication or lack of control that the doctor considers should be treated differently. 
8.8 Criteria for participant discontinuation 
8.8.1 Criteria for exclusion 
The following criteria will result in the mandatory exclusion of the study: 
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. 
 If the researcher considers that this can threaten the health of the subject. 
 If an important disease occurs that requires the prescription of a medication incompatible with the 
objective of the study. 
 If the progression or deterioration of the basal disease occurs as well as non-compliance with the TIOP 
according to its classification. 
- Need for another treatment according to the criteria of the medical investigator. 
- Pregnancy. 
- Any deviation to the protocol that affects the safety of the subject. 
 
 
 
 
 


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8.8.2 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. 
In case of discontinuation of the study treatment as a result of an event that requires immediate 
notification, the corresponding monitor, or the drug-surveillance contact (11.3.2) 1 will be contacted. 
9 TREATMENT OF STUDY SUBJECTS 
9.1 Managed treatments 
Pre-treated with GAAP Ofteno® for at least 2 months prior and under control of TIOP, they will begin 
to apply PRO-067 or GAAP Ofteno® without leaving the washing period as follows: 
Sequence A: 1 drop of PRO-067 ophthalmic solution prepared by Laboratorios Sophia S.A. of C.V. 
every 24 hours for 30 days at the end of which GAAP Ofteno® will be given, administered for an 
additional 30 days. 
Sequence B: 1 drop of GAAP Ofteno® every 24 hours for 30 days at the end of which PRO-067 
ophthalmic solution elaborated by Laboratorios Sophia S.A. of C.V. will be administered equally for 
30 more days. 
 
9.2 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. 
9.3 Previous and concomitant treatments 
Prohibited treatments 
Table 5 shows the list of prohibited treatments before and during the study. 
If a prohibited treatment is absolutely necessary during the study, the subject should be removed. 
 
 
 
 
 
 
 


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Table 5: Main prohibited treatments - Rest periods to be respected 
medicine 
 
 
 
Group 
Prototype 
Route 
of 
administration 
Rest periods 
Artificial 
tears 
with 
conservative. 
 
Ophthalmic 
2 weeks 
Carbonic 
anhydrase 
inhibitor 
Acetazolamide 
Dorzolamide 
Oral, I.V, ophthalmic 
1 month 
Parasympathetic-
mimetic 
Pilocarpine 
Ophthalmic 
1 month 
Selective 
alpha 
agonists 
Brimonidine 
Ophthalmic 
1 month 
Beta-Non-selective 
blocker 
Timolol 
Ophthalmic 
2 weeks 
 
9.4 Authorized treatments before and during the study 
 Tretacaine Hydrochloride 
 Tropicamide / Phenylephrine Hydrochloride 
 Artificial tear without conservator 
 
9.5 Treatment compliance 
-  Quantification of the weight of the bottle that has been returned. 
- The subjects will have a "subject’s diary" where they will have to write down the time of application of 
the drop and any incident or setback at the time of the application of the drop, e.g., forgetfulness in the 
application of the drop, application of extra drops, etc. 
- The adherence to treatment must be greater than 80%. 
After the discontinuation of the study treatment, the subject will return with the previously used 
treatment. 
10 VALUATION OF EFFECTIVENESS 
10.1 Efficiency measurements 
In the research schedule, the effectiveness measurements made in each visit or treatment period are 
indicated. 
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. 
 


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Primary security parameters: 
Frequency of adverse events, visual capacity, data of the anterior segment biomicroscopy and fundus 
examination. 
10.2 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. 
A guide will be made available for the interview to be carried out in each of the visits. 
The subject must complete self-score questionnaires: 
The researcher will explain to the subject the self-score questionnaires; the subjects will fill them in the 
visits of days 1, 30 and 61. 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 a distance of 3m 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). 
 
 


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- 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 
 
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 
 
 


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1.- Very Mild                  2. Mild                        3.- Moderate               4.- Severe 
-Foreign body sensation 
-Burning 
-Lachrymation 
These symptoms will be described as present or absent, in case there is a discharge, it will have to be 
described. 
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. 
Defects of the corneal and conjunctival epithelium will be reported. 
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. 
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. 
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. 
11 EVALUATIONS OF SECURITY 
11.1 Safety measurements 
Table 2 shows the safety measures that are carried out in each visit or treatment period. 
The safety measurements are the following: 
- Adverse events. 
- Visual acuity and visual ability. 
- Previous biomicroscopy data. 
- Concomitant medications. 
- Fluorescein staining. 
- Taking IOP with Goldman. 
11.2 Specific procedures by type of visit. 
Clinical examination 
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. 


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The female sex subjects who have presented their menarche will undergo an 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. 
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. 
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. 


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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. 
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: 
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. 
Final visit (Day 60) In this 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. 


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11.2.1 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. 
11.3 Adverse events 
All adverse events should be a matter of follow-up and must be documented in a complete and accurate 
manner in order to make possible the assessment of the safety of the study drug. 
11.3.1 Responsibilities of the researcher 
11.3.2 Record of adverse events in the Case Report Form 
-Events to register 
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. 
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. 
 Results in persistent or important disability. 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. 
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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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). These cases must be reported on separate "Adverse 
Event" paper pages that will be provided to the centers, and should be sent immediately by fax to the 
responsible person (see Table 6) 
 A pregnancy that occurs during the study. 
 
11.3.2.1 Methods for registration 
Adverse events must be documented in an "Adverse Event" form. Some sections of the page must always 
be filled out in full, whether the event is serious or not serious. The other sections will be filled only when 
the event requires immediate notification. 
In case of progression of the disease by episodes (chronic disease): 
If the disease was already known when the subject entered the study, only be documented as an adverse 
event when there is a worsening (increase in frequency and / or intensity of episodes / attacks), 
If the disease is detected during the study and the repetition of the episodes allows diagnosing a chronic 
disease, episodes that clearly describe the diagnosis will be grouped in the same "Adverse event" form. 
 
11.3.2.2 Adverse events follow-up 
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 subjects 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 subjects follow-up, so that you can obtain additional 
information to report it in an "Adverse Event" form. 
 
 
 
 
 


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11.3.2.3 Procedure for a serious adverse event 
In the setting of a serious adverse event that is presented: 
- 
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: 
Write down the date in the participant's medical record 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 
being informed about this event, filling out a "Serious Adverse Event" form, and without waiting for the 
clinical results or the results of additional investigations, the sponsor will be informed (Clinical Research 
Department and Pharmacovigilance Department) by telephone or fax, or after business hours to the 24 
hour telephone line. 
Provide to the people designated below, as they are available, anonymous copies of documents that offer 
useful additional information, such as admission hospital reports, consultation reports, laboratory tests 
reports or other exam reports that help the diagnosis (when possible, pre-treatment assessments must 
be attached to compare them against the results obtained with the treatment), or the autopsy report, if 
it has been done. 
- Comply with their regulatory obligations before the Competent Authorities and / or before the Ethics 
Committee, in compliance with local regulatory requirements. 
Table 6 - Structures of the contacts in case of a serious or not serious Adverse Event. 
Responsible for Pharmacovigilance: 
Dr. Alicia Paulina Melgarejo 
Sophia Laboratories, S.A. of C.V. 
Av. Paseo del Norte, 5255 
Col. Guadalajara Technology Park. 
C.P. 45010 Zapopan, Jalisco. Mexico. 
Tel. 01 33 30 01 42 83 (Direct) 
01 33 3001 4200 Ext. 1029 
Cell phone. 044 33 1043 1474 
Direct helpline, toll free: 01 800 7102 254 
E-mail: farmatec@sophia.com.mx 
If an initially non-serious adverse event worsens and becomes serious, this should be reported 
immediately in the "Serious Adverse Event" form. If a woman subject in the study becomes pregnant, the 
researcher should:             - Suspend the study treatment for the subject. 
- Communicate with the assigned monitor to receive details for the report. 
 


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11.3.2.4 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. 
In general, the reasonable causal expression relationship means linking evidence or arguments to suggest 
a causal relationship. 
 
11.3.3 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. 
 
11.4 Biosecurity aspects 
The research protocol does not contemplate the performance of any procedure that involves the use of 
ionizing radiation or genetic engineering techniques. It also does not involve the use or transport of 
infectious materials or dangerous chemicals. 
 
12 Statistics 
Statistical analysis 
The analysis of the study will be carried out using the statistical software SPSS version 19 as soon as all 
the efficacy and safety data of the study are available, and the obligatory steps defined in section 15.2 
"Data Management" have been carried out. 
Evaluation criteria 
Efficacy criteria 
The main criterion will be the maintenance of the TIOP throughout the study. 
The secondary criteria will be: burning, hyperemia, lacrimation, foreign body sensation, fluorescein 
staining, ocular comfort index score and VF 14 questionnaire evaluation. 
 
 
 


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The analytical approach is the change from the initial value to the last value in the final visit after the 
application of the test treatment. 
Security criteria 
Visual capacity, anterior segment biomicroscopy, fundus examination and frequency of adverse events. 
The analytical approach is the change from the initial value to the last value in the final visit after the 
application of the test treatment. 
Statistical elements 
The type I error of the statistical tests will be set at 5% (unilateral situation), which is consistent with the 
objective of demonstrating the non-inferiority in terms of maintaining the TIOP + 2mmHg than the 
comparator study. 
The following descriptive statistics will be provided, depending on the nature of the variables: 
Quantitative variant: Before normal distribution: they will be expressed as mean ± standard deviation, 
minimum and maximum values and if the variable does not have a normal distribution: they will be 
expressed in median, minimum, and maximum range 
Qualitative variable: will be expressed as categories, frequencies, and proportions 
Analysis sets 
The Randomized Set (RS) will be defined as all the subjects included and assigned randomly (according to 
the subject selection procedure). 
The Complete Set of Analysis (CSA) will be defined according to the intention to treat principle and section 
5.2.1 of the ICH-E9 guidelines, as the subjects of the RS who were given at least one dose of the medication 
under study and that have a value at the beginning of at least one of the values after the initial in the main 
criterion throughout the period of pharmacological intervention. 
The Safety Set will be defined as all included subjects who were given at least one dose of the study 
medication. 
Statistical methodology 
A treatment group will be considered: PRO-067 
Result of the Study 
The evaluated variables will be described by treatment group and in general in the RS and the CSA. 
The treatment length, compliance, and in case of early withdrawal of a volunteer, the reasons for 
withdrawal, deviations from the protocol and concomitant treatments will also be described in the RS. 
 
 
 
 
 
 
 


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Effectiveness 
 
Main analysis 
To identify differences in the study group, considering ordinal and nominal variables, the following 
statistical test will be used: 
   Chi square test with Pearson's exact, assuming normal distribution, otherwise the Chi square test with 
Fisher's exact test will be applied. 
To identify differences in the study group, considering continuous quantitative variables, the following 
statistical test will be used: 
 Test t with paired samples, assuming normal distribution, otherwise the Mann-Whitney U test will be 
applied. 
 
Security 
All safety analyzes will be done by treatment group in the Safety Set in the periods from day 0 to day 60. 
Adverse events 
The number of adverse events emerging under treatment (until the last date of application of the study 
drug + 1 day), number and percentage of subjects reporting at least one adverse event emerging under 
treatment will be described by system organ class and / or preferred term 
The same analysis will be performed for serious adverse events (emergent or not). 
Adverse events reported after the treatment period will also be described. 
 
13 DIRECT ACCESS TO 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. 
 
14 QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 Supervision of the study 
 
14.1.1 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, 
 


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- 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. 
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. 
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. 
 
14.2 Electronic medical record 
If medical files are used, the researcher must guarantee the safety of the study data in the medical files 
by implementing security measures to prevent unauthorized access to the data and the computer system. 
The researcher undertakes to maintain: 
- All the impressions of the medical record signed and dated by him (principal investigator) in the record 
of the study, 
- If the computer system allows it, the changes made in the medical records of the file during the study  
- All original source documents (originals of specific exams, informed consent forms). 
 
 
14.3 Audit - Inspection 
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 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, 
 


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- Have direct access to the study data and source documents, 
- See all documents related to the study. 
15 ETHICS 
15.1 Ethics Committee 
The investigators, or the coordinators, or the sponsor will deliver to the Ethics Committees the study 
protocol, the informed consent, the researcher's manual, and the required documents in accordance with 
the 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. 
15.2 Conducting the study 
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). 
15.3 Information for the subject and informed consent form 
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 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 


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Investigator must document the date on which the informed consent was signed in the subject's 
medical history. 
At the moment in which 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. 
15.4 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, with the 
exception of 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. 
16 DATA MANAGEMENT AND CONSERVATION OF RECORDS 
16.1 Study data 
The investigator or the designated person on the team will fill out the Case Report Format (CRF) 
as well as all other documents provided by the sponsor (for example, documents related to 
handling the treatment ...). 
FRC 
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. 
 


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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. 
16.2 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, in order 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. 
After the double data capture, a data review will be done, and consistency checks will be made. 
If there are inconsistencies in the data, the clinical monitor will ask the researcher for its 
resolution. Whenever necessary, that is, when "queries" (questions), are generated, they will be 
sent to the researcher for resolution and signature and will be followed up until the corrections 
are resolved, entered in the database, and validated. 
16.3 File 
The investigator will keep all the information related to the study for at least 10 years after the 
completion of the study. 
17 OWNERSHIP OF THE RESULTS -POLICY OF PUBLICATION 
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 unicentric, 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, in the event that 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. 
 
 
 
 


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18 ADMINISTRATIVE CLAUSES 
18.1 Related to the sponsor and the researcher 
18.1.1 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 and the Director of the analysis 
laboratory. 
18.1.2 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 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. 
18.1.3 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. 
18.2 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). 
 
18.3 Related to the researcher 
18.3.1 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 


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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 as 
long as the confidential information has not been disclosed to the public by the sponsor. The 
protocol of the clinical study provided to the 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. The researcher will fill out and 
maintain a binnacle of selection of the subjects as well as the identification and list of enrollment 
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.) 
18.3.2 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. 
18.3.3 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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9 APPENDICES 
Appendix 1: Declaration of Helsinki of the World Medical Association 
DECLARATION OF HELSINKI WORLD MEDICAL ASSOCIATION 
Ethical Principles for Medical Research in Human Beings 
Adopted by the 18th General Assembly of the AMM, Helsinki, Finland, June 1964, and amended by: 
29th General Assembly of the AMM, Tokyo, Japan, October 1975 
35th General Assembly of the AMM, Venice, Italy, October 1983 
41st General Assembly of the AMM, Hong Kong, September 1989 
48th General Assembly of the AMM, Somerset West, Republic of South Africa, October 1996 
52nd General Assembly of the AMM, Edinburgh, Scotland, October 2000 
53rd General Assembly of the AMM, Washington 2002 (Explanatory note added in paragraph 29) 
55th General Assembly of the AMM, Tokyo 2004 (Explanatory note added in paragraph 30) 
General Assembly 59th of the AMM, Seoul, 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. 
2. 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. 
3. Although the Declaration is intended primarily for physicians, the AMM encourages other 
participants in medical research involving human subjects to adopt these principles. 
4. 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. 
5. 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. " 
6. 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. 
7. In medical research involving human beings, the wellbeing of the research subject must take 
precedence over all other interests. 
 
 


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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
8. 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. 
 
9. In medical practice and in medical research, most interventions involve risks and burdens. 
10. 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. 
11. 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 
12. 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. 
13. 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. 
14. Appropriate precautions should be taken when performing medical research that may harm 
the environment. 
15. 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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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
16. 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. 
17. 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. 
18. 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. 
19. 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. 
20. Clinical studies should be recorded in a database with access to the public before recruiting 
the first subject. 
21. 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. 
22. 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. 
23. 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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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
24. Every precaution must be taken to protect the privacy of the research subjects, as well as 
their personal information, in order to minimize the impact of the study on their physical, 
mental, and social integrity. 
25. 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. 
26. 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. 
27. 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. 
28. 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. 
29. 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. 
 
 
 
 
 


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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
30. 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 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. 
31. 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL ATTENTION 
32. 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. 
33. 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. 
34. 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. 
35. 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. 
36. 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 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 
 
 
 
 
 
 
 
 
 
 


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Appendix No. 4: calculation of sample size 
Sample size Protocol PRO-067 
The sample size was calculated according to the formula for continuous quantitative variables: 
 
n=2[ (Zα−Z1−β)(δ)d]2 
                d 
With a statistical confidence of 95% that corresponds to the type I error, and is equal to 1.96, 
with a power of 80% that corresponds to the type II error, and is equal to 0.84. A standard 
deviation for the decrease in intraocular pressure of 2.5 mmHg1 was considered, with an 
expected difference of at least 0.417 mmHg. 
Based on the above, the result was 41 patients, which increased 20% due to the loss, with a total 
of 50 patients per group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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